Twentieth Century Neurology: The British Contribution

Twentieth Century Neurology

Imperial College Press

Twentieth Century Neurology The British Contribution

Twentieth Century Neurology The British Contribution

Editor

F. Clifford Rose London Neurological

Centre, UK

Imperial College Press

Published by Imperial College Press 57 Shelton Street Covent Garden London WC2H 9HE Distributed by World Scientific Publishing Co. Pte. Ltd. P O Box 128, Farrer Road, Singapore 912805 USA office: Suite IB, 1060 Main Street, River Edge, NJ 07661 UK office: 57 Shelton Street, Covent Garden, London WC2H 9HE

British Library Cataloguing-in-Publication Data A catalogue record for this book is available from the British Library.

TWENTIETH CENTURY NEUROLOGY The British Contribution Copyright © 2001 by Imperial College Press All rights reserved. This book, or parts thereof, may not be reproduced in any form or by any means, electronic or mechanical, including photocopying, recording or any information storage and retrieval system now known or to be invented, without written permission from the Publisher.

For photocopying of material in this volume, please pay a copying fee through the Copyright Clearance Center, Inc., 222 Rosewood Drive, Danvers, MA 01923, USA. In this case permission to photocopy is not required from the publisher.

ISBN

1-86094-245-8

Printed in Singapore by Uto-Print

CONTENTS

List of Contributors

ix

Preface

xv

1. Sir Charles Sherrington, O.M., P.R.S. (1857-1952) W.C. Gibson

1

2. Henry Head (1861-1940) Christopher Gardner-Thorpe

9

3. The British Contribution to Aphasiology Klaus Poeck

31

4. The Concept of Hemispheric Lateralisation John Stein

47

5. James Hinshelwood (1859-1919) and Developmental Dyslexia Wilhelmina M.H. Behan

59

6. Wilfred Harris (1869-1960) Eric Nieman

77

7. Sir Gordon Holmes (1876-1965) t Wilder Penfield

87

8. Sir Gordon Holmes: A Personal Reminiscence ^Macdonald Critchley

91

vi

Twentieth Century Neurology — The British Contribution

9. Gordon Holmes' Work on Sensation and His Association with Henry Head ^Ronald Henson 10. Looking and Seeing — Gordon Holmes' 1936 John Mallet Purser Lecture Revisited Christopher Kennard

99

107

11. Kinnier Wilson (1878-1937) and His Books Bryan Ashworth & Ernest Jellinek

115

12. Movement Disorders Kalyan B. Bhattacharyya

129

13. Kernicterus Beryl Corner

153

14. The Watershed of Neurosurgery James R. Heron

169

15. Sir Victor Horsley (1857-1916) Revisited John Lyons

179

16. Neurosurgery in the Nineteen-Twenties and Thirties Boleslav Lichterman

197

17. Neurolathyrism Dan F. Cohn & Diana Paleacu

219

18. From Treponemes to Prions: The Emergence of British Neuropathology Jennian Geddes

227

19. Mitochondrial Myopathies Hannah R. Cock and Anthony H V. Schapira

255

20. British and American Neurologists Meet: London, 1927 Michelle Flye & James Toole

283

Contents

vii

21. The Influence of British Neurology on Harvard Neurology and Vice Versa H. Richard Tyler

291

Index

305

tdeceased

LIST OF CONTRIBUTORS

Bryan Ashworth Consulting Neurologist 13/5 Eildon Terrace Edinburgh EH3 5NL UK Wilhelmina M H Behan MD FRCP (Glas) FRCPath Senior Lecturer Department of Pathology University of Glasgow Western Infirmary Glasgow Gil 6NT UK Dan F Cohn MD Department of Neurology Tel-Aviv Medical Center and Sackler Faculty of Medicine Tel-Aviv University Ichilov Hospital 6 Weizman Street Tel Aviv 64239 Israel

IX

x

Twentieth Century Neurology — The British Contribution

Kalyan B Bhattacharyya MBBS MD DTM&H DM MAMS Associate Professor Department of Neurology Calcutta National Medical College & Hospital 2/V Cornfield Road, Ballygunge Kolkata 700 019 India Hannah R Cock BSc MD MRCP Clinical Lecturer University Department of Clinical Neurology Room 617, Institute of Neurology Queen Square London WCIN 3BG UK Beryl D Corner MD FRCP MD (Hon) Bristol FRCPCh (Hon) Emeritus Consultant Paediatrician Flat 4, Chartley The Avenue Sneyd Park Bristol, BS9 1PE UK tMacdonald Critchley MD FRCP Consulting Neurologist National Hospital (Queen Square) and Kings College Hospital London, UK Christopher Gardner-Thorpe MD FRCP Consultant Neurologist Exeter Neurosciences Royal Devon & Exeter Hospital and Peninsular Medicare School Barrack Road Exeter, EX2 5DW UK

List of Contributors

Michelle Garren Flye American Neurological Association Archives Wake Forest University School of Medicine Medical Center Boulevard Winston-Salem NC 27157 USA Jennian F Geddes FRC Path Senior Lecturer in Neuropathology St. Bartholomew's and The Royal London School of Medicine and Dentistry, Whitechapel London El IBB UK William C Gibson MD(McGill) D Phil(Oxon) 4666 Alpine Road, Portola Valley Callifornia 94028 USA ^ Ronald A Henson Consulting Neurologist Maida Vale and London Hospitals London, UK James R Heron Emeritus Professor of Neurology Willowbrake, Granville Avenue Newcastle- Under-Lyme Staffordshire ST5 1JH UK Ernest H Jellinek Consulting Neurologist 7 Oxgang Road Edinburgh EH10 7BG UK

xi

xii

Twentieth Century Neurology — The British Contribution

Christopher Kennard Professor of Neurology Division of Neuroscience and Psychological Medicine Imperial College School of Medicine Charing Cross Hospital, Fulham Palace Road London W6 8RF UK Boleslav Lichterman Fadeeva sti 5-21 Moscow 125047 Russia John B Lyons Department of the History of Medicine Royal College of Surgeons in Ireland 123 St. Stephen's Green Dublin 2 Ireland Eric Nieman Emeritus Consultant Neurologist 24 Woodside Avenue, Highgate London N6 4SS UK t Wilder Penfield Neurosurgeon, Montreal Neurological Institute Montreal Canada Diana Paleacu Department of Neurology Tel-Aviv Medical Center and Sackler Faculty of Medicine Tel-Aviv University Tel-Aviv 64239 Israel

Klaus Poeck FRCS Emeritus Professor of Neurology Rheinisch-Westfalische Technische Hochschule Pauwels str 30, D52074, Aachen Germany F Clifford Rose London Neurological Centre 110 Harley Street London WIG 7JG UK Anthony H V Schapira Professor and Head Department of Clinical Neurosciences Royal Free Hospital School of Medicine Rowland Hill Street London NW3 2PF UK John Stein University Laboratory of Physiology Parks Road Oxford, OX1 3PT UK H Richard Tyler MD Professor of Neurology Harvard Medical School One Brookline Place Suite 123, Brookline Massachusetts 02146 USA

xiv

Twentieth Century Neurology — The British Contribution

James F Toole President, World Federation of Neurology Department of Neurology Wake Forest University School of Medicine Medical Center Boulevard Winston-Salem, NC 27157 USA '''deceased

PREFACE

On the occasion of the 225th anniversary of the founding of the Medical Society of London in 1773, its Council recommended a Mansell Bequest Symposium on the British contribution to Neurology. In the year 2001, it is apposite to give an account of twentieth century neurology. Neurology has been used in its widest sense to include such neuropsychological topics as aphasiology (Chapter 3), hemispheric lateralisation (Chapter 4) and dyslexia (Chapter 5), as well as neurosurgery (Chapters 14-16) and neuropathology (Chapter 18). Neurogenetics is a rapidly expanding field so that it is appropriate to include an up-to-date account of the development of knowledge in the mitochondrial myopathies (Chapter 19). We felt it appropriate to include three original papers (Chapters 7-9) given in 1976 by distinguished contributors, now deceased, on the occasion of the centennial symposium of Gordon Holmes birth, the leading clinical neurologist of the twentieth century. The close links between the British and the American neurology are shown by the two final presentations (Chapters 20 and 21). Clearly, this volume is not the definitive work on twentieth century British neurology but, with the advent of the new millennium, these original contributions reflect the background to the rapid advances that have taken place in the past 100 years.

F Clifford Rose London 2001

XV

TWENTIEH CENTURY NEUROLOGY The British Contribution © 2001 by Imperial College Press

Chapter 1

SIR CHARLES SHERRINGTON, O. M., P. R. S. (1857-1952) W. C. Gibson

In a life extending over ninety-five years, Sherrington (Fig. 1) was a major influence in the development of the neurological sciences in many countries, though mainly in Britain.

l^iy

Fig. 1. Sir Charles Scott Sherrington (portrait by R.S. Eves, 1997).

/ € . ! W&, 1

2

W. C. Gibson

Even before he received his medical degree from Cambridge, he was drawn into the fierce neurological debate concerning Professor Goltz's demonstration, to the International Medical Congress in London in 1881, of the performance of a dog in which he had removed part of its brain. In true British fashion a committee was set up, under J.N. Langley the Cambridge physiologist. His student, Sherrington, reported on the precise anatomical structures involved, thus launching his career in the realm of scientific publications, a career in which he produced 320 papers. At the same boisterous meeting David Ferrier demonstrated the contralateral effect, on a monkey, of removing part of its brain. (Ferrier was Sherrington's hero, to whom 20 years later he dedicated his Integrative Action of the Nervous System). Thus began in 1881 Sherrington's interest in cerebral localisation of function. A growing interest in pathology next took Sherrington to study with Rudolf Virchow in Berlin. There he had the additional education of seeing Virchow's enemy Bismarck berating the Reichstag (Virchow believed that the ruling family of Prussia consisted of the father who had softening of the brain, the grandfather had hardening of the brain, and the grandson who had no brain at all!) On returning to London, Sherrington was made a lecturer in physiology at St. Thomas' Hospital Medical School. The nerve cells of the mammalian spinal cord occupied much of his research time, along with studies on cerebral circulation, still highly regarded. In four years at St. Thomas', he published a dozen papers. At the same time he served as Honorary Secretary to the Physiological Society. In 1893, he was awarded for his research the Fellowship of the Royal Society. He little realised then that he would be President, in the years 1920-1925, of that prestigious body. His histological work developed in concert with his physiological and he showed in 1894 that the "muscle spindles" of his friend Ruffini were sensory informants of the neuromuscular system. The Purkinje cells of the cerebellum were demonstrated by Golgi Stain. As Foreign Secretary of the Royal Society he invited the rising star of the histology of the nervous system, Santiago Ramon y Cajal of Madrid, to give the Croonian Lecture in London in 1894. There the boutons terminaux, the axonal endings on nerve cell bodies next in the circuit, were superbly

Sir Charles Sherrington, O. M., P. R. S. (1857-1952)

3

shown through silver stains. Cajal had applied these techniques developed in his unsung laboratories in his homeland, cut off by language and the Pyrennees from world science. Some years later, Sherrington was to give the Croonian lecture himself on "The mammalian spinal cord as an organ of reflex action." The Cambridge professor of physiology, Sir Michael Foster, asked Sherrington to take on Part III of the "Textbook of Physiology," on the nervous system. Sherrington wrote of this enormous burden: "I felt the need of some name to call the junction between nerve cell and nerve cell (because the place of junction now entered physiology as carrying functional importance). ... I suggested using "syndesm." He consulted his Trinity friend Verrall, the Euripidean scholar... and Verrall suggested "synapse" (from the Greek "clasp") and as that yields a better adjectival form it was adopted for the book." His appointment to the Chair of Physiology at Liverpool in 1895 gave him an opportunity not only to teach students, but also allowed him to branch out from spinal cord physiology to his early field of cerebal localisation. In this, he was joined for a short period by the rising neurosurgeon from America, Harvey Cushing, who contributed drawings, of high calibre, of the cerebal cortex exposed in primates. Sherrington's major contributions were brought together in his Silliman Lectures at Yale University in 1904, from which his remarkable volume The Integrative Action of the Nervous System was published. Its reception was overwhelming. This volume became the touchstone of neurologists and psychologists for many years. The British clinician, F.M.R. Walshe, said of the volume: "In physiology it holds a position similar to that of Newton's Principia in physics. Here is the imprint of scientific genius." Russell Brain was later to ask: "Is it altogether inappropriate to compare The Integrative Action to De Motu Cordis of Harvey?" On the strength of these lectures, Sherrington was invited to the chair of physiology at the University of Toronto and to that of Columbia University in New York. He elected to stay at Liverpool however. In the nine years following the Yale lectures, he published 77 papers, including his Croonian lecture of 1913.

