The Pseudotumor Cerebri Syndrome: Pseudotumor Cerebri, Idiopathic Intracranial Hypertension, Benign Intracranial Hypertension and Related Conditions

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The Pseudotumor Cerebri Syndrome The condition known most widely as the pseudotumor cerebri syndrome is of diagnostic interest and clinical importance not just to neurosurgeons, but also to neurologists, ophthalmologists and headache specialists. In this book three clinicians with extensive experience of pseudotumor cerebri provide a comprehensive review of the condition, which has also been variously called idiopathic intracranial hypertension, benign intracranial hypertension, and other names over the century or so since it was first recognised. It argues for the grouping of all these conditions under the name of pseudotumor cerebri syndrome on the basis of a common underlying mechanism
an impairment of CSF absorption due to abnormalities at the CSF/venous interface. Giving a detailed account of the history of the condition, the authors review the development of ideas around some of the more contentious issues, including mechanism, nosology and nomenclature. They then deal in depth with aetiology, investigative findings and strategies, treatment and outcome, based on an extensive patient series and a wide ranging review of the clinical literature. The book concludes with a chapter on experimental studies, considering the possibility of establishing a suitable experimental model to facilitate analysis of some of the unresolved issues, and pointing the way to a more complete understanding of this controversial condition. Ian Johnston is Associate Professor (emeritus) in the Department of Surgery at the University

of Sydney. Brian Owler is a Consultant Neurosurgeon at the Westmead Hospital, Sydney, and at The Children’s Hospital at Westmead, Sydney. John Pickard is Professor of Neurosurgery at the University of Cambridge and Chairman and Clinical Director of the Wolfson Brain Imaging Centre.

The Pseudotumor Cerebri Syndrome Pseudotumor Cerebri, Idiopathic Intracranial Hypertension, Benign Intracranial Hypertension and Related Conditions

Ian Johnston Brian Owler John Pickard

CAMBRIDGE UNIVERSITY PRESS

Cambridge, New York, Melbourne, Madrid, Cape Town, Singapore, São Paulo Cambridge University Press The Edinburgh Building, Cambridge CB2 8RU, UK Published in the United States of America by Cambridge University Press, New York www.cambridge.org Information on this title: www.cambridge.org/9780521869195 © Cambridge University Press 2007 This publication is in copyright. Subject to statutory exception and to the provision of relevant collective licensing agreements, no reproduction of any part may take place without the written permission of Cambridge University Press. First published in print format 2007 eBook (EBL) ISBN-13 978-0-511-27802-0 ISBN-10 0-511-27802-0 eBook (EBL) hardback ISBN-13 978-0-521-86919-5 hardback ISBN-10 0-521-86919-6

Cambridge University Press has no responsibility for the persistence or accuracy of urls for external or third-party internet websites referred to in this publication, and does not guarantee that any content on such websites is, or will remain, accurate or appropriate. Every effort has been made in preparing this publication to provide accurate and up-todate information which is in accord with accepted standards and practice at the time of publication. Although case histories are drawn from actual cases, every effort has been made to disguise the identities of the individuals involved. Nevertheless, the authors, editors and publishers can make no warranties that the information contained herein is totally free from error, not least because clinical standards are constantly changing through research and regulation. The authors, editors and publishers therefore disclaim all liability for direct or consequential damages resulting from the use of material contained in this publication. Readers are strongly advised to pay careful attention to information provided by the manufacturer of any drugs or equipment that they plan to use.

To Alistair Paterson

Contents

Preface

page ix

1

Introduction

1

2

History of the pseudotumor cerebri concept

6

3

Disease mechanism

30

4

Nosology, nomenclature, and classification

60

5

Aetiology

82

6

Clinical features

127

7

Clinical investigations

148

8

Treatment

189

9

Outcome

232

10

Experimental studies

246

11

Conclusions

275

Bibliography Index

283 351

vii

Preface

The syndrome we have termed the pseudotumor cerebri syndrome (PTCS) was first characterized as a distinct clinical entity in the papers by Quincke and Nonne, published a little over a hundred years ago. The condition has subsequently received a somewhat bewildering variety of names and its mechanism has also remained controversial. Moreover, it is probably not as rare as was originally thought. In addition, the insights gained by the study of its pathophysiology and management undoubtedly have more general implications for our understanding of intracranial dynamics in other conditions. For these reasons, and because there has been a considerable proliferation of literature on the subject in recent decades, we thought it would be timely to bring together the later observations with the extensive older literature. The original intention was to have this book ready for publication in 2004 to mark the centenary of Nonne’s paper which introduced the name ‘pseudotumor cerebri’ for a condition sporadically described during the four decades prior to that paper. Like many such endeavours, the present work took rather longer to complete than initially anticipated. Nonetheless, the belated acknowledgement of Nonne’s paper does signify one of the central arguments of this monograph
that the name he proposed for the condition, a name that has endured despite many challenges, should be retained. The only proposed modification is the addition of the term ‘syndrome’ to embrace the collection of conditions which, in practice, share a common presentation, clinical picture, treatment strategy, and outcome, as well as, it is argued, a common mechanism. Whether this argument is successful must be left to readers to decide, but none would disagree that a consensus on nomenclature is desirable. We believe that there is a close analogy between PTCS and hydrocephalus. Whether or not they do finally prove to have a similar mechanism, that of impaired CSF absorption, with differences being attributable to such factors as the site and cause of obstruction, the rigidity of the cranium, and other things as yet unidentified, remains to be seen. What is undeniable is that the two conditions ix

x

Preface

Alistair Paterson

do share a number of common aetiological factors, a similar significant proportion of cases for which there is no recognizable aetiological agent, similar clinical features insofar as these are the manifestations of intracranial hypertension without localization, and a similar dramatic therapeutic response to effective CSF drainage. The book itself falls into three sections buttressed between brief introductory and concluding chapters. The first (Chapters 2
4) comprises the ‘theoretical’ section, dealing with the history of the condition, the theories on disease mechanism, and the vexed issues of nosology, nomenclature and classification. The second (Chapters 5
9) comprises the clinical section, and has two patient databases
a detailed study of two personal series of Ian Johnston covering approximately 60 years and 270 patients, and a comprehensive analysis of the burgeoning literature on the subject. The third section is a single chapter (Chapter 10) which examines experimental studies pertaining to the condition and has the underlying purpose of drawing attention to possibilities for establishing a satisfactory experimental model of PTCS which would surely help resolve some of the outstanding issues. The three authors are closely linked, not only by their interest in the condition, but also personally, having worked together in different combinations in the three units whose patients are featured in the clinical chapters: the Institute of

xi

Preface

Neurological Sciences in Glasgow, the neurosurgical units associated with the University of Sydney, and the neurosurgical unit at the University of Cambridge. During our long association we have become indebted to many colleagues, both clinicians and researchers, within our own units and elsewhere. Because so many people have been involved we have decided, with regret, that they are too numerous to mention individually, but our debt is substantial. Individual mention must, however, be made of Alistair Paterson (pictured) who might justifiably be regarded as the instigator of this study which started more than thirty years ago and is still continuing. We are very happy to be able to dedicate the book to him as a mark of our enduring gratitude. We are also especially grateful to Peter McCluskey, Scott Dunkley, Marek Czosnyka, Nicholas Higgins and Nicholas Sarkies who have each made specific contributions to several of the chapters in relation to their respective specialties. Richard Barling and Rachael Lazenby at the Cambridge University Press deserve our thanks for their interest in this somewhat esoteric field, and their help generally with the project, not to mention their tolerance of the delay in delivery of the manuscript. Finally, our hope is that this monograph might play a role in resolving some of the key issues in the continuing debate on this intriguing condition. At least it should provide an up-to-date summary of what has become a very substantial literature on the subject. To this end we have made the bibliography extensive, including papers not specifically referred to in the text but included in collected figures or influential in general analysis. We do hope that this monograph will stimulate new work and lead to further advances in the management of this distressing condition for the benefit of our patients. Ian Johnston Brian Owler John Pickard

Life with Benign Intracranial Hypertension

What’s in a name? I’m angry, cross, annoyed At a very misguided man The one who names diseases With inappropriate, ill suited titles. Benign Intracranial Hypertension is the label That doctors place on me. If I met that man face to face I would demand that he justify that name. And tell me what’s benign:

xii

Preface

I find the word an insult to my suffering. It implies it’s OK, harmless, curable, Slight, superficial, easily treatable. I know it’s not life-threatening In a mortal sense, But it’s killing my living. I haven’t worked for months In the job I love, Had countless lumbar punctures And needles in other parts. Operations with tubing and valves Inserted in unsymmetrical patterns around my body. Symptoms too numerous to list. My marriage is under constant strain And my children suffer, That really hurts. Will I be home next week or not? I want to get on with living, Have a routine or normality. Yes, I’m angry all right What right did he have to label all this benign. I have a right to be exasperated, infuriated With his lack of imagination and understanding. Surely he could have come up with something, Something just a little more grand, Something to portray my distress, To evoke a little understanding in people standing near, To induce a little sympathy for me. Come on someone please, Start now with this disease Let’s have a renaming ceremony, But please, remember, invite me. Liz Galfskiy, Winchester, UK

1

Introduction

The condition or syndrome to be considered in this monograph has been a clearly recognized clinical entity since the descriptions given by Quincke (1893, 1897) and Nonne (1904, 1914) over 100 years ago. However, reports of cases which were almost certainly examples of the same condition undoubtedly antedated their pioneering accounts by almost four decades. The essential elements of the syndrome are the symptoms and signs of intracranial hypertension without ventricular dilatation and without an intracranial mass lesion. For reasons which will be made clear in the following chapters, we shall call it the pseudotumor cerebri syndrome (PTCS) although quite a variety of terms have been applied to it. It is a particularly intriguing condition for a number of reasons, as follows: 1. Clinically the condition presents an essentially pure picture of raised intracranial pressure (ICP) without focal neurological disturbance and without investigative evidence of structural disturbance, either focal or general. As such, it is a condition which manifests, in isolation, what is a critical component of many neurological and neurosurgical conditions, i.e. intracranial hypertension, thereby creating a situation in which the pathological effects of this component exist in a pure form. 2. Despite much speculation and numerous clinical and laboratory studies (although clinical investigations are constrained by the exigent circumstances of the condition and laboratory studies by lack of a suitable model) there is still no clear consensus on its mechanism, although the predominant view is that the intracranial hypertension is due to a disturbance of cerebrospinal fluid (CSF) dynamics. 3. In the absence of a clear understanding of mechanism, there is no agreement on the nomenclature. Since the condition was first recognized a series of quite distinct names have enjoyed relatively transient popularity, although only pseudotumor cerebri (Nonne’s coinage) has endured. The use of the other terms has depended, in part, on which specialty was mainly responsible for management and, in part, on which theory of mechanism was in vogue. 1

2

Introduction

Some of the more tenacious examples, in approximate temporal sequence, are serous meningitis, hypertensive meningeal hydrops, otitic hydrocephalus, benign intracranial hypertension, and, most recently, idiopathic intracranial hypertension. 4. Again related to uncertainty about mechanism, there has been notable variation in methods of treatment. As with nomenclature, different treatments have had a period of popularity only to be discarded or replaced as side-effects and complications became apparent or as ideas of mechanism changed. What can be said is that all the major forms of treatment employed over the past century have been effective to a significant degree. This is to judge, at least, by the relatively crude criteria of ultimate resolution of the condition and patient survival without apparent neurological deficit, although persistent ophthalmological and possibly psychological disturbances may occur. The evolution of ideas on these four aspects, and other related points, will be examined in the following chapter on the history of the ‘pseudotumor cerebri’ concept. An attempt will then be made to provide a critical analysis of the different theories of mechanism which will include an examination of the fundamental question as to whether there is, in fact, a single mechanism involved or not. Having come to a conclusion about mechanism, however tentative, the vexed question of nomenclature and the related issue of classification will be addressed. Clearly, if mechanism is securely established, nomenclature may become more logically based. The question of classification will, of course, depend on resolution of the issue of whether there is, indeed, one basic mechanism, or at least one final common pathway, as we shall argue. These three chapters, on history, on mechanism, and on nosology and nomenclature, comprise the theoretical component of this monograph. At this point a provisional conclusion will be reached that we are dealing with a defined syndrome, the underlying mechanism of which is impairment of CSF absorption at the point of transfer of the fluid from the subarachnoid space into the venous system; that is, at the arachnoid villi. The suggestion is, then, that an increase in the fluid component of the intracranial and spinal spaces due to impaired CSF absorption in the face of continuing production at normal rates is the cause of the increase in intracranial pressure, although precisely where and how this excess of fluid is accommodated remains to be determined. The basic abnormality at the point of absorption may be due to one of three mechanisms: 1. A change in the arachnoid villi themselves 2. A change in the cranial venous outflow adversely affecting the pressure differential across the arachnoid villi on which CSF absorption depends 3. A change in the physical nature of the fluid being absorbed

3

Introduction

For each of these three primary causes there exists a number of secondary causes. Despite this multiplicity of causative factors, and the obvious lacunae in our knowledge of how precisely these factors operate, there is a clearly definable clinical entity to which, in the absence of exact delineation of the disease mechanism, a somewhat non-specific but appropriate name should be given. The term ‘pseudotumor cerebri syndrome (PTCS)’, it will be argued, most satisfactorily serves this purpose, at least at present. In the chapters subsequent to these theoretical deliberations, the practical clinical aspects of the syndrome are considered in chapters following the conventional sequence, i.e. aetiology, clinical features, investigative findings, treatment and outcome. In each of these five chapters a similar format will be followed, beginning with a summary of our own clinical experience based on two substantial series of cases comprising 260 patients investigated and treated in two large centres (the Institute of Neurological Sciences in Glasgow and the Royal Prince Alfred Hospital and Royal Alexandra Hospital for Children in Sydney) over a period of almost 60 years. This will be followed by a detailed review of the literature and conclude with a brief general summary of each section. With respect to aetiology, one of the more remarkable aspects of PTCS is the large number of putative aetiological agents that have been identified. In many instances, however, the question of whether a particular agent has a true causal relationship to PTCS, rather than being merely a chance association, is not satisfactorily elucidated. Moreover, many of the inculpated agents, whether drugs or other medical conditions, are used or occur very widely, whilst only very few instances of a conjunction with PTCS are recorded. All the supposed aetiological agents will be tabulated and considered, as will the presumed nature of the often somewhat tenuous connection between the particular agent and PTCS in each case. We shall also consider from a practical point of view the issue which bears particularly on the question of nomenclature; that is, whether there are forms of the condition that do arise sui generis and might properly lay claim to the title ‘idiopathic intracranial hypertension’, setting aside etymological questions about the term ‘idiopathic’. In considering the clinical features of PTCS, initial consideration will be given to the rather striking epidemiology of the condition. What is the significance of the uniformly observed preponderance of young obese women in any large series of cases and, in particular, does this have any bearing on the issue of mechanism? In relation to the presenting symptoms and signs, details will be given of their relative frequency and range of severity. Attention will also be directed at two ‘minority’ groups: patients who are diagnosed as having PTCS despite lacking either symptoms or signs of intracranial hypertension, and patients who have symptoms or signs other than those directly attributable to intracranial hypertension.

4

Introduction

This latter group bears on the issue of the applicability of the so-called ‘Dandy criteria’, considered in detail in Chapter 4. In considering the investigation of patients with possible PTCS, the history of the changing pattern of investigative strategies is outlined before considering in turn each of the methods that have been used or are currently in use. Despite this changing pattern, the two key components of investigation have remained the same. The first is the demonstration of raised CSF pressure, whether by direct puncture and simple manometry or by more elaborate monitoring techniques. The second is exclusion of some other cause of raised CSF pressure, now most satisfactorily achieved by magnetic resonance imaging (MRI). As with clinical features, there are issues relating to how rigidly diagnostic criteria should be applied with respect to CSF pressure measurements, CSF composition, and the normality or otherwise of imaging studies which will be considered here. Attention will also be given to another important practical aspect of investigation
how far investigations should be pursued. Specifically, should the role of clinical investigations be simply to exclude conditions other than PTCS, or should they also be directed towards the identification of some causative factor for the PTCS? The treatment of PTCS remains problematical, and there are still no methodologically satisfactory studies establishing the efficacy of a particular treatment, or properly comparing one treatment against others. There is also the important issue of how vigorously treatment should be pursued in the individual case, weighing up the risks to the patient of continuing intracranial hypertension against those of the treatment in question. The treatments considered are the medical options of serial lumbar punctures, acetazolamide (DiamoxÕ ), other diuretics, steroids, weight loss, and a miscellaneous group of other agents used in small numbers of cases, and the surgical options of subtemporal decompression (STD), optic nerve sheath decompression (ONSD), CSF shunting and various direct approaches to cranial venous outflow tract occlusion. It is a striking fact that almost all the treatment methods employed to any extent over the past hundred years, since the disease was first recognized, are still in use. One aspect of the treatment issue, touched on above, is the question of whether therapy can be ‘tailored’ to the individual case, based for example on the degree of severity. Another, and related aspect is what to regard as the ‘end-point’ of treatment, i.e. how important is it to attempt to return the patient’s ophthalmological status and/or CSF pressure to normal, or as close to normal as possible, and as soon as possible? This issue is obviously linked to the natural history of the condition and studies of outcome in treated cases. Outcome will be the subject of Chapter 9 in which three aspects in particular will be brought into focus. The first is the time course of resolution of PTCS and the relationship of this to its initial severity and method(s) of treatment.

5

Introduction

The second is the likelihood of sequelae, especially ophthalmological and psychological sequelae, and how these relate to the severity and duration of the condition. The third is the possibility of error in the initial diagnosis, with some other cause of the intracranial hypertension subsequently coming to light that invalidates the initial diagnosis of PTCS. The penultimate chapter will consider the various experimental studies that relate particularly to PTCS, and will include a discussion of some of the theoretical issues raised by these studies. Broadly, two groups of experimental studies will be considered. The first group consists of studies of three factors with a well-established aetiological relationship to PTCS
cranial venous outflow impairment, hyper- and hypo-vitaminosis A, and steroids, both prolonged use and withdrawal. All these are factors that have been shown to have the capacity to alter CSF dynamics. Moreover, all of them, and possibly other agents such as tetracycline and its derivatives, offer possibilities as far as establishing an experimental model of PTCS is concerned. The second group consists of various agents which have been shown to have a marked effect on CSF formation, an action which has been assumed to be relevant to the treatment of PTCS. In the concluding remarks (Chapter 11) the aim will be to summarize the findings and conclusions of the preceding chapters seriatim and, in so doing, to come up with a defensible working hypothesis on disease mechanism, to make a logical recommendation on nomenclature, to bring some clarity to the murky waters of aetiology, to define the basic clinical picture and its acceptable variations, to recommend practical strategies for investigation and treatment, to document the range of outcomes in PTCS, and how these relate to severity on presentation and vigour of treatment, and, finally, to make some suggestions as to how further experimental studies might shed some light on the still obscure aspects of this remarkable condition.

2

History of the pseudotumor cerebri concept

Introduction The evolution of the pseudotumor cerebri concept has depended on a combination of precise clinical description and continuing technological advances in the methods used for investigation. Tracing the history of the concept is not only of intrinsic interest but also helps to clarify how our present ideas on disease mechanism, nomenclature, classification, and treatment, all areas of on-going contention, have been arrived at. It must be said, however, that while discussion of the history of ideas on the condition does undoubtedly provide insights into some of its fundamental aspects, it also has the somewhat sobering effect of bringing into focus how little progress has actually been made. For example, on mechanism, the idea of a disturbance of CSF circulation as being at the root of the condition was originally canvassed in the very early years before being discarded, but is now returning to favour. On aetiology, cranial venous outflow impairment, which featured so strongly in early accounts, has now re-surfaced as a major consideration. In treatment, optic nerve sheath decompression, which was initially advocated over 100 years ago before quickly being abandoned, has now returned to a position of prominence. In these three aspects the wheel has turned full circle. In presenting this outline of history, the papers of Quincke (1893, 1897 (Figure 2.1)) and Nonne (1904, 1914 (Figure 2.2)) are taken as pivotal, signalling the start of attempts to define a specific clinical syndrome. These papers will be given relatively detailed consideration. It is clear, however, that a number of reports of what would appear to be the same condition antedated those of Quincke and Nonne. A general survey of these will be given. Two particular developments of far-reaching significance that were also critical for the recognition of PTCS were first, the invention of the ophthalmoscope by von Helmholtz in 1851 and its application to neurology pioneered by von Graefe, Albutt, Hughlings Jackson and others, and second, the introduction of the 6

7

Figure 2.1

Introduction

Heinrich Quincke (1842
1922) who studied under such notables as von Ko¨lliker, Helmholtz and Virchow. For many years he held a chair in medicine but later moved to Frankfurt-am-Main to continue his neurological work. Apart from his pioneering studies of PTCS, which he called meningitis serosa, important contributions included his description of angioneurotic oedema and his studies on the mechanism of body temperature. Particularly notable was his introduction of lumbar puncture as a technique.

technique of lumbar puncture by Quincke around the start of the twentieth century, which allowed for the first time objective measurement of the CSF pressure and analysis of its content. The century from Nonne’s first paper in 1904 to the present will be somewhat arbitrarily divided into three periods. The divisions are marked most notably by major radiological advances; in the first instance, the development of ventriculography/encephalography and angiography, and in the second, by the development of computed tomography and subsequently magnetic resonance (MR) scanning. The periods, then, are 1904
1936, 1937
1970, and 1971 to the present. The first transition was of major importance in that it marked the abandonment of the idea of a CSF circulation problem as causative, at least for the time being; and the second, because it marked the introduction of very sophisticated technology, not only the scanning methods mentioned but also radionuclide and infusion methods of investigating CSF dynamics, which might reasonably have been expected to clarify the disease mechanism. Unfortunately, the hoped-for elucidation has not altogether eventuated, as will be made particularly apparent in the

8

Figure 2.2

History of the pseudotumor cerebri concept

Max Nonne (1861
1959) who studied in Heidelberg, Freiburg and Berlin before receiving his doctorate in Hamburg in 1884 where he worked as a neurologist from 1889. His teachers included Erb and von Esmarch. In 1889 he became chief physician in the department of internal medicine at the Red Cross Hospital, and in 1896, chief physician in the neurology department at the Eppendorf Hospital. In 1919 he received the teaching appointment in neurology at the newly founded University of Hamburg where he worked with Jakob. Nonne was one of the four physicians asked to consult on V.I. Lenin during his final illness.

following chapter on mechanism. The five epochs identified are, in summary, as follows. 1. The period prior to Quincke and Nonne, i.e. 1860
1897 marked by the first reports of cases which appear to be cases of PTCS without their being identified as a specific syndrome. 2. The period distinguished by the reports by Quincke (1893, 1897) and Nonne (1904, 1914). 3. The period following these reports and prior to the development of neuroradiological techniques, i.e. 1912
1936. Notable during this period were the writings of Passot (1913), Warrington (1914), Frazier (1930), and Symonds (1931, 1932). 4. The period of neuroradiological investigation, i.e. 1937
1970 during which the demonstration of normal ventricular size led to the abandonment of the idea of PTCS as a disorder of CSF dynamics. Important studies in this period were those of Dandy (1937), Davidoff (1956), Foley (1955), and Sahs and Joynt (1956).

9

Period 1: 1866
1896

5. The period from 1971 to the present, notable for major technological developments, the return of the concept of PTCS as a disorder of CSF circulation, and the re-emergence of cranial venous outflow obstruction as an important aetiological factor, and of optic nerve sheath decompression as a treatment option. Period 1: The first descriptions (1866
1896) Possibly the first description of a case of PTCS was that of Bouchat in 1866 (reported by Passot, 1913) who, interestingly, introduced the ‘pseudo’ concept, speaking of ‘pseudo-meningitis’. In reviewing these early descriptions, not all of which will be specifically referred to, two particular points emerge. The first is the association of the, as yet, unnamed syndrome with a number of the factors still recognized today as having a close, and possibly aetiological, association with the condition, and the second is the use of several of the treatment methods that are now enjoying something of a renaissance. On the issue of the association with other conditions, the period from 1880 to 1900 saw several reports linking the clinical presentation of a spontaneously resolving raised ICP picture with amenorrhoea, ear disease, anaemia, head injury, and intracranial venous occlusion. One of the earliest articles in English is a long section on diseases of the optic nerve in the Transactions of the Ophthalmological Society of the UK for 1880
1. Three descriptions within this report stand out. The first is Hughlings Jackson’s reference to reports by several ophthalmic surgeons of ‘ . . . a recoverable optic neuritis in young women suffering from uterine derangement’. Apropos this, there is the earlier observation by Foerster, quoted in several papers, that all that is known about the connection between optic nerve disease and menstruation is that it exists. The second is W.R. Gowers’ report of a 16-year-old girl with relatively transient bilateral ‘optic neuritis’ and a VIth nerve palsy, and the third is the description by Broadbent of a young girl with a 2-year history of headache and vomiting with ‘double optic neuritis’ associated with amenorrhoea whose symptoms and signs resolved, and in whom menstrual regularity was restored. Although her presenting symptoms resolved, she remained blind from the effects of the papilloedema. Elsewhere, also in 1881, Lawford described a 12-year-old girl with a history of purpura, who developed bilateral papilloedema with reduced visual acuity but without other signs, and who later improved progressively over 9 months. Gowers reported two sisters, both of whom developed the characteristic clinical picture in association with anaemia, in relation to whom he wrote that the clinical progress did ‘ . . . not afford the slightest ground for suspicion of intracranial disease.’ He also referred to another case described in his book,

10

History of the pseudotumor cerebri concept

Medical Ophthalmoscopy. In relation to ear disease, Taylor wrote in the 1890 edition of The Practice of Medicine : It is important to remember what has now been verified in numerous cases that in mastoid suppuration there is often double optic neuritis with an entire absence of meningitis or of abscesses proved by post-mortem examination, or by recovery after simple trephining of the mastoid cells.

He described a typical case in his 1894 review of optic nerve disorders (case 6). In an interesting article analysing 57 patients who died from complications of otitis media, Newton Pitt, in 1890, described three other patients, all of whom had ear disease with papilloedema but no other neurological signs, and who recovered, one having had the lateral sinus explored, clot removed and the internal jugular vein ligated. On the matter of treatment, Carter, in two papers in 1887 and 1889, respectively, described the use of optic nerve sheath decompression to alleviate the ophthalmological effects of raised ICP, referring to the initial description of the technique by de Wecker (1872), with whose surgical approach he disagreed. In the first article, Carter described the case of a 26-year-old lady’s maid who, 10 days after a minor head injury, developed headache and lost her vision, and had marked bilateral papilloedema but no other findings. Despite treatment (iodide of sodium and mercurials), her eye signs worsened and she had a left optic nerve sheath decompression. There was subsequent improvement with resolution of her papilloedema. Victor Horsley, who had for a brief period advocated de Wecker’s operation, became a proponent of cranial decompression for optic neuritis due to raised ICP in general, and spoke of the benefits in the discussion following Taylor’s article referred to above. One other report that deserves mention is that of Jacobi who, in 1896, wrote of ‘rhachitical hydrocephalus’ in children with bulging anterior fontanelle and/or choked discs, and remarks that the outlook is ‘by no means unpromising’. Finally, mention must be made of the rather remarkable article by Williamson and Roberts which appeared in 1900, after Quincke’s two articles. In this, the authors analyse 100 cases of ‘double optic neuritis’. The article is brief but their groups IX and X probably constitute the first good description of PTCS within the diagnostic limitations of the time. There are, in these groups, 21 cases comprising 13 females of average age 16.8 years (range 10
22 years) and 8 males of average age 17.1 years (range 10
40 years). Of particular importance is that the follow-up for 20 of the cases averages 4.4 years. On the question of incidence, they mention that: ‘Most medical men who have paid much attention to cerebral diseases will have met with a case or cases of this kind.’ Other salient features in this article include recognition of the importance of looking for an association with ear disease and haematological disorders, and the exclusion of Bright’s disease and

11

Period 2: 1897
1904

syphilis. With respect to treatment, they speak of the importance of Horsley’s advocacy of cranial decompression and also the possibility of lumbar punctures. By the end of this first period then, there had been quite a number of descriptions of a condition characterized by the symptoms of raised intracranial pressure without neurological signs or ophthalmological signs other than the papilloedema which could by now be recognized with the development of the ophthalmoscope. Before Quincke, however, there was no objective measurement of CSF pressure. Several enduring associations of the condition, specifically middle ear infection, menstrual disturbance and haematological abnormality had been recorded. In addition, three enduring methods of treatment had been employed: a direct approach to venous sinus obstruction, ONSD, and cranial decompression. Period 2: The definition of a syndrome (1897
1904). The key papers of Quincke and Nonne The four papers already referred to, two by Quincke and two by Nonne, are generally taken as the start of recognition of a specific syndrome. Two points should, however, be borne in mind. First, as outlined above, there were clearly prior descriptions of cases with the condition and second, most of the cases described by the two authors would not fit the criteria for diagnosis even taking into account the limitations of investigative methods at the time. Quincke, in his major article in 1897, defined a clinical entity which he called serous meningitis (meningitis serosa). He attributed the clinical features in this condition to raised ICP and presumed the cause to be hypersecretion of CSF mediated through the autonomic nervous system. His list of aetiological agents included head injury, stress, alcohol excess, pregnancy, influenza, and otitis media. He described 10 cases: three males (ages 12, 23, and 39 years) and seven females (ages 13
22 years). All the males can quite clearly be disqualified from the diagnosis of PTCS on present criteria. Thus, two presented in coma, one of these dying early in the clinical course, whilst the third (a 12-year-old boy) had in addition to raised ICP, mental deterioration, incontinence, gait ataxia, and a VII nerve palsy, and would seem to have been a case of hydrocephalus, as Quincke himself suggested. Of the seven females, two presented with loss of consciousness although in other respects they would conform to the current concept of PTCS. Both had headache, papilloedema, and measured increase in CSF pressure with fluid of normal composition. One showed deterioration of visual acuity. In one of the two females there was improvement after lumbar puncture and neither showed later deterioration. Four of the seven females were without papilloedema. Two of these patients had normal CSF pressure on lumbar puncture whilst in the

12

History of the pseudotumor cerebri concept

other two the pressure was only marginally raised (190
200 and 200 mmH2O). Both the latter two had a rapid and apparently complete spontaneous recovery. The seventh patient would definitely be disqualified in that she had focal neurological signs and, in fact, died shortly after presentation. The main point of Nonne’s 1904 article was to identify cases which had the clinical appearances of an intracranial tumour, including raised ICP, but whose course subsequent to diagnosis appeared to preclude this diagnosis. He described, in all, 18 cases which are clearly a miscellany in terms of cause, mechanism, and outcome. The first eight cases (four males and four females, age range 18
47 years) all had signs and symptoms of raised ICP. CSF pressure at lumbar puncture pressure was recorded as raised in four and normal in one. All had some degree of focal disturbance and all recovered spontaneously, usually within a short period of time, of the order of 2 weeks. It was this group which was taken to support Nonne’s thesis that signs and symptoms highly suggestive of intracranial tumour may not, in fact, represent such a diagnosis, this conclusion being based on subsequent history. The majority of the patients were followed for several years. In his analysis of this group, the author argued against the alternative diagnosis of hydrocephalus on the grounds of no apparent cause, the presence of focal signs, and the clinically fluctuating course. The second group of 10 patients was more of a potpourri. Two of the patients had post-mortem demonstration of a tumour and two of severe hydrocephalus. Of the remaining six patients, three died within a year of diagnosis without demonstration of any neurological cause (one of heart failure and two without post-mortem). One case, a 55-year-old woman who presented with headache, ataxia, and papilloedema, developed severe dementia and may well have had progressive hydrocephalus. It is the remaining two cases who represent the only patients of the 18 who might be accepted as having had PTCS according to current diagnostic criteria. The first of these, a 25-year-old man, was concussed in a fight. Shortly thereafter he developed severe headache and was described as having IIIrd, IVth and VIth nerve palsies with severe bilateral papilloedema and CSF pressure of 660 mmH2O. After a series of six lumbar punctures with drainage of 15
20 mL on each occasion, he recovered and subsequently remained well. The second patient, a 27-year-old woman, had a 2-year history of chronic suppurative otitis media followed by a 2-week history of headache, dizziness, vomiting, and diplopia. On examination, she had bilateral papilloedema and a left VIth nerve palsy. Based on a diagnosis of cerebral abscess, operative exploration was carried out which revealed only a thrombosed transverse sinus on the left. She subsequently recovered spontaneously with only mild residual optic atrophy. Nonne concluded that she had had hydrocephalus secondary to transverse sinus thrombosis due to her suppurative otitis media.

13

Period 3: 1905
1936

Thus the cases which Nonne described in his first report as pseudotumor cerebri are not those which would be so described today and clearly represent a different aetiology and mechanism. Among his other cases (the second group of 10 cases), there were those with hydrocephalus secondary to an identifiable cause (in two cases, tumour) which he described to make a distinction with the pseudotumor cases. Within this group there were, however, two cases which might equate with pseudotumor cerebri on present day criteria, although multiple cranial nerve palsies in the first patient might preclude such a diagnosis. In summary then, Quincke claimed to have identified a syndrome to which he gave the name ‘serous meningitis’ and suggested a causative mechanism. Nonne rather focused on a recurring diagnostic dilemma and applied a name, pseudotumor cerebri, to those cases that initially appeared to have an intracranial tumour but were proved not to have one by subsequent events. There was no suggestion as to a specific mechanism nor any attempt to identify a syndrome as such. In fact, in Passot’s detailed review of ‘serous meningitis’ written almost 10 years after Nonne’s first report, there is no reference to the latter. Nonetheless, although Nonne’s endeavour might be considered less ambitious than that of Quincke, it his nomenclature that has proved the more enduring. Period 3: The pre-neuroradiological period (1905
1936). Passot, Symonds, and the identification of ‘otitic hydrocephalus’ Two notable papers from the early part of this period are those of Oppenheim and Borchardt in 1910 describing the condition following Nonne’s report and proposing the name ‘Nonne’s disease’ (‘die Nonnesche Krankheit’) and Nonne’s own further paper in 1914, this time using the title ‘pseudotumor cerebri’. Otherwise, the important developments of this period were: first, a consolidation of the connection of the syndrome with middle ear disease; second, the further reports linking the syndrome with other conditions, in general with ones already reported such as minor infections and blood dyscrasias; and third, the increasing involvement of the developing specialty of neurosurgery with the syndrome along the lines prefigured in Nonne’s study. Here pseudo-abscess was added to pseudotumor, reflecting the strong connection with ear disease. The culminating studies of this period were undoubtedly those of Symonds who coined the term ‘otitic hydrocephalus’ because of this frequent association with middle ear disease. Each of the key studies from this period will be considered individually, followed by a summary of other reports of significance. The next important work after Nonne was that of Passot who presented a thesis in Paris in 1913 entitled Me´ningitis et E´tats Me´ninge´s Aseptiques D’origine Otique. This is referred to by a number of early writers and clearly contains several

14

History of the pseudotumor cerebri concept

concepts which have continued through the subsequent speculation on PTCS. The most important aspect of Passot’s study is his systematic analysis of aseptic meningitis of otitic origin, of which he identifies two kinds: les me´ningites vraies and les e´tats hypertensifs. In the first, there was a mild meningitis in which the CSF showed an excess of cells and protein. In the second, the CSF composition was normal but the pressure was increased. These he called les e´tats me´ninges hypertensifs. The second form was subdivided into cases of l’hydropisie me´ninge´es with excess fluid in the subarachnoid space, and those having internal hydrocephalus with focal signs. In the first subdivision there was, on occasion, postmortem evidence of congestion of the choroid plexus, and oedema of the ependyma and subependymal tissue. In operative cases there was evidence of increased CSF volume and a distended subarachnoid space, an observation that was to recur in many later descriptions. It is the first, which he also calls hydropisie me´ninges, which corresponds to PTCS. His description of an increase in ICP due to hyperproduction of CSF in the subarachnoid space and ventricles, with no elements or albumin in the fluid, occurring in association with ‘banale’ ear disease in children and young adults, and immediately and definitively relieved by drainage of CSF is, apart from the speculation on mechanism, still applicable. Two other points of interest are, first, the description of a similar condition due to a blow to the head rather than ear disease, and second, his claim that a clear clinical distinction is possible from hydrocephalus. In this study, too, the value of lumbar puncture, both diagnostic and therapeutic, is stressed. Close on the heels of Passot’s study came the detailed clinical observations of Warrington, reported in 1914. The latter, incidentally, does not refer to the former. Warrington’s paper was entitled ‘Intracranial Serous Effusions of Inflammatory Origin’ and subtitled ‘Meningitis or Ependymitis Serosa?
with a note on Pseudotumours of the Brain’. In the introduction he wrote: From time to time the clinical observer is confronted with patients who on the one hand present acute and alarming signs of intracranial disease or on the other hand more chronic manifestations of increased pressure within the skull. The course of the disease or the evidence from post-mortem shows that the cause of the symptoms is not due to the common form of meningitis or to cerebral tumour and a less known pathology has to be sought for. Complete or partial recovery is the rule in the acute cases about to be related whilst the more chronic not infrequently terminate fatally, hence their pathology is better understood.

The concept of PTCS would obviously be included within this description and in his classification on page 95 there is what he terms generalized or localized (external) pseudotumor cases under the heading of sero-meningitis or inflammatory oedematous distension of the arachnoid membrane. Of the eight cases described in detail, only one would, however, fit the criteria of PTCS. This was

15

Period 3: 1905
1936

a 13-year-old boy with a 7-month history of chronic bilateral suppurative otitis media who presented with a 4-week history of headache, vomiting, dizziness, and diplopia, and who, on examination, had severe bilateral papilloedema, a left VIth nerve palsy and nystagmus. There were no other signs. On lumbar puncture he had ‘clear fluid under pressure without cell elements and little excess of albumin’. ‘Calomel at night time from time to time’ was the only treatment, and he recovered over a 6-week period. The author drew attention to Gradenigo’s earlier description of a triad of symptoms: pain in the temple and occipital region, bilateral abducens paralysis, and optic neuritis, associated with acute middle ear inflammation. The other seven cases were something of a miscellany but clearly do not include instances of PTCS. Later, he gave a brief description of four cases under the heading ‘Cases, chiefly in children, in which all symptoms of intracranial pressure disappeared for an indefinite time perhaps permanently, without any specific treatment.’ Although the descriptions were brief, all four cases would appear to correspond to current ideas of PTCS. During this period there were three reports of particular note by neurosurgeons. Thus, Frazier, in 1930, reported a series of 22 cases of what he called cerebral pseudotumor, 14 of whom had had some preceding infection, typically of a rather non-specific nature. Most of these cases were treated by surgical decompression. Nineteen of the 20 were described as being alive and well 1
25 years after diagnosis. Earlier, Adson, in 1924, under the title of ‘Pseudo-brain abscess’, described three cases who presented with raised ICP and other CNS signs following ear infection but who were not found to have a demonstrable abscess. These cases he attributed to localized encephalitis without abscess formation. Finally, Cairns, writing in 1930, reported one case of a pure intracranial hypertension syndrome after mastoiditis, and raised the possibility of excess formation or deficient absorption of CSF as a causative mechanism. A number of papers during this period reported small numbers of cases which further consolidated the connection of the syndrome with middle ear disease. Amongst these may be mentioned the following: Lillie and Lillie, in 1925, described four cases of ‘choked disc’ with surgical mastoid disease but without abscess formation, and without visible sinus thrombosis. These were apparently typical cases of post-otitic PTCS as were the two cases described by Mygind in 1922. The first of Mygind’s cases was a 17-year-old girl with acute suppurative otitis media who initially had 26 lymphocytes in her CSF and a lumbar puncture pressure of 400 mmH2O. More than a week later she developed papilloedema and a VIth nerve palsy, and 2 weeks later, headache and vomiting. At that time her CSF pressure was 950 mmH2O but the fluid was, by then, of normal composition. Her signs and symptoms had almost cleared after 6 months although her CSF pressure remained significantly elevated (600 mmH2O). The second case was similar

16

History of the pseudotumor cerebri concept

without the initial abnormality of CSF composition. Aboulker, in 1919, recognized two syndromes of aseptic meningitis: diffuse with excess of cells and protein, and hypertensive with fluid of normal composition, the latter obviously corresponding to PTCS. Liedler, in 1928, was probably the first to describe PTCS after ligation of one or both internal jugular veins in the treatment of chronic ear disease. Continuing the connection with haematological and endocrine disorders, Schink in 1923 described a case of raised ICP, confirmed on lumbar puncture, associated with thrombocytopenic purpura, which resolved spontaneously. In addition, Albrecht in 1923 reported a case of idiopathic tetany with papilloedema. Possibly of more importance from the endocrine viewpoint, but in ways that are still not understood, was the report by Thomas in 1933 of two patients with generalized oedema occurring only during the menstrual period, both of whom had severe headache and blurring of vision. One of the two was documented as having papilloedema and raised CSF pressure on lumbar puncture. This was the first clear suggestion of a possible endocrine basis of a more widespread nature underlying the condition, particularly in obese young women who later came to be recognized as typically being afflicted by the disease. The first recognition of another significant but uncommon aetiological factor came with Cameron’s report in 1933 of marked bilateral papilloedema with impaired visual acuity in chronic respiratory disease. Sir Charles Symonds published three papers in the 1930s, the first in 1931. In this, following a detailed review of the literature, he described three cases, all children who developed raised ICP in association with middle ear disease. He was impressed by the large volumes of CSF drained by lumbar puncture in these patients (as, indeed, Passot had been) and concluded that there was free communication throughout the CSF-containing spaces. His postulate was that after otitis media and with a variable relation to venous sinus involvement there might develop a condition of ‘ . . . increased ICP due to the presence of an excess of normal CSF’ and suggested the term otitic hydrocephalus as a title which ‘ . . . implies no active process of inflammation and being deprived of the qualification internal or external will include fluid both within the ventricles and the subarachnoid space.’ As a mechanism, he proposed ‘ . . . either an excessive secretion from the choroid plexus or a defective absorption through the arachnoid villi’ and recommended drainage of CSF by lumbar puncture as the rational form of treatment. In two subsequent papers, in 1932 and 1937, he elaborated this concept and, of particular interest, described several other cases with a similar syndrome associated with infection of non-otitic origin but also attributable to cranial venous sinus involvement. One such case, separately described by Ellis, was an infant with an umbilical vein infection who showed multiple venous thromboses and developed hydrocephalus seen on

17

Period 4: 1937
1970

ventriculography and related to superior sagittal sinus thrombosis, demonstrated by direct sinography. None of Symonds’ own cases, incidentally, had ventriculography, hence his persistence with the term ‘hydrocephalus’. Of interest is that Symonds wrote a further (and final) paper on the subject in 1956 in which he moved away from increased CSF volume as significant. This will be considered below but, on a personal note, Symonds wrote to one of the authors in 1973 after publication of a paper advocating a return to the idea of reduced CSF absorption as the basic abnormality (Johnston, 1973), supporting this proposal. This third period thus came to an end with at least the illusion of genuine progress. Symonds, in particular, had drawn together the increasing number of clinical observations to define a clinical entity
otitic hydrocephalus
in which complications of middle ear infection, particularly lateral sinus occlusion, produced a disturbance of CSF circulation with a resulting increase in CSF volume. The problems were that this syndrome was not by any means limited to cases with a prior ear infection and, more importantly, there was no hydrocephalus in the accepted sense of the word, as the radiological developments of the 1930s were soon to show. Period 4: The introduction of neuroradiology and new treatments (1937
1970) The main developments of importance in relation to PTCS during this period were, at the investigative level, the introduction of several neuroradiological techniques (angiography, venography, ventriculogaphy, and encephalography) and, at the therapeutic level, the introduction of steroids, acetazolamide, and antibiotics. The neuroradiological advances allowed for the first time confident early exclusion of other causes of intracranial hypertension. They also cast serious doubt on the possible causative role of increased CSF volume, thus leading to the abandonment of the concept of otitic hydrocephalus. Moreover, they put the diagnosis and management of PTCS firmly into the hands of neurosurgeons. The therapeutic advances, at a somewhat later point, changed substantially the approach to treatment of PTCS in the case of steroids and to a lesser extent acetazolamide and, in the case of antibiotics, reduced sharply the incidence of chronic middle ear infection. The start of the period is marked by two key papers of neurosurgical/ neuroradiological origin, those of Davidoff and Dyke (1937) and of Dandy (1937), which were the first to delineate the ventricular system in PTCS. The cases described were similar, but the conclusions as to mechanism were quite different. Davidoff and Dyke described 15 patients, 11 females and 4 males, with an age range of 4
43 years, all of whom had a more or less pure intracranial hypertension syndrome. Six patients had a history of either otitis media or some other infection

18

History of the pseudotumor cerebri concept

whereas, interestingly, nine had no antecedent abnormalities. In all cases, air studies were essentially normal and all, apart from one who did not require any treatment, responded well to cranial decompression (13 subtemporal, one posterior fossa). The authors noted, however, that despite the rapid symptomatic improvement the ‘ . . . final disappearance of papilloedema required from six months to several years’. They had one patient who died 3 months after treatment from unrelated causes in whom post-mortem examination of the brain was unremarkable. On the issue of mechanism, these authors concluded that there was a disequilibrium between CSF production and absorption. Fremont-Smith appended the following comment to their article
a comment which might be considered somewhat prescient in the light of modern views: ‘My hunch is that the majority of cases will turn out to be due to the failure of absorption rather than an excessive production of fluid.’ Dandy described 22 cases, all with normal ventriculography, who were treated predominantly by subtemporal decompression (STD). Whilst Davidoff and Dyke had used the name ‘hypertensive meningeal hydrops’; Dandy preferred the quite non-committal (in terms of mechanism) and rather cumbersome name ‘intracranial pressure without brain tumour’. All his patients recovered, a significant number being later reviewed and reported in the study by Zuidema and Cohen in 1954. In this later report, 12 of Dandy’s original 22 patients were traced. Ten were alive and well whilst two had died
one from an intracranial aneurysm 15 years after the initial diagnosis and one from multiple sclerosis. To Dandy may be attributed the origin of the controversy as to which intracranial compartment, brain, blood or CSF is primarily responsible for the increase in ICP in PTCS. Prior to his paper, all attention, including that of Davidoff and Dyke who were the first to report normal ventricular size, had focused on a disorder of CSF hydrodynamics with a resultant increase in CSF volume. Dandy, however, felt, as have many subsequent writers, that the absence of ventricular dilatation precluded a significant increase in CSF volume. He also thought that the chronicity of the condition precluded cerebral oedema as a cause. What particularly impressed him were the observed rapid fluctuations in tension of the subtemporal decompressions in patients so treated. In his view the time course of these fluctuations could best be accounted for by changes in cerebral blood volume. Two other papers from the late 1930s that should be mentioned are those of McAlpine in 1937 and Gardner in 1939. In the first, the author described cases of what he called ‘external’ or ‘toxic’ hydrocephalus, these being cases of a pure intracranial hypertension syndrome following an infection other than of the middle ear, an aetiological agent that has remained of significance. He likened these cases to Quincke’s description of meningitis serosa and

19

Period 4: 1937
1970

postulated an over-production of CSF as the cause. All of Gardner’s 10 cases were, on the other hand, associated with ear infection, the majority also having transverse sinus occlusion. He, like a number of writers, was impressed by the large volumes of CSF drained by lumbar puncture in this condition, but stressed that such volumes did not necessarily mean an overall excess of CSF. He also argued that the oft-observed distension of the subarachnoid space did not necessarily mean excess CSF in that compartment, but might rather reflect local accumulation due to release at that site. This was an idea later taken up by Foley in his 1955 paper discussed further below. In large part due to World War II there was very little published work on the subject of PTCS for over a decade, just as had occurred after Warrington’s detailed study published in 1914. Indeed, a literature search yielded only 12 papers published in the 1940s and these were neither novel nor substantial. Four papers, those of Loman and Damashek (1944), Tinney et al. (1943), Watkins et al. (1941) and Drew and Grant (1945), called attention to the connection of PTCS with polycythemia vera and other blood disorders. Two papers, those of Sutphin et al. (1943) and Levy (1947), reported single cases associated with hyperparathyroidism, whilst three papers (Meadows, 1946; Beaumont & Hearn, 1948; Simpson, 1948) reported cases associated with chronic respiratory disease and cardiac failure, adding to Cameron’s report referred to earlier. In Simpson’s report of three cases with emphysema it is noteworthy that while two had a measured increase in CSF pressure on lumbar puncture, in all three cases central venous pressure was normal. Of the remaining three papers, that of Evans in 1942 gave further evidence of a PTCS following bilateral internal jugular vein ligation although, in reviewing other reports as well as his own cases, he found that none of the seven patients having bilateral internal jugular vein ligation for non-otitic problems developed papilloedema while the three cases having bilateral ligation for ear problems all did. Of six cases who had unilateral ligation for bilateral ear disease, only one developed papilloedema. There was also one article reporting raised ICP with the Guillain-Barre´ syndrome in two cases, a subject which will be discussed further below. Finally, there was the report by McCullagh (1941) of an association of PTCS with recurrent menstrual oedema, as previously noted by Thomas (1933). The 1950s saw a resurgence of interest in PTCS, with the appearance of a number of important papers, three from new contributors and three from authors who had previously written on the subject. The first of the new contributors were Ray and Dunbar (1950, 1951). Building on the initial report of Frenckner (1937), who introduced venous sinography and first raised the possibility of the superior sagittal sinus being involved by extension from the transverse sinus, Ray and Dunbar (1951) reported four cases investigated by direct sinography.

20

History of the pseudotumor cerebri concept

In this technique a catheter was inserted directly into the anterior part of the sagittal sinus via a small midline burr-hole. Two were patients who were identified as having pseudotumor cerebri, without any antecedent factors, who had failed to respond satisfactorily to subtemporal decompression. Both showed evidence of obstruction in the posterior part of the superior sagittal sinus with elevation of intra-sinus pressure, and one went on to have direct clot removal with apparent benefit. The third case had an acute presentation with high fever, seizures, focal neurological signs, and raised CSF pressure. The fourth case was described by the authors as a typical case of otitic hydrocephalus, and was found to have complete obstruction of the right transverse sinus and a small left transverse sinus. In this case there was an elevation of superior sagittal sinus pressure (320 mmH2O). The second of the new contributors was Foley (Figure 2.3) who presented a detailed study in 1955 in which he defined two subgroups of cases of PTCS: otitic, secondary to dural sinus thrombosis after ear disease, and toxic, although noting that as often as not there was no history of antecedent infection. In the main body of the paper he reviewed 46 cases of otitic benign intracranial hypertension (a term he introduced) from the literature and analysed 60 cases of his own of which 13 were otitic or cerebral venous in origin. He also recognized a group of patients with apparent bilateral disc swelling, but without other evidence of raised ICP and looked at the ophthalmological differential diagnosis in this group. On the issue of mechanism, he carried out some rudimentary studies on cerebral blood flow using the N2O technique, finding somewhat high values but nothing on which to base any substantial conclusion. He defined the syndrome to which he applied the term benign intracranial hypertension (BIH) as follows: . . . prolonged intracranial hypertension without ventricular abnormality, focal neurological signs or disturbance of awareness or intellect, the most frequent symptoms being headache of moderate degree, obscurations of vision, diplopia and sometimes tinnitus; marked papilloedema and abducens palsies are the only signs. The CSF is normal in composition and the prognosis is almost invariably good, the condition subsiding within a few weeks or months.

The third of the new contributions came from Zuidema and Cohen who, in their 1954 paper, reported 61 cases using the term pseudotumor cerebri. The importance of this paper was two-fold. First, in including a large number of cases, the range of clinical and investigative findings was given attention, and second, the issue of long-term outlook, and particularly the possibility of an initial diagnostic error overlooking some other cause of the intracranial hypertension was considered. On this second point, the paper was of particular interest in that it included follow-up on some of Dandy’s original cases as described above. Of the 61 patients in the study, 22 were from Dandy’s earlier report and 39 were their own cases.

21

Figure 2.3

Period 4: 1937
1970

(a) Schematic representation of the three components of the intracranial system, the incompressible brain tissue (shaded), the vascular system open to atmosphere, and the C.S.F. (dotted); (b) during ventricular obstruction; (c) when there is obstruction at or near the points of outlet of the C.S.F.; (d) when there is obstruction of the venous outlet. (John Foley, 1955.)

Long-term follow-up was obtained in 38 cases, 12 of Dandy’s patients and 26 of their own. In 4 of these 38 cases there was death from neurological disease, but it is doubtful whether in any case there was a direct connection between what was diagnosed as PTCS and the actual cause of death. They also reported a case of recurrence, a matter which had not hitherto attracted attention. The three writers of note who returned to the subject, Symonds, Davidoff, and Sahs, all did so in 1956. Symonds, in a reflective paper, reconsidered the application of the term otitic hydrocephalus which he had introduced in 1931

22

History of the pseudotumor cerebri concept

and changed his views on mechanism, coming around to Gardner’s postulate that venous engorgement provoking cerebral oedema was a significant contributing factor. He also described the only case of a patient dying after lumbar puncture 3 weeks after the onset of acute right otitis media with obstruction of both lateral sinuses. On the question of treatment, he felt that many patients did well if left alone but, if treatment was required, serial lumbar punctures should be the first line, followed by subtemporal decompression if the CSF pressure was not settling. He clearly did not conclude from the case dying after lumbar puncture that coning was a significant risk, although he did raise the matter in discussing his preference for ventriculography over encephalography. Davidoff wrote again on the subject 20 years after his initial contribution with the neuroradiologist Dyke. In the first paper they had used Quincke’s term, serous meningitis, in the title and suggested introducing the new name ‘hypertensive meningeal hydrops’, calling to mind Passot’s contribution. Davidoff now abandoned both these names in favour of pseudotumor cerebri, although he also included BIH, just introduced by Foley. In fact, the 1956 paper was titled ‘Pseudotumor cerebri (BIH)’ and was basically a detailed clinical report of 61 cases followed up over a long period (1
22 years). There were no new insights into mechanism and the clinical features were now clearly defined along the lines described by Foley. Davidoff did, however, draw attention to the growing recognition of the association with intracranial venous sinus occlusion, initially known by observation to those who had carried out operative treatment of chronic middle ear disease, but also by this time becoming demonstrable by radiological methods. Sahs also returned to the subject in 1956, this time writing with Joynt. In the initial study with Hyndman in 1939, four cases had been described using the nonspecific term ‘intracranial hypertension of unknown cause’ but speculating on the likelihood that cerebral oedema was, in fact, causative. In the later paper, in which they put the initial hypothesis to the test, 17 cases were included, all of whom would qualify for the diagnosis of PTCS on current criteria. All had raised CSF pressure on lumbar puncture and in none was there an abnormality of CSF composition (12 normal, 5 not examined). In the 16 who underwent ventriculography, there was normal ventricular size in each case. There was a characteristic range of aetiological factors and all 17 patients were alive at follow-up from 1 to 16 years (average 8.7 years) later. The authors reported intracellular and extracellular oedema in brain biopsy specimens, taken at the time of decompression (or presumably at ventriculography in the one case who did not have a decompression) in all 10 of the 17 cases so studied. An analysis of the reliability of these findings and comparison with other studies is deferred to the following chapter on disease mechanism. Suffice it to say that the 1956 paper signalled

23

Period 4: 1937
1970

something of a volte-face in the thinking about mechanism although it failed to address the very considerable theoretical problems associated with the oedema hypothesis (discussed in detail in the next chapter). Starting in the 1950s, by which time the concept of PTCS, termed either pseudotumor cerebri or benign intracranial hypertension, had become quite clearly defined in the form which has persisted to the present, there was an increasing recognition of the multiplicity of aetiological factors with numerous reports linking the syndrome to particular drugs (e.g. antibiotics, corticosteroids, and a miscellany of other agents), to disorders of endocrine function involving adrenal, thyroid, parathyroid, and pituitary glands, to blood disorders and so on. Indeed, through the 1960s much of the attention directed to the syndrome focussed on aetiology. Thus Greer, who wrote extensively on the subject during this period, published a series of papers linking the condition to various aetiological factors, mostly previously recognized at least in single case reports, such as steroid administration (Greer, 1963a), mastoiditis and sinus occlusion (Greer, 1962), pregnancy (Greer, 1963b), the menarche (Greer, 1964b), menstrual cycle dysfunction (Greer, 1964a) and obesity (Greer, 1965). In a review article, published in the Handbook of Clinical Neurology in the following decade (Greer, 1974), he subdivided the identified aetiological factors into six subgroups, a classification which remains more or less applicable today: venous problems, endocrine disorders, haematological disorders, vitamin A, drugs, and miscellaneous. Two of the identified agents
vitamin A deficiency or excess, and steroid administration or withdrawal
merit particular attention, especially in relation to mechanism, but also with respect to aetiology and treatment. In relation to vitamin A, it became clear from the experimental work of Millen et al. (1953, 1954) and Eaton (1969) among others, that dietary changes in vitamin A intake could result in a disturbance of CSF circulation with raised CSF pressure which might go on to frank hydrocephalus. A clinical counterpart appeared with a PTCS in hypervitaminosis A in humans, particularly affecting children. Persson et al. (1965) attributed the first clinical description of hypervitaminosis A to Joseph in 1944 and described five cases of their own, all children aged 1 to 6 months who had clinical evidence of raised ICP. Prior to that, Marie and See in 1954 described three cases, one with a measured pressure increase on lumbar puncture. Feldman and Schlezinger (1970) described two cases of a typical PTCS in adults associated with chronic hypovitaminosis A and, in a detailed review of the literature, identified six other cases in adults reported prior to 1970. A relationship of PTCS with corticosteroids, either endogenous or therapeutic, was first indicated by the reports in the 1950s of an association between Addison’s disease and raised ICP (Walsh, 1952; Jefferson, 1956). Jefferson, who described

24

History of the pseudotumor cerebri concept

four cases of Addison’s disease with papilloedema, attributed the increase in ICP to cerebral oedema, but noted that in 11 of Addison’s original cases coming to post-mortem there was no pathological evidence of oedema. Nevertheless, Klippel in 1899 had described a condition of ‘encephalopathy addisonienne’ which he attributed to brain oedema. The report by Laurence et al. in 1960 was the harbinger of a series of reports of PTCS occurring in association with prolonged steroid medication (both oral and topical) and also with steroid withdrawal after prolonged therapy. Walker and Adamkiewicz in 1964 were able to collect 24 such cases reported up to that time. In summarizing this fourth period, it was marked particularly by the need to come to terms with the finding of normal or small ventricles on ventriculography/ encephalography. To a lesser extent, angiographic findings also had to be taken into account. These observations seemed to exclude an obstruction of CSF circulation as causative and the focus turned to brain oedema or changes in CBV as being responsible for the raised ICP. The former was supported by the histological findings, albeit very limited, and also by the therapeutic response to newly introduced agents active against oedema
glucocorticoids and diuretics. There was also, in this period, a name change with Foley’s introduction of the term benign intracranial hypertension (BIH). Period 5: The modern period (1971
2005). New techniques, old theories, and old therapies During the last 30 years, approximately, there has been a veritable explosion of papers on PTCS. It is difficult, therefore, to identify a few key studies in the way that was possible for the earlier periods. Unfortunately, the great increase in the literature has not been accompanied by a commensurate advance in our understanding of the condition. ‘New techniques’ in the heading above refers to investigative methods, an area in which there have been marked advances; computed tomography (CT) scanning, magnetic resonance imaging (MRI), greatly improved angiography with micro-catheter techniques, positron emission tomography (PET) scanning, radionuclide techniques, ICP monitoring, and CSF infusion methods. All these might have been expected to contribute in their particular ways to clarification of pathophysiological mechanisms and to some extent they have
just not to the extent that might have been anticipated. ‘Old theories’ refers particularly to both a robust return to the idea of the condition as basically a disorder of CSF dynamics, and to a significant re-emergence of the idea of the importance of cranial venous outflow impairment. ‘Old therapies’ refers to the return to very early methods of treatment, specifically ONSD and CSF drainage, although the latter is now generally continuous by way of a shunt

25

Period 5: 1971
2005

rather than intermittent by means of serial lumbar punctures. In giving an overview of the developments of the last three plus decades, those of note will be summarized under the headings of the areas of particular relevance. All these aspects will, of course, be dealt with at length in the appropriate chapters to follow. Epidemiology

For the first time there were attempts to gather information about the overall incidence and distribution of the condition apart from simply recording the basic clinical features
for example, the initial reports by Durcan et al. (1988) and Radhakrishnan et al. (1986, 1993a,b) and the recent studies of Craig et al. (2001), Kesler and Gadoth (2001), and Carta et al. (2004). Aetiology

The last several decades have seen a very substantial increase in the number of reports linking PTCS to putative aetiological agents. The majority of these reports concern very small numbers of patients, often a single case, and unless the factor in question can be subsumed under a more general heading referring to a relatively established link, for example different specific causes of cranial venous outflow obstruction or hypertension, the link is often tenuous and the mechanism of the proposed relationship between cause and effect often obscure. Several studies have, however, attempted to address the issue of possible aetiological agents using an appropriately rigorous methodology but these have, by and large, been hamstrung by the limited numbers of cases evaluated. Mechanism

Encouraged particularly, and to some extent misleadingly, by the developing investigative techniques of the period, the late 1970s and early 1980s saw several papers which attempted to grapple with the vexed question of mechanism by weighing the practical findings and analysing theoretical issues. Among these may be numbered the papers by Johnston (1973, 1975), Fishman (1979, 1984), Rottenberg et al. (1980) and Donaldson (1981). The consensus, such as it was, favoured a primary disorder of CSF dynamics, with the creation of an imbalance between formation and absorption resulting in an increase in CSF volume. None of these papers, and indeed no other study, was able to marshal compelling evidence and arguments so, from the historical point of view, the situation has, in a sense, returned to that of the early decades of the recently ended century. There are, however, three studies or groups of studies which pursue a particular line on mechanism and should be mentioned here, although they will be dealt with in greater detail in the following chapter. They are those of Reid et al.

26

History of the pseudotumor cerebri concept

(1980, 1981) favouring brain oedema based on CT evidence of ventricular size, those of Sugerman et al. (1995, 1999) arguing for causative role for obesity, and those of King et al. (1995) and Karahalios et al. (1996) suggesting a much expanded causative role for increased cranial venous outflow pressure. All these issues remain contentious. Nomenclature

On this still unresolved matter there is presently something of a division along party lines with one major party adhering to a hard-line, doctrinaire ‘idiopathic intracranial hypertension’ (IIH) view, using the term introduced at the start of the last period now being considered, and the other major party taking a broader approach by using the ‘umbrella’ terms PTC or PTCS. The first group is exemplified particularly in the 2002 paper by Corbett and Digre, whilst the latter at its most all-encompassing is exemplified by Johnston et al. (1991a) and, indeed, the present monograph. There is also still a minority party of ‘BIHists’, exemplified by Sussman et al. (1998), although this review paper begins with a poem from a patient drawing attention to the problems of the epithet ‘benign’ (see chapter 4). Clinical features

This has been a less controversial area although clearly one’s position here is in no small measure dependent on one’s position in relation to disease definition and nomenclature. Problems in these areas notwithstanding, there is broad agreement on what, over the period in question, have come to be called the ‘modified Dandy criteria’. A number of papers have listed these with only slight variations; for example, Ahlskog and O’Neill (1982), Corbett (1983), Radhakrishnan et al. (1994). Two further points should be made. First, there have been several studies involving relatively large numbers of cases (over 100) with comprehensive follow-up which have consolidated the clinical picture of the condition and provided further useful information on outcome and, specifically, the likelihood of diagnostic error. These studies include the reports of Greer (1968), Johnston and Paterson (1974a), Boddie et al. (1974), Weisberg (1975a) and Corbett et al. (1982). Second, there has developed a much greater awareness of the ophthalmological problems associated with the PTCS, at the time of presentation, during the course of the disease, and as late sequelae. These studies have made use of increasingly sophisticated techniques of ophthalmological examination and are representative also of the increasing involvement of ophthalmologists in the diagnosis and management of the condition which has characterized the ‘modern’ period. In this

27

Period 5: 1971
2005

regard the studies of Orcutt et al. (1984) and of Wall and George (1987) merit particular mention. Investigations

As in the 1930s, the 1970s and 1980s saw very significant developments in investigative techniques with particular or sole relevance to neurological disease. These techniques, listed at the start of this section, might have been expected to contribute significantly not only to the ease of diagnosis of PTCS, but also to clarification of its mechanism. As was noted above, the methods have been somewhat disappointing. This is as much a function of the disease itself as of any limitations in the methods insofar as its relative rarity and overall good outcome have meant that most clinical studies are limited to rather unsystematic examinations of small numbers of cases with the investigators constrained with respect to the number of examinations. In practice, CT scanning and MRI have become the basis for the diagnosis of exclusion. Implicit in this is Nonne’s original concept and the enduring relevance of the name he introduced. What has failed to eventuate from these two techniques is any unequivocal information on what is actually increased in terms of intracranial volume to produce the marked increases in intracranial pressure, long known from lumbar puncture but more precisely documented by intracranial pressure monitoring. For those who believe in a much greater significance of cranial venous outflow pathology, the possibility of detailed studies of the cranial venous outflow tract and the measurement of intra-luminal cranial venous sinus pressures using catheter angiography and venography techniques is of importance but evaluation of their degree of importance remains incomplete, both in terms of clarifying diagnosis and mechanism, and in offering therapeutic opportunities. Radionuclide studies, although reported, were never consistent enough or contributory enough to find a role in diagnosis or clarification of mechanism. More or less the same may be said for CSF infusion studies, CBF/CBV measurements and PET scanning, although all have contributed something in terms of mechanism, as will be discussed in the following chapter. Treatment

The recent history of the treatment of PTCS might be summarized to a significant extent as a return to the past. Each of the main methods currently in use will be briefly considered in an historical context. Acetazolamide, and other diuretics of different types including furosemide and the chlorothiazides, were introduced in the 1960s. Subsequent decades have shown them to be relatively ineffectual, relegating them to a position of adjunctive treatment or sole use in mild cases only. Steroids, also introduced in the 1960s, have an obviously complex relationship to PTCS as the studies referred to earlier made clear. They are certainly effective in

28

History of the pseudotumor cerebri concept

a significant proportion of cases (Johnston et al., 1981) but recent decades have brought an increasing awareness of the complications of steroid use generally and this has prompted a move away from these agents in PTCS, particularly in patients who are already markedly obese. CSF shunting, which was reintroduced into the treatment of hydrocephalus in the 1960s after its initial materials-related failure at the end of the 19th century, has been used in PTCS probably starting with the report by van der Ark et al. in 1971. It is, of course, the logical extension of serial lumbar punctures and is clearly very effective, although the clinical information on efficacy and complications of shunting in PTCS remains scanty. It is clear, however, from its use in hydrocephalus, that the complication rate is high and this makes it a very problematic treatment in PTCS. Despite this reservation, shunting remains the only treatment to date that can be said to produce a sustained normalization of CSF pressure, at least while the shunt remains patent. The other three forms of treatment to be mentioned here, subtemporal decompression (STD), direct treatment of venous outflow obstruction, and optic nerve sheath decompression (ONSD), are all treatments which were used very early in the history of PTCS. The one most used, STD has had a minor revival as evidenced by the paper from Kessler et al. in 1998, and we have also gone back to it to a small extent. Direct treatment of venous obstruction is, however, enjoying a significant resurgence due to the development of microcatheter techniques which have allowed a much readier demonstration of the type of abnormality reported by Ray and Dunbar (1951) and, importantly, have allowed effective endovascular treatment methods (Kollar et al., 2001; Higgins et al., 2002; Owler et al. 2003b). ONSD has had the most notable return to use. Following several earlier reports, beginning with Smith et al. (1969) and Davidson (1969, 1972), the series of articles in Archives of Ophthalmology in 1988 stimulated widespread use of ONSD. The situation that has developed over the last 20 years, with respect to treatment in general, is that the method of management used in the individual case depends heavily on whom the patient is referred to, being governed by the treating doctor’s theories of the disease and the techniques available to him or her. Summary

In summarizing this final, ‘modern’ period, it has seen the application of a considerable number of very technologically advanced investigative methods to the analysis of the PTCS without bringing real enlightenment. There has been a further name change with the replacement of ‘benign’ by ‘idiopathic’ for some, but the retention of the pseudotumor idea by others. In treatment, there has been the re-discovery of two of the pre-Quincke methods, direct treatment of venous obstruction and ONSD, although the former had never been entirely abandoned, only very little used due to the technical difficulties of is application and lack of

29

Period 5: 1971
2005

convincing evidence of its efficacy. There has been a considerable increase in the number of putative aetiological agents but their identification is by no means always secure. There has been further accumulation of evidence inculpating several of the long-recognized factors, particularly cranial venous outflow compromise, haematological abnormalities and obesity/menstrual disturbance without significant clarification of their precise mechanism of action. There has been notable attention to what have become known as the ‘modified Dandy criteria’ but continued debate on how strictly these should be applied, this being linked closely to the issue of nomenclature. In overall summary, it must be said that the condition of PTCS, if it is one condition and whatever one chooses to call it, remains quite perplexing despite a century or more of investigation and study. In several aspects of the condition the wheel has turned full circle. On mechanism, the thinking has gone back to a disturbance of CSF dynamics as fundamental, after a significant flirtation with cerebral oedema and some dalliance with increased CBV. On aetiology, many new factors have been identified but the old factors, as mentioned above, remain the most securely established. On treatment, there has been a significant return to very early methods but there is still no consensus on which is best, on whether any one is truly satisfactory, on whether or to what degree CSF pressure is normalized regardless of clinical resolution, and if it is not normalized, how important this is. This review of the history of PTCS might, then, be seen as both sobering and stimulating.

3

Disease mechanism

Introduction There has been considerable debate about the underlying disease mechanism in PTCS, as recent reviews attest (Sussman et al., 1998; Kosmorsky, 2001; Walker, 2001). As yet, there is no definitive resolution. Several key questions which must be answered if the elucidation of the disease mechanism (or mechanisms) in PTCS is to be achieved may be enumerated as follows: 1. Is there one of the three intracranial compartments (brain parenchyma, blood, CSF) primarily involved in the volume increase which causes the increase in ICP that characterizes PTCS, or is there a combination of volume increases? 2. Is it always the same compartment or combination of compartments, or might different compartments be involved in different circumstances, to give the same clinical manifestations? 3. Is there a single causative mechanism, or at least a ‘final common path’ for the volume increase, either of the primary compartment or the combination of compartments? 4. What are the compensatory mechanisms involved? Whichever of the three intracranial compartments is involved primarily or in combination, the increase is fluid. This is obviously so in the case of blood and CSF but must also be so with respect to brain, there being no evidence at all for an increase in solid brain tissue. Moreover, the increase must be capable of being sustained over a long period of time, given the often very chronic nature of the condition. Further, the increase must be such that it allows normal brain function to continue, which is a characteristic feature of PTCS, although the issue of the adverse effects of chronically raised ICP per se have not been sufficiently considered. Finally, the increase in fluid volume may be corrected therapeutically by reduction of intracranial fluid volume either by chemical means (e.g. acetazolamide, steroids) or by physical means (acute or chronic CSF drainage) 30

31

Evidence from clinical studies

without, in the latter case, any immediate deleterious effects due to inter- or intracompartmental shifts. Evidence from clinical investigative studies Brain imaging studies

These include, in historical sequence, ventriculography or encephalography, CT scanning, and MR scanning, the last increasingly with the utilization of additional sequences to examine venous anatomy, tissue fluid and CSF flow. Each has contributed to the debate on mechanism but in no case conclusively. The critical contribution of ventriculography/encephalography was to demonstrate that the ventricles were small or normal in size in PTCS which initially and subsequently has been the main plank of the argument against it being a CSF circulation disorder. Two additional points that should be made in relation to these studies are first, that there is a small number of cases in whom the ventricular size is increased (vide infra) and second, the oft-repeated observation that during ventriculography the subarachnoid space at the burr-hole site often appeared distended. In what follows, the focus is only on mechanism. Instances of patients with PTCS and abnormal imaging, particularly the role of MR in the recognition of venous outflow abnormalities, will be considered in subsequent chapters. With respect to CT scanning, this is typically normal. Indeed, a normal CT has been taken to be a sine qua non of diagnosis. Some CT studies have, however, been specifically directed at the issue of possible brain oedema, either through attempted quantitation of ventricular size, reduced size being taken as evidence of increased brain volume, or studies of brain tissue density specifically directed at identifying brain oedema. Considering ventricular size first, whilst it is often stated that ‘small ventricles’ are characteristic of PTCS, the actual evidence is conflicting. In an analysis of 537 cases taken from our own series and from the literature, but excluding the reports of Reid et al. (1980, 1981) and Weisberg (1985) considered separately below, there were 61 cases with an abnormal CT. Of these, only 20 were said to have abnormally small ventricles (Johnston, 1992). In specific early studies, Huckman et al. (1976) found normal ventricular size and normal density histograms in 17 patients with PTCS compared to age-matched controls whilst Vassilouthis and Uttley (1979) found no evidence of oedema in 28 patients with PTCS. In a later study, Jacobson et al. (1990) found no evidence of small ventricles. In the two studies by Reid et al. (1980, 1981), the first reported ventricular volumes of 1.3 + 4.9 ml (mean 4.9 ml) in 18 patients with PTCS compared with values of 4.5 + 22 ml (mean 11.7 ml) in age-matched controls. The second study reported a return towards normal ventricular size in some of the patients after successful

32

Disease mechanism

treatment. Weisberg (1985) described evidence of ‘brain swelling’ in one half of his large series of cases, this consisting of small ventricles, poorly defined basal cisterns, and enlarged optic nerves. Second, on the question of abnormal tissue density consistent with brain oedema, there is no positive evidence from CT studies. Reid et al. (1980) attempted to explain their failure to find abnormal Hounsfield numbers on the grounds of low CSF protein levels, but this argument is not without difficulty, as indeed is the case with measurements of ventricular volume (Wyper et al., 1979; Sussman et al., 1998). Turning to MR studies, the results have also been somewhat conflicting and inconclusive. In early reports, Condon et al. (1986) examined CSF volume in one patient with PTCS (among a number of other cases) and found a value of 11.0 mL for ventricular CSF volume compared with 25.5 + 4.6 ml in controls, and a value of 68.7 ml for extraventricular CSF compared with 97.6 + 6.6 ml in controls. Moser et al. (1988), in a series of 11 patients with PTCS, reported a normal MR in 8 cases but increased signal intensity in the periventricular white matter in two cases which they described as being consistent with ‘low level oedema’. On the other hand, Silbergleit et al. (1989), who studied six patients with IIH (all females, age range 17
41 years, five obese), found no white matter signal abnormality, even in the periependymal spaces, and no difference in ventricular volumes although the subarachnoid spaces were significantly larger compared with agematched controls. There have been several MR studies using specific techniques and again the results are conflicting. In a series of three reports, one group claimed to have found evidence of altered brain water diffusion leading to diffuse brain oedema in PTCS (Sorensen et al., 1989; Gideon et al., 1995). In a recent study using more refined techniques, Bastin et al. (2003) failed to confirm these findings and concluded that there was no evidence of changes in transependymal water flow giving rise to diffuse brain oedema. Further, apart from the issue of brain water, advanced techniques of MR examination have provided evidence for a very high incidence of cranial venous outflow obstruction in PTCS (Farb et al., 2003; Higgins et al., 2004). These studies do not, however, resolve the issue of whether the demonstrated morphological changes in the cranial venous outflow tract are primary and causative of the raised CSF pressure, or secondary and consequent upon the CSF pressure increase, the latter being the current position taken by King et al. (2002) as a result of their second manometric study considered in the following section. This issue will be discussed further in Chapter 10. Angiography and venography

Angiography was widely used in the period before the development of CT scanning in the 1970s as part of the exclusion of other lesions to account for the

33

Evidence from clinical studies

raised ICP. Other than contributing to the recognition of venous outflow tract abnormalities as presumed causes, the technique made no contribution to an understanding of mechanism. In a review of cases of PTCS with reported angiographic results (either carotid alone or carotid and vertebral) collected from the literature to 1991, of 445 cases only 8.8% were abnormal and all the abnormalities were in the venous outflow tract (Johnston, 1992). A significant proportion of the abnormal studies were either in patients suffering from conditions associated with hypercoagulability (DLE, Behc¸et’s disease) or those with middle ear disease. Venography, with digital subtraction and microcatheter techniques, is clearly the most satisfactory method of demonstrating structural abnormalities in the venous outflow system and will be considered in this light in Chapter 7 on investigative methods. In some of the early studies of cranial venous outflow pressures, Loman and Damashek (1944) studied intrajugular venous pressure in one patient with polycythaemia rubra vera, Ray and Dunbar (1951) studied superior sagittal sinus pressure in three cases of sinus obstruction, and Caudill et al. (1953) studied superior sagittal sinus pressure in one patient with PTCS associated with a depressed skull fracture over the sinus. In all five cases there was an elevation of intra-sinus pressure with values between 200 and 480 mmH2O. In none of these cases was the CSF
SSS pressure gradient reversed at the time of measurement, although in one it was zero. The next significant study was that of Janny et al. (1981). In 11 patients with PTCS and a patent venous outflow system, the CSF
SSS pressure gradient was maintained, although resistance to CSF absorption was increased. In contrast, in five patients with demonstrated venous outflow obstruction the CSF
SSS gradient was reversed but resistance to CSF absorption was only marginally increased, which the authors took to indicate that alternative absorptive channels were in play. There is here also the question of what CSF outflow resistance studies actually measure. Two recent studies, both using cranial venography including intra-sinus pressure measurements, claimed a much more substantial incidence of venous outflow impairment in PTCS than previously thought. Karahalios et al. (1996) studied 10 patients, five of whom had evidence of mechanical obstruction (one, bilateral sigmoid; one, unilateral sigmoid; one, unilateral transverse; one, jugular bulb; one, unilateral transverse and sigmoid), and five of whom did not. In the five cases with demonstrated obstruction, SSS pressure was raised in two and not measured in three, although one of these three cases had a raised pressure in the sigmoid sinus proximal to the stenosis. In the five cases without demonstrated obstruction, all young women with morbid obesity, SSS was raised (14
24 mmHg; average, 17.4 mmHg; normal, 4
10 mmHg) and elevated right atrial pressures. The authors suggested, on the basis of these findings,

34

Disease mechanism

that ‘ . . . elevated intracranial venous pressure may be a universal mechanism of PTCS of different etiologies’. King et al. (1995) studied 11 PTCS patients and three ‘controls’. They found elevated pressure in the SSS and proximal transverse sinus in nine cases (eight females, one male) with a sharp pressure drop at the distal third of the transverse sinus. All nine cases had simultaneous measurement of CSF pressure which was, in all cases, elevated, but with preservation of the CSF
SSS pressure gradient. The two PTCS patients without elevated sinus pressure were adolescents who developed PTCS after minocycline treatment. However, in a further study in 2002, these same authors re-examined the issue and concluded that the elevated sinus pressures were, in fact, secondary to the elevated CSF pressures and apparent narrowing of the venous outflow tract was secondary to the CSF pressure also (King et al., 2002). Finally, Johnston et al. (2002), who looked at the incidence of demonstrated structural cranial venous outflow tract abnormalities in a large series of PTCS cases (188 cases, 1968
1999), found an overall incidence of 19.7%. This figure rose, however, to 31.0% when only the last decade, with much better investigative techniques, was considered (87 cases). Cerebral blood flow and volume studies

There are few studies of either CBF or CBV in PTCS. The first claim that blood flow or volume changes might underlie the condition came as a result of Dandy’s observations on the fluctuations in tension observed in subtemporal decompressions in patients with the condition (Dandy, 1937). He surmised that vascular variations were most likely to account for the observed time course of such changes, although he did not exclude the possibility of changes in CSF volume. With the advent of ICP monitoring (Guillaume & Janny, 1951; Lundberg, 1960) it became apparent that transient changes of pressure, often of considerable magnitude, were characteristic of intracranial hypertension regardless of cause, although it remains uncertain to what extent vascular changes are a common component of these variations. Actual studies of CBF/CBV in PTCS began, however, with Foley (1955). He reported three cases with measurement of CBF using the N2O method and found a tendency to high values. More precise studies with greater methodological sophistication were carried out by Mathew et al. (1975) and Raichle et al. (1978). In the former, two female patients, who clearly met the diagnostic criteria of PTCS, were studied, measuring CBV and rCBF. In both patients there was a significant increase of CBV (mean 85%) but a slight decrease in rCBF (mean 10%). In both cases, reducing CSF pressure reduced CBV with values returning to normal after clinical improvement. These authors postulated extreme dilatation of the capacitance vessels to account for the increase in CBV but also were of the view that both brain oedema and reduced CSF absorption were present. In the latter, 14 patients were studied.

35

Evidence from clinical studies

All were women, predominantly young and obese, who appeared to meet the required diagnostic criteria, CBF and CBV being measured using 15 O-labelled oxyhaemoglobin, carboxyhaemoglobin and water. In all cases there was ‘a significant increase in CBV, a significant reduction in CBF, and an unchanged CMRO2’. Again, these authors postulated a dilatation of cerebral capacitance vessels to account for the increased CBV and also presumed that an increase in tissue volume due to oedema was the major contributing factor to the apparent fall in CBF. Reference was made to the CT study of Spallone (1981) to support this contention. They therefore concluded that raised ICP in PTCS was associated with a major dilatation of intraparenchymal cerebral vessels with increased CBV, but that this was unlikely to account for the rise in ICP. On the basis of their calculations, the increase in CBV would only account for a 1% increase in the overall volume of the cranial contents whereas a 4% increase was necessary to produce CSF pressure changes of the magnitude observed in this condition. Two further studies using PET were reported in 1985, both failing to find evidence of significant changes in the parameters evaluated. Thus, Gjerris et al. (1985) studied 14 patients using xenon inhalation and PET methods and found all to have normal CBF (59 + 9 ml 100 gm
1 min
1), although two of the patients did have local low flow areas. Brooks et al. (1985), using a PET scanning technique with C15O2, 15O2 and 11CO, found no changes in rCBF, cerebral oxygen utilization or CBV in patients with PTCS. This was in comparison with 15 age-matched controls. Moreover, in their study, one patient showed no change in the measured parameters after insertion of a lumbo-peritoneal shunt and overall, there was no correlation with cerebral perfusion pressure for ICP levels up to a maximum in excess of 40 mmHg. In a recent study of a single patient with PTCS, using PET and 15 O-labelled water, no reduction in rCBF was found during a period of marked reduction of cerebral perfusion pressure (Kabeya et al., 2001). Radionuclide studies

As with CBV and CBF, there are few actual studies using radionuclide methods. In the initial study using conventional non-quantitative or semi-quantitative methods, Bercaw and Greer (1970) reported three patients, two females and one male, with PTCS using radionuclide cisternography with a 131I tracer. Both women had clearly abnormal studies. The first had only an 8.5% recovery in the plasma at 48 h compared to normal values of 37
60% and also showed excess activity along the superior sagittal sinus at 24 h which persisted for 72 h. The second female patient had 24% plasma recovery at 24 h with abnormal persistence of activity over the cerebral convexities. The third, and male patient had a normal study with 45% recovery at 24 h. Using the same technique a marked reduction in

36

Disease mechanism

plasma recovery was also found in one patient with PTCS associated with primary hypoparathyroidism (Sambrook & Hill, 1977). Johnston and Paterson (1974b) studied a total of 8 patients, six with radionuclide cisternography using 111 In-DTPA and four with radionuclide ventriculography using technetium (two patients had both studies). Five of the six patients studied had an abnormal cisternogram with a marked delay in passage through the subarachnoid space without ventricular reflux, and a delayed recovery in the urine. In one patient in whom the diagnosis was unclear (negative fluorescein angiography and questionable intracranial hypertension) the cisternogram was normal. The two patients having ventriculography only had a slight delay in clearance of the isotope from the ventricles, while the other two, both of whom had marked delay in cisternography, had normal ventricular clearance. Bortoluzzi et al. (1982) also demonstrated delayed clearance with no flow over the hemispheres, but what appeared to be flow through the subarachnoid space in a single case using radionuclide cisternography. Set against these apparently positive findings, there are several negative reports. Thus, Frigeni et al. (1971) reported four normal radionuclide cisternograms in patients with PTCS whilst James et al. (1974), using radionuclide cisternography, reported normal studies in nine of 10 patients, finding basal activity in all nine patients at 2 h, and at 6 h convexity activity in five, but Sylvian fissure activity only in four cases. All patients had activity over the convexity at 24 h and none had ventricular reflux. Three patients who had quantification of the cisternography all showed normal values quite different from the findings in communicating hydrocephalus. The one patient who had CSF to blood transfer determined showed an abnormality and one patient had a definite delay of flow from lumbar region to the basal systems of the sort seen in the studies of Johnston and Paterson (1974b). It should be noted, however, that six of the 10 patients studied by James and his colleagues had already been treated. Janny et al. (1981) carried out radionuclide cisternography in 12 patients who were also studied with regard to resistance to CSF absorption as described below. Ten patients had a normal study while two had a slight delay without ventricular reflux. Patients who had quantification of the cisternography all showed normal values quite different from the findings in communicating hydrocephalus. The one patient who had CSF to blood transfer determined showed an abnormality and one patient had a definite delay of flow from lumbar region to the basal systems of the sort seen in the studies of Johnston and Paterson (1974b). Intracranial and CSF pressure monitoring

A series of studies of long-term CSF pressure monitoring in PTCS appeared during the 1970s and 1980s using a variety of devices and either a cranial or lumbar site

37

Evidence from clinical studies

(Johnston & Paterson, 1974b; Gu¨cer & Viernstein, 1978; Bulens et al., 1979; Janny et al., 1981; Bjerre et al., 1982; Gjerris et al., 1985). The technique and its diagnostic role will be considered in Chapter 7. From the point of view of mechanism, there are several aspects of relevance. First, the patterns of ICP change are essentially the same as for other conditions causing raised ICP, with the same wave forms appearing. If evidence was needed to counter Dandy’s suggestion that the transient nature of tension changes in cranial decompressions point to alterations of blood volume as primary in PTCS, then chronic ICP monitoring provided it. Second, there is clear evidence of a correspondence between cranial and spinal pressures, evidence of a free communication between intracranial compartments and between the cranial and spinal compartments. Third, the time course of return of pressure levels after CSF drainage to those before drainage is in keeping with a normal rate of CSF formation and not what would be expected if drainage of CSF was effecting transient reduction in pressure in a situation in which one of the other compartments was primarily responsible for the increase (Johnston & Paterson, 1974b). Fourth, the demonstration of marked falls in cerebral perfusion pressure with preservation of normal neurological function is suggestive of the CBF changes seen in experimental studies where the increase in ICP is produced by fluid infusion rather than by a brain lesion or artificial mass lesion (Johnston et al., 1972). Finally, and this is relevant to classification also and so is returned to in the next chapter, in a number of the studies there were instances of patients diagnosed as having PTCS who had more or less normal ICP level. One such case is that reported by Djindjian et al. (1987) where a patient with clinically raised ICP (i.e. papilloedema) and a reversal of the normal positive CSF to SSS pressure gradient had a mean recorded ICP level of 1
6 mmHg. CSF infusion studies

The most consistently positive investigative findings have been those of the CSF infusion test measuring the resistance to CSF absorption. Martins was the first, in 1973, to report the use of an intrathecal saline infusion test based on the technique of Katzmann and Hussey (1970) in PTCS. In five cases (albeit without clinical details) abnormalities were demonstrated, with impaired absorption of CSF which the author attributed either to abnormalities of the arachnoid villi or partial obstruction of venous outflow. The same type of investigation was subsequently carried out by a number of authors. Calabrese et al. (1978) found an abnormal result in nine out of 10 patients with PTCS, the one normal patient having been free of headache for 5 days. Mann et al. (1979) examined CSF absorption and formation in 10 patients with PTCS compared with four normal controls. The mean resting CSF pressure for the pseudotumor group was 329 + 62 ml min
1 with a value of 141 + 20 ml min
1 for the controls. Against this pressure

38

Disease mechanism

background, outflow resistance was found to be seven times greater in the PTC group while CSF formation was estimated at 287+207 ml min
1 in the affected group compared with 467 + 127 ml min
1 in the control group. Two patients treated with prednisone (40 mg day
1) for 4 weeks had a marked reduction in CSF outflow resistance accompanied by reduction in CSF pressure. Ahlskog and O’Neill (1982) found a pattern of absorption defects similar to communicating hydrocephalus in 14 of 16 patients with PTCS, the two exceptions being one case in remission and one case after subtemporal decompression. Gjerris et al. (1985) found abnormally low conductance in 12 of 14 cases of PTCS (mean 0.042 ml min
1, control 0.080 ml min
1) with two normal values being recorded in patients after commencement of treatment. Janny et al. (1981) studied two groups of cases totalling 16 patients with PTCS (eight with an aetiological factor and eight without) which included five patients having complete or partial superior sagittal sinus obstruction. These patients were compared with six patients who had intracranial hypertension from another cause. All cases had increased resistance to flow compared with a normal value of 10 + 5 mmHg ml
1 min
1. Those with sinus obstruction had a mean value of 14.5 mmHg ml
1 min
1 with reversal of CSF to SSSP gradient (mean
3.16 mmHg) whilst those without sinus obstruction had a mean resistance value of 46.6 mmHg ml
1 min
1. Resistance to flow was also abnormal in the control group (four patients with chronic meningitis, one with meningioma en-plaque and one with intracranial arteriovenous malformation). Guess et al. (1985) studied 14 patients using a rather complicated method to estimate CSF absorption and provided further evidence of a primary absorption defect which, in one case, was relieved by steroid administration. Sklar et al. (1979), using a lumbar infusion technique, reported significantly abnormal findings with CSF absorption in ‘nearly all’ of 10 patients with PTCS (probably eight out of 10 although there is some uncertainty about the lower limit of normal). Thus all reported studies have consistently shown an abnormality of CSF absorption usually of considerable magnitude, the few exceptions being patients in remission or on treatment. The studies listed give a total of 95 patients with only seven reported normal studies including two patients in remission and three patients after treatment. In interpreting infusion studies it must, however, be borne in mind that there is evidence in some individuals that sagittal sinus pressure may increase with increasing CSF pressure leading to artefactually high resistance calculations. Pathology: macroscopic and microscopic

There are very few studies of pathology in PTCS, which is not surprising given the nature of the condition. Considering biopsy studies, those few that have been done have severe technical and other limitations: for example, small specimens, artifacts

39

Evidence from causal factors

due to surgical removal, light microscope examination only, and variable relation to active disease. These studies are, however, invariably quoted in discussions of disease mechanism, particularly that of Sahs and Joynt, in their 1956 paper entitled ‘Brain Swelling of Unknown Cause’, which was very influential at the time. These authors described 17 cases, all of whom would qualify for the diagnosis of PTCS on current criteria. All had raised CSF pressure on lumbar puncture, none had any abnormality of CSF composition (12 normal, five not examined), and 16 had normal ventricular size. All 17 were alive at follow-up from 1 to 16 years (average, 8.7 years) later and there was a characteristic range of aetiological factors. The authors attributed the increased ICP to cerebral oedema on theoretical grounds, as indeed Sahs, in an earlier article with Hyndman, had done (Sahs & Hyndman, 1939), and in putting their hypothesis to the test, found intracellular and extracellular oedema on brain biopsy, taken at the time of decompression or ventriculography in 10 of the 17 cases. It must be stressed, however, that the specimens were very small and were examined by light microscopy only. Contrary to these findings, there has been a small number of other biopsy and post-mortem examinations which have not demonstrated any oedema (Davidoff & Dyke, 1937; Levin & Daughaday, 1955; Greer, 1965, 1974). Most recently, Wall et al. (1995) reported post-mortem macroscopic and light microscopic studies on two patients with PTCS who died of other causes. In one the disease was clearly still active although there had been prolonged treatment. The disease status at the time of death in the other (cause of death unknown) is less clear but this patient had also had prolonged treatment. In neither case was there any evidence of brain oedema. The authors also re-examined surviving specimens from three of the cases from the study of Sahs and Joynt and failed to confirm the earlier reported finding of cerebral oedema. Evidence from putative causal factors Vitamin A excess and deficiency

There are now several studies documenting the effects of vitamin A deficiency or excess on CSF dynamics. These studies are considered in greater detail in Chapter 10 but, in summary, studies in animals, particularly rats, rabbits and calves, have shown that vitamin A deficiency will lead to an increase in resistance to CSF flow in the arachnoid villi accompanied by structural changes in the villi themselves and raised CSF pressure (Millen et al., 1953, 1954; Calhoun et al., 1967; Eaton, 1969; Hayes et al., 1971). In the studies by Millen et al. (1953, 1954) there was outright hydrocephalus in the majority of animals born to vitamin A-deficient mothers. Kazarskis et al. (1978) applied the Katzman and Hussey type of infusion

40

Disease mechanism

test to vitamin A deficient rats and found a marked increase in CSF outflow resistance with decreased CSF production and unchanged compliance along with structural changes in the arachnoid villi. Experimental hypervitaminosis A also causes changes in CSF dynamics, Eaton (1969) finding in calves that it caused a decrease in CSF production with an increased permeability of the ventricular walls and possibly a decreased resistance to bulk absorption of CSF. Steroid administration and withdrawal

Steroids have a curious relationship to PTCS, both administration (usually prolonged) and withdrawal after prolonged use apparently causing the syndrome. On the other hand, administration is also curative in a large proportion of cases even if it does not return CSF pressure levels to normal in the short term. Several aspects of the effects of steroids on CSF dynamics and pressure have been the focus of studies. First, steroids have been shown to reduce brain bulk in states of cerebral oedema (Rasmussen & Gulati, 1962; Long et al., 1966), presumably by inducing fluid changes, although the actual mechanism is unknown (Davson & Segal, 1996). Interestingly, a greater effect is seen if the steroids are given prior to the oedemacausing insult (Taylor et al., 1965). Second, several studies have convincingly demonstrated that steroids can cause a substantial reduction in CSF formation or secretion (Sato et al., 1973; Lindvall-Axelsson et al., 1989; Pollay, 1992). Third, in a study of the effects of steroid administration and acute steroid withdrawal on CSF absorption in dogs, Johnston et al. (1975a) found that a 4-week period of high dose steroid administration had no effect on CSF absorption, measured both by the infusion test of resistance to outflow and by a radionuclide recovery method, nor did it affect CSP or SSS pressures, brain weight or ventricular size. However, animals studied 6 to 8 days after acute cessation of steroids showed a marked delay in CSF clearance with increased resistance to absorption, but again no changes in the other parameters and no ventricular enlargement. Cranial venous outflow obstruction

There is a very considerable body of experimental work on this subject which will be examined in detail in Chapter 10. Only a brief summary, particularly in relation to the mechanism of PTCS, will be given here. First, it must be said that the results of experimental studies remain somewhat conflicting. Cranial venous outflow obstruction whether intra-cranial or extra-cranial may indeed produce raised intra-cranial pressure, although by no means invariably. It will, however, certainly produce raised venous outflow pressure. In the majority of studies, there is either no intracranial hypertension, transient intracranial hypertension or intracranial hypertension without ventricular dilatation. There is only one report where there has been quantitative evaluation of CSF absorption, and this did seem

41

Evidence from causal factors

to show a significant impairment without evidence of increased resistance to CSF flow (Johnston, 1973, 1992). There is also one report where frank hydrocephalus was produced (Bering & Salibi, 1959). The evidence on the fate of the CSF to sagittal sinus pressure gradient is also conflicting, some reports showing maintenance of the gradient and others reversal. Both in clinical (Janny et al., 1981) and laboratory studies there does not appear to be any change in the resistance to CSF absorption (Johnston, 1992). The failure of reversal of the pressure gradient to alter resistance to absorption despite the apparent reduction of CSF absorption is probably a reflection of maintenance of the physical characteristics of the absorptive channels in keeping with the concept of these as open channels through which flow is passively pressure dependent. The reduction in absorption is therefore accounted for by inactivation of a proportion of the total population of channels by the reversed gradient and these inactivated channels subsequently respond normally when challenged by the infusion test. In other situations, both clinically in the PTCS and experimentally as with steroid withdrawal, it is possible that the physical characteristics of the whole population of channels undergo a change leading to increased resistance and reduced absorption. This is clearly an area requiring further investigation. Combining the evidence from both clinical and experimental reports it may be concluded that cranial venous outflow obstruction will produce, if somewhat unpredictably, an intracranial hypertension syndrome. This may be due to venous stasis with increased cerebral blood volume, cerebral oedema with or without frank infarction, impaired CSF absorption, or a combination of these things. Endocrine disturbances

There are two aspects of the possible causal role of endocrine abnormalities in PTCS. First, there is the question of a primary endocrine basis for a proportion of cases (even a significant proportion of cases) of PTCS and a possible link with obesity (vide infra), and then there is the occurrence of the condition secondary to a number of primary endocrine disorders. Considering the first aspect, it can be said with some confidence that there is no evidence of any significance to suggest an underlying endocrine cause for PTCS in general. In fact, apart from Oldstone’s (1966) demonstration of an attenuated metapyrone response in a small group of patients with PTCS, the search for a definable endocrine abnormality in this condition has been completely unrewarding. Thus Weisberg (1985), in a study of 15 patients with PTCS, found normal diurnal cortisol, ACTH stimulation, urinary ketogenic steroids, metapyrone response, cortisol response to insulin hypoglycemia, basal prolactin, FSH, LH and diurnal temperature regulation. Johnston and Paterson (1974b) found no evidence of adrenal malfunction in eight patients. Chen et al. (1979), looking for a abnormality of plasma renin and aldosterone,

42

Disease mechanism

also found no abnormality in a group of patients with PTCS. Likewise, the studies by Reid and Thomson (1981), Bates et al. (1982) and Sørensen et al. (1986a) found no evidence of any underlying endocrine disturbance in PTCS. The second aspect, the occurrence of PTCS as a result of some overt pre-existing endocrine disorder or its treatment, is a different issue and will be considered in more detail in the chapter on aetiology (Chapter 5). Suffice it to say here that the majority of endocrine glands have been implicated and, in the case of the adrenal gland particularly, in relation to both hypo- and hyper-function. In terms of mechanism, no conclusions can be drawn other than, perhaps, the very vague one that in some as yet undisclosed way various hormones and hormone replacements affect brain fluid dynamics in a very small number of cases, possibly by causing cerebral oedema, judging from the evidence of hypoadrenalism and the administration of excess oestrogen to rats referred to in the following section. Obesity

This is a particularly interesting factor and one that has occasioned much speculation. There is general acceptance of the clinical finding of a high proportion of obese young women, often with menstrual irregularity, in those affected by PTCS. The number has been reported to be as high as 78.7% (Wilson & Gardner, 1966) and it does seem to be the patients in this group particularly that have no other identifiable aetiological factor. Thus, in the Glasgow series, of 110 cases there were 35 obese women of whom 27 had no other recognizable aetiological factor. There were 12 patients in the 110 who gave a history of menstrual irregularity and 10 of these were also obese. It is noteworthy also that the majority of familial cases are obese (Johnston & Morgan, 1991) and further, as Wilson and Gardner (1966) remark, few of those who are obese seem to be able to lose weight. In terms of mechanism, there are two quite different proposals. The first is that there is some underlying endocrine disturbance responsible for both the obesity and the PTCS. The most persistent of the theoretical arguments is that based on a presumed link between an endocrine disturbance and cerebral oedema. There are several aspects to this argument. First, there is the experimental evidence of rats given excess oestrogen who develop cerebral oedema (Greer, 1974). Next there is the observation of cerebral oedema in Addison’s disease (Jefferson, 1956). Based on findings such as these, the theoretical construction is that in PTCS excess oestrogen occurring naturally, for example, at the menarche and in pregnancy (Greer, 1974; Moffat, 1978) is presumed to lead to secondary adrenal cortical insufficiency which is then thought to cause cerebral oedema. There are variations of the argument to incorporate the common occurrence of PTCS in obesity with the claim either that androstenedione is, in obese subjects, metabolized to oestrone by adipose tissue or by the hypothalamus giving, as a result, high oestrone levels

43

Evidence from causal factors

which, as above, are thought to give rise to cerebral oedema (Orefice et al., 1984). It has also been suggested that steroids are held in adipose tissue to give relative hypoadrenalism. The second, and more recent, proposal is that put forward by Sugerman and his associates in a series of papers (1995, 1997, 1999a,b). This is that obesity is primary and acts to cause PTCS by increasing intra-abdominal and intra-thoracic pressures which, in turn, increases central venous pressure and also possibly arterial PCO2 with a resultant adverse effect on ICP. If, however, obesity is the cause of PTCS, the question must be asked as to why are there so many obese people, particularly men, and so few with PTCS and, further, why are so many of the patients with PTCS not obese, again particularly men? There clearly must be some other factor or factors, and on present evidence there is nothing of sufficient substance to link obesity causally to the raised ICP in PTCS, and of particular relevance here, no evidence from the known association with obesity that throws light on the issue of mechanism. In addition, Sugerman’s studies are open to methodological criticism especially with respect to controls. Thus, whilst obesity in young women is unquestionably connected with the condition of PTCS, there is no satisfactory explanation for the relationship and the relationship itself throws no light on disease mechanism. Haematological and related abnormalities

There is a considerable number of primary haematological disorders which have been documented as occurring in conjunction with PTCS and thought to have a causative role. Some, but not all, of these are known to be associated with increased blood coagulability (thrombophilia, hypofibrinolysis). By related conditions are meant those conditions which, although not primarily haematological, are associated both with changes in the physical properties of the blood and with PTCS
conditions such as SLE, Behc¸et’s disease and POEMS. There are, broadly, two ways of examining the connection of these diseases or abnormalities with PTCS. The first is to document the observed associations of the diseases and the mechanism by which they might cause PTCS. The second is to start with cases of PTCS and look for changes in blood factors. Both these aspects will be considered in detail in Chapter 5 on aetiology and Chapter 7 on clinical investigation. From the point of view of disease mechanism in PTCS, the apparent common feature is cranial venous outflow impairment. Abnormalities of CSF composition

It has been known for some considerable time that PTCS can occur as a result of increases in CSF protein or cells or both together. The various conditions and the reports of the connection are considered in the following chapter and in Chapter 5

44

Disease mechanism

on aetiology. From the viewpoint of mechanism, irrespective of whether CSF absorption occurs by active transport or through open channels, or through dynamic transendothelial vacuoles creating temporary open channels (Tripathi, 1977; McComb, 1983; Davson & Segal, 1996), there is a size cut-off with regard to what can pass and be absorbed, probably around 6 mm. Another factor which must be taken into account is that pressure does not seem to increase the size of the channels. Thus cells, or clumps of cells, and large protein molecules or aggregates can act to obstruct flow across the villi and so produce syndromes of impaired CSF absorption, either communicating hydrocephalus or PTCS (Johnston & Teo, 2000). If, then, it is accepted that the syndrome of chronic intracranial hypertension occurring in such diverse primary conditions as poliomyelitis (Ayer & Trevett, 1934; Weimann et al., 1957), Guillain
Barre´ syndrome (Janeway & Kelly, 1966; Ropper & Marmarou, 1984), spinal cord tumour (Arseni & Maretsis, 1967), and several kinds of chronic meningitis (e.g. Diaz-Espejo et al., 1987; Cremer et al., 1996), in which the common factor is an abnormality of CSF composition, either cells or protein or both, the obvious assumption would be that there is a causative defect of CSF absorption at the level of the arachnoid villi. Familial cases

Since the first report by Buchheit et al. (1969), there have been several reports of multiple members of a single family developing PTCS. The initial reports concern obese sisters, raising the possibility that the same genetic factor might be involved in both the obesity and the intracranial hypertension. Subsequent reports have shown a greater diversity in those affected, including male siblings, those who are not obese, and different generations. These reports are considered further in Chapter 5 on aetiology. With respect to mechanism, there are two points to be made here. The first relates to a family in which the mother and two daughters were affected and all were markedly obese. One son in this family presented in the first year of life with infantile macrocephaly which settled spontaneously. He then re-presented early in the second decade with communicating hydrocephalus requiring shunting. This rather remarkable family does suggest a possible link between the three conditions (PTCS, idiopathic megalencephaly, communicating hydrocephalus) obviously on the basis of a CSF circulation disorder (Johnston & Morgan, 1991). The second concerns a family in which three siblings developed PTCS, two obese females in the second decade and one male of normal weight late in the first decade. What was of particular interest was that one of the females had bilateral congenital narrowing of the jugular foramen with measured increase in intracranial venous sinus pressures and a drop across the stenoses whilst the other two siblings had normal skull base anatomy and normal cranial sinus pressures (Johnston & Hallinan, unreported).

45

Evidence from related conditions

Evidence from possibly related conditions Communicating hydrocephalus

Communicating hydrocephalus (CH) has a number of aspects in common with PTCS which may be enumerated as follows: 1. Common aetiological factors, particularly cranial venous outflow impairment in infants and children (see Owler et al., 2005, Table 2, p. 122 for a list of reported conditions), and alterations of CSF composition. 2. Common clinical presentation as raised intra-cranial pressure alone, although other signs are more likely to be present in CH, particularly when chronic. 3. Common benefit from lumbar CSF drainage indicating free communication of the cranial and spinal CSF spaces. 4. Common treatment methods, particularly the use of L
P shunting and of acetazolamide in milder cases in both conditions. 5. There is an incidence of spontaneous arrest in both conditions so no treatment is needed. 6. In both conditions there is a significant proportion of cases in which there is no apparent aetiology. Some of the more notable points of difference include the fact that in CH the increase in intracranial fluid volume in the CSF compartment is readily visible and there may also be periventricular oedema. Also, the site of obstruction to CSF circulation is almost always proximal to the arachnoid villi although CH due to dysplastic villi has been reported (Gilles & Davidson, 1971; Gutierrez et al., 1975). In addition, if untreated, progressive CH will go on to impair mental function, even if it does not give rise to focal signs, whereas PTCS does not, or at least not to nearly the same extent. The argument can, we think, be made that PTCS and CH have a common mechanism to the extent that both are conditions due to an extra-ventricular impairment of CSF flow and hence of CSF absorption. Salman (1997), who examines this possibility, lists the following factors as critical in determining which condition follows such an impairment: (1) brain compliance (influenced by brain water content, state of myelination, brain maturity, brain size); (2) the state of the cranial sutures; and (3) the insult and its nature. These factors are clearly important, but he does not give sufficient attention to the site of obstruction, which is arguably the critical factor. Normal volume hydrocephalus

This is not a satisfactory term but is used here to indicate cases with treated hydrocephalus who have a recurrence of intra-cranial hypertension due to shunt malfunction without visible increase in the size of the CSF compartment on CT or

46

Disease mechanism

MR scanning. It includes cases with ventricles of smaller than normal size, the so-called ‘slit-ventricle syndrome’ (Engel et al., 1979: Venes, 1987). As with CH considered above, there are similarities to PTCS but they are fewer and different. The main points of similarity are the increase in ICP without focal signs and particularly without evidence of enlargement of the CSF compartment, and the rapid resolution effected by CSF drainage despite the absence of this enlargement. There may or may not be periventricular oedema but in chronic cases there usually is not. The most striking differences are the often rapid deterioration in brain function of a non-focal nature, even leading to death if not effectively treated, and the adverse effects of lumbar CSF drainage. Both of these differences are probably reflections of the lack of free communication of the overall fluid spaces which means that inter-compartmental pressure gradients and tissue displacement may follow drainage of fluid from the ‘wrong’ compartment. What such cases do unequivocally show is the possibility of a primary CSF circulation abnormality producing severe intracranial hypertension without ventriculomegaly, one of the main stumbling blocks to the CSF circulation disorder concept of PTCS itself. Infantile macrocephaly

This term, also admittedly unsatisfactory, is used here to refer to infants who develop apparently asymptomatic intra-cranial hypertension manifested only by an abnormal rate of head growth. It might more appropriately be termed ‘benign external (or communicating) hydrocephalus of infancy’. Regardless of nomenclature, when measured, CSF pressure is likely to confirm the clinical diagnosis of raised ICP. There is, typically, CT or MR scan evidence of an increased CSF volume in the form of a markedly distended subarachnoid space and, in a number of cases, mild ventricular dilatation. Other salient features are that there is not uncommonly a family history of ‘large heads’, sometimes involving the two previous generations, occasionally mild symptoms such as irritability, and an uneventful clinical course ending in spontaneous resolution within the first 12
18 months of life (Portnoy & Croissant, 1978; Kendall & Holland, 1981; Prassopoulos et al., 1995). It is our thesis that this represents an infantile form of PTCS, a view further discussed in the following chapter. It would certainly appear to be a problem of CSF dynamics, with an increase in CSF volume leading to intracranial hypertension. The distribution of the abnormal CSF volume throughout at least the entire intracranial CSF compartment, and the limitation of clinical manifestations to those of raised ICP alone (as with PTCS generally) suggest that the problem lies at the final point of absorption. As to exact mechanism, this line of reasoning, coupled with the typical time course and frequent family history, suggests an abnormality of the absorptive process prior to development or maturation of the arachnoid villi, perhaps on a genetic basis. This argument

47

The intracranial compartment involved

is strengthened by the link with other disorders of CSF dynamics
hydrocephalus and PTCS
as has been demonstrated in isolated instances and reported in several members of one family (Johnston & Morgan, 1991; Johnston et al., 1991).

Which intracranial compartment is involved? Particularly in recent analyses of the mechanism of PTCS, whether in articles specifically devoted to the topic (Johnston, 1973, 1975; Fishman, 1979, 1984; Rottenberg et al., 1980; Walker, 2001), or in general reviews (e.g. Sussman et al., 1998), the evidence is gathered under the headings of the three intracranial compartments: blood, brain, and CSF. Indeed, even before more formal and extensive considerations were given to the matter, it was often approached like this, as, for example, in Dandy’s 1937 article. This same arrangement will be repeated here but will be prefaced by some general comments. First, there is no intrinsic reason why more than one compartment, in fact even all three, should not be involved. A multi-compartment problem could exist even if a single underlying cause were to be identified. For example, if impaired CSF transfer at the junction of the CSF and venous compartments was primary, and caused an increase in CSF volume, because there would be no trans-mantle pressure gradients in a freely communicating CSF space, it might be argued that there would be no ventricular dilatation. The excess fluid would then be accommodated in the most readily distensible part of the space, i.e. the subarachnoid space both cranial and spinal. There could, however, also be transfer of fluid into and out of the brain parenchyma, particularly over the cerebral convexities, so there could also be an increase in extracellular brain water in a readily transferable state, including transfer out by artificial CSF drainage. Further, there could be direct passage of fluid into the venous system with a resulting increase in CBV. Added to this, if the cause of the altered CSF dynamics is on the venous side, there could be both venous distension and direct passage of fluid from the vascular compartment to the brain parenchyma. The same general argument can be applied if the primary problem is some form of brain oedema or cranial venous distension. So, in summary, an overall build-up of fluid of whatever origin in the cranial and spinal compartments could be variously accommodated in the brain parenchyma, the blood vessels and the CSF spaces. The relative proportions held in each sub-compartment would depend on the precise circumstances, with the possibility of intra- and inter-compartmental shifts, the time-courses and extents of which would again be dependent on the particular circumstances. Having made this general proviso, the specific issue of mechanism in PTCS will again be considered here under compartments, or rather,

48

Disease mechanism

sub-compartments, summarizing the evidence outlined in the previous sections of this chapter and including additional considerations. Brain parenchyma

In relation to the oedema concept, there are two lines of direct evidence. The first is pathological, both macroscopic and microscopic. It is obvious from the studies discussed above that there is no substantial evidence to either support or refute the existence of brain oedema in PTCS, nor whether such oedema, if present, is primary or secondary. On the positive side there is only the report of Sahs and Joynt (1956) which is clearly open to criticism on several grounds and cannot be accepted in any way as conclusive. The negative reports, while perhaps less open to methodological criticism, are equally unconvincing. The same may be said for the other line of direct evidence
brain imaging studies. Whilst there has been some evidence, both of a direct observational nature (see the sections on CT and MR scanning in Chapter 7), and inferential (Reid et al., 1980, 1981), to support the presence of brain oedema, there has been at least an equal weight of contrary evidence. Moreover the inferential evidence from ventricular size is itself very problematical, given the inaccuracy in the method of estimation as pointed out by Sussman et al. (1998). There is also the fact that a number of cases of PTCS with some degree of ventricular enlargement have been documented over the years (see Chapter 7). In determining whether oedema is present or not, MR has superseded CT in resolution. Here again the evidence is to some extent conflicting but the balance is clearly against an increase in brain water and certainly against frank oedema as discussed above. Another aspect, considered above, which relates to direct evidence in other conditions, is the situation in treated hydrocephalus with normal or small ventricles and shunt obstruction. Certainly in some such cases there is clear CT or MR evidence of increased brain water with intracranial hypertension, but in some cases there is no periventricular oedema despite the raised CSF pressure. Turning to more theoretical considerations, three points are commonly stressed. First, in active PTCS there is characteristically preservation of normal neurological function including a clear sensorium and a normal or nonspecifically abnormal EEG (Sidell & Daly, 1961; Hooshmand, 1974; Bulens et al., 1979). The possibility of long-term cognitive problems, considered elsewhere, does not bear on the present discussion. The point is, of course, that it is very difficult to accept a coincidence of cerebral oedema of sufficient severity to produce the recorded levels of intracranial hypertension with the observation of normal CNS function. Reid et al. (1980) have attempted to address this difficulty by claiming that disturbance of brain function depends on the nature of the oedema, differentiating vasogenic and cytotoxic oedema. According to these

49

The intracranial compartment involved

authors, neurological function and its electrical correlates may be preserved in vasogenic oedema unless secondary factors supervene. They have also attempted to account for the failure to find CT evidence of oedema by the argument that the low protein content of the fluid means there is no change in the Hounsfield numbers. The second point is the impunity of patients with PTCS to lumbar CSF drainage, indeed the actual benefit from such a procedure. There have been one or two reports of apparent brain shift with adverse effects considered in Chapter 8, but these are in no way adequate to undermine the argument. The extension of the benefit of (and impunity from) lumbar puncture CSF drainage to lumbar subarachnoid space shunting strengthens this argument, the complication rate of this shunting, and of CSF shunts in general, notwithstanding. Of course, as stated previously, if there is rapid exchange of fluid between the brain extracellular space, the CSF compartment and possibly the vascular compartment, lumbar CSF drainage could still be harmless and even beneficial. CSF drainage has a non-specific beneficial effect on intracranial hypertension from whatever cause as long as trans-compartmental gradients with brain shift and impaction are not precipitated. The third point is that PTCS can, and often does, have a prolonged clinical course which, as pointed out by Dandy initially and reiterated by many since, is hard to correlate with any form of primary cerebral oedema. There is also what might be termed the endocrine/metabolic argument. In this, it is claimed that endocrine effects on brain volume may be mediated through fluid and electrolyte disturbances. There is little support for such a postulated metabolic disturbance. Of course, severe anaemia and hypoxia do give cerebral oedema and this may in part be due to a disturbance of fluid and electrolyte metabolism, but this has little application to PTCS apart perhaps from cases occurring in various forms of anaemia and in chronic respiratory disease. It seems unlikely, however, that the abnormalities of haemoglobin and of PaO2 are of sufficient magnitude in these patients to cause diffuse cerebral oedema. The only other specific area where a fluid and electrolyte disturbance has been directly implicated is in those very few cases of PTCS in bulimia and in the chronic use of lithium carbonate where writers have proposed alterations in ATPase function with intracellular oedema (Saul et al., 1985). There is also what might be called the ‘common cause argument’ in which a variety of factors known to cause the PTCS are seem to be linked through the mechanism of cerebral oedema. This argument has been advocated for example by Hagberg and Sillanpaa (1970) who included hypoxia, electrolyte disturbances, allergies, toxic mechanisms, and endocrine failure, all known causes of PTCS, as all causing an increase in intracranial pressure through the medium of cerebral

50

Disease mechanism

oedema. Other authors have speculated on the role of allergic mechanisms, as they have in relation to vascular changes. In summary, therefore, there is very little substantial support for the brain oedema theory of PTCS. The direct observations of oedema in a small number of biopsies is in part countered by the converse finding, both on biopsy and postmortem examination, also in a small number of cases. Radiological evidence for oedema, based largely on the studies of Reid et al. (1980, 1981) of ventricles smaller than normal without change in the Hounsfield numbers and the questionable interpretations of Moser et al. (1988), is more than countered by the several normal studies discussed above showing no evidence of oedema, normal ventricular size and enlarged subarachnoid spaces. The theoretical arguments are also unconvincing. The argument based on the concept of an underlying endocrine disorder of the sort which may cause brain oedema is invalidated by the repeated failure to identify any such endocrine disturbance. The argument from the failure of ventricular enlargement is also unconvincing for reasons which have been touched on above and will be considered more fully in the next section. The additional findings of failure of CSF drainage to precipitate brain shift, the occurrence of low pressure symptoms with CSF drainage, the preservation of normal neurologic function, and the frequent chronicity of the condition, in combination all seem to present an insurmountable obstacle to the acceptance of generalized brain oedema as the primary cause of PTCS. Cerebral blood volume

As with the studies relating to cerebral oedema, those examining CBV and related parameters have failed to provide sound objective evidence of significant changes in these parameters. Moreover, the studies that have been reported (vide supra) have been few in number, using small numbers of patients and employing different techniques making comparison somewhat difficult. Even in one of the two studies which appeared to show a definite increase in CBV, the authors concluded that the measured increase was insufficient to account for the rise in ICP (Raichle et al., 1978). Quite apart from the very limited number of studies, it must be recognized that there are difficulties in measuring CBV, particularly with methods requiring anaesthesia and the injection of contrast agents. Turning to more theoretical considerations, there are the conclusions drawn from certain clinical situations. Thus there are two other clinical situations in which PTCS occurs in association with a factor postulated to be responsible for an increase in CBV. The first is in chronic respiratory disease which, in a few instances only, may be accompanied by the PTCS (Simpson, 1948; Conn et al., 1957; Westlake & Kaye, 1954). Here the increased PaCO2 has been inculpated as the

51

The intracranial compartment involved

cause of vascular dilatation and therefore of an increase in CBV, particularly as there is said by some writers to be a significant increase in venous pressure (Simpson, 1948). Certainly changes of PaCO2 of the order which might be seen in chronic lung disease can give rise to a substantial increase in CBF. Thus an increase from 40 to 70 mmHg in experimental studies in dogs gave a 100% increase in CBF (Harper, 1969). As there appears to be a linear relationship between CBF and CBV, there may be presumed to be a substantial increase in CBV. If extrapolation from these experimental figures to the clinical situation in PTCS is legitimate, an increase of the order measured by Mathew et al. (1975) might be expected to occur. In attempting to implicate an increased CBV secondary to hypercapnia as a cause of PTCS in chronic respiratory disease there are, however, several points to be borne in mind. First, even a 100% increase in CBV would raise intracranial volume by around 10% without allowance for any compensatory adjustment of other compartments, so the question arises as to whether this is sufficient to produce the levels of intracranial pressure measured in this condition. Second, if hypercapnia were to be a satisfactory and sufficient explanation of the PTCS, it might be expected to occur in a much higher proportion of patients with chronic respiratory disease. Third, it seems that plateau waves of intracranial hypertension of whatever cause may themselves be responsible for substantial secondary increases in CBV (Risberg et al., 1969), so that hypercapnia may be acting on an already largely dilated vasculature. The second situation which suggested possible distension of the capacitance component of the cerebral vasculature and is a known cause of PTCS is venous obstruction, both extra and intracranial. Many years ago, Gardner (1939) proposed that this was the mechanism in transverse sinus thrombosis but the claim remains unsubstantiated. The relationship between impairment of cranial venous outflow and intracranial hypertension is a complex one and is considered in detail in Chapter 10. The only other point to be mentioned here is that several authors have postulated an allergic mechanism in the production of the PTCS mediated through a change in vessel calibre, possibly by serotonin release resulting in an increase in CBV (Lecks & Baker, 1965; Absolon, 1966). To summarize, there is little direct evidence for an increase in CBV, there being two studies only supporting and one study opposing this view. Even by the authors finding such an increase in CBV, primacy in the mechanism of the disease is not claimed. It is probable, therefore, based on the calculations for measured increases and on other considerations referred to earlier, that CBV changes are secondary to the intracranial hypertension. Nevertheless, the finding of a consistently high CSF pressure in patients with chronic emphysema even without the PTCS (Westlake & Kaye, 1954) does raise the possibility that CBV changes may

52

Disease mechanism

have a greater significance than previously acknowledged, although it should be mentioned that these patients were also suffering from anoxaemia, raised venous pressure and/or arterial hypertension. Certainly, this is an area which needs further study. There would also need to be identification of the mechanism of increase in CBV in the majority of patients with PTCS where there are no such changes in haemodynamics as mentioned in the two special situations above. Cerebrospinal fluid

Despite a number of pieces of somewhat indirect observational evidence, as well as some quite persuasive theoretical considerations, there is actually no incontrovertible proof of an increased CSF volume in PTCS. The one attempt made at direct evaluation, reported by Condon et al. (1986) using an MR technique, failed to show an increase in volume of the CSF in either ventricles or subarachnoid space. However, only one patient was examined and the study was done in the early days of MR technology. The CSF perfusion techniques of the kind described by Pappenheimer and his associates (Pappenheimer et al., 1962; Heisey et al., 1962), which would give values for CSF volume, have not been applied to cases of PTCS, there being no justification for their use in this condition, or in clinical situations generally. There is, however, a good deal of more or less indirect evidence, some of which has been detailed in the first section of this chapter. This may be summarized here under five headings: Direct observations

These are the distended subarachnoid space often noted in earlier studies at the time cranial decompression or burr-hole placement for ventriculography, and the often large volumes of CSF drained at the time of therapeutic lumbar puncture when a compensatory reduction in the CSF compartment would be expected if one of the other compartments was increased to give the raised ICP. Clinical measurements

First, and particularly in early studies, the often low CSF protein and the changed Ayala index was taken to be a dilutional effect due to an increase in CSF volume, although this interpretation is open to challenge. Second, the increased resistance to CSF absorption, which is a common finding on CSF infusion studies, has been taken to mean a resultant increase in CSF volume. Counter to this there is the suggestion that changes on infusion studies are the result of the raised ICP and not themselves primary. The argument, as advanced by Raichle et al. (1978) and Rottenberg et al. (1980), is that an increase in brain bulk or cerebral blood volume

53

The intracranial compartment involved

creates compression of the ventricular system and the subarachnoid space which, in turn, leads to a further increase in resistance to outflow and a further build up of intracranial volume etc. This matter should be capable of analysis by examining the effects of a reduction of brain bulk by, for example, an osmotic diuretic on the resistance to CSF outflow in PTCS. Third, there are the findings of radionuclide studies but these, like many of the investigations into PTCS, suffer from small numbers and inconsistent results. Associated conditions

These are the conditions in which there is definite evidence from other sources, particularly experimental studies, to show significant changes in CSF dynamics, specifically reduced absorption and/or increased volume and which are known associations of PTCS: hyper- and hypo-vitaminosis A, steroid administration and withdrawal, and cranial venous outflow compromise, the last of which is also an established cause of hydrocephalus, at least in infants with open cranial sutures. Theoretical considerations

In essence, this is the attempt to relate the various aetiological factors identifiable in PTCS to the factors which determine CSF absorption, the CSF to venous sinus pressure gradient and the resistance to flow across the absorptive channels, so giving, in theory at least, a ‘final common path’ to explain mechanism. Therapeutic considerations

Undoubtedly the majority of effective treatments either reduce CSF volume (LPs, shunting, acetazolamide) or increase the volume capacity of the cranial compartment (subtemporal or other cranial decompression) and are therefore neutral in this argument. Of the other two treatments, glucocorticoids and ONSD, the first has a complex and incompletely understood mechanism of action but may well act on CSF dynamics whilst the second has been claimed to reduce CSF volume although the evidence for this is inconclusive. On ONSD, there is no conceivable mechanism by which it could benefit cerebral oedema primarily and, further, it has been shown not to reduce ICP in PTCS (Jacobson et al., 1999b) although clearly it can benefit the optic nerves directly. In summary, then, there is no direct or incontrovertible evidence of a primary defect of CSF absorption in PTCS, nor of an increase in CSF volume, although in both areas the indirect evidence is, at least, persuasive. The single strongest argument against a primary role for altered CSF volume is, as it was for Symonds and Dandy, the failure to demonstrate actual enlargement of any part of the CSF compartment.

54

Disease mechanism

Theoretical considerations The basic mechanism and determinants of CSF absorption are broadly agreed upon (McComb, 1983; Davson & Segal, 1996). These have been formulated in the equation which makes the absorption of CSF directly proportional to the pressure differential between the CSF and superior sagittal sinus (SSS) pressures across the arachnoid villi and inversely proportional to the resistance to flow through the villi themselves. At least this is taken to apply to species that depend on arachnoid villi for CSF absorption and at time when these structures have developed sufficiently to function. Unquestionably this is something of an over-simplification in considering fluid movement into and out of the CSF compartment. In particular, it ignores the role of alternative channels of absorption, transfer of fluid across brain surfaces including the ependyma, and direct movement into and out of vessels other than those supplied with villi. Other factors which must contribute to the constant in the proportionality equation are the physical properties of the fluid being absorbed and the physical state of the channels themselves, although the latter should be included in the resistance value. There are other considerations to be taken into account when one of the determining factors changes or when the system is defective. For example, if the CSF pressure changes there is evidence that CSF formation stays the same, at least over a certain range which includes unquestionably pathological levels (Cutler et al., 1968; Lorenzo et al., 1970). Does this apply to the very considerable increases in CSF pressure that may be found in PTCS? Also, what actually happens to CSF absorption in intracranial hypertension in PTCS if, in fact, there is a secondary rise in cranial venous outflow pressure as suggested, for example, by King et al. (2002)? One of the effects of increased CSF pressure, at least in a freely patent CSF compartment, is that the increased pressure is transmitted to the cortical veins and that the pressure relationship between these vessels and the SSS is altered (Johnston & Rowan, 1974). Again, if the SSS pressure rises, what happens to CSF pressure? The evidence suggests that it rises then falls (see Chapter 10), although detailed long-term studies are very few. In both situations, i.e. a rise in both CSF and SSS pressures, what changes occur in the arachnoid villi to affect absorption? Does the physical nature of the channels change to compensate for alterations in the driving pressure differential or are there other changes? Also what triggers the use of alternative absorptive paths and what are the physical determinants of absorption through these? The point of raising these issues here is, in part, to draw attention to how deficient our basic knowledge of the pathophysiology of CSF absorption actually is. The main theoretical argument against a primary CSF circulation disturbance is the absence of ventricular dilatation. However, there are cases of PTCS

55

Theoretical considerations

(admittedly few) where an increase in ventricular size has been noted (Bradshaw, 1956; Johnston & Paterson, 1974a; Janny et al., 1981; Malm, 1994). The importance attributed to this finding may be exemplified by the statement of Sahs and Joynt (1956), the main protagonists for the oedema theory, that ‘it is impossible to have a CSF absorption problem without ventricular enlargement’. Attempts to account for the absence of ventricular dilatation have taken several directions. First, there has been the proposal that the excess CSF volume is accommodated in a distended subarachnoid space (Johnston & Paterson, 1974b; Johnston, 1975) and that is borne out by the oft-repeated finding of a distended subarachnoid space on burr-hole or subtemporal decompression (although this has been taken to be artifactual
Foley, 1955), and a similar finding in some cases on CT scan. It has been claimed that PTCS is different from communicating hydrocephalus by virtue of the freely patent CSF compartment with the outflow impairment occurring at the arachnoid villi. This is said to preclude the development of gradients between ventricles and subarachnoid space which are thought to be necessary for ventricular enlargement (Hoff & Barber, 1974; Sussman et al., 1998). The issue of the absence of ventricular enlargement has been addressed theoretically by Levine (2000) who has argued that small, normal, or slightly enlarged ventricles are all consistent with the diagnosis of PTCS, although his formulations applied only to a rigid, non-expansible cranium thereby precluding infants. Saint-Rose et al. (1984) also theorized, in relation to the specific situation of increased venous sinus pressure, that what happens to ventricular size depends on whether the cranium itself is open or closed. With an open cranium there is enlargement and this would be like those children presenting with so-called idiopathic macrocephaly, which it is argued, in Chapter 4 following, is the form of PTCS occurring in a non-rigid cranium. If the cranium is closed, equalization of pressure and the absence of gradients does not allow ventricular enlargement. Rottenberg et al. (1980) also argued for the importance of a CSF circulation disorder and have claimed that if the resistance to absorption, although increased as demonstrated, remains lower than the resistance to transependymal flow then ventricular enlargement will not develop. It has, however, also been suggested that the increased volume of CSF is in part accommodated within the brain parenchyma by trans-ependymal flow and that this is rapidly reversible to account for the efficacy of CSF drainage (Fishman, 1979, 1984; Johnston, 1973, 1975). Whether this argument is compatible with the idea of the absence of pressure gradients is debatable. The important bearing that the finding of normal or small ventricles in treated hydrocephalus with shunt obstruction and intracranial hypertension has on these considerations should not be overlooked. It is noteworthy that a marked

56

Disease mechanism

distension of the sub-arachnoid space is a common finding at the time of shunt revision in such patients. There are similar theoretical issues with cerebral oedema. Whilst in some cases there is an obvious connection between a causative agent, such as trauma or metabolic derangement, and the development of oedema, this conforms to a model which applies to tissues generally, although the particular nature of the brain extracellular space must be taken into account. In the case of PTCS, what hypothesis could be advanced to explain the presence of chronic cerebral oedema in the absence of any precipitating agent? In the case of cranial venous outflow obstruction, there is not such a problem in that the basic formulation of the Starling hypothesis supplies the grounds for fluid transfer into the tissues. However, the oedema in acute outflow obstruction is associated with marked disturbance of CNS function and visible oedema radiologically, neither of which circumstances pertain to PTCS with venous outflow compromise. Another theoretical difficulty for those who would support the oedema theory is to account for the striking absence of any complication of lumbar puncture or lumbar CSF drainage in patients with PTCS. Surely with oedema of the degree required there would, in such cases, be the establishment of trans-compartmental gradients with resultant brain shift as can occur in all other situations where there is a focal or diffuse increase in brain bulk. A further aspect of this argument is why cerebellar tonsillar descent can occur chronically in PTCS patients treated with a lumbar
peritoneal shunt when such displacement does not occur acutely with lumbar puncture. Salman (1999) has attributed this finding to differences in brain stiffness in acute PTCS compared to chronic, treated PTCS. Further, it is hard to explain the normal volumes of CSF drained in patients with PTCS; CSF volume should undergo a significant compensatory reduction to allow for the increase in brain bulk. It is also particularly difficult to account for the low-pressure symptoms seen not uncommonly after lumbar shunting. Surely if, as those supporting the oedema view must claim, the benefits of lumbar CSF drainage are those of a reduction in volume of a non-affected cranial compartment, the increase in brain bulk should quite preclude the development of low pressure symptoms. Other inferential arguments include those based on the natural history of the disease. Untreated or partially treated cases may remain symptomatic for many years with only disturbance of visual function as an indicator of functional disturbance. It is hard to imagine chronic oedema of this nature which has no other parallel in any condition, a point made many years ago by Dandy (1937). It is also hard to relate oedema to many of the established precipitating causes particularly the occurrence of PTCS at an interval after a minor head injury or in patients taking steroids, one of the most effective forms of treatment

57

Conclusions

of brain oedema, although some authors have attempted to do this, as noted above. Another component of the argument against oedema is that based on the concept of the secondary PTCS, considered further in the following chapter (see also Johnston et al., 1991a). In essence, this argument is that there is a number of instances of conditions with intracranial hypertension without ventriculomegaly in which there is either clear evidence of a CSF circulation disorder such as in the so-called ‘slit-ventricle syndrome’ in treated hydrocephalus (Engel et al., 1979), or in chronic meningitis (Custer et al., 1982), or in circumstances where brain oedema is almost impossible to contemplate, i.e. spinal cord tumours (Hansen et al., 1987), or late in the course of either poliomyelitis or the Guillain
Barre´ syndrome (Ayer & Trivett, 1934; Ropper & Marmarou, 1984). Finally there is the finding of some cases of PTCS with increased ventricular size (Bradshaw, 1956; Johnston & Paterson, 1974a) as well as the more frequent finding of a distended subarachnoid space, both discussed earlier. Finally, with CBV there are also theoretical difficulties. Can it be argued that sufficient additional blood volume could be accommodated in the capacitance compartment of the cerebral vasculature to raise ICP to the levels noted in PTCS even after compensatory changes in the other cranial compartments have taken place? The deliberations of Raichle et al. (1978) on this matter have been noted earlier. Again, as with oedema, what could trigger such a change in CBV, particularly in the significant number of cases where there is no anatomical or physiological factor identifiable which could change the circumstances of the outflow system? Also why are there not visible changes in the brain parenchyma reflecting the altered fluid distribution? Conclusions The first conclusion must be that the issue of disease mechanism in PTCS remains unresolved. How much progress is deemed to have been made on this matter depends in large part on how the condition is viewed. If there is thought to be a condition appropriately named IIH then it cannot, by definition, be due to an abnormality elsewhere such as in the cranial venous outflow tract. Other conditions of raised ICP without ventricular enlargement, that is those without a visible cranial or extracranial mass but with an apparent cause such as venous outflow obstruction, vitamin A deficiency or excess or steroid administration or withdrawal, conditions such as those included under the umbrella of PTCS, must be considered separately. If the PTCS concept is accepted, and if it is thought acceptable to extrapolate from secondary or primary cases with aetiology to primary cases without apparent aetiology (i.e. IIH), in terms of mechanism

58

Disease mechanism

there is then a strong case for a disturbance of CSF dynamics as the basic mechanism. In summarizing the matter under the four headings of investigative findings, putative causal agents, possibly related conditions, and theoretical aspects related to the intracranial sub-compartments of blood, brain, and CSF, the main sections of the present chapter, what may be said is as follows. First, the investigative findings are singularly disappointing. The only consistent finding, apart from the demonstration of raised ICP, is that of an increased resistance to CSF absorption on infusion studies and even this has been questioned on theoretical grounds. In the case of everything else studied, the results are either equivocal or inconsistent, involve only small numbers of patients and are often acquired at different stages of the disease, or are inadequately controlled. Second, with respect to putative causal agents, the situation is clearer, although this clarity does not extend to an understanding of the link with obesity in women, nor is there any persuasive evidence of an underlying endocrine basis. What there is, however, is solid evidence linking cranial venous outflow impairment, vitamin A excess or deficiency, alterations of CSF composition, and steroid administration or withdrawal, all established causes of PTCS, with disturbed CSF dynamics, particularly insofar as the first three are also established causes of hydrocephalus. Why, in some cases, there is hydrocephalus and in others PTCS is a further issue which has been addressed in part above but is still inadequately understood. Third, in the case of possibly related conditions, the postulated links with communicating hydrocephalus, normal (or small)-ventricle treated hydrocephalus with shunt obstruction and infantile macrocephaly encourage certain conclusions with regard to the primacy of a CSF circulation disorder. Fourth, and finally, in relation to the three intra-cranial sub-compartments, the most favourable evidence for an increase in CSF volume (theoretical considerations apart) is that drainage of CSF (by lumbar puncture or shunting) or reduction of CSF formation (by acetazolamide or corticosteroids) is the most effective treatment for the condition, although it is possible that fluid removal is affecting extra-cellular brain water also. The least favourable evidence for increased CSF volume is the failure to demonstrate an increase in the volume of the CSF compartment on imaging studies. In respect to brain oedema, the most favourable evidence is the demonstration of normal or small ventricles. However, if there is significant brain oedema, the ventricles should be consistently smaller than normal, repeated CSF drainage should quite quickly cease to be effective, brain function should be affected, and trans-compartmental gradients with brain shift would be expected with lumbar CSF drainage. In regard to increased CBV, the most favourable evidence is that it fits well with a venous outflow impairment theory and there is some support from investigative findings. Countering these factors, however,

59

Conclusions

there are the problems first, of accepting that a sufficient increase of CBV is possible to account for the marked increases in ICP and second, to relate increases in CBV to the other three factors mentioned above (CSF composition, vitamin A, steroids). All in all, an abnormality of CSF dynamics with increase of intra-cranial fluid, whether in the CSF compartment itself or in a rapidly transferable from in the brain parenchyma or both, seems the most likely pathophysiological mechanism if, indeed, there is one single mechanism. It may be also that an increase in CBV makes a variable contribution to the overall volume increase depending on the cause. Clearly, however, it remains to be shown that there is such an increase of CSF volume, where and how precisely it is accommodated, and how it is linked with the several established causative factors.

4

Nosology, nomenclature, and classification

Introduction One of the fundamental questions regarding this syndrome, to which a rather bewildering variety of names has been applied, is whether there is, in fact, a single disease with a sufficiently distinct clinical picture but an as yet unidentified mechanism, or several separate conditions gathered together on practical or theoretical grounds. The practical grounds would be the uniformity of the clinical picture or the applicability of a uniform therapeutic approach whilst the theoretical grounds would be a variety of causative factors acting through a single common mechanism or a common pathology, for example, diffuse extracellular oedema, or an increase of CSF volume located in an ultimately identifiable part of the overall CSF compartment, or an increase in CBV, or some combination of these pathologies. These questions were addressed in the previous chapter and from the findings and speculations considered there it is obvious that the situation remains quite unresolved. All that can be said with any confidence is that there is a clinically identifiable condition of raised intracranial pressure without focal or general neurological signs, at least in the great majority of cases, and which in some cases runs a short, benign and self-limiting course, but in others a prolonged course that is not self-limiting, and that carries considerable risk to visual function and possibly some risk to cognitive function. Basically, two approaches are taken to this condition or conditions at the present time. One approach, which might be termed the ‘strict’ approach, is to categorize it as a specific condition conforming entirely to what have become known as the ‘Dandy criteria’ (although Dandy himself does not speak of criteria in his 1937 article), but with an as yet unidentified aetiology or causative mechanism. The other approach, which might be termed the ‘expansive’ approach, is to accept relaxation of the ‘Dandy criteria’ in several aspects and to recognize a significant proportion of cases with an identifiable aetiology, albeit without necessarily having a clear understanding 60

61

Nomenclature

of precisely how the different putative aetiological agents actually act. Despite the documented deficiencies in our understanding of the basic aspects of the condition, an attempt will be made in the chapter to take a position on this issue. Nomenclature The position taken on the issues raised above is reflected in the name used for the condition. The adherents of the ‘strict’ approach will favour the title idiopathic intracranial hypertension (IIH) whilst to those taking the ‘expansive’ approach pseudotumor cerebri (PTC) or pseudotumor cerebri syndrome (PTCS) will seem more appropriate. A third position, proposed for example by Corbett (2004), is to append the putative causative agent to the term intracranial hypertension when such an agent is identified and to call whatever cases remain IIH. Some consideration will now be given to the various names that have been used, not from the historical standpoint taken in Chapter 2, but from the point of view of applicability. A broad division of these names may be made as follows: (1) those clearly identifying some increase in CSF volume
terms such as ‘otitic hydrocephalus’; (2) those making no assumptions about mechanism but simply highlighting the need for elimination of other more common causes of raised ICP
terms such as ‘pseudotumor cerebri’; (3) those assuming a specific condition with an as yet unidentified mechanism and pathology
terms such as ‘idiopathic intracranial hypertension; and (4) eponymous terms. Increased CSF volume

It is the terms in this group that dominated the early literature. They may be listed in approximate chronological order as follows: meningitis serosa/serous meningitis (Quincke, 1893, 1897); e´tats me´ninge´s hypertensifs (Passot, 1913); otitic hydrocephalus (Symonds, 1931, 1937); toxic external hydrocephalus (McAlpine, 1937); hypertensive meningeal hydrops (Davidoff, 1956); and reduced CSF absorption syndrome (Johnston, 1973). None of these names has endured. Particularly with the earlier examples, some inflammatory leptomeningeal condition was at least implied, and in the cases reported middle ear disease was prominent. By the time of Symonds’ papers it did, indeed, look as though there was an increase in CSF volume in association with chronic middle ear disease and oftentimes uni- or bilateral lateral sinus occlusion. The term hydrocephalus was quickly discarded, however, with the demonstration of normal ventricular size, although external hydrocephalus was less exceptionable, as in McAlpine’s study linking the condition with infections

62

Nosology, nomenclature, and classification

other than those of the middle ear. The term ‘reduced CSF absorption syndrome’ is cumbersome and has not been used although it might yet prove to be an accurate designation of the basic mechanism underlying the different forms of the condition. Diagnostic elimination

The four terms in this group are pseudo-meningitis (Bouchut, 1866
cited by Passot, 1913), pseudo-brain abscess (Adson, 1924), and pseudotumor cerebri (Nonne, 1904, 1914), together with the proposed modification of the last to pseudotumor syndrome or pseudotumor cerebri syndrome (Johnston et al., 1991a), and also Dandy’s (1937) ‘intracranial pressure without brain tumour’. The first, coined prior to the use of lumbar puncture, could not survive the demonstration of normal CSF composition whilst the second reflected the then close association with another major complication of middle ear disease and was no longer applicable once the latter declined and many other associations of the raised ICP were recognized. Pseudotumor cerebri (PTC) has, on the other hand, endured, and remains the most commonly used term in the literature (vide infra). It has three particular merits. First, it reflects the major diagnostic concern of the clinician to whom the patient presents in practice. Second, it makes no unwarranted assumptions about mechanism
indeed it makes no assumptions at all! Third, it (and more obviously its proposed variant, pseudotumor cerebri syndrome) allows inclusion of all cases which might be thought to have the same mechanism and be amenable to the same therapeutic approach. Specific terms

The two terms in this group are benign intracranial hypertension (Foley, 1955) and idiopathic intracranial hypertension (Buchheit et al., 1969). Both terms remain in use but the latter is the one now used more frequently. Both names may be objected to on the basis of the initial epithet. The condition is only ‘benign’ in comparison with other, more ‘malignant’ diagnostic possibilities, and in those cases that are self-limiting and of short duration, leaving no sequelae and not recurring. However, in a considerable number of cases, none of these descriptions apply and there is, especially, the distinct possibility of permanent and often severe ophthalmological deficit with poor quality of life. Clinicians now are reluctant to use the term ‘benign’ in relation to this condition. A good indication of its non-benign nature as far as the patient is concerned is given by the poem written by such a patient and recorded in the article by Sussman et al. (1998). ‘Idiopathic’ is a more problematic term. The locus classicus for this term is Galen’s De locis affectis I.3 (Ku¨hn VIII.30
31) where ‘idiopathy’ is used in

63

Dandy criteria

contrast to ‘sympathy’ and indicates, in essence, a condition primarily arising in a specific part and not related to some condition in another part. Usage has, not surprisingly, changed somewhat so that a current definition is: ‘arising spontaneously or from an obscure or unknown cause’ (Webster’s Third Dictionary, 1976). This, then, clearly precludes all cases in which some aetiological or causative factor is identifiable. Such identification, in turn, depends on the extent of the investigations. On this point, it should be noted that a great many cases of IIH reported in the literature could be questioned on the grounds of inadequate investigation. A further objection is that the term ‘idiopathic intracranial hypertension’ could equally well apply to a substantial proportion of cases of hydrocephalus in which there is intracranial hypertension but no identifiable aetiological agent. Eponymous terms

Rather surprisingly for a condition in which a clearly understood mechanism remains elusive, an eponymous title has not found more widespread use. In the German literature at least there was an early attempt to recognize Nonne’s role in identifying the condition by referring to it as ‘die Nonnesche Krankheit’ (e.g. Oppenheim & Borchardt, 1910) but there has been no such attempt in the English literature. A case could be made for terming it ‘Quincke
Nonne disease (or syndrome)’. This issue will be discussed further after the criteria have been considered and some illustrative cases have been given. The Dandy criteria In the original paper by Dandy (1937) describing 22 cases, the author does not actually list the diagnostic criteria as such, although he does set out in very clear fashion the clinical features of the condition. It is of interest, moreover, to note that two of Dandy’s cases had a minor additional neurological sign and two others had a mild abnormality of CSF composition. Probably the first specific listing of what are now referred to as the ‘modified Dandy criteria’ was that by Smith in 1985, his list being as follows: 1. Signs and symptoms of increased intracranial pressure (headaches, nausea, vomiting, transient obscurations of vision, papilloedema) 2. No localizing neurological signs otherwise, with the single exception being unilateral or bilateral VI nerve paresis 3. Cerebrospinal fluid which can show increased pressure but with no cytological or chemical abnormalities otherwise 4. Normal to small symmetrical ventricles must be demonstrated (originally required ventriculography, but now demonstrated by computed tomography)

64

Nosology, nomenclature, and classification

These ‘modified’ criteria have themselves been modified in subsequent papers. For example, Radhakrishnan et al. (1994) have the following list: 1. Signs and symptoms of increased intracranial pressure 2. No localizing neurological signs, in an awake and alert patient, other than abducens nerve paresis 3. Normal neuroimaging except for small ventricles or an empty sella 4. Documented increased pressure (250 mm of water or more) but a normal composition of the cerebrospinal fluid 5. Primary structural or systemic causes of elevated intracranial venous sinus pressure excluded (for example, sinovenous thrombosis, hyperviscosity syndromes, and right heart failure) Other studies to address this issue include those of Ahlskog and O’Neill (1982), Corbett (1983) and Carlow et al. (1987). In their recent review, Sussman et al. (1998) add a sixth criterion: benign clinical course apart from visual deterioration. A complete list, covering all the criteria included in the different studies, might read as follows: 1. Signs and symptoms of raised intracranial pressure 2. Absence of focal neurological signs 3. Measured increase in CSF pressure 4. CSF of normal composition 5. Normal imaging studies (including MRI/MRV) apart from possibly small ventricles and an empty sella 6. Not attributable to another cause 7. Benign clinical course apart from possible adverse effects of raised CSF pressure on the optic nerves This last is a slightly expanded version of the recent list offered by Friedman and Jacobson (2004). Working from this third list above, let us consider each criterion in turn, what exceptions there might be, and what implications these possible exceptions might have for the diagnosis. Criterion #1: Signs and symptoms of raised ICP

This is very close to being a sine qua non of the condition. However, variations are possible without invalidating the diagnosis. Thus, there are descriptions of cases of PTCS with symptoms only, unaccompanied by clinical signs of intracranial hypertension, but with measured increase in CSF pressure. Conversely, cases have also been observed with signs only, and there are also cases without either symptoms or signs but with clearly abnormal CSF pressure (see Chapters 6 and 7). This last particularly applies to medically treated cases who, on clinical assessment, show no residual symptoms or signs, but who have, nonetheless, a persistent measured increase in CSF pressure (Johnston et al., 1981). There is also the report

65

Dandy criteria

of higher than normal CSF pressure levels in obese people without any symptoms or signs of intracranial hypertension. Criterion #2: Absence of focal neurological signs

There are two aspects relating to this criterion. First, there is, in PTCS, undoubtedly an incidence of physical signs other than the ophthalmological signs directly attributable to raised ICP. Even in the cases described by Dandy, he of the criteria, this was so. In the Glasgow series the incidence was 8.7% whilst in a review of 1572 cases collected from the literature up to 1990 the incidence was 6.7%. The range of signs noted is considered in Chapter 6. Second, there may be neurological signs attributable to the underlying condition causing the PTCS itself. This particularly applies to cranial venous outflow impairment and is exemplified by case 5 below. Criterion #3: Measured increase in CSF pressure

As with criterion #1 above, this is almost, but not quite, a sine qua non. There are three possible situations in which a normal CSF pressure may be found. First, as is now widely recognized, increases in ICP are characteristically episodic regardless of the cause of the intracranial hypertension. PTCS is no exception to this. A single lumbar puncture measurement of CSF pressure may, then, be made at a time of normal pressure. Secondly, there may actually be normal pressure cases as there are in hydrocephalus in which even low pressure situations occur that are still relieved by CSF drainage (Owler et al., 2001). Case 9 on p. 74 exemplifies this situation. Third, there are reports of cases of PTCS presenting with CSF rhinorrhoea, the CSF leak reducing CSF pressure to normal (vide infra). Criterion #4: Normal CSF composition

Considering abnormalities of CSF composition, the first report of a PTCS with abnormal CSF composition was probably that of Wickmann in 1907 who described raised ICP in poliomyelitis. There has been a number of other such cases, with elevated CSF protein and/or an increased cell count (Ayer & Trevett, 1934; Weiman et al., 1957) as well as two cases with normal CSF composition (Gass, 1957). Likewise, there have been several reports of similar cases associated with the Guillain
Barre´ syndrome, characteristically showing an elevated CSF protein (Ford & Walsh, 1943; Gardner et al., 1954; Joynt, 1958; Janeway & Kelly, 1966; Ropper & Marmarou, 1984; Hartemann et al., 1986). Most authors have concluded that there is physical obstruction to the passage of protein or cell laden fluid across the arachnoid villi, although Joynt (1958), no doubt wedded to the concept of cerebral oedema causing the PTCS as a result of the light

66

Nosology, nomenclature, and classification

microscope study done in conjunction with Sahs (Sahs & Joynt, 1956), raised the possibility of underlying cerebral oedema. More recently, other forms of chronic meningitis have been linked with a PTCS of raised ICP due to a presumed CSF circulation disorder without ventriculomegaly; syphilitic meningitis (Bakchine et al., 1987), brucella meningitis (Diaz-Espejo et al., 1987), cryptococcal meningitis (Custer et al., 1982; Cremer et al., 1996). It is clear that there is, in these cases, a link with hydrocephalus in that this also may complicate chronic meningitis. In this regard, the report of Janeway and Kelly (1966) of a case with the Guillain
Barre´ syndrome, who had initially a PTCS but subsequently went on to develop communicating hydrocephalus, is of particular interest. In addition, dating from the report of Gardner et al. (1954) who inculpated increased CSF protein secondary to one intraspinal and one intracranial extraxial tumour (as well as one case of Guillain
Barre´ syndrome), there have been other descriptions of patients with elevated CSF protein secondary to neoplasms, particularly spinal, who have been shown to have a PTCS (Arseni & Maretsis, 1967). More recently, Hansen et al. (1987) described four cases, two with increased CSF protein and two with increased CSF cells, who had such a syndrome and were also shown to have abnormal CSF conductance similar to that found in PTCS, normal pressure hydrocephalus, and ordinary hydrocephalus. They postulated, as did their predecessors, impaired CSF absorption due to the abnormal component. Criterion #5: Normal imaging studies

This is, perhaps, the most contentious of the criteria. In short, cases categorized as IIH should have entirely normal imaging studies. If the concept is broadened to one of PTCS then clearly a significant proportion of cases will have radiological or MR abnormalities, specifically those involving the cranial venous outflow tract. The occurrence of PTCS in conjunction with cranial venous outflow impairment dates back to the very earliest descriptions of the condition as discussed in Chapter 2. In a recent study of the occurrence of demonstrable venous outflow abnormalities in a series of 188 cases dating back to 1968, an overall incidence of 19.7% was found. When, however, only the last 10 years of the study was considered the incidence rose to 31.0% (Johnston et al., 2002). Clearly, the incidence found depends very much on the degree of diligence with which the investigations are pursued. This is well exemplified by the recent studies of Farb et al. (2003) and Higgins et al. (2004) referred to earlier. Many of the cases reported as IIH in recent decades have had no adequate examination of the cranial venous outflow tract. Another abnormality, specifically accepted within the criteria, is the empty sella. This obviously has implications for mechanism, suggesting a CSF circulation disorder, particularly

67

Nomenclature: the alternatives

those occasional cases that go on to develop CSF rhinorrhoea (Osveren et al., 2001; Owler et al., 2003a) Another occasional association which might relate to mechanism is the presence of an arachnoid cyst (Maixner et al., 1992; Johnston & Teo, 2000). Criterion #6: No identifiable cause

A considerable number of causative factors of widely varying nature has been implicated in the production of PTCS. Detailed lists are given, for example, by Johnston (1992), Sussman et al. (1998), and Mathews et al. (2003)
see also Chapter 5. From these tables the major groupings of proven or probable associations include obesity/weight gain, cranial venous outflow obstruction/ hypertension, haematological disorders (in part acting through venous pathology), nutritional disorders, and at least nine distinct medications. All would agree that in any series of PTCS the sum of cases attributable to one or more of these factors is not inconsiderable, especially if detailed investigation is carried out. To exclude cases on the basis of this criterion seems unreasonable. Criterion #7: Benign clinical course (other than ophthalmological)

Despite the rejection of the epithet ‘benign’ on the grounds of the sometimes severe and irreversible ophthalmological loss, and also the degree of disruption to the life and well-being of the patient in intractable cases, it can be said that the clinical course is, in fact, benign, at least in the context of intracranial hypertension generally. There is, however, the possibility of residual disability associated with the cause of the intracranial hypertension, related for example to venous outflow impairment, the adverse effects of medications such as corticosteroids, primary haematological disorders etc. There is also the question of impairment of cognitive function in chronic cases in whom the intracranial hypertension is poorly controlled (Sørensen et al., 1986b; Kaplan et al., 1997). It is, in our view, questionable whether this criterion actually adds to the characterization of the disease. Nomenclature: The alternatives First, it should be stressed that it is important to establish an agreed name or names for the condition or conditions under consideration. Not only is there obvious benefit in day-to-day practice, but also it would be very helpful in relation to the considerable amount of literature which is now being published on the subject. In summarizing our views on the most appropriate name, and we think one name is desirable, we shall consider the three names currently in use in the reverse order of time of introduction and hence length of use.