4

W. C. Gibson

His invitation to Oxford in 1913 was assured when the Regius Professor, the Canadian Sir William Osier, assembled the Board of Electors to the Waynflete Chair. Then began a parade of Medical Rhodes Scholars — Penfield and Davison from Princeton, Holman from Stanford and Kluver and Krige from South Africa. The three Americans' kymograph tracings were used to illustrate Sherrington's "Mammalian Physiology; A Course of Practical Exercises." One reviewer of this entirely new approach faulted the author for using illustrations from British workers only. The workers were his American students! All went on to be professors; Penfield at McGill, Davison at Duke, and Holman at Stanford. In 1920, Sherrington became President of the Royal Society of London and for five years carried this demanding post to great heights, while continuing to inspire his Oxford students, several being Rhodes Scholars: Florey and Eccles from Australia, Miller from Canada, Denny-Brown from New Zealand, and Fulton from America. Of these, Florey and Eccles were to became Nobel laureates, following by some years Sherrington's Nobel Prize of 1932. A Swedish neurophysiologist in the Oxford laboratory, Ragnar Granit, also achieved the Nobel Prize. With Royal Society duties in London and lectures and laboratories in Oxford, his days were hectic. His visitors were legion; some came to talk about his poetry — much of which he wrote while punting on the river. His conversations varied from the financing of the Universities of Oxford and Cambridge to that of the Medical Research Council of Britain on which he was asked by the Prime Minister to serve for two terms. One of his visitors had been a medical student researcher with Alexander Forbes at Harvard; Forbes had been a Sherrington pupil at Liverpool. This visitor to Oxford was Dr. Alan Gregg, the "wise man" of the Rockefeller Foundation. Gregg asked Sir Charles what he saw as Oxford's future. The quiet, diminutive professor replied: "After some hundreds of years of experience we think that we have learned here in Oxford how to teach what is known. But now with the undeniable upsurge of scientific research... we must learn how to teach the best attitude to what is not yet known. We cannot escape this new challenge, nor do we want to."

Sir Charles Sherrington, O. M , P. R. S. (1857-1952)

5

Sherrington's neurological contemporaries, and those more senior, kept in close touch with him. Thus, we find him dining with Charles Ballance in London and there meeting his aging friend, David Ferrier. He reported that Ferrier was "reading Thucidides in the original to enjoy a few months' stay in Sicily the more. I got an interesting account out of him of his original brain experiments that started the modern physiology of the cortex. He was so modest about all that first-rate work, done in a little private room in a Yorkshire asylum, by himself and very little to guide or help him; and the results so clearly and simply set forth in those early papers by him." Ballance later wrote: "It was Ferrier, not any surgeon who was the originator and founder of modern cerebral surgery." A much needed break in Sherrington's too busy life came when he and Cushing were invited to participate in the opening, in 1922, of new buildings for the biological sciences of McGill University in Montreal. The Oxford professor ended his address with the charge "Do not, O my brothers, forget research. Science calls us all to it — and the call is from humanity as well." The 1920s saw the concentration, in Sherrington's laboratory, upon synaptic mechanisms, muscle reflexes and muscle relaxation. At first his equipment was minimal, but the Nobelist A.V. Hill built for him, and delivered to Oxford, a modern stimulator and recording system. He wrote to Hill: "All yesterday we were working with your "stimulator"... . We had power enough for a whole room full of cats." In 1930, the Clarendon Press invited Sherrington to write a book on his laboratory's recent work. So with Eccles, Liddell, Creed, and Denny-Brown, he produced, for publication in 1932, "The Reflex Activity of the Spinal Cord." The final one third of the volume was written by the professor. No sooner had this book appeared than Sherrington was awarded the Nobel Prize, an honour shared with his close friend Edgar Adrian of Cambridge. Since 1902, Sherrington had been recommended for the prize, by 134 scientists, but the nomination was annually blocked by the same committee member until 1932. His Nobel lecture was on "Inhibition as a coordinative factor," going back even to the views of Descartes. Three years later, at the age of 78, he retired from his professorship and built a delightful house near his boyhood town of Ipswich. There he

6

W. C. Gibson

maintained his large correspondence with pupils and others around the world. His writing of poetry continued and he concentrated on his historical and philosophical interests. He had given the Rede lecture at Cambridge on "The Brain and Its Mechanism," at age 76. In 1937 and 1938, he gave his Gifford lectures — 12 in all — at the University of Edinburgh, entitled "Man on His Nature." The pent-up biliary drainage of the professional philosopher was soon to be displayed, but 60 years later, "Man on His Nature" still claims readers, whether they be scientists, theologians or the laity. There are few examples of the English language which surpass Sherrington's wonderful prose in these lectures. The seventh was entitled "The Brain and Its Work," in which he writes of the waking brain: "Swiftly the head mass becomes an enchanted loom where millions of flashing shuttles weave a dissolving pattern... a shifting harmony of subpatterns". A second edition brought forth fewer critics and many more readers. In 1946, Cambridge University Press published his small volume "The Endeavour of Jean Fernel", the early French physiologist and pathologist — the most notable physician-philosopher of the early 16th century in Paris. Before concluding, I might be permitted to inject a personal note. When in October 1935, I arrived at Oxford to be a Demonstrator in Physiology, Sir Charles invited me to tea. He said with gusto, "Yours is the last illegal appointment I have made!"; he talked of Ramon of Cajal's histological techniques which I had come, on Wilder Penfield's recommendation, to apply to Jack Eccles' synaptic studies. Over the ensuing three years, I had opportunities to meet Sir Charles for tea at his favorite library in London at the Royal College of Surgeons. At other times, I visited him at his home overlooking the Valley at Ipswich. There he carried on his correspondence and historical writings in the garden in a wonderful little glass house which rotated with the sun. On the occasion when I drove the refugee Professor Rio-Hortega over to see him, Sir Charles, the ever charming host, produced some Spanish phrases which he had learned in Spain in 1885! In 1951,1 visited Sir Charles who by then was in a nursing home on the South Coast at Eastbourne. Despite his arthritis, he was as jovial as ever. When I told him I had been at the International Poliomyelitis Congress in

Sir Charles Sherrington, O. M , P. R. S. (1857-1952)

7

Copenhagen with 600 doctors he smiled and asked, "Now Gibson, did any good ever come from 600 doctors getting together?" He wanted to know if we, in Vancouver, were keeping green the memory of his great friend of his Cambridge days, Frank Wesbrook, our founding President at the University of British Columbia. I assured Sir Charles I was trying to do that by writing Wesbrook's biography. With that he gave a cheery "good journey home." He died a year later, aged 95, one of the most decorated scientists in history, the recipient of 90 honorary degrees and fellowships.

TWENTIEH CENTURY NEUROLOGY The British Contribution © 2001 by Imperial College Press

Chapter 2

HENRY HEAD (1861-1940) Christopher Gardner-Thorpe

HEAD'S BIRTH AND EARLY LIFE Henry Head1 (Fig. 1) was born2 on 4 August 1861 at 6 Park Road, Stoke Newington, an area of London inhabited by Quakers. His parents were of Quaker stock but joined the Church of England soon after he was born. His father, an insurance broker at Lloyds, was also called Henry Head and was the third son of Jeremiah Head, late Mayor of Ipswich and of Mary Howard his wife. Henry Head's mother was Hester, daughter of Richard Beck and of Rachel (daughter of Samuel Lucas of Hitchin). Richard Beck went into partnership with his uncle Joseph Jackson Lister in a wine business at 5 Tokenhouse Yard in Stoke Newington. Joseph Jackson Lister married Isabella and their first two children were born there, and the other four (including Joseph, later Lord, Lister) were born at Upton Park. Lord Lister (1827-1912) was thus Henry Head's first cousin once removed.3 Henry Head was also related through his mother to E.V. Lucas, the author. The family moved to Stamford Hill where William Morris decorated their house. Head attended two day schools; then at the age of eleven went as a weekly boarder to the Friend's School, Grove House, Tottenham. Head, said his Master, Ashford, was "one of the best teachers of natural science I have ever encountered. To this man I owe the fact that I was firmly grounded in the elements of natural science at an age when boys at an 9

10 C. Gardner-Thorpe

Fig. 1. Henry Head in his later years.

ordinary school in my day were ignorant of the very existence of the subject." At the age of 13 Head was sent to Charterhouse where he received private tuition in dissection and cutting microscopic sections. From an early age he wished to study medicine. UNIVERSITY YEARS Head studied physiology and histology for six months at the University of Halle where he learned German and also at Prague. He introduced soccer to Czechoslovakia.4 After two years he returned in October 1880 to Trinity College Cambridge to complete anatomy and physiology and after a year became a Demonstrator. He intended to become a physiologist. He proceeded BA in 1884 with First Class Honours in both parts of the Natural Science Tripos. In September 1884 he went to Cologne to visit the Austrian physiologist, Heinrich Ewald Hering (1866-1948) who, in 1868, with Breuer had

Henry Head (1861-1940)

11

described the reflex later named the Hering-Breuer Reflex; in 1923, Hering described the nerve named after him which is a branch of the ninth cranial nerve, afferent from the carotid sinus. Head published in German.5 He studied the physiology of respiration, carried out experiments with the vagus, learned histology and listened to Hering's account of research into colour vision. At some time before 1889 Head had designed a cuffed endobronchial tube, well ahead of the general introduction of such tubes into anaesthetic practice in the 1930s. Head described the negative after-action, the inspiratory effort made even after respiration has been stopped by inflation of the lungs of an experimental animal (Head's Paradoxical Reflex).

EARLY MEDICAL CAREER (1890-1904) In 1890 Head qualified in medicine (MRCS) at University College Hospital and became House Physician there. Junior posts followed at the City of London Hospital for Diseases of the Chest and the County Asylum, Rainhill. He proceeded MRCP in 1894 and in 1896 became Medical Registrar at The London Hospital. Within four months he was elected Assistant Physician, a post he held until he became Consulting Physician in 1919. He worked at the National Hospital under Thomas Buzzard but it appears was never appointed to the staff either there6 or at Maida Vale Hospital.7 Head was a natural teacher and like many neurologists mimicked patients' involuntary movements and postures. He used the term neurologist. First Studies on Pain Head's Cambridge MD thesis (1892) was entitled On disturbances of sensation with especial reference to the pain of visceral disease subsequently published in Brain in 1893.8 In 1894 he wrote about pain in dermatomes (Head's Areas) produced by visceral disease after studying herpes zoster9 and later contributed a chapter on this topic to Allbutt's textbook.10 The second edition (1910) contains articles by Head on herpes zoster11 and trigeminal neuralgia.12 He commented on the dermatomal distribution of zoster and on the occasional

12 C. Gardner-Thorpe

manifestations affecting the same myotome as the dermatome. In trigeminal neuralgia he noted how important it is to find the organ in which the pain originates, thus differentiating true nerve-induced pain from end-organ pain masquerading as trigeminal neuralgia. While living at 6 Clarence Terrace in London13 Head was elected to the Fellowship of The Royal Society in 1899.14 He became FRCP in 1900 and continued his interest in general medicine throughout his career. He delivered a Goulstonian Lecture in 190115 on mental changes associated with visceral disease. The Famous Peripheral Nerve Experiment in 1903 From 1901 Head and Sherren had observed patients with injuries of the peripheral nerves and William Halse Rivers Rivers (1864-1922), doctor, psychologist and anthropologist, had been interested in the psycho-physical aspects of the work. Head described in immense detail methods of examination of the sensory system. On 25 April 1903 a human experiment was carried out on a subject named H who was aged 42 and in perfect health. He had always been healthy, had not smoked for two years and did not take alcohol except on holiday. His only wounds had occurred in the post-mortem room. The radial and external cutaneous nerves in Head's left forearm were divided and resutured.16 The observations were published with Rivers. Sensation to cotton wool, pinprick and hot and cold were lost at once but deep pressure was maintained.17 On 25 October 1903 Head had also observed a cabinet maker whose forearm had been cut by a broken window. The external cutaneous and superficial radial nerves had been cut and Head observed the changes in sensation until the patient's last visit on 11 September 1905. Head and Rivers believed that protopathic and epicritic nerve fibres had separate evolutionary significance. The protopathic system allows the recognition of pain and temperature beyond the normal thresholds though these can not be localised. The epicritic system concerns light touch, temperature close to that of the skin, accurate localisation of the stimulus and the discrimination of two simultaneous contacts. Protopathic sensation

Henry Head (1861-1940)

13

returns first after nerve injury with excessive reaction and false reference, returning to normal when the epicritic function returns and controls the protopathic. Nowadays these functions are thought to have greater representation in the central nervous system.

MARRIAGE TO RUTH MAYHEW IN 1904 In 1904 at the age of 42 Head married Ruth Mayhew whom he had already known for seven years. She was Headmistress of Brighton High School for girls and the daughter of Anthony Lawson Mayhew, Fellow and Chaplain of Wadham College in Oxford. They did not have children. Ruth wrote: "George Eliot should have the statue erected to her in the College of Physicians for the service she had done for young doctors in her Middlemarch. I don't care who they married before 30 — it s bound to be the wrong women. " Ruth wrote novels and also A Simple Guide to Pictures (by Mrs. Henry Head) published in 1914 by Chatto and Windus18 with colour illustrations and a discourse on pictures from Giotto to Morland. Both Henry and Ruth made reference to medicine in their writing.