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Nosology, nomenclature, and classification

Idiopathic intracranial hypertension (IIH) is an unsatisfactory name for several reasons. First, it separates off approximately half the cases which have been included under the various other terms used over the past century, without any sound basis for doing so. Most series have around a 50% incidence of cases with some identifiable aetiological agent which would render the term IIH inappropriate. This is before the advanced techniques for investigation of the cranial venous outflow tract referred to earlier have been applied. Corbett’s (2004) approach is cumbersome and fails to group cases into what is, in practice, a clearly recognizable group, that is in terms of diagnosis, prognosis and therapeutic approach. It would be more appropriate in a classification of causes of intracranial hypertension generally. What is to be done with these cases as far as nomenclature is concerned? Second, it is entirely probable that a significant number of cases labeled IIH since the introduction of the term in 1969 are not idiopathic, this term only being in any sense applicable because of the incompleteness of the investigations. For example, in their paper entitled ‘Idiopathic intracranial hypertension: lack of histological evidence for cerebral oedema’, Wall et al. (1995) provide two case reports. In the first, a single CT scan is mentioned, without saying whether contrast was used, as the only investigation apart from CSF pressure measurement and fluid analysis. In the second, there is no mention of any radiology or imaging at all. Cranial venous outflow pathology, for one, cannot be excluded without at least MRV and probably requires venography. Finally, the term IIH seems to offer no improvement over the other terms in use (BIH, PTC/PTCS), even though it has found temporary favour with some journal editors. Benign intracranial hypertension (BIH) can, as discussed above, be objected to on the grounds of the condition not being benign in terms of its effects on visual function, and to a degree on the patient’s quality of life, depending on how refractory to treatment the condition is in the individual case. It is, however, certainly benign in the context of intracranial hypertension generally, in contrast to intracranial mass lesions, and that is a striking and consistent feature of the condition. At another level, the term benign also reflects the clinician’s relief when other, more sinister conditions are excluded. BIH would seem, in fact, to be an acceptable term, and one sanctioned by 50 years of use. Pseudotumor cerebri or pseudotumor cerebri syndrome (PTC/PTCS) would appear to have at least five specific advantages as follows: 1. It has by far the longest period of uninterrupted use and acknowledges one of the pioneers in identifying the condition (Nonne). 2. It allows the inclusion of all cases which seem to have the same or a similar mechanism and require the same forms of treatment. In the Galenic sense it allows, then, inclusion of both idiopathic and sympathic cases.

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Definition of PTCS

3. It makes absolutely no assumptions about mechanism in a condition in which mechanism is not yet clearly understood. 4. It highlights a key diagnostic concern
the exclusion of a neoplastic intracranial mass lesion. 5. It clearly reflects the continuing lack of certainty about a basic underlying cause. It is, in our view, clearly the most appropriate term. On these grounds, venerable coincides with applicable. With regard to current usage, a review of the terms used to identify the condition over the last 7 years shows a continuing preference for the use of PTC or PTCS. In an examination of over 300 papers appearing from 1998 to the present, PTC or PTCS was the main term used in 50.5%, IIH in 32.7%, and BIH in 16.8%. In a number of instances, more than one term was used in the same paper, whilst in a very small number of instances a different term (e.g. ‘isolated intracranial hypertension’) was used. Could a case be made for a new name altogether and, if so, what could it be? The strongest theoretical argument would be if a name could be found which identified the basic mechanism. The strongest practical argument would be if a name could be found that would meet with universal approval. An eponymous term could be devised, as has in fact been proposed
Nonne’s disease or Quincke
Nonne disease or syndrome. Or an assumption could be made on mechanism and a name like ‘reduced CSF absorption syndrome’ or ‘normal ventricle hydrocephalus’ could be applied. However, not only are such terms cumbersome, but also agreement on mechanism is not so far advanced as to ensure their wide acceptability. Finally, the ‘pseudo’ concept could be retained but applied to hydrocephalus, i.e. pseudohydrocephalus, but while this may have some appropriateness in terms of relationship of mechanism, it too is cumbersome and unlikely to find wide acceptance. Definition of the pseudotumor cerebri syndrome (PTCS) The term PTCS is, then, used to apply to all those conditions in which there is an increase in ICP, or at least the clinical manifestations of such an increase, without evidence of frank hydrocephalus, either in terms of pathological ventricular enlargement (increase in the size of the subarachnoid space and mild ventricular enlargement being acceptable), or in terms of an adverse effect on neurological function, and without evidence of any intracranial mass lesion including diffuse cerebral oedema. Typically, there is a normal neurological examination and preservation of higher functions, although in some cases additional neurological signs may be present. CSF pressure is elevated on direct measurement in the great majority of cases and CSF composition is normal in the majority, but normal CSF

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Nosology, nomenclature, and classification

pressure, particularly on a single measurement, and abnormal CSF composition are acceptable within the diagnosis. Imaging studies are commonly normal, but in a significant number of cases, depending on how far they are pursued, abnormalities of the cranial venous outflow tract may be seen at any point from the SSS to the heart. Also, as above, some visible enlargement of the CSF compartment is acceptable, particularly of the subarachnoid space, and particularly in infants. An empty sella and other focal collections of CSF (arachnoid cyst, enlarged Meckel’s cave) may also occur. The most effective immediate treatment of the raised ICP is drainage of CSF. All other treatments so far used to any extent (diuretics, steroids, ONSD, STD) characteristically fail to return CSF to normal in the short term despite, in many cases, providing relief of symptoms and signs. The recently re-introduced techniques for direct treatment of presumably causative venous outflow tract abnormalities look promising (Kollar et al., 2001; Higgins et al., 2002, 2004; Owler et al., 2005), but to date there is no adequate information on either the short or long term effects on CSF pressure. Such studies of other apparently clinically effective therapies suggest caution on this point. The underlying mechanism of the syndrome is still unknown
even, in fact, whether there is a single mechanism
but the evidence that is available, including theoretical considerations, points to a disturbance of CSF absorption as primary. Classification A proposed classification of the pseudotumor syndrome is as follows: 1. Group I: Primary pseudotumor cerebri syndrome (primary PTCS) (a) No recognized cause (idiopathic PTCS, IIH) (b) Recognized precipitating cause (apart from venous outflow impairment pathology) 2. Group II: Secondary pseudotumor cerebri syndrome (secondary PTCS) (a) Cranial venous outflow impairment (b) Abnormal CSF cytology (c) Abnormal CSF protein 3. Group III: Atypical pseudotumor cerebri syndrome (atypical PTCS) (a) Occult PTCS
either symptoms, or signs, or both absent (b) Normal pressure PTCS (c) Infantile PTCS 4. Group IV: Pseudo-pseudotumor cerebri syndrome (pseudo-PTCS) (a) Occult mass lesion (b) Normal volume hydrocephalus Examples will be given of each of these categories in the form of summarized case histories.

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Classification

Group I: Primary PTCS, no recognized cause Case 1

A 12-year-old girl presented with a 2-week history of severe and frequent headaches, diplopia, blurring of vision, and neck stiffness. There was nothing of note in her past history and she was not obese. The only abnormalities on examination were severe bilateral papilloedema with haemorrhages, and reduced visual acuity bilaterally. CSF pressure was greater than 40 cmH2O with fluid of normal composition. A CT scan without and with contrast was entirely normal. A percutaneous LP shunt was inserted with rapid resolution of her symptoms and signs. After 2 years the shunt was clipped. She remained well for a further year, after which the shunt was removed. Shortly afterwards she had a recurrence of headache and mild papilloedema which resolved with acetazolamide. She was followed for a further 5 years and remained well with normal visual function. Case 2

An 18-year-old girl presented with a 1-week history of severe headache and loss of vision. She was markedly obese, had severe bilateral papilloedema, reduced visual acuity (VAR 6/36, VAL 6/12), and peripheral field constriction. CT and MR scans were entirely normal with normal ventricular size. There were no specific studies of cranial venous anatomy. CSF pressure was 450 mmH2O with fluid of normal composition. She was initially treated with dexamethasone, acetazolamide, and a right ONSD. Her symptoms persisted and her visual status worsened. A cisterno-atrial shunt was inserted with rapid resolution of her symptoms and her papilloedema. At 3-year follow-up her corrected VA was 6/9 bilaterally and there was some pallor of the right disc. She was otherwise entirely well. Group I: Primary PTCS, recognized precipitating cause Case 3

A 28-year-old woman presented with a 6-month history of headache and blurring of vision. A year previously she had been diagnosed with acute myeloid leukaemia and had been receiving treatment with methotrexate and intermittent steroids. On examination she had moderately severe bilateral papilloedema. CSF pressure was markedly elevated with fluid of normal composition. CT scan without and with contrast was completely normal. A cisterno-atrial shunt was inserted as there was a history of low back pain. There was rapid resolution of the symptoms and signs of intracranial hypertension. At 4-year follow-up she was free of PTCS symptoms and ophthalmological examination was normal. She had had, during the interval, a recurrence of her leukaemia, which had again gone into remission, and a lumbar

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Nosology, nomenclature, and classification

discectomy. The presumed precipitating cause was steroid withdrawal which preceded the onset of symptoms. Group II: Secondary PTCS, abnormal CSF composition Case 4

A 30-year-old woman presented with a 7-month history of increasingly severe headaches and a 1-month history of mild ataxia, photophobia, and neck stiffness. On examination, the only abnormalities were a low-grade fever, meningism, and moderately severe bilateral papilloedema. On lumbar puncture, her CSF pressure was greater than 350 mmH2O, and the fluid contained 208 white cells (60% mononuclears, 26% neutrophils, 14% lymphocytes), 0.55 g l
1 of protein and 3.0 g l
1 of glucose. CT scan without and with contrast was normal with ventricles of normal size. Extensive microbiological examination failed to identify a causative organism. She was started empirically on anti-tuberculous triple therapy and dexamethasone. No organisms were ever identified and despite the dexamethasone her headache worsened as did her papilloedema, with the appearance of retinal haemorrhages. Further CT scans were normal as was radionuclide cisternography. In view of her worsening intracranial hypertension a percutaneous L
P shunt was inserted 4 months after presentation. There was rapid resolution of her headaches and papilloedema. Other treatment was discontinued. Ventricular size on CT scans following the L
P shunt remained the same as pre-operatively. After 6 months the shunt was removed due to sciatic pain. Subsequently she remained well and after one year had a CSF pressure of 150 mmH2O with fluid of normal composition. Group II: Secondary PTCS, intracranial venous outflow impairment Case 5

A 16-year-old boy presented with a 2-week history of right retroauricular pain followed by headache, vomiting, and photophobia. On examination, he was afebrile, drowsy, and without ophthalmological or neurological signs. Initial investigative findings included a low prothrombin index (0.55), a lumbar CSF pressure of 330 mmH2O, a CSF cell count of 3 mononuclears, and a CSF protein level of 1.11 g l
1. Over the following days he had a number of simple partial seizures, some with generalization, and developed a left hemiparesis. He then developed severe bilateral papilloedema with intraretinal haemorrhages. CSF pressure remained high but the composition returned to normal. CT scan at this point showed normal brain parenchyma and normal ventricular size, but filling defects in the SSS. DSA confirmed thrombosis of the SSS and right transverse sinus. His seizures were controlled with anti-convulsants and his hemiparesis resolved, but his headache and papilloedema worsened. A further CT scan showed

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Classification

an area of gyral enhancement consistent with venous infarction. Despite treatment with high-dose dexamethasone, his papilloedema remained and his visual acuity began to diminish. An L
P shunt was inserted with rapid and complete resolution of the symptoms and signs of raised ICP. He was subsequently found to have significant urinary excretion of homocystine, while the low prothrombin index was found to be due to factor VII deficiency. He required three shunt revisions over the first 3 months. He then remained well for 3 years and had his shunt first clipped and then removed after 4 years. Last follow-up was at 7 years when he was entirely well without symptoms and without ophthalmological or neurological signs. Case 6

This patient initially presented in 1978 as a 24-year-old, very obese woman with a 4-week history of headache, dizziness, tinnitus, and blurring of vision. On examination, she had bilateral papilloedema and slight reduction of visual acuity on the left. CT scan was normal. CSF pressure was 250 mmH2O on two occasions and the fluid was of normal composition. She was treated with acetazolamide and dexamethasone over a period of months. Her symptoms resolved but she continued to have low-grade papilloedema. In 1983 she had a recurrence of symptoms with worsening of her papilloedema. This time she failed to respond to steroids and a percutaneous L
P shunt was inserted. She could not tolerate this because of low pressure symptoms but even the short period of shunting (2 weeks) normalized her fundi. Subsequently, her papilloedema did return but she was relatively symptom-free until 1996 when she had again a recurrence of papilloedema. Several CT scans over the years were all normal. She was too heavy to have an MR (4140 kg). A cisterno-atrial shunt was inserted and her symptoms and signs resolved. She did, however, require five shunt revisions over an 18-month period, on two occasions shunt malfunction being indicated by CSF rhinorrhoea. DSA, with particular attention to the venous phase, was carried out in 1997 and showed bilateral transverse sinus narrowing at a time when her CSF pressure was under control with her shunt. As her clinical status stabilized after the fifth shunt revision nothing further was done, although the possibility of direct treatment of her venous sinus abnormalities was considered should she have further shunt problems. Group II: Secondary PTCS, extracranial venous outflow impairment Case 7

A 29-year-old woman was admitted for elective gastric stapling for severe obesity. She had no neurological symptoms or signs. One week after the procedure she

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Nosology, nomenclature, and classification

developed an infective thrombosis of the right internal jugular vein which was being used for parenteral alimentation. A few days later she developed severe headache and diplopia followed by rapidly progressive and severe bilateral papilloedema and bilateral VIth nerve palsies. CT scan without and with contrast was normal. On lumbar puncture, the CSF pressure was greater than 350 mmH2O. The fluid was of normal composition. A left cisterno-atrial shunt was inserted with rapid and complete resolution of her symptoms and signs. She subsequently lost over 32 Kg (approx. 70 lbs) weight and the shunt was clipped in the hope that her PTCS had resolved. Unfortunately, symptoms of raised ICP rapidly returned so the shunt was re-established. She remained well during a 17-year follow-up, apart from two shunt revisions. Two attempts at clipping her shunt prior to possible removal were not tolerated. Over the period of follow-up MR scans were normal on two occasions. Group III: Atypical PTCS, symptoms or signs or both absent Case 8

A 12-year-old girl presented with a 3-month history of increasingly severe headaches. She was of normal weight and had no neurological or ophthalmological signs. There was a history of low-dose tetracycline use for acne over a period of months. Both CT and MR scans were entirely normal. She had two lumbar punctures with CSF pressures of 300 and 280 mmH2O. CSF composition was normal on both occasions. ICP monitoring over 24 h via a lumbar catheter showed a high baseline with intermittent A and B waves. She was initially treated with acetazolamide but failed to respond so an L
P shunt was inserted. Following this she developed low pressure symptoms which gradually settled. She remained well for 3 years then developed recurrent symptoms but again no signs of raised ICP. Her L
P shunt was found to be blocked and was revised with resolution of her headaches. She remained well for a further 3-year follow-up period. Group III: Atypical PTCS, normal CSF pressure Case 9

A 13-year-old boy presented with visual loss and was found to have a scotoma in the inferior nasal quadrant of the right eye with papilloedema in that eye. There was no headache. A full CT examination including orbits was normal. No diagnosis was made and his signs resolved over 2 months. Two years later he returned with progressive visual field loss, again in the right eye. Investigations were again negative. Four months later bilateral papilloedema was noted. There was extensive loss of the peripheral visual field on the right with preservation of central vision. The left blind spot was notably enlarged. CSF pressure was

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Classification

130 mmH2O and the fluid was normal in composition. CT and MR scans were normal with ventricles and optic nerves of normal size. Fluorescein angiography confirmed papilloedema with no evidence of drusen, inflammation, infarction or infiltration. Throughout this time he remained free of headache. No diagnosis was made. He was started on corticosteroids and his visual status stabilized. Then, 6 months later, approximately 2 months after cessation of steroids, he complained of blurring of vision in the left eye. VAR was 6/4 and VAL 6/9. There were no afferent papillary defects. The right visual field was restricted to a 3  5° island while that on the left showed a markedly enlarged blind spot and restriction of peripheral isopters. The right disc was pale and atrophic whilst the left disc showed severe papilloedema. Imaging of the brain and orbits was again entirely normal as was radionuclide cisternography. CSF pressure monitoring over a 36-h period via a lumbar subarachnoid catheter was entirely normal. CSF composition was again normal. Because of the parlous state of his vision, and despite the investigative findings, a percutaneous L
P shunt was inserted. There was rapid resolution of his severe left papilloedema and stabilization of his visual fields. During the subsequent years he had several episodes of shunt obstruction with recurrence of papilloedema resolving with shunt revision. It is notable that his CSF pressure was markedly elevated at the times of shunt blockage. Group III: Atypical PTCS, infantile PTCS Case 10

A 3-month-old girl presented with an abnormal rate of head growth. She had a head circumference 490th percentile and a full, tense anterior fontanelle. There were no other abnormalities. CT scan showed marked distension of the subarachnoid space and a marginal increase in ventricular size. A radionuclide CSF clearance study was normal. CSF pressure monitoring via a right frontal Rickham reservoir showed high base-line levels with abnormal waves. No treatment was initiated. She was re-studied after 3 months with essentially the same findings apart from some reduction in ICP levels. Again, no treatment was given. Over the next 12 months her rate of head growth returned to normal although the actual circumference remained above the 90th percentile. Development and neurological function were normal throughout. After 3 years the reservoir was removed. Case 11

A 5-month-old boy presented with a 3-week history of irritability and increased anterior fontanelle tension. His head circumference was above the 90th percentile and there had been an abnormal rate of head growth. Neurological examination

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Nosology, nomenclature, and classification

was normal. CT scan showed a notably enlarged subarachnoid space and a marginal increase in ventricular size. CSF pressure on lumbar puncture was greater than 300 mmH2O. The fluid was normal in composition. He was considerably less irritable after the lumbar puncture. No treatment was undertaken initially but his symptoms persisted and his head circumference continued to increase at an abnormal rate. He was then treated with serial lumbar punctures and dexamethasone but without improvement. In fact, he developed a unilateral VIth nerve palsy. Two months after presentation, a percutaneous L
P shunt was inserted with rapid and complete amelioration of his symptoms and signs. He had a recurrence of raised CSF pressure after 9 months, due to shunt blockage, which resolved with revision. After 3 years, the shunt was removed following a period of clipping which was uneventful. He remained entirely well for a further 2.5 years of follow-up. Case 12

A 9-month-old boy initially presented in 1973 with an abnormal rate of head growth and a head circumference 490th percentile. There was a history of chronic ear infection but he was otherwise well with normal development and no neurological signs. He had very slight ventricular enlargement on ventriculography. No treatment was undertaken and he remained well over a nine year follow-up. CT scans over that period showed no change in ventricular size which was essentially normal. He re-presented at age 11 with headache, behavioural change, and deterioration in school performance. His head circumference was 490th percentile but examination was otherwise normal. A further CT scan showed increased ventricular size, radionuclide ventriculography showed communicating hydrocephalus, and ICP monitoring revealed moderate intracranial hypertension. A right ventriculo-peritoneal shunt was inserted with rapid and sustained improvement. He remained well for a further 14 years of follow-up. During that time his mother and two of his older sisters were diagnosed with PTCS (Johnston & Morgan, 1991). Group IV: Pseudo-PTCS, occult mass lesion Case 13

A 35-year-old woman initially presented in 1976 with a 12-month history of increasingly severe headaches and a 2-week history of visual disturbance. The only findings on examination were chronic bilateral papilloedema and a left central scotoma. Carotid angiography and ventriculography were normal. A diagnosis of PTCS was made and she was treated with dexamethasone. There was some symptomatic relief but her papilloedema persisted over the next 12 months. There were no other abnormalities on examination. Further investigations, including

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Classification

a radionuclide scan and EMI (CT) scan, were normal. She was treated intermittently with steroids. She returned after a further 12 months with recent onset of dizziness, worsening of vision, and diplopia. Her papilloedema was now severe and her visual acuity had fallen considerably. Apart from a markedly Cushingoid appearance, examination was otherwise normal. CT scan, of which she had had several, was again normal. A percutaneous L
P shunt was inserted but within 24 h of insertion she died from cardio-respiratory arrest secondary to cerebellar tonsillar herniation. On post-mortem she was found to have gliomatosis cerebri. Case 14

A 14-year-old girl presented with a 4-week history of headache and blurring of vision. Apart from moderately severe bilateral papilloedema, there were no abnormalities on examination. CT scan without and with contrast was normal. CSF pressure was 320 mmH2O with fluid of normal composition. On a presumptive diagnosis of PTCS, she was started on prednisolone and acetazolamide with improvement in her headache and papilloedema. Further CT scans and lumbar punctures were normal apart from increased CSF pressure. Several attempts were made to reduce her steroid dosage but on each occasion there was recrudescence of her headache and papilloedema. After 2 months, a percutaneous L
P shunt was inserted with rapid and complete resolution of both headache and papilloedema. After a further 2 months, she was readmitted with a mild recurrence of both headache and papilloedema. A radionuclide shunt study suggested blockage of the L
P shunt. Her condition improved spontaneously so no revision was undertaken. A month later there was again recurrence. CT scan was again normal. A lumbar puncture was carried out to relieve her raised CSF pressure (270 mmH2O). Following this, however, her headache became severe, she became drowsy and developed a left hemiparesis. She was subsequently found to have a diffuse, deep right cerebral hemisphere astrocytoma. She was treated with radiotherapy and chemotherapy but died two and a half years after presentation. Group IV: Pseudo-PTCS, ‘normal volume’ hydrocephalus Case 15

A 13-year-old boy initially developed hydrocephalus in the neonatal period secondary to streptococcal meningitis. On investigation he had marked ventricular enlargement with apparent aqueduct stenosis. A right ventriculo-peritoneal shunt was inserted which controlled his hydrocephalus and returned ventricular size to normal. Over the ensuing years he had multiple shunt revisions necessitated either by obstruction (particularly of the ventricular catheter) or

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Nosology, nomenclature, and classification

infection. At the time of the readmission under consideration, he was complaining of headaches and irritability. Apart from a degree of mental retardation, he had no clinical signs, in particular no signs of raised ICP. The shunt was in good position on X-ray. CT scan showed normal ventricular size with no evidence of parenchymal oedema. A radionuclide shunt study was suggestive of ventricular catheter obstruction. ICP monitoring via an intraparenchymal transducer showed moderately severe intracranial hypertension. At shunt revision the ventricular catheter was found to be blocked and was replaced via a new burr-hole. The subarachnoid space was noted to be distended. Comments on the cases Group I

Two cases (#1 & #2) are given which exemplify typical PTCS without identifiable aetiology. These cases could be included under the term IIH, although in neither was the level of investigation sufficient to exclude cranial venous outflow tract abnormalities. Another point is that while both were young females, one was markedly obese whilst the other was a slim young girl. The third case (#3) was also an obese young women but the prior occurrence of acute leukaemia and the treatment of this, which included intermittent steroids, were taken to be in some way causative in the light of previous reports. Group II

The first case (#4) is an example of a typical PTCS associated with an unexplained abnormality of CSF composition. The second case (#5) demonstrates a situation where an abnormality in blood coagulation resulted in cranial venous sinus thrombosis which in turn resulted in PTCS. The PTCS outlasted the acute haemodynamic effects of the venous outflow occlusion. This patient had additional significant neurological symptoms and signs (epilepsy, hemiparesis) and demonstrable radiological abnormality related to venous infarction yet, from the point of view of the raised ICP, both its time course and its response to treatment by shunting were characteristic of PTCS. The third case (#6) is important in that at presentation it would be taken as typical of IIH
a very obese young woman with headaches and papilloedema with associated ophthalmological findings but no focal neurological abnormalities, normal neuroradiology as far as it went, and normal CSF apart from increased pressure. She subsequently showed several noteworthy features: (1) She had marked low pressure symptoms with an L
P shunt which necessitated shunt removal despite the fact that it completely reversed her eye signs. This could be taken to exclude cerebral oedema, or at least

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Comments on the cases

intra-parenchymal fluid not rapidly transferable into the CSF compartment. (2) The later cisterno-atrial shunt did effectively deal with her condition but shunt obstruction was associated with CSF rhinorrhoea. (3) The chronicity of the condition was marked
17 years from initial diagnosis to effective treatment. (4) Almost 20 years after the initial diagnosis there was DSA demonstration of venous outflow tract abnormality at a time when her CSF pressure was under control. The DSA was done with the thought of possible treatment if such an abnormality could be demonstrated and her shunt gave further trouble. The fourth case (#7) is also unusual in that she developed PTCS as a result of surgical treatment for morbid obesity. Moreover, the PTCS did not resolve despite very marked weight loss. This situation was quite possibly affected by the presence of the shunt and by the fact that one internal jugular vein was used for the shunt. Group III

This is a somewhat heterogeneous collection of three sub-groups of what we have classified as ‘atypical’ PTCS. The first sub-group (case #8) is uncontroversial. There is now quite a number of reports of patients with PTCS who have symptoms of raised ICP without signs, or signs of raised ICP without symptoms, or raised ICP without either signs or symptoms (Johnston et al., 2001). The important matter here is to be aware of these possibilities, although why or how such situations arise is also a question of considerable interest, even if not immediately relevant in the present context. The second sub-group (case #9) is more problematical but there seems little doubt, in the ways events unfolded, that this is a case of PTCS. It is also not the only case of this sort that we have encountered and there are also reports in the literature of ‘normal pressure PTCS’ (see Chapter 7). By analogy with hydrocephalus, such an occurrence is not altogether surprising. The third sub-group (cases #10 to #12) is somewhat problematic. The condition, variously named, in which infants show evidence of raised ICP without disturbance of function but with an enlarged subarachnoid space and often some degree of ventricular enlargement, is not uncommon. It is not usually classified with PTCS (see Chapter 3 and Johnston & Teo, 2000). In our view it is clearly a form of PTCS and the three illustrative cases have been selected to support that view. The first (case #10) is the common form of the condition although more investigative information than is usual was gathered in this instance. The usual clinical course was followed, there being spontaneous resolution. The second case (case #11) seemed at first to be likely to follow the same course but did not, showing worsening of the intracranial hypertension to the point of requiring treatment and appearing indistinguishable from ‘standard’ PTCS. The third case (case #12), reported in detail elsewhere (Johnston & Morgan, 1991), is of particular interest. Not only did he show the typical, apparently benign

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Nosology, nomenclature, and classification

head enlargement of infancy but he went on, over a decade later, to develop frank communicating hydrocephalus. During this time his mother and two of his sisters developed PTCS, the family, as a whole, strongly suggesting a link between the three conditions, that is PTCS, benign macrocephaly of infancy, and communicating hydrocephalus. Group IV

The first two cases included in this group underline the continuing relevance of the name ‘pseudotumor’. The first case (#13) in particular is noteworthy in that the diagnosis of PTCS seemed very appropriate. The time course was long and repeated investigations negative. Further, she demonstrated dramatically and tragically the different response to L
P shunting of a patient with PTCS and a patient with a diffuse increase in brain bulk. This case also has a bearing on the proposal by Salman (1999) that increased brain stiffness is important in preventing downward displacement after lumbar puncture in patients with PTCS, given the undoubted stiffness of the diffusely gliomatous brain. The second case (#14) also responded adversely to lumbar puncture after having benefited from the compensatory reduction in CSF volume by L
P shunt for a short period. As argued earlier, what would be expected from CSF drainage in a situation of diffuse increase in brain bulk would be only temporary improvement in the raised ICP. The final case (#15) is just one example of the very frequent occurrence of shunt obstruction with marked intracranial hypertension but without any visible enlargement of the CSF compartment on imaging studies
the PTCS situation. One question of particular interest is why ventricular enlargement occurs in some cases of hydrocephalus with shunt obstruction and not in others, a matter which bears on the mechanism of PTCS. This is clearly a complex issue as demonstrated particularly by the case discussed by Johnston & Teo (2000) where the same patient with hydrocephalus had two episodes of ventricular catheter obstruction in one week. With the first, she had quite marked ventricular enlargement, but on the second occasion the ventricles, which had returned to normal size after the first revision, remained normal despite marked intracranial hypertension. Conclusions In this chapter an attempt has been made to resolve the central issues in PTCS relating to nosology, nomenclature and classification, based on the conclusions from the preceding two chapters. In the first of these earlier chapters, a review of the history of the condition made it very clear how closely descriptions of the disease are wedded to identified causative factors, particularly cranial venous outflow impairment, middle ear and other infections, haematological and

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Conclusions

endocrine disorders, and more recently, certain drugs and vitamins. In the second of these chapters, the conclusion drawn was that PTCS is almost certainly due to an increase in intracranial fluid volume, and fluid that is at least readily and rapidly transferable into the CSF compartment. Where and how this excess fluid is accommodated in the active disease, and where it originates from, are matters still in dispute. The action of the various aetiological factors should be explicable within this theory and most are. In the present chapter then, the disease definition offered should be that of such a condition, and should take into account the variations in the effects that the different causative factors produce. The introduction of what are called the ‘modified Dandy criteria’ is a very recent development. In our view it is one that detracts rather than adds to the understanding of the condition, and the clinician’s ability to recognize it, by being too strict and exclusive. In addition, it is argued that another recent introduction
the name idiopathic intracranial hypertension
is unhelpful, and even confusing and inappropriate. Its use shows a lack of awareness of how the whole concept of pseudotumor developed historically quite apart from being etymologically suspect. The situation with PTCS is clearly analogous to that in hydrocephalus insofar as a significant number of cases of the latter are ‘idiopathic’, but this is not taken as a reason for applying a different term, as the clinical features, investigative findings, and particularly the treatment options are the same. So, in conclusion, we argue that the pseudotumor concept should be retained and should itself retain its long-standing range of included causes, and that the ‘modified Dandy criteria’ should be abandoned in favour of the kind of disease description that Dandy himself gave. It is on this basis that we offer the disease definition and classification above, the latter taking into account not only the several securely identified causal factors, but also closely related conditions with, we would argue, the same features and/or mechanism.

5

Aetiology

Introduction Several obstacles stand in the way of any attempt at a definitive analysis of the aetiology of PTCS. First, there is the issue of definition. If the concept of a condition properly called idiopathic intracranial hypertension (IIH) and the application of the so-called Dandy criteria are both rigidly adhered to, then any discussion of aetiology is necessarily going to be speculative and short. If, on the other hand, the broader concept of PTCS is accepted, the matter of aetiology becomes one of considerable importance, as well as being one of considerable complexity. It is this latter concept which is advanced in the present work, and is, moreover, de facto accepted in most of the literature on the subject, whatever actual term is used for the condition. In the first accounts of the syndrome a number of putative aetiological agents were identified and this number has been progressively added to over subsequent years. It is worth noting that the majority of the early recognized factors
for example, cranial venous outflow compromise, haematological disorders, non-specific infections, endocrine disturbances and minor head injury
have retained a place in the ever-growing list of possible aetiological factors. The secure identification of an aetiological agent in a particular case demands both careful history-taking and detailed investigation. The latter particularly is often lacking in reported cases, especially in relation to possible cranial venous outflow abnormalities, and also the haematological abnormalities which might underlie such problems. More generally, the identification of a specific aetiological agent requires, in broad terms, a demonstration that any presumed causal factor is not merely a chance association and, ideally, an explanation of how the putative causal agent acts to produce the condition. Specifically, there are four ways in which the desired demonstration and explanation can be achieved: 1. By statistical analysis of a relatively large number of cases using appropriately matched controls, i.e. case
control studies 82

83

Introduction

2. By the documention of cases in which the condition is closely connected in time with the presumed agent, resolves when the agent is no longer active, and recurs if the agent is again active. There should also be an absence of other possible aetiological factors and other treatment methods 3. By linking the presumed agent convincingly to the underlying mechanism of the condition 4. By appropriate experimental studies Even a cursory glance at this list gives some idea of the difficulties facing an adequate analysis of aetiology in PTCS. First, the relative rarity of the condition and the vagaries of referral make it almost impossible to gather a sufficient number of non-selected cases to provide the material for a case
control study. Second, the exigencies of treatment of the intracranial hypertension make it impossible to await the effects of controlling or withdrawing the presumed causative factor without taking other measures. Third, the continuing uncertainty about the precise pathophysiology of the PTCS introduces a significant element of speculation into any attempts to link a particular factor to the underlying disturbance producing the increase in CSF pressure. Fourth, there is the absence of any satisfactory experimental model with establishment of the basic parameters of the condition. These problems notwithstanding, a long list of presumed aetiological factors has emerged as shown in Table 5.1. Those with respect to which the causal link Table 5.1. Possible aetiological agents in PTCS

1. Female-specific factors • Obesity (particularly recent weight gain)a • Menstrual irregularity • Pregnancy • Exogenous oestrogens (contraceptive agents, HRT) • Polycystic ovary syndrome (PCOS) 2. Familiala 3. Cranial venous outflow obstruction or hypertension • Congenital abnormality of cranial venous outflow tract • Dural venous sinus compression or obstruction • Extracranial obstruction to cranial venous outflow • Intracranial venous hypertensiona 4. Haematological abnormalities • Anaemia (iron-deficiency, pernicious, aplastic) • Leukaemia • Polycythaemia • Myeloma

84

Aetiology Table 5.1. (cont.)

5.

6.

7. 8.

9.

10.

a b

• Platelet, factor and other abnormalities • POEMS (syndrome of peripheral neuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, and skin changes) Endocrine disorders • Thyroid (hypothyroidism, thyroid replacement therapy)a • Adrenal (hyperadrenalism, Addison’s disease, Cushing’s syndrome) • Parathyroid (hypoparathyroidism, pseudohypoparathyroidism) • Pituitary (growth hormone replacement therapy, acromegaly)a • Other (Turner’s syndrome, hypophosphatasia, adipisic hyponatraemia) Infections • Middle ear infection/mastoiditis (particularly with venous sinus involvement)a • Non-specific viral infection • Lyme disease • Chronic meningitis (syphilitic, brucella, cryptococcal) • Poliomyelitis, Guillain
Barre´ syndrome • Other viral (varicella, enterovirus 71, URTI) • Other bacterial (UTI, frontal/paranasal sinusitis, gastroenteritis, typhoid, psittacosis) Head injury Other diseases • Systemic lupus erythematosusa • Behc¸et’s diseasea • Renal diseasea • Cardiac and respiratory disorders (CCF, emphysema, Pickwickian syndrome) • Sleep disorders • Psychiatric disorders (depression, bulimia) • Enzyme deficiencies (galactosaemia, 11-beta-hydroxylase, alpha-chymotrypsin) • Miscellaneous (18 listed in the textb) Nutritional disorders • Rickets (vitamin D deficiency) • Malnutrition and renutrition (failure to thrive, deprivation dwarfism, cystic fibrosis) • Hypovitaminosis Aa Drugs and chemicals • Vitamin A and related substancesa • Steroidsa • Tetracycline and related compoundsa • Nalidixic acid • Other agents (danazol, lithium carbonate, perhexiline maleate, amiodarone, penicillin, ciprofloxacin, nitrofurantoin, nitroglycerin, mesalazine, and 15 agents with single case reports)

Well-accepted causal factors. See the section ‘Miscellaneous’ on p. 118.

85

Overview of aetiology in PTCS

is at least relatively well-established are indicated with an a. In considering the aetiology of PTCS, the present chapter will be divided into two sections. In the first, the question of aetiology will be looked at in a general way. That is, the focus will be on the incidence of the various factors and their relative frequency in various series. In the second, specific consideration will be given to each of the agents listed. An overview of aetiology in PTCS This overview of aetiology in PTCS is divided into four sub-sections. In the first, a summary of the findings from the Glasgow and Sydney series is given. These two series comprise a total of 264 patients and span a period of almost 60 years. The second sub-section presents the aetiological findings from a collection of large and relatively large series of PTCS patients reported during the period from 1954 to 1988. These series established the baseline for aetiological information but also included a number of factors about which doubt could be entertained as far as their causal role was concerned. The third sub-section summarizes four studies which appeared in the early 1990s, aimed at resolving some of the doubt and confusion. The purpose of these, using in three instances case
control methods (Ireland et al., 1990; Guiseffi et al., 1991; Radhakrishnan et al., 1993b), was to place concepts of aetiology on a more secure scientific footing. The remaining study specifically analysed the information on medications (Griffin, 1992). The fourth and final sub-section is an examination of all studies reported over the last 10 years which bear entirely or primarily on the issue of aetiology in PTCS. The Glasgow and Sydney series (Tables 5.2 and 5.3)

The Glasgow series comprises 116 patients diagnosed with PTCS at the West of Scotland Neurosurgical Unit, Killearn (subsequently the Institute of Neurological Sciences, Glasgow) between April 1942 and April 1972. This might be considered a relatively representative group of PTCS patients insofar as the unit in question was the only neurosurgical service for the region and the only place equipped to investigate patients with clinical evidence of intracranial hypertension. The Sydney series comprises 154 patients treated by one of the authors (I.J.) over the period from January 1974 to January 1999 at either the Royal Prince Alfred Hospital or the Royal Alexandra Hospital for Children. This is a less representative series in that it includes a relatively high proportion of both refractory cases secondarily referred because of the clinician’s interest in the condition, and of children because the RAHC was the major paediatric neurosurgery referral unit for the state of New South Wales.

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Aetiology Table 5.2. Incidence of aetiological factors: Glasgow series (n ¼ 116)

Aetiology No aetiology Aetiology Venous occlusion Ear infection Other infection Steroids Nalidixic acid Head injury Renal disease Anaemia Endocrine Other

Adult female

Adult male

Child female

Child male

Total

35 26 (1) 8 6 0 1 3 1 1 2 4

12 15 0 5 3 0 0 7 0 0 0 0

6 8 (1) 2 2 2 0 2 0 0 0 0

4 10 0 6 3 0 0 1 0 0 0 0

57 59 (2) 21 14 2 1 13 1 1 2 4

Table 5.3. Incidence of aetiological factors: Sydney series (n ¼ 154)

Aetiology No aetiology Aetiology Venous occlusion Ear infection Other infection Steroids Tetracycline Amoxil Vitamin A Head injury Renal Disease Endocrine Familial Multiple Other

Adult female

Adult male

Child female

Child male

Total

46 36 13 0 1 5 2 0 0 1 2 2 3 5 2

4 8 2 0 3 0 0 0 0 0 1 0 0 0 2

19 16 1 5 0 2 2 1 1 1 0 0 2 0 1

9 16 3 3 1 0 0 1 0 5 0 1 1 0 1

78 76 19 8 5 7 4 2 1 7 3 3 6 5 6

For the Glasgow series, the figures have changed slightly from those given by Johnston and Paterson (1974a) due to a re-working of the material. In this series, 56 of 116 cases (48.3%) were deemed to have had some aetiological factor (other than obesity or pregnancy) in their history at the time of the initial diagnosis of PTCS. In three of the four sex/age groups considered (male adults,

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Overview of aetiology in PTCS

male and female children), cases with a presumed aetiology outnumbered those without (33 to 22), the difference being most pronounced in male children. In female adults, only 23 of 61 patients (37.7%) were thought to have an aetiological factor. Of the remaining 38 female adults (62.3%), 25 (65.8%) were obese, three (7.9%) were pregnant at the time of diagnosis (two of the three were also obese) and eight (21.1%) had a history of menstrual irregularity. Six of the 23 female adults with an identifiable aetiology were also obese. In the other three sex/age groups, comprising 55 patients, only four were obese and all were females. Of the aetiological agents inculpated, middle ear infection was the most common, accounting for 21 of the 56 cases (37.5%) with an apparent aetiology. Middle ear infection was relatively evenly distributed across the sex/age groups and in two instances was associated with visible occlusion of one lateral sinus at the time of surgery for the ear disease. These are the two instances of venous occlusion recorded in parentheses in Table 5.2. The two other main aetiological factors were other infections (14 of 59, 23.7%) and minor head injury (13 of 59, 22.0%). In the Sydney series the proportion of cases with a presumed aetiological factor or factors identified at the time of diagnosis was almost identical to that of the Glasgow series: 49.4% compared to 48.3%. Considering the four sex/age groups, there was a preponderance of patients with a presumed aetiology in both male adults and male children whereas this was reversed in females particularly in female adults. Amongst all females, 52 (44.5%) had an apparent aetiology whilst 65 (55.5%) did not. In the patients without an apparent aetiology, there was, as in the Glasgow series, a marked preponderance of females: 65 of 78 cases (83.3%). Of the 46 adults in this group, 33 (71.7%) were obese and of the 19 children, five (26.3%) were obese. The individual factors identified in the five patients listed as having multiple aetiological factors were as follows: • Clotting abnormality, venous sinus thrombosis, familial, amiodarone, thyroid replacement, obesity • Idiopathic thrombocytopenic purpura, thyroid replacement, inderal, venous sinus occlusion • Chronic renal failure, superior sagittal sinus thrombosis • Recurrent URTI, steroids, multiple antibiotics, obesity • Systemic hypertension, topical steroids, non-steroidal anti-inflammatory drugs, anti-depressants In comparing the two series, the main points of similarity are, first, the close correspondence in the overall incidence of what are taken to be aetiological factors identified at the time of initial diagnosis. Second, there is the preponderance of patients with such an aetiological factor amongst males, and particularly

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Aetiology

amongst male children. Third, there is the high incidence, both absolute and relative, of obese female adults in the group of patients without an identifiable aetiological factor. The most striking difference between the two groups is the high incidence of cranial venous outflow tract pathology in the later series. The incidence given for the Sydney series is 12.3% overall
25.0% of patients with an identifiable aetiology and 36.1% of female adults in this category. The incidence of identifiable venous outflow tract abnormalities rose when later investigations, undertaken as part of a specific study, were included (Johnston et al., 2002). Of course, the discrepancy between the two series on this point largely reflects the improved diagnostic measures available during the later series and the increasing interest in attempting to demonstrate cranial venous outflow pathology in PTCS. Large series from 1954 to 1988

This was the period when reports of large and relatively large series of cases of PTCS established the basic features of the syndrome. Considering the larger reported series over this period which contain a breakdown of presumed aetiological factors, a total of 467 cases was collected from the following ten series: Zuidema and Cohen (1954), 54 cases; Foley (1955), 60 cases; Davidoff (1956), 61 cases; Bradshaw (1956), 42 cases; Rish and Meacham (1965), 34 cases; Boddie et al. (1974), 51 cases; Weisberg and Chutorian (1977), 38 cases; Bulens et al. (1979), 36 cases; Vassilouthis and Uttley (1979), 28 cases; Rush (1980), 63 cases. Of the 467 cases, 196 (42%) were deemed to have a recognizable aetiological agent, leaving 271 (58%) cases without any identifiable aetiology. The most common aetiological factor was middle ear disease with or without cranial venous sinus involvement (76 cases, 16.3%). Other factors in order of frequency were respiratory or other infection (45 cases, 9.6%), head injury (26 cases, 5.6%), steroids or other drugs (26 cases, 5.6%), endocrine disorders (10 cases, 2.1%), haematological disorders (3 cases) with a miscellaneous group of 10 cases. It should be noted, however, that there was a considerable variation between the series in the proportions of cases with and without a presumed aetiology. This variation is strikingly shown in three large series from the same period for which the absence of detailed information on aetiology precludes inclusion in the analysis given. Thus, Corbett et al. (1982) with 118 cases and Weisberg (1975a) with 120 cases found respectively 96 and 110 cases to be without identifiable aetiology whereas Greer (1968) found only 19 cases without a recognized aetiological agent in a series of 105 cases. In part, these discrepancies reflect a reluctance or otherwise to impute an ‘endocrinological’ aetiology to cases with menstrual irregularity and obesity. Apart from this, however, a real discrepancy does exist.

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Overview of aetiology in PTCS

Two groups which, to some degree, merit special attention are men and children. In the series referred to above, there is the usual female preponderance, but in all cases there is no subdivision of aetiological factors according to age or sex. In the one study which examines aetiology in men specifically, Digre and Corbett (1988) found the following distribution: no aetiology, 16; head injury, six; drugs, four (tetracycline, two; vitamin A, two); thyroid disease, two; DLE, one; body building (!), one. There was a close correspondence to an otherwise (than gender) comparable group of females apart from a higher incidence of head injury (six males, one female) and the incidence of pregnancy and use of the contraceptive pill in females (five cases). With respect to children, a summary of the findings from six series concerning children only (Greer, 1962; Lecks & Baker, 1965; Greer, 1967; Rose & Matson, 1967; Grant, 1971; Couch et al., 1985), yielding a total of 171 cases, showed a preponderance of patients with an identifiable aetiological factor (106, 61.2%). The majority of these were cases attributed to ear disease (45 of 106, 42.5%). In part, at least, the high incidence of ear disease must reflect the fact that five of the six reports were from 1971 or earlier. The other individual factors identified were respiratory or other infection, 21 of 106 (19.8%); drugs (particularly steroids), 15 of 106 (14.2%); head injury, nine of 106 (8.5%); psychosocial and/or nutritional deprivation, six of 106 (5.7%); cystic fibrosis, four of 106 (3.8%); and haematological disorders, three of 106 (2.8%), leaving three of 106 as miscellaneous. Case
control and related studies

Dissatisfaction with the unsubstantiated nature of many of the claims of aetiological significance for various factors in PTCS led to attempts to introduce greater rigour into the analysis of putative factors. In the first of the three case
control studies from the early 1990s, Ireland et al. (1990) included 40 patients with a diagnosis of IIH (PTCS) whom they compared with 39 ageand sex-matched controls. Attention was directed at all the major postulated causes of IIH (PTCS) including the various other diseases and conditions, allergies, and medications or chemicals hitherto associated with the condition. In particular, attention was directed at the co-existence of menstrual irregularities, pregnancy, and the use of oral contraceptives. No evidence of an increased frequency of any of these factors was found in the IIH (PTCS) group. In fact, the only positive associations were with obesity, recent weight gain, and systemic hypertension. The study has, however, significant limitations as the authors clearly realize. First, the number of cases is small. Second, they are all adult females which obviously limits the study’s relevance to the aetiology of PTCS in general. Third, only 40 of 63 patients approached actually responded to the questionnaire. There is, too, the problem of recall bias which the authors also acknowledge.

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Aetiology

The second study, similar in scope and magnitude, is that of Guiseffi et al. (1991). These authors included 50 cases diagnosed with IIH (PTCS) whom they compared with 100 age- and sex-matched controls. In terms of aetiology, the findings were also similar to the previous study in that only obesity and recent weight gain were found to have a significant association with IIH (PTCS). They concluded that the apparent association with systemic hypertension did not hold up when obesity was controlled for and when the likelihood of spuriously high readings due to the use of a standard sphygmomanometer cuff in obese patients was taken into account. This study is open to the same criticisms as those levelled against the study of Ireland et al. (1990). Although the number of cases is slightly greater and some males as well as some children in the second decade are included, the group studied is still skewed in the direction of women in their reproductive years. The third study is that of Radhakrishnan et al. (1993b) in which data was collected from 40 consecutive IIH (PTCS) patients, all females, and compared with data from 80 ‘related and unrelated (hospitalized) females’. These authors confirmed the association between IIH (PTCS) and both obesity and recent weight gain but not that between IIH (PTCS) and arterial hypertension. On the matter of menstrual irregularity, they write: ‘Patients more frequently reported a change in menstrual pattern in the year prior to reference time. Although a relationship to the pathogenesis of IIH (PTCS) is at present uncertain, changes in the menstrual pattern shortly before the diagnosis were noted frequently in the case
control study by Ireland et al. (1990), as well.’ Despite their shortcomings, these three studies do, however, draw attention to the dangers of reaching conclusions about the aetiology of PTCS on the basis of inadequate and unsatisfactory information, as well as demonstrating one way in which more secure conclusions could be reached if a sufficiently large number of truly representative cases could be studied. The fourth study to be considered here is that of Griffin (1992) which is directed at identifying drugs and other chemicals that might have an aetiological role in PTCS. This study uses the data from large-scale surveys and reports of adverse drug reactions as well as reports from the literature more generally. Griffin’s conclusion is that the frequency of reported associations with the following short list of agents is sufficient to at least raise the question of whether they might be true causative factors in PTCS or may be causative in subjects who are particularly susceptible in some undefined way. The list is: tetracycline and minocycline; vitamin A and retinoid analogues; these two groups used in combination; danazol; steroids; lithium carbonate; ethinyl oestradiol; thyroid replacement medications; nalidixic acid. As the author points out, however, it is difficult to frame any hypothesis about these agents which links them to PTCS through some common mechanism.

91

Overview of aetiology in PTCS

The conclusions from these studies, promising as they are in concept, are somewhat disappointing. In the three case
control studies, only obesity and recent weight gain have been shown to have a significant aetiological connection with PTCS (or at least the IIH sub-group), although how these factors operate is not addressed in the studies. In the detailed analysis of reported drug effects, the well-known agents appear, but again there is no indication of how, in whom, or with what frequency, they might operate. Recent developments in the aetiology of PTCS

In reviewing the literature on the aetiology of PTCS over the last decade or so, that is, with the introduction of more modern scientific methods into the analysis, several things are immediately apparent. The first is that the aetiology of PTCS continues to be an actively investigated and reported on topic. The second is that the type of report continues to be, to a significant extent, the description of a single case or a small number of cases more or less speculatively linking the condition to the presumed aetiological agent. Thus, in a review of 234 papers primarily or substantially devoted to aetiology, more than one half are reports of a single case: 119 reports (50.9%). The only solid evidence for a causal connection is in those instances where withdrawal of the implicated agent or treatment of the associated condition by methods that do not themselves affect intracranial pressure leads to resolution of the intracranial hypertension. More convincing still are the occasional instances where re-introduction of the agent is associated with recurrence of the PTCS. Third, the great majority of reports over this recent period concern factors already identified as possibly causal in the PTCS. To some degree, with respect to these factors, the evidence for a causal connection has been strengthened, as will be discussed below, but for the most part it is rather a matter of a continuing accumulation of cases. Notable also is the absence of large general series of the kind considered in the section ‘Large series from 1954 to 1988’ on p. 88, considering, inter alia, the distribution of aetiological factors in the condition. There are, however, two reports addressing this issue specifically in children. The first is that of Scott et al. (1997) who collected 348 cases aged 18 years or less and found some associated and possibly causative factor in 185 (53.2%). The incidence was higher in the later series of Youroukos et al. (2000) who found some aetiological factor in 28 of 36 cases (77.7%) aged between three and one half and 14 years (20 males, 16 females). They did, however, include obesity as such a factor, although the most common factor was ear infection, as was found to be the case in earlier studies. The three factors having a well-established connection with PTCS that have been the particular focus of investigation over recent years are cranial

92

Aetiology

venous outflow compromise, obesity, and haematological abnormalities likely to cause thrombotic incidents. What is of interest is not only the additional evidence relating to these factors individually, but also the reports suggesting some connection between them (e.g. Glueck et al., 2005; Weksler, 2005). Each of these factors will be considered in detail in the second part of this chapter, but the important points to emerge from recent studies can be summarized as below. In the case of cranial venous outflow compromise, the evidence from some recent studies suggests that this might be a much more common aetiological factor than hitherto realized
indeed, in two studies even a claim for universality has been made (King et al., 1995; Karahalios et al., 1996). Doubt has, however, been introduced as to whether manometrically demonstrated cranial venous outflow tract hypertension is really primary in PTCS or, in fact, secondary to the increase in CSF pressure (King et al., 2002). Nonetheless, over recent years, there have been numerous reports of intra- and extra-cranial compromise of cranial venous outflow leading to a PTCS. Obesity, likewise, continues to be a focus of particular interest in the aetiology of PTCS. See, for example, Balcer et al. (1999) in children, Rowe and Sarkies (1999a), Bloomfield et al. (1997), Sugerman et al. (1997, 1999a,b), and Glueck et al. (2003, 2005). While the long-recognized association of obesity with PTCS in women in the reproductive period remains uncontested, there is the issue of what, precisely, the role of obesity is in causation. Does it act through increasing intracranial venous outflow pressure by increasing intra-abdominal pressure as Sugerman et al. (1997) suggest, or is there a relationship with other factors possibly increasing thrombophilia (Glueck et al., 2005). In fact, the issue of thrombophilia itself is of particular interest in that, apart from any connection with obesity, and apart also from overt thrombosis in the cranial venous outflow tract, it could be responsible for more subtle thrombotic episodes, escaping standard radiological detection, which nevertheless have an adverse effect on CSF absorption. Turning to reports of new agents to add to the already extensive list of possible causative factors in PTCS, the two factors that feature most prominently in recent reports are biosynthetic growth hormone (rhGH) and all-trans-retinoic acid (ATRA) in the treatment of leukaemia. The latter is, of course, linked to the wellestablished agent vitamin A. More generally, there is also increasing clinical evidence for a link between PTCS and two of the conditions for which these two agents are used: chronic renal failure and leukaemia. These matters will be considered further below. Other relatively recently claimed associations, simply listed here but considered further below, are, for conditions: sleep apnoea, cystinosis, typhoid, POEMS, familial hypomagnesaemia
hypercalciuria, HIV
AIDS, and cryptococcal meningitis; and for agents: mesalazine, desmopressin, fluticasone proprionate, and valproate.

93

Individual factors

Individual factors in the aetiology of PTCS These will be considered under the groupings listed in Table 5.1. Female-specific factors

The factors listed under this heading are obesity (including recent weight gain), the menarche, menstrual irregularity, pregnancy, exogenous oestrogens, and polycystic ovary syndrome. In the case of obesity, there has been a long-standing recognition of the high proportion of females in any sizeable non-selected group of patients with PTCS and also of the predominance of obese women aged between 18 and 50 years within this female sub-group. This predominance is particularly apparent when cases without any other identifiable aetiological factors are considered, as was shown, for example, by Foley (1955) who collected 60 such cases from the literature to which he added 31 cases of his own. Also, Wilson and Gardner (1966), in reviewing cases of PTCS seen at the Cleveland Clinic between 1935 and 1961, found 48 obese women between the ages of 20 and 40 years in 61 cases of PTCS. Our own findings were as follows. In the Glasgow series, taken to be unselected, there were 75 females (64.7%) and 41 males (35.3%). Of the females, 61 were adults (18 years or over) and of these 38 had no identifiable aetiological factor. Within this sub-group, 25 of the 38 were obese (65.8%), some markedly so, and seven of the 25 had a history of menstrual irregularity. In comparison, of the 23 adult females with an identifiable aetiological factor only five were obese and only one had a history of menstrual irregularity. The overall incidence of obesity in females was almost 50% (37 of 75) whereas in males it was zero (0 of 41). In the Sydney series, with a preponderance of refractory adult cases and paediatric cases, there was a relatively greater number of females (117 of 154, 75.9%) whilst 37 (24.1%) were males. Among the 117 females, there were 46 without any other identifiable aetiology and of these, 32 (69.6%) were obese compared with only one of 37 among males. In female patients with an identifiable aetiology, 11 of 36 adults and one of 16 children were obese in comparison with none of 24 males. The figures, then, for the incidence of obesity in adult females without other apparent aetiology were high, and also very similar in the two series: 65.8% and 69.6%, respectively. Even among adult female patients with an apparent aetiology, the incidence of obesity was relatively high in both series: 21.6% and 30.6% respectively. The significance of obesity (including recent weight gain) in females as an aetiological factor in PTCS was, in fact, the one thing that really held up in the three case
control studies referred to in the section ‘Case
control and related studies’, on p. 89. Much more contentious are the other female-specific factors: menarche, menstrual irregularity, pregnancy, and exogenous oestrogens.

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Aetiology

Of these four factors, the first three are discounted, being included under the heading of ‘associations no longer accepted’ in the recent review by Sussman et al. (1998). In fact, in the first of the three case
control studies, Ireland et al. (1990) wrote: ‘All forms of menstrual abnormalities, incidence of pregnancy, and the use of . . . oral contraceptives were equal in both groups (i.e. IIH and control groups). Each of these factors will be considered in more detail. Menarche

Greer (1964b) was the first to claim an association of PTCS with the menarche, reporting 10 girls aged between 11 and 13 years, all of whom had the onset of the condition at that time. One was also on high-dose vitamin A treatment. The clinical features were entirely characteristic of PTCS. Endocrine studies (such as were available at that time) were unremarkable, as in other cases of PTCS. A number of the girls subsequently had irregular menstruation and some had transient recurrence of symptoms during menstrual periods. Greer speculated here, as elsewhere, about the possible role of relative adrenal cortical insufficiency secondary to oestrogen over-production, but had no objective evidence to support this view. We found a further nine cases linked to the menarche in the 1013 cases from the literature review (Rish & Meacham, 1965; Rabinowicz et al., 1968; Hagberg & Sillanpaa, 1970; Janny et al., 1981; Tessler et al., 1985a,b). Apart from the Rish and Meacham (1965) report of four cases associated with the menarche in a series of 39 PTCS patients, the menarche does not feature as a possible aetiological connection in large series. Thus in three series totalling 119 children, there were no cases with such an apparent connection (Lecks & Baker, 1965; Rose & Matson, 1967; Grant, 1971). Likewise, in six large general series totalling 295 cases, there was no such connection (Zuidema & Cohen, 1954; Davidoff, 1956; Wilson & Gardner, 1966; Boddie et al., 1974; Bulens et al., 1979; Vassilouthis & Uttley, 1979). As, then, with a number of putative aetiological factors, there is no substantial evidence to link the menarche with PTCS. Menstrual irregularity

The same comment applies to menstrual irregularity per se, a factor which was discounted, for example, in the case
control series. However, there remains a definite clinical impression that a history of menstrual irregularity is a relatively common finding in the typical obese young woman with PTCS. More will be said on this below when the polycystic ovary syndrome is considered. Pregnancy

A number of writers have reported an association of PTCS with pregnancy, there being a total of 52 cases in the collected series of 1013 cases with an apparently

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Individual factors

identifiable aetiology. Also, in the Glasgow series, there were three cases who presented during pregnancy among the 61 adult females. Two of these patients were also obese and one had a past history of recurrent eclampsia. The most detailed study of the relationship between PTCS and pregnancy is that of Digre et al. (1984) who, in a retrospective analysis of 109 cases with PTCS presenting between 1966 and 1982, found 28 who had at least one pregnancy associated with PTCS. They identified three groups: those with onset during pregnancy (11 cases); those with onset prior to pregnancy but with recurrence during pregnancy (five cases); those with onset prior to pregnancy but without recurrence during pregnancy (12 cases). The majority of cases occurring during pregnancy did so during the first trimester (81.8%), the remainder occurring during the second trimester. In other reports, Greer (1963b) described eight cases of PTCS associated with pregnancy, the majority occurring in the second trimester. All eight patients showed rapid resolution, in four cases without treatment, whilst one recurred. Koontz et al. (1983) subsequently described nine cases of PTCS associated with pregnancy, five with onset during pregnancy (4
20 weeks) and four with onset prior to pregnancy in whom the condition worsened with the advent of pregnancy. Seven of the nine patients went on to normal delivery, one had a spontaneous abortion, and one had a termination due to progressive worsening of the PTCS. These authors found that those cases which persisted through pregnancy resolved rapidly after parturition, and that recurrence in subsequent pregnancies was very unusual, there being only three reported cases. Nickerson and Kirk (1965) reported two cases of PTCS recurring during pregnancy, the first occurring on both occasions during the fourth month of the third and fourth pregnancies and the second in the third and fifth pregnancies, the former ending in a spontaneous abortion. Other reports of PTCS in pregnancy include seven reports of single cases and reports of two (Bashiri et al., 1996), three (Peterson & Kelly, 1985), and four (Kassam et al., 1983) cases. Recently, in their study of polycystic ovary syndrome (PCOS) and PTCS which will be considered more fully below, Glueck and his colleagues (Glueck et al., 2003) found four instances of pregnancy in their first series of 38 cases (10.5%) and five instances of pregnancy (7.7%) in their second series of 65 cases (Glueck et al., 2005). Finally, Deev et al. (1995), in a Russian study seen only in abstract, identified pregnancy as an aetiological factor in 17 of 76 females (22.4%) in a series of 80 patients with PTCS. Exogenous oestrogens

The association of PTCS with oral contraceptives dates back to the report of Walsh et al. (1965) who described four patients with neurological complications attributed to these agents. In one of the four cases the complication was PTCS. In the collected series of 1013 cases of PTCS with identifiable aetiology, there were

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18 cases attributed to oral contraceptives, whilst Corbett et al. (1982) reported seven cases in their series of 118 patients with PTCS. It should also be mentioned that in one series of patients with superior sagittal sinus thrombosis, there were two on oral contraceptives (Thron et al., 1986). Nevertheless, oral contraceptives were discounted as aetiological factors in PTCS in the three case
control studies referred to earlier (Ireland et al., 1990; Giuseffi et al., 1991; Radhakrishnan et al., 1993b). This may be due more to the failings of these studies than the absence of a connection, particularly given the established association of these agents with cerebral venous thrombosis (de Bruijin et al., 1998). In fact, Glueck and his colleagues found 23 of the 38 cases in their first series of PTCS patients were on exogenous oestrogens and 18 of 65 patients in their series of PTCS patients were on oestrogen/progesterone contraceptives (Glueck et al., 2003, 2005). In addition, PTCS is accepted as an uncommon complication of contraceptive implants (e.g. Singh & Chye, 1998), there being 39 cases in the review of Norplant reports (Wyskowski & Green, 1995). Recently, also, Ivancic and Pfadenhauer (2004) described a case of PTCS which they attributed to hormonal emergency contraception. Apart from contraceptives, there is also the suggestion that hormone replacement therapy (HRT) may be an aetiologically significant factor in PTCS. Thus, Glueck et al. (2005) in their second series of cases, found six of the 65 women (9%) were on HRT at the time of diagnosis. Polycystic ovary syndrome (PCOS)

This is a recently identified association with PTCS due to the work of Glueck and colleagues referred to above. They reported two separate series of cases in which women with known PTCS (IIH) were investigated for PCOS as well as blood factor abnormalities conducive to thrombophilia. In the first series (Glueck et al., 2003), there were 38 women with established PTCS (IIH). In this series, four men and two women were excluded, the latter because one had SLE and the other had a contraceptive implant. Of these 38 women, 15 (39%) were found to have PCOS which the authors described as, ‘. . . a marked enrichment over the general unselected female population, in which the prevalence is estimated to be 7%’. In this group of 15 women, 14 were obese (BMI 430 kgm
2), 10 extremely so (BMI 40 or greater). In the second series, which comprised 65 women with PTCS (IIH), 10 men having been excluded (Glueck et al., 2005), the figure was higher: 37 of 65 (57%). Again, obesity was marked in this sub-group with 16 (43%) being obese and 19 (51%) extremely obese. The figures for the women without PCOS were 16 obese (57%) and six extremely obese (21%). The basis of the authors’ hypothesis is that PCOS and also morbid obesity, which is common in women with PCOS as it is in women with PTCS, lead to paradoxically high levels of endogenous oestradiol which, they say, ‘. . . could superimpose endogenous oestrogen-mediated

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Individual factors

thrombophilia on hereditable thrombophilia, hypo-fibrinolysis, or both, in severely obese women with PCOS and concurrent IIH’. In concluding this section, an attempt will be made to identify mechanisms through which these factors might act in the causation of PTCS and to suggest how the factors may be linked together. In considering obesity specifically, and trying to identify what aetiological role it may have in PTCS, there are four aspects which must be taken into account: 1. Obesity in PTCS is, to a significant extent, limited to women in their reproductive years. 2. Obese women in this age group who do develop PTCS represent only a minute fraction of the overall number of obese women. 3. Obesity is predominantly found in women with PTCS who have no other identifiable aetiological factor. 4. There is no evidence to connect obesity to PTCS in children (Balcer et al., 1999) or in men. These facts make it difficult to advance any theory which puts obesity per se at the centre of aetiological considerations. Nonetheless, this is what is done by a number of recent investigators (e.g. Sugerman et al., 1999a,b) who postulate that obesity acts through increasing intra-abdominal pressure thereby increasing cranial venous outflow tract pressure which in turn adversely affects CSF absorption. This claim is based on two findings. First, there is the direct measurement of an increase in the relevant pressures in PTCS in obese women. Second, there is the evidence of improvement in, or resolution of, the condition with successful treatment of the obesity. The first finding must be accepted as a valid observation whilst the second could be accounted for by the improvement in obesity alone whatever way this effect is mediated. An example of the second point is the recent suggestion by Glueck and his associates that obesity acts through adversely affecting blood coagulation mechanisms in the direction of thrombophilia in susceptible women by altering endogenous oestrogen levels (Glueck et al., 2003, 2005). In their view the susceptibility applies to the propensity for thrombophilia but could also apply to other factors. For example, Donaldson (1979, 1981) has suggested the possibility of increased CSF production mediated through endogenous oestrogens, supporting this view with the demonstration of oestrone in the CSF in a small group of patients with PTCS. His theory involves the extra-ovarian production of oestrogen by adipocytes. Of course, these several mechanisms could all act in concert. There is also the suggestion that the obesity itself may be due to intracranial hypertension (Jain & Rosner, 1992; Hannerz et al., 1995). Turning to the other factors included in this section
menarche, irregular menstruation, pregnancy, exogenous oestrogens, and polycystic ovary

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syndrome
it is, we believe, reasonable to assume on current evidence that all are to some extent implicated in the aetiology of PTCS, the results of the incompletely investigated small samples of cases in the case
control studies considered earlier notwithstanding. Possible mechanisms are the direct effect of obesity on cranial venous outflow pressures and on the production of endogenous oestrogens, the effects of an excess of endogenous oestrogens however produced and associated, for example, with menarche, irregular menstruation, pregnancy, and PCOS on coagulation mechanisms, and the similar effects of exogenous oestrogens used as contraceptive agents or in HRT. Familial

Since the first report by Buchheit et al. (1969) on the familial incidence of PTCS, at least 12 further reports have appeared as listed in Table 5.4. This table also includes two additional unreported instances of our own, making a total of 14 instances of two to four members of the same family being affected by PTCS. In 11 of the Table 5.4. Reports of familial cases of PTCS (listed under first author only)

Report

Number and sex

Number of generations Comment

Buchheit (1969) Howe (1973) Rothner (1974) Traviesa (1976) Shapiro (1980)

2F 2F 1F, 1M 3F 2F

1 1 2 1 2

Coffey (1982)

2F

1

Torlai (1989) Johnston (1991)

2M 4F

1 2

Kharode (1992) Rogel Ortiz (1994) Gardner (1995) Fujiwara (1997) Santinelli (1998)

2F 1M, 1F 2M 2F 1F, 2M

2 2 1 1 2

Johnston (unreported cases)

4F, 1M

1

Obese sisters Obese sisters Mother and son, both obese 3 obese sisters (2 with menstrual disturbance) Mother and daughter, both obese, empty sella in mother 2 sisters with depression (one on oral contraceptives) Homozygous male twins (onset same time) Obese mother, 3 daughters, 2 obese, 1 not, 1 son with communicating hydrocepalus Mother and daughter (obesity, asthma) Father and daughter Fraternal twins, both obese and on tetracycline Homozygous twin sisters Mother (not obese, empty sella) and 2 sons with PTCS as children (14 and 9 years) (i) 2 adult sisters, one with multiple factors (ii) 3 siblings: 2 obese adolescent sisters, 1 with congenital narrowing of the jugular foramina, 1 non-obese brother, onset aged 7

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Individual factors

14 instances, the affected family members are from the same generation whilst in the other four instances they are from two successive generations. Within the group overall there are three pairs of twins, two heterozygous and one homozygous. The total number of cases comes to 35 with 28 females and seven males. Apart from establishing the occurrence of a familial form of PTCS, there is little that can be concluded from these cases, particularly with regard to the mode of transmission and what it is that is actually inherited. Nevertheless, there are some notable points. The first is the high incidence of obesity in the female cases, 17 of 26 where this information is available, compared to only one of seven in the male cases. Second, there is the role of several of the other well-known aetiological and related factors. These include tetracycline in two cases, depression in two cases, oral contraceptives in one case (also with depression), congenital narrowing of the jugular foramina with cranial venous outflow hypertension in one case, and multiple factors (clotting abnormality, venous sinus thrombosis, amiodarone therapy, and thyroid replacement therapy) in one case as well a menstrual irregularity in two cases. Indeed, the small series of 35 cases is a microcosm of any large unselected series of patients with PTCS: a high proportion of females with the majority being obese, a similar age profile, and a similar scattering of aetiological factors with instances of several occurring in the same patient. Third, there is the coincidence in one family of an obese mother and three of four daughters (two obese) with PTCS, and a son with communicating hydrocephalus who, in the first year of life, was diagnosed as idiopathic megalencephaly (Johnston & Morgan, 1991). In general, then, it might be suggested that what is inherited is some incapacity of the CSF absorptive mechanism which may require an additional triggering factor or factors to become clinically manifest as intracranial hypertension. Perhaps if the CSF absorptive capacities of relatives of patients with PTCS were to be examined in comparison with a control group, there might be a demonstrable difference due to some genetically determined factor. Cranial venous outflow tract compromise

An aetiological link between cranial venous outflow tract compromise and PTCS has been recognized since the earliest descriptions of the latter condition. It is, moreover, a link which has come into particular focus at certain times in the history of the study of PTCS. The first was when it was recognized that transverse sinus thrombosis was an important component of acute or chronic middle ear infection which itself was an important cause of PTCS in the first decades of last century. The second was with the introduction of direct sinography by Frenckner in 1937 and its subsequent use specifically for PTCS by Ray and Dunbar (1950, 1951). And the third is currently, with the

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development of highly sophisticated methods of delineating the cerebral venous outflow tract structurally and analysing it functionally utilizing MRV and retrograde venography with manometry. This focus is particularly relevant now, with the availability of direct microcatheter approaches to sinus occlusion and venous stenting which provide an important treatment option in certain cases of PTCS. Whilst there is no doubting the causal link between cranial venous outflow tract hypertension, either secondary to obstruction or otherwise, and PTCS, uncertainty remains on at least three aspects of this relationship. The first is the exact nature of the causal sequence, the second is the relative incidence of cranial venous outflow obstruction or hypertension in PTCS, and the third is whether measured cranial venous outflow tract hypertension and observed structural abnormalities of the tract itself are secondary to the intracranial hypertension rather than its cause. These and related issues will be discussed further in Chapter 10. Our intention in this chapter on aetiology is to outline the range of causes which may themselves be causes of cranial venous outflow tract hypertension and to summarize the relative importance of these identified causes in the overall incidence of PTCS. The various conditions, divided primarily on an anatomical basis, which may give rise to impaired cranial venous outflow are listed in Table 5.5. With respect to the three anatomical subdivisions, intracranial venous sinus pathology causative of PTCS is virtually restricted to the major superficial sinuses (superior sagittal, transverse, and sigmoid) although there is one report of PTCS following compromise of the straight sinus secondary to embolisation of a vein of Galen AVM (Kollar & Johnston, 1999). At the craniocervical junction the involvement is limited to the distal sigmoid sinuses and origin of the internal jugular veins, whilst extracranially it may be of the internal jugular or brachiocephalic veins, the superior vena cava, or the right atrium. A brief comment only will be made on each of the listed causative factors, bearing in mind Woodhall’s (1936) finding that in a significant number of people one transverse sinus is essentially rudimentary, which may render individuals so affected particularly susceptible to some of the listed factors. The incidence of developmental abnormalities of the cranial venous sinuses is unknown. In relation to PTCS, George et al. (1984) found five cases of developmental abnormalities with sinus obstruction in 10 cases of PTCS. In three cases, the cause was craniostenosis and in two cases hypoplasia. There is also the case described by van der Bergh et al. (1984) of anomalous venous drainage in Aarskog’s syndrome with PTCS who showed on angiography absence of the straight sinus, an abnormally large vein of Galen and a defect in the superior sagittal sinus. Apart from these specific cases, there is the point that a number of structural changes seen in recent

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Individual factors Table 5.5. Causes of cranial venous outflow impairment

Intracranial obstruction or hypertension • Developmental: hypoplasia, septa, congenital narrowing, craniostenosis • Trauma: depressed skull fracture, extradural haematoma • Infection: middle ear disease + mastoiditis • Neoplasia: primary or secondary, intraluminal obstruction or extraluminal compression (or both) • Thrombosis: primary blood dyscrasias, exogenous oestrogens, other diseases (SLE, Behc¸et’s disease) • Dural AVMs with sinus thrombosis • Surgical occlusion • High-flow parenchymal AVMs Craniocervical junction obstruction • Congenital narrowing of jugular foramina • Glomus jugulare tumours Extracranial obstruction or hypertension • Thrombosis: involving internal jugular or brachiocephalic veins secondary to infection or cannulation • Surgical ligation: internal jugular vein(s) (radical neck dissection, other reasons) • Neoplasia: compression of internal jugular veins, superior vena cava • High right atrial pressure: right heart failure

studies (see Owler et al., 2005) may be of developmental origin. A preliminary post-mortem study with this possibility in mind showed cases of septum formation in otherwise normal transverse sinuses (Subramanian et al., 2004). A number of traumatic cases has been described in which a depressed skull fracture impinges on either the superior sagittal or one of the transverse sinuses (e.g. Uzan et al., 1998). There is also a case of PTCS attributed to compression of a dominant transverse sinus by a relatively small occipital extradural haematoma (Owler & Besser, 2005). Infection is particularly represented by middle ear infection and mastoiditis in which there is a significant but unknown incidence of secondary transverse sinus thrombosis. The patient is presumably more likely to develop PTCS if a dominant transverse sinus is involved. It is clear from the early reports, however, that PTCS secondary to middle ear disease can occur without overt transverse sinus involvement (Hamberger, 1946; Ray & Dunbar, 1951; Davidoff, 1956; Greer & Beck, 1963). It is also clear that where a transverse sinus is involved, the thrombotic process can extend to the superior sagittal sinus (Frenckner, 1937; Greer & Beck, 1963). Neoplastic disease can cause partial or complete sinus obstruction, either by intraluminal occlusion or by

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extraluminal compression. Reported examples include torcular epidermoids (Kuker et al., 1997; Lam et al., 2001), cholesteatoma (Powers et al., 1986), metastatic tumours (Plant et al., 1991; Kim & Trobe, 2000), and meningioma (Soma et al., 1996). Thrombosis with complete or partial occlusion of one or more venous sinuses may be due to a variety of factors including primary blood dyscrasias (D’Avella et al., 1980), exogenous oestrogens (de Bruijin et al., 1998; Glueck et al., 2005) and other diseases associated with a thrombotic tendency such as SLE (Shiozawa et al., 1986; Parnass et al., 1987) and Behc¸et’s disease (Ibrahimi et al., 1983; Harper et al., 1985). In the latter two instances, there may or may not be demonstrable sinus involvement with PTCS. Green et al. (1995), in a review of 21 cases of SLE with PTCS (18 from the literature and three of their own), found evidence of a hypercoagulation state in 58% and suggested this might be occurring even where frank sinus involvement is not present. Dural AVMs have a well-documented association with PTCS probably mediated through major venous sinus thrombosis (Cognard et al., 1998). Surgical damage to a transverse sinus with thrombosis was recorded in five of 107 cases following translabyrinthine and suboccipital craniectomy by Keiper et al. (1999). One case in the Sydney series developed PTCS due to occlusion of a sigmoid sinus during repair of a posterior fossa bony defect causing recurrent meningitis. High-flow parenchymal AVMs can also cause PTCS, presumably by raising intrasinus pressure (Weisberg et al., 1977; D’Avella et al., 1980; Convers et al., 1986). Involvement of the cranial venous outflow tract at the skull base causing PTCS is rare. Two identified examples are, firstly, compression of the distal sigmoid sinus/proximal internal jugular vein by a glomus jugulare tumour (Beck et al., 1979; Angeli et al., 1994) or damage to these structures during surgical removal of the tumour (Johnston, unpublished), and secondly, congenital narrowing of the jugular foramina bilaterally (see the section on familial cases above). This latter has also been implicated as a cause of hydrocephalus in achondroplasia (Lundar et al., 1990). Extracranial causes of cranial venous outflow impairment, whilst not frequent, are well documented, and may clearly be associated with the development of PTCS. Such causes include unilateral or bilateral surgical ligation of the internal jugular veins, in early cases for middle ear disease (Liedler, 1928; Evans, 1942) and later during radical neck dissection (Sugarbaker & Wiley, 1951; Marr & Chambers, 1961; Fitz-Hugh et al., 1966), involvement of the internal jugular veins in tumours, e.g. rhabdomyosarcoma (Kikuchi et al., 1999), thrombosis of either the jugular or brachiocephalic veins due to cannulation (Molina et al., 1998), superior vena cava syndrome and right heart compromise (see the section ‘Other diseases and conditions’ on p. 115).

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Individual factors

In concluding this sub-section, something must be said about the complex, and as yet unresolved, question of the actual incidence of cranial venous outflow impairment as an aetiological factor in PTCS. This issue is relevant to clinical practice in that it is the key factor in determining how far abnormalities of the cranial venous outflow tract should be pursued in the investigation of patients with PTCS. This is a matter which was brought into particularly sharp focus by the two studies in the mid-1990s referred to earlier which purported to show a very high (King et al., 1995) or even universal (Karahalios et al., 1996) incidence of cranial venous outflow pathology in PTCS. Now, a decade on, these studies are unconvincing. The authors of the first paper published a follow-up study retracting their earlier conclusion, claiming instead that the noted increases in cranial venous outflow pressures were secondary to the intracranial hypertension rather than primary and causative (King et al., 2002). The authors of the second study have not followed up their initial report of 10 cases. The response to the second paper by King et al. (2002) was varied. In an editorial, Corbett and Digre (2002), whilst acknowledging the complexity of the issue and also that the measured elevation of intra-sinus pressure, although secondary, might contribute to the perpetuation of intracranial hypertension, basically accepted the volte face. On the other hand, two of the three letters published in response to the second paper by King et al. maintained the position that the observed structural abnormalities in the transverse sinuses were, indeed, of primary importance in the development of PTCS (Quattrone et al., 2002; Higgins & Pickard, 2002). Both these groups published evidence elsewhere to support their views (Quattrone et al., 2001; Higgins et al., 2004). It is this view that has found practical expression in the treatment of demonstrated structural abnormalities by venous stenting which has been found successful, at least in the short term, in two small groups of cases from Cambridge and Sydney (Owler et al., 2005). There are also the claims of the advocates of bariatric surgery in the treatment of PTCS in markedly obese patients that the lowering of intra-abdominal pressure corrects cranial venous outflow tract hypertension and allows resolution of PTCS which is secondary to this (Sugerman et al., 1999b). As for structural studies, the results are also conflicting. Thus, Lee and Brazis (2000), in a prospective study of 22 consecutive young obese women with IIH (PTCS), found none with evidence of cranial venous outflow tract pathology on MRV examination. In contrast, Farb et al. (2003), who carried out a prospective study of 29 patients with IIH (PTCS)
21 females of whom 18 were obese and eight males of whom five were obese
using sophisticated MR and MRV techniques, found what they described as ‘substantial bilateral sinovenous stenoses’ in 27 of the 29 patients with IIH compared with four of 59 controls. Another positive study was that of Higgins et al. (2003) who examined 20 patients

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Aetiology

with PTCS and 40 control subjects (matched for age and sex). In the PTCS patients there were bilateral transverse sinus flow gaps in 13 (65%) and only one patient with entirely normal transverse sinuses whereas there were no flow gaps in the transverse sinuses in any of the controls who were absolutely asymptomatic with no history of significant headache. Further, in a large series of 188 patients with PTCS investigated with various methods over the period 1968 to 1999, there was an overall incidence of cranial venous outflow tract pathology in 19.7% which rose to 31.0% (27 of 87) when only the last decade was considered (Johnston et al., 2002). In addition, in a number of these cases the demonstration of cranial venous outflow tract abnormalities was made as part of a follow-up study after the raised ICP had been treated. A provisional conclusion is that there is a significant incidence of cranial venous outflow tract abnormalities in PTCS, the actual incidence in any group of cases depending on how assiduously such pathology is sought, and what techniques are available and employed. It may be that in a proportion of such cases the demonstrated abnormalities are secondary to the raised intracranial pressure rather than primary and causative, but this does not mean that they are not contributing to the elevation of CSF pressure at the time of their recognition. For practical purposes, then, this presumptive significant incidence should be taken into account in investigating all patients with PTCS, or at least all those who do not readily respond to simple measures, and this is especially so now that there is increasing evidence to support the efficacy of direct methods of treatment of cranial venous outflow abnormalities (Owler et al., 2005). Haematological disorders

Haematological disorders as a whole constitute a very uncommon cause of PTCS. Indeed, of the 1013 cases with an identifiable aetiology collected from the literature, only 37 were considered to have a haematological disorder as an aetiological factor, either entirely or in part. This is a particularly low incidence, especially when viewed in the light of the frequent occurrence of a number of these diseases such as iron-deficiency anaemia. Among the haematological conditions accorded causal significance, anaemia was the most common with 15 cases. Next was polycythaemia vera with eight cases, then platelet disorders with six cases, and finally, a miscellaneous group of eight cases which included one case of leukaemia. The picture is, however, a rapidly changing one. Primarily, this is to do with the increasing recognition of the occurrence of abnormalities in factors and other plasma constituents (Sussman et al., 1997; Dunkley & Johnston, 2004; Glueck et al., 2003, 2005
vide infra). Also, there is the increasing number of cases of PTCS reported in association with leukaemia, although these relate for the most

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Individual factors

part to treatment agents rather than the disease itself. Each of the haematological subgroups listed will be considered in order. Anaemia, the largest subgroup, is most commonly of the iron-deficiency type, accounting for 13 of the 15 collected cases, the other two being pernicious anaemia. All but one of the cases with iron-deficiency anaemia were single case reports (Lubeck, 1959; Ikkala & Laitinen, 1963; Aoki, 1985) or a single case in a larger series (Boddie et al., 1974; Weisberg, 1975a; Spence et al., 1980; Couch et al., 1985). The exception was the report of two cases by Buenaventura et al. (1984). There were two single-case reports of PTCS in association with pernicious anaemia, that of Reid and Harris (1951) and that of Murphy and Costanzi (1969). In the combined Glasgow and Sydney series (270 cases), there were two cases attributed to anaemia: one to iron-deficiency anaemia and one to a combined iron-deficiency and pernicious anaemia. Neither with iron-deficiency anaemia nor with pernicious anaemia is there any clear indication of the nature of a possible causal connection. Moreover, in a number of the reported cases there is some other factor, not itself definitely connected with the anaemia, which may have been related to PTCS. A notable example is superior sagittal sinus occlusion in Aoki’s case. However, in favour of a causal role for the anaemia, there is strong tendency towards a rapid response of the intracranial hypertension to the treatment of the anaemia, both with iron-deficiency as described by Lubeck (1959) for his own case and 11 other cases collected from the literature, and with B12 as described by Reid and Harris (1951) in their single case. Since the 1992 analysis (Johnston, 1992), there have been several additional reports including that of Biousse et al. (2003) who reported six cases of PTCS linked to iron-deficiency anaemia and collected a further 30 cases from the literature of which 13 were excluded because of either another possible aetiological factor (11 cases) or cerebral venous thrombosis (two cases). Yetgin et al. (2006) reported a single case of a child with recurrent pseudotumor cerebri and vitamin B12 deficiency. Taylor et al. (2002) reported one case of haemolytic anaemia presenting as PTCS whilst there were two reports linking PTCS to aplastic anaemia
that of Nazir and Siatkowski (2003) who described one idiopathic case and added one case from the literature, and that of Jeng et al. (2002) who described two cases of acquired haemolytic anaemia both of whom required other treatment apart from correction of their anaemia to control intracranial hypertension. Leukaemia accounted for only one of the 37 haematological cases in 1013 collected cases of the 1992 review. To this case may be added three cases from the combined Glasgow/Sydney series, although one of these three patients was on a tapering dose of steroids at the time of diagnosis of PTCS whilst the other two patients had not long finished courses of steroids. Recently, however, there has been a number of reports of PTCS in association with leukaemia. In at least two

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Aetiology

instances the relation was made between PTCS and leukaemia per se (Saitoh et al., 2000; Pavithran & Thomas, 2002) but in the large majority of instances PTCS has been attributed to one of the treatment agents or methods. Most commonly this is all-trans-retinoic acid (ATRA), but arsenic trioxide, cyclosporin A, cytarabine hydrochloride, and bone marrow transplantation (BMT) have also all been implicated. In a series of 107 patients treated by the GIMEMA-AIEOP AIDA protocol for acute promyelocytic leukaemia, reported by Testi et al. (2005), PTCS occurred in 10 cases. The pattern with reported cases attributed to ATRA is that PTCS resolves when the drug is withdrawn. Myeloma and POEMS have both been implicated in the aetiology of PTCS but on the basis of very few cases. Thus, Wasan et al. (1992) described three cases of BIH (PTCS) in association with myeloma but did not speculate on mechanism. In two of their three cases the PTCS did respond to treatment of the myeloma although both required additional treatment. The two reports of POEMS (itself, of course, a rare condition) in association with PTCS suggest a high incidence of the latter in patients with the former, but again on the basis of very few cases (Casale Turu et al., 1992; de la Pena et al., 1996). Polycythaemia vera has also been reported in relation to PTCS, albeit rarely. Drew and Grant (1945) described a single case of polycythaemia vera with persistent papilloedema going on to optic atrophy and unilateral blindness over a 2-year period. They refer to 17 previous cases in the literature starting with the report by Knapp in the nineteenth century. De Schweinitz and Woods (1925), who identified Behr’s 1911 report as the first, also described coincidence of the two conditions. There was a total of eight cases of PTCS supposedly secondary to polycythaemia vera in the 1013 cases with identifiable aetiology collected from the literature. One of these cases had a significant increase in internal jugular vein pressure which may have been the key factor in the intracranial hypertension. Some idea of the incidence of PTCS in polycythaemia vera can be gained from the figures of Tinney et al. (1943) who, in a series of 163 cases, found 127 with central nervous system involvement of whom four had papilloedema. Platelet, factor, and other plasma constituent abnormalities are becoming increasingly recognized as associations with PTCS, although there are few reports only of the association of PTCS with specific conditions involving these components. In the collected series of 1013 cases (Johnston, 1992), there were six cases associated with a platelet abnormality as exemplified by the reported association with essential thrombocythaemia (Esack et al., 1989) and the recent report by Jacome (2001) of a single case of PTCS in association with haemophilia A. During the last decade, however, there has been a number of

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Individual factors

studies linking PTCS with various combinations of factors and plasma components if these are looked for with detailed studies of the clotting mechanism. A summary of the three most important studies is as follows: Sussman et al. (1997) studied 38 of 44 patients diagnosed as having BIH (PTCS), mostly retrospectively (3 months to 13 years after diagnosis), but in nine cases prospectively. They found antiphospholipid antibody in 32% of cases and also found cases of familial deficiency of antithrombin III, thrombocytosis, and polycythaemia. Also, an increased concentration of plasma fibrinogen was detected in 26% of cases. Importantly, they noted that these abnormalities were more likely to be detected in patients who were not obese and in those tested within 6 months of onset of the PTCS. Dunkley and Johnston (2004) studied a consecutive series of 25 patients with PTCS admitted to hospital over a 2-year period. The majority were patients with a previously established diagnosis of PTCS being admitted for shunt malfunction. All had been investigated for cranial venous outflow abnormalities (at least to the extent of MRV), which were present in four cases only. Moreover, all had a normal platelet count and screening coagulation tests. In this group (23 females, two males, average age 30 years) thrombophilic defects were found in 68%. These included positive ACA (six), APCR and FVL (four), positive LA (three), PT20210 (two), low PS levels (two), and elevated fasting homocysteine (two). Glueck et al. (2003, 2005) reported two studies involving 38 and 65 cases of IIH (PTCS) respectively, all women with a high incidence of obesity and polycystic ovary syndrome. In the first study they found high levels of factor VIII in 24% of IIH (PTCS) cases, high plasminogen activator inhibitor factor in 24%, high lipoprotein A (associated with hypofibrinolysis) in 35% and a prolonged APTT (in some cases accompanied by lupus anticoagulant) in 26%. All were significant in relation to a control group. The findings were similar in the second study, with the addition of the finding of high incidence of IIH (PTCS) patients who were homozygous for the thrombophilic C677T MTHFR mutation in comparison with controls. In the collected cases from the literature, there were also three cases of PTCS in association with the Marchiafava
Micheli syndrome of whom one at least was being treated with steroids at the time of development of PTCS. In addition, there was one case of PTCS associated with HBSC disease occurring during pregnancy and recurring in two further pregnancies. Recently, Henry et al. (2004) reported three cases (all children) of PTCS in association with sickle cell disease, one with SCD-SC and two with SCD-SS. Two of the three cases had a normal DSA.

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Endocrine disorders

Since the initial reports of Thomas (1933) and McCullagh (1941) relating PTCS to menstruation, and the increasing recognition, first clearly formulated by Wilson and Gardner (1966), of the high incidence of PTCS in obese young women with menstrual irregularities, there has been a persistent but unsubstantiated view that some endocrine abnormality underlies a significant number of cases of PTCS, particularly in the group of patients just referred to. However, repeated and detailed efforts to define such an abnormality have so far proved fruitless (Joynt & Sahs, 1962; Oldstone, 1966; Chen et al., 1979; Reid & Thomson, 1981; Bates et al., 1982; Sørensen et al., 1986a). Nevertheless, there have been small numbers of cases of PTCS associated with a variety of specific endocrine disorders
either the disorder itself or its treatment. In the combined Glasgow and Sydney series there were seven patients with an endocrine abnormality
three cases on thyroid replacement, three cases with a pituitary microadenoma, one case with congenital adrenal hyperplasia, and one case with diabetes mellitus. Several of these cases had other possibly significant aetiological factors. In the earlier review (Johnston, 1992), 39 of the 1013 cases with a presumed aetiology had what was considered to be a causative endocrine disturbance. Most common was thyroid disease accounting for 16 cases, then adrenal disorders nine cases, parathyroid disease eight cases, and four miscellaneous cases. Since that time, more cases have been reported but most striking has been the recognition of what appears to be a clear link with growth hormone replacement therapy and consolidation of the evidence for a link with thyroid disease, particularly thyroid replacement therapy. In what follows the pituitary, thyroid, parathyroid, and adrenal glands and their products, either natural or artificial, will be considered in order, followed by a brief comment on other cases. There are very few case descriptions of an association of PTCS with pituitary tumours. The three cases in our own series were all non-secreting intrasellar tumours not thought to be related causally to the PTCS. Gjerris et al. (1985) also reported a case with an intrasellar tumour. We have found only five other cases as follows: Mueller et al. (1981) reported two cases of PTCS associated with an intrasellar tumour and acromegaly, Weissman et al. (1983) reported PTCS after transsphenoidal removal of a microadenoma for Cushing’s disease, whilst Atkin et al. (1994) reported two cases with hyperprolactinaemia who were intolerant of bromocriptine and were being treated with quinazolide. These two patients developed PTCS 2 weeks after the treatment was stopped and had resolution of PTCS when the treatment was restarted. In addition, Futterweit (1982) reported a case of PTCS in association with hyperprolactinaemia and the galactorrhoea
amenorrhoea syndrome. This patient had an empty sella.

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There does appear to be a well-established connection between growth hormone replacement therapy and PTCS. There have been at least 17 reports on this connection since 1992. Several of the more important ones are as follows: • Malozowski et al. (1993, 1995). In the first of these reports, 23 cases (22 children, one adult) treated between 1986 and 1993 who developed PTCS are described. The majority were being treated for either chronic renal failure (eight) or growth hormone deficiency (seven) and in 13 of the 23 cases the onset of PTCS occurred within eight weeks of starting treatment. In the second report, 13 children (eight males, five females) being treated for growth hormone deficiency are described. Most developed PTCS within 2 weeks of starting treatment and showed resolution when the growth hormone was stopped (eight of 13). In two cases PTCS recurred when growth hormone was restarted. • Koller et al. (1997). These authors found 15 of 1670 patients with renal impairment who developed PTCS on growth hormone treatment. The male to female ratio was 6.5:1. Again, there was the finding of resolution of PTCS when the growth hormone was stopped and recurrence when it was restarted. • Crock et al. (1998). These authors found four cases of PTCS in 3332 children, aged 10.5 to 14.2 years, treated with growth hormone therapy between 1986 and 1996. They, like other authors, concluded that the risk was greater with ‘biochemical’ growth hormone. • Blethen et al. (1996). From their analysis of a very large number of cases
19,000 children with 447,000 treatment years
these authors found that children receiving rhGH for renal disease were the most ‘at risk’ group for PTCS. In the case of thyroid disease, it would appear that PTCS can occur in both untreated hypothyroidism and, more commonly, during the early period of replacement therapy. Of the 16 cases related to thyroid disease in the 1992 review (Johnston, 1992), six were attributed to untreated hypothyroidism, although CSF abnormalities might be more widespread in this condition. Thus, Thompson et al. (1929) found that 13 of 17 patients with myxoedema had abnormal CSF protein levels and one of these patients had a raised CSF pressure. On this point, Nickel and Frame (1958), in a general review of the neurological manifestations of myxoedema, wrote that ‘. . . a disturbance of CSF dynamics as evidenced by increased spinal fluid pressure from 200 to 430 mmH2O has been observed occasionally’. As to the mechanism of the increase in CSF pressure, in the case described by Levin and Daughaday (1955) of a patient with myxoedema and raised ICP who died, it is significant that no cerebral oedema was found at post mortem. There has been a further recent report of a case of myxoedema with raised CSF pressure and papilloedema (Frost et al., 2004). The majority of cases associated with thyroid disease have occurred during replacement therapy for hypothyroidism. This accounted for 10 of the 16 cases

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linked with thyroid disease in the earlier review (Johnston, 1992) to whom may be added three cases from the combined Glasgow/Sydney series and the cases reported by Campos and Olitsky (1995), Raghavan et al. (1997) and Serratrice et al. (2002). Despite the paucity of reports, Lessell, in his 1992 review of PTCS in children, felt able to state that: ‘Sufficient examples of pseudotumor cerebri developing in children after initiation of thyroid replacement therapy have now been documented that no one should doubt the validity of the association’. He also draws attention to the report of a child treated twice for hypothyroidism with an interval of 3 years who developed PTCS on both occasions (McVie, 1983). Van Dop in 1985, speculating on the findings to that date, suggested that the syndrome which occurs at the start of replacement therapy for primary hypothyroidism, and with tertiary hypothyroidism could have two different mechanisms. First, if a patient has pan-hypopituitarism and receives thyroid replacement alone, there may be a rapid fall in plasma cortisol due to increased cortisol metabolism which might be responsible for PTCS whereas, second, carotenaemia, which is common in hypothyroidism, might show a reduction with treatment and possibly an overshoot linking the increase in CSF pressure to variations in vitamin A levels. With respect to adrenal disease, there were nine cases with associated PTCS in the 1013 cases of the 1992 review (Johnston, 1992) to which may be added one case from the Sydney series (congenital adrenal hyperplasia) and five cases from post1992 case reports
three cases of Addison’s disease (Alexandrakis et al., 1993; Condulis et al., 1997; Leggio et al., 1995) and two cases of primary aldosteronism (Weber et al., 2002), giving a total of 15 cases in all. The majority of the cases associated with PTCS (9 of 15) were of hypoadrenalism, although in two of these PTCS occurred during replacement therapy. Of these two cases, one resolved when the dose of replacement steroids was increased and one occurred during reduction of steroid replacement. Jefferson (1956), who made a particular study of the association of increased ICP with Addison’s disease, described four patients with the condition who developed PTCS. Of these patients, two died and both were said to have shown cerebral oedema at post mortem. One patient had resolution of PTCS with treatment of the Addison’s disease and in the remaining case there was no adequate information. Although Jefferson attributed the raised ICP to cerebral oedema, thought to be on a metabolic basis, he noted that of Addison’s original 11 cases who died the four who had a post-mortem examination of the brain had no evidence of cerebral oedema. Klippel, however, who coined the term ‘encephalopathie Addisonienne’ in 1899, did report cerebral oedema in this condition. Of the remaining six cases of PTCS related to adrenal disease, there were two with primary aldosteronism, both men in their fifties in whom PTCS occurred before the diagnosis of aldosteronism was made (Weber et al., 2002).

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One had adrenal hyperplasia and the other an adrenal adenoma. There were two cases of PTCS with Cushing’s disease, the first having an adrenal adenoma and empty sella (Britton et al., 1980) and the second high cortisol and ACTH levels (Newman et al., 1980). The other two patients, one from the Sydney series and one reported by Gordon and Kelsey (1967), both had congenital adrenal hyperplasia and were on treatment at the time of diagnosis of PTCS. Hypoparathyroidism is cited as a cause of PTCS, but again very few cases have been reported. Sugar (1953), in a review of the neurological complications of hypoparathyroidism, noted that Albrecht, in 1923, was among the first to draw attention to an association between hypoparathyroid tetany and papilloedema, listing 10 previous cases and adding one case of his own. According to Sugar, there were 10 further cases between the time of Albrecht’s report and 1947, whilst he himself, in describing four cases with neurological complications of hypoparathyroidism, included one with a PTCS-like clinical picture. Of the other cases referred to above, by no means all would fall within the diagnostic criteria for PTCS. Among the 1013 collected cases of PTCS with aetiological details (Johnston, 1992), there were eight cases in all, including two of those already considered. Of the other six cases (Sutphin et al., 1943; Levy, 1947; Moore, 1959; Greer, 1974; Radhakrishnan et al., 1986; Sheldon et al., 1987), one also had iron deficiency anaemia, and in one case PTCS occurred many years prior to the treatment of hypoparathyroidism. There are two other points of interest in relation to PTCS and hypoparathyroidism. The first is the study by Sambrook and Hill (1977) who found a reduction of CSF absorption in patients with primary hypoparathyroidism and papilloedema using 131I-labelled serum albumin, with absorption returning to normal after the correction of hypocalcaemia. The second is the claim by de Jong et al. (1985), in reviewing two cases of PTCS with nutritional rickets (considered in the section ‘Head injury’ on p. 113), that PTCS can occur with both hypercalcaemia (in hyperthyroidism, hypophosphatasia, and pseudohypoparathyroidism) and hypocalcaemia (hypoparathyroidism and pseudohypoparathyroidism). Over the last decade, there have been only two reports of the association of PTCS with hypoparathyroidism (Lopez et al., 1997; Azar et al., 2001). There are few reports of other endocrine conditions related to PTCS. Donaldson and Binstock (1981) described one case in association with Turner’s syndrome but this patient was also obese. There have been other reports in cases with Turner’s syndrome but attributed to the therapeutic use of rhGH (e.g. Price et al., 1995). There is a report of one case of a patient with a feminizing tumour of the testicle with galactorrhoea and a low testosterone level (Hughes et al., 1994). This patient, who had a normal DSA, still had PTCS two weeks after removal of the tumour and return of the testosterone level to normal. There is one report of a case of PTCS associated with an ovarian hyperstimulation syndrome

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Aetiology

(Lesny et al., 1999) and one of a patient with adipisic hyponatraemia and an empty sella (Verdin et al., 1985). Diabetes mellitus is sometimes listed as an aetiological factor in PTCS but is not included here. Even on a subject where solid evidence is hard to come by generally, that for diabetes mellitus is particularly flimsy. Infections

In many series, infection
viral, bacterial or fungal
is the commonest of the aetiological agents in PTCS. Thus, in the Glasgow series some antecedent infection was deemed aetiological in 35 of 116 (30.2%) cases, and in 35 of 56 (62.5%) cases in whom some aetiological factor was identified. In children, the figures were 13 of 28 (46.4%) and 13 of 18 (72.2%) respectively. In the Sydney series, the incidence of infection given aetiological importance was somewhat lower: 13 of 154 (8.4%) cases overall and 13 of 76 (17.1%) cases with an identified aetiology. In children, the proportion was again higher: 12 of 60 (20.0%) cases overall and 12 of 32 (37.5%) cases with a presumed aetiology. The fall in the percentage of cases with infection as a presumed aetiology seen in the later series represents a general trend, particularly associated with a diminution of the frequency and severity of bacterial middle ear infections and mastoiditis. This is borne out by comparing figures from other series separated by 20 years. In the 1013 cases collected from the literature in the earlier review (Johnston, 1992), infection accounted for 230 (22.7%). Of these, 162 were attributed to bacterial middle ear infection/mastoiditis, an unknown number of these having secondary venous sinus involvement. Considering paediatric cases alone, Scott et al. (1997), in their review of data on 374 patients under 18 years of age collected from the literature, found an identified aetiology in 185 of 344 (53.2%) for whom aetiological information was available. Of these 185 patients, 87 had infection identified as the aetiological factor, and in 55 of the 87 the infection was a middle ear infection. As alluded to above, there is insufficient data on which to base any confident statement about the incidence of frank transverse sinus and/or other venous sinus thrombosis. Lessell (1992), based on Greer’s earlier figures, suggests a figure of slightly more than 25% but no systematic study exists. In a small study, Reul et al. (1997) found occlusion of a transverse sinus in 4 of 11 children with PTCS secondary to middle ear disease. With respect to other infections, it is something of a pot-pourri. In the report by Scott et al. (1997) on PTCS in children (referred to above), ‘viral infection’ and ‘febrile illness’ accounted for 11 cases and 8 cases respectively of the 87 cases with a presumed aetiology. URTI, gastroenteritis, UTI and frontal/paranasal sinusitis are also frequently included in aetiological lists for PTCS. Several infections with specific, identified pathogens have also been reported in association with PTCS. These include varicella (Konrad et al., 1998; Lahat et al., 1998),

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Individual factors

enterovirus 71 infection (McMinn et al., 2001), roseola infantum, typhoid (Vargas et al., 1990; Balasubramanian et al., 2003); psittacosis (Prevett & Harding, 1993), infectious mononucleosis (Benitez et al., 1987), and acute rheumatic fever. The total number of reported cases of PTCS associated with these conditions amounts to only a few in each instance so the connection, if any, is a very tenuous one. The one finding which might support some common underlying factor is that of Konrad et al. (1998) who reported one case 3 weeks after varicella who also had ilio-femoral thrombosis and elevated levels of anti-protein S antibodies. There are three other points to be made in this section. First, there are now several reports of an association of PTCS with Lyme disease. Kan et al. (1998) reported one case, an 8-year-old girl, and collected 12 other cases to that time. There have been several other single case reports since, both children and adults (Jacobson & Frens, 1989; Raucher et al., 1985; Zemel, 2000). One feature of these cases is that PTCS generally resolves with treatment of the Lyme disease by ceftriaxone, strengthening the argument for an aetiological link. The second point is the association of PTCS with poliomyelitis, and the Guillain
Barre´ syndrome and its variants. For inclusion of such cases, the so-called Dandy criteria must be relaxed, as is proposed in the previous chapter, to accommodate cases with abnormal CSF composition. With respect to poliomyelitis, reports of PTCS date back to Wickmann (1907). Other reports include those of Ayer and Trevett (1934) and Weiman et al. (1957) of cases with an elevated CSF protein and/or increased cell count as well as cases with a normal CSF composition at the time of analysis (Gass, 1957). There is the same picture with the Guillain
Barre´ syndrome where there is generally an increase in CSF protein (Ford & Walsh, 1943; Gardner et al., 1954; Joynt, 1958; Janeway & Kelly, 1966; Ropper & Marmarou, 1984; Hartemann et al., 1986). With the Guillain
Barre´ syndrome there has also been a report of PTCS without an increase in CSF protein (Kharbanda et al., 2002). The third point, and one bearing on the same issue, is the association of PTCS with chronic meningitis, for example, syphilitic meningitis (Bakchine et al., 1987), brucella meningitis (Diaz-Espejo et al., 1987) and cryptococcal meningitis (Custer et al., 1982; Cremer et al., 1996; Schoeman et al., 1996). Head injury

Minor head injury as a possible aetiological factor is not included in the several case
control studies already referred to (Ireland et al., 1990; Guiseffi et al., 1991; Radhakrishnan et al., 1993b), in all of which there is a marked female preponderance and, in the first, a restriction to adults. Head injury has, however, a long association with PTCS and is included as a aetiological factor in both Quincke’s and Nonne’s early descriptions (Quincke, 1897; Nonne, 1904). In series which are, at least, relatively unselected, there is likely to be a small but significant

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Aetiology

proportion of cases with a history of recent minor head injury. In some instances the head injury is more remote (several months to years). For example, in our own two series the incidence in the Glasgow series was 13 of 116 patients (11.2%) with a moderate preponderance of males (eight males, five females). The incidence in the more selective Sydney series was slightly less (11 of 154 patients, 7.1%). Again there was a preponderance of males (seven males, four females) and, in this series, of children (10 children, 1 adult). In addition, of the three girls in whom PTCS occurred shortly after a relatively minor head injury, one was on a tapering dose of steroids and one also had an URTI for which she was taking Amoxil. In four other representative series including from 38 to 61 cases, the incidence of head injury ranged from 3.9% to 5.3% (Bradshaw, 1956; Boddie et al., 1974; Rush, 1980; Couch et al., 1985). Millichap (1959) suggested that there was a higher relative incidence in children, but although this was apparent in the Sydney series, there were only 3 of 79 children with this aetiology in Grant’s (1971) series. Overall, in the collected cases from the literature, there were 55 patients in whom a minor head injury was identified as the causative factor. This figure does not, however, include the contributions from Foley (1955) and Davidoff (1956) both of which bracket minor head injury with infection to give a total of 39 patients in the combined series of 121 cases. There are three small series devoted entirely, or almost entirely, to post-traumatic PTCS (Martin, 1955; Beller, 1964; Spence et al., 1980), this being the identified aetiological factor in 19 of 21 cases. The PTCS described after minor head injury does not appear to differ in any way from other forms of PTCS. Excluded from the above considerations are cases where a head injury is associated with a depressed skull fracture compromising cranial venous sinus blood flow, there being several reports of such cases (e.g. van den Brink et al., 1996; Uzan et al., 1998). In the cases here being considered, the causative mechanism attributable to the injury is not clear. There is, also, the need to account for the variability of the reported time between the injury and the onset of PTCS which may vary from a few days to two and one half years in one of the cases described by Spence et al. (1980). Particularly with such a long time-interval, it is difficult to know what process may be operative which could account for the development of intracranial hypertension. Speculation has centred on chronic cryptic venous sinus involvement. Martin (1955) originally suggested that damage might occur to the dura in the wall of a sinus or that there may be extension inward of thrombosis in scalp and emissary veins. Beller (1964) subsequently proposed complete or partial thrombosis of one of the major sinuses, referring to post-mortem studies where this has been found without any apparent clinical concomitant. Of course, the majority of cases considered above were not subject to detailed delineation of the cranial venous outflow tract such as is available with current techniques.

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Other diseases and conditions

In the total of 1013 collected cases with aetiological information, there were 98 (9.8%) that came under the heading of ‘other diseases’ (Johnston, 1992). As with a number of the aetiological groups, these appeared mostly as reports of single or several cases. It is notable that this aetiological category was only sparsely represented in a number of large series of PTCS. Thus, there was only one case in a total of 596 cases from ten series comprising 28 cases or more. In our own combined series there were 11 of 270 cases attributed to other diseases. The range of conditions in the group is broad, as indicated in Table 5.1, and this range extends from diseases that are themselves very uncommon (e.g. alpha-chymotrypsin deficiency) to common conditions such as congestive cardiac failure. It is more probable that the association of PTCS with various diseases as listed will be under-represented with the common conditions than with the uncommon conditions. Certainly the figures cannot be taken as true indicators of the incidence of association of PTCS with a particular condition due to the vagaries of reporting, a proviso that applies, of course, to most discussions of aetiology in PTCS. The main associations will be considered individually, followed by a brief listing of the more uncommon presumed connections. Systemic lupus erythematosus

There is a long-standing association between PTCS and SLE. In the 1013 collected cases there were 11 with the latter condition. Gold et al. (1972), who had no cases of PTCS in their own series of 61 cases of SLE, collected a total of 13 cases of PTCS from a total of 1328 cases of SLE reported in the literature in eight series of the latter condition. In a later review, Green et al. (1995) reported 21 cases of PTCS in association with SLE, 18 cases from the literature plus three of their own. Their observation was that PTCS generally accompanied the more severe cases of SLE and they reported hypercoagulable states in 58% of the affected cases. Certainly some of the cases of SLE who developed PTCS had thrombotic occlusion of the superior sagittal sinus (Shiozawa et al., 1986; Parnass et al., 1987; Flusser et al., 1996). Also, there have been at least two reports of patients with SLE suffering two separate episodes of PTCS (Horoshovski et al., 1995; Yoo et al., 2001). Behc¸et’s disease

There also seems to be an established, albeit rare, connection between PTCS and Behc¸et’s disease. In the 1013 cases collected from the literature, there were nine cases with Behc¸et’s disease of whom seven had demonstrated venous occlusion, either extracranial or intracranial, combined or in isolation. On this point, Farah et al. (1998), in a series of 41 cases of Behc¸et’s disease (34 males, 7 females),

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Aetiology

reported 11 cases with raised ICP of whom 10 had confirmed dural venous sinus thrombosis, whilst Daif et al. (1995) found a high incidence of Behc¸et’s disease (25%) in their 40 cases of cerebral venous thrombosis of whom 19 had PTCS. An example of extracranial venous occlusion associated with PTCS in Behc¸et’s disease is the case reported by Terzioglu et al. (1998) who had SVC obstruction. Renal disease

In recent years there has been a number of reports linking PTCS with chronic renal disease and its treatment, including haemodialysis and renal transplantation. For example, single cases related to dialysis have been reported by Wingenfeld et al. (1995), Belson et al. (2001) and Shaw et al. (2002) whilst cases related to renal transplantation have been reported by Giordano (1995), one case; Katz (1997), one case; and Obeid et al. (1997), two cases. With respect to transplantation, Francis et al. (2003) reported nine cases following renal transplantation which represented 4.4% of all cases undergoing renal transplantation at their institution over an 11-year period. In the specific instance of cystinosis, Dogula et al. (2004) described eight cases of this condition who developed PTCS. Five of the eight cases also had renal transplantation, whilst six of the eight cases had one or more of the following medications prior to the onset of PTCS: prednisone, growth hormone, cyclosporin, oral contraceptives, vitamin D, and L-thyroxine. This report underscores the complexity of trying to identify an individual aetiological agent for PTCS in chronic renal disease specifically, as well as more generally. Cardiac and respiratory diseases

At the time of the 1992 review (Johnston, 1992), there were only 15 cases of PTCS related to cardiac and/or pulmonary disease among the 1013 cases with aetiological information, starting with the initial report of PTCS linked to pulmonary emphysema by Cameron in 1933. Amongst this group, emphysema was the most common condition accounting for 11 of the 15 cases (Cameron, 1933; Meadows, 1946; Simpson, 1948; Westlake & Kaye, 1954; Carter & Fuller, 1957; Conn et al., 1957). The report of Westlake and Kaye (1954) is notable in that they studied CSF pressure in a group of 12 patients with emphysema of whom three had papilloedema but 10 had a single CSF pressure reading 4200 mmH2O and in five instances 4300 mmH2O. All of these patients had increased venous pressure, hypercapnoea and hypoxia. Apart from the 11 patients with emphysema, there were two patients with chronic cardiac failure associated with chronic respiratory disease (Beaumont & Hearn, 1948; Arseni et al., 1968), one with the Pickwickian syndrome with respiratory impairment and increased central venous pressure (Meyer et al., 1961), and one with respiratory acidosis, although this patient was also on steroids (Manfredi et al., 1961). Over the past decade we have

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found only two further reports; one of a case who was markedly obese and had raised ICP at night with hypoventilation giving hypercapnoea and hypoxia (Kirkpatrick et al., 1994) and one of a case diagnosed as having the Pickwickian syndrome (Wolin & Brannon, 1995). There are also three reports of PTCS following repair of congenital cardiac abnormalities
septal defects (Chappell, 1982; Jicha & Suarez, 2003) and PDA (di Liberti & O’Brien, 1975). Sleep disorders

There is now some evidence of a connection between sleep disorders and PTCS. Thus, Purvin et al. (2000) reported four cases of PTCS in patients with obstructive sleep apnoea, all males with an average age of 46.5 years. Subsequently, Marcus et al. (2001) studied 53 patients with IIH (PTCS) and found 37 who had a suggestive history of snoring, difficulty sleeping and daytime somnolence. Fourteen of the 37 cases had polysonography of whom 12 were females and two males, aged between 24 and 58 years, and all were obese. Amongst this group, sleep apnoea was identified in six cases and upper airways resistance syndrome in seven cases. Psychiatric disorders

There were 10 cases of PTCS linked to psychiatric disorders in the 1013 collected cases apart from those cases attributed to lithium carbonate (see the section ‘Vitamins, drugs, and chemicals’, on p. 120). Ross et al. (1985) described five cases of PTCS associated with depression. Four of these patients were either obese or had had recent weight gain whilst the remaining patient had a past history of nephrotic syndrome treated with prednisone. There were three cases of PTCS associated with bulimia. The two patients described by Pelosi and David (1985) were both obese young women one of whom had a history of menstrual irregularity. The other case wih bulimia was also very obese (Krahn & Mitchell, 1984). Of the remaining two cases, one suffered depression and had been treated with thioridazine and then chlorpromazine whilst the other, an 18-year-old female with a depressive psychosis, developed PTCS while on a high dose of vitamin A (Restak, 1972). To these 10 cases might be added the two sisters described by Coffey et al. (1982) and included in the section on familial cases (p. 98). The prevalence of other aetiologically significant factors in this small group of cases is readily apparent so there is very little evidence to support a link between psychiatric disorders per se and PTCS. Enzyme deficiencies

In the 1013 collected cases (Johnston, 1992), there were six cases with an enzyme deficiency. We have found no further reports since that review. Of the six cases,

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three were patients with galactosaemia described by Huttenlocher et al. (1970) and one was a case of 6-galactokinase deficiency (Littman et al., 1975). In all four cases, PTCS responded to treatment of the primary disorder. Of the two other cases, one was a 20-year-old woman with partial deficiency of alpha-1 anti-chymotrypsin which the authors thought was unrelated to her PTCS (Lorier et al., 1985), and the other was a 12-year-old boy with 11-beta-hydroxylase deficiency in whom the PTCS may have been related to rapid steroid withdrawal (Zadik et al., 1985). Thus, while galactokinase deficiency would appear to have a genuine claim to association with PTCS (Bosch et al., 2002), the other examples would not.

Miscellaneous

The following is a list of diseases and conditions reportedly associated with PTCS giving the number of cases found and relevant references: • Sarcoidosis: six cases (Allison, 1964; Byrne & Lawton, 1983; Phanthumchinda et al., 1984; Redwood et al., 1990; Akova et al., 1993; Pelton et al., 1999). • HIV-AIDS: five cases (Javeed et al., 1995; Schwarz et al., 1995; Prevett & Plant, 1997; Lisk et al., 2000). • Spinal cord tumours: four cases (Love et al., 1951; Arseni & Maretsis, 1967; Hansen et al., 1987). • Allergic disease: four cases (Devanney & Shea, 1952; Lecks & Baker, 1965). • Bartter’s syndrome: three cases (Konomi et al., 1978; Larizza et al., 1979; Mendonca et al., 1996). • Post epidural anaesthesia: two cases (Porta-Etessan et al., 2000; Johnston, unreported). • Aneurysmal bone cyst: two cases (Chateil et al., 1997). • Vasculitis/polyarthritis syndromes: two cases (Feig et al., 1976; Drucker & Bookman, 1985). • Histiocytosis X: one case (Jackson & Griffith, 1975). • Langerhans cell histiocytosis: one case (Modan-Moses et al., 2001). • Sydenham’s chorea: one case (Chun et al., 1961). • Peripheral nerve sheath tumour: one case (Hills & Sohn, 1998). • Familial Mediterranean fever: one case (Gokalp et al., 1992). • Familial hypomagnesaemia
hypercalciuria: one case (Gregoric et al., 2000). • Tolosa
Hunt syndrome: one case (Nezu et al., 1995). • Goldenhauer’s and Daune’s syndrome: one case (Tillman et al., 2002). • SSPE: one case (Tan et al., 2004). • Following occipito-cervical arthrodesis and halo immobilization: one case (Daftari et al., 1995).

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Individual factors

Nutritional disorders

The small group of nutritional disorders linked with PTCS predominantly relates to young children. Moreover, not only is the group of conditions small, but also the number of reported cases is very small. In the analysis of aetiological factors made on the 1013 cases of PTCS up to 1990 with adequate details of aetiology, there were 37 cases attributed to a nutritional disorder (Johnston, 1992). The majority of these cases (27) were children suffering malnutrition, and in 10 cases there was the association of vitamin D deficiency rickets. In most of these cases PTCS occurred during restoration of nutrition. On this point, Tibbles et al. (1977), who described four cases associated with deprivation dwarfism in children from 1 to 5 years prior to nutritional restoration, observed a further increase in suture separation during the first month of treatment. This they attributed to a rapid increase in brain volume. It is also of interest to note that one of three cases who developed PTCS during hyperalimentation (one with Hurler’s syndrome, one with persistent diarrhoea, one with intestinal atresia) went on to develop mild communicating hydrocephalus which resolved spontaneously. It is clear, at least in this patient, that the cause of the increase in ICP was not an increase in brain volume per se. Of the remaining 10 cases in this group, seven were associated with cystic fibrosis (Bray & Herbst, 1973; Roach & Sinal, 1980; Couch et al., 1985) and in a number of these, PTCS occurred during treatment and a period of rapid weight gain. In the other three cases, the link was with rickets, in two cases nutritional (de Jong et al., 1985) and in one case vitamin D deficient (Hochman & Mejlszenkier, 1977). Since the collection of these 37 cases, we have found two that are more recent. One is a case of rickets presenting as PTCS with seizures (Salaria et al., 2001) and the other a case of non-organic failure to thrive, a child suffering psychological and physical deprivation who developed PTCS during treatment and catch-up growth which was attributed to recovery of a poor growth hormone response to clonidine stimulation (Alison et al., 1997). As for the mechanism of PTCS in the group as a whole, there are several possibly significant factors: general nutritional deficiency, specific vitamin deficiencies (particularly vitamin D), and the effects of sudden restoration of a satisfactory nutritional state including rapid growth. In the case of nutritional rickets, de Jong et al. (1985) suggest a link between the PTCS occurring in this condition and that occurring in other disturbances of calcium and phosphate metabolism. Also, as Lessell (1992) points out, the possibility of dural venous sinus thrombosis due to inanition, something not investigated in any of these cases, must be taken into account. In addition, Lessell (1992) refers to a personal communication (Vitale, 1991) relating to a group of malnourished infants in Africa who developed raised ICP during renutrition. They were said to have retained ‘considerable hepatic

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Aetiology

stores of vitamin A that contributed to vitamin A intoxication when supplementary vitamin A was administered’. Hypovitaminosis A has been added to the group of nutritional deficiencies. Lessell (1992) collected 12 reported cases of PTCS attributed to vitamin A deficiency
11 were infants aged 3 to 8 months and one was a 12-year-old girl who also had hyperthyroidism. The causes of the vitamin A deficiency included dietary inadequacy, cystic fibrosis, malabsorption, and biliary atresia. As he points out, the nutritional deficiencies in such cases are likely to be much wider than vitamin A alone, although, of course, hypovitaminosis A like hypervitaminosis A has been shown to adversely affect CSF dynamics in experimental studies (Millen et al., 1953, 1954; Eaton, 1969; Hayes et al., 1971). More recently, Panozzo et al. (1998) described a case of hypovitaminosis A occurring 5 years after gastric by-pass for obesity. This patient presented with PTCS and other manifestations of vitamin A defiency, all of which resolved with restoration of adequate vitamin A levels. In summary, then, there are several factors in this group of nutritional disorders which might be linked to the development of PTCS. The most obvious is vitamin A, given its well-established importance in relation to CSF formation and absorption. Other specific factors like vitamin D may be important as well as the more general effects of malnutrition with a possible predilection to thrombotic events. Also, the process of renutrition itself might be of significance. Vitamins, drugs, and chemicals

Although none of the substances listed under this heading qualified as a genuine aetiological agent in the case
control studies referred to earlier (Ireland et al., 1990; Guiseffi et al., 1991; Radhakrishnan et al., 1993b), at least four are by common consent accepted as such. These are vitamin A and related compounds, steroids, tetracycline and related compounds, and nalidixic acid. Apart from these substances, there is a whole range of agents which are more or less persuasively linked with PTCS but, as with a number of other putative aetiological factors, on the basis of very few cases despite the wide use of the agents in question. The four relatively secure associations will be considered in order first, before summarizing the remaining less well substantiated agents under the headings of ‘other antibacterials’ and ‘other agents’. Vitamin A and related compounds

There are strong reasons for accepting these agents as causative of PTCS based on a number of experimental studies of vitamin A or its lack on CSF dynamics. These studies will be considered in Chapter 10. The clinical evidence alone is, however, quite weighty. First, the association of vitamin A excess with increased intracranial pressure has a long history antedating the recognition of a PTCS

121

Figure 5.1

Individual factors

Gerrit de Veer was the ship’s doctor on Willem Barents’s third voyage to find the North-east Passage (1596
7). He described in his diaries not only the Novaya Zemlya effect but also the severe headaches and prostration that accompany the ingestion of polar bear liver. This engraving depicts an attack by three polar bears. Van Heemskerck and De Veer are holding off the bears while the unfortunate crew member is still stuck in the ice. The remainder of the crew are running towards the ship to distract the wild animals. (Amsterdam University Library (UvA), Special Collections, OF63-802.)

(Friedman, 2005). Second, there have been at least 30 clinical reports linking vitamin A with PTCS since the first description by Marie and See in 1954. Third, cessation of the excessive intake of vitamin A in cases of PTCS generally leads to resolution of the PTCS with, in the case of vitamin A itself, restoration of normal serum levels. Fourth, there is the study of Baqui et al. (1995) which was a doubleblind, randomized, placebo-controlled trial of vitamin A use in 167 infants in Bangladesh. Nine infants receiving vitamin A had episodes of bulging anterior fontanelle (10.5%) compared with two in the control group (2.5%), a statistically significant difference (p < 0.05). Moreover, episodes were increasingly frequent as usage progressed. In addition, Selhorst et al. (1984), who described five cases of PTCS with excessive liver ingestion, speculated that 30
50% of people with vitamin A excess might develop PTCS. Further, there are also several recent investigative reports which support a wider connection between vitamin A and related substances and PTCS. Thus, Jacobson et al. (1999a), who studied 16 female patients with IIH (PTCS) compared with 70 normal controls, found a significant

122

Aetiology

increase in serum retinol in the IIH (PTCS) group, although there was no difference in vitamin A intake between the groups. Along the same lines, Selhorst et al. (2000) found a raised serum retinol-binding protein in 7 of 30 cases of IIH (PTCS) whilst Warner et al. (2002) investigated three groups
patients with IIH (PTCS), patients with raised ICP due to other causes, and patients with normal ICP
and found significantly higher levels of CSF vitamin A in some of the IIH (PTCS) patients. There are several different vitamin A related substances that have a therapeutic use, particularly in skin conditions (Friedman, 2005) but also, in the case of alltrans-retinoic acid (ATRA), in the treatment of leukaemia. So, apart from naturally occurring vitamin A in foodstuffs such as liver and carrots, and vitamin A preparations, there are the following: isotretinoin, etretinate, and ATRA. The matter is well reviewed by Friedman (2005). There are far fewer reports of the association of PTCS with hypovitaminosis A. Of 46 cases of vitamin A-related PTCS in the 1013 collected cases (Johnston, 1992), 42 cases were due to hypervitaminosis A whereas only four cases were due to hypovitaminosis A. The latter has been considered in the previous section. We have collected 19 reports of vitamin A-related PTCS since 1995 not including that of Baqui et al. (1995) referred to above. Of these, 12 cases were ATRA-related, two cases involved vitamin A preparations, two cases were associated with isotretinoin (including its use in conjunction with tetracycline in the treatment of acne vulgaris
e.g. Lee, 1995), two cases had excessive dietary intake, and two cases were of hypovitaminosis A. Steroids

There is also a combination of cumulative clinical evidence and experimental evidence to support the association of corticosteroids and PTCS. Steroids are particularly interesting as an aetiological agent because not only may they apparently cause PTCS through prolonged usage, especially during or after withdrawal, but they are also an effective therapeutic agent in the condition, although amelioration of symptoms and signs is not necessarily accompanied by a restoration of normal CSF pressure (Johnston et al., 1981). Of the 1013 cases with identified aetiology collected from the literature, steroids were inculpated in 70 patients (6.1%) (Johnston, 1992). In our own combined series there were nine cases in 270 patients (3.3%). In the 70 collected cases, the majority occurred during steroid administration. There were 47 such cases, of which four were during the use of topical steroids for eczema (Roussounis, 1976; Hosking & Elliston, 1978; Couch et al., 1985) whilst 23 cases occurred during withdrawal or after cessation of steroids. Characteristically, PTCS occurred during prolonged use of steroids for such conditions as nephrotic syndrome, asthma, eczema and

123

Individual factors

rheumatic fever. There were two cases of PTCS associated with steroid use in endocrine disorders; one patient during steroid withdrawal following treatment of the adrenogenital syndrome (Chaptal et al., 1968) and one during treatment of Addison’s disease with deoxycorticosterone at the time of dose increase (Walsh, 1952). At least by 1992 this evidence was not enough to alleviate the doubts of at least one investigator as Lessell’s (1992) account of Wall’s objections makes clear. Nonetheless, reports continue to accumulate. Not only are there the specific cases, particularly related to steroids in the treatment of chronic bowel conditions
see, for example, Levine et al. (2001), Chebli et al. (2004)
but also the fact steroids are commonly part of the treatment of several other conditions linked with PTCS, either the disease itself or the treating agents, for example, chronic renal disease, leukaemia and SLE. As alluded to above, there is also experimental evidence particularly linking steroid withdrawal to increased resistance to CSF absorption (Johnston et al., 1975a). This will be considered more fully in Chapter 10. Tetracycline and related compounds

Unlike the previous two agents, tetracycline and the related compounds minocycline and doxycycline are linked to PTCS through clinical evidence alone. They are by far the most frequently reported anti-bacterial agents linked with PTCS. In the review of 1013 cases of PTCS from the literature with an identified aetiological factor (Johnston, 1992), they accounted for 24 of the 39 cases attributed to antibiotics. The majority of the cases described were in children or adolescents, especially in the prolonged antibiotic treatment of acne vulgaris. In the majority of cases also, PTCS appeared to resolve with cessation of the drug without the need for additional treatment (although vide infra). Two particular points of interest were first, that in one case, an infant, PTCS was reported as developing after a single 75 mg dose of tetracycline (O’Doherty, 1965) and second, that in the five cases described by Walters and Gubbay (1981), one patient who had a second exposure to tetracycline did not again develop PTCS, whilst another patient had a recurrence of PTCS at 18 months quite unrelated to further drug use. Since the 1992 review, reports have continued, particularly of PTCS in association with the use of minocycline for acne vulgaris in adolescents. Thus, Chiu et al. (1998) reported 12 such cases, 9 of whom developed PTCS within 8 weeks of starting minocycline treatment whilst Quinn et al. (1999) reported 6 such cases seen over a 10-year period. Two other recent studies of relevance are first, that of Grasset et al. (2003) who reviewed 76 contributions reporting a total of 250 cases of cycline complications between 1997 and 2001. The most commonly offending drug was minocycline, with PTCS being reported in 24 cases. Second, Kesler et al. (2004), in a retrospective review of 243 patients with PTCS (195 females, 48 males), found 20 cases (8.2%) with a prior history of minocycline

124

Aetiology

or tetracycline use prior to diagnosis of PTCS. Of interest too is that only 6 of 18 patients with follow-up of 1 year or more had a simple clinical course whereas 12 had prolonged problems despite cessation of the antibiotic. Two further points worthy of mention are that there are several cases of PTCS occurring in connection with the combined use of tetracycline and isotretinoin for acne vulgaris (Benrabah et al., 1995; Lee, 1995) and there is also the report by Gardner et al. (1995) of twin sisters who both developed PTCS in relation to tetracycline use. Finally, the case reported by Confavreux et al. (1994) is of interest. This was a 60-year-old man, having treatment with doxycycline and ampicillin for a dog bite, who developed PTCS after 5 days of therapy. He was, in fact, found to have thrombosis in the posterior part of the superior sagittal sinus and also reduced protein C levels. Nalidixic acid

Although case reports linking nalidixic acid with PTCS are noticeably fewer than with the three previously considered agents and, as with tetracycline, there is no experimental evidence nor theoretical reason to link this agent with altered CSF dynamics, the case for it having an aetiological role in PTCS is at least relatively strong. First, as Lessell (1992) points out, it is not a frequently used drug so particularly in children the number of case reports linking it with PTCS is rather high. Second, there is the finding reported in two separate studies of resolution of PTCS after cessation of the drug followed by recurrence of PTCS after re-exposure and again resolution with cessation (Boreus & Sundstrom, 1967; Fisher, 1967). Further, there is the report by Mukherjee et al. (1990) of 12 infants developing BIH (PTCS) within 24
48 h of starting a very high dose of nalidixic acid for bacillary dysentery. In a recent study, Riyaz et al. (1998), who reviewed 20 cases of infants and children developing PTCS with nalidixic acid, comment that in all cases the amounts given were higher than the recommended dose. Finally, in the collected series of 1013 cases there were eight cases of PTCS attributed to nalidixic acid (Johnston, 1992) whilst in the combined Glasgow and Sydney series of 270 cases there was one case, an adult female. Other agents

Data has been gathered from our own earlier review (Johnston, 1992), from Griffin’s (1992) review and from a survey of 234 reports relating to the aetiology of PTCS between 1993 and 2005. The following agents have been implicated in more than one instance: danazol, 13; lithium carbonate, 9; amiodarone, 7; perhexilene maleate, 6; penicillin, 5; ciprofloxacin, 2; nitrofurantoin, 3; nitroglycerin, 2; leuprorelin, 2; and mesalazine, 2. With respect to danazol, amiodarone and perhexilene maleate, it was characteristic for PTCS to resolve when the drug was stopped. Also, in one of the three cases associated with danazol described

125

Individual factors

by Shah et al. (1987), there was a recurrence of PTCS when the drug was reexhibited after a 2-year break. There are reports of single cases in relation to the following agents: nitrous oxide, indomethacin, stanozolol, phenytoin, divalproate, beta human chorionic gonadotrophin, ketoprofen, ketamine, fluticasone proprionate, ofloxacin, trimethoprim
sulfamethoxazole, amoxil, budesonide, octreotride, desmopressin, and the insecticide chlordecone. The significance of these single reports is, of course, very questionable. Finally, there are also several agents used in conjunction with other more established factors in the treatment of leukaemias and chronic renal disease such as cyclosporins, cytarabine hydrochloride, and arsenic trioxide. It is very difficult to separate any possible effect of such agents from the disease itself and other components of therapy. In concluding this review of aetiology in PTCS, two of the most striking aspects are the large number and wide range of factors implicated, and the overall paucity of conclusive evidence linking the various factors to the disease. The latter is due both to the uncommon occurrence of PTCS itself and to the as yet incomplete understanding of the disease mechanism. Nonetheless, there are some factors that clearly stand out as much more securely linked aetiologically with PTCS than the majority of those listed. These are, following the order of Table 5.1, female gender and obesity, endogenous and exogenous oestrogens, impaired cranial venous outflow, thrombophilia and hypofibrinolysis, endocrine/metabolic abnormalities involving steroids and calcium as well as growth hormone and thyroid replacement, abnormal vitamin A levels, tetracycline/minocycline and nalidixic acid, and alterations of CSF composition with increase of cells or protein. To these must be added the evidence of a genetically determined abnormality. Theoretically, these factors can be, for the most part, gathered under two headings related to CSF absorption: 1. Factors that adversely affect the pressure differential between CSF and venous blood which drives CSF bulk flow: cranial venous outflow tract hypertension, thrombophilia and hypofibrinolysis, and oestrogens via increasing thrombophilia 2. Factors which adversely affect the passage of CSF through the arachnoid villi: steroid and calcium abnormalities, abnormal vitamin A levels, and alterations of CSF composition The odd ones out from the immediately preceding list are thyroid and growth hormone replacement, tetracycline and related compounds, and nalidixic acid. Both the hormone replacement substances and the anti-bacterials should be studied with respect to two questions: do they affect clotting mechanisms, and do they affect CSF absorption? So, in conclusion, it must be recognized that it will be very difficult ever to achieve adequate case
control studies involving a sufficiently large number of sufficiently non-selected cases. However, it should be possible,

126

Aetiology

first, to investigate all cases to the extent of establishing whether there is impairment of cranial venous outflow or CSF absorption, and whether there is thrombophilia or hypofibrinolysis, and second, to attempt to link any putative aetiological factor to the condition by understanding how it affects CSF absorption. There is still the problem of why so few people who are exposed to often very common agents, or are affected by what are often very common conditions, develop the syndrome. It is here that a developmentally or genetically determined predisposition may be important.

6

Clinical features

Introduction The clinical features of PTCS are well-established and largely uncontroversial, unlike, for example, the issues pertaining to disease mechanism and treatment. Thus, there are now several epidemiological studies which provide sound information on the incidence of the syndrome in the general population as well as some indication of differences in geographically different populations. These studies also confirm the quite distinctive age and sex distribution patterns of PTCS which are apparent in clinical studies. Likewise, the symptoms and signs of PTCS are well-established. Thus, the four most common symptoms are headache, nausea and vomiting, disturbances of visual function, and diplopia, whilst the four most common signs are papilloedema, reduction of visual acuity, restriction of visual fields, and VIth nerve palsy. There are, however, notable if infrequent variations in the ‘standard’ clinical presentation which clinicians need to be aware of. These involve the absence of one or more of the four main symptoms and absence of one or more of the four main signs. Less commonly, there is the presence of additional symptoms and/or signs. Also, there are to some extent variations in the nature of the clinical presentation in children and, to a lesser extent, in men which should be recognized. In this chapter, after reviewing the epidemiology, the nature, frequency, and duration of the clinical signs will be considered, followed by identification of some of the atypical presentations, and finally, a consideration of issues relating to differential diagnosis.

Incidence, age, and sex distribution The actual incidence of PTCS in a general population is somewhat difficult to ascertain. Problems are presented by the uncommon nature of the condition, by the vagaries of reporting, and by the issues relating to the definition of the 127

128

Clinical features

syndrome addressed in Chapter 4. Prior to the studies of Durcan et al. (1988), information on incidence relied on clinical studies, generally from a single institution over a period of time. As Radhakrishnan et al. (1993b) point out, the impression gained from such hospital-based clinical series is that PTCS is a rare condition. This is exemplified by the Glasgow series from 1942 to 1972 where, in the only neurology/neurosurgery unit providing adequate facilities for the investigation of intracranial hypertension (i.e. prior to CT scanning) for a population of over three million people, altogether only 110 cases were seen over a 31-year period (Johnston & Paterson, 1974a). The number of cases for each 5-year period within the 31 years ranged from 14 to 28 and was relatively constant (14 to 20) apart from the high figure of 28 in the final period. Since (and including) the studies by Durcan et al. (1988), we have found a total of seven reports on the epidemiology of PTCS pertaining to quite widely separate parts of the world. The results are summarized in Table 6.1. As can be seen, the periods of survey were short in a number of instances and the number of cases small. Nonetheless, a pattern does emerge of a corrected annual incidence of around 1 case/100,000 with a notable preponderance of women, particularly those in the child-bearing years, and particularly those in that age range who are obese.

Table 6.1. Epidemiological surveys of PTCS from 1988 to 2004

Study Radhakrishnan 1986
Libya Durcan et al. 1988
Iowa Durcan et al. 1988
Louisiana Radhakrishnan 1993a
Rochester Craig et al. 2001
Nth Ireland Kesler and Gadoth 2001
Israel Carta et al. 2004
Parma

Annual incidence (per 100,000)

Annual incidence, females

Annual incidence (F, reproductive years)

Annual incidence (obese F, reproductive years)

Duration (years)

No. of patients

7

81

2.2

4.3

12.0

21.4

1

27

0.9

-

3.5

19.3

1

48

1.1

-

-

14.9

15

9

1.0

1.6

3.3

7.9

4

42

0.5

0.9

-

-

2

91

0.57
0.94

1.82

4.02

-

10

10

0.28

-

0.65

2.7

129

Incidence, age, and sex distribution

With regard to age and sex distribution, the epidemiological studies are in accord with the findings in clinical series. Thus, in the Glasgow series the age range for the whole group was 1 to 55 years with a single peak in the third decade and a female preponderance of 1.82 to 1 (Figure 6.1). When the cases are divided into those without and those with an aetiological factor, it is seen that in the latter group the female preponderance is noticeably less marked and the age distribution more even, although the peak in the third decade remains (Figure 6.2). As mentioned earlier, the Sydney series is skewed towards the paediatric age group, and towards refractory adult cases which tend to be obese females between 20 and 40 years of age. The actual figures for age are as follows: 1. Age range for both sexes. The overall age range was 3 months to 74 years with an average age of 22.5 years; for adults (i.e. from 18 to 74 years) the average age was 32.3 years; for children (i.e. from 3 months to 17 years) the average age was 8.2 years. 2. Age range for females only. The age range for females was from 3 months to 54 years with an average age of 24.2 years; for female adults (i.e. from 18 to 54 years) the average age was 30.8 years; for female children (i.e. from 3 months to 17 years) the average age was 9.5 years. 3. Age range for males only. The age range for males was from 6 months to 74 years with an average age of 17.2 years; for male adults (i.e. from 23 to 74 years) the average age was 42.7 years; for male children (i.e. from 6 months to 16 years) the average age was 6.3 years.

Figure 6.1

Age and sex distribution in 110 cases of PTCS
Glasgow series. (With permission from Brain.)

130

Figure 6.2

Clinical features

Age and sex distribution in 110 cases of PTCS divided on basis of known aetiology (below) and no known aetiology (above)
Glasgow series. (With permission from Brain.)

In this series the overall female to male ratio was 3.1:1 (113 females, 37 males) and the ratio of adults to children was 1.5:1 (89 adults, 61 children). In adults, the female to male ratio was 7.1:1 whilst in children it was 1.3:1. The age pattern is generally constant through other series. Thus, in 48 separate series, some quite small, in which an average age was given, in 21 this was in the third decade, in 16 it was in the fourth decade, and in the remaining 11 series was spread between the first (6), second (2) and fifth (3) decades. In a total of 1779 cases collected from the literature, without differentiation on the basis of aetiology or otherwise, there were 1271 females and 508 males, a ratio of 2.31 to 1. The female preponderance was

131

Presenting symptoms

most pronounced in those cases without an identifiable aetiology. Thus, in a total of 286 cases without aetiology from six series each of more than 20 patients, the female to male ratio rose to 3.76 to 1 (Dandy, 1937; Davidoff, 1956; Rish & Meacham, 1965; Lysak & Svein, 1966; Greer, 1968; Radhakrishnan et al., 1986). In those cases with an aetiology this preponderance is significantly less marked, as shown in Figure 6.2, whilst in children it is least marked or even reversed (vide infra). In summary, the picture that emerges is one of a condition with an overall non-adjusted annual incidence of approximately 1/100,000 of population, but with a marked female preponderance (greater than 2:1). All ages are susceptible, but the greatest incidence falls in the second to fifth decades, particularly in females, and especially in obese females. Neither the female preponderance nor the association with obesity are apparent in pre-pubertal children. The same probably applies to the relatively few cases occurring in the elderly but there are no specific figures on this.

Presenting symptoms Tables 6.2 to 6.4 show the relative incidence of the various presenting symptoms encountered in PTCS in three series of patients: the Glasgow series which might be considered as an unselected series, the Sydney series with a bias towards both paediatric and refractory cases, and a total of 1589 cases collected from the literature. As can be seen from a comparison of the three tables, there is a quite uniform distribution. Variations that do occur can be attributed to different ratios of adults to children and of females to males reflecting variations in referral patterns. Aspects of the individual symptoms will be briefly considered below. Table 6.2. Incidence of presenting symptoms: Glasgow series

Symptom Headache Disturbance of vision Diplopia Nausea and vomiting Dizziness Altered consciousness Tinnitus Paraesthesiae Other

No aetiology (62 patients) Aetiology (48 patients) Total Percentage 59 40 19 15 7 6 7 2 9

40 23 20 20 7 5 2 1 6

99 63 39 35 14 11 9 3 15

90.0 57.3 35.5 31.8 12.7 10.0 8.2 1.8 13.6

132

Clinical features Table 6.3. Incidence of presenting symptoms: Sydney series

Symptom

All cases

Female adult

Male adult

Female child

Male child

No. of cases Headache Disturbance of vision Diplopia Obscurations of vision Nausea and vomiting Tinnitus Other Obesity

150 80.0% 40.0% 25.3% 10.0% 16.7% 0.2% 19.3% 31.3%

78 82.1% 57.7% 14.1% 16.7% 6.4% 3.8% 6.4% 47.4%

11 81.8% 27.3% 9.1% 0 0 0 18.2% 9.1%

35 97.1% 22.9% 54.3% 5.7% 31.4% 0 25.7% 25.7%

26 50.0% 15.4% 26.9% 0 0 0 50.0% 0

Table 6.4. Incidence of presenting symptoms: 1589 cases from the literature

Symptom Headache Disturbance of vision Diplopia Nausea and vomiting Dizziness Altered consciousness Tinnitus Other Asymptomatic (Menstrual irregularity)

No. of cases

Percentage

1271 603 346 346 125 43 42 59 23 78

80.1 37.9 21.8 21.8 7.9 2.7 2.6 2.8 1.4 4.9

Headache

Headache is clearly the major symptom. The figures from Tables 6.2 to 6.4 of 80
90% may be taken as a fair representation of its incidence in PTCS. There is, however, some variation as exemplified by the figure for male children in Table 6.3. Obviously, in very young children intracranial hypertension is likely to present in other ways (vide infra). There is also some variation to be found in reports from the literature. Thus, both Radhakrishnan et al. (1986) and Sørensen et al. (1988) reported a 100% incidence of headache whereas, in the series of Rush (1980) and of Smith (1958), the incidence was 74.6% and 69.0% respectively. Orefice et al. (1984), in a study of PTCS in 20 obese women (mean age 37.6 years), found headache to be the sole symptom in only three cases compared with visual disturbance as the sole symptom in five cases. The headache of

133

Presenting symptoms

PTCS does not appear to have any distinctive features. According to Digre (2002) it is indistinguishable from the headache of migraine, with clues to the cause of the headache being found in the nature of any accompanying symptoms. In an interesting study of 82 cases of IIH (PTCS) after diagnosis and treatment, Friedman and Rausch (2002) found that 68% still had a headache disorder: in 50% this was episodic tension headache and in 20% migraine without aura. This has significance for treatment, especially in shunted cases. Disturbances of vision

This is the next most common symptom, at least in adults. Patients may complain of simple blurring of vision, or of actual loss of acuity of varying degrees of severity, or of obscurations of vision, or, indeed, any combination of the three. The overall incidence of visual disturbance is variable but may be taken as being in the range of 35
50% with blurring of vision the most common complaint. Obscurations of vision are typically transient, lasting a few seconds only and occurring with a variable frequency. They may be attributable to hypotension in the visual pathway caused by transient changes in ICP (Corbett, 1983) and may be associated with postural change which supports the idea of a transient change in the local circulation as causative, but they can also occur with the patient entirely at rest. The reported incidence of obscurations of vision is quite variable. Thus, in the Sydney series it was 10%, predominantly in adult females, whilst Wall and George (1991) found an incidence of 20% in an analysis of 1020 reported cases. In some recent series a much higher incidence is recorded. For example, Wall and George (1991) give a figure of 72% for their own series of 50 cases (almost all obese females) whilst Guiseffi et al. (1991) give a figure of 68% in their series of 50 cases. In one more recent series of 62 cases (47 females, 15 males), the incidence of transient obscurations of vision was also high at 60% (Celebisoy et al., 2002). Obscurations of vision are not predictive of permanent visual loss, as several authors have pointed out (Rush, 1980; Corbett et al., 1982), although they are generally an encouragement to the clinician to institute rapid and vigorous treatment. Diplopia

Disturbance of ocular motility is almost invariably due to partial or complete paralysis of one or both VIth nerves as a result of raised ICP, and is manifest as horizontal diplopia. The overall incidence ranges from 20 to 35% in most series. The VIth nerve weakness may be subtle and only apparent on saccadic eye movement, or it may be marked and easily detected as an obvious limitation or loss of abduction on testing the range of eye movements. Diplopia is relatively more common in children than in adults and the incidence may exceed that of

134

Clinical features

disturbances of visual acuity in the paediatric age group (see Table 6.3). Vertical diplopia may also occur due to a IVth nerve palsy where it may be accompanied by hypertropia of the affected eye, increased adduction, and ipsilateral head tilt. Speer et al. (1999) described three such cases, all under 18 years, seen over a 20-year period. Nausea and vomiting

Like diplopia, a non-specific symptom of intracranial hypertension, nausea and vomiting occur in around 20
30% of patients with PTCS. Also like diplopia, the relative incidence tends to be higher in children. As with the headache of PTCS, there are no particular distinguishing features to the nausea and vomiting. Tinnitus

This is an important, albeit relatively infrequent symptom of PTCS. In fact, Meador and Swift (1984) reported four cases of PTCS presenting with tinnitus alone and there is also the more recent report of a similar finding by Lee (1996). The incidence in the collected cases from the literature was 2.8% comparable to the 3.8% incidence in adult females in the Sydney series. A higher incidence (8.2%) was noted in the Glasgow series. Looked at from another aspect, in a series of 145 patients with pulsatile tinnitus collected over the period 1981
1996, Sismanis (1998) found BIH (PTCS) to be the most common cause, being responsible for 56 of the 145 cases. Other symptoms

A variety of other symptoms have been described. The most common of these are probably dizziness and neck stiffness, both of which could reasonably be attributed to intracranial hypertension. The same may also apply to disturbances of consciousness ranging from drowsiness through syncopal episodes to frank epilepsy, although the connection with raised ICP is arguably more tenuous here and the possibility of other diagnoses must be considered. Round and Keane (1988) made a specific study of what they called the ‘minor symptoms of increased intracranial pressure’ referring to a retrospective analysis of 101 cases of BIH (PTCS). The symptoms which they drew attention to were neck stiffness, tinnitus, distal extremity paraesthesias, joint pains, low back pain, and gait ‘ataxia’ (Table 6.5). There have also been reports of facial pain (Hart & Carter, 1982), facial paresis (Chutorian et al., 1977), hemifacial spasm (Benegas et al., 1996), severe neck, arm and back pain (Bortoluzzi et al., 1982), and neck stiffness with torticollis in children (Straussberg et al., 2002).

135

Presenting symptoms Table 6.5. Symptoms of PTCS (BIH): from Round and Keane (1988)

Symptom

R&K (101 cases)

Weisberg (120 cases)

Rush (63 cases)

J&P (110 cases)

Bulens (36 cases)

Headache Visual obscurations Vomiting Dizziness Diplopia Decreased vision Neck stiffness Tinnitus Paraesthesias Arthralgias Back/leg pain Ataxia

95% 53 39 30 26 21 31 27 22 13 5 4

99% 5 40 50 20 25 -

75% 46 21 35 68 -

99% 32 13 36 57 8 2 -

83% 6 44 25 47 31 17 19 14 11 11

R & K ¼ Round & Keane (1988); J & P ¼ Johnston & Paterson (1974a). Obesity and menstrual irregularity

Both are accompaniments of PTCS although, whilst case
control studies have confirmed the former, they have rather discredited the idea of an association with menstrual irregularity. Both factors have been considered in the previous chapter but some further aspects will be briefly dealt with here. In the Glasgow series, 31.8% of the 110 cases were described as having moderate to severe obesity. All were females, and 77.1% of them (27 of 35) were in the group without identifiable aetiology. The figures in the Sydney series were almost identical
an overall incidence of obesity of 31.3% with all but one of the affected patients being female. However, the findings were slightly different with respect to menstrual irregularity. In the Glasgow series, the incidence of this symptom was 16.9% of the women and all but two were also obese whereas, in the Sydney series, the incidence of menstrual irregularity was low. In the cases collected from the literature, there were 452 obese females and only six obese males giving an incidence of 35.5% for obesity in females compared to 1.1% for males. Greer, in a series of papers in the 1960s (1964a,b, 1965), reported small groups of women in whom PTCS was particularly associated with menstrual irregularity, the menarche (also discounted in case
control studies), and obesity respectively. Of the 20 patients described with obesity, all females, there were six with a history of menstrual irregularity. In two other series concentrating on PTCS in obese women, those of Wilson and Gardner (1966) and Orefice et al. (1984), the former reported ‘a few cases’ of

136

Clinical features

menstrual irregularity and the latter none. On the other hand, Wessel et al. (1987), in a series with a preponderance of obese women, reported a 5.7% incidence of menstrual irregularity. Duration of symptoms

This is quite variable although, in the majority of cases, the history is less than 3 months at the time of presentation. Tables 6.6 and 6.7 show the figures for duration of symptoms for the Glasgow and Sydney series, the emphasis being slightly different in the two instances. In Table 6.6, figures are given separately for headache and visual symptoms as a whole, and for cases without and with an apparent aetiology. The following four points are apparent: 1. In almost 60% of cases the duration of symptoms is less than 3 months, with approximately half of these cases having a history of less than one month. 2. This applies equally to headache and visual disturbance. Table 6.6. Duration of presenting symptoms in PTCS: Glasgow series

Duration

Symptom

<1 month

1
3 months

4
6 months

7
12 months

412 months

Headache, no aetiology Headache, aetiology Headache, all cases Visual symptoms, no aetiology Visual symptoms, aetiology Visual symptoms, all cases % Headache, all cases % Visual symptoms, all cases

12 13 25 12 15 27 22.7 24.5

21 15 36 23 14 37 32.7 33.4

5 2 7 7 3 10 6.4 9.1

9 4 13 6 2 8 11.8 7.3

12 6 18 3 3 6 16.4 5.5

Total 59 40 99 51 37 88

Table 6.7. Duration of presenting symptoms in PTCS: Sydney series

Duration Age, sex

<1 month

1
3 months

4
6 months

7
12 months

412 months

Female adults Male adults Female children Male children Total Total (percentage)

15 3 23 12 53 40.2

21 2 8 3 34 25.8

5 1 1 3 10 7.8

4 0 0 1 5 3.8

17 4 4 5 30 22.7

137

Presenting symptoms

3. This applies more or less equally to cases without and with an apparent aetiology. 4. In cases with a history longer than 12 months, headache is the most common symptom. In Table 6.7, division is made on the basis of age and sex but no division is given for the type of symptom. The following points are apparent from this table: 1. In the majority of patients the duration of symptoms is again less than 3 months. 2. The higher proportion of patients in the <1 month group is a reflection of the high incidence of a short history in children. 3. The converse of this is the higher proportion of adults with a long history, i.e. 412 months. The literature confirms the above findings in broad terms. Thus Weisberg (1975a), reporting 120 cases, found the following breakdown: <1 month, 50%; 1
3 months, 30%; 3
12 months, 13%; 412 months, 7%. For children, Weisberg and Chutorian (1977) gave the following figures for 38 cases: <2 weeks, 19 cases; 2
4 weeks, 9 cases; 1
2 months, 8 cases, with two cases being diagnosed on routine assessment. There are certainly isolated reports and small numbers of cases in larger series with a long history, even extending to years (particularly with prolonged visual symptoms) but these are very much in the minority. There are also some series in which there is a relatively long duration of symptoms overall. Thus, Smith (1958), reporting 36 cases, gave an average duration of 8.2 months with a range from 5 days to 4 years whilst Radhakrishnan et al. (1986), reporting 23 female patients with a high incidence of obesity (74%), found an average duration of symptoms of 11.8 months (range 1 week to 4 years). In summary, it may be said that in the majority of cases of PTCS the history is short, less than 3 months, and this is irrespective of sex or identifiable aetiology. In children, the incidence of a short history is greater than in adults. On the other hand, a number of patients do have a long duration of symptoms, and if untreated, symptoms may persist for many years. Atypical presentations

What follows is a brief summary of a number of unusual types of presentation of PTCS, of which clinicians should be aware. Asymptomatic PTCS

There are two categories to be considered here. The first is the asymptomatic patient who is also without physical signs. Three such cases were described by Johnston et al. (2001), all of them children and all previously treated for PTCS.

138

Clinical features

At the time of re-assessment, all were entirely free of symptoms or signs but had a demonstrable increase of CSF pressure. More common, however, are asymptomatic patients who are found on examination to have clinical signs of intracranial hypertension, notably papilloedema. For example, Weig (2002) reported three children who were found to have papilloedema on examination for some unrelated condition. In the Sydney series of 150 cases, there were three patients, all adult females, who were found incidentally to have papilloedema and were subsequently diagnosed as having PTCS. There was also one male child with an apparently asymptomatic squint who was found on investigation to have PTCS. As shown in the table giving presenting symptoms in patients collected from the literature (Table 6.4), there were 23 of 1589 cases (1.4%) who were asymptomatic at the time of diagnosis. It is, not surprisingly, difficult to establish the incidence of asymptomatic PTCS. In one recent report (Galvin & Van Stavern, 2004) the figure was put as high as 24.7%. In relation to this group as a whole, it is of interest to note that in treated patients, although there may be resolution of symptoms and improvement in signs, the CSF pressure may still be significantly raised, and this has been documented in treatment with steroids, subtemporal decompression, and optic nerve sheath fenestration (Johnston et al., 1981; Jacobson et al., 1999b). Headache without eye signs

Beginning with the report by Lipton and Michelson (1972), followed by the reports of Scanarini et al. (1979) and of Spence et al. (1979), there has been increasing awareness of the fact that PTCS can occur without any of the characteristic physical signs being present. The incidence of such a presentation may not, in fact, be insignificant. Thus, in the Sydney series, there were 10 such cases, 7 females (average age 27.5 years) and 3 males (average age 12.3 years). More recently, there have been larger studies of this matter. For example, Wang et al. (1998) reported a case
control study from a headache centre covering the period from 1989 to 1996 in which they found 25 cases of PTCS, taking as their criterion two LP measurements of CSF pressure 4200 mmH2O. In these cases the headache was indistinguishable from other kinds of headache. Predictors were obesity (odds ratio 4.4) and pulsatile tinnitus (odds ratio 13.0). Quattrone et al. (2001) studied 114 patients with chronic daily headache (CDH) using MRV. Of the group, 103 patients had a normal MRV, 6 had a unilateral transverse sinus flow abnormality, and 5 had a bilateral transverse sinus flow abnormality. In 27 of the first sub-group, CSF pressure on lumbar puncture was normal whereas in the second and third sub-groups, 1 of 6 and 4 of 5 respectively had a CSF pressure 4200 mmH2O.