FROM 1904 TO 1910 In 1905 Head published with James Sherren, Surgeon at the London, on peripheral nerve injuries.19 With Theodore Thompson (1878-1935), Assistant Physician at the London Hospital, Head researched the spinal cord. In 1908 Head was awarded a medal by the Royal Society and also in 1908 The Marshall Hall Medal of the Royal Medical and Chirurgical Society. Marshall Hall (1790-1857) advocated the establishment of a hospital for epileptics in 1852, now The National Hospital and he introduced the terms reflex arc and spinal shock.

14 C. Gardner-Thorpe

HEAD'S INTEREST IN SPEECH 1910-1926 In 1897 William Elder, MD FRCP Edinburgh, Physician to Leith Hospital, published the greater part of his Edinburgh University MD Thesis. In the Introduction he wrote: "The power that man possesses of communicating his thoughts to his fellow-men by means of language is one of the most characteristic of the many points that distinguish him from the lower animals. That some of the lower animals do possess the power of communicating with each other there can be little doubt, but it can hardly be said of them that they possess the faculty of speech.20" In 1910 Head lived at 4 Montagu Square in London.21 He became interested in aphasia in 1910 when investigating the sensory effects of cortical lesions. From that time onwards he started to test speech systematically. After 1914 he tested many patients with war injuries. His published work on speech brought together many of the earlier ideas on the subject. In 1911 he delivered the Croonian Lectures at The Royal College of Physicians. He was interested in the psychophysiological approach of Hughlings Jackson (1835-1911) with whom in 191522 he discussed the subject. Head's fluency in French and German helped his work as Editor of Brain from 1910 to 1925 and in that journal from 1915 to 1918 he reprinted Hughlings Jackson's long-forgotten papers on aphasia. Head collaborated with Sir Gordon Holmes (1876-1965) on the sensory functions of the optic thalamus and cerebral cortex.23 Edwin Clarke and Dewhurst,24 neurologist and psychiatrist respectively and noted neurohistorians, state that in relation to cortical localisation and the concept of the body scheme Head and Holmes described a "preconscious physiological function." Head and Holmes described the body scheme as the psychological function for comparing the position of a movement with one immediately preceding it and so each individual has a constantly changing postural model. Past impressions are stored in the sensory cortex. An image is constantly appreciated but a scheme is a preconscious organised module.

Henry Head (1861-1940)

15

Edwin Greaves Fearnsides (1883-1919), a Yorkshireman who qualified at the London Hospital, was Head's pupil and published on neurosyphilis25 and on intracranial aneurysms.26 In due course Head was to write Fearnsides' obituary.

THE FIRST WORLD WAR 1914-1918 During the First World War, Head became Civilian Consultant to the Empire Hospital for Officers in Vincent Square. He was joined by George Riddoch (1888-1947) who had qualified in 1917 at Aberdeen and was appointed Resident to the West End Hospital for Nervous Diseases where he worked with Purves Stewart, publisher of a popular neurology textbook.27 Together Head and Riddoch studied gross injuries of the spinal cord and in particular traumatic paraplegia, the automatic bladder, excessive sweating and the mass reflex.28 Pat Barker's Trilogy Head's name has been introduced to the non-medical world again by Pat Barker, winner of the 1995 Booker Prize, in The Trilogy?9 Barker describes in part fiction and part fact Head's work in 1917 with Rivers,30 then an Army neurologist and psychologist based at Craiglockhart. There Head treated Siegfried Sassoon, the First World War poet. To Rivers when contemplating a skull is given the quotation31: "This blown eggshell had contained the only product of the forces of evolution capable of understanding its own origins." To Head, keen general physician, is attributed the quotation32: "It's an interesting atmosphere, dealing with physical trauma and neurosis in the same hospital. You would like it." Head predicted33 that in the Royal Flying Corps pilots broke down but less frequently and less severely than troops who manned observation

16 C. Gardner-Thorpe

balloons possibly because in the latter prolonged strain, immobility and helplessness did the damage rather than sudden shocks or bizarre horrors. The Poetry of War During the First World War Head's friendships included Siegfried Sassoon (1886-1967), Robert Graves (1895-1985) and Robert Nichols (1893-1944). Graves was impressed by Head's scientific integrity and writing. Nichols noted that Head was an authority on Leonardo. Russell Brain stated "had Henry Head not adopted medicine as a profession, he might have been equally distinguished as a writer". Head's bibliography was published in the Henry Head Centenary issue of Brain.34 Head was deeply affected by World War I and the personal links with his work as Civilian Consultant to the Empire Hospital for Officers and this is reflected in his poetry. He sent his first poem to Cushing who published it in the Yale Review in 191635: I Cannot Stand and Wait How can I serve who am too old to fight? I cannot stand and wait With folded hands, and lay me down at night In restless expectation that the day Will bring some stroke of Fate I cannot help to stay. Once, like the spider in his patterned web, Based on immutable law, Boldly I spun the strands of arduous thought, Now seeming naught, Rent in the sudden hurricane of war. Within my corner I will take my place, And grant me grace Some delicate thing to perfect and complete With passionate contentment, as of old

Henry Head (1861-1940)

Before my heart grew cold. This in the Temple I will dedicate, A widow's mite, Among more precious gifts, obscured from sight By the majestic panoply of state. But when triumphal candles have burned low And valorous trophies crumbled into dust, Perchance my gift may glow, Still radiating sacrificial joy Amid the ravages of moth and rust. There are similarities to Milton's Sonnet on his blindness36 When I consider how my light is spent, Ere half my days, in this dark world and wide, and so on, to They also serve who only stand and wait. Homing Wings was published in 191637 and Destroyers in the Review in 191738: Destroyers On this primeval strip of western land, With purple bays and tongues of shining sand, Time, like an echoing tide, Moves drowsily in idle ebb and flow; The sunshine slumbers in the tangled grass And homely folk with simple greeting pass, As to their worship or their work they go. Man, earth, and sea Seem linked in elemental harmony, And my insurgent sorrow finds release In dreams of peace.

18 C. Gardner-Thorpe

But silent, gray, Out of the curtained haze, Across the bay Two fierce destroyers glide with bows a-foam And predatory gaze, Like cormorants that seek a submerged prey. An angel of destruction guards the door And keeps the peace of our ancestral home; Freedom to dream, to work, and to adore, These vagrant days, nights of untroubled breath, Are bought with death. Next was published The Price in 1917 39 and then in the Yale Review in 191840: Died of His Wounds Death set his mark and left a mangled thing, With palsied limbs no science could restore, To weary out the weeks or months or years, Amidst the tumult of a mother's tears Behind the sick-room door, Where tender skill and subtle knowledge bring Brief respite only from the ultimate Decree of fate. Then, like the flowers we planted in his room, Bud after bud we watched his soul unfold; Each delicate bloom Of alabaster, violet, and gold Struggled to light, Drawing its vital breath Within the pallid atmosphere of death. That valiant spirit has not passed away, But lives and grows

Henry Head (1861-1940)

19

Within us, as a penetrating ray Of sunshine on a crystal surface glows With many-hued refraction. He has fled Into the unknown silence of the night, But cannot die till human hearts are dead. The next poem was published in 191841: To Courage Seated We wandered through the chill autumnal Park, And spoke of courage and the youthful dead, And how the boldest spirit may be cowed By indiscriminate terror. Overhead, The moon rode high on her predestined arc, Steadfast through tidal waves of sombre cloud. Like vast antennae, search-lights swept the sky, When, suddenly, as if in swift reply, Out of the south, with jets of luminous smoke, And coughing clatter, hidden guns awoke. And we fell silent at the thought of death. We were too old to leap with panting breath Into the turmoil of the bloody strife, And dance upon the razor-edge of life To fame or to oblivion. We must wait Like senators of old, with folded hands, In silence, seated, for the stroke of Fate. One boon alone an ardent soul demands, To die before its passion waxes cold, Enthusiasm fails, or Love grows old. Head's war poems42 were combined in 1919 into the volume Destroyers and Other Verses published at Oxford. Two other volumes of verses preceded this and two followed. Many were dedicated to his wife.

20

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AFTER THE GREAT, FIRST WORLD WAR Shortly after the First World War Head preceded his guest, Grantly DickRead, into the hospital dining room. Read heard Head's shuffling footsteps. Head turned and said, "Ah I see that I have taught you too well!" The first features of Parkinsonism led Head to retire from The London Hospital in 1919. Shortly afterwards Sassoon suggested he go to live in Dorset as a neighbour of Thomas Hardy (1840-1928) who had moved to Max Gate in August 1887 and who wrote much of his poetry there in the last few years of his life. Ruth compiled an anthology of Thomas Hardy's writing for which Henry wrote an introduction. It was in Dorchester that Head was visited by Harvey Williams Cushing (1869-1939) with whom he discussed the body image and sensory projections. Samuel T Orton, researcher in dyslexia, also visited Head to discuss the cause of word blindness.43 Head, an inspiring teacher, was full of ideas. He described how a stick and a dental plate became a projection of the user's body — a sort of reverse phantom limb. Head's first large work, Studies in Neurology, was published in 1920 in two volumes.44 Henson45 published the famous photograph of Head and Rivers at work in Rivers' rooms at St John's College, Cambridge. Henson summarised Head's hierarchical view of sensation (1886-1921) as consisting of the peripheral nervous system (with its deep sensibility, protopathic sensibility and epicritic sensibility), the grouping of afferent impulses in the spinal cord, the thalamus and the nature of the sensory activity of the cerebral cortex. Over-riding this is the concept of duality in the somatosensory system with the lemniscal system (dealing with tactile and kinaesthetic impulses) and the spinothalamic or anterolateral system (dealing with pain, heat, cold and sexual sensations). In 1920 Head delivered the Hughlings Jackson lecture and in 1921 the Croonian lecture at The Royal Society. In 1921 at the age of 60 he disliked the sensation in an aircraft when looping the loop. By 1926 he had proceeded LLD Edinburgh. Head published two important papers on speech in 1920 46 ' 47 and another in 1923.48

Henry Head (1861-1940)

21

HEAD'S BOOK ON APHASIA Head's Interest in Speech49 In 1926, when he had suffered from Parkinsonism for some years, Head published his next two volume work entitled Aphasia and Kindred Disorders of Speech.™ This was dedicated to Walter Holbrook Gaskell MD FRCS, Fellow of Trinity Hall Cambridge and physiologist, to Ewald Herring and to John Hughlings Jackson. In the same year Kinnier Wilson published his small monograph on aphasia.51 Head stated on page one of his book "The evolution of our knowledge of cerebral localisation is one of the most astonishing stories in the history of medicine". He described how nearly forty years had passed since his interest in aphasia had been aroused. In November 1886 an elderly woman with nominal aphasia and right hemianopsia but without paralysis had been admitted to Addenbrooke's Hospital in Cambridge. Some weeks later she died. A large and recent haemorrhage was demonstrated in the right hemisphere and a smaller well-defined lesion beneath the left supra-marginal and angular gyri. It was necessary to plead a special case to explain many of the classical examples of aphasia. Head surmised that higher brain lesions cause defective recognition of certain relationships between sensory stimuli and the perceptions to which they give rise.

Head's Historical Overview In his historical overview, Head noted the contributions made by Hippocrates, Vesalius, Herder and William Jones, and by Gall and Spurzheim with phrenology. WS Gilbert observed in Phrenology52: "Observe his various bumps, His head as I uncover it; His morals lie in lumps All round about and over it. " Head discussed the work of Soemmering, Bouillaud, and Marc Dax in whom Critchley later became especially interested, Broca, Trousseau,

22

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Hughlings Jackson, David Ferrier, Bastian, William Broadbent and Julius Wagner von Julius. Head reprinted Jackson's work in Brain from 1915 to 1918. Jackson said "Put down what the patient does get at and avoid all such terms as amnesia etc." and "destructive lesions never cause positive effects, but induce a negative condition which permits positive symptoms to appear". Speech suffers in proportion to the mental complexity of the task and the following should all be examined — — — — —

Sign making Writing Understanding verbal command Word repetition Understanding what is read yet unable to read.