139

Presenting clinical signs

CSF rhinorrhoea

There are now several reports of such a presentation (Clark et al., 1994; Camras et al., 1998; Osveren et al., 2001; Owler et al., 2003a). In our own experience, which includes the last of the reports listed above and one unreported case, such a presentation occurred in patients with a previous history of PTCS apparently in remission. Sleep apnoea

In recent years there have been several reports of sleep apnoea in patients with PTCS (Purvin et al., 2000; Marcus et al., 2001; Lee et al., 2002). These studies have been of the investigation for sleep apnoea in patients known to have PTCS. Thus Marcus et al. (2001) investigated 53 patients with IIH (PTCS) of whom 37 had a history suggestive of sleep apnoea. Of the 14 patients investigated with polysomnography (12 females, 2 males), six had sleep apnoea and seven upper airways resistance syndrome. In a similar study of 32 cases of IIH (PTCS) in men, Lee et al. (2002) found six cases with sleep apnoea. There have not been any reports of patients presenting with sleep apnoea being investigated for PTCS, but this should, perhaps, be considered as a diagnostic possibility. Other

There have been isolated reports of other presentations, notably as hemiplegic migraine (Stanley, 2002), hemifacial spasm (Benegas et al., 1996; Grassi et al., 2001), pulsatile tinnitus (Lee, 1996), atypical brachial plexopathy (Awada et al., 1999), and stiff neck with torticollis in children (Straussberg et al., 2002).

Presenting clinical signs Tables 6.8 to 6.10, show the relative incidence of the clinical signs noted at presentation for the Glasgow and Sydney series and for cases collected from the literature respectively. In the Glasgow series a division is made into patients without and with an identifiable aetiological factor. Overall, there was a very high incidence of papilloedema and a relatively high incidence of reduced visual acuity. There was, however, a low incidence of visual field abnormalities. There was no appreciable difference in physical signs between the group without and the group with an identifiable aetiology. In the Sydney series, a division was made on the basis of age and sex. The overall incidence of papilloedema was lower than in the Glasgow series, this reflecting a relatively low incidence in males. The incidence of reduced visual acuity was also less and was evenly spread over the four age/sex categories. There was a closely similar incidence of visual field

140

Clinical features Table 6.8. Incidence of physical signs: Glasgow series

Physical sign (no.)

No aetiology (62 patients) Aetiology (48 patients) Total Percentage

Papilloedema None Mild Moderate Severe Not recorded

0 4 27 30 1

0 4 20 23 1

0 8 47 53 2

0 7.3 42.7 48.2 1.8

Visual acuity Normal Mild reduction Marked reduction Not recorded

31 18 12 1

25 13 7 3

56 31 19 4

50.9 28.2 17.3 3.6

Other signs Enlarged blind spots Visual field defect Ocular palsy Other visual Other neurological

22 11 11 7 2

13 5 15 6 7

35 16 26 13 9

31.8 14.5 23.6 11.8 8.2

Table 6.9. Incidence of physical signs: Sydney series

Physical sign (%) Papilloedema Reduced visual acuity Restricted visual fields Unilateral VI nerve palsy Bilateral VI nerve palsy Other signs

All cases

Female adults

Male adults

Female children

Male children

80.0 24.7 15.3 12.0 7.3 12.0

80.8 29.5 21.8 6.4 5.1 3.3

63.6 27.3 18.2 0 0 0

94.3 20.0 5.7 22.9 6.4 4.0

65.4 15.4 7.7 19.2 7.7 4.7

abnormality which also tended to be less in children. There was a comparable incidence of VIth nerve palsy in the two series, this sign showing a higher incidence in children. The two series showed a relatively similar incidence of other signs. In the collected cases, all reported before 1992, there was a very high incidence of papilloedema and, as in the other series, an approximately 20% incidence of VIth nerve palsy. The incidence of both reduced visual acuity and visual field abnormality was noticeably lower. We shall return to this point in what follows, which is a brief consideration of each of the listed symptoms.

141

Presenting clinical signs Table 6.10. Incidence of physical signs: cases from the literature

Physical sign

Total

Percentage

Number of cases Papilloedema VIth nerve palsy Reduced visual acuity Visual field loss Tense anterior fontanelle Miscellaneous

1572 1460 321 193 93 61 106

92.8 20.4 12.3 5.9 3.9 6.7

Papilloedema and related findings

Papilloedema is almost universally present and is likely to be absent only in very young children and the occasional atypical older child or adult. As Corbett (1983) has pointed out, there are no apparent differences in the nature of the papilloedema found in PTCS and that in other conditions with raised CSF pressure. Its various concomitants such as haemorrhages (splinter or subretinal) and exudates (‘hard’ and ‘soft’) are seen in a significant proportion of cases. In a small number of cases the papilloedema may be unilateral, due either to pre-existing pathology in the non-papilloedematous eye (which accounted for three of the four cases with unilateral papilloedema in the Sydney series), or for some other reason. The generally accepted view on the latter, based largely on the experiments and opinions of Hayreh (1964, 1966, 1977), is that the difference depends on the variability of patency of the subarachnoid sheath around the optic nerve and hence the capacity of the CSF pressure to be transmitted to the nerve itself and therefore to affect axoplasmic flow. On this point, it is interesting to note that one patient in the Sydney series who presented with severe headache and unilateral papilloedema subsequently developed papilloedema on the originally non-affected eye during a recurrence of PTCS after the initial episode had been successfully treated. Of the 1460 cases with papilloedema in the collected series, there were 12 with unilateral papilloedema and there have been several specific reports of this finding
those of Kirkham et al. (1973), Sher et al. (1983), and Maxner et al. (1987) giving a total of nine cases, all women, of whom six were described as obese. More recently, Huna-Baron et al. (2001) studied 15 patients with unilateral swollen disc (10 with IHH/PTCS) and found no reason for the asymmetry on imaging studies. In making a diagnosis of papilloedema due to intracranial hypertension, other possible causes of optic disc swelling must be borne in mind. These include ocular hypotony, chronic uveitis, vasculitis of the optic disc, granulomatous infiltration of the optic disc, drusen, unusual refractory error,

142

Clinical features

severe arterial hypertension, anterior ischaemic optic neuropathy, lesions compressing the optic nerve, and inflammatory optic papillitis. Optic atrophy may also be found in PTCS but is obviously more likely to be a late finding subsequent to papilloedema. It was reported as a finding on presentation in 4% of cases in the collected series and was noted in 2 of the 150 cases of the Sydney series. Other disc changes related to increased pressure in the optic nerve sheath have also been described. These include chorioretinal folds (Bird & Sanders, 1973; Jacobson, 1995), changes in optociliary shunt vessels (Eggers & Sanders, 1980; Perlmutter et al., 1980; Lagreze & Kommerell, 1996), and juxtapapillary subretinal neovascularization with or without subretinal haemorrhages (Jamison, 1978; Troost et al., 1979; Morse et al., 1981; Coppeto & Montiero, 1985; McCasland et al., 1999). There are also reports of drusen co-existing with papilloedema in PTCS (Reifler & Kaufman, 1988; Katz et al., 1988; Krasnitz et al., 1997). Extraocular movement abnormalities

These are almost invariably due to unilateral or bilateral VIth nerve palsy which occurs in approximately 20% of cases at presentation. There is more likely to be unilateral than bilateral involvement and children are more likely to be affected than adults. There is also a small incidence of IVth nerve palsy either alone (Speer et al., 1999), in association with VIth nerve palsy (Patton et al., 2000), or as part of a complete external ophthalmoplegia (Snyder & Frenkel, 1979). McCammon et al. (1981) described one patient with painless unilateral IIIrd nerve palsy in PTCS who went on to develop bilateral IIIrd nerve involvement as well as a unilateral VIIth nerve palsy. Other gaze palsies have also been described (Baker & Buncic, 1985; O’Duffy et al., 1998). Reduced visual acuity

There is general agreement that reduced visual function in papilloedema reflects changes at the optic nerve head due to axoplasmic flow stasis and the resultant intraneuronal ischaemia (Rowe & Sarkies, 1998; Wall, 2000). The actual incidence of loss of visual acuity, whether at presentation or subsequently, varies considerably between reports. Thus, comparison of the figures in Tables 6.8 to 6.10 shows a range from 50% down to 11.9%. This same variation is reflected in other large series, ranging from the 5% quoted by Weisberg (1975a) in his series of 120 cases to figures similar to the Glasgow and Sydney series, i.e. a range from 30 to 50% (Dandy, 1937; Bradshaw, 1956; Bulens et al., 1979). Recent studies report similar figures, for example, Celebisoy et al. (2002) quote 27% and Craig et al. (2001) 21%. Corbett et al. (1982), who made a detailed study of visual loss in PTCS, found an at presentation incidence of only 16% which rose to around 25% with progression of

143

Presenting clinical signs

the disease and the later effects of papilloedema. In a subsequent review, Corbett (1983) concluded that some degree of visual impairment will occur in about 50% of patients and that there will be serious unilateral or bilateral visual loss in about 25% of cases. Gutgold-Glen et al. (1984) gave a figure of 10
20% for permanent visual loss. It is noteworthy that papilloedema can be very chronic in PTCS without significant visual loss. Thus Rabinowicz et al. (1968) studied eight patients with PTCS in whom papilloedema had been present for 3 to 6 years and found all to have normal visual acuity, although three had visual field abnormalities (two cases, inferior nasal quadrant loss; one case, general peripheral constriction) and two cases had mild optic atrophy without loss of acuity. On the other hand, acute loss of visual acuity can certainly occur, particularly related to subretinal haemorrhages as described above, or to central retinal artery occlusion (Baker & Buncic, 1984). Restriction of visual fields

Similar comments on relative incidence apply to visual field abnormalities as to loss of visual acuity. The difference is that the range is much wider and this largely reflects the increasing diligence with which visual field abnormalities are sought and the improved techniques used in assessment. Of course, enlargement of the blind spots, attributed by Huber (1971) to displacement of the peripapillary rods and cones by the swollen axons, is demonstrable in most instances of papilloedema, although it is very variably reported in PTCS. There was a suggestion that plotting the blind spots might be a simple and useful way of following progress in PTCS (Jefferson & Clark, 1976), but Corbett (1983) has drawn attention to the unreliability of this measure. As to incidence, the low figures given in Tables 6.8 to 6.10 (all <20%) should be compared with the recent reports of Celebisoy et al. (2002) and Craig et al. (2001) giving figures of 71% and 62%, respectively. In a study of 37 children, Phillips et al. (1998) gave a figure of 27.0% for visual field abnormality compared to 10.8% for reduced visual acuity. Rowe and Sarkies (1998), who identified the common types of visual field disturbance as arcuate defects, nasal steps, and global constriction, found an overall incidence of visual field loss at presentation and during follow-up of 87% with Goldman perimetry and 82% with Humphrey perimetry. The actual range of visual field defects in PTCS is broad. Wall and George (1987) made a detailed study of visual fields in 20 cases of PTCS (13 with active disease, one on the point of resolution, and six after resolution) using a glaucoma screening technique and automated threshold perimetry as well as Goldman perimetry (Table 6.11). Baker and Buncic (1985), who made a similar but less detailed study in children, found the following abnormalities: enlarged blind spots, 20 cases; concentric

144

Clinical features Table 6.11. Types of visual field loss in 20 patients (40 eyes) with PTCS: from Wall and George (1987)

Type of visual field loss

Octopus perimetry

Goldman perimetry

Constriction Inferonasal loss Superior arcuate defect Nasal loss Inferior temporal loss Cecocentral scotoma Superior loss Inferior arcuate defect Central scotoma Paracentral scotoma Temporal island only Superior temporal loss Inferior loss Normal eyes

15 13 4 12 1 4 2 2 0 3 0 1 1 10

20 18 4 3 2 2 2 1 1 1 1 0 0 9

constriction, 4 cases; nasal or inferonasal defect, 4 cases; arcuate scotoma, 2 cases; permanent irregular enlargement of the blind spot, 5 cases; central or paracentral scotoma, 2 cases. One point alluded to earlier is also noted by Wall and George (1987). These authors, quoting the high incidence of visual field and acuity disturbances in series with detailed examination of the visual fields
49% of 114 eyes with field loss (Corbett et al., 1982), 44% of cases with field and/or acuity loss (Orcutt et al., 1984), 32% of cases with field loss (Rush, 1980)
stress that detection of visual field loss is very dependent on examination strategy, and that, particularly in early series, the incidence may have been substantially under-reported. Other signs

The issue of the presence of other signs at presentation (apart from the signs of raised CSF pressure peculiar to infants) is a somewhat complex one insofar as, strictly speaking, such signs preclude the diagnosis of PTCS. Conversely, if the broader definition of PTCS is accepted, the presence of other signs is also acceptable; for example, in cases with cranial venous sinus pathology, or alterations of CSF composition as in the Guillain
Barre´ syndrome or poliomyelitis. Among the 1589 cases collected from the literature, the following signs were reported: increased head circumference with tense anterior fontanelle, 61 cases; nystagmus, 40 cases; ataxia, 24 cases; focal motor disturbance, 8 cases; focal sensory loss

145

PTCS in children

(including trigeminal area loss), 5 cases; hearing loss, 3 cases; positive Romberg’s sign, 3 cases. In subsequent reports the following additional signs have been noted: facial nerve palsy both unilateral and bilateral (Selky et al., 1994; Capobianco et al., 1997), trigeminal sensory disturbance (Davenport et al., 1994; Arsava et al., 2002), hearing loss (Dorman et al., 1995), Lhermitte’s sign (Comabella et al., 1995), panuveitis (Margalit et al., 2005), and orthostatic oedema (Friedman & Streeten, 1998). PTCS in males In general, male patients with PTCS form a small proportion of any series of cases, and apart from the association with obesity which characterizes the condition in women, are thought to show the same basic clinical picture. There have been one or two studies which have looked at this matter specifically. Thus, Digre and Corbett (1988) noted a wide range of relative incidence of PTCS in males in reports generally, but when they focused on large series (450 cases) they found the number of males to range between 17 and 35% which was in accord with their own finding of 16%. Comparing 29 males suffering from PTCS with the same number of age-matched females, they found the signs and symptoms to be essentially similar other than obesity being less of a factor. They did note, however, that there was a greater incidence of obesity in the men with PTCS than in controls. More recently, Kesler et al. (2001), addressing the same issue in a series of 134 cases of PTCS (18 males, 116 females), reported 77% of the women as being obese compared with 25% of the men, but found the condition was otherwise the same in the two sexes both in terms of clinical features and of outcome. PTCS in children In the case of children, there are some significant differences when compared to adults. Before briefly enumerating these differences, reference is made to the study of Gordon (1997) which is the one study to consider incidence in children specifically. In a survey carried out in Nova Scotia over the period 1979
1994, he identified 29 cases aged between 3 and 15 years which worked out as an annual incidence of 0.9/100,000. In this study, the cases were 2.7 times more likely to be female and twice as likely to be adolescent, suggesting that some younger cases may have been overlooked. The points of difference are as follows, taking children as patients under 18 years: 1. There is an apparently equal distribution of the sexes as opposed to the marked female preponderance in adults. Thus in the Sydney series (a series with a paediatric bias) in a total of 150 cases, there were 89 adults and 61 children.

146

Clinical features

The sex ratio F:M was 1.4:1 in children compared to 7.1:1 in adults. In the 374 paediatric cases collected by Scott et al. (1997), there were 199 females compared to 175 males (1.1:1). 2. There is a greater incidence of apparent causative factors in children. Thus, in the Sydney series, such factors were present in 19 of 35 females (54.3%) and 17 of 26 males (65.4%) giving an overall incidence of 59.1%. Scott et al. (1997) give a closely similar figure of 53.2%. In the smaller individual series reported by Phillips et al. (1998), the figure was even higher: of 35 patients under 18 only 10 were described a as ‘idiopathic’ giving an incidence of 71.4% for an apparent causative factor. 3. There is a lower incidence of obesity in PTCS in children. Nonetheless, there does appear to be a definite association with obesity in females in the second decade (Gordon, 1997; Kesler & Fattel-Valevski, 2002) although the numbers on which such a conclusion is based are small. The latter authors concluded that in pre-pubertal children there is no female preponderance and no association with obesity and that is borne out in our own experience. 4. There are differences in clinical presentation. This predominantly applies to infants and young children and reflects the different presentation of intracranial hypertension generally in this group; i.e. irritability, abnormal rate of head growth, increased anterior fontanelle tension, and abnormal head circumference. In our own series, neck pain and stiffness and back pain were also notable symptoms in children and are symptoms also remarked upon by Lessell (1992).

Aspects of diagnosis PTCS has traditionally been considered a diagnosis of exclusion. However, there is less basis for such a description now with the increasingly clear definition of the clinical picture, although the element of exclusion of other possible causes of raised ICP remains important. From what has been said of the clinical features above, a readily recognizable presentation emerges. To summarize, patients typically complain of persistent, severe headache possibly associated with changes in visual acuity and diplopia, present for 1
3 months. The examination findings are typically limited to bilateral papilloedema and alterations of visual acuity and/or fields attributable to the papilloedema as well as a possible VIth nerve palsy. This is against a background of a clear sensorium and the absence of other neurological signs. Other factors which suggest a diagnosis of PTCS are the patient being a female in the 15
45 years age group, obesity, and the presence of one of the known precipitating factors. In children the presentation is largely similar,

147

Aspects of diagnosis

the differences being the nature of the manifestations of raised ICP in the very young, a shorter history, and a higher likelihood of both a VIth nerve palsy and an identifiable causative factor. The clinical diagnosis is less obvious where headache is the only symptom, especially if eye signs are absent. As was noted above, there appear to be no distinguishing features of the PTCS headache so, in such instances, PTCS becomes a component of the differential diagnosis of migraine and chronic daily headache generally (Huff et al., 1996; Mathew et al., 1996). If there are visual symptoms only, with the clinical finding of papilloedema and related functional abnormalities, or even the incidental finding of papilloedema, PTCS is high on the list of possible diagnoses. Here primary visual pathology including drusen (Krasnitz et al., 1997), or congenital disc anomalies (Collett-Solberg et al., 1998) must be considered. Again, the presence of significant predictive factors should direct the diagnosis towards PTCS. Another aspect of diagnosis is the recognition of the co-existence of the syndrome with other conditions such as cranial venous sinus occlusion or conditions which alter CSF composition. The process of establishing the diagnosis will be considered in detail in the following chapter but, in general, the elimination of other causes of raised ICP is readily and reliably achieved by current imaging techniques. Difficulties may be posed by conditions which show no distortion of the brain parenchyma such as gliomatosis cerebri (Weston & Lear, 1995) and diffuse leptomeningeal neoplasms (Kim et al., 2000; Ebinger et al., 2000). Once any lesion with the capacity to cause inter-compartmental brain shift has been satisfactorily excluded, the diagnosis can be confirmed by the demonstration of raised CSF pressure on lumbar puncture. Again, this will be considered in the following chapter. The purpose of the present chapter has been to detail the now well-defined clinical picture of the PTCS and to indicate the range of variation in this picture, particularly by identifying the more atypical forms of clinical presentation.

7

Clinical investigations

Introduction The four basic objectives in the clinical investigation of PTCS may be enumerated as follows: 1. To establish the existence of raised CSF pressure 2. To evaluate its severity 3. To exclude other causes of raised CSF pressure, leaving PTCS as a diagnosis of exclusion as it has traditionally been 4. To identify any aetiological factors responsible for the PTCS To these may be added investigations aimed at clarifying the mechanism of PTCS generally. Of course, these are not an essential component of the clinical investigation of a particular patient, a comment which also applies to some extent to the fourth category above. The first category includes direct measurement of CSF pressure
either a single measurement by lumbar, cervical, cisternal or ventricular puncture, or continuous monitoring over a period of time from an intracranial or lumbar site
and fluorescein angiography as an ancillary and indirect method. The second category includes continuous CSF pressure monitoring again, as well as, more indirectly, neuro-ophthalmological evaluation, electroencephalography (EEG), and neuropsychometric assessment. The third category includes analysis of CSF composition, and scanning methods, either CT or MR. The fourth category includes MR venography, DSA and venography, the latter with manometry, and detailed haematological analysis aimed at identifying thrombophilia and/or hypofibrinolysis. Investigations which at this stage are more or less limited to specialist centres are specialized MR techniques aimed at evaluating brain water content or CSF volume and dynamics, radionuclide studies of CSF dynamics, CSF infusion studies to quantitate resistance to CSF absorption, and metabolic or endocrine studies. In the present chapter, the material will be organized under these headings. Table 7.1 illustrates the way the pattern of investigation of PTCS has 148

149

CSF pressure Table 7.1. Investigations used in the diagnosis of PTCS during different time periods from 1900 to the present

Time period

‘Positive’ investigations

‘Negative’ investigations

Other investigations

Pre-1930

CSF pressure via LP

CSF composition Skull X-rays EEG

1930
1970

CSF pressure via LP

CSF composition Skull X-rays Pneumoencephalography Ventriculography Angiography Radionuclide scanning

Venous studies Metabolic/endocrine studies

1971
2005

CSF pressure via LP CSF pressure monitoring Fluorescein angiography

CSF composition CT scanning MR scanning

CSF infusion studies MR venography MR for brain water MR for CSF volume Radionuclide studies CBF/CBV studies Clotting studies Metabolic/endocrine studies

changed since the condition was first recognized. What are listed as ‘positive’ investigations are those used to establish the existence of intracranial hypertension whilst the ‘negative’ investigations are those used to exclude causes of intracranial hypertension other than PTCS. Data from the Glasgow and Sydney series will be presented, together with a review of the literature culminating, in each case, with an assessment of the applicability, value and shortcomings of the method under consideration. In reviewing the literature, data from some 500 papers is included. These are too numerous to mention individually except where some particular point is being made. Cerebrospinal fluid pressure Measurement of a raised CSF pressure is almost, but not quite, a sine qua non of diagnosis in PTCS. The exceptions include cases in whom the diagnosis is correctly made without a CSF pressure measurement for some reason, the ‘indirect’ evidence for raised CSF being taken as adequate, cases in whom a single manometric reading is normal, being taken at a relatively low point in a fluctuating state of raised CSF pressure, and the occasional case of ‘normal pressure’ PTCS

150

Clinical investigations Table 7.2. CSF pressure measured at lumbar puncture (Glasgow and Sydney series)

CSF pressure

Glasgow series

Sydney series

<10 mmHg 10
20 mmHg 420 mmHg Not recorded

3 16 77 14

3 22 96a 20

a

Total 6 (2.4%) 38 (15.1%) 173 (68.9%) 34 (13.5%)

Includes 24 patients who had CSF pressure measured by continuous monitoring rather than lumbar puncture and simple manometry.

(vide infra). In the great majority of cases, CSF pressure is evaluated by lumbar (or occasionally cervical) puncture and simple manometry. In a minority of cases, continuous CSF pressure monitoring is carried out. These two methods will be considered separately. Lumbar puncture

In the Glasgow series, CSF pressure was measured manometrically at lumbar puncture in 96 of 110 patients (Table 7.2). Of these patients, 70.0% had a CSF pressure greater than 20 mmHg, 14.5% had a highest recorded level between 10 and 20 mmHg, and 2.7% had a maximum recorded pressure less than 10 mmHg. In 12.7% of cases no lumbar puncture was carried out. In the three patients with a CSF pressure less than 10 mmHg at lumbar puncture the measurement was made shortly after ventriculography. In one of these patients a subsequent ventricular puncture showed a raised CSF pressure. Of the 14 patients in whom CSF pressure was not measured at lumbar puncture, seven were estimated to have raised pressure on ventricular puncture for ventriculography. The figures in the Sydney series were closely comparable. That is, 68.1% of patients had a moderate to marked increase in CSF pressure and 15.6% of patients had a mild to moderate increase. Of the three patients with a CSF pressure <10 mmHg on lumbar puncture, two subsequently were found to have increased CSF pressure on continuous monitoring via a lumbar catheter. The remaining patient had normal CSF pressure levels over a 24-h period of continuous monitoring. This patient had typical PTCS symptomatology with marked bilateral visual loss and was treated by lumbar CSF shunting with significant improvement. During later episodes of shunt malfunction in this patient the CSF pressure at lumbar puncture was consistently raised. Of the 20 patients (15 adults, 5 children) diagnosed without lumbar puncture, 13 had both a typical clinical picture of PTCS and a clear-cut aetiological factor (venous sinus pathology, 5; ear disease, 2; family history, 2; thyroid disease, 1; steroid withdrawal, 1; prolonged tetracycline use, 1;

151

CSF pressure Table 7.3. Range of measured CSF pressures in two series of PTCS patients

CSF pressure (mmCSF) Weisberg (1975a) Weisberg and Chutorian (1977)

<200

200
300

301
400

401
500

4500

Total

0 2

12 2

72 20

30 9

6 5

120 38

multiple factors, 1), three had radiological evidence of intracranial hypertension (empty sella, 2; separated sutures on skull X-rays, 1), one had a coincident Chiari malformation (Sinclair et al., 2002), and 3 had a typical clinical picture only. Several of these 20 patients were treated entirely as out-patients. There was no instance in this group of patients of evidence later emerging to suggest an incorrect initial diagnosis of PTCS. From the literature review of 1418 cases, a raised CSF pressure at lumbar puncture was recorded in 1208 cases (85.2%) with values ranged from 200 to 600 mmCSF. A breakdown of values from the series of Weisberg (1975a) and Weisberg and Chutorian (1977), the latter consisting of children only, is given in Table 7.3. In 136 cases (9.6%) no CSF pressure measurement was given. In a proportion of these cases a lumbar puncture was carried out but the CSF pressure was either not measured or not recorded. In the majority of these cases, however, lumbar puncture was not done, due either to the presumed certainty of diagnosis without this investigation, or to concern about the possibility of precipitating tentorial or tonsillar herniation. In 74 cases (5.2%) a normal CSF pressure was recorded. In one large series (Guidetti et al., 1968), 39 of 100 patients were said to have had a normal CSF pressure on lumbar puncture. In a number of those cases with an initial normal CSF pressure reading on lumbar puncture subsequent lumbar punctures or continuous CSF pressure monitoring did show an abnormal pressure. Continuous CSF pressure monitoring

This technique may be used with either a lumbar or ventricular catheter connected to a remote transducer, or with one of a number of other devices available for intracranial pressure monitoring. It was used in 20 patients in the Glasgow series making use of the ventricular catheter inserted for ventriculography. A particular study of the nature of ICP abnormalities in PTCS was made in the Glasgow series (Johnston & Paterson, 1974b) and the findings will be outlined here before focusing on the diagnostic relevance of the technique. In the 20 cases from the Glasgow series mean ICP levels ranged from 1 to 35 mmHg. The patients were divided into two groups: those with unequivocally raised ICP levels (13 patients) and those with normal or equivocal ICP levels

152

Figure 7.1

Clinical investigations

Low amplitude, 1/minute intracranial pressure (ICP) waves in PTCS. (From Johnston and Paterson, 1974b; reproduced with permission.)

(7 patients). Of the 13 patients in the first group, 10 had fluorescein angiography to confirm papilloedema and this was positive in all cases. In addition, radionuclide cisternography was abnormal in the three patients in this group in whom it was carried out. In the second group, fluorescein angiography was positive in two patients (mean ICP levels 11 and 14 mmHg) and negative in five patients (mean ICP levels 1
13 mmHg). Radionuclide cisternography was carried out in two patients in this group and was abnormal in one of the two patients with a positive fluorescein study and negative in one of the five patients with a negative fluorescein study. In the 13 group one cases (mean ICP 4 15 mmHg) the basic level ranged between 10 and 20 mmHg in three cases, between 20 and 30 mmHg in seven cases, and between 30 and 40 mmHg in three cases. In all cases wave-like increases in ICP of different types were superimposed on the basic level. The most common waves, seen in all 13 cases, were of low amplitude (10 to 20 mmHg) and an approximate frequency of 1 minute. Typically, such waves built up slowly but terminated abruptly after a sharp peak, occurred in clusters, long runs or irregularly, were interrupted by other wave forms, and were not associated with any changes in clinical state (Figure 7.1). Plateau waves, varying in amplitude from 50 to 80 mmHg and in duration from 5 to 20 min, were seen in 8 cases (Figure 7.2). In all instances they were separated by relatively long intervals (60 to 120 min) and were followed by a drop in the basic pressure to its lowest recorded levels with a return to pre-plateau levels over 30 min or more from the end of the wave. Plateau waves were not accompanied by any change in the patient’s clinical state (Figure 7.3), although in two patients they did appear to be precipitated by drinking.

153

Figure 7.2

CSF pressure

Typical plateau wave of ICP in a patient with PTCS. (From Johnston and Paterson, 1974b; reproduced with permission.) VFP ¼ ventricular fluid pressure.

Figure 7.3

Lack of association between headache and ICP in a patient with PTCS. (From Johnston and Paterson, 1974b; reproduced with permission.)

Other plateau-like waves, again unaccompanied by any change in clinical state, were seen in eight patients. These were of lower amplitude (30 to 40 mmHg) and shorter duration (5 to 10 min) than the typical plateau waves and occurred in clusters lasting 20 to 40 min, each cluster being followed (with one exception) by low ICP levels and a relatively featureless trace. A gradual build-up of ICP then preceded the next cluster of such waves. In one patient with high ICP, waves were essentially absent. In this patient the general level was high and showed frequent increases to levels around 50 mmHg which persisted for over 1 h (Figure 7.4). In 2 of the 13 cases with raised ICP in whom monitoring was repeated (intervals 4 and 18 months) the mean ICP levels were lower on the second occasion (35 to 23 mmHg and 29 to 10 mmHg respectively) and pressure waves were less noticeable. Most of the seven patients with mean ICP levels <15 mmHg had flat, featureless ICP traces with only occasional 1/minute waves. In one case, however, who had

154

Figure 7.4

Clinical investigations

Sustained elevation of ICP without waves in a patient with PTCS. (From Johnston and Paterson, 1974b; reproduced with permission.)

Figure 7.5

Correspondence between ventricular and lumbar CSF pressures in a patient with PTCS. (From Johnston and Paterson, 1974b; reproduced with permission.)

a positive fluorescein angiogram and abnormal radionuclide cisternography, the 1/minute waves were frequent and occasional atypical plateau waves were also seen. This patient’s symptoms, which initially settled without treatment, recurred and further ICP monitoring after an interval of 2 years showed a similar pattern. At this point the patient was treated for PTCS. Simultaneous monitoring of ventricular and lumbar CSF pressures was carried out in five patients for periods of 1 to 2 h. The two pressures corresponded extremely closely throughout in all five cases (Figure 7.5). Lumbar drainage of 15 to 25 ml of CSF was sufficient to reduce the ICP to normal levels in each of these five patients. The average time taken for the ICP to return to pre-drainage levels was 82 min. If it is assumed that the return of the ICP to pre-drainage levels was due to production of the same volume of CSF as was drained, this corresponds to an estimated rate of CSF formation of 0.26 ml min
1 (Table 7.4). None of the patients with raised ICP had an abnormally high blood pressure. Simultaneous monitoring of intracranial and arterial pressures was carried out

155

CSF pressure Table 7.4. Effect of lumbar CSF drainage on ICP and estimated rate of CSF formation in PTCS (mean values from five patients)

Figure 7.6

Parameter

Result

Initial ICP Final ICP Recovery time CSF volume (drained) Estimated CSF formation rate

30 mmHg 7 mmHg 82 minutes 21 ml 0.26 ml min
1

Variations, including a marked fall, in cerebral perfusion pressure (CPP) during episodic changes in ICP in a patient with PTCS. (From Johnston and Paterson, 1974b; reproduced with permission.) MAP ¼ mean arterial pressure.

over several hours in three patients. Arterial pressure showed little change with increases in ICP. Indeed, during high amplitude plateau waves the arterial pressure barely increased, leading to a marked fall in cerebral perfusion pressure (Figure 7.6, see also Figure 7.8). During some high amplitude sharp waves (B-waves), however, there could be a noticeable transient increase in arterial pressure (Figure 7.7). Continuous CSF pressure monitoring was used in 38 cases in the Sydney series, in 31 via a lumbar catheter and in 7 using the Camino intracranial pressure monitoring device. The nature of the ICP changes was very similar to that found in the Glasgow series apart from one case who had long runs of high amplitude

156

Figure 7.7

Clinical investigations

Simultaneous recording of ICP and blood pressure during episodic increases in the former in a patient with PTCS. (From Johnston and Paterson, 1974b; reproduced with permission from Brain.) VFP ¼ ventricular fluid pressure; SAP ¼ systemic arterial pressure.

B-waves (Figure 7.9) which were not seen in the Glasgow cases. In this patient PTCS followed cranial venous outflow impairment. In 37 of the 38 cases the ICP was clearly raised, including two cases who had normal CSF pressure measurements on single lumbar punctures. In the one remaining case CSF pressure was normal on lumbar manometry on several occasions (highest value 140 mmCSF) and was also entirely within the normal range over a 24-h period of continuous monitoring via a lumbar catheter. This patient, a 14-year-old boy, had an otherwise typical picture of PTCS with papilloedema confirmed on fluorescein angiography and quite marked loss of visual acuity and visual fields. He was successfully treated by lumbar
peritoneal shunting and would qualify for the description of ‘normal-pressure PTCS’ (Johnston et al., 1991a and vide infra). There are a number of reports of ICP monitoring in PTCS in the literature, the two largest series being those of Krogsaa et al. (1985) (20 cases using an epidural transducer) and Sorensen et al. (1988) (24 cases). In both series ICP was elevated in all cases. Janny et al. (1981) reported ICP findings in 16 cases, finding unequivocally raised levels (15
38 mmHg) in 14 and a level of 13 mmHg in two cases, both of whom showed abnormal pressure waves. Using an epidural transducer in 13 patients and a lumbar catheter in one patient, Gjerris et al. (1985) found increased ICP (20
30 mmHg) in nine cases, borderline levels (15
18 mmHg) in four cases, and a normal level in one case. Bjerre et al. (1982), who studied ICP in eight PTCS patients, reported the following levels (all in mmHg): 5
8, 10
15, 10
20, 15
20, 15
40, 20
40, 30
50, 30
60. They emphasized the considerable variability of ICP levels in PTCS and the

157

Figure 7.8

CSF pressure

Recording of arterial pressure (ABP), intracranial pressure (ICP), cortical laser Doppler blood flow (LDF) and middle cerebral artery blood flow velocity (FV) during a plateau wave. The plateau wave was triggered by a sudden drop in arterial blood pressure which seemed to initiate a vasodilatatory cascade. Cortical blood flow decreased and diastolic blood flow velocity decreased. Towards the end of the wave, the pulsatility of blood flow velocity increased (distance between systolic and diastolic parts of the waveform), marking a gradual vasodilatation due to the decrease in cerebral perfusion pressure. Similar plateau waves have been recorded in PTCS patients. (Courtesy of Dr M. Czosnyka.)

Figure 7.9

ICP tracing showing a run of high-amplitude B-waves in a patient with PTCS secondary to cranial venous outflow impairment.

158

Clinical investigations

occurrence of normal levels in some cases. An example of ‘normal-pressure PTCS’ was reported by Djindjian et al. (1987), whose case showed a mean ICP between 1 and 6 mmHg despite clear clinical evidence of raised ICP and reversal of the CSF to superior sagittal sinus pressure gradient. This matter has also been considered by Green et al. (1996) and by Biousse et al. (1997). In summary, while demonstration of raised CSF pressure is clearly an important component of the diagnosis of PTCS and can, in most instances be satisfactorily achieved by manometry via lumbar puncture, there will be cases with genuine PTCS in whom a single manometric pressure measurement on one or more occasions will be normal. This will be due either to the measurement being carried out during a trough in the ICP level (most instances) or to genuine ‘normalpressure’ PTCS in a small but unknown proportion of cases. Continuous ICP monitoring may be useful in distinguishing between these two sub-groups and also, in some instances, in evaluating treatment. Modern practice is to use electronic recording of CSF pressure via a pressure transducer for at least 15 min particularly where patients have had to be sedated or anaesthetized to secure reliable measurements. When anaesthetized, the arterial carbon dioxide tension has to be controlled around 40 mmHg. Cerebrospinal fluid composition Demonstration of a normal CSF composition is taken to be a basic component of the diagnosis of PTCS. There are two issues regarding this assumption. The first, and the one addressed here, is the incidence of relatively minor departures from normality and whether any significance is to be attached to such abnormalities. The second, which is considered in Chapter 4, is whether conditions with a quite marked abnormality of CSF composition, involving either cells or protein or both, should be included in an expanded concept of PTCS on the grounds that it is the CSF abnormality itself which is the cause of the PTCS in that it falls within the range of factors which bring about reduced CSF absorption without ventricular enlargement. In the Glasgow series, 93 patients (84.5%) had CSF of normal composition whilst eight patients (7.3%) had a minor abnormality of CSF composition: in four patients there was a slight increase in CSF protein and in four patients there was a slightly abnormal cell count. In nine patients (8.2%) there was no examination of CSF composition. In one of the patients included as normal there was a marked proportional increase in gamma globulin but a normal total protein level. Figures were closely comparable in the Sydney series. Of 141 patients, 115 (81.6%) had CSF of normal composition whilst six (4.2%) had minor abnormalities: in two cases a slight increase in CSF protein and in four cases an abnormal cell count.

159

CSF infusion studies

In two patients from this second small group the increase was in red cells and was associated with cranial venous sinus thrombosis. The number of patients who did not have an analysis of CSF composition was slightly higher in the Sydney series (20 patients, 14.2%). In none of the patients with abnormal CSF composition did anything subsequently emerge to cast doubt on the diagnosis of PTCS. In a literature review reports on a total of 1193 patients were examined. The corresponding figures were as follows: normal CSF composition in 1047 patients (87.8%), abnormal CSF composition in 44 patients (3.7%), and no CSF examination in 102 patients (8.5%). Of the 44 patients with an abnormality, this was an increased protein level in 21 cases, an abnormal cell count in 20 cases, and both in 3 cases. As with the Glasgow and Sydney series, in general the abnormality was slight and none of these patients was reported as having had a subsequent change of diagnosis, although follow-up in this large group was quite variable. In summary, then, whilst a normal CSF composition may be taken as a basic feature of diagnosis in PTCS, minor abnormalities may be acceptable and do not appear to have any sinister significance. Further, in some cases a satisfactory diagnosis may be reached without analysis of CSF composition. In several of the larger early series of PTCS cases a high incidence of patients with a low CSF protein (values <20 mg%) and an abnormal Ayala index was commented on and taken as suggesting a dilutional effect (Weisberg, 1975a; Weisberg & Chutorian, 1977; Orefice et al., 1984) but it is questionable whether this is of any significance. Cerebrospinal fluid infusion studies When Katzmann and Hussey (1970) introduced what they termed ‘a simple constant infusion manometric test for measurement of CSF absorption’, one of the 31 cases in the clinical study (Hussey et al., 1970) was a 14-year-old girl with PTCS in whom CSF absorption, as measured by the method, was described as ‘severely abnormal’. Over the next 20 or so years a number of reports of the use of the method (there are several variations in the actual technique) in cases of PTCS appeared (Martins, 1973; Calabrese et al., 1978; Mann et al., 1979; Sanborn et al., 1979; Sklar et al., 1979; Janny et al., 1981; Gjerris et al., 1985; Malm et al., 1992; Malm, 1994). The characteristic finding was an increased resistance (decreased conductance) to CSF outflow. For example, in the study by Mann et al. (1979, 1983), in 10 cases of PTCS the CSF outflow resistance was ten times greater than in controls (four cases, P < 0.001). Moreover, in four of the 10 patients with PTCS there was a marked reduction in CSF outflow resistance after 4 weeks treatment with steroids. There were, however, exceptions to this common finding. Thus, in the report by Sklar et al. (1979), there were two cases (of 10) with normal values, but this study included cases under active treatment. Of more importance are the

160

Clinical investigations

reports by Janny et al. (1981) and by Malm and his colleagues (1994). In the first of these reports, six of 16 PTCS patients had cranial venous outflow obstruction and in this sub-group the mean CSF outflow resistance (in mmHg ml
1 min
1) was 14.5 compared to 10 + 5 for controls and 46.6 for the 10 PTCS patients without venous outflow compromise. Similarly, Malm (1994), who studied 15 patients with IIH (PTCS), reported that nine cases had normal or slightly decreased conductance, the increased CSF pressure being attributed to increased superior sagittal sinus pressure, while six cases, all with long-standing elevation of CSF pressure, had very low conductance values with low or normal superior sagittal sinus pressures (one of the six cases had initially normal conductance but was later similar to the others). The conclusion from these studies was that increased CSF outflow resistance was a uniform finding in PTCS, at least in those cases without venous outflow tract abnormalities, and that this might be the basic abnormality in the condition. It must be remembered, however, that there are theoretical issues and assumptions involved in the method (Owler et al., 2005).

Figure 7.10 CSF infusion study in middle aged lady with PTCS. Baseline ICP of 20 mmHg, increased pulse amplitude, outflow resistance of 14 mmHg (ml
1 min
1) and a vasogenic wave on the plateau. (Courtesy of Dr M. Czosnyka.) ICP ¼ intracranial pressure; AMP ¼ ICP pulse amplitude.

161

Ophthalmological investigations

The question of particular importance here is whether the method has a role to play in clinical evaluation of PTCS. This issue was addressed in a hitherto unpublished study in the Sydney series (Jacobson, 1998) involving 30 patients with PTCS. In 10 of the 30 cases an infusion study was carried out during initial evaluation or when treatment was proving unsuccessful. The mean baseline ICP in this group was 21.3 mmHg (range 9
34 mmHg) with only two cases having an opening pressure less than 15 mmHg. Pressure waves (mainly B waves) were present in all but one case. CSF outflow resistance measurements ranged from 4 to 60 mmHg ml
1 min
1 with six patients having a resistance less than 12 mmHg ml
1 min
1. In 20 of the 30 cases, the infusion study was carried out after shunting as part of the evaluation of possible shunt malfunction. The mean baseline ICP in this group was 13.3 mmHg (range 2
28 mmHg) and there were pressure waves in 63% of recordings. CSF outflow resistance ranged from 0 to 34 mmHg ml
1 min
1 with a mean of 12.5 mmHg ml
1 min
1. In summary, the conclusion drawn from this and the other reported studies was that while CSF infusion studies will reveal an abnormally high resistance to CSF outflow in PTCS patients, this is not an invariable finding, particularly where a venous outflow tract abnormality is present. The method may, however, provide useful confirmatory evidence, in conjunction with a short period of ICP monitoring prior to the study, which can help to establish the diagnosis of PTCS or evaluate the efficacy of treatment generally and shunt patency specifically. Ophthalmological investigations There are two aspects of importance in the ophthalmological assessment of patients thought to have PTCS. The first is the recognition and staging of papilloedema, vital in establishing the diagnosis and severity of the condition. The second is the evaluation of visual fields, crucial in assessing severity and visual prognosis in PTCS, and charting progress during follow-up. Papilloedema

Papilloedema (Figure 7.11) is best defined as optic disc swelling in the presence of raised intracranial pressure and must be distinguished from other, predominantly local, causes of disc swelling which are listed below: 1. Vascular: Ischaemic optic atrophy, central retinal vein occlusion, diabetic papillopathy 2. Inflammatory: Uveitis, papillitis 3. Neoplastic: Primary or secondary tumours involving the optic nerve or nerve sheath

162

Clinical investigations

4. Infiltrative: Sarcoid, lymphoma, leukaemia, carcinoma 5. Other: Ocular hypotony, hamartoma, angioma It is noteworthy that in these predominantly local conditions visual failure tends to occur early as opposed to the characteristic late visual loss in papilloedema due to raised intracranial pressure. Further, papilloedema must be distinguished from pseudo-papilloedema, e.g. refractive (high hypermetropia), small anomalous discs, and optic disc drusen. Finally, papilloedema may be difficult to distinguish from the bilateral optic disc swelling seen in malignant hypertension, although the latter is typically accompanied by hypertensive vascular changes in the fundi. Several investigative techniques are available to aid in the diagnosis and evaluation of papilloedema. Historically the first, and the most widely used in PTCS to date, is fluorescein angiography. The first reported use of this method in PTCS was by Miller et al. (1965) who studied 20 cases with the particular purpose of differentiating between papilloedema and pseudo-papilloedema. Two of the 20 cases had PTCS and in both instances fluorescein angiography confirmed the presence of papilloedema. In the Glasgow study, fluorescein angiograms were done in 17 of 20 patients thought to have papilloedema who had continuous ICP monitoring. Thirteen of these patients had mean ICP levels 415 mmHg, and in the 10 of these cases in whom fluorescein studies were done they confirmed the clinical impression of papilloedema. Characteristic features included the appearance of numerous small tortuous and dilated vessels around the disc in the arteriolar and early venous phases whilst in the later phases there was marked leakage of dye around the disc with oedema of the disc extending into the peripapillary region and surrounding retina. The 7 patients with mean ICP levels <15 mmHg were all thought to have undoubted papilloedema on ophthalmoscopic examination. In only 2 of the 7 cases was this confirmed by fluorescein angiography; one a case with a mean ICP level of 14 mmHg and one a case with prominent 1/minute waves, atypical plateau waves and abnormal CSF circulation. The remaining 5 cases had normal fluorescein studies. In an earlier review of the literature (Johnston, 1992) 45 cases of suspected PTCS having fluorescein angiography were collected. In all instances, apart from the cases reported by Spence et al. (1979
vide infra), fluorescein studies confirmed the presence of papilloedema, the most extensive use of the method being reported by Danze et al. (1984) who had 12 cases all with positive fluorescein angiograms. Some points of interest with regard to the method are, first, its use to demonstrate or confirm the clinical impression of papilloedema in patients with normal CSF pressure measurements (Shekleton et al., 1980; van Zandijcke & Dewachter, 1986); second, the report by Spence et al. (1979) who found negative fluorescein angiography in 5 of 9 patients diagnosed as having PTCS without papilloedema; and third,

163

Ophthalmological investigations

there are reports of the use of the method to differentiate between papilloedema and drusen or to confirm their co-existence (Katz et al., 1988; Reifler & Kaufman, 1988). More recently, the technique of confocal scanning laser ophthalmoscopy (CSLO) using the Heidelberg instrument has been introduced to refine the diagnosis of papilloedema and, particularly, to quantitate its severity (Mulholland et al., 1998; Trick et al., 1998; Tamburrelli et al., 2000; Salgarello et al., 2001; Trick et al., 2001). The findings with this method have been shown to correlate well with other techniques for the assessment of optic nerve status. One difficulty with this technique in following progress is that the development of optic atrophy cannot be distinguished from the resolution of papilloedema. Optical coherence tomography, which measures retinal nerve fibre layer thickness, may also have a role confirming the presence of papilloedema but not in differentiating true papilloedema from pseudo-papilloedema (Karam & Hedges, 2005). In summary, the diagnosis of papilloedema is primarily dependent on a detailed clinical ophthalmological examination, preferably using the slit-lamp. This should include an attempt at staging or classification using the following categories: early, acute, chronic, vintage, and atrophic (Sanders, 1997; Figure 7.11). Fluorescein angiography may be useful when the diagnosis of optic disc swelling is uncertain or there are confounders such as a history of uveitis or other ocular disease, in that it helps to distinguish intraocular causes of disc swelling from papilloedema and the latter from pseudo-papilloedema and drusen. Additionally, autofluoresence of buried optic disc drusen may aid in the differentiation of pseudo-papilloedema due to buried disc drusen. High resolution computerized tomography is also very useful at detecting calcification in buried disc drusen in such patients. CSLO can be helpful in the diagnosis of PTCS and particularly in the evaluation of progress by quantitating the degree of papilloedema whilst optical coherence tomography may also have a role. Visual field assessment

There has been a progressive refinement in the techniques for mapping visual fields, a matter of considerable importance in the initial evaluation and subsequent follow-up of PTCS patients. In recent times, computerised static perimetry has largely replaced standard Goldmann perimetry (Figure 7.12). Patients with PTCS are now typically followed with central field automated threshold perimetry using perimeters such as the Humphries Visual field analyser and strategies such as the 30-2 or 24-2 algorithms which were originally developed to follow patients with glaucoma. Such visual field strategies have the advantage of being sensitive, reproducible, and reliable in most patients. There are also sophisticated statistical analyses that can be performed on the results, and these may aid in the detection

164

Figure 7.12

Clinical investigations

Goldmann visual fields to show enlargement of the blind spots before treatment (above) and after treatment (below) with optic nerve sheath fenestration. (Courtesy of Mr N. Sarkies.)

of early changes and progression of visual field loss. Newer computerised perimetric strategies, such as short wavelength automated perimetry (SWAP) and frequency doubled threshold perimetry (FDT) may be useful, but they remain largely untested in PTCS patients. Objective perimetry using multifocal visual evoked potentials, such as that performed by the Accumap perimetry system, could also be useful in following patients who are unable to perform or co-operate with conventional perimetry. Electroencephalography Like a number of the investigations considered in this chapter, EEG studies no longer play a significant part in the investigation of patients with possible PTCS. In the past, however, the method was used to a considerable extent. Thus, in the Glasgow series, an EEG was obtained in 66 of the 110 patients. This was normal in 43 cases (65.2%) and abnormal in 23 cases (34.8%). In 21 of these 23 cases,

165

Electroencephalography

the abnormality was minor and diffuse whilst in one case there was a definite focal abnormality, and in 1 case what was described as a severe generalized abnormality. In contrast, only 7 of 144 patients in the Sydney series had an EEG carried out, 4 of which were normal and 3 abnormal, showing bilateral diffuse slowing in one case, a mild right frontal abnormality in one case, and a generalized nonspecific abnormality in one case. A total of 677 cases of PTCS having EEG studies was collected from the literature. Of these, 425 (62.7%) were essentially normal whilst 252 cases (37.3%) showed abnormalities of various sorts but predominantly nonspecific. The following is a list of recorded abnormalities in order of decreasing frequency: diffuse, 87; mild/minor, 63; not specified, 49; generalized, 15; paroxysmal high voltage, 13; focal, 10; bilateral slowing, 10; posterior slowing, 4; irregular slow waves, 3; multifocal spikes and sharp waves, 1. Clearly, the most commonly applied descriptive terms were mild, diffuse and generalized. There have been four papers specifically devoted to the topic of EEG findings in PTCS. Mani and Townsend (1964) reported on 14 patients with PTCS, most of whom were said to have had a slightly abnormal EEG with burst activity as a common feature. These authors described the results as similar to those seen in patients with obstructive hydrocephalus but with slightly more burst activity in PTCS patients. They attributed the findings in both conditions to raised ICP. Hooshmand (1974) examined the EEG findings in 13 patients with PTCS, finding the record before treatment to be normal in 12 cases and borderline in one case, and after treatment to be normal in 12 cases and abnormal in one case (a temporal spike). He concluded that the EEG was essentially normal in PTCS but showed slightly faster background activity after treatment. Bodensteiner and Matsuo (1977) made a retrospective study of EEG findings in 26 patients with PTCS and found an abnormal record in 10 patients, all under 20 years of age. Three patients had a mild abnormality with a slight excess of slow waves without focal features whilst seven patients had a more definite abnormality: in one this was brief paroxysms of 3/second spike and wave activity, in one diffuse slowing of the dominant rhythm, in two bilaterally synchronous slow-wave burst activity with frontal predominance, and in three localized slow waves. Finally, Sidell and Daly (1961) examined the EEG in 16 cases of PTCS, finding it to be normal in 12 cases, borderline in 2 cases, and definitely abnormal in 2 cases, with bursts of theta activity. Comparing these findings with the reported high incidence of EEG abnormalities in obstructive hydrocephalus, and taking into account the lack of experimental evidence of EEG changes in pure intracranial hypertension, they agreed with Foley’s (1955) view that the EEG was likely to be normal in PTCS unless there was major venous sinus occlusion.

166

Clinical investigations

Skull X-rays This is now an investigation of more or less historical interest only. In the Glasgow series, in which almost all of the cases had skull X-rays, there were 16 patients in whom these showed changes indicative of long-standing intracranial hypertension. Reflecting the changes in investigative patterns, only 15 of the first 64 patients in the Sydney series had skull X-rays. Of these, 13 were normal, one (a child) showed separation of the sutures, and one confirmed known osteopetrosis. In the earlier literature review (Johnston, 1992), there were 942 skull X-rays reported on, of which 706 (74.9%) were normal and 236 (25.1%) were abnormal. The incidence of various abnormalities was as follows (some studies showing more than one abnormality): separation of the sutures, 76; thinning of the dorsum, 54; generalized signs of increased ICP, 44; enlargement of the sella, 30; mastoiditis, 21; cranial vault fracture, 8; increased digital markings, 7; other abnormalities, 7. In large series in which specific figures were given, the incidence of abnormal findings ranged from 6% (Boddie et al., 1974) through 10% (Weisberg, 1975a) to 40% in children (Grant, 1971). Angiography Angiography (carotid + vertebral) has had two periods of particular relevance in the investigation of patients with possible PTCS. In the first, extending from the development of the technique to the introduction of CT scanning, angiography along with ventriculography/encephalography played a major role in the exclusion of other causes of raised intracranial pressure. In this role it was supplanted by CT scanning. With the increasing focus on possible cranial venous outflow impairment as a causative mechanism in PTCS, and particularly where the identification of such pathology offers therapeutic options, DSA has been used to delineate intracranial venous anatomy. In this role in the investigation of PTCS, it has now been supplanted by MR venography and retrograde venous angiography with manometric studies. Comparison of the use of angiography in the Glasgow and Sydney series well illustrates these two roles. In the Glasgow series, carotid angiography was carried out in 43 of the 110 patients and was found to be normal in 42 patients, with the remaining patient showing a questionable abnormality in the right cerebral hemisphere. In the Sydney series, 25 patients had angiography. In 12 patients the study was normal, eight cases being prior to the introduction of CT and MR scanning and four subsequent to this. In the other 13 patients, cranial venous outflow tract abnormalities were demonstrated: in eight instances these involved the transverse/sigmoid sinuses, in two instances the superior sagittal sinus was primarily

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Ventriculography and encephalography

involved, in 2 instances there were long-standing multiple venous abnormalities, and in one case there had been occlusion of deep venous drainage following embolisation of a vein of Galen aneurysm (Kollar & Johnston, 1999). In one other case, not included in the Sydney series, a young male patient presented with a PTCS and was found on angiography to have a large temporo-parietal AVM with high-flow venous drainage into the superior sagittal sinus. His PTCS responded well to treatment with acetazolamide without any treatment of the AVM at that point. A total of 445 PTCS patients who underwent angiography (carotid + vertebral) was collected from the literature. Of these cases, 406 (91.2%) had normal angiograms with 39 (8.8%) being reported as abnormal. In all the abnormal cases the findings were of cranial venous outflow tract abnormalities involving the sagittal, transverse or sigmoid sinuses, the internal jugular veins, or a combination of two or more of these vessels. A significant proportion of the abnormal studies occurred in cases of PTCS related to conditions with abnormal coagulation such as DLE or Behc¸et’s, disease or, in the case of transverse sinus involvement, with chronic middle ear disease. More recently, there have been reports of angiography revealing dural arteriovenous fistulae in cases of PTCS (Adelman, 1998; Cognard et al., 1998). In summary, standard angiography (DSA) would appear to have very little to add to the investigation of patients with possible PTCS. In excluding other causes of intracranial hypertension, MR imaging is superior to it, and in delineating cranial venous outflow tract abnormalities a combination of MRV and retrograded venography with manometry is to be preferred. Angiography may still be of value in clarifying the diagnosis in cases with PTCS secondary to venous outflow tract hypertension due to high-flow AVMs, or due to sinus occlusion with DAVFs.

Ventriculography and encephalography Once the mainstays of the diagnostic investigations, these methods are now no longer used. Nevertheless, the findings are of relevance in relation to the issue of ventricular size and the bearing of this on concepts of disease mechanism. In the Glasgow series, ventriculography or encephalography (positive or negative contrast) was carried out in 104 patients. Of these studies, 91 (87.5%) were completely normal whilst 13 (12.5%) showed mild ventricular enlargement. In the Sydney series, only seven patients had encephalography, all pneumoencephalograms, of which six were normal whilst one showed marked distension of the subarachnoid space. Reports of findings on ventriculography or pneumoencephalography were obtained from the literature for 978 PTCS patients.

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Of these, 900 (92.0%) were normal and 78 (8.0%) abnormal. Under the heading of ‘normal’ there was a significant proportion of cases described as having small ventricles; for example, 20 of 89 (Guidetti et al., 1968), whilst Greer (1968) spoke of a 20% incidence of small ventricles. Contrary to this, Foley (1955) showed that ventricular size was not reduced in his 58 cases whilst Janny et al. (1981) reported a normal Evans ratio (0.29 + 0.02) in 16 cases. Wilson and Gardner (1966) also stressed that in 42 normal PEGs in obese young women, the ventricles could in no instance be described as small whilst in eight cases there was a prominent subarachnoid space. In the 78 abnormal studies referred to above, the findings were as follows: mild to moderate ventricular enlargement in 56 cases; empty sella in 12 cases; marked distension of the subarachnoid space in five cases; minor asymmetry in three cases; septum pellucidum cyst in two cases. It is clear, then, that the finding of small ventricles is very far from being a uniform feature of PTCS and that a small but significant number of patients do have some degree of ventricular enlargement with or without dilatation of the subarachnoid space. This finding has been reproduced with the techniques that have supplanted ventriculography and encephalography (CT, MR) and is difficult to reconcile with theories of diffuse cerebral oedema in PTCS.

Computed tomography scanning For a period of approximately two decades from the early 1970s to the early 1990s, CT scanning became the key ‘negative’ investigation in the diagnosis of PTCS before being superseded by MR scanning. In essence, CT scanning was superior to prior techniques in excluding other causes of intracranial hypertension, particularly parenchymal lesions, and also of some benefit in identifying causative factors of the PTCS itself. In the Sydney series, a total of 114 patients (79.2%) had a CT scan as part of the initial investigation. Thirty of these patients, that is 20.8% of the whole series, also had an MR scan during the initial investigations. Of the 114 CT scans, 94 (82.5%) were normal and 20 (17.5%) were abnormal. In three patients there were two abnormalities on the one CT scan. The abnormalities were as follows: venous sinus abnormalities in six cases; mild ventricular dilatation + an enlarged subarachnoid space in five cases; an empty sella in three cases; venous infarction in three cases; and single instances of a pituitary microadenoma, congenital narrowing of the jugular foramina, a bony defect in the right petrous bone, an arachnoid cyst, a depressed skull fracture overlying one transverse sinus, and a small meningioma adjacent to the superior sagittal sinus. In an earlier literature review extending to 1992 (Johnston, 1992), a total of 480 cases was collected, excluding the reports of Reid et al. (1980) and Wessel et al.

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CT scanning

(1987) which will be considered separately. Of the 480 CT scans, 426 (88.7%) were normal whilst 54 (11.3%) were abnormal. Among the cases with an abnormal CT scan, there were 20 with abnormally small ventricles, 18 with an empty sella or other sella abnormality, and two with enlarged ventricles. The remainder had a miscellaneous group of abnormalities including optic nerve thickening, enlargement of the cisterna magna, basal ganglia calcification in a case of PTCS in parathyroid disease, nonspecific evidence of raised ICP, and patchy enhancement of questionable significance. Reid et al. (1980) made a particular study of ventricular size on CT scanning in patients with PTCS. Using data from 18 cases, they found a ventricular volume of 1.3 + 11.5 ml (mean 4.9 ml) in PTCS compared with values of 4.5 + 22 ml (mean 11.7 ml) in age-matched controls. In a subsequent study (Reid et al., 1981), they reported an increase in ventricular volume in PTCS patients after successful treatment. Wessel et al. (1987), in a CT study of 35 PTCS patients, found a 46.7% incidence of optic nerve enlargement, a 45.7% incidence of empty sella, and an 11.7% incidence of small ventricles and possible brain oedema, although in six patients in this series who also had an MR scan, no evidence of oedema was found. In a later study, Kesler et al. (1996) used CT scanning to evaluate four specific things
optic nerve sheath diameter, reversal of the optic nerve head, empty sella, and ventricular, sulcal and cisternal sizes
in 13 patients with PTCS compared to 20 age-matched controls. The findings in summary were: (1) a greater optic nerve sheath diameter in PTCS patients; (2) an increased incidence of reversal of the optic nerve head (4 PTCS patients, 0 controls); (3) an increased incidence of empty sella (6 PTCS patients, 1 control). There were, however, no differences in size of the CSF spaces. In a study using CT scanning to examine the optic nerves specifically, Jinkins (1987) reported optic nerve sheath dilatation in four ‘primary’ PTCS cases on static studies with evidence of reduced perfusion in two of these cases on dynamic studies. In a further four cases in whom PTCS was secondary to demonstrated venous sinus pathology there were similar findings. In summary, CT scanning was an effective ‘negative’ investigation in establishing the diagnosis of PTCS but has now been largely superseded by MR scanning, the latter being the more sensitive examination. This point is made in the recent report by Said and Rosman (2004) of a case of a 10-year-old boy diagnosed as having PTCS on the basis of a negative CT scan who was found to have a diffuse anaplastic oligodendroglioma on MR scan. With both CT and MR scanning there is a not insignificant incidence of abnormal studies in cases which are, despite these abnormalities, diagnosed as PTCS. The issue of ventricular size, as it bears on the question of whether diffuse brain oedema is the underlying cause of intracranial hypertension in PTCS, has not been definitively resolved by CT scanning.

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Magnetic resonance techniques Static MR scanning has now taken over the key role as the ‘negative’ investigation which is essential in establishing the diagnosis of PTCS, having superseded CT scanning in this respect. Other forms of MR imaging also play a significant part in the diagnosis and investigation of PTCS. These include MR techniques aimed at evaluating brain water content and intracranial CSF volume and flow, MR imaging of orbital contents, MR angiography (MRA), and particularly MR venography (MRV). Each aspect of MR investigation of PTCS will be considered in turn. Standard static magnetic resonance

This is, of course, the most sensitive available technique for excluding other causes of raised ICP in cases of possible PTCS, especially when used with gadolinium enhancement. The incidence of other pathologies causing intracranial hypertension being mistaken for PTCS was already low, even prior to CT scanning (Johnston & Paterson, 1974a). With MR scanning, it should be vanishingly low and we are not aware of any reported situation where such an error has occurred. What might be expected to occur with MR is, however, that in true PTCS cases there will be a higher incidence of abnormal studies than with previous forms of investigation, these abnormalities being either related to the cause of the PTCS or themselves incidental findings (Figure 7.13). For example, in the Sydney series 18 of 54 (33.3%) of MR scans carried out as initial investigations were abnormal compared with 20 of 114 (17.5%) of CT scans. The MR abnormalities were as follows: venous sinus pathology, 9 cases; empty sella, 3 cases; type 1 Chiari malformation, 2 cases; ventricular enlargement, 1 case; pituitary microadenoma, 1 case; suprasellar arachnoid cyst, 1 case; and a small meningioma adjacent to the superior sagittal sinus, 1 case. Two cases of particular interest are, first, the case just referred to, in which the meningioma was thought to be a possible cause of venous outflow tract compromise. In fact, when investigated with digital retrograde angiography and manometry, there was no pressure gradient across the sinus narrowing due to the meningioma but there was a marked pressure gradient more distal in the venus outflow tract (Cremer et al., 1996). Second, there was one case diagnosed as PTCS, in part on the basis of what was accepted as a normal non-enhanced MR scan without enhancement, who was later shown, on a gadolinium-enhanced MR scan, to have multiple meningiomata, one of which was compressing a dominant transverse sinus. Magnetic resonance studies of brain water and CSF distribution

This was the initial focus of the early studies of MR in PTCS, carried out with the primary intention of trying to clarify the underlying mechanism of the condition

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MR techniques

Figure 7.13 MR scan of patient with PTCS to demonstrate various abnormalities. (a) Excess sulcal CSF; (b) excess CSF within the optic nerve sheath; (c) partial empty sella; (d) severe narrowing of the right transverse sinus on MR venography.

by resolving the issue of whether there was an increase in parenchymal brain water or CSF volume. The question of mechanism was examined more fully in Chapter 3, but it may be said here that the early MR studies were inconclusive on this point. The first report of MR scanning in PTCS was that of Condon et al. (1986) in one case (among other conditions) with the technique being used to assess CSF volume. A value of 11.0 ml was given for ventricular volume and 68.7 ml for extraventricular CSF volume in the one case, compared with control values of 25.5 + 4.6 ml and 97.6 + 6.6 ml respectively. Wessel et al. (1987) reported six cases of PTCS with a normal MR, in particular without evidence of increased brain water, whilst Grogan and Narkun (1987) also reported one normal MR. Moser et al. (1988), who studied the MR findings in 11 patients with PTCS, reported normal scans in eight cases, but in two cases found areas of increased signal intensity in the periventricular white matter which they described as being consistent with ‘low-level oedema’. In contrast, Silbergleit et al. (1989) reported their findings in six cases, all females with an age range of 17 to 41 years of

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Clinical investigations

whom five were obese, and comparing these with six age-matched controls, found both ventricular size and subarachnoid space volume greater in the PTCS patients than in controls, the former not significantly so but the latter with significance (P ¼ 0.004). One of these patients had a high signal intensity in one of the dural venous sinuses indicating slow flow. In this small group of patients there was no evidence of white matter oedema, even in the periventricular region. More recent studies have continued to provide somewhat conflicting results. Thus, several reports from the same group (Sorensen et al., 1989, 1990; Gideon et al., 1995) appeared to show increased brain water. The finding in the first study was that self-diffusion of water was higher in grey than in white matter and the assumption was made that this was due to accumulation of brain water either intra- or extracellularly. In the next report, Sorensen et al. (1990), using a similar technique (single spin-echo pulse sequences with pulsed magnetic field gradients of different magnitude), 10 PTCS patients (8 women, 2 men) were studied and compared with 7 healthy control subjects. All the PTCS patients had a documented increase in CSF pressure at the time and all also had an abnormal resistance to CSF outflow measured by a lumbo-lumbar perfusion study. All the PTCS patients had normal standard MR spin echo images and otherwise normal MR scans but all had abnormal diffusion images. The authors concluded that the PTCS patients had ‘a convective transependymal flow of water causing an interstitial brain oedema and in addition an intracellular brain water accumulation’. The subsequent study (Gideon et al., 1995) essentially confirmed the earlier findings of a small but significant amount of brain oedema in PTCS. However, the reports by Bastin et al. (2003) in 10 cases and Owler et al. (2005) in five patients have not borne this out, finding no evidence of any significant degree of brain oedema. Further studies of the distribution of fluid both in the CSF pathways and the brain parenchyma are clearly indicated, although of no immediate diagnostic relevance in the individual case. Magnetic resonance of orbital contents

The findings from a detailed MR analysis of orbital contents in patients with PTCS have been documented in a number of recent reports (Manfre´ et al., 1995; Gass et al., 1996; Brodsky & Vaphiades, 1998; Hutzelmann et al., 1998; Mandelstam & Moon, 2004). These are listed as follows in the report by Brodsky and Vaphiades (1998) who examined orbital MR scans in 20 PTCS patients and 20 controls: (1) flattening of the posterior sclera; (2) enhancement of the pre-laminar optic nerve; (3) distension of the peri-optic subarachnoid space; (4) intra-ocular protrusion of the pre-laminar optic nerve; (5) vertical tortuosity of the orbital vessels. They also mention the occurrence in PTCS patients of an empty sella, claiming that this plus

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MR techniques

the five orbital abnormalities gave a 90% reliable prediction of the diagnosis of PTCS. The other reports mentioned focus primarily on one of the five orbital abnormalities listed. Magnetic resonance angiography

The only specific role for this aspect of MR scanning in PTCS would be to identify arterial vascular lesions which might be causative of PTCS. These could be parenchymal AVMs with high flow drainage into the venous outflow tract creating venous outflow tract hypertension or dural arteriovenous fistulae (DAVF) with dural venous sinus thrombosis (Alexander et al., 1999; Malek et al., 1999). Magnetic resonance venography

Since the increased focus on venous outflow tract pathology as a possible cause of PTCS, even in patients with normal conventional imaging studies and, moreover, the increasing availability of methods to correct such pathology, MRV has assumed a place of importance in the investigation of patients with possible PTCS. There are, as discussed elsewhere, two issues here. The first is how prevalent venous outflow tract pathology is in PTCS, and the second is whether abnormalities demonstrated by the more sophisticated methods now available are primary or secondary in the individual case. Uncertainty remains on both these issues. In recent studies most relevant to the role of MRV in resolving them, the evidence appears to be in favour of a quite high incidence of venous outflow tract abnormalities in PTCS (Figure 7.14), although the technique is not, in itself, equipped to resolve the second issue. Considering the studies in chronological order, Leker and Steiner (1999) found that when 46 patients with PTCS and normal CT scans were investigated with MRI/MRV, 12 (26%) had evidence of venous sinus thrombosis. However, Lee and Brazis (2000), who carried out MRI/MRV studies on 22 consecutive cases of PTCS (all obese females), found no case with dural venous sinus pathology. This contrasts with the report by Bateman (2002), who found 7 of 12 cases of PTCS to have cranial venous outflow tract obstruction when examined by MRV and MR flow quantitation. The two most recent and prospective studies using MRV both favour a high incidence of venous outflow tract pathology. In the first, Farb et al. (2003) used three-dimensional gadolinium enhanced MRV to examine the venous outflow tract of 29 PTCS patients compared with 59 controls and expressed their results in terms of an ‘average combined venous conduit score’ (ACCS) which ranged from 2 to 8, 2 representing bilateral hypoplasia or severe stenosis and 8 bilateral normal patency. Altogether, 93.1% of the PTCS patients had an ACCS of less than 5 compared with only 6.8% of controls. That is, an ACCS of less than 5

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Clinical investigations

Figure 7.14 Axial MRVs of two different PTCS patients. (a) Dominant right transverse sinus with absence of flow in the distal third; (b) dominant right transverse sinus. Both patients also have an obstruction in a small left transverse sinus confirmed by DRCV and manometry.

had a 93% specificity and sensitivity for PTCS. There was no apparent correlation between CSF pressure and ACCS. There was an approximately 3:1 preponderance of ‘extraluminal’ to ‘intraluminal’ compression in the PTCS patients, ‘extraluminal’ being used to describe ‘a relatively long segment of smooth tapering of the opacified lumen’ and ‘intraluminal’ to describe ‘a sharply demarcated acutely marginated filling defect within the opacified lumen’. In the second study, Higgins et al. (2004) examined MRVs in 20 PTCS patients, comparing them with 40 control studies in age- and sex-matched patients without neurological abnormalities. In the PTCS patients, there were ‘flow gaps’ in 13 of the 20 cases (65%) compared to none in the control group. In only one of the PTCS patients were the transverse sinuses quite normal bilaterally. In summary, static MR with gadolinium enhancement is clearly the investigation of choice for exclusion of other causes of intracranial hypertension in patients being investigated for PTCS. It is also useful in detecting causes of PTCS operating through compromise of the cranial venous outflow tract. Such causes include not only intra-luminal thrombosis and extra-luminal compressive lesions but also intra-luminal giant arachnoid granulations and fat deposits which may have a causative role (Owler et al., 2005). The addition of MRA will increase the likelihood of detection of parenchymal or dural arterio-venous abnormalities which may affect venous outflow. More importantly, the addition of MRV adds significantly to the sensitivity of MR imaging in detecting all forms of venous

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Cranial venous outflow studies

outflow tract abnormality, although the issue remains as to what role such an abnormality may be playing in PTCS in the individual patient. MR examination of the orbits is useful in detecting the secondary effects of raised ICP in PTCS and may be useful in monitoring progress. Detailed MR studies of intracranial fluid volumes and distribution, while as yet somewhat inconclusive, may help in clarifying the underlying pathology of the condition. Cranial venous outflow tract studies Apart from the somewhat limited information on venous anatomy available from standard angiographic techniques, there has been relatively little investigation of the cranial venous outflow tract in PTCS despite the acknowledged importance of venous outflow tract pathology in the condition. This situation has changed quite significantly over the last decade, however, with the development of MR venography and catheter techniques for digital retrograde venous angiography (DRVA), as will be discussed below. Before considering these recent developments, some of the earlier investigative techniques and findings will be briefly considered. Although direct sinography was introduced by Frenckner in 1937, the first report of its use in PTCS was that by Ray and Dunbar (1950, 1951). In three cases in whom both anatomical patency and intra-sinus pressures was studied following direct sinus puncture, they recorded pressures (in mmH2O) of 480, 200 and 320 compared with CSF pressures of 480, 300 and 400 (i.e. no pressure gradient reversal). Superior sagittal sinograms in these same patients showed obstruction in all three cases; in two cases at the junction of the middle and posterior third of the superior sagittal sinus itself and in one case in a dominant right transverse sinus just distal to the torcular Herophilii. Loman and Damashek (1944) had previously studied venous pressure in one patient with polycythaemia rubra vera and PTCS, finding an internal jugular vein pressure of 300 mmH2O compared with a CSF pressure of 380 mmH2O and a general venous pressure of 80 mmH2O. Subsequently, Caudill et al. (1953) measured superior sagittal sinus pressure in one patient with a depressed fracture over the sinus and PTCS finding a value of 420 mmH2O compared with a CSF pressure of 560 mmH2O. There are several reports of sinograms, six showing obstruction, one being the case described by Caudill et al. (1953) referred to above, and five being cases of Behc¸et’s disease with PTCS reported by Ibrahimi et al. (1983), while four were described as equivocal (Bradshaw 1956) and one as normal (Moore, 1959). The most detailed study of venous sinus patency and intra-sinus pressures prior to the recent reports considered below was that by Janny et al. (1981). In 11 patients with PTCS and a patent cranial venous outflow tract, they found that the

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Clinical investigations

positive pressure gradient between the CSF space and the superior sagittal sinus was maintained, although resistance to CSF absorption was increased. In contrast, in five patients with PTCS in association with cranial venous outflow obstruction, the CSF to sinus pressure gradient was reversed but the resistance to CSF absorption was only marginally increased, suggesting that in these cases alternative channels of CSF egress were being brought into play. In a single case reported in the same year, Djindjian et al. (1987) described a patient with an intradiploic dermoid obstructing the torcula Herophilii and giving rise to PTCS. In this patient, although both ICP and superior sagittal sinus pressures were normal at the time of measurement, there was an apparent gradient reversal. The recent resurgence of interest in direct venous studies arose from two reports by King et al. (1995) and Karahalios et al. (1996) respectively. In the former, 14 patients were studied by retrograde venous sinography, of whom 11 were diagnosed as IIH/PTCS (2 following tetracycline therapy), whilst two were being investigated for pulsatile tinnitus, and one had viral meningitis. The nine PTCS patients apart from the two cases following tetracycline therapy had raised superior sagittal sinus pressures and a distinct pressure gradient between proximal and distal transverse sinuses. The two post-tetracycline patients did not, despite having similar elevation of CSF pressure to the major sub-group. None of the other three patients had raised CSF pressure or raised sinus pressure. In the latter study, 10 PTCS patients were studied by retrograde venous angiography. Five of the 10 cases showed radiological evidence of cranial venous outflow obstruction (congenital stenosis, 2 cases; thrombosis, 2 cases; tumour compression, 1 case) whilst 5 (all young, morbidly obese females) did not. Intra-sinus pressure measurements were not uniformly carried out nor, in the cases that were studied, were the findings as clear-cut as those described by King et al. (1995). Comparing DRCV with MRV, three of the four patients with abnormalities on the former also showed abnormalities on the latter but one did not, whilst one patient had no abnormality on either study. In a later study, King et al. (2002) reported their findings on DRCV with manometry in 21 cases of PTCS. This group included eight of the nine nontetracycline related cases from the first study and also reported the effects of drainage of CSF via lateral cervical puncture in eight cases, none of whom were included in the first study. Of the 21 cases, all had elevated CSF pressure (260
620 mmCSF) and 19 of the 21 cases had elevated proximal venous sinus pressure (14
48 mmHg) whilst two cases did not. The 19 cases with raised proximal sinus pressures had a gradient between proximal and distal transverse sinus ranging from 9 to 46 mmHg. With regard to the eight cases who had CSF drainage via lateral cervical puncture (20
25 ml), the post-drainage sinus pressures were somewhat incomplete but there was definitely abolition of the

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Cranial venous outflow studies

gradient in four of the seven cases who had a gradient prior to drainage. On the basis of the findings the authors concluded that ‘the venous hypertension in PTCS is due to compression of the transverse sinuses by raised intracranial pressure and not due to a primary obstructive process in the cerebral venous sinuses’. This study brought forth an interesting correspondence (Neurology 59:963
964, 2002). Two of the correspondents (Quattrone et al., Higgins & Pickard) took issue with the conclusions of King et al. (2002). The former drew attention to the nature of the demonstrated obstruction in their own reports (Quattrone et al., 1999, 2001) and made the point that the obstruction, in their experience, typically occurred in the distal transverse sinus and was likely

Figure 7.15

Various forms of focal venous sinus obstruction in the transverse sinuses of four patients. Intrinsic filling defects are obvious in the top two radiographs being an arachnoid granulation (a) and a broad based undulating lesion (b). Of the lower two, the radiograph on the left (c) could be a focal stricture or extrinsic compression while the radiograph on the right (d) appears to indicate secondary venous sinus compression or irregularity due to old thrombus. (From Owler et al., 2005; reproduced with permission.)

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Figure 7.16

Clinical investigations

Venous sinus manometry and CSF pressure recording in a patient with PTCS. The venous catheter has been pulled back across the point of stenosis during pressure recording, demonstrating the venous sinus pressure gradient. (From Owler et al., 2005; reproduced with permission.)

to be ‘. . . due to an intra-luminal process (prominent arachnoidal granulations, thrombus forming on arachnoidal granulations, or venous thrombosis) . . .’ whereas, if the obstruction was secondary to raised intracranial pressure, the narrowing should be more diffusely spread over the length of the sinus. The latter, after some theoretical considerations on the inter-relationship between intracranial, cerebral venous and dural sinus pressures, noted that dilatation of the stenotic area reduced CSF pressure and related symptoms in some patients with PTCS. The Cambridge group also acknowledge that there are many patients with PTCS in whom the transverse sinus narrowing appears to be secondary to raised CSF pressure. They have confirmed that CSF drainage will abolish the venous pressure gradient in some but not all patients (Figures 7.17 and 7.18). CT venography is able to detect these changes in morphology of the transverse sinus with CSF drainage in many cases. Longer term studies are needed to determine whether the response of the transverse sinus pressure gradient and morphology to CSF drainage is an accurate predictor of outcome following stenting (Dr N. Higgins, personal communication). The third contributor (Lee) referred to the MRV study by Lee and Brazis (2000) considered in the section ‘magnetic resonance venography’ (p. 173) in which no venous sinus pathology was found on MRI plus MRV in 22 consecutive obese young women with IIH (PTCS), raising the issue of whether MRV may be confounding rather than clarifying in the diagnosis of PTCS. King et al., in their reply, defended their basic position (i.e. that apparent

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Figure 7.17

Cranial venous outflow studies

Lateral and antero-posterior views of the left transverse sinus in a case of PTCS before and after CSF drainage. (Courtesy of Dr N. Higgins.)

transverse sinus stenosis in PTCS is likely to be secondary to raised ICP rather than causative), but they did acknowledge the possibility that relief of the stenosis may be therapeutically effective in PTCS. On the matter of MRV, they reiterated their comment in the original paper that MRV is inferior to DRCV in delineating venous sinus abnormalities and reported that they ‘. . . found the MRV lacked adequate definition in the transverse sinus, and flow voids could easily be misinterpreted as sinus thrombosis’. They also make the point that T2- and T1-weighted MRI can exclude thromboses and arachnoid granulations. In the most recent report on the findings on DRCV and manometry in PTCS from the Cambridge and Sydney centres, Owler et al. (2005) presented their results in 22 patients. There was evidence of cranial venous outflow obstruction in 11 cases (50%) which was bilateral in seven cases and unilateral in a dominant transverse sinus in four cases (Figure 7.15). In all the cases with obstruction there was a pressure gradient ranging from 7 to 41 mmHg (mean 18.6 + 10.6 mmHg) across the stenosis (Figure 7.16). The mean superior sagittal sinus pressure in the group with obstruction was 27.9 + 9.3 mmHg compared with 15.0 + 6.8 mmHg in the no obstruction group. However, five of the patients in the latter group did have superior sagittal sinus pressures greater than 15 mmHg, although none had

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Clinical investigations

Figure 7.18 CT venogram in a case of PTCS with compressible veins: immediate effects on the transverse sinuses of CSF withdrawal by lumbar puncture. (Courtesy of Dr N. Higgins.)

gradients reaching 5 mmHg. That is, some of the patients without demonstrated obstruction or focal pressure gradients did have raised dural venous sinus pressure. The obstructing lesions found were always within the distal two thirds of the transverse sinus. In some instances they were well-defined, rounded filling defects consistent with an intra-luminal lesion, in some there was a tight primary stenosis, and in some the obstruction was less well-defined and possibly consistent with extrinsic compression. In summary, the long-standing association of cranial venous outflow pathology and PTCS has been borne out by modern techniques, of which the most sensitive is undoubtedly DRCV with manometry. Three important issues remain to be resolved before the role of this technique in the investigation of possible PTCS can be satisfactorily defined. The first is the extent of the superiority of DRCV over MRI and MRV. The second is the matter of whether the high incidence of reported abnormalities in the transverse sinuses represents primary and causative pathology or is secondary to raised ICP due to a primary PTCS. The third, and in practice the most important, is whether direct treatment of demonstrated venous outflow tract abnormalities is a safe and effective long-term therapy in PTCS which is, to some extent, independent of the issue of whether it is primary or secondary. Radionuclide studies There are three aspects to be considered under this heading: standard static and dynamic brain scans, cisternography and related techniques, and shunt patency

181

Radionuclide studies

studies. Little need be said about the first. Standard radionuclide brain scans have now been superseded in the investigation of patients with possible PTCS. In the Sydney series, 15 such studies were done and all were normal apart from two instances of impaired blood flow in one transverse sinus. A further 257 studies were collected from the literature and, in the case of static scans, all were unequivocally normal apart from two instances of a questionable abnormality in the series reported by Bulens et al. (1979). As in the Sydney cases, there were a few reports of a distal venous sinus abnormality on dynamic scans. Radionuclide cisternography offered some promise of helping to clarify mechanism in PTCS insofar as the technique was able to demonstrate a CSF circulation abnormality. In the Glasgow series, radionuclide cisternography was carried out in six patients with an established diagnosis of PTCS. In five of the six cases there was a marked delay in CSF circulation, there being hold-up of the radionuclide in the spinal subarachnoid space without passage into the ventricular system. One of these patients, in whom 111In-DTPA was used for cisternography, also showed delayed recovery of the tracer from the urine over 24 h confirming the delay in absorption of CSF. Three of the five patients with abnormal cisternograms had measured intracranial hypertension and positive fluorescein angiography, one had a positive fluorescein angiogram but a mean ICP <15 mmHg (this patient did, however, have frequent 1/minute and also atypical plateau waves on the ICP trace), whilst in the remaining patient intracranial hypertension was diagnosed on clinical grounds alone. Radionuclide ventriculograms were carried out in four patients. In two cases, who had previously shown marked delay in CSF circulation on cisternography, there was normal clearance of tracer from the ventricles. In the other two patients, who had not had cisternography, there was a slight delay in clearance of the tracer from the ventricles. In the Sydney series, there were six PTCS patients who had radionuclide cisternography. Two of the six patients had an abnormal study showing delayed passage of radionuclide over the cerebral convexities and, in one case, early ventricular filling, whilst four patients had normal studies. The results from the relatively few other reports of radionuclide CSF flow studies in PTCS show the same variation as is evident above. Thus the high incidence of abnormality reported by Bercaw and Greer (1970) and seen in the Glasgow study was not repeated in the study by James et al. (1974) who found only one abnormal cisternogram in 10 cases examined, nor in the report by Janny et al. (1981) of two cases in eight with slight delay over the cerebral convexities. Likewise, Frigeni et al. (1971) reported four normal radionuclide cisternograms in four PTCS patients studied whilst Weisberg (1975a) found only two abnormal cisternograms in 14 PTCS patients examined. On the other hand, Spence et al. (1980) found that all three of their nine cases of PTCS

182

Clinical investigations

without papilloedema who had radionuclide cisternography had an abnormal study with delay in the subarachnoid space and at the superior sagittal sinus. Overall, 47 PTCS patients having radionuclide cisternography were collected from the literature. Of these 35 were normal (74.5%) and 12 were abnormal (25.5%). The final component of radionuclide investigations is the use of the method in shunt studies, particularly where lumbar-peritoneal shunts are concerned. Although no figures are available, the method was used extensively in the Sydney series and, when taken in conjunction with the CSF pressure and composition on lumbar puncture for the radionuclide injection, the findings were highly diagnostic. Retention of the tracer in the subarachnoid space indicated lumbar catheter problems, partial movement along the tubing indicated valve malfunction, and failure to disperse freely in the peritoneal cavity suggested distal malfunction. In summary, standard static and dynamic radionuclide brain scans are of no diagnostic relevance now, although the technique was, for a time, part of the range of investigations for excluding other causes of raised ICP. Radionuclide studies of CSF circulation have shown inconsistent results, although some studies have supported the concept of PTCS as a CSF circulation disorder. The method has no relevance diagnostically. On the other hand, radionuclide methods for evaluating CSF shunt function are very useful, particularly with lumbar
peritoneal shunts which are the type most commonly used in PTCS.

Cerebral blood flow and volume studies Despite Dandy’s (1937) early speculation that alterations of CBF and CBV might underlie the intracranial hypertension in PTCS, based on his observations of the time course of changes in tension in areas of subtemporal decompression, very little work has been done on measuring these parameters in the condition. Foley (1955) initially studied CBF and CBV in three patients with PTCS using the nitrous oxide method and found values that were high but not significantly so. Subsequently, Mathew et al. (1975) studied CBF and CBV in two patients with PTCS, finding a mean reduction of 10% in the former and a mean increase of 85% in the latter. With reduction of CSF pressure, the CBV returned to normal and all values were normal when the patients were in remission. Raichle et al. (1978) studied the same parameters in a larger group of 14 PTCS patients using a carotid injection of 15O-labelled oxyhaemoglobin and also found a reduction in CBF and an increase in CBV without change in the CMRO2. They concluded that the increase in CBV was due to dilatation of the cerebral veins but could only account

183

Haematological investigations

for an increase of 1% in the intracranial volume, quite insufficient to explain the measured elevation of ICP. On the basis of the recent study by King et al. (2002), suggesting that venous hypertension is a consequence of the raised ICP rather than the cause, at least in some cases, it may be that the increased CBV due to venous distension is a secondary phenomenon. Subsequent studies with newer techniques have not supported the early findings, however. Thus, Gjerris et al. (1985), who studied 14 patients using xenon inhalation and PET methods, found all cases to have normal CBF (59 + 9 ml 100 g
1 min
1), although two patients did have focal low flow areas. Also in 1985, Brooks et al., who used the PET scanner with C15O2, 15O2 and 11CO, found no changes in CBF, oxygen utilization or CBV in their PTCS patients compared with age-matched controls. One patient measured serially before and after LP shunting showed no change following the procedure and there was no variation with cerebral perfusion pressure changes with ICP levels of 45 mmHg. This last finding was borne out by the study of Kabeya et al. (2000) who measured CBF during plateau waves of ICP using PET scanning (15O-labelled H2O) and found no changes in CBF despite severe reduction of cerebral perfusion pressure. Finally, there have been two studies using SPECT with 99mTc-HMPAO. In the first of these Bakar et al. (1996) found impaired rCBF in 9 of 17 PTCS patients whilst in the second study (Lorberboym et al., 2001) perfusion abnormalities were found in 6 of 11 patients with PTCS (mild to moderate in one, severe in 5). In summary, the findings with regard to CBF and CBV in PTCS are few and conflicting. The techniques certainly do not have any role in clinical diagnosis or evaluation at present but the studies should be pursued with a view to clarifying whether the intracranial hypertension of PTCS does have relatively subtle adverse effects which escape current methods of evaluation. If such effects were to be identified and linked with demonstrable PET or SPECT abnormalities, then these methods might have a role to play in assessing severity and monitoring treatment. Haematological investigations PTCS is associated with a number of haematological abnormalities as considered in Chapter 5. Of the six groups of haematological abnormality listed as possible aetiological factors in PTCS in Table 5.1 of that chapter, the first four (anaemias, leukaemias, polycythaemia and myeloma) should be identifiable on standard haematological evaluation. The sixth factor, POEMS, is a rare cause of PTCS and should be apparent on combined clinical and haematological grounds. It is the fifth group, categorized as ‘platelet, factor and other abnormalities’, which is the

184

Clinical investigations

particular focus here. The two issues are, firstly, which PTCS patients should have a detailed haematological analysis, and, secondly, which of the various factors should be examined. In general terms, those PTCS patients with evidence of venous thrombosis as a possible causative factor are the ones who should be studied, and the factors examined particularly should be those associated with venous thromboembolism generally. However, these should not be considered absolute criteria insofar as thrombophilia can exist (and may be significant) in PTCS patients in the absence of documented intracranial venous thrombosis (Dunkley & Johnston, 2004; Glueck et al., 2005) and the list of possible culpable factors is not necessarily exhaustive. The three recent studies of the various platelet, factor and other abnormalities in PTCS have been considered in Chapter 5 but may be summarized here as follows: Sussman et al. (1997), in a study of 38 patients diagnosed as having BIH (PTCS), found antiphospholipid antibody in 32% of cases and also found cases of familial deficiency of anti-thrombin III, thrombocytosis, and polycythaemia. In addition, an increased concentration of plasma fibrinogen was detected in 26% of cases. Importantly, they noted that these abnormalities were more likely to be detected in patients who were not obese and in those tested within 6 months of onset of the PTCS. Dunkley and Johnston (2004), in a study of 25 PTCS patients (the majority were patients with a previously established diagnosis of PTCS being admitted for shunt malfunction), found thrombophilic defects in 68% of cases. These included positive ACA (6 cases), APCR and FVL (4 cases), positive LA (3 cases), PT20210 (2 cases), low PS levels (2 cases), and elevated fasting homocysteine (2 cases). All had been investigated for cranial venous outflow abnormalities, at least to the extent of MRV, which were present in four cases only. Moreover, all had a normal platelet count and screening coagulation tests. Glueck et al. (2003, 2005), in two studies involving 38 and 65 cases of IIH (PTCS) respectively (all women with a high incidence of obesity and polycystic ovary syndrome) found high levels of factor VIII in 24% of cases, high plasminogen activator inhibitor factor in 24%, high lipoprotein A (associated with hypofibrinolysis) in 35% and a prolonged APTT (in some accompanied by lupus anti-coagulant) in 26%. All were significant in relation to a control group. The findings were similar in the second study with the addition of the finding of high incidence of IIH patients who were homozygous for the thrombophilic C677T MTHFR mutation in comparison with controls. The main factors that are known to be associated with venous thrombosis and might be sought on investigation, which can be hereditary or acquired, are briefly listed below. It should be borne in mind that other factors, such as oral contraceptives, pregnancy or the post-partum state, surgery, trauma, and prolonged immobilization can also contribute to hypercoagulability and venous stasis.

185

Metabolic and endocrine studies

1. Factor V Leiden (G1691A) mutation and the prothrombin gene (G20210A) mutation. The former causes resistance of factor Va to breakdown by activated protein C and the latter is associated with an elevation in prothrombin levels. There is a relatively high incidence of these gene mutations in Caucasian populations (5% and 2%, respectively). They may act as co-factors with other risk factors, particularly oral contraceptives, to increase the risk of venous thrombosis (van der Meer et al., 1997; Martinelli et al., 1998). 2. Plasma homocysteine. Elevation of plasma homocysteine is a risk factor for both venous and arterial thrombosis, acting through a complex mechanism involving endothelial cell activation, protein C, and factor Va. There is also a high incidence of this abnormality, around 5%, in Caucasian populations, and it is associated with a doubling of the risk of venous thromboembolism in general. 3. Other factor elevations. These include fibrinogen, von Willebrand’s factor, factor VIII, factor IX, factor XI, plasminogen activator inhibitor, and plasma D-dimer. 4. Other deficiencies. These include anti-thrombin deficiency, protein C and protein S deficiency. Deficiencies of these substances, which play an important role in control of the coagulation cascade, are relatively rare (1 in 500
1000 people), but carry a striking familial pattern of inheritance, and are associated with a high relative risk of thrombosis 10
30-fold (van der Meer et al., 1997). 5. Antiphospholipid antibodies. These include IgM and IgG anticardiolipin antibodies and the so-called lupus anti-coagulant (LA). In summary, quite a variety of haematological disorders or abnormalities are associated with an increased risk of venous thrombosis and, through this connection, may play a causative role in the PTCS or cerebral venous disease more generally. This is particularly so if other risk factors are operative. How far haematological investigation should be pursued in PTCS is an open question. At present, the more detailed investigations should probably be reserved for cases of established cranial venous outflow pathology, cases in which factors such as oral contraceptive use, pregnancy etc are present, and research studies. Metabolic and endocrine studies Since the recognition of a high incidence of PTCS in young, obese females, often with a history of menstrual irregularity, there has been an unsubstantiated belief that the condition is associated with some underlying metabolic and/or endocrine abnormality, particularly one which might link obesity, hormonal irregularities and PTCS. Such an abnormality has, however, proved elusive although it must be said that studies of the matter are few, involve small numbers of cases, and have

186

Clinical investigations

been unsystematic. The subject was examined in the Glasgow series in which 35 of the 110 PTCS patients were moderately or grossly obese females. Of the 35 patients, 27 fell into the group having no identifiable aetiological factor. A history of menstrual irregularity was present in 12 cases, 10 of whom were obese. In a group of 8 patients (5 women, 3 men) estimations of plasma and urinary steroids were carried out but did not show any consistent abnormality. Of the 5 women in the group, 3 did show high levels of plasma cortisol, whilst in one the normal diurnal variation was absent. Urinary steroids were normal apart from one women with a high level of 17-hydoxy steroids. Estimations in the 3 men showed one to have low plasma cortisol and urinary steroids with absence of diurnal variation. The remaining 2 men had virtually normal steroid levels apart from a raised evening level of plasma cortisol on one. Urinary gonadotrophins were estimated in 3 patients and were normal in each case. No specific endocrine or metabolic studies were carried out in the Sydney series. Turning to the literature, since the initial report by McCullagh (1941), the few studies of possible endocrine or metabolic factors have been similarly unhelpful despite the increasing evidence of an association of PTCS with steroid usage and with a variety of primary endocrine conditions (see Chapter 5). Despite some suggestive findings by Oldstone (1966), the report of elevation of oestrone, oestriol, androstenedione and testosterone in one young, obese woman with PTCS (Donaldson & Binstock, 1981), as well as the finding of elevated CSF prolactin in PTCS (Bates et al., 1982; Goldman & Rabin, 1984), the findings have been largely negative or inconclusive (Joynt & Sahs, 1962; Foley & Posner, 1975; Weisberg, 1975a; Reid & Thomson, 1981; Orefice et al., 1984; Sørensen et al., 1986a). Perhaps the most promising development has been the recent studies of Glueck et al. (2003, 2005) linking PTCS with polycystic ovary syndrome and haematological abnormalities in obese women. Their findings have been considered in detail in Chapter 5. There are scattered reports of other abnormalities but none have been in any way definitive in terms of diagnostic value, clarification of disease mechanism, or therapeutic relevance. Among the more recent reports may be mentioned the studies of serum retinol (Jacobson et al., 1999a; Selhorst et al., 2000). Thus, the former found elevated serum retinol levels when comparing 16 female IIH (PTCS) patients with 70 controls (752 mgl
1 compared to 530 mgl
1). Subramanian et al. (2004) reported normal plasma ghrelin levels in obese patients with PTCS. Inshasi et al. (1995) reported four cases of PTCS who were positive for the intrathecal synthesis of immunoglobulin (Ig)G. In summary, metabolic and endocrine studies have, as yet, nothing to offer from the diagnostic viewpoint in PTCS nor, indeed, with respect to disease mechanism. Nonetheless, this is an area of investigation which should be pursued

187

Conclusions

in a systematic way insofar as the clear clinical association of PTCS with obesity in women (but not in men), and particularly women of a child-bearing age, must have some explanation which, if understood, might well throw some light on disease mechanism. Conclusions There are, in summary, three major requirements in the investigation of patients with PTCS: 1. Establishing the presence of raised ICP 2. Excluding other possible causes of raised ICP 3. Identifying the cause of the PTCS if present and where possible. In addition, investigations may be of importance in evaluating the severity of the condition, in monitoring progress with or without treatment, and also in clarifying its underlying mechanism. In practice, lumbar puncture with manometric measurement of CSF pressure meets the first major requirement, although a characteristic clinical history coupled with unequivocal ophthalmoscopic findings, supported if necessary by fluorescein angiography and CSLO, may be sufficient in some instances. Static MR imaging, preferably with the addition of gadolinium enhancement, meets the second major requirement although, if this is not available, CT scanning with contrast will generally suffice. Thus, lumbar puncture and MR scanning are enough to establish the diagnosis. Greater precision can be added to the former by continuous monitoring of CSF pressure either via a lumbar subarachnoid catheter (+ a CSF infusion study) or via an intracranial monitoring device. Such measures are particularly applicable where a single manometric measurement(s) is normal despite a typical clinical picture. In this situation, the majority of cases will show abnormalities on continuous monitoring or infusion studies. Some may not and may represent cases of ‘normal pressure PTCS’. Greater precision can be added to the latter by including MRA (to exclude parenchymal and dural AVMs) and MRV, although MRV is primarily directed at the third major requirement, that is, identifying the cause of the PTCS. Other investigations directed to this end include analysis of CSF composition, DRCV with manometry, and haematological studies where venous outflow tract pathology is present or suspected. With respect to the other requirements, severity is established primarily by the ophthalmological evaluation but also, to some extent may be indicated by CSF pressure monitoring and infusion studies to measure CSF outflow resistance. The same investigations are central in monitoring progress but may be augmented by further evaluation of the cranial venous outflow tract (MRV, DRCV), possibly PET or SPECT studies and also neuropsychological assessment (not considered

188

Clinical investigations

in the present chapter). As for disease mechanism, CSF infusion studies, special purpose MR studies, radionuclide CSF studies, simultaneous measurements of CSF and cranial venous outflow tract pressures (the latter by DRCV), CBF/CBV studies, metabolic/endocrine studies, and haematological investigations have all contributed to clarification and may continue to do so in that unresolved issues still remain. The other investigations considered above (skull X-rays, EEG, standard angiography, and ventriculography/encephalography) are of historical relevance only.

8

Treatment

Introduction The treatment of PTCS is a somewhat complex matter although, in clinical terms, it might be described as relatively successful. In any analysis of the treatment of PTCS there are at least five aspects reflecting this complexity which need to be considered. 1. PTCS is a condition of quite variable natural history with cases ranging from those which resolve spontaneously or rapidly with either correction/withdrawal of an apparent causative factor, or with brief and simple treatment, to those cases that are chronic, progressive and refractory to treatment. 2. There are no methodologically satisfactory studies of the different treatment options. Thus, in a 2002 report reviewing ‘interventions for idiopathic intracranial hypertension’, Lueck and McIlwaine drew the following conclusion: ‘There is insufficient information to generate an evidence-based management strategy for IIH. Of the various treatments available, there is inadequate information regarding which are truly beneficial and which are potentially harmful. Properly designed and executed trials are needed.’ 3. The majority of treatments used over the past 100 years have all been successful, at least to a significant degree, and in a significant number of cases. The historical development of treatment methods is considered in detail in Chapter 2, but in summary these are serial lumbar punctures, subtemporal decompression, steroids, diuretics, acetazolamide, CSF shunting, optic nerve sheath decompression and direct treatment of cranial venous outflow obstruction. All are still in use and the choice of which to use in a particular patient often comes down to the desire to avoid a particular complication, or the specialty of the treating doctor. All, however, have a significant failure rate or complication rate, or, indeed, both. 4. A number, even the majority, of these treatments effect clinical resolution of the disease without necessarily restoring CSF pressure to normal levels. 189

190

Treatment Table 8.1. Primary treatments in PTCS: Glasgow and Sydney series

No. of cases No treatment Serial LPs Acetazolamide Steroids Diuretics CSF shunt ONSD Sub-temporal decomp. Other Single treatment Combined treatment Initial Rx successful Further Rx required

Glasgow series

Sydney series

118 22 80 3 20 0 1 0 5 3 103 15 74 (62.7%) 44 (37.3%)

144 6 11 67 49 4 29 7 0 2 117 27 85 (59.0%) 59 (41.0%)

5. None of the treatments, with the possible exception of the direct treatment of cranial venous outflow obstruction in certain cases, is directed at the actual cause of the disease. In what follows, each of the common treatments will be considered individually. The figures and impressions from the Glasgow and Sydney series, as well as the recent Cambridge series on direct intervention for cranial venous outflow pathology, will be given first, followed by evidence from the literature. The chapter will conclude with a summary of our present views on each of the treatment methods and some suggestions regarding future directions. Before considering the different treatments individually, the relative frequency of their use in the two series is shown in Table 8.1. The most obvious point to be noted is the marked difference in the relative frequency of use of different primary treatments, with a preponderance of serial LPs in the Glasgow series compared to the main reliance on acetazolamide and steroids in the Sydney series. Despite this, there was a closely comparable success rate for the primary treatment used in the two series. Not shown in Table 8.1 is a similar difference in the frequency of use of secondary treatments in those cases not responding to the initial treatment, with a predominance of subtemporal decompression in the Glasgow series compared to CSF shunting in the Sydney series. What is notable is the close similarity in overall outcome in the two series despite these marked differences in the relative use of different primary and secondary treatments.

191

No treatment

No treatment In the Glasgow series, there were 22 patients (20%) who received no treatment apart from one or two lumbar or ventricular punctures for diagnostic purposes. In this group, there was a preponderance of men (13 males, 9 females) and a high proportion of children, 50% being 15 years or younger. In addition, there was a relatively high incidence of cases with a putative aetiological factor: minor head injury, three cases; middle ear disease, three cases; other recurrent infections (bacterial or viral), four cases; chronic renal disease, one case; and chronic bronchitis and emphysema, one case. All these patients, apart from one case later diagnosed as having multiple sclerosis, showed resolution of the PTCS within a short period (only two cases 43 months). One patient, a young woman, had two recurrences, 1 and 3 years after the initial diagnosis, and was finally treated with steroids. There were only six cases in the Sydney series that were not treated, apart, in one instance, from the withdrawal of tetracycline taken over a long period for acne. Of these six cases, four showed resolution within 3 months and the remaining two from 4 to 6 months. Turning to the literature, a total of 277 cases not initially treated was collected in an earlier study to 1992 (Johnston, 1992). This number did not include the series of Grant (1971) and Bradshaw (1956), with a total of 121 patients, in which the authors state that most cases did not receive treatment but do not give precise details. Examining ten relatively large series (415 cases) with a full age range, and for which accurate figures on treatment are available (Dandy, 1937; Zuidema & Cohen, 1954; Paterson et al., 1961; Greer, 1968; Guidetti et al., 1968; Boddie et al., 1974; Weisberg, 1975a; Vassilouthis & Uttley, 1979; Bulens et al., 1979; Rush, 1980), of a total of 549 patients, 113 were not treated (20.6%). As far as can be determined, all but one of these patients showed resolution and, although the time course is not always made clear, the time to resolution was characteristically short. Thus Weisberg (1975a), in whose series of 120 patients, 27 did not receive treatment (22.5%), stated that the duration of persistent symptoms in this subgroup was short, whilst Boddie et al. (1974), who reported 11 of 34 patients not receiving treatment (32.4%), found an average duration of continuing symptoms of 3 months. Bulens et al. (1979), reporting 5 of 36 cases not requiring treatment, found the time for resolution of papilloedema to range from 1 to 12 months, whilst in Bradshaw’s (1956) series of 42 patients, most of whom were described as not requiring treatment, the condition usually resolved in months but sometimes took years. In three paediatric series (Rose & Matson, 1967; Amacher & Spence, 1985; Couch et al., 1985) totalling 84 patients, 28 cases did not require treatment (33.3%). In only one of the 28 cases was subsequent treatment found to be necessary. In Grant’s (1971) series of 79 children with PTCS, most were not

192

Treatment Table 8.2. Cases treated by removal of presumed causative factor only

Responsible factor Vitamin A excess/deficiency Growth hormone treatment Antibiotics Steroid use/withdrawal Other drugs and agents Pregnancy Thyroid disease Jugular vein ligation Other conditions Total

No. of cases

Outcome

29 24 11 9 12 11 8 4 22

All resolved All resolved All resolved All resolved 10 resolved, 2 persisted All resolved 7 resolved, 1 persisted 3 resolved, 1 persisted All resolved

130

126 resolved, 4 persisted

treated. Papilloedema was said to have resolved by 1 month in 47%, by 1 year in 54%, and by 10 years in 86%. The follow-up in these paediatric series was, however, poor. In a group of 62 cases collected from small reported series (<10 cases) a somewhat different pattern is seen. Of 35 non-treated cases, excluding 3 patients for whom follow-up is uncertain, only 17 of the remaining 32 showed rapid resolution of the disease (53.1%) with 15 (46.9%) having persistent symptoms or signs or both. Indeed, several patients had papilloedema lasting for years, in some cases with loss of visual function (Dersh & Schlezinger, 1959; Rabinowicz et al., 1968). In a separate collection of 130 cases from the literature, where treatment consisted only of correction or removal of a presumed causative factor, the outcome figures were much better. Details of the agents concerned and the outcome are summarised in Table 8.2. In conclusion, it seems reasonable to assert that in a small proportion of cases of PTCS the disease will be self-limiting. Such cases are likely to be those with relatively mild disease at presentation and those with a clear-cut causative factor that can be corrected or withdrawn. When the latter is the case, the likelihood of resolution without additional treatment is high. The situation is less clear in cases without such a factor. Here the probability of resolution without treatment may be of the order of 10
20% but such a figure is necessarily tentative, given the vagaries of reporting and the variability of follow-up in reported cases. Serial lumbar punctures Initially the major form of medical treatment prior to the advent of steroids and diuretics, serial lumbar punctures is a treatment not now widely used for PTCS.

193

Serial lumbar punctures

This change is reflected in the comparison of the treatments used in the Glasgow and Sydney series, spanning a period of 60 years from 1940 to 2000. In the combined series of 134 patients, predominantly from the Glasgow series, reported in 1981 (Johnston et al., 1981), serial lumbar punctures was the sole initial treatment in 67 patients (50.0%). It proved adequate in 26 of the 67 patients (38.8%) who required an average of nine punctures each. There were no recurrences amongst these 26 patients (mean follow-up 12.7 years), and 23 were clear of symptoms and signs within three months. However, in 11 of the 26 patients, the initial CSF pressure was relatively low (mean 210 mmCSF), suggesting the possibility of a mild form of the disease. Serial lumbar punctures proved inadequate in 41 of the 67 patients (61.2%), these patients failing to improve clinically, with persistence of symptoms and papilloedema and, in three instances, deterioration of vision. In none of these 41 patients was the initial CSF pressure less than 300 mmCSF, and all required other forms of treatment after an average of 24 punctures. In a further 12 patients, serial lumbar punctures were combined with steroids, subtemporal decompression or acetazolamide as initial therapy. In 10 of these 12 cases there was rapid resolution of the PTCS whilst two required further treatment. The efficacy of repeated lumbar punctures is usually gauged by the daily level of CSF pressure, although this may be misleading due to the quite marked spontaneous variations in pressure that can occur. In five patients, CSF drainage by lumbar puncture during continuous intracranial pressure monitoring showed a mean reduction from 30 to 7 mmHg with removal of a mean CSF volume of 21 ml. Typical intracranial pressure waves were absent for up to 60 min after drainage. In all patients, however, the intracranial pressure rapidly returned to prepuncture levels (average time, 82 min). Comparison of the effects of lumbar CSF drainage and steroid administration on ICP over a 36-h period is shown in Figure 8.1. As with other forms of treatment, the proportion of patients treated by this method varies considerably from series to series. Thus, in the series of Rush (1980) and of Boddie et al. (1974), the proportion was low
one of 61 in the former and five of 34 in the latter (all in conjunction with steroids and diuretics). On the other hand, in Weisberg’s (1975a) series of 120 cases, 88 patients were treated with lumbar punctures: in 28 cases alone, in 50 in combination with steroids, in five in combination with acetazolamide, and in five in combination with glycerol. It is not clear how treatment was related to outcome in these sub-groups. In two other reports, covering a full age-range of patients, Greer (1968) reported the use of serial lumbar punctures in 43 of 110 cases (39.1%): in 21 alone, in 21 in conjunction with subtemporal decompression, and in one with a subsequent lumbar CSF shunt. The PTCS was said to have resolved in all cases.

194

Figure 8.1

Treatment

Comparison of the effect of lumbar CSF drainage and steroid administration on CSF pressure in a patient with PTCS. Bars indicate the number of minutes the pressure was within each 10 mmHg range over a 12 hour period. (From Johnston et al., 1981; with permission.) ICP ¼ intracranial pressure.

Bulens et al. (1979) used serial lumbar punctures with or without diuretics in 36 patients with PTCS and found resolution of papilloedema in all cases over periods ranging from 2 weeks to 8 months. These authors also stressed the rapid return of CSF pressure to pre-drainage levels as noted above.

195

Serial lumbar punctures

In a series of 38 children, Weisberg and Chutorian (1977) used lumbar punctures alone in 16 cases, draining 20
50 ml CSF per puncture, and reported resolution in all instances, in some after only a single puncture. In a further 16 cases in this series, lumbar punctures were used with steroids, and again all cases resolved initially, although there were six recurrences. Also in children, Couch et al. (1985) reported the use of lumbar punctures in 15 cases, as part of a combination therapy involving steroids or acetazolamide or both. All cases showed initial resolution but there were two recurrences. Apart from these series, a further 134 cases treated by lumbar punctures, either alone or in combination, were collected from the literature. Of the 84 patients treated by lumbar punctures alone, there was resolution in 67 cases (79.8%), with as few as three punctures in some cases. Within this sub-group, there were, in all, three recurrences whilst in 12 cases resolution was described as slow, taking 15 months in one instance. In five patients there was what was described as ‘improvement’, meaning amelioration of symptoms but persistence of papilloedema, and in 12 cases failure of resolution necessitating other forms of treatment. There were 50 cases in whom serial lumbar punctures were part of a combined treatment, for the most part with steroids or acetazolamide or both. In 29 of the 50 (58.0%), there was resolution but, as with lumbar punctures alone, this was slow in a number of cases. There were 21 patients (42.0%) who failed to respond to serial lumbar punctures as part of a combined initial treatment, and at least one instance of further visual deterioration during such treatment (lumbar punctures, steroids, glycerol) (Lessell & Rosman, 1986). In summary, assuming a normal rate of CSF production in PTCS (and there is no evidence to the contrary), the theoretical objection to serial lumbar punctures as treatment is that volumes around 20
30 ml will be restored in a very short time so, unless some other factor is operative, there will not be a sustained reduction in CSF pressure. It has been suggested, however, that repeated punctures may create a leak, even a fistula, at the puncture site(s) which can produce the required sustained effect. Such a leak must be considered as unpredictable, both in its occurrence and its presumed effect. There is also the possibility that reduction of CSF pressure by drainage might favourably influence a cycle of events involving venous sinus collapse, a topic considered further in Chapter 10. On present evidence, however, the most that can be said is that a small percentage of cases of PTCS do show resolution on treatment with repeated lumbar punctures, but how much this is due to the punctures themselves is an unresolved issue. Further, the treatment is distressing to the patients so, given the other options available, the method is no longer applicable. If lumbar drainage of CSF is thought to be desirable, it should more effectively be achieved by a period of continuous drainage via a lumbar subarachnoid catheter.

196

Treatment

Acetazolamide (DiamoxÕ ) Despite the demonstration of a significant reduction in CSF production with acetazolamide (Rubin et al., 1966), in addition to its diuretic action, the drug has been relatively disappointing in the treatment of PTCS. In an early report on the combined Glasgow and Sydney series (Johnston et al., 1981), acetazolamide had been used in only three patients, in all cases in conjunction with other forms of treatment. In one case there was complete resolution within three months but the other two cases required further treatment. In the final figures from the Sydney series, acetazolamide alone was the primary treatment in 45 of 144 cases analysed (31.3%)
23 of 83 adults (22 of 73 females and one of 10 males) and 22 of 61 children (14 of 35 females and eight of 26 males). These tended to be cases judged as mild to moderate on initial presentation. In summary, it was effective in 21 of the 45 cases (46.7%%), effective but followed by immediate recurrence on cessation in three cases (6.7%), ineffective or only partially effective in 19 (42.2%), and stopped due to complications in two cases (4.4%). In terms of time course, resolution of the PTCS occurred within 3 months in 16 of the 21 patients for whom the drug was an effective single treatment. Acetazolamide was used in conjunction with other forms of non-surgical treatment in 21 cases: 15 adults (12 females, 3 males) and 6 children (3 females, 3 males). In 10 patients there was a combination of acetazolamide and steroids. In only two of these 10 cases was there resolution of the PTCS. Of the remainder, six cases had no response while two cases showed resolution followed by more or less immediate recurrence on cessation of treatment. In one of these patients the sequence was repeated before resorting to CSF shunting. Of seven cases in whom acetazolamide was combined with serial LPs, only two showed a response and one of the two cases had an immediate recurrence on cessation of treatment. Of two patients who were treated with a combination of acetazolamide, another diuretic, LPs and weight reduction (in one of the two), one showed resolution and one had no response. One patient was treated with acetazolamide in conjunction with elevation of a depressed skull fracture compressing a dominant transverse sinus. This patient, a 6-year-old boy, had rapid and complete resolution of his PTCS. The other two cases with combined treatment had a combination of acetazolamide, steroids and 5 to 7 days of continuous lumbar CSF drainage. Both showed rapid resolution (in <1 month) but in both the follow-up has been short. Turning to the literature, it can be said that the place accorded to acetazolamide in the treatment of PTCS depends to a significant degree on the concept of disease mechanism held by those treating the condition. Given the drug’s established effect on CSF production, it will clearly appeal much more to those who believe that impaired CSF absorption is the primary abnormality in PTCS as opposed

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to those who favour other mechanisms. This is reflected in the rather variable use in large series. Thus, Boddie et al. (1974) and Bulens et al. (1979) did not use acetazolamide at all in a total of 70 cases whilst Greer (1968) stated that the drug was ineffectual and did not use it in a series of 110 cases. In children, Grant (1971) reported its use in only one of 79 cases. In three series the drug was used in a small number of cases: 11 of 61 (Rush, 1980), 5 of 120 (Weisberg, 1975a), 9 of 61 (Davidoff, 1956). At the other end of the scale, Guidetti et al. (1968) used acetazolamide, either alone or in combination, in 52 of 100 patients whilst Radhakrishnan et al. (1986) used the drug in all 23 patients (all females) in their series. The variability in use is mirrored in the variability of effect. In an earlier review (Johnston, 1992), a total of 39 cases was collected in whom acetazolamide was used alone, in four instances after failure of another form of treatment (steroids, two cases; frusemide, one case; digoxin, one case). Discounting the eight cases reported by Guidetti et al. (1968) in whom the outcome was not clear, there was a satisfactory response (i.e. resolution or substantial improvement) in 21 cases but a poor or no response in 10 cases. Of the 21 patients who responded, one still had a marked increase in CSF pressure despite complete resolution of symptoms and signs whilst one had a recurrence after 3 years. Apart from two reports (Spence et al., 1979; Amacher & Spence, 1985) in which acetazolamide was used in 12 patients, the patients comprising the group of 31 cases came from reports of one or two cases only. In the first of the two reports referred to, Spence et al. (1979) found acetazolamide to be effective in two of six patients who had PTCS without papilloedema but ineffective in four, all of whom went on to lumbar CSF shunting. In the second report (Amacher & Spence, 1985), also of six patients, acetazolamide was effective in four cases. In a recent series of 36 children (3.5 months to 14 years) with PTCS, Youroukos et al. (2000) reported that 47.1% (8 of 17 cases) treated with acetazolamide alone showed resolution but when steroids were added in combination the percentage rose to 91.7% (22 of 24 cases). A further 163 cases were collected in whom acetazolamide was used in combination with other forms of medical treatment: lumbar punctures, steroids, diuretics (including osmotic diuretics), cardiac glycosides and weight reduction. Of these 163 cases, 59 (36.2%) had resolution of the PTCS, 45 (27.6%) did not, and in 59 (36.2%) the outcome was unclear. In summary, acetazolamide clearly has a role in the management of PTCS and might legitimately be regarded as the first line of medical treatment. Although, as with other methods of treatment for PTCS, there is no definitive study of the use of the drug, the impression from available reports is that it is likely to be effective in approximately 20
40% of cases with a greater chance of success in children and adult males, particularly if there is a causative factor for the PTCS which can

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be withdrawn or corrected. Acetazolamide is generally well tolerated with a low incidence of side effects and is suitable for prolonged use if the clinical situation so dictates. Some patients are intolerant of acetazolamide, however, and in all cases regular assessment of blood electrolyte levels is advisable. Whether it is better to use acetazolamide alone or in combination with other treatments such as lumbar punctures, steroids, other diuretics or even cardiac glycosides is an unresolved question. However, the addition of weight reduction where relevant is an obviously appropriate measure. In pregnancy, acetazoleamide should only be used after appropriate counselling about the experimental but unproven clinical teratogenetic effects of acetazolamide (Lee et al., 2005). Topiramate is an alternative carbonic anhydrase inhibitor which has recently been tried in some patients with PTCS. It is approved for the treatment of epilepsy and migraine prophylaxis and also causes anorexia which has merit for many patients with PTCS. However, some cases of acute secondary angle-closure glaucoma have been reported (Alore et al., 2006). Diuretics Very little use was made of diuretics other than acetazolamide in either the Glasgow or Sydney series. In the initial combined group of 134 patients (predominantly from Glasgow), frusemide (Lasix) was used in three cases, in combination with steroids in two cases and with lumbar punctures in one case (Johnston et al., 1981). In two of these three patients there was resolution of the PTCS whilst the third patient needed additional treatment. There was the occasional use of other diuretics and magnesium sulphate in the early cases but always in combination with one or more of the major forms of treatment. In the final figures from the Sydney series the use of other diuretics (frusemide) was also confined to three cases, all in conjunction with other forms of treatment. In the one successful case there was an early recurrence necessitating another form of treatment. Turning to the literature, three papers merit particular attention in relation to the use of diuretics as the primary form of treatment in PTCS. First, in the series of 100 patients reported by Guidetti et al. (1968), five were treated with oral glycerol alone and 44 with intravenous 40% glycerol (40 ml 4
8 times per day for two weeks) in conjunction with acetazolamide. Of the remaining 51 patients, 14 received no treatment, 8 were treated with acetazolamide alone, and 29 with steroids, in some instances in combination with glycerol. Outcome figures are given but only for the group as a whole. Of 80 patients followed up, all showed resolution of PTCS over an average time of 10 weeks, but 12 were left with persistent abnormalities of vision. Second, Jefferson and Clark (1976) reported

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Weight reduction

a series of 30 cases (28 females, 2 males) of whom 25 were treated with ‘dehydrating agents’ (chlorthalidone, 11; hydroflumethazide, 8; glycerol, 7; urea, 1) in conjunction with dietary measures in patients who were obese. These authors found such treatment efficacious, noting an improvement in all cases presenting with reduced visual acuity. The other five patients in the group of 30 were treated by subtemporal decompression. Third, Krogsaa et al. (1985) reported a series of 20 cases of PTCS in which diuretics were the first line of treatment, usually in combination with digoxin, acetazolamide or, in two cases, steroids. Eleven of these 20 patients showed resolution over 3 to 6 months whilst eight had persistent papilloedema with disc gliosis and abnormal VERs and one went on to optic atrophy. Four of the eight ‘non-responders’ were subsequently shunted. In the combined figures from the literature (Johnston, 1992), there were 55 cases treated with diuretics alone for whom specific outcome data were available. The diuretics used were as follows: chlorothiazide and related diuretics, 20; glycerol, 15; frusemide, 6; urea, 1; unspecified, 13. The majority (48 of 55, 87.3%) showed resolution while in seven cases the treatment was clearly unsuccessful. In a further 75 cases diuretics were used in conjunction with other forms of treatment, usually multiple involving steroids, acetazolamide and serial lumbar punctures. Of these patients, 48 (64%) showed resolution but in five cases this was described as slow and there were at least two recurrences. In addition, one patient suffered irreversible loss of visual acuity during treatment. In summary, very little can be said about the use of diuretics other than acetazolamide in the treatment of PTCS. There are clearly some cases in whom they will be successful, and resolution has been reported with ‘standard’ diuretics, particularly chlorothiazide and related compounds and frusemide, and with osmotic diuretics such as glycerol and urea. There is, however, no evidence from which to draw any conclusions about their relative merits, either with respect to each other or with respect to other treatment methods. Weight reduction One of the best established associations with PTCS is obesity in females, predominantly those in the second to fifth decades. The issue of whether the obesity is a causal factor or a non-aetiological association has been discussed in Chapter 5, as has the nature of the possible aetiological connection; that is, some metabolic effect of the excess adipose tissue on circulating hormones, or an obesity-related increase in intracranial venous outflow pressure. Whatever the connection, and whatever the aetiological mechanism if there is one, the possibility exists that weight reduction might be an effective treatment in the obese sub-group of PTCS patients. In the first of two early studies on this point,

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Newborg (1974) reported on nine obese women with PTCS who were treated with a rice-based reduction diet. All nine patients showed resolution of their PTCS over a period ranging from 2 to 14 months (average 5.9 months). Subsequently, Noggle and Rodning (1986) reported one obese patient who showed improvement with weight reduction followed by recurrence which resolved after gastric stapling and significant weight loss. In this patient there was a further recurrence at 3 years after breakdown of the stapling, followed by resolution after repeat stapling. More recently, there has been increase in interest in weight reduction as a treatment of PTCS with the use of radical surgical methods for the treatment of morbid obesity. Considering first non-surgical methods, Johnson et al. (1998) reported 15 obese women with IIH (PTCS) treated with a combination of attempted dietary weight loss and acaetazolamide over a 24-week period. Of these 15 patients, 10 had complete resolution of their PTCS, one had partial resolution, while four had no change. All those showing resolution did have weight loss whereas those in whom the treatment failed did not lose weight. In the study reported by Kupersmith et al. (1998), a comparison was made between two groups of obese women with PTCS, one group (38 patients) showing weight loss ¸2.5 kg in any 3-month period, and one group (20 patients) without weight loss. The authors found no difference between the two groups in final visual acuity or visual fields, although they did find a more rapid improvement in the weight loss group. Surgical treatment has particularly been advocated by Sugerman and his colleagues. In an early paper (Sugerman et al., 1995), they reported eight female patients with PTCS (two with a blocked V
P shunt) who underwent gastric by-pass surgery. The mean CSF pressures before and after surgery were 353 + 35 mmCSF and 168 + 12 mmCSF, respectively, and the mean weight loss 57 + 5 kg. All eight patients showed clinical improvement in their PTCS. In a later study, Sugerman et al. (1999b) described 24 cases of PTCS in obese females who underwent bariatric surgery (23 gastric by-pass, one laparoscopic adjustable gastric banding). Of the 24 cases, 19 were followed up, the other five being lost to follow-up. In the 19 cases the average weight loss was 45 + 12 kg (71 + 18% of the excess weight). All but one were reported as showing resolution of the symptoms and signs of PTCS. However, 7 of the 19 (36.8%) regained both weight and the PTCS. Michaelides et al. (2000) described 16 female patients with PTCS and pulsatile tinnitus who underwent weight loss surgery effecting an average loss of 45 + 17 kg. The average CSF pressures before and after weight loss were 344 + 103 (220
520) mmCSF and (in four patients only) 198 mmCSF, respectively. Of the 16 patients, 13 showed complete resolution of their PTCS (87%) whereas three did not, despite weight loss. Nadkarni et al. (2004) reported two female

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patients with PTCS and increased pressure in the transverse sinuses and right atrium who responded to weight loss surgery and remained well over a 1-year follow-up period. In summary, there is evidence that weight reduction can be effective in treating PTCS in obese females, particularly perhaps very obese females. Weight reduction is, however, difficult to achieve by non-surgical means, and not necessarily easy to sustain even when surgical methods are employed. On this point, long-term follow-up information on the small number of PTCS reported as treated by this method is also lacking.

Steroids Beginning with the report by Paterson et al. in 1961, steroids (prednisone, prednisolone, methylprednisolone, betamethasone, dexamethasone) were, for a time, the first choice treatment for PTCS in a number of centres. There was also, during this time, an increasing awareness of the complicated relationship existing between PTCS and steroids since not only did steroids appear effective in treatment but also there were reports of cases of PTCS occurring in patients being treated with steroids for other conditions, particularly during staged withdrawal of the agent. An example of a large series of patients with PTCS in which steroids were a major form of treatment is the combined Glasgow/Sydney series reported in 1981 (Johnston et al., 1981). Altogether, 48 patients were treated with steroids (prednisolone, betamethasone, dexamethasone). In 37 of the 48 cases (77.1%), steroids were used alone as the initial treatment. In fact, in 2 of the 37 cases, PTCS had developed during reduction of steroid therapy for a pre-existing condition. In 30 of the 37 cases (81.1%), steroid treatment resulted in resolution of all symptoms and signs. In the remaining 7 cases additional treatment was required, either because of side-effects of the steroids or due to persistent disease. In addition, 5 of the 37 patients who initially responded well, subsequently had a recurrence of PTCS. Of these five patients, three showed resolution with a further course of steroids whilst two required additional treatment. In 9 of the 48 patients (18.8%), the initial treatment consisted of steroids in combination with either serial lumbar punctures or acetazolamide. All nine patients showed rapid resolution of their intracranial hypertension, although there were two late recurrences. In the remaining two of the 48 patients (4.1%), steroids were added late in treatment after other measures had failed, with good effect in both cases. Thus, in this series, the initial success rate with steroids alone was 81.1% with a recurrence rate of 13.5%. Complications of steroid therapy included

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Treatment

diabetes mellitus, peptic ulceration, fluid retention, marked obesity, and psychotic symptoms. Significant complications occurred in 3 of the last 23 PTCS patients treated with steroids in this series, a rate of 13%. Seven patients from this series who were successfully treated with steroids had their intracranial pressure evaluated by continuous monitoring before, during, and after treatment. In five of the seven patients, prednisolone was used: in two cases an initial dose of 40 mg was followed by 10 mg every 6 h, and in three cases an initial dose of 80 mg was followed by 20 mg every 6 h. The other two patients received equivalent doses of dexamethasone. In all patients steroids were gradually reduced over a 2-month period and then stopped. CSF pressure was monitored via the lumbar route at 1 week in five patients and at 3 months (i.e. 1 month after cessation of treatment) in all seven patients. In addition, fluorescein angiograms were done pre-treatment and 1 month after the end of treatment to confirm resolution of papilloedema. All seven patients were completely free of symptoms and signs at 3 months. Despite this, the CSF pressures, which were essentially unchanged at 1 week, were still above normal at 3 months, although there was a significant reduction (pre-treatment mean 27.2 mmHg, SD5.7; 1-week mean 27.3 mmHg, SD4.0; 3-month mean 21.2 mmHg, SD 6.5, P < 0.1) (Figure 8.2). In contrast, one patient, who developed PTCS while steroids being given for an unrelated condition were being withdrawn, showed a marked reduction in CSF pressure after 1 week of increased steroid dosage. Finally, another patient with marked delay in CSF absorption on radionuclide cisternography still had

Figure 8.2

CSF pressures before and one month after a 2-month course of steroids in a patient with PTCS. (From Johnston et al., 1981; with permission.)

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Steroids

delayed absorption after 4 weeks of steroid treatment despite considerable clinical improvement. In the final figures from the Sydney series, steroids were used in 49 of 150 cases (32.7%) which represented a decreased use from the earlier series, although there was some overlap in the two series (1942
1980 in the first and 1974
1999 in the second). In 31 of the 49 cases (63.3%), steroids alone were the initial treatment and the results were not nearly as good as in the earlier series. Thus steroids alone were effective in only 11 of the 31 cases (35.5%) and one of these patients had two later recurrences (both responding to further steroids), whilst two patients had persistent elevation of CSF pressure despite resolution of symptoms and signs at 3 months. Of the 20 cases in whom steroids were ineffective, 14 had a poor initial response and went on to other treatment, two had an early recurrence and had other treatment, whilst in two cases steroids were abandoned due to undesirable side effects. In 18 of the 49 cases (36.7%), steroids were used as the initial treatment in conjunction with other treatments and in only four instances (22.2%) was the particular combination successful. The details are as follows: in nine cases with acetazolamide, two resolved, seven went on to further treatment; in four cases with unilateral ONSD, all required additional treatment; in two cases with acetazolamide and a 5-day period of continuous lumbar CSF drainage, both showed resolution; in two with serial lumbar punctures, both resolved but one subsequently had two recurrences and went on to further treatment; in one with cranial decompression, further treatment was required. Looking at the literature, it is apparent that even during the period of greatest popularity of steroids in the treatment of PTCS, there was considerable variation in the extent of their use. For example, in the series reported by Greer (1968), Jefferson and Clark (1976) and Bulens et al. (1979), totalling 176 cases, steroids were not used at all whereas in Rush’s (1980) series of 61 patients steroids were used in 51 (83.6%): alone in 31 patients, in combination with diuretics in 12 patients, and prior to surgical treatment in eight patients. Occupying an intermediate position are the series of Guidetti et al. (1968) and Weisberg (1975a). In the former, 29 of 100 patients were treated with steroids (12 in combination with glycerol) and in the latter 50 of 125 patients were treated with steroids, all in combination with lumbar punctures. In a total of 234 patients treated with steroids collected from the literature (Johnston, 1992), steroids were the sole agent in 152 cases and were part of combination therapy in 82 cases. Of the patients treated with steroids alone, 119 of 152 (79.3%) showed resolution with a single course of treatment. Of the remaining cases, four were described as improved but with persisting disease whilst 29 (19.1%) showed failure of resolution. Within the group overall, there were 16 recurrences (10.5%), 3 of the 16 cases having multiple recurrence.

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One patient was described as having multiple and significant side effects whilst three patients experienced visual deterioration during treatment. In a number of the patients described as showing resolution, the actual resolution was slow with evidence that the clinical improvement with steroids was not necessarily accompanied by a reduction in CSF pressure. For example, Di Lauro et al. (1984) monitored ICP in four patients after 3 weeks treatment with steroids and found that there had been no perceptible reduction in pressure. In patients who develop PTCS while steroids prescribed for an unrelated condition are being withdrawn, there is generally a good response to increasing the steroid dosage for a period before starting a more cautious and gradual withdrawal. However, Liu et al. (1994b), who reported three cases who developed PTCS while steroids being administered for chronic bowel disease were being withdrawn, found a rather mixed response. In one case there was resolution of the PTCS over 3 months with an increased steroid dosage plus acetazolamide; in one case, who initially responded to increased steroids plus frusemide, there were subsequently three recurrences of PTCS; in the third case there was persistence of PTCS over 2 months. Of the 82 patients in whom steroids were used in combination, 34 had three or more treatment modalities employed, usually concurrently, the most common combination being steroids, serial lumbar punctures and a diuretic (usually acetazolamide). Of these 34 patients, 23 showed resolution whilst in 11 cases the combined treatment failed. In nine patients steroids were used in combination with acetazolamide alone, successfully in four cases and unsuccessfully in five cases. Other diuretics were used in combination with steroids in 10 patients (osmotic diuretics in four) with resolution in seven cases, improvement in one case, and failure in two cases. In 22 cases steroids were used in conjunction with serial lumbar punctures, successfully in 21 instances and unsuccessfully in one instance. In the remaining seven patients the precise nature of the combined treatment was not specified. In six of these cases the combined treatment failed, proving successful in only one instance. On the combination with acetazolamide specifically, Liu et al. (1994a) described four cases of PTCS with severe visual problems who were treated with intravenous steroids plus acetazolamide. Three of the four cases showed lasting improvement whereas the fourth patient did not. The authors found no complications with the treatment apart from acne. In their study of 36 children with PTCS, Youroukos et al. (2000) had good success with the combination of steroids and acetazolamide, reporting resolution in 22 of 24 cases so treated. In summary, steroids are clearly an effective form of treatment of PTCS in a significant proportion of cases. The actual proportion may be as high as 80% although the discrepancy between the high figure from the combined Glasgow and

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Subtemporal decompression

early Sydney series, and the final Sydney series must cast some doubt on this. On the debit side, there is undoubtedly a moderate recurrence rate for PTCS after steroid treatment (probably between 10 and 20%), and a definite incidence of complications some of which are of a serious nature. Steroids are probably more effective in combination with either acetazolamide or serial lumbar punctures, or both, although there are no properly conducted studies to support this impression. In the uncommon cases of PTCS occurring during withdrawal of steroids being administered for an unrelated condition, restoration of a higher dose of steroids followed by a more gradual withdrawal is the primary treatment but this may have to be supplemented by another agent. Currently, however, the use of steroids is limited to cases of rapidly deteriorating vision including cases of cerebral venous thrombosis in combination with CSF drainage. Subtemporal decompression Subtemporal decompression (STD), introduced in the late nineteenth century by Horsley and others as a means of alleviating or controlling intracranial hypertension not amenable to more direct treatment, has in the past occupied a significant place in the therapeutic armamentarium against PTCS. Increased recognition of the often benign and remitting course of the disease, together with the use of new or rediscovered methods such as steroids, acetazolamide, CSF shunting and optic nerve sheath decompression (ONSD), have largely resulted in the abandonment of STD in the management of patients with PTCS. Nevertheless, because it has been a substantial component of treatment in the past and because it may still have a role today, as advocated for example by Kessler et al. (1998), it is worth reviewing in some detail. In the Glasgow series, unilateral subtemporal decompression (STD) was the most commonly used surgical treatment. In only five patients, however, was it the initial treatment. In four of these five cases this was due to the severity of the papilloedema on presentation whilst in the remaining patient it was due to the patient’s inability to tolerate serial lumbar punctures. STD alone proved adequate in only one of these five patients. In a further 38 patients STD was used as a second or third line of treatment, mainly after serial lumbar punctures had failed to control the intracranial hypertension. Of the total of 43 patients who underwent STD, 30 showed resolution of all symptoms and signs within 6 months of the procedure and a further seven within 12 months. However, in 13 of the 43 patients additional treatment was required, whilst 5 of these 13 patients had further deterioration of vision after the procedure. Post-STD lumbar punctures in 12 of these 13 patients showed that the procedure appeared to have had relatively little measurable effect on the CSF pressure (Figure 8.3). Complications following

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Figure 8.3

Treatment

Mean CSF pressures over the days before and after unilateral subtemporal decompression (STD) for PTCS. Data from 12 cases. (From Johnston et al., 1981; with permission.)

STD included epilepsy (12 patients), hemiparesis (one patient), and late bacterial meningitis (one patient). There were also two patients with late recurrence (2 and 14 years respectively) after initial treatment with serial lumbar punctures and STD. In neither case, however, was further treatment necessary. There were only four patients in the Sydney series whose treatment included STD. In three instances bilateral STD was carried out in patients with continuing disease after shunt complications. All three showed definite improvement with stabilization of vision in two cases. One patient had an unusual complication with impaired jaw movement. The remaining patient had had a bilateral STD as well as unilateral ONSD and prolonged medical treatment (diuretics, steroids) without significant improvement. In this case complete resolution was effected by a lumbo-peritoneal shunt although the patient has had her share of shunt problems. A total of 217 cases of PTCS treated by STD was collected from the literature, excluding those in the review by Davidoff (1956) and the report by Frazier (1930) in which it is stated that most of the 22 cases were so treated. The proportion of cases treated by STD in the series included showed considerable variation from almost all (17 of 18, Jacobson and Shapiro, 1964; 18 of 22, Dandy, 1937), through approximately one half (45 of 110, Greer, 1968; 32 of 61, Wilson and Gardner, 1966), to very few (4 of 120, Weisberg, 1975a; one of 61, Rush, 1980). In terms of outcome, there is also notable variation. On the most favourable side are the reports of Jacobson and Shapiro (1964) with 17 of 18 patients showing resolution, of Dandy (1937) in whose series all 18 patients treated by STD showed resolution, and of Wilson and Gardner (1966) who reported that all 32 cases treated by STD

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Subtemporal decompression

(of a total of 61 cases) improved, with resolution over 4 months, reversal of impaired visual acuity in 10 of 10 cases, and improvement in visual field loss in three of six cases. In the group of 45 patients in Greer’s (1968) series treated by STD, 21 cases (46.6%) required additional treatment whilst Weisberg (1975a), who had only four patients treated by STD, reported that one was cured, one developed epilepsy, one required further treatment and one died of pulmonary embolism
a poor result indeed. The rate and extent of resolution in those patients who do benefit from STD is also quite variable. Thus Wilson and Gardner (1966), in the study referred to above, reported resolution within 4 months in all 32 cases whereas Bulens et al. (1979), who reported four patients treated by STD in a group of 36 cases of PTCS, found that even in this small group the time of resolution varied from 2 weeks to 2 years and that the measured CSF pressure showed little difference before and after the procedure. Davidoff (1956) differentiated between a symptomatic improvement which was rapid in all 13 of his initial cases and the substantially slower resolution of papilloedema. The variability noted in the efficacy of STD as a treatment of PTCS and the time course of resolution when this occurs must be influenced by the severity of the disease itself and by the extent of the decompression, in particular whether it is unilateral or bilateral. Early series, from the period when STD was one of the mainstays of treatment, are likely to include a significant proportion of patients with a relatively mild and remitting form of the disease. Where the criteria for surgical treatment are more strict, and only a small number of patients within a large series are treated by STD, these are likely to be those patients with a relatively intractable and non-remitting form of the disease. It is difficult to draw accurate conclusions about complication rates for STD in PTCS as in most reported series the follow-up is short. The main complications are epilepsy, focal neurological disturbance, meningitis and otorrhoea. Greer (1968) reported complications in 5 of 45 patients (11.1%), the complication being either epilepsy or otorrhoea. In some of the larger series of STD in PTCS (e.g. Dandy, 1937; Wilson & Gardner, 1966) complication rates are not recorded. Both Weisberg (1975a) and Moffat (1978), in general reviews, quote a 12% complication rate for STD in PTCS, the main complications being epilepsy and meningitis. There have been six deaths reported after STD for PTCS. In two patients death was due to meningitis in patients with ‘otitic hydrocephalus’ and may not have been due to the procedure per se. One patient died of pulmonary embolism (Weisberg, 1975a), one of ‘other causes’ (Davidoff & Dyke, 1937), while in two cases the cause of death was not reported (Frazier, 1930; Jacobson & Shapiro, 1964). In addition to the complications directly related to the procedure, there are also those attendant upon the failure to control the raised

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Treatment

intracranial pressure adequately. Thus, Bradshaw (1956) reported six patients treated with STD in a series of 42 cases of PTCS, of whom two showed further visual deterioration going on to blindness whilst Corbett (1983) mentions one patient who became worse after medical treatment followed by STD. Rush (1980) reported one patient in a series of 61 cases who had a STD after steroid therapy and suffered severe and permanent visual loss following the procedure. In a recent study, Kessler et al. (1998) suggested that STD should be given greater prominence in the treatment of PTCS, a view supported by Ransohoff in his comments on the article. They based this conclusion on a group of eight patients, all obese females aged between 10 and 46 years (average 27.0 years) in all of whom medical treatment (various combinations of steroids, acetazolamide, lumbar punctures and weight reduction) had failed to control the PTCS. The group was notable for its long follow-up, mostly 420 years (8
26, average 21.3 years). The authors reported that all eight patients showed prompt resolution of papilloedema and visual disturbance within 1 month of the STD. However, five of these eight patients did go on to have a lumbar CSF shunt (peritoneal or pleural) for persistent headache associated with a bulging decompression. In two cases there was a late visual deterioration which responded to revision of the decompression (in one, presumably one of the children, the decompression had re-ossified). No other complications were reported. In summary, it does appear that STD still has a place in the management of PTCS, albeit a somewhat limited one. Thus, it might be employed in patients who have proceeded to one of the other surgical treatments (optic nerve sheath decompression or CSF shunting) and have continuing problems, either failure to control the disease (ONSD), or recurrent malfunction, or other complications (shunting). If, in such refractory cases, STD is decided upon, it should probably be bilateral and large with a careful technique including splitting of the dural layers to form over-riding flaps, or scoring the dura with multiple lines without penetrating it, to protect the cortical surface. Optic nerve sheath decompression This technique has a long history in the treatment of papilloedema from whatever cause, dating from the initial reports which appeared over a century ago (de Wecker, 1872; Carter, 1887, 1889). Although PTCS was not a recognized clinical entity at the time of these first reports, some of the first reported cases treated by ONSD may, in fact, have been cases of PTCS. Curiously, when one considers that papilloedema with its attendant risks to vision is the major disturbance of function in PTCS, there were no further reports of the use of ONSD in PTCS until those of Smith et al. (1969) and Davidson (1969, 1972). Following

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Optic nerve decompression

these reports, and particularly the three reports together with an editorial which appeared in the 1988 issue of Archives of Ophthalmology (Brourman et al., 1988; Corbett et al., 1988; Keltner, 1988; Sergott et al., 1988), there has been a considerable resurgence of interest in the method in PTCS. Updated descriptions of the technique were offered by Davidson (1972), Galbraith and Sullivan (1973) and Keltner et al. (1979). In essence, the optic nerve immediately behind the globe is approached via an orbitotomy and the dura mater of the nerve sheath incised for a distance of up to 1.0 cm. The approach may be via either a medial or lateral orbitotomy and the sheath incision superolateral or inferonasal. The procedure may be carried out unilaterally or bilaterally and, if the latter, either at the same time or staged. The use of additional measures such as mitomycin and Molteno dura has been suggested by Spoor et al. (1994). Recently, a modified transnasal endoscopic technique has been described (Gupta et al., (2003). As a means of reducing the need for re-operation, Anderson and Flaharty (1992) advocated the lateral approach and the creation of a large dural opening. There is no unanimity as to the mechanism of action of ONSD in the relief of papilloedema. Some have claimed that a persistent CSF fistula is created at the site of the nerve sheath incision which allows long term drainage of CSF into the orbit resulting in a sustained reduction of CSF pressure. The evidence for such a fistula is largely indirect and scanty. First, there is the variable finding of improvement in the general symptoms of intracranial hypertension, particularly headache, after ONSD, as well as improvement in contralateral papilloedema after unilateral nerve sheath incision. Keltner (1988), an apologist for the ‘filtration’ theory, summarized in his editorial the findings on this point from two of the studies referred to (Corbett et al., 1988; Sergott et al., 1988): in a total of 33 patients treated by unilateral ONSD, 21 had resolution of papilloedema in both eyes and 23 had amelioration of headache. Second, there is the report by Keltner himself, in an earlier study (Keltner et al., 1977), of the histopathological demonstration of a fistula at the site of the sheath incision in one patient who died 39 days after bilateral ONSD for papilloedema due to a glioblastoma. Third, Brourman et al. (1988), who reported improvement of headache in four of six patients treated by ONSD, found in these four cases patency of the subarachnoid space around the optic nerve with no evidence of any obliteration, using intrathecal iopamidol and CT scanning. They did not, however, demonstrate any CSF leakage or fistula formation, but argued that rapid absorption of leaking CSF by the vascular tissue of the orbit might prevent sufficient accumulation of dye-containing CSF to allow identification on the CT scan. Finally, there is some MR and ultrasound evidence in favour of fistula formation (Hamed et al., 1992; Spoor et al., 1994; Sallomi et al., 1998), as well as further histological evidence from sheath biopsies using mitomycin (Taban et al., 2001).

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Treatment

The alternative view, put forward by Davidson (1972) in particular, is that ONSD leads to fibrosis and obliteration of the subarachnoid space around the orbital course of the optic nerve, thus preventing the transmission of the raised CSF pressure to the nerve itself. The reduction of pressure on the optic nerve axons allows improved perfusion and resolution of papilloedema (Mittra et al., 1993). Davidson’s initial claim was supported by histopathological findings and is also supported by the pathology findings in the case reported by Tsai et al. (1995) of a patient dying (of gastro-intestinal haemorrhage) 7 weeks after ONSD. They were unable to find any evidence of a patent fistula, although they did suggest that filtration might still occur through an enclosed bleb or fibrotic tissue. The ‘fibrosis’ theory is also supported by two reports in which there was failure to demonstrate a CSF fistula using radionuclide techniques (Billson & Hudson, 1975; Kilpatrick et al., 1981), by the failure of ONSD, either unilateral or bilateral, to relieve headache in a significant proportion of cases, and by the failure of unilateral ONSD to consistently relieve bilateral papilloedema. In one case in the Sydney series, who presented with unilateral papilloedema without headache, unilateral ONSD, while effectively relieving the papilloedema in the affected eye, was rapidly followed by the onset of headache and papilloedema in the initially non-affected eye. On this point, the occurrence of unilateral papilloedema in PTCS or other conditions of raised CSF pressure (Smith et al., 1969; Kirkham et al., 1973; Sher et al., 1983; Maxner et al., 1987) is itself probably evidence of how non-patency of the perineural subarachnoid space may protect an optic nerve from the effects of increased CSF pressure. Hayreh (1964), in his detailed experimental study, concluded that intraorbital decompression rarely lowered CSF pressure or relieved contralateral papilloedema in monkeys. This is borne out clinically by the findings of Jacobson et al. (1999b) who reported persistently high CSF pressures after ONSD in six cases of PTCS despite variable but often significant clinical and ophthalmological improvement. In considering the results of ONSD in PTCS, there were no cases treated by the method in the Glasgow series whereas 11 patients, all adult females, were so treated in the Sydney series. In 6 of the 11 cases, ONSD was used as the initial treatment, either alone in two cases, or in combination with steroids (three cases) or steroids and acetazolamide (one case) in four cases. In four of the six cases, the ONSD was unilateral and in two cases bilateral. In none of the six patients was the treatment successful, all patients going on to CSF shunting. In 5 of the 11 cases ONSD (two unilateral, three bilateral) was used after failure of medical treatment (various combinations of steroids, acetazolamide and other diuretics). In two of these five patients ONSD was successful but the other three patients required further treatment.

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Optic nerve decompression

With regard to reports of ONSD in PTCS in the literature, these will be considered in three groups: reports prior to the 1988 studies in the Archives of Ophthalmology, those reports themselves, and subsequent reports. In the first group there were 47 cases. In only three of these cases was ONSD the primary treatment based, in two instances, on the unilateral nature of the visual abnormality. In the remaining 44 cases ONSD was used following failure of medical treatment in 29, predominantly steroids with or without the addition of diuretics and/or lumbar punctures. In six cases CSF shunting had been used and in one case STD whilst in the other cases the nature of the initial treatment was not specified. In those cases deemed to have had failure of prior surgical treatment, it would appear that ONSD was carried out in an attempt to improve vision already lost at the time of the initial surgical treatment (Galbraith & Sullivan, 1973; Corbett et al., 1982), although in none of the reports is the situation entirely clear. In terms of outcome, in 32 cases (excluding the series of Kilpatrick et al., 1981), 17 showed improvement, eight had no significant improvement, four became worse, and in three there was no outcome data. When the time of improvement was indicated this tended to be long (1 to 5 months in 5 of the 17 improving patients). Of note was the fact that 8 of the 17 improving patients had documented evidence of persistent intracranial hypertension with high CSF pressures on lumbar puncture and/or persisting symptoms and signs. One of the improving patients developed a bilateral VIth nerve palsy and one had a late deterioration of visual acuity. In the series reported by Kilpatrick et al. (1981), of the six patients with visual failure treated by ONSD, one continued to deteriorate whilst five either stabilized or improved. Of six patients with other symptoms of intracranial hypertension, three had resolution with ONSD whilst three did not. One patient who had post-ONSD ICP monitoring showed persistent intracranial hypertension. Three of the 14 patients in this series had a recurrence of PTCS after ONSD (21.4%) whilst 11 were described as well after follow-up intervals from four months to ten years. Of two patients who had radionuclide studies of CSF circulation after ONSD, one had a leak demonstrated at the site of the dural sheath incision and one did not. The three reports in the 1988 Archives of Ophthalmology, accompanied by Keltner’s editorial, argued strongly for a significant role for ONSD in the treatment of PTCS and were a major factor in establishing the method. Considering the three studies individually, Brourman et al. (1988) reported six cases of PTCS treated by ONSD, four bilateral and two unilateral (i.e. 10 eyes). Visual acuity was improved in 3 of the 10 eyes (although in two of these cataract surgery was also carried out) and unchanged in seven eyes. In four of the six patients there was improvement or resolution of papilloedema whilst headache was also improved

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Treatment

in four patients but unchanged in the two others. Two patients had minor and transient complications: ocular motility disturbance in one and tonic pupil in one. One patient died in the early post-operative period from what was described as cerebral vasculitis. Four of the six patients were studied post-operatively with CT scanning using iopamidol and showed a patent subarachnoid space around the optic nerves but no CSF leak. The one patient who had a postoperative lumbar puncture showed a reduced but still abnormal CSF pressure (200 mmCSF). Sergott et al. (1988) reported 23 patients with PTCS treated by ONSD, 6 bilateral and 17 unilateral (i.e. 29 eyes). All were deemed to have failed medical treatment (mainly diuretics and steroids) whilst six had undergone prior LP shunting. Visual acuity was improved in 19 of the 29 eyes, unchanged in nine, and worse in one. Visual fields were improved in all cases. In the 17 cases undergoing unilateral ONSD, the non-operated eye was improved in 6 and unchanged in 11 cases. Seventeen of the 21 cases presented with headache and of these 13 were improved and 4 unchanged. Four of the 13 with initial improvement had, however, a recurrence of headache, a failure rate with respect to symptoms of almost 50%. There were only two minor and temporary complications. In the third study, Corbett et al. (1988) reported the results of ONSD in 28 cases, 12 bilateral and 16 unilateral (i.e. 40 eyes). Visual acuity was improved in 12 eyes, unchanged in 22 eyes, and worse in 6 eyes. Of the last group, two had a VA of better than 20/30 preoperatively and four a VA between 20/40 and 20/100. Visual fields were improved in 21 eyes, unchanged in 10, and worse in 7 (one patient who died of pulmonary embolism is not included in the VF figures). Papilloedema either improved or resolved in all but two cases and in nine cases improved in the non-operated eye. Eleven of 17 patients with headache improved but six did not. There was a relatively high incidence of complications in this series with 16 patients developing a permanent tonic pupil and/or a temporary and variable accommodation paresis attributed by the authors to operative damage to the short ciliary nerve, the ciliary ganglion or its blood supply. There were five patients (eight eyes) who had loss of vision within 1 month of surgery. Subsequent reports have largely borne out the findings of these studies on ONSD in PTCS, which might be summarized by saying that the great majority of operated eyes will show resolution of papilloedema and improvement or stabilization with respect to visual acuity and visual fields, and that, commonly, similar results are noted in an affected but non-operated eye after unilateral ONSD. The benefits as far as headache is concerned are less predictable, although 50% or more of cases may be improved, at least initially. It is also apparent that there is a complication rate. For example, Banta and Ferris (2000) reported

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Optic nerve decompression

complications in 39 of 86 patients treated by ONSD, although they described these complications as mostly ‘transient and benign’. They did, however, have one case with permanent and severe visual loss whilst Brodsky and Rettele (1998) reported one case of prolonged post-surgical blindness. Mauriello et al. (1995) reported 5 of 108 patients treated by ONSD who had subsequent visual loss: one was attributable to haemorrhage at the operative site, one to infection, whilst three had gradual but progressive loss arrested by insertion of an LP shunt; presumably the ONSD had failed to control the intracranial hypertension. Spoor and his colleagues, in a series of studies (Spoor & McHenry, 1993 Spoor et al., 1994, 1995), drew the broad conclusion that 80
90% of patients will show an improvement in visual acuity after ONSD but that around 35% of those who show an initial improvement will later deteriorate. Some idea of the range of reported results may be obtained by comparing the findings of Banta and Ferris (2000), who reported an improvement or stabilization rate of 94% for visual acuity and 88% for visual fields in their series of 86 cases (158 eyes) already referred to, with those of Acheson et al. (1994) who reported that 5 of 14 patients treated by ONSD needed further surgery (four shunts, one STD) for unrelieved headache in two cases, continuing progressive visual loss in two cases, and both together in the remaining case. There are some reports of the use of ONSD in PTCS in children. Thus, Lee et al. (1998) reported two cases of their own and added 10 from the literature. Of the 12 cases, 66% showed improved visual acuity and 33% improved visual fields but 17% became worse in one respect. Finally, mention should be made of several investigative techniques that may have a role in evaluating the efficacy of ONSD. For example, Mittra et al. (1993) used a coloured Doppler technique to evaluate the caliber of the ophthalmic, short posterior ciliary and retinal arteries in 20 patients (20 eyes) after ONSD and found 13 improved, 8 unchanged and 3 worse. Lee et al. (1998) studied retinal vein caliber in nine cases and found a significant reduction in both operated and contralateral non-operated eyes. Sallomi et al. (1998) used MR of the orbits to show decreased CSF volume around the optic nerves and increased fluid in the orbit in five patients who improved following ONSD but the absence of such findings in three patients who did not improve. In summary, ONSD has a high success rate in improving or stabilizing visual function in PTCS, at least in the short to medium term. It is less effective in dealing with headache, and over time a significant number of patients will require further treatment, whether it be repeat ONSD, medical treatment or other surgical measures, either to control headache or to deal with later visual deterioration. There is a moderate complication rate for the procedure although the great majority of complications are either minor or transient or both. Instances of severe loss of visual function do, however, occur and this must be

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Treatment

weighed against the visual outcome for the disease overall and for the other methods of treatment. The issue of how ONSD works remains unresolved but there is strong evidence that it does not consistently achieve a normalization of CSF pressure. Cerebrospinal fluid shunting If the concept of PTCS as a disorder of CSF circulation is correct, then CSF shunting is the most rational of the available forms of treatment. The fact that it is so successful in relieving intracranial hypertension in the condition is itself strong confirmatory evidence in favour of the CSF circulation disorder concept of mechanism. There are, however, the well-known and significant complications of CSF shunting, extensively documented in relation to the use of the technique in the treatment of hydrocephalus, which must be taken into account. Also to be taken into account are reported instances of failure of CSF shunting in PTCS as well as complications attributed to brain shift. These matters will be considered after the overall results for CSF shunting have been given. In the Glasgow series only six patients were treated with CSF shunting. In all cases shunting followed failure of other forms of treatment and in all cases the shunt was ventriculo-peritoneal. Of these six patients, four showed complete resolution of all symptoms and signs without further treatment whilst in the other two cases, one required an early revision before responding and one had the shunt removed due to infection. Three of the six cases did develop a late and minor recurrence of PTCS but in none was further treatment required. In the Sydney series the picture was very different in that CSF shunting was the most common form of treatment, being used in 91 cases (60.3%). As this represents the largest group of shunted patients in PTCS and is otherwise unreported (although early results were given by Johnston et al. 1988), the results are set out in some detail below and summarised in Tables 8.3 and 8.4. Shunted cases

In the 91 cases there were 49 female adults, 18 female children, 18 male children and 6 male adults, accounting for 62.8%, 51.4%, 69.2% and 50.0%, respectively, of all patients in these age and sex groups. In 28 of the 91 cases (30.8%) shunting was the primary form of treatment, the decision to use it being based for the most part on the severity of the condition at presentation, although other considerations such as the potential complications of other forms of treatment did come into play in some instances. Of the remaining 63 patients CSF shunting was the second or third line of treatment after the failure of medical treatment in 52 cases (57.1%), this including ONSD in 6 instances and STD in one instance, and after recurrence

215

CSF shunting Table 8.3. Details of patients treated by CSF shunting CSF: Sydney series

Female adults

Male adults

Female children

Male children

Total

No. of cases shunted

49 (62.8%)

6 (50.0%)

18 (51.4%)

18 (69.2%)

91 (60.3%)

Reason for shunt Severity Failed med Rx Failed med and surg Rx

18 22 9

1 5 0

5 13 0

5 12 1

29 52 10

Initial shunt Lumbar percutaneous Other lumbar (valve) Cisternal

18 16 15

2 4 0

13 1 4

13 3 2

46 24 21

Final shunt None Lumbar Cisternal Ventricular

6 19 22 2

0 5 1 0

5 5 6 2

5 7 4 2

16 36 33 6

140 2.1

12 2.7

72 1.6

45 3.7

269 2.3

49 7 3

6 0 1

18 8 1

18 3 1

91 18 6

Revisions Total Average time/revn (years) Outcome Resolution Complications Death

Table 8.4. Incidence of revision in shunted patients: Sydney series

Age and sex No. of cases No revisions 1 Revision 2
5 Revisions 6
10 Revisions 410 Revisions Shunt removed Mean follow-up (years)

Female adults

Male adults

Female children

Male children

49 22 9 8 6 4 6 6.3

6 2 1 3 0 0 0 5.3

18 7 3 4 1 3 6 6.0

18 5 3 7 3 0 5 9.8

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of PTCS following initially successful medical treatment (plus ONSD in one instance) in 11 cases (12.1%) or combined medical and surgical (ONSD, STD) treatment. Types of shunt

Four types of shunt were used as follows: Lumbar percutaneous

In these cases the lumbar catheter was inserted using a Tuohy needle technique whilst the distal catheter was, in early cases, simply the valveless epidural catheter from the Tuohy needle pack and later (and most commonly) a James catheter with a distal slit valve. In almost all cases the distal catheter was peritoneal but in some instances pleural placement was used. This was the primary form of shunting in 46 cases (50.1%) and was also used after failure of another form of shunting in a further four instances. Lumbar valved

The lumbar catheter was inserted either via a Tuohy needle technique or through a mini-laminectomy. In most instances the valve used was an HV valve situated in a subcutaneous pocket created in the flank. In some cases a valve was placed subcutaneously immediately after the exit of the lumbar catheter through the lumbar fascia. Several different valves were used including the standard Hakim valve (mainly high-pressure), the Sophy adjustable valve, and the Medos programmable valve. The distal tubing was predominantly peritoneal but occasionally pleural. This was the primary form of shunting in 24 cases (26.4%) and was also used to replace another form of shunt in a further 19 cases. Cisternal shunting

In this technique, described by Johnston and Sheridan (1993) and introduced in an attempt to obviate the problems of low-pressure symptoms and the acquired Arnold-Chiari malformation (Johnston et al., 1998), a flanged ventricular catheter was placed in the cisterna magna after removal of a small amount of bone from the posterior rim of the foramen magnum. This was connected to a valve situated beneath the scalp over the occipital bone in most instances, with the distal catheter being passed into the right atrium via the common facial vein. In some instances the valve was place over the scapula and the distal catheter inserted into the pleural space or the peritoneal cavity. Valves used included particularly the Sophy, Medos, and Codman adjustable valves, but standard Hakim high- or medium-pressure valves were also used. This was the primary from of shunting in 21 cases (23.1%) and a subsequent form of shunting in a further 29 instances.