Speech is tied up with thinking; single words are meaningless. Speech is internal and external. Internal speech includes the formulation of propositions. A proposition antecedes internal and external speech. To receive a proposition and to form one are different things. The speechless patient not only cannot speak aloud but he cannot propositionise internally. Loss of speech is the loss of power to propositionise. He cannot say anything to himself and therefore has nothing to write but he can form images. The aphasiac does not have a problem with general intelligence but there is a disturbance of certain activities of the mind associated with those lesions of the brain which could affect speech. In 1874, Karl Wernicke (1848-1905), German psychiatrist, published a pamphlet based on Maynert's projection systems of the cortex. Nerve cells are neither motor nor sensory. The posterior part of the brain is sensory and the anterior part motor with pathways between them. In 1877 Adolf Kussmaul (1822-1902) regarded speech as an organised reflex. Head wrote that in 1903 Wernicke published "A case of isolated agraphia"; no better example could be chosen of the manner in which the writers of this period are compelled to lop and twist their cases to fit the procrustean bed of their hypothetical conceptions. Henschen showed that limited lesions of the area striata produced distinct local defects of the visual fields, and concluded that each retina was

Henry Head (1861-1940)

23

represented point by point on the surface of the calcarine cortex; he assumed hearing had similar representation in the upper temporal lobe, and theorised that reading and writing might be represented similarly. Head wrote that these observers "failed to appreciate that the logical formulae of the intellect do not correspond absolutely to physical events and that the universe does not exist as an exercise for the human mind. To them an explanation that appealed directly to reason must of necessity correspond to the facts of observation. The time was right for a ruthless destruction of false gods and a return to systematic empirical observation of the crude manifestations of disease". In 1906, Marie, French lawyer and later neurologist, published three papers, concluding that every true aphasiac had some want of comprehension of spoken words. Marie's first paper was entitled The third frontal convolution does not play any special role in the function of language. He introduced the term anarthria which was really Broca's aphasia but can exist alone with intellect intact. True aphasia therefore is Wernicke's aphasia, a topic that has been reviewed recently.53 Marie re-examined Broca's first two patients whose brains were preserved in the Musee Dupuytren and showed very extensive disruption in the first case and lack of significant damage to the third frontal convolution in the second. So Broca's aphasia was true aphasia with anarthria and damage to the the insula, claustrum, external and internal capsule, the caudate and lentiform nuclei, and Wernicke's area. Head emphasised that the examination of aphasia included the systematic examination of speech, understanding, reading and writing. Aphasia prevents understanding a command, for example, "lick the lips", but a person can imitate this or do it reflexly: when mimicry is impossible, sensory aphasia results. In 1913 Von Staffenberg noted a woman who had her first stroke at the age of 61 and when "shown some common object she at once asked to be allowed to handle it". She complained, "I see that something is there, I see it quite clearly to catch hold of and afterwards I don't see anything". Thus, unable to recognise a sponge held in front of her, she did so at once when she touched it with her hands. "Whenever it was possible she called in the aid of hearing, touch, smell or taste to help her out of her difficulty and visual perception".

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"The power to make words was developed at a late stage in the evolutionary history of man. Before he learnt to formulate his thoughts and desires in speech, he was capable of a wide range of accurate discrimination, which could express itself in action alone". "Any lesion gravely disturbing speech affects activities which are not usually classed with the use of language; the more carefully the patient is examined, the less certainly does his disorder correspond to any preconceived category". Head's Tests of Speech Head regarded a principle new to the study of aphasia to be the embodiment within his tests of an orderly series of observations. "The tests I am about to describe vary greatly in the difficulty they present to persons of normal understanding. Most of them, such as selecting or naming common objects and colours, the man, cat and dog tests, the coin-bowl tests are childishly simple and can be carried out perfectly by the stupidest individual. Such tests illustrate the importance of graduating the difficulty of the task set to the patient, if we are to arrive at any definite conclusion with regard to his powers of symbolic formulation and expression." The tests included the naming and recognition of six objects of daily use (such as a pencil, a key, a penny, a match-box, a pair of scissors and a knife) laid on the table. Before starting the observations it is well to record the actual position in which they lie to one another from the patient's point of view. They are then screened from his sight and a duplicate of one of them is shown to him; the screen is rapidly withdrawn and he is asked to point to the object on the table which corresponds to the one he has just seen. A footnote reads: "Sometimes with highly educated patients these familiar objects were replaced by wooden blocks cut into the form of geometrical figures such as a cube, a sphere, a pyramid, a

Henry Head (1861-1940)

25

cone etc. The tests were then carried out systematically exactly as with the articles of common use. " Head's wooden blocks (Fig. 2) might have been inspired by the work of Kohs54 who in 1923 described the use of a test to assess right posterior parietal function. Kohs' test was superseded by the block-design test of the Wechsler Adult Intelligence Scale. This work precedes that of Piaget in 1948 (La Representation de l'espace chez l'en/ant and La Geometrie spontanee de I'enfant) in which very young children are asked to identify common objects such as a pencil, comb, key, spoon and so on and to compare with others which they can see, whereas older children are started straight off with a series of cardboard cut-outs in the shape of geometrical figures such as a circle, ellipse, square, rectangle and so on. 55 Other workers subsequently devised geometric shapes in different colours and sizes, for example The token test in aphasics in 1962. 56 read various passages to his patients including the opening paragraphs from the Vicar of Wakefield, and "the great Cunard steamer was torpedoed by a German submarine and sunk off the South coast Ireland on 7 May 1915. She was within a few hours of harbour. were nearly 2000 persons on board and of these between 500 and 600 were

Fig. 2. Head's wooden blocks.

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C. Gardner-Thorpe

saved and landed at Queenstown. There were many hospital patients among the passengers and several of these had since died". This sounds like the Lusitania. Head's Conclusions Head concluded that centres for speaking, reading, writing and other forms of behaviour comprised in the normal use of language do not exist. The form of the aphasia differs with the site of the lesion and both cortical and sub-cortical mechanisms are important. Two aspects of language are the formulation of thought and its skilful expression. "The superb logician may have difficulty in expanding his ideas and we are familiar with the practised speaker whose words are jejune57 of thought". Nearly all of his 26 patients were tested with his six common objects. The clinical case reports are very detailed. The geometric figures are referred to in four cases. "But suppose some articles such as the knife, or even a geometrical figure, is placed in his hand out of sight, the patient has no difficulty in selecting its duplicate providing no words are employed. Moreover, if you have been given a pyramid cut out of a block of wood, he can match it with any pyramidal object, however greatly the two may differ in relative size and structure. He deduces from the multifarious sensations yielded by his hand certain characteristics, which are also possessed by the object within sight, and ignores any differences. In both percepts he reacts to a common quality, the pyramidal factor, although the one is a result of tactile and the other of visual impressions. "

THE FINAL FOURTEEN YEARS (1926-1940) After Thomas Hardy died the Heads moved to Hartley Court near Reading. In 1927 Head was awarded the moxon medal of the Royal College of

Henry Head (1861 -1940)

27

Physicians, in 1927 he was Knighted, in 1929 he was made an Honorary Fellow of Trinity College, Cambridge and in 1930 he received the gold medal of the Royal Society of Medicine. He was made LLD Edinburgh. Ruth died in 1939 and in October 1940 Head died at Hartley Court. The Death Certificate gives his occupation as Baronet (Physician) and the cause of death as bronchopneumonia and paralysis agitans.58 He was aged 78 and had been virtually immobilised by Parkinsonism for many years with great difficulty in speaking though his mind was still alert. He was cremated at Reading Crematorium on 11 October 1940 and his ashes scattered in the Gardens of Remembrance.59 Head bequeathed his residuary estate to The Royal Society in order "to promote the science of medicine in England". In 1989 the market value of the capital was £291,514. Among others, CE Lumsden of Leeds was a Henry Head Research Fellow (1951-1956).60 Notice of Death and a long Obituary appeared in The Times on 10 October 1940.61 Robert Nichols added a tribute five days later.62 A memorial is the Henry Head Centenary Edition of Brain published in 1961.63 Macdonald Critchley64 believed that Head's monograph constituted the finest and most significant volume in the whole literature of aphasia and yet he described it as prolix, repetitive and, in places, even contradictory, ambiguous or almost evasive. Head's battery of tests constituted a great advance over the traditional techniques but were time-consuming and somewhat repetitive. Head did not make any control studies and a group of normal college students later showed a bad score in a significant percentage. Like Jackson, Head emphasised speech is no more a localisable faculty than is eating. Brain disease can never affect speech alone. Acuteness and severity of onset of the lesion is more important than its extent. An aphasiac's performance is inconsistent.65 Head himself concluded in his book: "I have attempted to blaze a track through the jungle, but make no pretence at having reached the end of the journey. I can only hope that some ardent and adventurous spirit may follow in my path and find that my labours have helped him to the solution of the profoundly interesting and difficult problems of disorders of speech. "

28 C. Gardner-Thorpe

References 1. Biographical detail of Head is published in the work of Brain, Henson, The Dictionary of National Biography and Obituary Notices of Fellows of The Royal Society. 2. Birth Certificate number 466 for 1861, Stoke Newington, Middlesex. 3. Fisher, R.B. (1977). Joseph Lister 1827-1912. MacDonald and Jane's, London. 4. Poeck, K. (1998). Personal communication. 5. Ueber die negativen und positiven Schwankungen des Nervenstromes. Pfluger's Arch. ges. Physiol. 1886-1887, 40, 207. 6. Holmes, G. (1954). The National Hospital, Queen Square 1860-1948. E & S Livingstone Ltd, London. 7. Feiling, A. (1958). A History of the Maida Vale Hospital for Nervous Diseases. Butterworth and Co, London. 8. Head, H. (1893). On disturbances of sensation with especial reference to the pain of visceral disease. Brain 16, 1-133. 9. Brain 1894, 17, 331. 10. Allbutt, C. and Rolleston, H.D. (1910). A system of medicine by many writers. Volume 6. Diseases of the Muscles, the Trophoneuroses, Diseases of the Nerves, Vertebral Column, and Spinal Cord. Macmillan, London. 11. Pages 470-492. 12. Pages 540-567. 13. Printed List of Candidates of The Royal Society. 1899. 14. Bulloch's Roll. Index of Fellows of The Royal Society. 15. Brain 1901, 24, 345. 16. Brain 1908, 31, 323-450. 17. Studies in Neurology. Henry Head. (1920). Hodder and Stoughton, London. 2 volumes. 18. Copy examined in Exeter Public Library. 19. Brain 1905, 28, 116. 20. Elder, W. (1897). Aphasia and the Cerebral Speech Mechanism. HK Lewis, London. 21. Nisbet's Medical Directory (1910). James Nisbet and Co, London, p. 282. 22. Head, H. (1915). Hughlings Jackson on aphasia and kindred disorders of speech. Brain38, 1-42. 23. Head, H. and Holmes, G. (1911-1912). Sensory disturbances from cerebral lesions. Brain 34, 102-254.

Henry Head (1861 -1940) 29 24. Clarke, E. and Dewhurst, K. (1974). An Illustrated History of Brain Function. University of California Press, Berkeley and Los Angeles, pp. 131-132. 25. Brain 1914-1915, 37, 1. 26. Brain 1916, 39, 2240. 27. Purves-Stewart, J. (1924). The Diagnosis of Nervous Diseases. Sixth Edition. Edward Arnold, London. 28. Head, H. and Riddoch. (1917). The automatic bladder, excessive sweating and some other reflex conditions in gross injuries of the spinal cord. Brain 40, 188-263. 29. Barker, P. Regeneration (1991), The Eye in the Door (1995), The Ghost Road (1994). 30. Nickerson, K.G. and Shea, S. (1997). WHR Rivers: Portrait of a great physician in Pat Barker's Regeneration Trilogy. Lancet 350, 205-209. 31. The Ghost Road (1994). p. 238. 32. Regeneration, p. 165. 33. Regeneration, p. 222. 34. Bibliography of Henry Head. Brain 1961, 84, 567-569. 35. The Yale Review 1916, 5, 540. 36. Milton. On His Blindness. The Penguin Book of English Verse. Edited by John Hayward. Penguin Books (1963), pp. 147-148. 37. The English Review 1916, 23, 99. 38. The Yale Review 1917, 6, 473. 39. The English Review 1917, 24, 3. 40. The Yale Review 1918, 7, 307. 41. The Dublin Review 1918, 162, 129. 42. Reich, S.G. (1988) History of neurology. Archives of Neurology 1988, 45, 1257-1260. This article contains a good photograph of Henry Head in 1909. 43. Behan, Wilhemina (1998). Personal communication. 44. Studies in Neurology. Henry Head. (1920). Hodder and Stoughton, London. 2 volumes. 45. Henson, R.A. (1961). Henry Head's work on sensation. Brain 84, 535-550. 46. Head, H. (1920). Aphasia and kindred disorders of speech (the Linacre Lecture for 1920). Brain 43, 87-165. 47. Head, H. (1920). Aphasia; an historical review (the Hughlings Jackson Lecture for 1920). Brain 43, 390-411. 48. Head, H. (1923). Speech and cerebral localisation. Brain 46, 355-452.