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CSF shunting

Ventricular shunting

Standard techniques of insertion of ventriculo-atrial, peritoneal or pleural shunting were used. Various valves were used but with a predilection for adjustable valves. In a number of instances a frontal burr-hole was used in preference to the more usual parietal burr-hole and in some cases stereotactic placement of the ventricular catheter was used. In no case was ventricular shunting the primary form of shunting. It was used in eight cases only to replace another prior form of shunting. Outcome with shunting

In all cases CSF shunting brought resolution of the intracranial hypertension due to PTCS. High-pressure headache was invariably relieved but was replaced by lowpressure in a number of cases, this symptom being responsible for 18.2% of the 280 secondary shunt procedures (269 revisions, 11 re-insertions). Papilloedema was invariably relieved by a functioning shunt although a number of patients did show late optic atrophy. With respect to visual function in the 91 shunted patients, 33.7% showed improvement, 39.1% were unchanged with normal VA and VF prior to and post shunting, 5.4% had pre-shunt abnormalities which were unchanged, 2.2% (two patients) were worse having lost visual function during one or more periods of shunt malfunction, and in 19.6% (predominantly children) formal evaluation of vision pre and post shunting was inadequate. There were six deaths in the group of shunted patients. In one case death was directly attributable to a shunt complication (sub-phrenic abscess and septicaemia). Of the other five deaths, three were due to progression of the patient’s primary condition (chronic renal failure, cystic fibrosis and Hunter’s syndrome) and two were due to unrelated causes. Shunt revisions

In the series as a whole there were 269 shunt revisions in the 91 shunted patients, giving a revision rate of one revision every 2.3 shunt-years. There was some variation in the revision rate in the different age and sex groups, with the lowest rate in male children and the highest rate in female children, although it is difficult to attribute any significance to this. A breakdown of the numbers of revisions in the four age and sex groups is given in Table 8.4. The four main reasons for shunt revision were blockage (56.9%), low-pressure symptoms (17.5%), infection (10.0%), and migration (5.6%). The remaining 10% of revisions were for a miscellany of reasons including 14 of the 16 complications considered below. Apart from these complications, the two reasons for revision of lumbar shunts were CSF leakage along the lumbar catheter track giving rise to a subcutaneous CSF collection, and persistent sciatic pain. In the shunted group as a whole,

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Treatment

36 (39.6%) did not require a shunt revision and these cases were relatively evenly distributed amongst the four age and sex groups. There was a small percentage of patients (7.7%) who had repeated shunt revisions, listed in Table 8.4 as 410 but ranging from 11 to 27. All these patients were females but no particular significance is attributed to this. Shunt revisions in this small sub-group accounted for 116 of the 269 revisions overall (43.1%). In terms of the four types of shunt listed above, the frequency of revision was greatest with ventricular shunts and least with percutaneous lumbar shunts. The figures were as follows: ventricular shunts, one revision per 0.98 year; cisternal shunts, one revision per 1.6 years; valved lumbar shunts, one revision per 2.1 years; and percutaneous lumbar shunts, one revision per 2.7 years. However, for patients in whom a cisternal shunt was the initial form of shunting (21 cases), the revision rate improved to one revision per 2.3 years. As for the causes of revision, the figures for blockage were very similar for percutaneous lumbar, valved lumbar and cisternal shunts (56.5%, 50.0% and 52.6%, respectively), as were the figures for low pressure symptoms (17.7%, 19.1%, 20.7%, respectively). With ventricular shunts there was greater incidence of blockage as the cause for revision (76.5%) and a lower incidence of low pressure symptoms (8.8%). Migration was most common with percutaneous lumbar shunts, accounting for 17.7% of revisions compared to 7.4% for valved lumbar shunts, 0.9% of cisternal shunts and 0% for ventricular shunts. Infection accounted for 15.5% of revisions in cisternal shunts, 11.8% of revisions with valved lumbar shunts, 8.8% of revisions with ventricular shunts, and 3.2% of revisions with percutaneous lumbar shunts. Shunt complications

The most common of what have been labelled complications was the acquired Arnold
Chiari malformation which accounted for 7 of the 19 cases (36.8%). All of these acquired Arnold
Chiari malformations were attributable to lumbar CSF shunting. In one of the cases there was the prior development of syringomyelia which was treated effectively by syringostomy and retention of the LP shunt. In this case, the first in the series to show an acquired Arnold
Chiari malformation, the latter was treated by posterior fossa decompression without changing the shunt. The patient then remained well over a further 10 years of follow-up. In the remaining six cases the acquired Arnold
Chiari malformation was treated by re-siting the lumbar shunt making it either ventricular (four instances) or cisternal (two instances) (Figure 8.4). There were five cases who developed a cardiac arrhythmia, all associated with an atrial catheter. The majority responded to shortening of the atrial catheter. One of these five patients later developed a large right atrial thrombus, and required surgical removal

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CSF shunting

Figure 8.4

MR scans before (a) and after (b) conversion of a lumboperitoneal shunt to a cisternoatrial shunt in a patient with PTCS. (From Johnston et al., 1998; reproduced with permission from Acta Neurochirurgica.)

of the thrombus and re-siting of the shunt. The other complications were single instances of spinal arachnoiditis with a lumbar shunt treated by re-siting the shunt to the ventricles, a mild but persistent left hemiparesis following revision of the ventricular shunt in the same patient, and two cases of subphrenic abscess following multiple revisions of an LP shunt. In one of these cases this proved to be a fatal complication as noted above.

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Treatment

Shunt removal

In 16 patients (17.6%) the shunt was successfully removed after an interval ranging from 3 months to 11 years (average 3.4 years). In 10 of these patients the shunt removed was a percutaneous lumbar shunt and in the other six cases a valved lumbar shunt. Nine of the removals followed a trial clipping of a functioning shunt (demonstrated by a radionuclide shunt study), six were in asymptomatic patients with a demonstrated non-functioning shunt, and one was removed by a general surgeon during repair of an umbilical hernia. This patient, and one of those who had remained asymptomatic during a trial clipping, did develop a recurrence of PTCS after shunt removal but in both instances this responded to a course of acetazolamide. In seven other cases a trial of clipping resulted in rapid return of symptoms. Finally, two other patients (not included in Table 8.4) had removal of their shunts due to recurring problems with infection. Both had on-going symptoms and were treated with bilateral STD and in one instance venous sinus angioplasty with satisfactory control of their PTCS. Turning to the literature, in an earlier review (Johnston 1992) 110 cases of PTCS treated by shunting were collected, including one case in which the procedure was abandoned due to anaesthetic problems. In 75 of the 110 cases the indications for shunting were clear and were as follows: 1. Failure of on-going medical treatment in 58 cases. In 17 of these patients medical treatment consisted of a single agent (steroids, 13 cases; acetazolamide, three cases; serial LPs, one case) whilst in the other 41 cases, multiple treatments were used, most commonly steroids, serial lumbar punctures, and acetazolamide, but also other agents such as digoxin, osmotic diuretics, and other diuretics. 2. As the initial treatment in 11 cases. In only 3 of the 11 cases was the severity of visual loss given as the reason for proceeding directly to shunting. 3. Recurrence after initial resolution following medical treatment in six cases. In five of these six cases, steroids alone were the initial treatment whilst in the other case a combination of methods as used. The type of the initial shunt was clear in 100 of the 110 cases, this being lumbar
peritoneal (LP) in 71 cases, ventriculo-atrial (VA) in 19 cases and ventriculo-peritoneal (VP) in 10 cases. In two cases shunt problems led to a change of shunt type, one VP shunt being converted to an LP shunt after blockage (Kassam et al., 1983) and one LP shunt with early obstruction being converted to a cervico-peritoneal shunt (Beatty, 1982). Complications were mentioned in 26 of the 100 patients although it should be noted that follow-up information was lacking in the majority of cases, there being only 8 of the 100 cases with follow-up greater than 1 year. The complications recorded were blockage in 10 cases (in one case on three occasions), low-pressure symptoms in five cases, infection in

221

CSF shunting

three cases (one of these patients died), arachnoiditis in one case and sciatic pain in one case. In one patient an initial VP shunt was said not to have controlled the intracranial hypertension which did rapidly resolve with conversion to an LP shunt suggesting that the VP shunt was non-functioning. With regard to subsequent shunt removal, in the six cases reported by Amacher and Spence (1985), three had their shunts removed for ‘late low-pressure symptoms’ without recurrence of PTCS whereas in the two patients reported by Repka et al. (1984) where clipping (one case) or removal after 2 years (one case) were carried out, there was recurrence of intracranial hypertension necessitating re-establishment of the shunts. In terms of efficacy, in the great majority of shunted cases there was resolution of PTCS and, where the time course was indicated, this was rapid. The only situations in which further PTCS symptoms or signs occurred were those associated with shunt malfunction and these were, in all reported cases, relieved by shunt revision. The only discordant notes were struck by the reports of Subburam et al. (1984) and Sergott et al. (1988). The former carried out ONSD in three patients previously treated with an LP shunt because of persistent loss of visual acuity. It is not clear from their report, however, whether there was on-going intracranial hypertension nor to what extent vision was impaired prior to shunting. It is noteworthy that after ONSD there was only very minor improvement in one out of six eyes in the three patients so treated. The latter report concerned 6 of 23 patients having ONSD for PTCS who had a prior LP shunt, in two cases with three revisions and in one case with two revisions. Again it is not clear what precisely happened after the shunt; i.e. was there failure of already impaired vision to improve or was there further deterioration? The overall results from the 1992 review were, then, strongly supportive of the view that CSF shunting is a very effective treatment of PTCS, albeit one with the significant problems associated with shunting generally. Subsequent reports include both those dealing with shunting in PTCS specifically (Rosenberg et al., 1993; Eggenberger et al., 1996; Burgett et al., 1997; McGirt et al., 2004; Lee et al., 2004, a total of 141 cases) and those dealing with LP shunting for a variety of conditions including PTCS (Chumas et al., 1993; Babin et al., 2000). In the majority of these cases lumbar shunting was used, although McGirt et al. (2004) reported 36 VP shunts in the 115 procedures in their series of 42 cases. Also, the report by Lee et al. (2004) concerned cisternal shunting in five cases, in all of whom the procedure was effective, although the authors felt there was a higher revision rate with this procedure. On the issue of complications of shunting, there have been further reports of an acquired Arnold
Chiari malformation either alone or with syringomyelia (Owler et al., 2004; Padmanabhan et al., 2005), one case who developed bilateral visual loss and

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Treatment

simultagnosia after LP shunting (Miller, 1997) and one case who suffered subarachnoid and intracerebral haemorrhage after LP shunting (Suri et al., 2002). In summary, what is clear with regard to CSF shunting in PTCS is that, on presently available evidence, it is the most efficacious treatment for the condition and can be relied upon to bring about rapid and complete resolution in all cases. Unfortunately, this efficacy comes at a cost. First, shunting exposes the patient to the ever-present risk of requiring a shunt revision due to the high incidence of the several causes of shunt malfunction. Second, there are the other complications which may or may not require shunt revision: in the short term, low pressure symptoms, sciatic pain with lumbar shunts and cardiac arrhythmias with atrial catheters, and in the long term, the acquired Arnold
Chiari malformation with or without syringomyelia. Third, there is the theoretical possibility that at least in some cases shunting makes what would be a temporary condition with other forms of treatment something more permanent by inducing shunt dependence. There is, as yet, no evidence either for or against such a notion. As for the type of shunt, there is no overall consensus. The ventricles are often small and, even with stereotactic placement of a ventricular catheter, some patients are prone to repeated episodes of shunt obstruction. Such episodes may be transient as if the ventricular walls are collapsing onto the catheter; this behaviour can be seen on CSF infusion studies. It has proved possible in some cases to re-open an apparently blocked ventricular catheter simply by injecting saline into the reservoir of a programmable valve and pressing on the distal occluder so that there is a retrograde injection of fluid. In contrast, both the cisterna magna and the lumbar sac have the advantage of a large CSF space so that proximal obstruction is less of a problem. It is essential to use a relatively soft catheter in the cisterna magna (H. Rekate, personal communication). A new generation of anti-gravity systems may help reduce the incidence following a lumbo-peritoneal shunt of low pressure symptoms and secondary Chiari malformations with lumbo-peritoneal shunts. Cisterno-pleural shunts would avoid these last two problems but have the disadvantage of technical complexity and possibly an increased revision rate. Ideally, it would seem that shunting should only be employed as something of last resort after failure of maximal medical treatment. Randomized controlled trials are difficult to mount because of the relatively small number of shunts performed each year for PTCS; it is of the order of 100 operations per annum in the United Kingdom (UK Shunt Registry; Dr H. K. Richards, personal communication). Treatment of cranial venous outflow obstruction The direct treatment of cranial venous outflow compromise as a presumed cause of PTCS has a long history, as indicated in Chapter 2. Its role today has, however,

223

Treatment of cranial venous obstruction

still to be clearly defined. For the purposes of the present discussion, two groups of PTCS patients may be considered. The first group comprises those patients with PTCS who clearly have a primary pathological process involving the cranial venous outflow tract, whether this be compression or obstruction of one or more of the cranial venous sinuses, or involvement of the extracranial component of cranial venous outflow, particularly the internal jugular veins. The second group comprises patients with PTCS who do not have any apparent condition causative of cranial venous outflow impairment but who do have some narrowing of the cranial venous outflow tract, particularly the transverse sinuses, together with an intraluminal pressure gradient across the narrowed segment. The identification of such patients depends on retrograde cranial venography with manometric studies. It is this latter group which is controversial, as has been discussed in Chapters 3 and 5. The key issue is whether the demonstrated venous sinus involvement is primary and causative of PTCS, or secondary due to the increase in CSF pressure. Regardless of how this issue is ultimately resolved, it is obvious that there are at least some cases of PTCS in whom direct treatment of cranial venous outflow pathology might be beneficial, even curative. Nonetheless, very few patients have been treated by a direct approach to cranial venous outflow pathology. In addition, there are several different methods that have been or can be used, so the small number of cases becomes even smaller when the individual methods are considered, as will be done in what follows. Systemic anti-coagulant therapy

This is the most common treatment of cranial venous sinus thrombosis whether associated with PTCS or not. There are, however, few systematic studies of the efficacy of anti-coagulants in either case. An exception is the randomised trial reported by Einhaupl et al. (1991) which demonstrated an improved outcome in patients so treated over a 3-month period. In two recent studies of cranial dural venous sinus and vein thrombosis, those of Biousse et al. (1999) and of Saw et al. (1999), the proportion of patients who presented with a PTCS was 37% and 43%, respectively. In both studies systemic anti-coagulants were the most commonly used form of treatment, but typically in conjunction with other measures aimed at the intracranial hypertension. There are also reports of the use of anti-coagulants in cases of venous sinus involvement with PTCS in Behc¸et’s disease (Ibrahimi et al., 1983) and of anti-fibrinolytics in DLE with PTCS and sinus involvement (Shiozawa et al., 1986) effecting a successful outcome in conjunction with other treatment methods. There are similar reports in relation to primary haematological disorders (Mokri et al., 1993; Confavreux et al., 1994; Sareen et al., 2002). Clearly, the efficacy of systemic anti-coagulants will depend, at least in part, on the nature and cause of the thrombus and the duration of its existence. How effective

224

Treatment

such treatment is in cases of PTCS due to venous outflow involvement remains unknown, as does its relative efficacy compared to other, more invasive methods to be considered below. There are, however, cases of PTCS with demonstrated sinus recanalization following anti-coagulant therapy (Lam et al., 1992a). Direct surgical treatment

There are very few reports of direct thrombectomy, either in cranial venous sinus obstruction generally, or in that associated with PTCS in particular. Early reports have been briefly considered in Chapter 2. There are also cases in whom there has been direct removal of transverse sinus thrombus in the course of mastoidectomy for middle ear disease but no systematic attempt to relate this to the outcome of PTCS. One of the four cases of Ray and Dunbar (1951) was a 48-year-old woman with chronic PTCS which had not responded well to bilateral STD. Direct sinography, carried out by inserting a catheter into the anterior segment of the superior sagittal sinus via a burr-hole, demonstrated an obstruction at the junction of the middle and posterior thirds of the superior sagittal sinus. The superior sagittal sinus at the site of obstruction was explored via craniotomy and an aseptic thrombus removed. The patient’s PTCS showed improvement despite persistence of the obstruction at follow-up sinography at 6 weeks. At that time there was, however, a reduction in intra-sinus pressure and improved filling of collateral channels and other sinuses. By 3 months the PTCS had resolved, with normalization of CSF pressure and softening of the STDs. Apart from thrombus removal, there are several reports of direct treatment of other obstructive lesions such as depressed fractures and neoplasms (Britton et al., 1980; Powers et al., 1986; Wightman & Wheelock, 1991). Venous by-pass techniques

There are several reports of such methods being used in the treatment of venous sinus obstruction with a PTCS. These include the following: • Sindou et al. (1980), five cases. The cases were post-otitic sinus thrombosis, internal jugular vein ligation, torcular meningioma, dural AV fistula excision with sinus thrombosis (two cases). These authors used a saphenous vein graft in four instances and a Gore-Tex graft in one case. Systemic anticoagulation was maintained in the post-operative period. • Hitchcock and Cowie (1981), one case. ‘Otitic hydrocephalus’ not responding to medical treatment. They used a transverse sinus to common facial vein graft. • George et al. (1984), two cases. Both were post-otitic PTCS cases who had transverse sinus to extracranial vein grafts. • Van Coppenolle et al. (1986), one case. PTCS secondary to ear disease which responded well to a transverse sinus to external jugular vein graft.

225

Treatment of cranial venous obstruction

• Convers et al. (1986), two cases. Dural AVM with transverse sinus thrombosis treated with transverse sinus to cervical vein grafting. Overall, in this small group of 11 cases, the results in terms of resolution of the PTCS were good. Endovascular techniques

These may be broadly divided into two groups: ‘chemical’ methods aimed at clot lysis and ‘mechanical’ methods aimed at increasing the lumen of the affected sinus. Considering the former first, there are several reports of the endovascular delivery of urokinase or streptokinase to an obstructive thrombus in a venous sinus (Persson & Lilja, 1990; Barnwell et al., 1991; Smith et al., 1994), but the method has only been used in very few cases of PTCS secondary to sinus thrombosis. Thus, Karahalios et al. (1996) and King et al. (1995) briefly reported the unsuccessful use of urokinase in three patients with PTCS. In our own experience, direct delivery of urokinase coupled with systemic anticoagulants was initially successful in two cases of PTCS although one case relapsed after 8 months (Kollar et al., 2001). Turning to ‘mechanical’ techniques, there are at least five reported cases in which balloon angioplasty was used to relieve dural sinus stenosis in PTCS. Karahalios et al. (1996) used the technique in three cases, two with sigmoid sinus stenosis and one with jugular bulb stenosis. Two of the patients improved, although one of these suffered re-stenosis at 1 year, whilst the third patient had no resolution of PTCS despite what seemed to be a good haemodynamic result. A similarly disappointing result was reported by Keiper et al. (1999) in one case with venous sinus stenosis after a suboccipital and translabyrinthine approach to the C
P angle. In the case reported by Kollar et al. (2001), there was a significant resolution of PTCS but this was relatively short-lived and the patient went on to further surgical treatment eight months after the endovascular procedure (Figure 8.5). The use of the other ‘mechanical’ technique, stent placement, to treat obstructive lesions of the tranverse and sigmoid venous sinuses, dates from the reports of Marks et al. (1994) and Hunt et al. (2001). Including the two cases in the latter report, a total of 23 cases has been collected from the literature. Overall the results have been encouraging and are, in summary, as follows: • Hunt et al. (2001), two cases. PTCS secondary to venous outflow pathology in DLE in one case and following unilateral (right) radical neck dissection in the other case. A focal left-sided obstruction was demonstrated in the sigmoid sinus in one case and the transverse sinus in one case. After failed attempts at thrombolysis, the stenoses were stented in both instances with a good initial result.

226

Figure 8.5

Treatment

PTCS in a 32-year-old, non-obese woman. Left: MR phase contrast venogram showing marked narrowing of the right transverse sinus. Centre: Retrograde sinography and manometry showing focal obstruction of the right transverse sinus and associated intraluminal pressure gradient. The left-sided arachnoid granulation is designated ‘a’. Right: Repeat retrograde sinography and manometry post-dilatation showing improvement in flow and pressure gradient. All pressures in mmHg. (From Kollar et al., 2001; with permission.)

• Ogungbo et al. (2003), one case. PTCS with a focal obstructive lesion in a dominant right transverse sinus shown on MRV which, on manometry, had a pressure gradient of 25 mmHg across it. Stenting was followed by resolution of the PTCS although post-stent CSF pressure was still raised at 260 mmCSF. • Higgins et al. (2003), 12 cases. PTCS with a duration of symptoms ranging from 0.4 to 12 years. Five of these patients had had prior treatment including CSF shunting. Clinically, there was complete resolution in five cases, improvement but persistent headache in two cases, and no change in five cases. Three of the five cases with no change were previously shunted patients. Follow-up ranged from 2 to 26 months (mean 14.1 months). Complications included probable intraluminal thrombi in two patients successfully treated with thrombolysis, transient hearing loss on the stented side in two patients, and transient unsteadiness in one patient. • Owler et al. (2005), eight cases. PTCS with initial improvement in headache and vision in the seven cases followed up for any length of time, although two of these patients did have return of mild headache after a time. There was one serious complication, an acute subdural haematoma attributed to the radiological procedure. The patient recovered completely after surgical evacuation. There were also two cases with transient hearing loss on the stented side (Figure 8.6). In summary, the place of measures to correct demonstrated cranial venous outflow tract impairment in PTCS in the treatment of the condition remains ill-defined. There is, undoubtedly, a small group of patients in whom correction

227

Figure 8.6

Treatment of cranial venous obstruction

A case of a 9-year-old boy with a large dominant right transverse sinus. (a) Lateral DRCV demonstrating the significant right transverse sinus obstruction. There was a gradient of 11 mmHg across the obstruction. (b) Image during stent deployment. (c) Lateral DRCV of right transverse sinus with the stent fully deployed showing abolition of the obstruction. (From Owler et al., 2005; with permission.)

of some factor compromising cranial venous outflow is appropriate. The two subgroups within this group are those patients with thrombophilia and those with mechanical compression of the venous outflow tract by such things as depressed skull fractures and neoplasia. It is in the remaining large group of PTCS patients that the role of therapy directed at the cranial venous outflow tract is uncertain. If, as some studies suggest, obstruction to outflow in the distal components of the venous sinus system causing increased intra-sinus pressure is significant in a large number of PTCS patients, then a procedure such as stent placement may be effectively curative and relatively safe. There are no figures, however, on long-term efficacy. If such apparent venous sinus pathology is, in reality, secondary to the increase in CSF pressure in PTCS, as suggested by the second report by King et al. (2002), and by reports of the correction of stenosis by lumbar shunting in two cases (Higgins & Pickard, 2004; McGonigal et al., 2004) and lumbar puncture in one case (De Simone et al., 2005), then sinus stenting is obviously a less

228

Treatment

attractive option. Nevertheless, it might be argued that even if the creation of venous outflow tract hypertension is secondary to the intracranial hypertension, the relief of the former may be beneficial if this breaks a vicious circle and allows or facilitates resolution of the underlying condition. Other treatments There are several forms of medical treatment other than those already considered which have been used in small numbers of cases of PTCS. These include cardiac glycosides, specifically digoxin, which has been shown experimentally to effect a 61
78% reduction in CSF production, an effect more pronounced than that of acetazolamide (Neblett et al., 1972). This drug has, however, been disappointing in its very limited clinical use. Amacher & Spence (1985) used digoxin in 2 of 23 cases of PTCS, finding it effective as a single agent in one but ineffective when used in conjunction with diuretics in the other case. In a small series of cases of PTCS without papilloedema, Spence et al. (1980) used digoxin in three of nine cases, either alone or in combination, but found it ineffective in all instances. Likewise, in a single case, digoxin used after failed treatment with multiple agents over 13 months was also ineffectual (Schott & Holt, 1974). There is a single report of a single case of PTCS without papilloedema being successfully treated with Escin (15 mg 8 hourly by intravenous infusion followed by oral administration for 30 days), the patient showing resolution of intracranial hypertension without recurrence during a 6-month follow-up (Scanarini et al., 1979). There is also a single report of a single case of PTCS in Behc¸et’s syndrome where resolution was effected within 4 weeks using topirimate (Palacio et al., 2004). Further, Antaraki et al. (1993) reported three cases treated by octreotide who responded rapidly with lowering of CSF pressure but there was relapse when the drug was tapered. There is also a report of the use of hyperbaric oxygen in the treatment of PTCS in eight cases (Luongo et al., 1991). Finally, there is one report of significant reduction of CSF pressure with a single intravenous dose of indomethacin (350
500 mg) in seven patients (Forderreuther & Straube, 2000). Whether any of these agents merit further trial is a moot point. Conclusions The basic conclusion to be drawn from the preceding analysis is that the various treatments considered above all work with varying efficacy in PTCS, but that none is distinguishable as a treatment of choice. That is, all the treatments listed are more or less effective, but also all are more or less exceptionable for different reasons. There is, moreover, no rigorous study establishing the efficacy of any

229

Conclusions

one of the treatments, or the relative merits of one treatment over another or others, as the recent study by Lueck and McIlwaine (2002) makes clear. This uncertainty is exemplified by the comparison of the figures from the Glasgow and Sydney series in which quite different treatment strategies were used in a comparable number of patients with comparable results. Considering the individual treatment methods first, a summarizing statement on each is given as follows. No treatment

Clearly there is a group of patients in whom PTCS is self-limiting. This group particularly includes those cases in whom a specific causative factor can be withdrawn or corrected. So, if this is the case, or the condition is mild, an expectant approach, perhaps with the addition of symptomatic treatment of headache, might be pursued. Serial LPs

This treatment certainly can be effective, although available evidence suggests that any reduction in CSF pressure due to drainage is transient due to the rapid restoration of CSF volume. Further, it is an unpleasant treatment for the patient. If it is to be used, then a period of continuous CSF drainage via a lumbar catheter is more appropriate. Acetazolamide

Theoretical considerations suggest that this should be an effective treatment and indeed it is, albeit in a relatively small number of patients. The group most likely to benefit comprises patients with a less severe form of PTCS so it might be considered the first choice treatment in such cases. One point in its favour is that it is a well-tolerated drug with few side-effects. Steroids

Although the theoretical grounds are less clearly established than with acetazolamide, the actual efficacy of steroids is arguably greater. That is, steroids will bring resolution of symptoms and signs in a significant number of PTCS cases including those that are severe. However, side-effects are significantly more intrusive, the reduction of CSF pressure may be delayed and incomplete despite obvious clinical improvement, and there is a substantial recurrence rate. Optic nerve sheath decompression

This is also an effective treatment although its mechanism of action remains inadequately understood. It is particularly effective in protecting vision; less so in

230

Treatment

controlling headache. Also, its long-term efficacy remains in question and it is a procedure not without complications which themselves might adversely affect vision. There is also evidence that CSF pressure may remain high despite clinical improvement. Subtemporal decompression

This is also an effective treatment, particularly in protecting vision. It was the mainstay of treatment in cases refractory to medical treatment in early series, a place that has been largely usurped by ONSD and shunting. Given the long-term uncertainty of the former, and undesirable complications of the latter, the role of STD may be worthy of re-examination. Nevertheless, it too is a treatment with possible complications and also may fail to normalize CSF pressure. Cerebrospinal fluid shunting

This is undoubtedly the most effective of the currently available forms of treatment of PTCS, and the one certain way of bringing about a rapid and substantial reduction of CSF pressure. It is, however, the treatment most fraught with difficulties and complications. Approaches to cranial venous outflow tract obstruction

Apart from its use in the small group of cases in whom elimination of factors causing such obstruction is readily possible, the role of this therapeutic approach in PTCS is still to be established. All that can be said at present is the venous sinus stenting is possible and has been shown to be effective in a small number of patients in the short to medium term. It is certainly a method that deserves further study. Overall strategy

Turning to a consideration of patients as opposed to methods, a broad strategy might be outlined as follows: 1. For patients with mild disease, i.e. those without papilloedema, and those with papilloedema which has not affected visual function, and particularly if a causative factor of the PTCS can be identified and eliminated, an expectant approach or symptomatic treatment with weight reduction only may be appropriate. If this proves unsatisfactory, acetazolamide/topirimate should be the treatment of choice. 2. For patients with PTCS of moderate severity, i.e. troublesome headache and/or more severe papilloedema, but still without compromise of visual function, medical treatment should be employed using acetazolamide/topirimate and steroids with weight reduction, either one alone or both in combination.

231

Conclusions

3. For patients with severe PTCS, i.e. severe headache and papilloedema with impairment of visual acuity and/or visual fields, an initial trial of vigorous medical therapy should be undertaken using acetazolamide and steroids in combination, possibly augmented with a 5- to 7-day period of continuous lumbar CSF drainage. 4. For patients in any of the previous categories, but particularly the third, in whom medical measures are failing, consideration should be given to investigation of the cranial venous outflow tract with a view to some therapeutic intervention if appropriate. Otherwise, ONSD or CSF shunting should be resorted to, the decision between these methods being determined by the relative severity of headache and visual disturbance. 5. For patients who have had ONSD but who are still significantly troubled by headache, or in whom papilloedema does not rapidly resolve, CSF shunting should be used. 6. For patients who have been shunted, but who run into difficulties requiring multiple shunt revisions or other complications of shunting, bilateral STDs should be carried out and shunting abandoned.

9

Outcome

Introduction Whilst this subject has, in part, been considered in the previous chapter on treatment, there are several aspects pertaining to outcome which merit separate and particular consideration. These aspects, which include duration of symptoms, the outcome for visual function, the likelihood of recurrence, psychological sequelae and the development of other diseases (this last incorporating the risk of error in the initial diagnosis), will be addressed in turn in the present chapter. In each instance the data from the Glasgow and Sydney series will be given, followed by a review of the relevant literature. Duration of symptoms and signs In Table 9.1 the patients in the Glasgow series are divided according to whether an aetiological factor was identified or not. In neither group did symptoms persist for long after the start of treatment in the majority of cases. Thus, in 83 of the 99 patients (83.8%) initially complaining of headache and 69 of the 88 patients (78.4%) with visual symptoms at the time of presentation, symptoms had cleared within 3 months of starting treatment. Headaches persisted longer than 12 months in only seven patients (7.1%), and visual symptoms in only 10 patients (11.4%). The duration of papilloedema tended to be longer, however, persisting for between 4 and 12 months in 38 of 92 patients (41.3%), and for longer than 12 months in 14 of 92 patients (15.2%). Where other visual signs resolved, as they did in the majority of cases, they tended to do so more rapidly
within 3 months in 43 of 61 cases (70.5%). In all the aspects considered, the two groups were closely similar. The patients in the Sydney series were divided according to age and sex (Table 9.2). Again, a high proportion of cases showed resolution of symptoms and signs within three months from the start of treatment
54.4% across all 232

233

Duration of symptoms and signs Table 9.1. Duration of symptoms and signs after start of treatment: Glasgow series

<3 months

4
12 months

412 months

Unknown

Headache No aetiology Aetiology

46 37

7 2

6 1

0 0

Visual symptoms No aetiology Aetiology

39 30

5 4

7 3

0 0

Papilloedema No aetiology Aetiology

19 21

21 17

11 3

11 7

Visual signs No aetiology Aetiology

21 22

5 1

9 3

8 5

Symptom/sign

Table 9.2. Duration of disease after start of treatment: Sydney series

Category Male children Female children Male adults Female adults Total

< 1 month

1
3 months

4
6 months

7
12 months

412 months

7 5 1 13 26

8 14 4 28 54

2 4 2 3 11

0 3 0 4 7

9 9 3 28 49

groups
but this was noticeably less than in the Glasgow series. The other aspect of the variation was seen in the 49 patients in whom active disease was still noted after 12 months (33.3%). The reason for this high figure was the large number of patients treated by CSF shunting in whom any recurrence of symptoms due to shunt malfunction was counted as continuing disease. All but one of the 49 patients in this group were cases with shunt malfunction. This matter has been considered in the previous chapter. Whilst all patients who had a functioning shunt, whether at the initial insertion or after revision, had rapid resolution of their signs and symptoms, it remains the case that while ever there is a functioning and necessary shunt in place, the disease continues to be a factor in the patient’s life. As Table 9.2 shows, there were no significant differences between the subgroups as far as the time course of resolution of symptoms and signs was concerned.

234

Outcome

Figures from the literature are broadly similar, with a substantial proportion of patients showing early and rapid resolution. Nevertheless, there is a significant number of patients in whom symptoms and/or signs persist, either with or without treatment, or at least treatment other than CSF shunting. Thus, Rush (1980) reported 43 of a series of 61 cases (70.5%) treated medically as showing resolution within 4 months. On the other hand, there were 10 patients (16.4%) with either continuous or intermittent medical treatment who showed persistence of disease for a prolonged period, ranging from 13 months to 5 years. In other studies, Boddie et al. (1974) gave an average duration of symptoms of 3 months after diagnosis, whilst Guidetti et al. (1968) reporting 100 cases, of whom 80 were followed up, gave an average duration of symptoms of 10 weeks although in three cases there was persistence of disease for greater than 12 months. Considering papilloedema alone, Lysak and Svien (1966) found an average duration of 16 weeks in 63 patients. In children, and in patients with PTCS secondary to a known aetiological factor, the duration of symptoms and signs tends to be shorter. For example, in children Couch et al. (1985) found resolution within 1 month in 23 of 38 cases (60.6%), whilst Lecks and Baker (1965) reported 12 of 15 cases (80%) showing resolution in less than 3 months with nine cases resolving within 1 week. Clearly, the rapidity of resolution is treatment-related, an issue addressed by Bulens et al. (1979) whose figures are shown in Table 9.3. Even without treatment, as for example in the series of Bradshaw (1956), the majority of cases showed resolution within a period of several months, although very long-standing cases can occur either with or without treatment (Rabinowicz et al., 1968; Corbett et al., 1982). In the Glasgow series, there were 22 patients not treated, of whom 15 were seen at the late followup clinic, whilst three patients were found to have died from another, unrelated cause after an average period of 3.3 years. One patient later developed multiple sclerosis which may have been the correct initial diagnosis, whilst the remaining three patients were lost to follow-up, although even in these cases the average follow-up was 3.7 years and the shortest one year. The mean follow-up for the 15 cases seen at the clinic was 9.3 years for women and 7.9 years for men. Table 9.3. Duration of symptoms and signs after treatment (Bulens et al., 1979)

Treatment None Sub-temporal decompression Diuretics Repeated LPs Ventricular shunt

No. of cases 6 4 1 20 5

Duration of disease (months) 1
12 (mean, 5) 1
24 (mean, 9) Persistence 1
8 (mean, 2.5) 1
12 (mean, 4.5)

235

Outcome for visual function

Outcome for visual function This is an area of some considerable uncertainty, with figures dependent mainly on two factors: the type of patients examined (i.e. the proportion of young obese females with the more intractable form of the disease), and how assiduously defects of vision, predominantly visual field defects, are sought. The two series under particular examination represent series with a general cross-section of cases and without a major focus on visual function. In the Glasgow series, of the 19 patients with a marked reduction of visual acuity at the time of presentation, measurement of visual acuity was obtained at late follow-up in 13 cases. In all cases acuity had improved, although in 4 of the 13 cases there was still a quite significant defect. In the Sydney series there was adequate documentation of outcome for visual acuity in 115 of 152 (75.7%) of cases, and for visual fields in 111 of 152 (73.0%) of cases. In summary, for visual acuity, 66.4% of cases with adequate documentation had normal acuity throughout. Of those with impaired acuity at presentation (33.6%), the great majority (83.8%) improved, with only a small number showing either no improvement or deterioration. Only a small number had a significant persistent deficit (3.7% overall). The data for visual fields were similar: overall, the majority (58.3%) had normal visual fields throughout. Of those with field defects on presentation (41.7%), almost all showed at least some improvement (90.7%), but 7.8% of cases were left with a significant defect. The overall conclusion to be drawn from the figures of the two series is that whilst a significant number of patients with PTCS will have impaired visual acuity and/or visual field defects at presentation, the outlook for visual function across the whole range of treatments is good. However, as mentioned above, the figures from the literature are very variable. For example, Weisberg (1975a), in his series of 120 cases of PTCS, found that visual acuity returned to normal in all but two cases, both of whom had an initial acuity of less than 20/50 bilaterally. Both of these patients had a further, sudden loss of acuity while on medical treatment. There were three other patients in this series with residual optic disc pallor but without disturbance of acuity. In contrast, Corbett et al. (1982), in a detailed study of visual function in 57 patients from an initial series of 118 cases, followed for periods ranging from 5 to 41 years, found an incidence of significant impairment in approximately 50% of cases. A summary of their findings is as follows: 1. Overall. Fifty-eight of 114 eyes (in 57 patients) had either loss of VA or VF defects or both. 2. Visual acuity. Twenty-four eyes in 14 patients were either blind or had severe impairment. There were six patients with bilateral blindness and a further six with unilateral blindness, four of whom also had moderate impairment

236

Outcome

in the other eye. A further three patients had bilateral reduction of VA severe enough to interfere with function, whilst a total of 29 eyes were described as having a moderate loss of VA. 3. Visual fields. The abnormalities consisted of generalized constriction (4 eyes, 2 patients); enlarged blind spots (6 eyes, 12 patients); enlarged blind spots with nasal field loss (unilateral, 3 eyes, 3 patients; bilateral, 4 eyes, 2 patients). Considering persistent visual impairment, the range in reported series lies between the extremes of 1.7% (Weisberg, 1975a) and 76.5% (Sahs & Joynt, 1956), although the latter is a small series with scanty details on the actual disturbances of visual function. In an earlier analysis of visual outcome in a collected series of 563 patients from the literature (20 reports excluding Weisberg, 1975a and Corbett et al., 1982) with good follow-up of visual function, there was documented impairment in 106 cases giving an incidence of 18.7% (Johnston, 1992). This overall figure accords reasonably well with several other figures quoted in the literature, for example, 22% (Jefferson & Clark, 1976), 10
20% (Gutgold-Glen et al., 1984), and 4
12% (Ahlskog & O’Neill, 1982). In a recent report of 42 cases, Craig et al. (2001) found a persistent reduction of VA in 24% of cases compared with 21% at presentation, and a persistent abnormality of VF in 39% of cases compared with 62% at presentation. Rowe and Sarkies (1998) reported visual outcome to be good to excellent in 83% of cases. Considering children specifically, what figures there are show less variation. Thus, Baker et al. (1985b) found 10 of 36 paediatric patients had significant loss of vision at initial assessment or after medical treatment: four with rapid and severe loss of VA and alteration of VF, and six with moderate loss of VA with or without VF abnormalities. Of these 10 patients, six ended up with long-term loss of vision (16.7% overall). In one patient this was severe and in five patients moderate. Phillips et al. (1998), reporting on 30 of 35 children with PTCS who had adequate follow-up of vision, found only one with VA <20/40 in both eyes at follow-up, although six patients (17.1%) had residual VF abnormalities and 10 patients (33.3%) had some degree of optic atrophy. In the Sydney series, there were 41 children with adequate data on VA. Of these, 61% had normal VA throughout, 22% had abnormal VA on presentation which significantly improved, 9.8% had worse VA after treatment, whilst 7.3% had a significant permanent loss of VA. The corresponding figures for VF were 66.7% normal throughout, 25% improved, 5.6% worse, and 2.8% with significant permanent loss. As to the cause of loss of visual function with papilloedema, there is general agreement following the studies of Hayreh (1964, 1966, 1977) and others, that the primary mechanism is the adverse effect of increased pressure on axoplasmic flow in the optic nerve with resultant intra-neuronal ischaemia, the particular locus of damage being at the optic nerve head (Troost et al., 1979;

237

Outcome for visual function

Gutgold-Glen et al., 1984; Wall, 2000). In addition, Hedges et al. (1995) have documented retinal nerve fibre layer damage. In their study of 36 eyes in 27 patients, they found such damage in 67% of eyes, with the damage being five times more frequent in the superior as opposed to the inferior areas. VF loss was more prevalent in eyes with diffuse nerve fibre damage (89%). Talks et al. (1998) made a particular study of macular damage in 24 patients undergoing ONSD for PTCS. Macular changes were noted in 21 of 48 eyes (43.8%) and were associated with significant visual loss in the short term in five eyes and in the long term in three eyes. There is also the possibility of subretinal neovascular membrane formation (Morse et al., 1981; Coppeto & Montiero, 1985). Despite these observations, Ahlskog and O’Neill (1982) have claimed that the visual outcome in PTCS is not related to the duration of symptoms, the degree of papilloedema, the occurrence of visual obscurations, or the incidence or timing of recurrence. These are, however, the very factors which can introduce a sense of urgency into decisions on the timing and nature of treatment. One study which bears directly on this issue is that of Wall and White (1998). From 478 patients with papilloedema, they found 46 cases in whom the papilloedema was highly asymmetrical (a difference of two Frisen grades or more). In the nine cases who where studied at follow-up, inter-ocular comparison showed vision to be worse in the more papilloedematous eye for all outcome measures. On this point of visual outcome in PTCS, Rabinowicz et al. (1968) reported eight cases followed over 3 to 6 years who had persistent papilloedema despite medical treatment (acetazolamide, steroids, lumbar punctures). The duration of observed papilloedema ranged from 2 to 5 years with an average of 3.5 years. Three of these patients developed a field defect during the period of surveillance, in two cases an inferior nasal quadrant loss and in one case peripheral constriction. Davidoff and Dyke (1937) reporting 15 cases, 13 of whom were treated with subtemporal decompression, found that resolution of papilloedema took between 6 months and several years, whilst Corbett et al. (1982), in the study of 57 patients already referred to, found nine cases in whom papilloedema had persisted for periods from 5 to 13 years. In three of these patients there was severe loss of VA and, in general, post-papilloedematous changes were common. The observations of Troost et al. (1979) and Morse et al. (1981), also referred to above, were in both instances stimulated by individual patients with pronounced loss of vision as a consequence of chronic PTCS. In the former report, this was due to inadequate medial treatment, whilst in the latter, it was associated with recurrence after three years. It may be concluded, then, that although there are obviously patients with PTCS who can withstand prolonged intracranial hypertension and papilloedema with at least relative preservation of VA and VF, in broad terms the duration, degree,

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Outcome

and recurrence of papilloedema are closely linked with impairment of visual function. It is, moreover, clear that once visual function is lost there is a distinct prospect that the loss is more or less irreversible, and that the severity and duration of the loss are adverse prognostic factors. Thus, Corbett et al. (1982) found 17 of their 57 patients had significant permanent loss of vision, 6 being bilaterally and 6 unilaterally blind. Subburam et al. (1984) described 3 of 24 cases with marked loss of vision (hand movements, 3/60; hand movements, 6/24; 6/36, 1/60) who were unresponsive to medical treatment and subsequently went on to lumbarperitoneal shunting and ONSD. In only one of the six eyes was there improvement and then only from 6/36 to 6/24. In summary, it may be said that a significant proportion of PTCS patients will be left with permanent impairment of vision involving VA, VF or both, and while there is quite considerable variation in the reported incidence of such impairment, it is probably of the order of 10
20% with current methods of management and evaluation. In general, the likelihood of such loss is related to the chronicity and severity of the intracranial hypertension, this causing prolonged disturbance of axoplasmic flow in the optic nerves with secondary vascular changes which may themselves be irreversible, or which may lead to irreversible changes.

Recurrence In the Glasgow series, a total of 11 patients developed a recurrence of their original signs and symptoms after an interval ranging from 4 months to 14 years in those with no apparent cause of their PTCS (six patients) and from 4 months to 8 years in those with an apparent aetiology (five patients) after the initial presentation. The overall recurrence rate was, therefore, 10% with 3 of the 11 patients developing a second recurrence. In eight instances the recurrence occurred within a short time after the cessation of treatment with steroids, necessitating a further course of steroids which was successful in each case. Of the three remaining cases, one required revision of a ventriculo-peritoneal shunt, one a further series of lumbar punctures, and one a subtemporal decompression. In the Sydney series, there was a comparable recurrence rate: 14 of 152 cases (9.2%). This figure does, however, exclude those patients who required one or more shunt revisions due to shunt complications with return of intracranial hypertension. The frequency of shunt revision is considered in the previous chapter. Of the 14 patients referred to, three were male children and all had recurrence after initially successful treatment with steroids. In two instances, the recurrence occurred shortly after cessation of treatment whereas, in the third case, there were two recurrences, one 6 months

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Recurrence

after completion of the first course of treatment, and one 6 years after a second successful course of treatment with steroids. There were four female children with recurrence: one after initial treatment with steroids, one after initial treatment with acetazolamide (at 10 years), one after elective removal of an L
P shunt (this responded to a short course of acetazolamide), and one after cessation of vitamin A plus a course of steroids. This last patient had three further recurrences (at 3 months, 6 months, and 3 years) all of which responded to further steroids. There were seven recurrences in adult females. Five were at varying times (from 3 months to 5 years) after initially successful medical treatment whilst two followed removal of an L
P shunt, in one instance electively and in the other because of a symptomatic acquired Chiari malformation. The first responded to acetazolamide but the second failed to respond to a combination of acetazolamide and ONSD, going on to a cisterno-atrial shunt. The incidence of reported recurrence of PTCS in the literature varies considerably. Moffat (1978), in a review, gave a range of 0.2
12% but in reality the range is rather greater. Thus, in two series, that of Wilson and Gardner (1966) comprising 28 obese young women and that of Davidoff (1956) comprising 57 of 61 cases followed for 1 to 21 years, there were no reported recurrences. On the other hand, Zuidema and Cohen (1954), who followed up Dandy’s original 22 cases (Dandy, 1937) and added 17 cases of their own, achieving satisfactory follow-up in a total of 21 cases (with an additional 5 known to have died from other causes), reported 9 recurrences (34.6%). Rush (1980) found a similar incidence
23 recurrences in 63 cases, a rate of 37%. Moreover, in this series, 5 patients had two recurrences and 7 had three recurrences. In two large series, that of Corbett et al. (1982) comprising 118 cases of whom 57 were followed from 5 to 41 years, and that of Weisberg (1975a) with 120 cases, the recurrence rates were 8% and 11.1%, respectively. Considering males specifically, Digre and Corbett (1988) reported two recurrences in 29 cases (6.9%). For children, combining three series (Rose & Matson, 1967; Grant, 1971; Weisberg & Chutorian, 1977), there were eight recurrences in 140 cases, a rate of 5.7%. Clearly, reported recurrence rates will depend substantially on three major factors: duration of follow-up, the type of initial treatment, and the duration of the initial treatment. Many of the reported recurrences occurred well within the first 12 months from diagnosis and in part, at least, might be attributable to premature cessation of treatment. Likewise, as referred to above, shunt malfunction in shunted patients may be considered a recurrence, although this is different in nature from recurrence as usually understood. As is apparent from both the Glasgow and Sydney series, a number of patients developed recurrence long after the cessation of treatment. On this point, Lysak and Svien (1966) reported three patients with recurrent disease in a series of 46 patients, finding

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Outcome

recurrence at 13 and 14 years in one patient, at 3 years (twice) in one patient, and at 5 years in one patient. Similarly, Rush (1980) found that one third of his reported 23 recurrences occurred after more than 2 years. One further point on the issue of recurrence is that there are several reports of patients who developed PTCS related to some drug or other agent suffering a further episode of PTCS on reexposure to the culpable agent: Bird and Sanders (1973) for steroids; Parent (1969) and Mikkelson et al. (1974) for vitamin A; Fisher (1967) for nalidixic acid; Shah et al. (1987) for danazol; Kalanie et al. (1986) for phenytoin; Gardner et al. (1995) and Kesler et al. (2004) for tetracycline; Koller et al. (1997) for growth hormone replacement; and Rosa et al. (2003) for mesalazine. On the other hand, there are also reports of patients who initially developed PTCS following exposure to some presumed aetiological agent, who later had recurrent disease without re-exposure: Walters and Gubbay (1981) for tetracycline; Sanborn et al. (1979) for chlordexone; and the Sydney case noted above for vitamin A. Finally, there are several reports suggesting a high incidence of recurrence with a further pregnancy in those cases initially occurring during pregnancy (Nickerson & Kirk, 1965; Elian et al., 1968; Thomas, 1986).

Persistent elevation of CSF pressure It was evident from the findings using continuous ICP monitoring as part of the follow-up after clinically successful treatment of PTCS with steroids that despite the undoubted resolution of all clinical symptoms and signs, there could be a persistent and not insubstantial increase in CSF pressure (Figure 8.2). Using single manometric readings of CSF pressure on lumbar puncture, a similar claim could be made for apparently successful treatment by subtemporal decompression (Johnston et al., 1981, Figure 8.3). More recently, similar findings were obtained in a small group of patients treated by optic nerve sheath decompression (Jacobson et al., 1999b) and direct treatment of cranial venous outflow obstruction (Kollar et al., 2001). Similar findings have been reported in a number of other studies. The patients in these studies fall broadly into two groups: patients still undergoing treatment and patients who are asymptomatic and with resolution of signs after the cessation of treatment. With respect to the first group, Corbett and Mehta (1983) reported 18 chronic cases of PTCS 3 to 41 years after diagnosis who had an average CSF pressure on lumbar puncture of 253 mmH2O. In one of the patients who still had papilloedema, the CSF pressure was 350 mmH2O. Similar reports include those of Schott and Holt (1974), Traviesa et al. (1976), and Ross et al. (1985).

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Psychological and psychiatric sequelae

A greater number of reports is available concerning the second group, that is, patients with apparent resolution of the disease after the cessation of treatment. Thus, Greer (1968) reported 12 of 110 cases with increased CSF pressure more than 5 months after completion of treatment, who were entirely free of symptoms and signs. Interestingly, apropos disease mechanism, 4 of these 12 patients showed some increase in ventricular size. In Weisberg’s (1975a) series of 120 cases, 10 cases had a CSF pressure greater than 250 mmH2O on three consecutive occasions despite being symptom-free and no longer on treatment. Likewise, Couch et al. (1985) reported 2 of 23 patients in remission for more than 1 month who had a raised CSF pressure more than 1 year after initial diagnosis, whilst Cooper et al. (1979), who investigated eight cases of PTCS using long-term pressure monitoring, found one patient who became asymptomatic after 3 weeks of treatment with steroids and frusemide, still had very high CSF pressure levels at 8 months, with the highest levels being recorded 4 weeks after the cessation of treatment. A further two cases had a long-term elevation of CSF pressure without symptoms and without visual loss. There are also other reports of patients treated with ONSD who have a sustained elevation of CSF pressure despite significant amelioration of the disease (Billson & Hudson, 1975; Kilpatrick et al., 1981; Kaye et al., 1981; Knight et al., 1986). Clearly, these findings raise several questions. How many apparently successfully treated cases of PTCS have persistent elevation of CSF pressure after cessation of treatment, for how long do such elevations persist, what are the consequences of such sustained increases, and what are the implications for follow-up strategies?

Psychological and psychiatric sequelae Leading on from the question posed at the end of the previous section, there is the largely unexamined issue of whether there are significant psychological or psychiatric problems associated with PTCS, particularly if the condition itself is of long duration, but also if, as considered above, there is prolonged elevation of CSF pressure despite amelioration of symptoms and signs. Two early reports on the subject are those of Klein (1978) and of Klosterko¨tter (1982). In the former, a dissertation reported by Sørensen et al. (1986b), 104 cases were included not all of which, apparently, were cases of PTCS. In the group overall, 10% complained of persistent cognitive dysfunction and 7% of reduced working capacity. There was, however, no detailed examination, of psychological function. The latter is a report of a single case PTCS with intellectual impairment over a four year course. In the study reported by Sørensen et al. (1986b), 20 consecutive cases of PTCS were included. Of these 20 cases, 5 (3 females, 2 males) with a protracted course

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Outcome

complained of persistent learning and memory problems. On detailed psychometric assessment these five patients showed some degree of intellectual impairment (the authors use the term ‘light’) most marked in verbal tests. They reported that these changes were reversible with vigorous treatment. There is also the relatively recent report by Kaplan et al. (1997) of a single case of a depressed patient with PTCS who complained of concentration and memory problems but was found to have a normal neuropsychometric evaluation. As mentioned in the section on disease associations, there are several reports of a coincidence of PTCS and depression, including two cases in twins (see Chapter 5) and a possible relationship with lithium carbonate in the treatment of depression. The only formal examination of a possible association is the study by Kleinschmidt et al. (2000) who compared three groups of patients: IIH (PTCS) patients, n ¼ 28; age and weight-matched controls, n ¼ 30; age-matched controls of normal weight, n ¼ 30. They found higher levels of depression and anxiety, and a greater number of adverse health problems in the IIH (PTCS) group compared to both control groups whereas there were no differences with respect to non health-related psychosocial problems.

Other diseases and diagnostic error There are here two distinct issues. First, there is the question of error in the initial diagnosis, PTCS being confused with some other cause of the clinically presenting intracranial hypertension. Second, there is the question of whether PTCS is associated with, or predisposes to, any other condition. This latter excludes those conditions taken to be in some way causative, which are considered in Chapter 5 on aetiology. The first question was a particular focus of the Glasgow series in which attention was paid to gathering complete and detailed follow-up information on a large series of cases. To this end, a total of 124 patients with the initial diagnosis of PTCS was collected covering a 30 year period from 1942 to 1972. Of the 124 patients, 21 were found to have died by the time of analysis. In these cases the cause of death was ascertained from post-mortem reports or from the death certificate. Of the 103 remaining patients, 76 were seen at a special follow-up clinic whilst in 22 follow-up was by letter, either from the patient directly, or from their current general practitioner, or in most cases both. Only five patients could not be traced, the follow-up periods in these patients being 6 months (two cases), 2 years, 13 years and 20 years. Ten patients were excluded because the clinical details were inadequate. In only 4 of 110 remaining patients was the initial diagnosis of PTCS later proven incorrect by the recognition of another cause of the intracranial

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Other diseases and diagnostic error

hypertension. Two of these four patients were found to have an intracranial tumour after intervals of 1 and 14 months from the initial, incorrect diagnosis. One patient was later found to have sarcoid meningitis and another, multiple sclerosis, after intervals of 9 and 5 months, respectively. In two of these four patients, correct diagnosis had to await post-mortem examination. All four patients had some disquieting feature at the time of initial investigation: in three cases a slightly raised CSF protein, and in two cases a minor abnormality on contrast radiology. All four patients died at intervals of 1 to 14 months from the initial, incorrect diagnosis. The diagnostic error rate was, therefore, 3.5% and the errors were not long delayed in coming to light. In the Sydney series there were three patients in whom the initial diagnosis of PTCS was subsequently proven incorrect, the error rate here being 1.9%. The subsequent correct diagnosis was gliomatosis cerebri in one case, a diffuse left cerebral hemisphere astrocytoma in one case, and diffuse leptomeningeal gliomatosis in one case. As with the Glasgow cases, the correct diagnosis was not long delayed in coming to light. All three cases occurred in the early days of CT scanning, there being no such diagnostic errors since the advent of MR scanning. A fourth patient, who did fall into the post-MR period, had an MR study without contrast at the time of initial diagnosis. She was subsequently found to have multiple meningiomata, the largest of which was compressing a dominant transverse sinus. It could be argued that in this case the diagnosis of PTCS was correct if the relaxed criteria advocated in the present treatise are accepted. Information from the literature on diagnostic error is quite scanty. Rish and Meacham (1965) quoted an error rate of 3.3% which represented three patients in their series, one of whom had a glioma, one a chronic subdural haematoma, and one a choroid plexus papilloma. In addition, one of their other patients later died of gliomatosis cerebri. In the series reported by Bulens et al. (1979), one of 41 patients was later found to have an intracranial tumour (meningioma), whilst in Greer’s (1968) large series there were two patients later found to have an intracranial tumour; one a chemodectoma and one a metastatic neuroblastoma. Marr and Chambers (1966) described two cases initially diagnosed as PTCS who were later found to have meningioma en-plaque with venous sinus involvement. As with the patient in the Sydney series, it could be argued that PTCS was the correct initial diagnosis. Zuidema and Cohen (1954), in their follow-up of Dandy’s original cases, did not find any in whom a different cause of intracranial hypertension subsequently came to light. Finally, there are several recent reports of initial confusion with either gliomatosis cerebri or other diffuse neoplasms (Weston & Lear, 1995; Ariochane et al., 1993; Ebinger et al., 2000; Kim et al., 2000). In summary, then, the likelihood of initial diagnostic error with current investigative methods must be extremely low indeed. The most likely candidates

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Outcome

on differential diagnosis are gliomatosis cerebri or diffuse leptomeningeal neoplasia. On the question of association with other diseases, information is also somewhat scanty. In the Glasgow series, a total of 32 patients developed some other disease after the symptoms and signs of PTCS had resolved. In 10 cases the further development was neurological as follows: five patients developed epilepsy, all after subtemporal decompression, two died from cerebrovascular disease long after the initial diagnosis of PTCS, one developed a focal neurological deficit following ventriculography done during a recurrence of her original symptoms, and one developed bacterial meningitis after an interval of 14 years. Four of the 32 patients, all from the group with an identifiable cause, subsequently developed an endocrine disorder: diabetes mellitus in three instances and Simmond’s disease in one instance. In the other 18 patients the subsequent disease was non-neurological. The only illness to occur more than once in this group was endogenous depression (three patients). In the Sydney series, there were six patients who died during follow-up. In four instances death was due to the condition which was originally taken to be the cause of the PTCS: chronic renal disease in two cases, cystic fibrosis in one case, and Hunter’s syndrome in one case. One patient died due to the complications of an infected shunt (sub-phrenic abscess and septicaemia) and one from unrelated cardiovascular disease. The only other neurological diseases in the series were three cases of symptomatic acquired Chiari malformation attributed to lumbar CSF shunting. One of these patients also developed syringomyelia. In the late study of Dandy’s original 22 cases already referred to (Zuidema & Cohen, 1954), two patients had died of neurological disease. In both instances this was taken to be unrelated to the earlier PTCS (intracranial aneurysm, disseminated sclerosis).

Conclusions Because of the often exigent nature of the visual problems in PTCS, not to mention the disturbance caused by persistent headache, one or both of which typically demand immediate treatment, there is no information of substance on the natural history of the syndrome. What can be said, however, is that in a proportion of patients, at least, the condition is self-limiting. This can be inferred from the relatively small number of reported untreated cases, although such cases are going to be predominantly from the less severe end of the spectrum and include a high proportion of cases in whom an identifiable causative agent is withdrawn or corrected. There is some slight evidence that the disease will persist for a prolonged period, if not indefinitely, when untreated, but this is based on very few cases.

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Conclusions

Our own findings from patients treated by CSF shunting have shown that the disease can still be active over 20 years from diagnosis if there are shunt problems, although of course the presence of a functioning shunt complicates the picture. What can be said with confidence is that rapid resolution is the rule after the initiation of the accepted forms of effective treatment, but there are exceptions to the rule, at least with all forms of treatment other than shunting. The outcome for vision is less certain, but the figures do suggest that vision can be stabilized and very often improved if treatment is initiated rapidly and effectively. However, the proportion of patients with some persistent abnormality of vision (predominantly visual field defect) may be high if such defects are assiduously sought during follow-up. The outlook for psychological function and with regard to possible psychiatric disturbance is a subject that has been neglected and one that certainly requires further study. There is clearly a recurrence rate. For non-shunted patients, this is probably around 10% whereas, in shunted patients it will approximate to the shunt malfunction rate. There will, however, be a proportion of shunted patients who will become shunt-independent whether this is actually recognized or not in the individual case. There does not appear to be any predilection to other neurological disorders in patients with PTCS. Finally, the likelihood of diagnostic error at the time of presentation has always been low but is now very low indeed, given the highly refined diagnostic techniques available, not only those used to exclude other causes of raised ICP, but also those used to identify causative factors giving rise to PTCS itself.

10

Experimental studies

Introduction The creation of an experimental model of PTCS would represent a critical step in the understanding of the pathophysiology of this complex condition. Some of the key issues which such a model might help resolve are as follows: 1. If, as the current evidence seems to suggest, PTCS is primarily a disorder of CSF absorption with a resulting increase in CSF volume as the cause of the intracranial hypertension, where and how is the excess fluid accommodated, and why is there typically no increase in ventricular size? 2. If, on the other hand, the intracranial hypertension is due to some form of parenchymal oedema, again where precisely is the fluid located, and how do neurological functions, particularly higher functions, remain apparently unaffected? 3. What is the significance of the elevated cranial venous outflow tract pressure and the often marked proximal to distal pressure gradients within the tract which have been a frequent feature of recent clinical manometric studies. In particular, is the increased venous pressure a cause or consequence of the increase in CSF pressure? 4. Related to #2 above, how do PTCS patients with marked increases in ICP unaccompanied by commensurate increases in arterial blood pressure tolerate the significant drop in cerebral perfusion pressure with apparent impunity? Unfortunately, no experimental model has yet been developed, although several of the known aetiological agents such as venous outflow obstruction, vitamin A, steroids and even tetracycline and its derivatives, do suggest themselves as possible agents in attempting to establish a suitable model. There is already some experimental evidence on the first three of these agents and this will be reviewed in the present chapter. There is also some experimental data on other agents used in the treatment of PTCS which will be considered here. 246

247

Theoretical considerations

Theoretical considerations The most widely accepted concept of the mechanism of PTCS, and the one argued for in Chapter 3, is that it is a condition due to a reduction in CSF absorption at the point of transfer into the vascular compartment, in the face of a continuing normal rate of production. The resulting imbalance produces an increase in CSF volume sufficient to cause an increase in CSF pressure which can be both marked and prolonged. A satisfactory defence of this concept requires a detailed knowledge of all aspects of CSF dynamics as well as an understanding of the pathophysiology of intracranial hypertension generally. Because there are deficiencies in our present knowledge in both these areas, there are still uncertainties in the understanding of PTCS, not only in relation to mechanism, but also with respect to treatment and outcome. Some of the theoretical issues of particular relevance are as follows. What determines CSF formation and how is it affected by alterations in CSF pressure?

The prevailing, and well substantiated, view on CSF formation is that intraventricular choroid plexus is the main source of CSF, which is formed as a result of an active transport mechanism effecting transfer of a plasma filtrate from the vascular compartment to the CSF compartment (Figure 10.1). There are

Figure 10.1

Working model of ion transport mechanisms across the choroid plexus epithelium. (From Brown et al., 2004; with permission.)

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Experimental studies

several aspects of CSF formation which are of particular relevance to PTCS. The first is whether an increased rate of CSF formation can itself be implicated in the causation of the syndrome, as suggested by Donaldson (1979) among others. In theory, this mechanism is possible, but to date there is no evidence to support it, and what little evidence there is suggests that CSF formation rate is normal in PTCS (Johnston & Paterson, 1974b). There are, in fact, only two conditions associated with a proven increase in CSF product: choroid villous hypertrophy (Hirano et al., 1994) and choroid plexus tumours, but in the latter case several factors may be operative (Weller et al., 1993). In both situations there is obvious morphological change in the choroid plexus which has never been identified in PTCS. Second, there is the issue of the relationship between CSF formation and increased CSF pressure. Thus, if PTCS is due to an increase in CSF volume, whether due to increased formation or decreased absorption, does the increase in CSF pressure cause a compensatory reduction in CSF formation? For the most part, the evidence suggests that the rate of CSF formation is independent of CSF pressure (Cutler et al., 1968; Lorenzo et al., 1970; Welch, 1975; Sklar et al., 1980). There is some evidence to the contrary (Hochwald & Sahar, 1971; Sahar, 1972), and there is also the question of relevance of these studies to PTCS. Thus, if CSF formation is independent of CSF pressure, does this independence continue to apply with the often very high pressures found in PTCS? Third, to what extent are other sources of CSF production operative under normal conditions, and under abnormal conditions such as PTCS? Such possible sources include the brain extracellular fluid (Cserr et al., 1977, 1981, 1985) and the spinal cord (Sato et al., 1972), but this is an area that needs further clarification. Fourth, why do substances such as carbonic anhydrase inhibitors and cardiac glycosides (considered further below), which have been demonstrated experimentally to be very effective in reducing CSF formation by the choroid plexus, have relatively little success in the treatment of PTCS? What determines CSF absorption and how is it affected by increased CSF pressure?

The generally accepted view of CSF absorption is that it occurs primarily via the arachnoid villi, although these are structures which show quite marked species variation, both in number and site. How much of the total volume of CSF absorbed are they responsible for, and what is the mechanism by which they effect absorption? Ideas have changed somewhat since the early concept advanced by Weed in particular (Weed, 1923; Figures 10.2 and 10.3), with evidence from electron microscopy suggesting a system of vacuoles transferring CSF from the subarachnoid space to the venous system, rather than the fluid passing between the cells of the villi. This concept, which is due largely to the work of Tripathi (Tripathi, 1968, 1973; Tripathi & Tripathi, 1974; Tripathi, 1977; Figure 10.4), is

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Figure 10.2

Theoretical considerations

Weed’s early diagram of the mechanism of CSF drainage. A difference of colloid osmotic pressure (COP) was thought to aid withdrawal of CSF into blood. (From Davson and Segal, 1996; with permission.)

not without points of contention. Other possible sites of absorption include the brain perivascular (Virchow
Robin) spaces, the spinal cord directly into venous channels possibly via arachnoid villi-like structures demonstrated in various species (Elman, 1923; Welch & Pollay, 1963) including man (Kido et al., 1976), and via lymphatic channels (Davson & Segal, 1996). In terms of physiology, the prevailing view is that the rate of CSF absorption is directly proportional to the pressure differential between the subarachnoid CSF and the superior sagittal sinus, and inversely proportional to the resistance to flow across the arachnoid villi, or the absorptive channels more generally. Davson and Segal (1996), for example, give the following equation: V Pcsf
Psss ¼ t R where V is the volume of CSF absorbed over time t. If Psss and R remain unchanged with increased Pcsf then a linear relationship should obtain, as described by Cutler et al. (1968). What is unknown is whether changes in Psss do, in fact, occur when Pcsf increases. This question will be considered in the following section. If they do not, and if R is also not affected by CSF pressure, then clearly an increase in Pcsf should lead to an increase in absorption rate which would tend to normalise Pcsf whatever the cause of the increase. There are no obvious theoretical reasons why Rout should change with increased Pcsf. This is due, at least in part, to the on-going uncertainty about the precise nature of the absorptive channels, and about the factors determining the involvement of the alternative pathways of absorption referred to above. The studies on CSF absorption in PTCS, particularly those using infusion techniques as discussed in Chapter 7, have shown an increase in Rout, but to what extent this is primary and to what extent secondary is not clear. So, in summary, with regard to CSF absorption, it is not known what proportion of CSF absorption occurs through the arachnoid villi, either in normal or abnormal circumstances, what effect increased CSF pressure has on the function of the

250

Figure 10.4

Experimental studies

Diagrammatic representation of Tripathi’s hypothesis of a cycle of vacuolation effecting CSF transfer. (From Tripathi, 1968; with permission.)

absorptive channels, and to what degree recruitment of alternative absorptive pathways is pressure dependent. What effect does raised CSF pressure per se have on cranial venous outflow tract pressure?

This has become an issue of particular relevance in PTCS, both theoretically with respect to mechanism, and practically with respect to therapy. In theory, cerebral venous pressure should remain above CSF pressure, and cranial venous sinus pressure should be independent of CSF pressure but dependent on right atrial pressure (Davson, 1967). Experimental studies on this matter have been somewhat conflicting. To some extent, variations may be attributable to the cause of the increased CSF pressure, and to differences between species in the precise anatomy of the cranial venous sinus system. For example, in the dog the torcula herophili and the transverse sinuses are encased in a bony channel which shields these structures from direct pressure effects. These sources of possible variation were addressed in part in the study by Johnston and Rowan (1974) who measured cortical vein pressure (at a point adjacent to entry into the superior sagittal sinus),

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Theoretical considerations

superior sagittal sinus pressure, and jugular bulb pressure in baboons subject to three different types of ICP increase: cisterna magna infusion, expansion of a supratentorial suddural balloon, and expansion of an infratentorial subdural balloon. With all three methods of ICP increase, cortical vein pressure rose progressively with increasing CSF pressure (Figure 10.5). Jugular bulb pressure remained low in all three groups, although there was a slight increase in the cisterna magna infusion group. The major difference between the three methods was seen in superior sagittal sinus pressure which, in three of the six animals in the cisterna magna infusion group, rose substantially with increasing ICP (Figure 10.6). It is, of course, the cisterna magna infusion model which most closely simulates the raised ICP of PTCS. Langfitt et al. (1966) also found an increase in sagittal sinus pressure with increased ICP due to a subdural balloon in rhesus monkeys. Other, earlier studies have shown variable results, as discussed in the review by Owler et al. (2005). In a relatively recent study, Jones and Gratton (1989), using rats of different ages subject to cisterna magna infusion, found that changes in transverse sinus pressure in response to increased CSF pressure were age-related, being most marked in young rats and diminishing to very little with increasing age. So, to the species differences noted above, age must be added as a potentially important factor, and this has a possible clinical correlate in the differing effects of venous outflow tract compromise in humans, i.e. hydrocephalus in infants/young children, PTCS in older children and adults.

Figure 10.5

Cortical vein pressures (CoVP) during progressive increase in ICP by three different means. (a) Cisterna magna infusion. (b) Inflation of a supratentorial subdural balloon. (c) Inflation of an infratentorial subdural balloon. (From Johnston and Rowan, 1974; with permission.)

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Experimental studies

Figure 10.6 Superior sagittal sinus pressures (SSP) during increasing ICP. (a) Cisterna magna infusion (n ¼ 6). (b) Inflation of a supratentorial subdural balloon (n ¼ 6). Data from all experiments in each group. (From Johnston and Rowan, 1974; with permission.)

There are several clinical studies of cranial venous outflow tract pressures in humans with different conditions causing raised CSF pressure: hydrocephalus (Shulman et al., 1964; Greenfield & Tindall, 1965; Shulman & Ransohoff, 1965; Norrell et al., 1969; Sainte-Rose et al., 1984); extracerebral haematoma (Osterholm, 1970); cerebral tumour (Martins et al., 1974a). These are apart from the studies in PTCS itself, for example those of Ray and Dunbar (1950, 1951), Janny et al. (1981), King et al. (1995, 2002), and Karahalios et al. (1996), considered further below and also in Chapters 3 and 7. The results of the non-PTCS studies are reviewed in detail by Owler et al. (2005) but, in summary, the findings appear to establish that venous sinus compression, particularly involving the transverse sinuses, is a possible, but not invariable, accompaniment of increased CSF pressure, that in hydrocephalus, for example, venous sinus obstruction may be primary and causative or secondary and consequent (SainteRose et al., 1984), and that the increase in venous outflow tract pressure can, at least in some cases, be reversed by relief of the increased CSF pressure. The situation is, then, closely similar to that which appears to obtain in PTCS; that is, some cases have a primary increase in cranial venous outflow tract pressure which might be expected to have an adverse effect on CSF absorption which might be partially compensated for by an increase in Pcsf, some cases have a secondary rise in cranial venous outflow tract pressure due to compression caused by the raised CSF pressure, and some cases will have no change in cranial venous outflow tract pressures. The practical questions are first, whether correction of a cranial venous

253

Theoretical considerations

outflow tract obstruction, even if long-standing, can correct the increase in CSF pressure, and second, whether correction of a secondary increase in cranial venous outflow tract pressure might also contribute to relief of the raised CSF pressure by breaking a vicious circle. How are CBF, CBV and cerebral metabolism affected by increased ICP?