30 C. Gardner-Thorpe 49. Macdonald Critchley wrote on Head's contribution to aphasia in Brain 84, 551-560. 50. Aphasia and kindred disorders of speech. Cambridge University Press (1926). 51. Kinnier Wilson, S.A. (1926). Aphasia. Psyche Miniatures and Medical Series. Kegan Paul, London. 52. Gilbert, W.S. The Bab Ballads. (1953). MacMillan and Co, London, p. 440. 53. Brais, B. (1992). The third left frontal convolution plays no role in language: Pierre Marie and the Paris debate on aphasia (1906-1908). Neurology 42, 690-695. 54. Kohs, S.C. (1923). Intelligence Measurement, a Psychological and Statistical Study Based Upon the Block-Design Tests. MacMillan, New York. 55. Holloway, G.E.T. (1967). An Introduction to the Child's Conception of Space. Routledge and Kegan Paul, London. 56. de Renzi, E. and Vignolo, L.A. (1962). The token test: A sensitive test to detect receptive disturbance in aphasics. Brain 85, 665-678. 57. Scanty, unsatisfying to the mind. 58. Death Certificate number 380, Registration District of Wokingham in the County of Berkshire. 59. Personal Communication (1997). Henley Road Cemetery, Reading Crematorium, All Hallows Road, Caversham, Reading, Berkshire, RG4 5LP. 60. Rowlinson, J.S. and Robinson, N.H. (1992). The record of the royal society of London. Supplement to the fourth edition for the years 1940-1989. The Royal Society, London. Pages 57-58, 126 and 206. 61. The Times (1940) 10 October, pp. 4 and 7. 62. Nichols, Robert (1940). Sir Henry Head, A tribute. The Times, London. 15 October, p. 7. 63. Volume 84, Part iv. 64. Critchley, M. (1961). Head's contribution to aphasia. Brain 84, 551-560. Reprinted in Critchley, M. (1970). Aphasiology and Other Aspects of Language. Edward Arnold, London, p. 67. 65. Critchley, M. (1970). Head's contribution to aphasia. Brain 1961, 84, 551-560. Reprinted in Critchley, M. (1970). Aphasiology and Other Aspects of Language. Edward Arnold, London, p. 67.

TWENTIEH CENTURY NEUROLOGY The British Contribution © 2001 by Imperial College Press

Chapter 3

THE BRITISH CONTRIBUTION TO APHASIOLOGY Klaus Poeck

For the neurologist interested in history there are three British clinicians who have made seminal contributions during the "classical" period of aphasiology: Hughlings Jackson, Henry Charlton Bastian and Henry Head. In their time, the main issues were the description of various kinds of language disorder and the impairment of underlying neuronal processes. The localization of lesions that might bring about variants of aphasia was not the main focus of their interest but these problems were discussed after World War II among others by Sir Russell Brain. The last great neurologist to summarize the clinical features of aphasia and related disorders was Macdonald Critchley whose book on aphasiology is still a pleasure to read and a source of inspiration to this day. I am going to pay tribute to these authors by summarizing the essence of their individual contributions, and will not elaborate extensively on the classical period of aphasiology between the end of the last century and the mid-fifties, but focus on the most remarkable contributions made by British cognitive psychologists, neurolinguists and speech therapists during recent decades. The wealth of these contributions is not paralleled by research in any other European country, so that the concepts, results and the persons behind these should be more widely known in the community of neurology. Before turning to the recent developments in research on language disorder it should be pointed out that the teaching of the "fathers of aphasiology", 31

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in retrospect, appears quite modern in that they anticipated some key issues of present day neuropsychology.

JOHN HUGHLINGS JACKSON Jackson (1835-1911) is considered the father of British neurology. After his medical studies he worked in London as a medical journalist before he became assistant physician to the National Hospital. Queen Square, in 1862. He was one of the founders of the journal Brain, but published many of his papers in journals not easily accessible to his contemporaries which was one of the reasons why in his time his writings were not very influential, and became widely known only through Henry Head's posthumous publication of Jackson's aphasia papers in Brain (1915). Another reason was his complicated style of writing adopted when he borrowed important concepts from Aristotle and Herbert Spencer. Jackson was interested in the processes of language and, in functional terms, followed Baillarger of Paris (1865) who distinguished voluntary and automatic verbal processes. The controlled/automatic distinction has been the object of study up to present day psychology and neuropsychology. Jackson's teaching that destructive lesions of the CNS induce a negative condition that permits positive symptoms to appear as release phenomena needs not be further discussed (see Chapters 8-10). Jackson viewed the nervous system as organized in hierarchical levels — a position that we would not maintain today — and he applied the concept of dissolution of function also to the phenomena of speech disturbance observed in his patients. Jackson discussed aphasia mainly in the context of hemiplegia or epileptic seizures. He was not a localizationist, but considered the organization of speech in the brain in terms of an interplay between the two hemispheres and was opposed to Broca's well-known views. Functionally, he also did not accept Broca's notion of a "faculty of speech" nor of any "faculty" of the brain. Jackson adopted the concept of proposition from Aristotelian logic (Riese, 1947). Like Aristotle, he considered words as symbols of things and written language as symbols of

The British Contribution to Aphasiology

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symbols, a view that is still valid in today's research. He was opposed to such psychological terms as "memoire des moyens de coordination" (Broca) and insisted that we have to deal with the physiological processes underlying speech but not with mind or mentality (Riese, 1947). Arnold Pick, that outstanding figure in aphasia research who was the first to be greatly influenced by the Prague school of linguistics, dedicated his monograph "Die aphasischen Sprachstorungen" to: Hughlings Jackson, the deepest thinker in neuropathology of the past century (1913).

HENRY CHARLTON BASTIAN Bastian (1837-1915) made shrewd bedside observations and described these in a clear and orderly style. In the field of language disorders, his theoretical views are remarkably modern, since he was interested in the neurology of mental functioning. In addition, he devoted much of his energy to studies in parasitology; when elected Fellow of the Royal Society at the age of 31, it was in recognition of these, and not of his neurological, studies. Bastian had few friends and no disciples, in marked contrast to Carl Wernicke who managed to found an influential school, perhaps the main reason why it is not widely recognised that Bastian described "sensory aphasia" two years before Wernicke. Bastian was the first author to describe word-deafness and word-blindness (1869), syndromes that we are used to associate with the hodologist (hodos, gr. = pathway, see also Geschwind) views of Dejerine. Bastian explained disorders of speech in terms of the destruction of auditory and visual or the affection of fibres between them and lower mechanisms for the speech musculature or the hand (for writing). In contrast to Dejerine and Geschwind, his famous aphasia diagram (1897) is an abstract psychological model and does not attempt to illustrate precisely the anatomical organization of the left hemisphere. Even though this schema is functional, Bastian is ready, "for the purpose of our discussion at present" to assume "that the two kinesthetic word centers are situated... in the posterior part of the superior temporal convolution and in the angular gyrus", respectively. Nevertheless he pronounced the remarkably modern

34 K. Poeck Cheiro-Kinaes. Centre

Vis. Word Centre

e

Glosso-Kinaes. Centre

Aud. Word Centre

Fig. 1. Bastian's diagram showing the approximate sites of the four word centers and their commissures (i.e. pathways connecting the centers) (Bastian, 1897).

view that centers were not topographically separate areas of brain substance but rather "distinct cell and fiber mechanisms existing in a more or less diffuse and mutually interblended manner" (1897). We would speak today of diffuse but functionally unified networks. Bastian discussed at length the role of the left hemisphere in speech and memory, and he considered that "the condition of amnesia may merge by insensible gradations into one of aphasia" all the more because the lesions which produce one or the other forms of amnesia are likely to be located "around the posterior extremity of the left Sylvian Fissure". Bastian dismissed the idea of massing together all the varieties of loss of speech under one name, such as "aphasia". He provisionally formulated a general law as a future working hypothesis: that the tendency to mental impairment will, other things being equal, increase as lesions of the left hemisphere recede in site from the third frontal convolution and approach the occipital lobe.

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35

HENRY HEAD Sir Henry Head (1861-1940) had studied at the University of Halle (Germany) and at the German University of Prague before he attended the University of Cambridge. In Czechoslovakia he introduced soccer to the country cf Hudson (1994). He served as Vice-President of the Royal Society, and was editor of Brain where he published important papers later summarised in his famous book "Aphasia and kindred Disorders of Speech" (1926). It is not so well known that he also published a book of verse giving his own poetry and translations from the German literature (Reich, 1988). Head was strongly influenced by Hughlings Jackson with whom he had long discussions on the functions of the central nervous system. It was only after Jackson's death that Head discovered the richness and depth of Jackson's papers on aphasia and republished them in Brain (1915) thus bringing them at last to the attention of a wider audience (see previous chapter). Head is generally known for his opposition to the diagram makers, and felt that the way diagrams are used in neurology simplify the complexity of symptoms exhibited by brain damaged patients; he considered neurological symptoms in psychological terms and may be regarded as a predecessor of cognitive psychology. Today we are not interested so much in signs and symptoms as in the underlying processes that bring these about, a view found in Henry Head's teaching that defects arise from an interaction of adaptive processes following a brain lesion. This dynamic concept is strictly in contrast to older views that a brain lesion reveals the elementary processes out of which an affected function is composed in their primary character. I will not elaborate elaborate on his classification of language disturbances, i.e. verbal, nominal, syntactical and semantic types which, as Macdonald Critchley (1961) remarked, is described at length but not defined. Neither was he very specific about his terms "symbolic formulation and expression". Suffice it to stress that his discussion of syntactic disorders reflects only what we would call agrammatism. He did not go deeply into what we call paragrammatism which is frequently regarded as the hallmark of Wernicke's aphasia — if one subscribes to that category. Head strongly takes issue with Wernicke and refers to the latter's diagram. It escaped his attention, as it obviously has escaped many aphasiologists,

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Fig. 2. Wernicke's drawing of the speech centers and their fiber connections. It is remarkable that this drawing of 1874 shows the right and not the left hemisphere and, in addition, the brain is monkey-like, and Wernicke was aware, of course, that monkeys cannot speak.

that Wernicke illustrated his schema or diagram with a view of the right, not the left, hemisphere, which illustrates the fallacies of the clinicians eye. Summing up, Head's contribution lies more on the critical side, a good example being the last sentence of his chapter on the Diagram Makers: The time was ripe to a ruthless destruction of false gods and a return to systematic empirical observation of the crude manifestations of disease.

MACDONALD CRITCHLEY Critchley (1900-1997) was a remarkable author of historical and clinical papers on aphasia. He was fascinated with the bedside examination of patients and compared his observations to notions expressed by previous authors during recent decades as well as in ancient times. His papers testify to a deep knowledge of classical neurological writings as well as a mastery of the European non-medical literature. He cultivated an upper class English prose as his scientific style of writing which makes his papers particularly attractive for a non-native speaker of English. In some places his attempts to generalize his observations and those of others to form concepts on the origin, cultural interdependence and the

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cerebral organization of language appear somewhat speculative. On the other hand, one is impressed by his openness to the teachings of neuropsychology and neurolinguistics. The collection of his aphasia papers (Critchley, 1970) still makes fascinating reading, my favorite being the paper on The Neurology of Psychotic Speech (Critchely, 1964). This is a goldmine that no-one has so far systematically worked up, for example, in an intensive care unit where, of course, you would need sophisticated recording devices to remove the background noise. On a person basis, I have experienced Macdonald Critchley as gracious, friendly and receptive to the opinion of younger colleagues.

STUDIES IN PARAGRAMMATISM While agrammatism has attracted the attention of many researchers in Europe and in the US, paragrammatism, i.e. blends of syntactical constructions, has hardly been studied systematically. The outstanding exception is the work of Brian Butterworth (Butterworth and Howard, 1987) who, in the course of extensive investigations into the production and comprehension of patients with jargon aphasia, has conducted a study on a large corpus of speech produced by five jargon aphasics as compared to the language output of five normal control subjects. An illustrative example for an agrammmatic sentence is: Two, three, four days... d... travelling by plane... sunshine and so on ... four days and two days... uh... unconscious and fall down. An example for a paragrammatic sentence is: I'll tell you, not like before, I must say that once the beginning happened in the beginning, as I arrived and naturally it was, of course, quite decisive. Butterworth and Howard examined four hypotheses that make different predictions on the pattern of paragrammatic errors. These are:

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— — — —

Syntactical disturbance Lexical selection impairment Monitoring failure Control impairment.

Butterworth was able to demonstrate that paragrammatic errors were not the consequence of "permanent loss or corruption of grammatical rules or grammatical knowledge". Also, the grammatical errors could not be attributed to a lexical selection deficit. Comparing paragrammatic production errors to auditory comprehension data they found a dissociation between the two performances. Under the premises that intact comprehension is necessary for intact monitoring, a monitoring failure could not explain the speech pattern. In contrast, the data supported the hypothesis that paragrammatic errors reveal a control impairment. Errors of the aphasic patients were of the same kind as errors in control subjects, and constructions could be found faulty as well as correct. These statements were also supported by data taken from the speech error literature. The authors' data demonstrated transient malfunction of an intact system and not "the permanent disruption of specific components". Butterworth and other authors have found that paragrammatic and agrammatic errors may be found in the same patient. It appeared that the omission of closed class, or function words and inflexions (as in agrammatism) is "simply part of a continuum of error processes". If this notion were generally accepted, then paragrammatism could not be regarded anymore as a distinct pattern of aphasic impairment.

CATEGORY-SPECIFIC SEMANTIC DISORDERS Under the heading of category-specific semantic disorder, Elizabeth Warrington has described, together with various co-authors, the phenomenon that brain damaged patients may be impaired in the processing of words belonging to one linguistic or semantic category but not, or much less so, in others. Examples for these categories are:

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— Abstract words (Warrington, 1975, 1981) — Proper names of people (McKenna and Warrington, 1978) — Inanimate objects (or: man-made artefacts) versus living beings (Warrington and McCarthy, 1983; 1987) — Living beings and food (Warrington and Shallice, 1984) — Manipulable versus non-manipulable (originally: indoor versus outdoor) objects (Warrington and McCarthy, 1987), — Action names (verbs) versus object names (nouns) (Baxter and Warrington, 1985; McCarthy and Warrington, 1985). The following types of behaviour may be observed: — — — —

The patient is unable to name the picture of a frog He/she is unable to give a verbal description of the meaning of "frog" He/she cannot draw the picture of a frog from memory He/she cannot colour the black outline of a frog green.

The first anecdotal reports of category specific deficits were received by neurologists with some scepticism, but prominent researchers in the field of cognitive neuropsychology have confirmed the observations and discussed the findings in the context of established models. These studies were conducted with a view to elucidating the functional structure of the semantic system or of lexical organization. It is hypothesised that semantic representation may be based on convergent sensory, or functional, information that contributes to its acquisition, but it is not an easy task to link semantic and linguistic categories to models of broader function. For example, along with living things, musical instruments and food are usually impaired while body parts are spared (Warrington and Shallice, 1984). Obviously, the living — non-living categories, like others mentioned above, are too broad or too simple to serve as the basis for cognitive modeling. The neurologist should note that we are not dealing here only with aphasic patients harbouring a single left-sided brain lesion. Some remarkable patients have bilateral brain lesions due to herpes simplex encephalitis. Gainotti et al. (1995) have tried to relate the data from cognitive psychology to neuroanatomical, i.e. imaging data.

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DEEP DYSLEXIA IN PATIENTS WITH LANGUAGE DEFICIT The last three decades have seen important studies on reading disorders that were conducted mainly by British authors. The starting point was the well known syndrome of Pure Alexia, that is, alexia without agraphia. Since the pioneer studies of Dejerine this has been considered a disconnection syndrome; in fact, this was one of the classical disconnection situations that inspired Geschwind to develop his teaching. Patients with pure alexia are poor at identifying written words — I am reluctant to call this process "naming" — which they read slowly and most often incorrectly. They can write but cannot read what they have written; can recognize words spelled aloud to them; have severe problems with the visual identification of letters but can single out Cyrillic letters in a string of latin ones and can identify letters written on their skin, of course without visual control. The errors the patients make while reading are in the first place semantic. Famous examples are orchestra for sympathy, Russia for czar. One of my patients responded to the stimulus word KENNEDY by saying "Poor man, he was murdered". The patients make, however, also visual errors, e.g. wife for life. Deep dyslexia is, as a rule, associated with other linguistic deficit characteristic of aphasia. The first patient described by Marshall and Newcombe (1973) sustained a left parieto-temporal bullet wound 20 years prior to the examination; his speech production was hesitant and agrammatic and he had some deficit of language comprehension. Cases of acquired dyslexia were described also under the heading of surface dyslexia (Patterson, Marshall and Coltheart, 1985). These patients are unable to read orthographically irregular words. They will read sweat as sweet. Patients with acquired reading disorder were taken as examples for the impairment in certain routes of processing operative in the normal process of reading. Shallice (1998) has discussed the functional status and the mechanisms possibly underlying deep dyslexia and concluded that this is not a syndrome in the traditional sense of the term but rather a functionally heterogeneous disorder.

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FUNCTIONAL IMAGING STUDIES OF COGNITIVE FUNCTIONS AND COGNITIVE DEFICIT The neurology minded researcher of cognitive functions wants, of course, to know to what extent the components isolated and connected in psychological models relate to the function of circumscribed areas of the brain, an aspect extensively studied in a collaboration of cognitive psychologists with the MRC research group at the Hammersmith Hospital headed by RSJ Frackowiak (now at Queen Square) and with other groups. The researchers took advantage of new imaging methods that not only show the activity of circumscribed areas of the brain while a subject or a brain damaged patient is engaged in the execution of motor or sensory tasks but also, of particular interest in the context of this chapter, in the solution of a linguistic or a cognitive task. The starting point is the fact that activation of a determined region of the brain enhances its local metabolism and, consequently, its regional blood flow which can be demonstrated with the use of appropriate isotopes. The first functional imaging studies were based on the subtraction method (Petersen et al, 1989) which is now called the categorical design. Here, the difference between the resting state and the solution of a task or between two tasks is measured. It is assumed that regional differences in brain activity indicate an area (or areas) of the brain critically involved in the solution of the task under study, but there were some problems with this paradigm. Most psychological tasks involve more than one modality. The more complex the psychological aspects of the task the more there arose the need for serial subtraction. Therefore, two more reliable paradigms have been introduced, i.e. parametric, or dimensional, and factorial design. The latter investigates interactions, i.e. the effect of one factor on the effect of another in the same experiment (Frackowiak et al, 1997). The following summary can be given on the basis of PET studies in normal subjects. Linguistic tasks lead primarily to the activation of areas in the distribution of the left middle cerebral artery, which is in line with traditional concepts but, quite unexpectedly, some areas in the right hemisphere are also activated. These areas are homotopic to the areas activated in the left hemisphere, particularly if the task requires language

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comprehension. It is an open question if right hemisphere participation is due to the linguistic or the acoustic properties of these comprehension tasks. The significance of Broca's area for processes related to the production of speech was confirmed but unexpected was that Broca's area was also activated during the solution of tasks that at first glance are not related to the production of language, e.g. categorisation of letters according to their phonetic structure, or the lexical decision whether two words rhyme. These findings would point to subvocal articulatory processes occurring during the solution of these and similar tasks. As far as healthy subjects are concerned, it would be premature to ascribe contralateral activation to linguistic functions of the right hemisphere that had been dormant while left sided language areas were functioning. This finding could be an epiphenomenon due to subvocal articulation or, in cases where there is collateral right sided temporal activation, to the processing of the acoustic properties of speech. By the same token, activation of Broca's area e.g. in lexical decision tasks, does not necessarily indicate linguistic processing. However, in a brain damaged patient, recovered language function has been reported by Kinsbourne (1971) to deteriorate after a second stroke in the homotopic area of the right hemisphere or after the injection of sodium amytal into the right internal carotid artery. Functional imaging has been applied also to a complex function such as reading (Frackowiak et al, 1997), a process that can be broken down to visual/orthographic processing, retrieval of phonology, word recognition/ semantic processing, and articulation. It was demonstrated that these components have a correlate in the activation of different brain areas under different experimental conditions and in different subjects/patients. Possibly, compensatory behaviour in patients with reading disorder can be correlated also to unexpected activation patterns.

SPEECH THERAPY FOR APHASIA The long lasting debate on whether speech therapy is efficacious or not needs not be recapitulated here. Professional therapy is provided today not

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by volunteers anymore (which was the reason for non-efficacy in some old studies) but by well-trained speech therapists who apply established techniques developed mostly on the basis of psycholinguistics and cognitive psychology. The first prominent speech therapist in Britain was Frances Margaret Hatfield (1916-1986) Originally, she had worked in biochemistry until at age 34 she began being trained as a speech therapist. Upon completion of her training she worked at the London Hospital where she became Head of the Speech Therapy Department in 1960. In 1966 she moved to Cambridge and joined an interdisciplinary group at Addenbrooke's Hospital where she soon was appointed Head of the Speech Therapy Department. Her mastery of Russian gave her the opportunity to study Russian aphasiology with A.R. Luria and E.S. Beyn and she performed the first cross-language study on agrammatism. For this work, at the age of 59, she obtained a Master's degree at East Anglia University. Margaret Hatfield was operative in the introduction of linguistics and cognitive psychology to the fields of aphasiology and speech therapy. She published with Oliver Zangwill on communication in aphasic patients, with John Morton on therapeutic strategies for naming and with Karalyn Patterson on dysgraphia. Together with David Howard she published a book on the history of aphasia therapy. Finally, it should be mentioned that she introduced presentation of daily life scenes on video into the therapy of aphasic patients (Springer, 1987). There are quite a few British speech therapists who have based their work on principles of, and findings in, neurolinguistics and cognitive psychology. If only one of these is mentioned here, this does not in any way imply a rating. Ruth Lesser of Newcastle University has worked with many of her prominent colleagues, her main theme being the pragmatic aspect of speech therapy. In order to be considered worthwhile, therapy must fulfill two requirements: generalisation to non-trained material and even to "non-targeted behaviours" (Lesser and Wilroy, 1993; Lesser and Alagar, 1995), and stability of improvement in everyday speech over time. In this connection, an interesting technique is conversational analysis. Here, the partner's judgment on the success of conversation provides the measure for improvement in social behaviour. The conversations are

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tape-recorded, transcribed and then subjected to analysis. The aim is not only to assess the patient's disabilities but also his/her compensatory strategies.

CONCLUSIONS Research on acquired language disturbances has undergone a profound change in methods and scope during recent decades. With the introduction of psychological reasoning, methods of assessment and elaboration of data it was recognised that the findings obtained in single case studies could be generalised only to a limited extent. Group studies with proper statistical work-up appeared to offer more reliable answers to questions about the occurrence and interdependence of psychological disorders observed in brain damaged patients. Also, imaging methods gave more reliable indications of the actual brain lesion at the time of examination of the patient than post mortem findings many years later. Group studies, however, gave little insight into the mechanisms of psychological function and dysfunction, a limitation which led again to the introduction of single case studies where the patient's deficit was investigated according to models of cognitive psychology. The uninitiated reader of the pertinent papers is somewhat bewildered if he/she reads that performance of GB differed in important aspects from FG who, in turn, was similar in some, but not all, respects to MR Looking at the graphic representation of cognitive models with boxes or clouds connected by arrows suggesting oneway or two-way flow of information, the neurologist who remembers models developed around the turn of the century admires the greater specification of the boxes, but still cannot help asking to what extent these models reflect the reality of the brain. Functional imaging studies may offer elucidation. An important test for the explanatory value of cognitive models will be the introduction of speech therapy procedures developed along these lines — provided they prove to be more effective than other procedures. On a theoretical level, the assumption implies a great step forward that "the mind's language system is organised in separate modules of processing, and that these can be impaired selectively by brain damage" (Kay, Lesser, and Coltheart, 1992).

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References Baillarger, J.G.F. (1865). De I'aphasie au point de vue psychologique. Masson: Paris. Bastian, H.C. (1869). On the various forms of loss of speech in cerebral disease. British and Foreign Medical and Chirurgical Review 43, 2109-2236, 470-492. Baxter, D.M. and Warrington, E.K. (1985). Category specific treatment of a lexicalsemantic deficit. A single case study of global aphasia. The British Journal of Disorders of Communication 24, 281-299. Butterworth, B. and Howard, D. (1987). Paragrammatism. Cognition 26, 1-37. Critchley, M. (1964). The neurology of psychotic speech. Brit. J. Psych. 110, 353-364. Critchley, M. (1961). Head's contribution to aphasia. Brain 84, 551-560. Critchley, M. (1970). Aphasiology and other aspects of language. Edward Arnold: London. Frackowiak, R.S.J., Friston, K.J., Frith, D.C., Dolan, R.J. and Mazziotta, J.C. (1997). Human Brain Function. Chapter 13: Functional Anatomy of Reading. Academic Press, pp. 301-328. Gainotti, G., Silveri, M.C., Daniele, A. and Giustolisi, L. (1995). Neuroanatomical correlates of category-specific semantic disorders: a critical survey. Memory 3, (3-4), 247-264. Head, H. (1915). Hughlings Jackson on aphasia and kindred affections of speech. Brain 38, 1-190. Head, H. (1926). Aphasia and Kindred Disorders of Speech. Cambridge University Press. Hudson, P. and Eling, P. (1994). Classics in Neurolinguistics, 4: Reader in the History of Aphasia. John Benjamins Publishing Company, p. 283. Kay, J., Lesser, R. and Coltheart, M. (1992). Psycholinguistic Assessment of Language Processing in Aphasia (PALPA): An Introduction. Lawrence Erlbaum Associates. Lesser, R. and Alagar. L. (1995). Towards combining the cognitive neuropsychological and pragmatic in aphasia therapy. Neuropsychological Rehab. 5, 67-92. Lesser, R. and Wilroy, L. (1993). Linguistics and Aphasia: Psycholinguistic and Pragmatic Aspects of Intervention. Longman: London.