In general terms CBF should be independent of cerebral perfusion pressure (in effect, MAP minus ICP) within the physiological range, and inversely proportional to cerebrovascular resistance (CVR). That is, with increasing intracranial pressure, the compensatory mechanisms available to maintain CBF within the normal range are, first, a decrease in CVR, effected by vascular dilatation in the process of autoregulation, and second, an increase in MAP. These mechanisms should allow preservation of an adequate CBF despite quite considerable increases in CSF pressure, and the clinical evidence is that they do. In PTCS, the few observations that are available suggest that changes in CVR are primary in that there may be little or no blood pressure response to marked increases in ICP (Johnston & Paterson, 1974b). The same may apply to other causes of raised ICP (Matsuda et al., 1979), although the Cushing response is, of course, a well-known clinical and experimental consequence of intracranial hypertension in some instances. There are two recent studies on this issue relating specifically to PTCS. Kabeya et al. (2001), who studied a single patient with PTCS during plateau waves of ICP with marked reduction of CPP using PET scanning with 15O-labelled water, found no reduction in rCBF. However, Lorberboym et al. (2001), using SPECT scanning, found regional perfusion abnormalities in five out of six patients characterized as severe cases of BIH (PTCS) compared to only one out of five patients characterized as mild to moderate cases of BIH (PTCS). The patients in this study were, however, on acetazolamide. The theoretical expectation with regard to CBV is, in general terms, that there should be a compensatory decrease in response to the presumed increase in CSF volume thought to be responsible for the increase in ICP in cases of PTCS. The situation in PTCS is, however, complicated when impairment of cranial venous outflow with increase in cranial venous outflow tract pressure occurs, whether this be primary or secondary. Again, there is very little in the way of direct observation on this point, but what studies there are (considered in Chapter 7) suggest an increase in CBV. As regards cerebral metabolism, obviously once CBF begins to fall with falling CPP in the more extreme forms of intracranial hypertension then one would expect a compromise of cerebral metabolism. The issue, which is of particular relevance to PTCS where raised ICP may be chronic, is whether there are adverse effects on cerebral metabolism in raised ICP despite maintenance of CBF within the normal range by effective autoregulation. There are no clear theoretical

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Experimental studies

expectations on this point, but there is some experimental evidence that adverse metabolic effects may precede any significant fall in CBF (Zwetnow, 1970; Sutton et al., 1987). This has an obvious bearing on a condition such as PTCS where the pathological consequences should be those of raised ICP alone. The slight evidence available from neuropsychological studies does at least raise the possibility of relatively subtle damage to function due perhaps to metabolic disturbances secondary to raised ICP. Does an increase in CSF pressure create pressure gradients within the cranial and spinal compartments and what effects might these have?

In theory, if CSF pressure is increased by a uniformly distibuted increase in volume of one of the intracranial (or intracranial and intraspinal) compartments, then no intracranial or or intraspinal gradients should be created. This is the situation presumed to obtain in PTCS, the increase in volume being in the fluid compartment, either CSF in the CSF spaces alone, or the CSF spaces in free communication with the parenchymal extracellular fluid space. In such circumstances, there should be no gradients and so no brain shift, even if fluid is drained from one compartment, and there should be no ventricular enlargement since no transmantle pressure gradients exist. Theoretically, if the volume increase in the fluid compartment reaches a sufficient level, one might expect to observe compensatory reductions in one or both of the other two compartments, i.e. tissue and CBV. This might be the case in those patients with PTCS who have radiologically demonstrable distension of the subarachnoid space or some degree of ventricular enlargement. Apart from the very occasional report of sudden brain shift with CSF drainage in PTCS (Sullivan, 1991), and the more chronic displacement associated with prolonged lumbar CSF drainage by shunting (Chumas et al., 1993; Johnston et al., 1998), there are no clinical or experimental observations to call these theoretical considerations into question. It would be of interest, however, to study possible pressure-driven movements of fluid, particularly exchange between parenchymal extracellular fluid and CSF, if a satisfactory experimental model of PTCS could be established. Cranial venous outflow obstruction The experimental studies of cranial venous outflow obstruction assume a greater relevance to PTCS now, given the increasing evidence of a more substantial role for such obstruction in the causation of the condition and particularly the development of the new techniques discussed in Chapter 8 for the direct and possibly definitive treatment of at least some of the causes of obstruction. In terms of mechanism, one point of particular importance is that many of the

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Cranial venous outflow obstruction

documented clinical causes of cranial venous outflow obstruction will, in some instances produce PTCS but, in other instances, will result in hydrocephalus. In part, which consequence follows depends on the age of patient at the time of obstruction. For the purposes of the present discussion cranial venous outflow impairment will be considered under the headings of extra-cranial and intra-cranial. Extra-cranial obstruction

There were several early studies of the effects of extracranial occlusion of the cranial venous outflow, recording acute changes in CSF and SSS pressures, the latter typically at the torcular. Thus, Dixon and Halliburton (1914) placed ligatures around the ‘veins from the head as near to the right auricle as possible but without opening the chest’ and measured CSF and SSS (torcular) pressures when these ligatures were tightened in three anaesthetized dogs. After occlusion, the mean SSS pressure rise was from 183.3 to 236.7 and the mean CSF pressure rise was from 151.7 to 165.0, all values in millimetres of saline. The result from one of the experiments is shown in Figure 10.7. Similar, but less pronounced, changes

Figure 10.7

CSF pressure, arterial blood pressure, and cranial venous outflow pressure measured at the torcula in dogs. Tracing shows the effects of compression of the neck veins. (From Dixon and Halliburton, 1914; with permission.)

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Experimental studies

were found with manual abdominal compression. It is notable that control values in all three animals showed a reversal of the normal CSF to SSS pressure gradient. Similar studies were carried out by Becht (1920) and by Weed and Flexner (1933), the latter using manual compression of the neck (i.e. the Queckenstedt test). The order of increase of CSF pressure was around 60% of the increase in venous pressure. More detailed studies were carried out by Bedford in two sets of experiments (Bedford, 1935, 1936). The first was in fully anaesthetized dogs and examined the acute effects of bilateral external jugular vein occlusion. The findings were of an acute rise in both CSF pressure and cranial venous outflow pressure (measured at the torcular) but, as with the earlier studies, the rise in venous outflow pressure was the greater, with reversal of the normal positive CSF to SSS pressure gradient (Figure 10.8). Both pressures fell quite quickly such that the CSF pressure returned

Figure 10.8

The effects of occlusion of the external jugular veins on CSF pressure and venous pressure at the torcular in dogs
occlusion at A and release at B. The ordinates represent either mm of normal saline (CSF and venous pressures) or mmHg (arterial pressure). CSF pressure: continuous line. Venous pressure: interrupted line. (From Bedford, 1935; with permission.)

257

Cranial venous outflow obstruction

to normal levels within 60 min. At that time the torcular pressure was still somewhat elevated and the gradient remained reversed. In the second set of experiments, five dogs who underwent external jugular vein occlusion were studied chronically (Table 10.1). The dogs were killed at intervals of up to 6 weeks. None showed hydrocephalus. As can be seen from the summarizing table, both pressures were elevated initially, but fell as time progressed. The CSF
SSS pressure gradient was reversed in two of five animals immediately, in two of five animals at 24 h, and in one of four animals at 7 days. Davson (1967), in reviewing Bedford’s results, attributed the apparently transient rise in CSF pressure to the effects of anaesthesia, and concluded that chronic extracranial venous outflow occlusion did not lead to a sustained increase in CSF pressure. Nevertheless, in humans undergoing bilateral internal jugular vein ligation associated with radical neck surgery, there was a sustained rise in CSF pressure lasting at least 12 days (Jones, 1951). The figures for mean CSF pressure given in that study were as follows: control 115.5 + 13.4; after 2 h, 388.5 + 86.3; after 12 days, 238.7 + 51.2 (all figures in mmH2O). There are also the results of Bering and Salibi (1959) to be discussed below. The distinguishing feature of the experiments described by Bering and Salibi (1959), also in dogs, was the extent of the venous occlusion in the neck. They describe their method as follows: The occlusion of the cephalic venous drainage was accomplished by ligating and removing a segment of both the internal and the external jugular veins low in the neck proximal to the junction with the facial vein, and bilaterally occluding the condyloid foramen at the base of the skull. This procedure blocks the major venous drainage of the head and the major anastomotic channels to the spinal venous system. One week following this procedure the neck dissection was carried out again, and any veins found were ligated and divided.

Normal values for CSF and SSS pressures were established using five control dogs and ‘similar pressure data from other experiments in the laboratory’. The values were 100 + 1.9 mmH2O for CSF and 88 + 3.6 mmH2O for the SSS. Of the 21 dogs successfully studied by this method, 13 (61.9%) developed Table 10.1. Summary of CSF and SSS pressures taken from Bedford’s study of the chronic effects of external jugular vein occlusion in dogs (Bedford, 1936)

Time from occlusion

Mean CSF pressure (mmH2O)

Mean SSS pressure (mmH2O)

Immediate (5 dogs) At 24 hours (5 dogs) At 7 days (4 dogs)

225.0 233.0 150.0

234.0 232.0 173.8

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Experimental studies

hydrocephalus whilst 8 (38.1%) did not. The first group comprised dogs examined 4 to 68 days after the second ligation and the second group comprised dogs examined 1 to 46 days after the second ligation. The combined data for the two groups is shown in Figure 10.9. The salient features of this study are first, that there was an initial increase of both CSF and SSS pressures to maximum levels, with both pressures subsequently falling over the period of study, and second, that initially the positive CSF to SSS pressure gradient was maintained but quite quickly (approximately 15 days judging by the pooled data) this gradient was reversed. The authors attributed the hydrocephalus which occurred in the majority of animals to either impaired CSF absorption or to increased ventricular pulse pressure. Of particular interest are the pressure findings in six of the eight animals which did not develop hydrocephalus (one of the eight was killed the day after ligation and one had what was considered to be an incomplete ligation). Apropos these six animals, the authors say: ‘All of these animals had significantly elevated CSF and SSS pressures, so that the reason that hydrocephalus did not develop is not entirely clear.’ In fact, these animals would appear to have had a PTCS. Finally, in our own studies, estimations of CSF absorption as well as CSF and SSS pressures were carried out in four dogs at an interval of 5 to 7 days after

Figure 10.9

CSF and SSS pressures in dogs following occlusion of the major cephalic venous drainage routes from the head. The lines represent the mean data from 21 experiments. (From Bering and Salibi, 1959; with permission.)

259

Cranial venous outflow obstruction

bilateral external jugular vein ligation in the neck. All four animals showed a marked and significant (P < 0.01) reduction in CSF absorption comparable to that seen with torcular occlusion (Figure 10.10). There was also an increase in SSS pressure (mean 10.3 + 3.3 mmHg compared to 4.5 + 1.9 mmHg for controls, P < 0.01) but no difference in CSF pressure (mean 8.5 + 3.1 mmHg compared to 8.3 mmHg for controls) or in resistance to CSF outflow (mean 41.9 + 19.9 compared to 42.7 + 9.6 mmHg ml
1 min
1 for controls). None of the animals showed evidence of hydrocephalus, and there was no difference from controls in brain weights or other parameters. Intra-cranial obstruction

There are rather fewer studies of the effects of obstruction of the intra-cranial venous outflow tract on venous and CSF pressures as well as CSF absorption. The majority involve obstruction of the ‘superficial’ component of the venous outflow system rather than the ‘deep’ component. Consideration of the former might start from the detailed study reported by Bedford (1935), already referred to, in which he compared the effects of external jugular vein and transverse sinus occlusion on CSF and venous outflow tract pressures in the dog. In the case of the latter, he occluded both transverse sinuses ‘midway between the torcular and the point at which they are joined by the basal vein’. At this point the author noted that the anterior wall of the sinus was ‘usually ossified’. Compression was with wax.

Figure 10.10 Mean percentage absorption of 111In-DTPA after injection into the cisterna magna in dogs following superior sagittal sinus occlusion at the torcular (n ¼ 5) and bilateral external jugular vein ligation (n ¼ 4). Values represent percentage recovery of injected radionuclide. (From Johnston, 1992.)

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Experimental studies

Obstruction of one transverse sinus had little effect on either proximal sinus or CSF pressure whilst obstruction of both transverse sinuses as described produced a similar effect to bilateral ligation of the external jugular veins (Figure 10.11). The increase in CSF pressure was slightly greater with sinus occlusion whereas the increase in proximal sinus pressure was much greater. In both cases the normal CSF to SSS pressure gradient was reversed and remained so over the period of observation (180 min in the figure given). In fact, the rise in CSF pressure was relatively transient, with a return to normal levels in less than 60 min. Beck and Russell (1946) reported an early attempt to study experimental occlusion of the superior sagittal sinus (SSS) in which they refer to only one previous attempt, that of Bize, in 1931 (cited by Beck and Russell, 1946) in which

Figure 10.11 The effect of occlusion of the transverse sinuses on CSF pressure and torcular venous pressure in the dog. Values and key as for Figure 10.8. (From Bedford, 1935; with permission.)

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Cranial venous outflow obstruction

the torcular was the site of the attempted obstruction by two different methods in two different dogs. Apparently, in neither dog were there any clinical or pathological changes. In the experiments described by Beck and Russell (1946) the middle segment of the SSS was the site of attempted obstruction by several different methods in both rabbits and dogs. Their attempts were essentially unsuccessful and other than documenting the failure of the particular methods used, nothing of consequence emerged from their study. What is of interest in the present context, however, is the opening statement of their article: ‘The experiments to be described were planned to throw light upon the problem of ‘otitic hydrocephalus’.’ Guthrie et al. (1970) studied the chronic effects of torcular occlusion in dogs with a particular focus on whether hydrocephalus resulted. Again, both CSF and proximal sinus pressures were raised, but the increases tended to be sustained over a period of observation ranging from 1 to 29 weeks (Figure 10.12a and b). The mean values given for pre- and post-obstruction pressures were 94 + 33 and 191 + 113 for proximal sinus pressure (P < 0.05) and 117 + 54 and 295 + 189 for CSF pressure (P < 0.05), all values in mmH2O. None of the animals showed evidence of hydrocephalus. In our own experiments (Johnston, 1992), the effects of venous sinus occlusion at the torcular on both CSF and proximal sinus pressures as well as CSF absorption were studied. In one group of five dogs the studies were carried out 5 to 7 days after occlusion of the SSS at the torcular. The mean CSF pressure post-obstruction was not significantly different from the pre-obstruction level (10.0 + 2.9 mmHg compared to a control value of 8.3 mmHg), whereas SSS pressure was significantly increased (13.0 + 3.5 mmHg compared to 4.5 + 1.9 mmHg, P < 0.01). Most striking, however, was the reduction in CSF absorption, measured by the mean recovery of 111In-DTPA over 4 h, in the torcular obstruction group: 15.5 + 9.9% compared to 42.7 + 9.6%, P < 0.01 (Figure 10.10). This reduction was associated with the maintenance of a normal level of resistance to CSF outflow measured by the infusion technique: 38.8 + 7.8 mmHg ml
1 min
1 compared to a control value of 42.7 + 9.6 mmHg ml
1 min
1. There were no changes in other measured parameters. In particular, brain weights were closely similar and there was no evidence of hydrocephalus. In the second series of experiments, also in dogs following occlusion of the SSS at the torcular, the focus was particularly on the CSF outflow resistance in the acute phase. Two groups of dogs were studied, a control group (n ¼ 5) and a torcular occlusion group (n ¼ 8). Measurements were carried out in both groups prior to torcular occlusion and repeated in both groups after torcular occlusion in that group. After torcular occlusion, SSS pressure exceeded CSF pressure in seven of the eight dogs studied. All five control animals had a normal CSF to SSS pressure gradient at both sets of readings.

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Experimental studies

Figure 10.12 (a) Sagittal sinus pressures after torcular block in 10 dogs. (b) CSF pressures after torcular block in 10 dogs. (Both diagrams from Guthrie et al., 1970; with permission.)

263

Vitamin A

The median RCSF before torcular occlusion was 112 mmHg ml
1 min
1 and that after torcular occlusion was 122 mmHg ml
1 min
1, the difference being insignificant (P 4 0.05). There are even fewer studies of the effects of occlusion of the ‘deep’ component of the cranial venous outflow tract despite the early claim that such obstruction was a cause of hydrocephalus (Dandy & Blackfan, 1914; Dandy, 1919). In these initial studies, several clinical cases were cited which were taken to be instances of hydrocephalus consequent upon obstruction of the vein of Galen/straight sinus. In an experimental study in 10 dogs, this channel was occluded at different points and examination for hydrocephalus carried out after 3 to 3.5 months. Only one of the dogs had some degree of hydrocephalus, this being the dog with the most proximal occlusion. On this basis, the claim was made that obstruction at a proximal point in the ‘deep’ component of the venous outflow tract could produce hydrocephalus by causing an increased production of CSF by the choroid plexus due to a change in venous pressure. Although support came from the study of Guleke (1930), Bedford’s detailed study, which included a careful review of the clinical cases cited by Dandy as well as a repeat of the original method of occlusion in 47 dogs who were examined after an interval of 3 to 6 months from the surgery, found no evidence of hydrocephalus in any of the dogs (Bedford, 1934). Bedford attributed the hydrocephalus described in the earlier reports (Dandy & Blackfan, 1914; Guleke, 1930) to ‘some form of meningo-encephalitis which has led to an obstruction of the normal circulation of CSF at the base of the brain’. The subject was revisited by Hammock et al. (1971) who studied 16 rhesus monkeys and six dogs and found no evidence of hydrocephalus when these animals were examined at various times from the immediate post-operative period to 6 months after occlusion. The only changes noted were dilatation of the major draining sinuses and cortical veins on angiography and microscopic dilatation of diencephalic and choroidal vessels. These changes were apparent after all intervals post-occlusion. Finally, on the question of changes in CSF dynamics with occlusion of the ‘deep’ component of the venous outflow tract, the case described by Kollar et al. (2001) of the development of PTCS following embolic occlusion of the vein of Galen in the treatment of a vein of Galen malformation is worthy of note. This patient was successfully treated with acetazolamide. Vitamin A The relationship of altered vitamin A levels to PTCS is somewhat complex, the complexity involving the relationship of the clinical findings to the experimental studies. As detailed in the chapter on aetiology, although both hyper- and hypo-vitaminosis A have an established association with PTCS, the great majority

264

Experimental studies

of reported cases have been connected with the former. Moreover, several recent clinical studies have found other evidence possibly relating PTCS to altered vitamin A metabolism. Thus, Jacobson et al. (1999a) studied serum retinol and retinyl ester in 16 women with IIH (PTCS) using 70 healthy young women as controls. The serum retinol level was significantly higher in the IIH (PTCS) group (752 mgl
1 compared to 530 mgl
1), although retinyl ester levels were no different. They corrected for obesity and also excluded the possibility of differences in vitamin A ingestion. Selhorst et al. (2000) also studied serum retinol as well as retinol-binding protein (RBP), comparing 58 IIH (PTCS) patients with 40 controls for the former and 30 IIH (PTCS) patients with 17 controls for the latter. Their findings were less conclusive in that although mean serum retinol levels were higher in the IIH (PTCS) group the difference was not significant, whilst for RBP, seven of the IIH (PTCS) patients had high levels compared to none of the controls. Finally, Warner et al. (2002), who studied vitamin A levels in CSF using high-pressure liquid chromatography in three groups of patients, those with IIH (PTCS), those with raised ICP from other causes, and those with normal ICP, found significantly higher concentrations of vitamin A in the CSF in some of the IIH (PTCS) group only. The non-human studies, in contrast, make a strong correlation between hypo-vitaminosis A and raised CSF pressure due to altered CSF dynamics whereas hyper-vitaminosis A is less well studied and also the findings are more variable, including an association with low CSF pressure. The several early reports linking hypo-vitaminosis A with high CSF pressure in different species including pigs, dogs, calves and lambs have been reviewed by Millen and Woollam (1958). In Mellanby’s (1939) study, young dogs deprived of vitamin A had CSF pressures nearly twice as high as those in animals receiving the vitamin. Moore and Sykes (1940) attributed the increased CSF pressure noted in calves to increased bone growth. Following these initial reports in animals, the matter was studied in detail by Millen and Woollam and their colleagues (Millen et al., 1953, 1954; Millen & Woollam, 1958; Woollam & Millen, 1956, 1958) in both rabbits and chicks. In the second of these studies, they reported their findings in 51 young rabbits born to dams fed a vitamin A deficient diet. Of the 51 rabbits examined, 47 had hydrocephalus. Further, there was no evidence of a structural abnormality underlying the hydrocephalus, in particular the earlier finding of possible aqueduct stenosis was not confirmed. They speculated that the hydrocephalus might have been due to over-production of CSF but there was no specific evidence on this point. In their 1956 article they also reported CSF pressures in 16 rabbits born to vitamin A-deficient dams that did not develop hydrocephalus. In these animals the CSF pressure ranged from 170 to 500 mmH2O. Further,

265

Vitamin A

when vitamin A was fed to deficient animals, there was a rapid reduction in CSF pressure. When they repeated their experiments in chicks there was no hydrocephalus, but the mean CSF pressure in the deficient birds was 174.28 compared to 141.31 mmH2O in controls. As mentioned above, the authors attributed the increased CSF pressure to over-production of the fluid but this was only speculation. In fact, in the discussion to their 1958 article, Mitchell raised the possibility of decreased absorption which, in the light of subsequent studies, seems the most likely cause (vide infra). In other studies, Rokkones (1955) reported the results of prolonged feeding of female rats with a vitamin A-deficient diet. In the first litter born to vitamin A deficient rats, there was a high incidence of increased CSF pressure without hydrocephalus whilst in subsequent litters hydrocephalus did occur. Subsequently, Moore (1957) reported that if vitamin A was withdrawn from the diet of calves they developed raised CSF pressure over a time period dependent on their initial vitamin A reserves and that, in fact, in calves, an elevated CSF pressure was the earliest specific change attributable to vitamin A deficiency. These findings were confirmed by subsequent studies which also included pigs (Nelson et al., 1964; Calhoun & Woodmansee, 1968). Thus, in the latter study, withdrawing vitamin A acid from vitamin A deficient calves (<2 mg100 ml
1) resulted in an increase of average CSF pressure from 282 mm saline to 534 mm saline over 21 days. They found also that the increased CSF pressure could be restored to normal levels by feeding vitamin A/carotene to the depleted animals. Similar results were given in a briefly reported study by Kazarskis et al. (1978) in rats. The possible mechanisms initially considered (Dehority et al., 1960) included increased production of CSF, reduction of the CSF spaces due to the faulty bone growth characteristic of vitamin A deficiency, and impaired CSF absorption. Several studies, but particularly those of Calhoun and his associates using a ventriculo-cisternal perfusion technique, demonstrated conclusively that the cause of the increased CSF pressure was impaired CSF absorption (Okamoto et al., 1962; Calhoun et al., 1967). There was some evidence that the impaired absorption was due to (or at least associated with) structural changes in and adjacent to the arachnoid villi. For example, Hayes et al. (1971) examined the arachnoid villi of calves with hypo-vitaminosis A and found some fibrosis of the interstitium associated with increased collagen and accumulation of PAS-positive electron dense debris in the villi. They were also of the view that arachnoid fibroblast activity was stimulated by vitamin A deficiency. Curiously, in view of the preponderance of hyper- over hypo-vitaminosis A in clinical cases of PTCS, the animal studies of the former showed, in some instances at least, a reduction rather than an increase in CSF pressure, both in calves

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Experimental studies

(Hazzard et al., 1964; Calhoun et al., 1965; Hurt et al., 1967), and in pigs and dogs (Hurt et al., 1966). Using a ventriculo-cisternal perfusion technique to compare six calves with hyper-vitaminosis A to eight controls, Hurt et al. (1967) found lower CSF pressures in the treated animals, in association with rates of CSF formation that were significantly lower. Moreover, bulk flow and bulk absorption tended to increase at a greater rate with an increase in imposed cisternal outflow pressure in the vitamin A excess group. In deliberating on the possible action of vitamin A excess in increasing CSF pressure, Fishman (2002) referred to two experimental studies on aquaporins (Manley et al., 2000; Badaut et al., 2002) and suggested that vitamin A might act to increase CSF volume and pressure by an effect on the aquaporins present in the membranes of the choroid plexus that control CSF secretion. He writes: Although it is possible that vitamin A intoxication might decrease pressure-dependent absorption of CSF by arachnoid villi, the ability of acetazolamide to reduce choroidal secretion, and the role of transthyretin in the transport of vitamin A, makes the choroid plexus the more likely locus for the toxic effect.

However, these speculations are based on clinical evidence of hyper-vitaminosis A causing increased CSF pressure and do not take into account the experimental evidence of the opposite effect. It should be mentioned, however, that in some early studies of vitamin A excess, focused on the occurrence of developmental defects generally, there were instances of hydrocephalus (Millen & Woollam, 1958). Clearly, further investigation of CSF dynamics and pressure changes in both hypo- and hyper-vitaminosis A would be well worthwhile in relation to the pathophysiology of PTCS. First, it would appear on present evidence that hypo-vitaminosis A might, in fact, be an excellent experimental model of PTCS, particularly in animals with arachnoid villi, and particularly if the elevation of CSF pressure is sustained without development of ventricular enlargement. Such a model, if confirmed, would allow detailed analysis of fluid distribution not only in the CSF-containing spaces but also in the brain parenchyma, as well as investigation of associated phenomena such as changes in venous outflow tract pressures which might be secondary to the increased CSF pressure. In addition, more detailed studies of structural changes in the arachnoid villi would be warranted. Second, attention should be given to the apparent discrepancy between laboratory and clinical findings in relation to hyper-vitaminosis A. The apparent preponderance of hyper- over hypo-vitaminosis A as a cause of clinical PTCS quite probably reflects nothing more than the greater clinical incidence of the former generally, but the discrepancy still needs to be explained more fully.

267

Steroids

Steroids At much the same time as reports began to appear detailing the efficacy of steroids in the treatment of PTCS (e.g. Paterson et al., 1961), reports also began to appear identifying prolonged steroid administration and steroid withdrawal after prolonged administration as causative factors in this condition (e.g. Benson & Pharaoh, 1960; Walker & Adamkiewicz, 1964). These initial findings on both aspects were borne out by subsequent studies as outlined in the chapters on aetiology and treatment. So steroids, particularly agents such as prednisone/ prednisolone and beta/dexamethasone, were at once causative and curative in PTCS. In attempting to clarify how steroids could have these apparently conflicting effects, and the bearing of the various findings on the basic question of the disease mechanism in PTCS, two areas of experimental work will be considered: the effects of steroids on CSF dynamics and the effects of steroids on cerebral oedema. Steroids and CSF dynamics

There is strong experimental evidence that steroids can bring about a significant reduction in CSF formation. Early studies were carried out by Weiss and Nulsen (1970), Sato et al. (1973), and Martins et al. (1974b). More recently, LindvallAxelsson et al. (1989), using a ventriculo-cisternal perfusion technique, found a 43% reduction in the rate of CSF secretion in rabbits after treatment with systemic betamethasone. This was associated with a small reduction in Naþ
Kþ-ATPase in the choroid plexus. Similar, but more detailed, findings were reported by Pollay (1992) who studied the effects of both intravenous and intraventricular dexamethasone on CSF formation in rabbits, finding a significant and dose-related reduction with both routes of administration (maximum values of 40% and 26%, respectively). The only reported laboratory study of the effect of steroids on CSF absorption, which also included an examination of the effects of steroid withdrawal after administration, is that of Johnston et al. (1975a). In this study, three groups of dogs were examined: controls (group 1), dogs given 125 mg of cortisone acetate per day in divided doses and 100 mg of hydrocortisone immediately prior to anaesthesia (group 2), and dogs also given cortisone acetate (125 mg daily) which was stopped abruptly after 4 weeks (group 3). In this last group each dog was studied 6 to 8 days from the last steroid dose. There were six dogs in each group. The three main parameters (or group of parameters) measured were as follows (see also Table 10.2). Measurement of CSF absorption

CSF absorption was measured by estimating the recovery of 111In-DTPA. After acute steroid withdrawal, radionuclide recovery was significantly less than

268

Experimental studies Table 10.2. CSF absorption, resistance to CSF outflow, and other parameters in anaesthetized dogs

Parameter CSF absorption (%)a Rcsf (mmHg ml-1 min-1) Mean ICP (mmHg) Mean SSS (mmHg) ICP
SSS gradient PaCO2 (mmHg) Brain weight (g) Ventricular index

Group 1, control

Group 2, on steroids

Group 3, steroid withdrawal

42.7 (+ 9.6) 42.7 (+ 9.6) 8.3 (+ 3.9) 4.5 (+ 1.9) 3.8 (+ 2.5) 36.0 (+ 3.4) 83.0 (+ 2.0) 0.75 (+ 0.25)

31.3 (+ 11.0) 40.2 (+ 10.6) 5.3 (+ 3.2) 4.3 (+ 3.4) 0.8 (+ 1.1) 37.4 (+ 3.1) 82.4 (+ 6.2) 0.60 (+ 0.28)

21.7 (+ 9.5)b 71.7 (+ 18.4)b 8.2 (+ 5.5) 3.4 (+ 0.8) 4.8 (+ 4.9) 33.6 (+ 1.6) 81.3 (+ 5.6) 0.53 (+ 0.28)

Group 1 ¼ controls (n ¼ 6), group 2 ¼ on steroid treatment (n ¼ 6), group 3 ¼ after steroid withdrawal (n ¼ 6). a CSF absorption is expressed as the percentage of injected isotope recovered over 4 h. b Indicates statistically significant results (P < 0.01).

in the control group, 21.7% compared to 42.7%, and was less also in group 2 (still on steroids) although for this group the difference was significant only over the first 2 hours. Patterns of radionuclide distribution in the photoscans were similar in all three groups; that is, initial concentration in the cisterna magna, followed by passage through the basal cisterns, and then over the posterior aspects of the cerebral hemispheres. Little of the radionuclide passed over the convexities of the cerebral hemispheres or down the spinal canal. The rate of radionuclide clearance from the cisterna magna and its subsequent passage through the subarachnoid space was noticeably slower in the steroid withdrawal group. Resistance to CSF absorption

Resistance to CSF absorption was measured using an infusion technique. Values corresponded closely in the control group and the group still on steroids with mean values of 42.7 mmHg ml
1 min
1 and 40.2 mmHg ml
1 min
1 respectively. After acute steroid withdrawal there was a marked increase in resistance to CSF flow, with values ranging from 65 to 94 mmHg in five of the six animals, the remaining animal having a value within the normal range. Statistically there was a significant difference between the steroid-withdrawal group (group 3) and the other two groups 1 and 2 (P < 0.05). There was no difference between groups 1 and 2.

269

Steroids

Intracranial pressure and other parameters

Mean values for ICP corresponded closely in the control and steroid-withdrawal groups (groups 1 and 3) being 8.3 and 8.2 mmHg, respectively. No group 3 animals had frank intracranial hypertension although two did have ICP levels of 15 mmHg. The group still on steroids (group 2) had a lower mean ICP (5.3 mmHg). Sagittal sinus pressures were similar in all three groups although slightly lower in group 3. The mean pressure gradient between CSF and superior sagittal sinus was similar in groups 1 and 3 but was lower in group 2 reflecting the lower ICP. Brain weights were closely similar in the three groups so there was no suggestion of brain oedema. Analysis of results

In analysing the results of these experiments it must be remembered, as discussed above, that the primary factors controlling CSF absorption are the CSF
superior sagittal sinus (SSS) pressure differential and the resistance to CSF flow across the absorptive channels (Davson et al., 1970). Other, secondary factors, such as the rate of CSF production, the chemical composition of the CSF, and the general patency of the subarachnoid space, as well as the involvement of other possible outlet paths, are undoubtedly also significant. In these experiments, both chronic steroid administration and acute withdrawal of steroids after chronic administration caused a reduction in CSF absorption, the effect being more marked after steroid withdrawal. However, the mechanism behind the reduced absorption appeared to differ in the two situations. Thus, chronic steroid administration caused only a slight reduction in the CSF
SSS pressure gradient and no change in the CSF outflow resistance. This suggests an effect on one of the secondary factors, possibly CSF production given the experimental results outlined at the start of this section. On the other hand, acute steroid withdrawal caused a marked increase in resistance to CSF outflow but did not alter the CSF
SSS pressure gradient. Mention should be made here of a preliminary study of the effect of steroids on CSF outflow resistance in PTCS patients reported by Mann et al. (1979, 1983). In their study, 10 patients with PTCS were found to have an increased resistance to CSF absorption and an increased resting CSF pressure compared with four controls using a CSF infusion test. In 2 of the 10 PTCS patients the infusion test was repeated after 4 weeks of steroid treatment (prednisone 40 mg/day) and in both cases there was a marked reduction in CSF outflow resistance and a decrease in resting CSF pressure of approximately 100 mmH2O.

270

Experimental studies

Steroids and cerebral oedema

Although early experimental studies appeared to show a beneficial effect of steroids on cerebral oedema (Taylor et al., 1965; Long et al., 1966), a finding borne out by clinical experience, the mechanism of action has not been clearly identified. There is also evidence that different types of cerebral oedema may respond differently to steroid administration. In vasogenic oedema, for example in cerebral tumours or inflammatory conditions, the oedema formation is secondary to increased vascular permeability. One possible mechanism of steroid action is through inhibition of phospholipase A2 when inflammation is involved (Ohnishi et al., 1990). More recently, with increased understanding of the molecular factors involved in the mechanisms of capillary permeability, there is evidence to suggest that expression of genes for proteins responsible for maintaining tight junctions between endothelial cells, namely occludin, claudin 1 and claudin 5, is reduced in vasogenic cerebral oedema. Steroids have been shown to increase expression of these proteins as well as decreasing phosphorylation of occludin, thus decreasing vascular permeability (Underwood et al., 1999; Antonetti et al., 2002; Romero et al., 2003). Steroids may act through such a mechanism in PTCS. Inhibitors of CSF secretion A number of drugs which fall into this category, including steroids considered separately above, have been used in the treatment of PTCS. In addition, the effects of these drugs and their mechanisms of action have implications for theories of the mechanism of PTCS and so offer possible avenues for further experimental studies. The main drugs studied to date are listed in Table 10.3, taken from Davson and Segal (1970). The most important of these drugs/groups of drugs will be considered individually below. Acetazolamide (DiamoxÕ )

Several studies on a range of species have demonstrated a consistent effect of this drug on CSF secretion attributed to its action as a carbonic anhydrase inhibitor. It is the best known of this group of drugs as far as its effect on CSF secretion is concerned and is, of course, quite widely used in the treatment of PTCS. In no small part its attraction as a therapeutic agent in PTCS is due to the fact that the drug is very well tolerated by mammals, including man, so that doses causing over 99.9% inhibition of the enzyme, carbonic anhydrase, can be used (Davson & Segal, 1996). Early studies (Tschirgi et al., 1954; Kister, 1956) demonstrated a reduction of CSF pressure by acetazolamide which was taken to be due to a reduced rate of

271

Inhibitors of CSF secretion Table 10.3. Experimental data on the effect of various substances on CSF secretion in rabbits and rats (from Davson & Segal, 1970)

Species

Inhibitor

Rabbit

Control Diamox Ouabain Diamox þ ouabain Spirolactone Amiloride Amphotericin Vasopressin Choline chloride 18% CO2 Puromycin Actinomycin Cycloheximide

Rat

Control Diamox

Number

Secretion rate (ml min-1)

Inhibition (%)

Significance (P)

23 10 6 7 5 8 10 8 6 5 5 5 5

12.9 + 0.7 4.6 + 1.1 5.8 + 0.7 4.0 + 0.5 3.7 + 0.8 6.4 + 0.9 3.8 + 0.8 6.4 + 0.7 9.6 + 1.1 10.0 + 1.6 11.0 + 1.0 12.7 + 1.4 10.4 + 1.4

64 55 69 71 50 70 50 26 22 0.3 0.9 19

0.001 0.001 0.001 0.001 0.001 0.001 0.001 0.05 0.1

6 3

2.1 + 0.9 0.9 + 0.1

57

0.02

0.2

formation, measuring the latter by the rate at which fluid dripped from a cannula in the subarachnoid space. More detailed studies, using ventriculo-cisternal perfusion techniques in rabbits (Davson & Pollay, 1963; Pollay & Davson, 1963) and dogs (Oppelt et al., 1964), confirmed the reduction of CSF secretion/ formation which was of the order of 40
50% of the normal rate. In the dog studies, the related drug methazolamide gave an even greater reduction. Combinations of acetazolamide and other drugs did not significantly enhance the inhibitory effect of the former (Davson & Pollay, 1963). Subsequently, this effect of acetazolamide was also demonstrated in man (Rubin et al., 1966). Finally, it has also been shown that acetazolamide quite substantially increases the effect of urea in reducing CSF pressure (see Figure 10.13) (Reed & Woodbury, 1962). Cardiac glycosides

These substances are thought to act through inhibition of Naþ
Kþ-ATPase which is critical for the action of the Naþ
Kþ exchange ‘pump’ in that it catalyses the hydrolysis of ATP. Ouabain is the most studied of this group of drugs but it does have toxicity problems that acetazolamide does not have. Nonetheless, these problems were overcome in ventriculo-cisternal perfusion studies

272

Experimental studies

Figure 10.13 Effect of acetazolamide on change in CSF pressure induced by urea. (From Reed and Woodbury, 1962.)

allowing demonstration of a reduction of CSF secretion from 55% in the rabbit (Davson & Segal, 1970) to effectively 100% in the cat (Brøndsted, 1970). Later studies in which the toxic effects of ouabain were blocked with propranolol showed 87% and 68% reduction of CSF secretion in rabbit and dog respectively (Pollay et al., 1985). Frusemide

This drug also acts as a carbonic anhydrase inhibitor and has an inhibitory effect on CSF secretion, although this effect is less marked than that of acetazolamide (Vogh & Langham, 1981), i.e. reductions of 23% and 56% with doses of 30 mg kg-1 for frusemide and 50 mg kg-1 for acetazolamide. These authors found that acetazolamide, frusemide and bumetanide had decreasing degrees of affinity for carbonic anhydrase, that of acetazolamide being 17
40 times greater than that of frusemide whilst that of frusemide was, in turn, 7 times greater than that of bumetanide. Davson and Segal (1996) suggest that frusemide and bumetanide may act to reduce CSF production by blocking the Naþ þ Kþ þ 2Cl
transport system. Other drugs

Two other drugs which have been studied are amiloride (a diuretic) which effected a 50% reduction in CSF secretion when studied by Davson and Segal (1970), and omeprazole, a drug which reduces gastric secretion, and which brought about a 35% reduction in CSF secretion in the study by Lindvall-Axelsson et al. (1992) using a ventriculo-cisternal perfusion technique in rabbits.

273

Conclusions

Conclusions The most important point to emerge from this review of experimental studies relevant to PTCS is that three of the factors most securely linked with the causation of the condition
cranial venous outflow occlusion, vitamin A and steroids (at least during withdrawal after chronic adminstration)
have been shown to bring about an increase in CSF pressure which is in some instances sustained, and which is associated with impaired CSF absorption. The first two of these factors may also cause hydrocephalus and the results of the experimental studies suggest that whether this or PTCS occurs depends largely on the magnitude of the applied ‘insult’. In the case of cranial venous outflow occlusion, this duplicates the clinical findings (Owler et al., 2005). In the case of vitamin A, one notable point is that whilst experimental studies producing increased CSF pressure + hydrocephalus have predominantly been with vitamin A deficiency, the clinical occurrence of PTCS is predominantly in association with vitamin A excess. This needs to be explained, especially in the light of some experimental evidence linking vitamin A excess with low rather than high CSF pressure. In the case of steroids, the situation is more complex as, indeed, is the clinical relation to PTCS. What the experimental studies have shown is that steroids will produce a reduction in CSF formation, will reduce cerebral oedema, and will also affect CSF resistance, at least when withdrawn after prolonged usage. It must be borne in mind, however, that the actual amount of experimental data is small (in some instances very small), is not always consistent, and is in some cases quite old, meaning that methods of analysis are not necessarily as good as they would be now. There is reason, then, to undertake further studies with these three factors, and perhaps with others such as tetracycline and its derivatives, and to extend the analysis of their demonstrated effects on CSF dynamics, in an attempt to resolve some of the questions raised in the present chapter. In particular, it would be important to establish the degree of increase in CSF volume and its determinants, and where it is accommodated, as well as examining secondary issues such as compensatory mechanisms for the presumed increase in CSF volume, and alterations of cerebral haemodynamics and brain metabolism caused by the increase in CSF pressure. The second point of importance concerns the experimental studies of the inhibition of CSF secretion/formation. The findings as detailed above seem unequivocal. Several agents, acting as carbonic anhydrase inhibitors or on other components of the active transport systems, will effect a substantial reduction of CSF formation. Moreover, some (notably acetazolamide) will do so at doses that can cause almost complete inhibition of the enzyme yet are well tolerated without significant toxic consequences. The obvious question apropos PTCS is why these drugs are not more effective as therapy. Again, this is a question that directs

274

Experimental studies

attention to some of the fundamental issues of CSF dynamics, especially the relative contributions of the choroid plexus, where the drugs are known to be active, and other sources in the formation of CSF. Certainly, the studies outlined in the present chapter should be pursued and their range extended, not only for the light they may throw on the mechanism of PTCS and the information they may provide regarding treatment of the condition, but also as a contribution to the elucidation of some of the more fundamental issues of CSF dynamics touched on above.

11

Conclusions

Historical background PTCS has been a well-recognized and clearly defined nosological entity for over a century despite its rather bewildering array of names. The two developments which were particularly instrumental in its identification were the invention of the ophthalmoscope by von Helmholtz and the introduction of lumbar puncture by Quincke. Although it has become conventional to date the recognition of the syndrome from the reports by Quincke and Nonne between 1893 and 1914, there were clearly other, and perhaps more precise, descriptions that antedated the reports of the two German neurologists. Three salient features which emerge from the historical survey in Chapter 2 are: 1. A consistent and readily recognisable clinical picture has existed throughout the period from Quincke and Nonne to the present, although it has often been described, with good reason, as a diagnosis of exclusion. 2. A definite group (albeit an expanding one) of causative factors has been identified, the main ones from the time of the earliest recognition of the syndrome itself. 3. It is a condition with a favourable outcome apart from the risk of the long-term adverse effects of papilloedema. Mechanism of PTCS What has been a problem is the failure to identify the basic mechanism of the condition, which has resulted in on-going difficulties with classification and nomenclature. The weight of evidence, as marshalled in Chapter 3, clearly favours the concept of PTCS as a disorder of CSF hydrodynamics, most probably of absorption, although questions do also remain regarding formation and circulation. The one thing that has prevented the accumulated evidence from being decisive is the continuing failure to demonstrate an actual increase in CSF volume 275

276

Conclusions

and to reveal where excess fluid is accommodated. What is required to settle this issue, given the obvious limitations of clinical studies, is the establishment of a satisfactory experimental model which would allow detailed analysis of CSF circulation using perfusion techniques, of cerebral blood volume and its distribution, and of brain water content and its exchangeability with the CSF compartment. The wherewithal to achieve such an objective almost certainly exists, given the recognition of several generally accepted causative factors which could be employed to create the condition in a suitable experimental animal, and the availabilty of the methodology to make the necessary assessments. Nomenclature Once the mechanism of the syndrome is established, rational solutions to the problems of classification and nomenclature become possible. The argument advanced in the present monograph has been that it is appropriate, on presently available evidence, to accept an inclusive approach to classification. Inclusive in the sense that under the rubric ‘pseudotumor cerebri syndrome’ (PTCS) should be included all cases presenting with a more or less pure clinical picture of intracranial hypertension, without clouding of consciousness, without any evidence of a structural intracranial mass lesion, without ventriculomegaly, but with the presumption of reduced CSF absorption. This last might be attributed generally to an imbalance in the relationship which is generally accepted as describing CSF absorption; that is, CSF absorption is directly proportional to the difference between the CSF pressure and the superior sagittal sinus pressure, and inversely proportional to the resistance across the arachnoid villi. The syndrome will then include cases in which the numerator is reduced due to elevation of the superior sagittal sinus pressure, and cases where the denominator is increased due either to primary changes in the arachnoid villi or physical changes in the CSF. Other factors possibly operative are secondary changes in CSF or superior sagittal sinus pressure in response to primary changes in either pressure, and the involvement of other channels of CSF absorption. What brings these cases, of obviously disparate aetiological possibilities, under a single heading is that all are instances of impaired CSF absorption at the point of transfer of CSF into the venous compartment, as distinct from hydrocephalus where the problem may be anywhere proximal to this point, and that there is, in broad terms, a similar approach to therapy, and a similar outcome. In naming such a condition an appropriately inclusive term should be adopted. The condition as defined in the present monograph is closely analagous to hydrocephalus in that it is a syndrome with a multiplicity of accepted aetiological

277

Aetiology

factors (some, notably, shared) operating through the same basic mechanism. There is also, as with hydrocephalus, a significant group of cases for which no clear aetiology can be identified, although the size of this group will, in part, depend on how diligently the investigation of possible aetiological factors is pursued. Of all the many terms so far adopted, our view is that pseudotumor cerebri or PTCS remains the most satisfactory. This view finds support in the fact that it is the one enduring term, and that even now, the coercive endeavours of certain journal editors notwithstanding, it is the most commonly used term in the literature. Of the other two terms commonly in use
idiopathic intracranial hypertension (IIH) and benign intracranial hypertension (BIH)
the initial epithet is, in both instances, exceptionable for the reasons considered. Perhaps the most suitable solution would be an eponymous term recognising the initial descriptions of Quincke and Nonne, but the time has probably passed for that. Aetiology In attempting to summarize what is known of the aetiology of PTCS, and to make sense of the long lists of putative aetiological factors that appear in many articles on the condition, this monograph included, two initial assumptions will be made. The first is that the idea of idiopathic syndrome is untenable because many cases labelled as IIH have not been sufficiently investigated to exclude a demonstrable causative factor. The second is that the reported case
control studies which appear to exclude every documented cause apart from obesity in women are too small and too selective with respect to the cases included to be accepted as in any way definitive. In what follows, then, the bases for inclusion in any list of possible aetiological agents are a long association with descriptions of the syndrome, a theoretical or experimental link with abnormal CSF hydrodynamics, and reversibility if the putative cause is withdrawn or eliminated. On these grounds, the factors that qualify, at least provisionally, as being aetiologically important in PTCS are as follows, divided into two groups depending on whether CSF absorption is reduced by increased cranial venous outflow pressure, or by increased resistance to absorption. 1. Factors increasing venous outflow pressure. Venous sinus thrombosis, occlusion due to external compression, or venous hypertension without obstruction. Examples of factors that fall into this category are conditions predisposing to thrombosis such as various haematological disorders, some infections, exogenous oestrogens, possibly abnormal levels of endogenous oestrogens which may be related to obesity, diseases such as SLE and Behc¸et’s disease, sinus compression by neoplasms and trauma, surgical interference with cranial venous outflow, intracranial AVMs which may be parenchymal delivering high

278

Conclusions

flow into one of the major sinuses or dural associated with sinus thrombosis, and high right atrial pressures from whatever cause. 2. Factors increasing CSF outflow resistance. These may be further divided into a first group of factors that might be presumed to affect the outflow channels themselves such as abnormal vitamin A levels and related compounds, corticosteroids, and possibly tetracycline and its derivatives as well as nalidixic acid, and a second group which adversely affect the rheological properties of the CSF, such as excess protein and/or cell associated with the Guillain
Barre´ syndrome, poliomyelitis, spinal cord tumours and the chronic meningitides. Familial cases may also fit into this overall group in that there may be a population which fall between the extreme of those few cases with frank hydrocephalus due to deficient or abnormal arachnoid granulations and the vast majority of people with normal absorptive channels. Such a population might have some members who develop the disease without any additional factors and some who are prone to develop PTCS when exposed to some of the known causative factors which are normally tolerated uneventfully. Clearly there is much that is speculative in this formulation, and clearly also there are many factors linked with PTCS in the literature that are not included. The latter indicates that the connection of the particular agent with PTCS is considered too tenuous on the basis of present evidence. Clinical picture The clinical picture of PTCS is readily characterized. It is, typically and predominantly, a presentation with the symptoms of intracranial hypertension (headache, disturbances of vision, nausea and vomiting, and sometimes tinnitus) accompanied by the appropriate signs (papilloedema, abnormalities of visual acuity and visual fields, and unilateral or bilateral VIth nerve palsy). Other less common symptoms and signs may also occur and have been listed in Chapter 6. In infants, the presentation is one of an abnormal rate of head growth with an abnormal head circumference, together with a full or tense anterior fontanelle, and possibly irritability. It has been argued in the earlier chapters that too strict a limitation to these symptoms and signs is not desirable. Thus other symptoms and signs may be acceptable within the diagnosis, especially if these are attributable to a causative factor in the PTCS. Notable examples are cases of PTCS secondary to cranial venous outflow impairment, to chronic meningitis, or to conditions associated with an elevated CSF protein. Other departures from the typical presentation must also be borne in mind, particularly where there is absence of one or more of those features that are commonly seen. Two particular examples are first, cases who have headache only without papilloedema and the visual

279

Treatment

disturbances which may accompany it, and second, asymptomatic cases who are found to have papilloedema on routine examination. Clinical investigations The focus in investigating patients suspected of having PTCS has remained more or less the same since the condition was first clearly recognized: to confirm the presence of raised CSF pressure and to exclude other possible causes of raised CSF pressure, most notably an intracranial mass lesion. What has changed over the years is the way these objectives are achieved. The cornerstones now are exclusion of another lesion by MR scanning with gadolinium followed by measurement of CSF pressure on lumbar puncture, using simple manometry supplemented as necessary by continuous pressure monitoring from a lumbar or cranial site, and possibly fluorescein angiography. Other important primary investigations include detailed documentation of visual status and analysis of CSF composition. If a cause of the PTCS is being sought then MRV and MRA, as well as retrograde cerebral venography with manometry are important, as well as a thorough haematological investigation, particularly if there is evidence of cranial venous outflow compromise. One issue of importance is how far to pursue the search for a possible cause of PTCS in the individual patient once the primary diagnosis is established. The basis of this decision should be the severity of the disease weighed against the invasiveness of any proposed investigation. A further point of importance is the acceptance or otherwise of abnormalities in investigations in making the diagnosis of PTCS. The position taken in the present monograph is that certain abnormalities are permissible within the diagnosis of PTCS under certain circumstances; specifically, a normal CSF pressure, an abnormal CSF composition, and abnormalities on imaging if these are directly related to the presumed cause of the PTCS or are incidental. Treatment The treatment of PTCS remains somewhat unsatisfactory insofar as all the methods available currently are bedevilled by either a relatively high failure rate, or a high complication rate, or both, and by the absence of any methodologically satisfactory studies comparing the different treatments. It is no surprise that the Cochrane Systematic Review has been critical of the absence of any randomized controlled trials. Currently, there are eight therapeutic options: 1. Expectant management with or without correction of a presumed causative factor 2. CSF drainage (by serial LPs, by continuous lumbar drainage, or by shunting)

280

Conclusions

3. 4. 5. 6. 7.

Cranial decompression, specifically bilateral subtemporal decompression Optic nerve sheath decompression Direct treatment of cranial venous outflow obstruction Weight reduction (by diet, or by surgical means) CSF formation inhibiting drugs (carbonic anhydrase inhibitors, cardiac glycosides) 8. Corticosteroids The first five methods listed have been in use, to varying degrees and in varying forms, since the first years of recognition of the condition. The last three listed methods are of more recent introduction but date back around 50 years, so recent decades have seen refinement of pre-existing methods rather than the introduction of new methods. The key to selection of the most appropriate treatment option in the individual patient is the assessment of the severity of the PTCS in that patient, based on the severity of symptoms, the severity of papilloedema, and on the detailed evaluation of visual function. Broadly, there are two categories of patients: 1. Those with mild/moderate disease in whom correction of a presumed cause, weight reduction and CSF formation inhibitors (a 3 to 6 month course) are the appropriate treatment options in that order assuming careful visual follow-up. 2. Those with severe disease and deteriorating vision in whom medical management is failing For this second category the Sydney group would use steroids and a 5- to 7-day period of continuous lumbar CSF drainage. In Cambridge, such patients are usually referred after medical management and multiple lumbar punctures have failed. Thereafter, in both centres, the options are CSF shunting, optic nerve sheath decompression, correction of venous outflow obstruction by venous sinus stenting, subtemporal decompression and weight reduction surgery. The choice amongst these should be determined by the particular circumstances. For example, CSF shunting is appropriate if both headache and visual deterioration are major factors, ONSD if visual problems predominate and local expertise is available, venous sinus stenting if a clear-cut abnormality can be demonstrated that does not resolve completely with CSF drainage, STD if other methods are beset by complications or are ineffectual, and weight loss surgery if there is extreme obesity and visual deterioration is not rapid. It is essential to include a neurologist expert in headache management as part of the multidisciplinary team, both before and, particularly, after surgical intervention. Some patients have persistent headache after successful resolution of their papilloedema and intracranial hypertension. What is required, difficult though it is to achieve, is some sort of methodologically sound study of the relative merits of these methods which

281

Outcome

would allow a more rational selection of a particular treatment option. To this end a first step would be a registry of all cases in a population akin to the United Kingdom Shunt Registry which could provide the baseline data on which a useful series of randomized controlled trials could be mounted. What is even more desirable is the development of a more definitive form of treatment, one that is relatively free of complications, but this will probably need to await elucidation of the basic disease mechanism.

Outcome In considering outcome in PTCS, it is possible to strike a note of restrained optimism. First, with current methods of investigation a secure diagnosis is the expectation, so the likelihood of some other, more sinister abnormality subsequently coming to light is now vanishingly small. Second, it should be possible to provide adequate relief of headache assuming there is no other contributory cause. Third, it should be possible to at least stabilize vision, and in a good proportion of patients in whom vision is impaired at presentation, to effect an improvement in either VA or VF, or both. Fourth, the likelihood of recurrence is relatively low, probably of the order of 10%, although this figure will vary depending on whether cases with a return of PTCS immediately after premature cessation of treatment, or with shunt obstruction in shunted cases, are included. Despite these favourable factors, some areas of concern remain. Foremost among these is the incidence of permanent loss of vision. The data on the true incidence of this remain unsatisfactory. A conservative figure would be around 10
20% of cases, but the figure may be significantly higher depending, in part, on how assiduously VF abnormalities are pursued. Further detailed studies on this point are required. Then there are the complications of the various treatment methods, particularly if one or more of the several surgical options are required. There is also the possibility of cognitive and psychological consequences, especially if the disease runs a prolonged course, which is an aspect requiring much more detailed consideration and study. So the optimism referred to above must be tempered with concern in view of these potentially adverse factors. Finally, what issues most clearly remain to be addressed with regard to PTCS? • Elucidation of the disease mechanism is a fundamental requirement, with a better understanding not only of the primary process itself, but also of other pathophysiological consequences such as effects on regional cerebral blood flow, reactivity, and brain metabolism. • Establishment of a satisfactory experimental model. It would seem that the means are available, given the known aetiological factors.

282

Conclusions

• Ideally, on the basis of a clear understanding of mechanism, agreement should be reached on the definition of the disease, its classification, and the knotty problem of nomenclature. • Order needs to be imposed on the burgeoning list of putative aetiological agents. Given the incidence and nature of the condition, the objective of proper case
control studies is always going to be hard to achieve. However, a realistic aim might be to take a more critical approach to acceptance of postulated aetiological factors, and to make more vigorous efforts to understand the mechanism of action of those agents that seem bona fide. • Whilst the current means of investigation might be accepted as satisfactory, it would be desirable to have a clear policy on investigative strategy, particularly how far to pursue possible causative factors. • Improvements are clearly needed in treatment which might come from the development of a new method with high success and low complication rates, based on a better understanding of disease mechanism, or through refinements in existing methods. Also, in developing a rational approach to treatment selection it would be highly desirable to have some methodologically sound studies of the treatment options currently available. • Finally, although the condition once enjoyed the epithet ‘benign’, there should be increased awareness of the possible long-term consequences of what is, in many patients, a long-term condition, with better documentation of visual and neuropsychological sequelae.

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66.

Index

Aarskog’s syndrome 100 acetazolamide (Diamox) 4, 27, 196–8, 229 historical background in PTCS 17 inhibition of CSF secretion 270–1 Addison’s disease 23, 110 adrenal disease 110 aetiology of PTCS 23, 25, 82–5, 277–8 individual factors cranial venous outflow tract compromise 99–104 endocrine disorders 108–12 familial factors 98–9 female-specific factors 93–8 haematological disorders 104–7 head injuries 113–14 infections 112–13 nutritional disorders 119–20 other diseases and conditions 115–18 vitamins, drugs and chemicals 120–4 overview 85 case control and related studies 89–91 Glasgow and Sydney series 85–8 large series (1954
1988) 88–9 recent developments 91–2 all-trans-retinoic acid (ATRA) 92, 106, 122 amenorrhoea, link with PTCS 9 amiloride 272 amiodarone 124 anaemia 104, 105 angiography 32–4, 166–7 digital retrograde venous angiography (DRVA) 175 MR studies (MRA) 173 anti-coagulant therapy, systemic 223–4 antiphospholipid antibodies 185 apnoea, during sleep 139 arachnoid villi 2 Arnold
Chiari malformation 218, 221, 222 arsenic trioxide 106 average combined venous conduit score (ACCS) 173 balloon angioplasty 225 Behc¸et’s disease 102, 115–16, 223, 228

351

benign intracranial hypertension (BIH) 2, 20, 24, 62, 68 betamethasone 201, 267 blood dyscrasias 102 bone marrow transplantation (BMT) 106 brain imaging studies 31–2 brain parenchyma 48–50 brucella meningitis 66, 113 bumetanide 272 carbonic anhydrase 272 cardiac diseases that may lead to PTCS 116–17 cardiac failure 19 cardiac glycosides, inhibition of CSF secretion 271–2 cases histories of PTCS group I 78 group II 78 group III 79 group IV 80 ceftriaxone 113 cerebral blood flow (CBF) 34–5 effect of increased intracranial pressure on 253–4 investigations for PTCS 182–3 cerebral blood volume (CBV) 34–5, 50–2, 57 effect of increased intracranial pressure on 253–4 investigations for PTCS 182–3 cerebral metabolism 253–4 cerebral oedema 56 effects of steroids 270 cerebral pseudotumor 15 cerebrospinal fluid (CSF) absorption 248 experimental studies 267 composition abnormalities 43–4, 65 investigations for PTCS 158–9 distribution MR studies 170–2 effect of steroids 267 laboratory study 267–9 failure of absorption 18

352

Index cerebrospinal fluid (cont.) formation 247 increased volume nomenclature and terminology 61–2 infusion studies 37–8, 159–61 involvement in PTCS 52–3 associated conditions 53 clinical measurements 52 direct observations 52 theoretical considerations 53 therapeutic considerations 53 pressure 4, 248, 249 continuous monitoring for PTCS 151–8 effect of pressure gradients on cranial and spinal compartments 254 effect on CBF, CBV and cerebral metabolism 253–4 effect on cranial venous outflow pressure 250–3 investigations for PTCS 149–50 persistent elevation 240–1 Pouisouille equation 249 rhinorrhoea 139 secretion inhibitors 270 acetazolamide 270–1 cardiac glycosides 271–2 frusemide 272 shunting 4, 28, 214, 217, 230 complications 218–19 Glasgow series 214 removal 220–2 revisions 217–18 shunted cases 214–16 Sydney series 214 types of shunt 216–17 Chiari malformation 222 children, clinical features of PTCS 145–16 chlordexone 240 chlorothiazides 27 chlorthalidone 199 chlorthiazide 199 cholesteatoma 102 chronic intracranial hypertension 44 chronic meningitis 44 chronic respiratory disease 19 ciprofloxacin 124 cisternal CSF shunts 216 classification of PTCS 1
primary pseudotumor cerebri syndrome (Primary PTCS) 70 no recognised cause 71 recognised precipitating cause 71 2
secondary pseudotumor cerebri syndrome (Secondary PTCS) 70 abnormal CSF composition 65 extracranial venous outflow impairment 73–4 intracranial venous outflow impairment 72–3 3
atypical pseudotumor cerebri syndrome (Atypical PTCS) 70 infantile PTCS 75–6

normal CSF pressure 70 symptoms/signs/both absent 74 4
pseudo-pseudotumor cerebri syndrome (Pseudo PTCS) 70 normal volume hydrocephalus 71–2 occult mass lesion 76–7 claudins 270 clinical features of PTCS 1, 26, 127, 278–9 aspects of diagnosis 146–7 atypical presentations 137–9 asymptomatic PTCS 137 CSF rhinorrhoea 139 headache without eye signs 138 other presentations 139 sleep apnoea 139 children 145–6 duration of symptoms and signs 232–4 incidence, age and sex distribution 127–31 males 145 presenting clinical signs 139–45 extraocular movement abnormalites 142 optic atrophy 142 other signs 144 papilloedema 141 reduced visual acuity 142 restriction of visual fields 143 presenting symptoms 131–9 diplopia 133 headache 132 nausea and vomiting 134 obesity and menstrual irregularity 135 other symptoms 134 tinnitus 134 visual disturbances 133 clinical investigations see investigations communicating hydrocephalus (CH) 45 computed tomography (CT) scanning 168–9 concussion 12 confocal scanning laser ophthalmoscopy (CSLO) 163 corticosteroids 23 cranial venous outflow effect of CSF pressure 250–3 impairment 5 investigations for PTCS 175–80 obstruction 40–1 experimental studies 254–5 treatment 222–3, 230 tract compromise 99–104 cryptococcal meningitis 66, 113 Cushing’s disease 111 cyclosporin A 106 cytarabine hydrochloride 106 danazol 90, 124, 240 Dandy criteria 26, 60, 63–4, 113 criterion 1
raised ICP 64–5 criterion 2
absence of focal neurological signs 65 criterion 3
increased CSF pressure 65 criterion 4
normal CSF composition 65–6 criterion 5
normal imaging studies 66–7

353

Index criterion 6
no identifiable cause 67 criterion 7
benign clinical course 67 dexamethasone 201, 202, 267 diabetes mellitus 112 diagnosis of PTCS 146–7 see also Dandy criteria diagnostic error 242–4 evidence from literature 243 Glasgow series 244 Sydney series 244 elimination of other conditions 62 Diamox see acetazolamide digital retrograde venous angiography (DRVA) 175 digoxin 199, 228 diplopia 133 diuretics 24 as treatment for PTCS 198–9 dizziness 134 doxycycline 123 dural AVMs 102 electroencephalography (EEG) 164–5 emphysema 19, 116 encephalography 167–8 encephalopathy addisonienne 24 endocrine disorders predisposing to PTCS 108–12 endocrine disturbances 41–2 endovascular techniques for PTCS 225–8 enzyme deficiencies that may lead to PTCS 117–18 epidemiology 3 epidemiology of PTCS 25 incidence, age and sex distribution 127–31 e´tats hypertensifs 14 e´tats me´ninge´s hypertensifs 61 ethinyl oestradiol 90 evidence from pathology 38–9 experimental studies 246 conclusions 273–4 cranial venous outflow obstruction 254–5 extracranial obstruction 255–9 intracranial obstruction 259–63 inhibitors of CSF secretion 270 steroids 267–70 theoretical considerations 247–54 CSF absorption 248 CSF formation 247 CSF pressure 248–53 vitamin A 263–6 calves as subjects 265–6 rabbits and chicks as subjects 264–5 extracranial venous outflow impairment 73–4 extraocular movement abnormalites 142 eyes and vision, signs and symptoms involving see also papilloedema diplopia 133 extraocular movement abnormalites 142 ophthalmological investigations 161 optic atrophy 142 optic nerve disorders 10 optic neuritis 9, 10 orbits MR studies of contents 172–3

papilloedema 161–3 reduced visual acuity 142 restriction of visual fields 143 visual disturbances 133 visual field assessment 163–4 factor V Leiden 185 familial cases 44 familial factors predisposing to PTCS 98–9 female-specific factors menarche 94 menstrual irregularity 94 oestrogens, exogenous 95–6, 102 polycystic ovary syndrome (PCOS) 96–8 predisposing to PTCS 93–4 pregnancy 94–5 fluorescein angiography 162, 163 Glasgow series 162 frusemide 198, 199, 272 furosemide 27 Glasgow series 93 age range of PTCS sufferers 129 angiography 166 CSF composition 158 CSF pressure, continuous monitoring 151 CSF shunting 214 diagnostic error 244 duration of symptoms and signs of PTCS 232 fluorescein angiography 162 incidence of PTCS 128 lumbar puncture 150 outcomes 242 recurrence of PTCS 238 subtemporal decompression 205 ventriculography/encephalography 167 glucocorticoids 24 glycerol 198, 199 growth hormone (rhGH) 92 replacement therapy 109, 240 Guillain
Barre´ syndrome 19, 44, 57, 65, 66, 113 haematological and related abnormalities 43 haematological investigations for PTCS 183–5 head injuries leading to PTCS 113–14 headache 132, 138 historial background of PTCS 6–9, 275 Period 1
first descriptions (1866
1896) 9–11 Period 2
definition of a syndrome (1897
1904) 11–13 Period 3
pre-neuroradiological (1904
1936) 13–17 Period 4
radiology and new treatments (1937
1970) 17–24 Period 5
modern period (1971
2005) 24–9 hydrocephalus, communicating see communicating hydrocephalus hydrocephalus, ‘external’ or ‘toxic’ 18 hydrocephalus, normal volume see normal volume hydrocephalus hydrocephalus, otitic see otitic hydrocephalus hydrocephalus, rhachitical 10

354

Index hydroflumethazide 199 hydropisie me´ninge´e 14 hyper- and hypo-vitaminosis A see under vitamin A (retinol) hyperparathyroidism 19 hypertension, benign intracranial see benign intracranial hypertension hypertension, idiopathic intracranial see idiopathic intracranial hypertension hypertension, intracranial see intracranial hypertension hypertension, intracranial 57 hypertensive meningeal hydrops 2, 18, 22, 61 hypoparathyroidism 111 hypothyroidism 109 idiopathic intracranial hypertension (IIH) 2, 3, 26, 61, 62, 68 idiopathic macrocephaly 55 indomethacin 228 infections that may lead to PTCS 112–13 intracranial hypertension 1 intracranial hypertension, benign see benign intracranial hypertension intracranial hypertension, idiopathic see idiopathic intracranial hypertension intracranial tumours 12 intracranial hypertension 57 of unknown cause 22 intracranial venous outflow impairment 72–3 intracranial/CSF pressure effects of steroids 269 monitoring 36–7 investigations for PTCS 27, 148–9, 187–8, 279 angiography 166–7 cerebral blood flow and volume studies 182–3 cranial venous outflow tract studies 175–80 CSF composition 158–9 CSF infusion studies 159–61 CSF pressure 149–50 continuous monitoring 151–8 CT scanning 168–9 electroencephalography (EEG) 164–5 haematological investigations 183–5 lumbar puncture 150–1 metabolic and endocrine studies 185–7 MR techniques 170 angiography (MRA) 173 brain water and CSF distribution 170–2 orbital contents 172–3 standard static MR 170 venography (MRV) 173–5 ophthalmological investigations 161 papilloedema 161–3 radionuclide studies 180–2 skull X-rays 166 ventriculography/encephalography 167–8 visual field assessment 163–4 leukaemia 105 leuprorelin 124 lithium carbonate 90, 124

lumbar percutaneous CSF shunts 216 lumbar puncture 4 historical background 7 investigation for PTCS 150–1 treatment for PTCS 192–5, 229 lumbar valved CSF shunts 216 Lyme disease 113 magnetic resonance (MR) techniques 170 angiography (MRA) 173 brain water and CSF distribution 170–2 orbital contents 172–3 standard static MR 170 venography (MRV) 173–5 males, clinical features of PTCS 145 Marchiafava
Micheli syndrome 107 mastoiditis 101, 112 mechanisms leading to PTCS 1, 2, 25, 30–1, 57–9, 275–6 clinical evidence angiography and venography 32–4 brain imaging studies 31–2 cerebral blood flow and volume studies 34–5 CSF infusion studies 37–8 evidence from pathology 38–9 intracranial/CSF pressure monitoring 36–7 radionuclide studies 35–6 intracranial compartments 47–8 brain parenchyma 48–50 cerebral blood volume 50–2 CSF 52–3 possible related conditions communicating hydrocephalus 45 infantile macrocephaly 46–7 normal volume hydrocephalus 45–6 putative causal factors cranial venous outflow obstruction 40–1 CSF composition abnormalities 43–4 endocrine disturbances 41–2 familial cases 44 haematological and related abnormalities 43 obesity 42–3 steroid administration and withdrawal 40 vitamin A excess and deficiency 39–40 theoretical considerations 54–7 men, clinical features of PTCS 145 menarche 94 meningioma 102 me´ningites vrais 14 meningitis, brucella 66 meningitis, cryptococcal 66 meningitis, syphilitic 66 meningitis serosa 61 menstrual irregularity 94, 135 mesalazine 124, 240 methylprednisolone 201 middle ear disease 101, 112 historical background of PTCS 13, 15, 16 minocycline 90, 123 myeloma 106

355

Index nalidixic acid 90, 124, 240 nausea 134 neck stiffness 134 nitrofurantoin 124 nitroglycerin 124 nomenclature of PTCS and related conditions 1, 26, 61, 276–7 alternative terms 67–9 diagnostic elimination 62 eponymous terms 63 increased CSF volume 61–2 specific terms 62–3 Nonne’s disease 13 nosology of PTCS 60–1 nutritional disorders that may lead to PTCS 119–20 obesity 42–3, 135 weight reduction 199–201 occludin 270 ocreotide 228 oestrogens, exogenous 95–6, 102 ‘old theories’ of PTCS 24 ‘old therapies’ for PTCS 24 omeprazole 272 ophthalmological investigations 161 papilloedema 161–3 visual field assessment 163–4 ophthalmoscope 6, 11 optic atrophy 142 optic nerve disorders 10 optic nerve sheath decompression (ONSD) 4, 28, 208–14, 229 historical background 10 optic neuritis 9, 10 orbitotomy 209 otitic hydrocephalus 2, 13, 16, 20, 21, 61 otitis media 12, 15–17 ouabain 271 outcomes 4, 232, 244–5, 281–2 CSF shunting 217 diagnostic error 242–4 duration of symptoms and signs 232–4 Glasgow series 242 persistent elevation of CSF pressure 240–1 psychological and psychiatric sequelae 241–2 recurrence 238–40 Sydney series 243 visual function 235–8 overall summary 235–6 papilloedema 236–8 PaCO2 50 papilloedema 19, 141, 236–8 historical background in PTCS 9, 10, 15, 16, 18 investigations for PTCS 161–3 penicillin 124 perhexilene maleate 124 phenytoin 240 phospholipase A-2 270 Pickwickian syndrome 116 pituitary tumours 108 plasma homocysteine 185

platelet disorders 104, 106 POEMS 106 poliomyelitis 44, 57, 113 polycystic ovary syndrome (PCOS) 95–8 polycythaemia vera 19, 104, 106 Pouisouille equation 249 prednisolone 201, 202, 267 prednisone 201, 267 pregnancy 94–5 propranolol 272 prothrombin index 72 pseudo-brain abscess 15, 62 pseudo-meningitis 9, 62 pseudotumor cerebri (PTC) 61, 62 pseudotumor cerebri syndrome (PTCS) definition 69–70 nomenclature 61, 68, 80–1 psychiatric disorders that may lead to PTCS 117 purpura 9, 16 radionuclide studies for PTCS 35–6, 180–2 recurrence of PTCS 238–40 Glasgow series 238 Sydney series 238 reduced CSF absorption syndrome 61 renal disease that may lead to PTCS 116 respiratory diseases that may lead to PTCS 116–17 retinoic acid, all-trans (ATRA) 92, 106, 122 retinoids 90 retinol see vitamin A retinol-binding protein (RBP) 264 rhachitical hydrocephalus 10 rhinorrhoea 139 sequelae of PTCS 5 serous meningitis 2, 11, 13 shunt types cisternal 216 lumbar percutaneous 216 lumbar valved 216 ventricular 217 signs and symptoms 1, 26 see also clinical features aspects of diagnosis 146–7 atypical presentations 137–9 asymptomatic PTCS 137 CSF rhinorrhoea 139 headache without eye signs 138 other presentations 139 sleep apnoea 139 children 145–6 Dandy criteria 63 criterion 1
raised ICP 64–5 criterion 2
absence of focal neurological signs 65 criterion 3
increased CSF pressure 65 criterion 4
normal CSF composition 65–6 criterion 5
normal imaging studies 66–7 criterion 6
no identifiable cause 67 criterion 7
benign clinical course 67 duration 232–4

356

Index signs and symptoms (cont.) males 145 presenting clinical signs 139–45 extraocular movement abnormalites 142 optic atrophy 142 other signs 144 papilloedema 141 reduced visual acuity 142 restriction of visual fields 143 presenting symptoms 131–9 diplopia 133 headache 132 nausea and vomiting 134 obesity and menstrual irregularity 135 other symptoms 134 tinnitus 134 visual disturbances 133 sinography 19 skull X-rays 166 sleep disorders that may lead to PTCS 117 sleep apnoea 139 slit-ventricle syndrome 46, 57 spinal cord tumour 44, 57 steroids 23, 27, 90, 122–3, 240 administration and withdrawal 40 experimental studies 267–70 cerebral oedema 270 CSF dynamics 267–9 effects on intracranial pressure 269 treatment for PTCS 201–5, 229 streptokinase 225 subtemporal decompression (STD) 4, 28, 205–8, 230 Glasgow series 205 Sydney series 206 superior sagittal sinus (SSS) pressure 54, 72 experimental occlusion 260 surgical treatments for PTCS 224 Sydney series 93 age range of PTCS sufferers 129 angiography 166 CSF composition 158 CSF pressure, continuous monitoring 155 CSF shunting 214 diagnostic error 244 duration of symptoms and signs of PTCS 232 lumbar puncture 150 outcomes 243 recurrence of PTCS 238 subtemporal decompression 206 ventriculography/encephalography 167 syphilitic meningitis 66, 113 syringomyelia 218, 221, 222 systemic lupus erythematosus (SLE) 102, 115 tetracycline 90, 123–4, 240 thyroid disease 109 thyroid replacement medications 90 tinnitus 134 topiramate 228

torcular epidermoids 102 toxic external hydrocephalus 61 treatments for PTCS 2, 4, 27, 189–90, 228–31, 279–81 acetazolamide 4, 27, 196–8, 229 historical background 17 cranial venous outflow obstruction 222–3, 230 CSF shunting 4, 28, 214, 217, 230 complications 218–19 shunt removal 220–2 shunt revisions 217–18 shunted cases 214–16 types of shunt 216–17 diuretics 198–9 effect of no treatment 191–2, 229 endovascular techniques 225–8 lumbar puncture 4 historical background 7 optic nerve sheath decompression (ONSD) 4, 28, 208–14, 229 historical background 10 other treatments 228 serial lumbar punctures 192–5, 229 steroids 27, 201–5, 229 subtemporal decompression (STD) 4, 28, 205–8, 230 surgery 224 systemic anti-coagulant therapy 223–4 venous by-pass techniques 224–5 weight reduction 199–201 Turner’s syndrome 111 urea 199 urokinase 225 vein of Galen 100 venography 32–4 MR studies (MRV) 173–5 venous by-pass for PTCS 224–5 venous obstruction 51 ventricular CSF shunts 217 ventriculography 167–8 visual acuity, reduced 142 visual disturbances 133 visual field assessment 163–4 visual field, restriction of 143 vitamin A (retinol) 23, 90, 120–2, 240 excess and deficiency 39–40 experimental studies 263–6 calves as subjects 265–6 rabbits and chicks as subjects 264–5 hypervitaminosis 5, 120, 264 hypovitaminosis 5, 120, 122, 264 vitamin D (calciferol) 119 vomiting 134 weight reduction as treatment for PTCS 199–201 X-ray investigations of skull 166

Figure 7.11 Composite photo of optic discs: acute, acute decompensated, chronic and ‘vintage’ papilloedema. (Courtesy of Mr N. Sarkies.)

Figure 10.3 Bulk flow drainage of CSF from the human brain. Arachnoid granulations and villi provide for the bulk flow of CSF from the subarachnoid space into the blood of the venous sinuses. (From Weller, 2005; with permission.)