46 K. Poeck Marshall, J.C. and Newcombe, F. (1973). Patterns of paralexia: A psycholinguistic approach. Journal of Psycholinguistic Research 2, 175-199. McCarthy, R.A. and Warrington, E.K. (1985). Category specificity in an agrammatic patient: The relative impairment of verb retrieval and comprehension. Neuropsychologia 23, 709-727. McKenna, P. and Warrington, E.K. (1978). Category specific preservation: A single case study. Journal of Neurology, Neurosurgery and Psychiatry 43, 571-574. Patterson, K.E., Marshall, J.C. and Coltheart, M. (eds.) (1985). Surface Dyslexia. Lawrence Erlbaum Associates. Petersen, S.E., Posner, M.J., Mintun, M. and Raichle, M.E. (1989). Positron emisson tomographic studies of the processing of single words. J. Cogn. Neurosci. 1, 153-170. Pick, A. (1913). Die agrammatischen Sprachstorungen. Springer. Reich, St. G. (1988). Destroyers and other verses. Henry Head, the poet. Arch. Neurol. 45, 1257-1260. Riese, W (1947). The early history of aphasia. Bulletin of the History of Medicine 21, 322-334. Shallice, T. (1988). From neuropsychology to mental structure. 5.2. In: Deep Dyslexia. Cambridge University Press, pp. 98-116. Springer, L. (1987). Paper read at the meeting of the Arbeitsgemeinschaft fur Aphasieforschung und -therapie. Warrington, E.K. (1981). Neuropsychological studies of verbal semantic systems. Philosophical Transactions of the Royal Society of London B295, 411-423. Warrington, E.K. (1975). The selective impairment of semantic memory. Quarterly Journal of Experimental Psychology 27, 635-657. Warrington, E.K. and McCarthy, R. (1987). Categories of knowledge: Further fractionation and an attempted integration. Brain 110, 1273-1296. Warrington, E.K. and Shallice, T. (1984). Category-specific semantic impairment. Brain 107, 829-854. Wernicke, C. (1874). Der aphasische Symptomenkomplex. Cohn und Weigert. Reprint Springer, 1974.

TWENTIEH CENTURY NEUROLOGY The British Contribution © 2001 by Imperial College Press

Chapter 4

THE CONCEPT OF HEMISPHERIC LATERALISATION John Stein

In this chapter, I want to make two main points. The localisation by Dax and Broca of the lesions that cause motor aphasia to the left frontal lobe was the first unequivocal evidence for the localisation of a particular function in one part of the cerebral cortex. Hence the idea that each hemisphere might have different functions is inextricably bound up with the basic concept of cortical localisation of function. Yet paradoxically, although they contributed greatly to the concept of cortical localisation, most British neurologists followed the British associationist tradition of resisting the idea that mental operations could ever be localised to a particular part of the brain. The second general point is almost the converse of the above: despite their opposition to attempts of localising mental functions to particular cortical areas, British neurologists were driven to the conclusion that there had to be some degree of localisation. They therefore introduced the idea that each hemisphere makes a distinctive contribution to mental operations; and so invented the concept of complementary specialisation, as opposed to the dominance of one hemisphere. Thomas Willis laid the foundations for whole concept of functional localisation by showing in his 1664 "Cerebri Anatome" that there were identifiably separate structures in the brain. This had to mean that each had a different function. Willis proposed that the organ of thought was the cerebral cortex, and taught that the basal ganglia and cerebellum were 47

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responsible for involuntary motor actions. Apart from his idea that vital functions such as breathing and heart beat were also mediated by the cerebellum, whereas we now believe the cerebellum plays only a calibrating role in vegetative reflexes, one could not quarrel with his scheme today. But further parcellation of the cerebral cortex into separate functional areas was not given serious consideration by scientists before the 19th century, and it was only on the Continent that this concept was pursued very enthusiastically. In Britain, Charles Bell demonstrated the spinal cord basis for reflex actions in 1811, but never suggested that these could explain more than purely automatic behaviour. Marshall Hall promoted both himself and the concept of reflexes applied to the cerebral cortex in the 1830s, thus bringing the word, reflex, into common usage. Thomas Laycock taught that all types of sensori-motor control could be considered in terms of cortical reflexes; but in his writings on the reflex functions of the brain he was clear that mental processes such as volition and emotion were of a different nature altogether. John Hughlings Jackson was briefly Laycock's house surgeon in York, and it was probably Laycock's influence that first set him thinking about these problems, and thus persuaded him that he could do more to help solve them by remaining a physician, than by following his inclination to take up philosophy. Thus the British tradition for explaining mental phenomena remained empirical associationist, rather than materialist localisationist. It had been well summed up in the previous century (1764) by Thomas Southwell who wrote "The Soul is not to be located in any specific part of the brain, because it alone remains when different parts are rotted. It can only be seated in a part of the brain that remains sound, and by no means in those parts that are rotted or otherwise consumed." Since any part might be damaged and yet the Soul — what we would now call consciousness — survived, consciousness cannot reside in any particular part but distributed over the whole brain. However Franz-Joseph Gall, who was a gifted anatomist, working first in Vienna, then in Paris, started looking at the cerebral cortex in a radically new way. He believed that the shape of an individual's skull indicated the size of the different cortical lobes underlying it, and that each correlated with the degree of development of a different mental faculty. His inspired

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correct location of speech in the frontal lobe derived from his observation that his most articulate friends had staring eyes — apparently pushed out by the overgrowth of the frontal lobe behind them. Most of his other evidence for his phrenological schemes was of a similarly weak nature. John Caspar Spurtzheim, also an anatomist by training, espoused Gall's ideas enthusiastically; but he was nothing like so influential or so financially successful in France. Magendie ridiculed the whole enterprise. He showed Spurtzheim a brain which he pretended was that of Laplace, the famous mathematician. Apparently Spurtzheim described the perfect convolutions of this brain with "extravagant admiration" — only to be told by Magendie gleefully, that actually the brain that he had so much admired was that of an imbecile. Temporarily deflated by that experience he tried his luck in England, where he was hardly more successful. He finally crossed the Atlantic to Boston, where the Americans with their characteristic enthusiasm for innovation were much more receptive. Flourens finally demolished the whole scientific basis of phrenology in the course of the experiments in animals that he was undertaking to disprove notions of localisation of function and to support his theory of cortical equipotentiality. After making lesions in different parts of the cerebral cortex he found none of the differences in the animals' behaviour that had been predicted by the phrenologists. So he concluded that there was no evidence for localisation of function and thus none for phrenology. Nevertheless, although scientifically disproved, the climate of opinion prepared by people thinking about the problems raised by the phrenologists' ideas meant that when Broca presented his evidence for the localisation of speech in the third frontal convolution, this Zeitgeist, combined with the high standard of his evidence and his high reputation, ensured that the idea was accepted remarkably rapidly. Initially, even Broca resisted the idea that if a lesion was to affect speech it had to be in the left hemisphere. Willis's observation together with the clear diagrams drawn by his gifted assistant, Christopher Wren, had established that the cerebral cortex consists of two separate hemispheres; and this observation led logically to the question, what are the separate functions of the left and right hemispheres? But in general this question

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was not even asked. Even the phrenologists adhered to Bichat's "law of symmetry", which stated that the two hemispheres are duplicates of each other and have identical functions. Hence Gall thought that his 25 areas were duplicated in the left and right hemisphere, as did his disciples in England and the USA, such as George Combe. By 1866 however, Broca's new cases plus those of Dax pere that had been drawn to his attention by his son, convinced him that speech was located in the left hemisphere and the concept of "/a gaucherie cerebrate", left cerebral dominance, was born. His acceptance of this degree of hemispheric specialisation was probably also influenced by the English neurologist, William Moxon, who had emphasised the bilateral symmetry of all animals. He thought that the left side is educated by the Will for the power of speech, and believed that if the right side were similarly educated it too could become as proficient at speech, an idea which was confirmed nearly a century later. On the whole however, the idea of precise localisation of function in the cerebral cortex was disparaged in Britain and regarded as a typical example of Continental excess. So British neurologists were presented with a thorny problem when they themselves provided more evidence for the localisation of some functions in the cerebral cortex and the concept became irresistible. Hughlings Jackson himself had predicted that there was a representation of different movements in the corpus striatum from the "march" of body parts affected during the development of a focal epileptic attack. David Ferrier confirmed that separate movements were represented, but in the precentral gyrus, rather than in the corpus striatum, with which Hughlings Jackson quickly concurred. Ferrier also confirmed Munk's localisation of the primary visual cortex in the calcarine fissure, after first making the mistake of localising it to the angular gyrus. He had found that stimulation there in monkeys caused the eyes to move to the opposite side and lesions there seemed to blind the animals on the contralateral side. But after he started using the antiseptic techniques of a colleague who had just arrived at Kings College Hospital, Joseph Lister, his animals survived their surgery for more than a few days, and he was able to confirm that they were not blind, merely neglectful of the contralateral side.

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But Hughlings Jackson also noted how commonly his patients with left sided lesions and aphasia could nevertheless still produce what he called automatic speech, swear words, jargon, singing etc. This was evidence that all of speech could not be located in the left frontal lobe. So he ascribed the machinery for voluntary speech production to the left third frontal convolution, but automatic speech to the right hemisphere. Pondering the inconsistency between the evidence for functional localisation in the cortex and his strong belief that mental functions could not be localised in the brain, Hughlings Jackson began to make an explicit distinction, not appreciated by Broca or his Continental followers, between physical or physiological functions which he now believed could be located precisely in the cortex, and mental functions which he still believed could not. He partitioned language into 3 separate systems: sensory input, internal speech (thought) and motor output, physical articulation as he called it. The input and output systems he believed could be physically localised, and activated automatically as in automatic speech; but he did not think that internal mental speech could be. Interestingly this is broadly in line with the scheme that modern imaging techniques have suggested today. Hughlings Jackson had also noted that after left sided strokes some patients, even if they had no paralysis, had severe difficulties performing voluntary skilled movements; in particular aphasic patients often had problems with protruding their tongues on demand or miming particular actions. He observed that they could often perform the same acts automatically in response to their normal trigger and suggested that such patients had problems in mentally conceiving the acts rather than performing them. It was Liepmann however who described such apraxias in greater detail, and who supplied our present terminology. But Jackson incorporated his observations on apraxia into his general conclusion that whilst input and output systems could probably be physically localised in different parts of the cerebral cortex, the mental events that occurred in between, carried out by Jackson's "highest level", were mediated by distributed systems that were not seated in localised areas of the brain. British neurologists have tended to follow Jackson's lead ever since. Henry Maudsley, Charles Bastian, Henry Head, even David Ferrier, rejected the simplistic localisation of the whole of language to the left third inferior

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frontal convolution. Their views are enshrined in Hughlings Jackson's famous dictum "to locate the lesion which destroys speech is not to localise speech". By this he did not mean that speech might be localised somewhere else. He meant that the language system embraced many other regions of the cerebral cortex, including parts of the right hemisphere as well, as was later confirmed by Wernicke and Dejerine and even more so by today's functional imaging techniques. In modern terms, language should be described as mediated by a parallel distributed network. So destroying one node may impair it considerably for a while; but other components can usually adapt to the new architecture of the network, and can restore function to a large extent, as Jackson commonly observed in his patients. Henry Maudsley, the strongly materialist "alienist" (we would now call him a psychiatrist), believed that the two sides of the brain were equipotent, and he ridiculed the idea that the whole of language could be mediated by one small area of the left frontal lobe. Likewise Charles Bastian and David Ferrier doubted that language could be treated in the same way as movement or the representation of the retina in the primary visual cortex, and whilst they agreed with Hughlings Jackson that only the left hemisphere could become "conscious in words", they believed that the right hemisphere played an important part in language, particularly in its perception. The British tradition of localising primary motor and sensory "physical" functions to separate parts of the brain, but not higher mental functions, continues to this day. Gordon Holmes wrote "mental processes cannot be regionally localised but the physiological machineries by which propositions can be expressed in spoken or written words, and those which underlie their comprehension are localisable, though probably less sharply than less highly evolved functions. As Hughlings Jackson pointed out years ago, localisation of a speech disorder does not justify the localisation of speech there. The use of such terms as "centres" which imply that they are sharply circumscribed is therefore inappropriate". Likewise Henry Head wrote of localisationists: "they have failed to contribute anything of permanent value to the solution of the problems of aphasia because they have been dominated by a philosophical fallacy They believed that for every mental act there had to be a corresponding

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neural element The time is ripe for ruthless destruction of these false gods and a return to systematic empirical observation". Francis Walshe was not only dismissive of the whole idea that mental functions could be localised in single areas of the cortex; but he took up the cudgels against the excessively punctate localisationists that he discerned in the school of John Fulton across the Atlantic. He adopted as his war cry Hughlings Jackson's remark that the motor cortex "thinks in terms of movements not muscles" — an argument that reverberates to this day. Macdonald Critchley in his book on aphasia wrote "it is wise to avoid as far as possible the term localisation and to speak instead of specialisation. Language is subserved by a whole system of interconnected structures." Even though some have criticised modern functional imaging as "modern phrenology", these techniques have confirmed the connectionist view with a vengeance. An extensive system of interconnected regions is activated during language tasks; and it requires sophisticated and taxing linguistic tests to show greater activation of the left hemisphere than the right. Likewise, even for such a "primary" perceptual function as colour appreciation, Alan Cowey and others have shown clearly that an extensive interconnected system of structures is activated and one cannot usefully talk about a single "colour centre". Hughlings Jackson's other objection to Broca's "la gaucheries cerebrate" the concept of left cerebral dominance, is that it ascribed no function at all to the right hemisphere. Indeed even in the 1950s, the late J.Z. Young who was the zoologist who introduced the squid giant axon to biophysicists, could write flippantly that it looked as if one could do without the right hemisphere because it had no apparent function; but, he added, "I think I'd prefer to keep mine just the same". Yet Hughlings Jackson had produced good evidence for "complementary specialisation" almost 100 years earlier. He had proposed that the right hemisphere was important for automatic speech and also for perception. One of his major reasons was that his left hemisphere patients with aphasia were not poor in their perceptual abilities, whereas he was able to collect quite a large number of patients with rightsided lesions with perceptual disturbances, "imperception", disordered higherorder perception such as topographical agnosia.

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Gordon Holmes then described visual neglect clearly in World War I soldiers with gunshot lesions that damaged the posterior parietal cortex. But it was not until after World War II that unilateral neglect began to be studied in greater detail. Russell Brain described many more patients with parietal lobe lesions who showed inattention and neglect and it was he who first pointed out that right-sided lesions cause neglect on the left side far more frequently than left-sided lesions do on the right. In World War II, patients survived head injuries much more frequently than in World War I as a result of the treatment innovations introduced by the Oxford neurosurgeon, Hugh Cairns, W. Ritchie Russell, Michael Espir and Freda Newcombe followed up on a large number of these subjects and confirmed Hughlings Jackson's views to an astonishing extent. They showed clearly that left sided lesions gave rise to problems with language as assessed by their verbal fluency and ability to learn nonsense words, whereas right sided lesions gave rise to visuospatial problems such as face recognition, and learning their way round a maze. In fact, the idea of complementary specialisation had been put forward by Arthur Wigan even before Hughlings Jackson, as early as 1844. He thought that the two hemispheres of the brain were complementary, and that insanity was the result of one not controlling the other properly. He had very little evidence for this inspired suggestion; but in memory of it Roger Sperry suggested that his re-discovery of the complementary specialisation of the functions of the right hemisphere in split brain patients should be called neo-Wiganism. Later in the 19th century, clear evidence became available that there are anatomical differences between left and right hemispheres that unequivocally supported the functional differences that Hughlings Jackson had suggested. D.J. Cunningham reported in 1892 that left sylvian fissure was more than 12% longer and flatter than on the right. Cunningham found that this was true even in IV2 month old foetuses, long before they acquire language, proving that the anatomical differences were innate and not acquired as a consequence of learning to speak. But an observation that he did not choose to dwell upon was that he also found the same differences between left and right sylvian fissures in chimpanzees, a finding incompatible with the idea that hemispheric differences were confined exclusively to humans to support

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their evolution of language. Cunningham's observations were so opposed to the prevailing views on language that they were almost completely neglected until the 1960s when Norman Geschwind confirmed and extended them. Now it is difficult to understand why they were so unpopular. Nevertheless until the late 20th century, neurologists and physiologists showed remarkably little interest in the functions of the right hemisphere or in the role of the corpus callosum linking the two. What little comment there was tended to be rather facetious. William McDougall, who founded the Psychology School at Oxford University before leaving for Harvard, asked Sir Charles Sherrington to cut through his corpus callosum if he contracted an incurable disease "If I am right I should retain one consciousness; but if the physiologists are right then I should have two." Roger Sperry's experiments on split brain patients proved the physiologists right in a sense, but McDougall died with his corpus callosum intact. Karl Lashley, who supported Flourens' antilocalisationist ideas, joked that the corpus callosum's only function seemed to be to prevent the hemispheres away from each other sagging and the neurosurgeon Walter Dandy was adamant that no symptoms ever followed from his dividing the corpus callosum to gain access to tumours. Although scientists were then disinterested and disparaging, the general public were fascinated, as they still are, by hemispheric differences. The British Ambidextrous Society was founded in 1903 in the belief that "each hemisphere is a distinct and perfect organ of thought, so both should be educated by cultivating ambidextrality, to counter the folly of wasting half the educational potential of future generations." But Sir James CrichtonBrowne, "the English Goliath of lopsidedness" according to the ambidextralists, attacked the movement vigorously. He "reaffirmed that it is by the superior skill of his right hand that man has gotten himself the victory. To try to undo his dextral pre-eminence is simply to fly in the face of evolution. The ambidextral movement is foolish, visionary and pernicious, including among its advocates those who are addicted to vegetarianism, hatlessness, anti-vaccination and other abhorrent beliefs." The ferocity of this attack by a neurologist is rather revealing, and suggests that official medicine felt threatened. Even today those who extol the powers of the right hemisphere tend to be regarded as cranks.

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Nevetheless, we still find difficulty explaining how we experience only one consciousness, even though the two halves of the brain can potentially lead different lives. Descartes attempted to locate the solution to the problem in the pineal gland, a midline structure which he wrongly believed was only found in humans. Here he believed the Cartesian theatre to be played out, observed by the Soul and ultimately by God. Richard Owen ascribed the same function to the "hippocampus minor" which was thought to be found only on the left, but now believed to have been an artefact. Today most of us have returned to Hughlings Jackson's views. We believe that mental functions are the product of a network of systems distributed within and between the hemispheres, linked by the corpus callosum. But quite how this generates a single self still eludes us. References 1. Willis, T. (1664). Cerebri Anatome, Martin, T. and Allistry, T., London. 2. Bell, C. (1802). The Anatomy of the Brain Explained in a Series of Engravings. Longman, London. 3. Hall, M. (1841). On Diseases and Derangements of the Nervous System. Bullier, J.B., London. 4. Laycock T. (1845). On the reflex functions of the brain. British and Foreign Medical Review 19, 298-311. 5. Gall, F.J. (1825). Sur les fonctions du cerveau. Bailliere, J.B., Paris. 6. Carmichael, A. (1833). A Memoire of the Life and Philosophy of Spurtzheim. Wakerman, W.F., Dublin. 7. Flourens, P.F. (1824). Recherches experimentales sur les proprietes et les fonctions du systeme nerveux dans les animaux vertebres. Craiveau, F., Paris. 8. Broca, P. (1860). Perte de la parole. Remarques sur le siege de la faculte du languge articulee suivi d'une observation d'aphemie. Bull, de la Societe 36, 330-357. 9. Bichat, X. (1805). Recherches physiologiques sur la vie et la mort. Gabon, R., Paris. 10. Combe, G. (1825). A System of Phrenology. Anderson, J., Edinburgh. 11. Dax, M. (1836). Lesions of the left of the brain coincident with loss of thought. In: The Roots of Psychology, ed. S. Diamond, Basic Books, New York 1974.

The Concept of Hemispheric Lateralisation 57 12. Moxon, W. (1866). On the connection between the loss of speech and paralysis of the right side. The British and Foreign Medico-Chirurgical Review 37, 481-489. 13. Jackson, J.H. (1873). On the anatomical and physiological localisation of movements in the brain. Lancet 1, 84-164. 14. Ferrier, D. (1876). The Functions of the Brain. Dawsons of Pall Mall, London. 15. Glickstein, M. (1985). Ferrier's mistake! Trends in Neuroscience 8, 341-345. 16. Jackson, J.H. (1874). The nature of the duality of the brain. In: Selected Writings of John Hughlings Jackson, Vol. 2, pp. 129-145. 17. Jackson, J.H. (1878). On affections of speech and diseases of the brain. In: Selected Writings of John Hughlings Jackson, Vol. 2, pp. 155-170. 18. Jackson, J.H. (1893). Words and other symbols in mentation. Medical Press and Circular 2, 205-208. 19. Maudsley, H. (1895). The Pathology of Mind — A Study of Its Distempers, Deformities and Disorders. Macmillan and Co, London. 20. Bastian, H.C. (1880). The Brain as an Organ of Mind. Kegan Paul, London. 21. Holmes, G. (1946). Clinical Neurology. Livingstone, London. 22. Head, H. (1926). Aphasia and Kindred Disorders of Speech. Cambridge, University Press. 23. Walshe, F.M.R. (1947). On the role of the pyramidal system in willed movements. Brain 70, 329-345. 24. Critchley, M. (1970) Aphasiology and Other Aspects of Language. Edward Arnold, London. 25. Heywood, C.A. and Cowey, A. (1992). Cortical area V4 and its role in the perception of colour. J. Neurosc. 12, 4056-4065. 26. Jackson, J.H. (1876). Case of large cerebral tumour with left hemisphere and imperception. In: Selected Writings of John Hughlings Jackson, Vol. 2, pp. 146-152. 27. Holmes, G. and Horrocks, G. (1919). Disturbances of spatial orientation and visual attention. Archives of Neurology and Psychiatry 1, 385-407. 28. Brain, W.R. (1941). Visual disorientation with special reference to lesions of the right hemisphere. Brain 64, 244-272. 29. Russell, W.R. and Espir, M.L.E. (1961). Traumatic Aphasia. Oxford, University Press. 30. Wigan, A.L. (1844). A New View of Insanity — The Duality of the Mind. Longman Brown, London.

58 J. Stein 31. Cunningham, D.J. (1902). Right handedness and left brainedness. Journal of the Royal Anthropological Institute of Great Britain and Ireland 32, 273-296. 32. Geschwind, N. and Levitsky, W. (1968). Human brain; left/right asymmetries in temporal speech region. Science 161, 186-187. 33. McDougall, W. (1911). Body and Mind. A History and Defence of Animism. Macmillan, New York. 34. Lashley, K.S. (1929). Brain Mechanisms and Intelligence. Chicago University Press. 35. Dandy, W.E. (1930). Changes in our conception of the localisation of function in the brain. American J. Physiology 93, 643. 36. Jackson, J.H. (1909). Ambidextrality — recent criticism; a reply to Sir James Crichton-Browne's lecture on dexterity and the bend sinister. The General Practitioner, February 6 and 13. 37. Crichton Browne, Sir J. (1907). Dexterity and the bend sinister. Proc. Royal Institution of Great Britain 18, 623-652. 38. Owen, R. (1894). The Life of Richard Owen. Murray, J., London.

TWENTIEH CENTURY NEUROLOGY The British Contribution © 2001 by Imperial College Press

Chapter 5

JAMES HINSHELWOOD (1859-1919) AND DEVELOPMENTAL DYSLEXIA Wilhelmina M.H. Behan

INTRODUCTION In 1900, just at the turn of the century and within two months of each other, two boys, one aged 10 years and the other aged 11 years, were brought to Glasgow Eye Infirmary by their respective fathers for a consultation with Dr. James Hinshelwood, the ophthalmic surgeon. Each father told the same story: the boy was intelligent and bright, spoke well, had an excellent memory and was good at mathematics but he could not read. After more than five years at school, he could not even recognise all the letters of the alphabet, let alone more than a handful of words — and the latter only if he spoke each letter out loud before attempting the whole word (Hinshelwood, 1900). There was no question of any visual defects in these children and they were referred specifically to Dr. Hinshelwood because he was known to have an interest in the cerebral causes of visual problems, especially "wordblindness" (Behan and Behan, 1989). Up to this time he had only seen the condition in adults who had had a stroke and developed what appeared to be sudden "acquired illiteracy" (Hinshelwood, 1895; 1896a; 1898; 1899a). He knew of the possibility that congenital cases existed, however, because one of his published articles had attracted the attention of Dr. Pringle Morgan, a general practitioner in the seaside town of Seaford where there used to be many boys' preparatory schools. Dr. Morgan wrote a letter to the British 59

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Medical Journal (Morgan, 1896) describing an intelligent 14-year-old boy who appeared to be incapable of learning to read and sent Hinshelwood a reprint of his contribution with a covering letter as follow: "It was your paper — may I call it your classical paper? — on word-blindness and visual memory published in the Lancet on the 21st December, 1895 which first drew my attention to this subject and my reason for publishing this case was that there was no reference anywhere, so far as I knew, to the possibility of this condition being congenital" (Hinshelwood, 1917). There had in fact been one previous, very brief reference to such cases by Dr. James Kerr, Medical Officer of Health to the City of Bradford, in his essay on "School Hygiene in its Mental, Moral and Physical Aspects" for which he was awarded the Howard Medal by the Royal Statistical Society in 1896. He commented that among schoolchildren: "besides the generally dull there are the mentally exceptional Almost unique cases are found with the most bizarre defects A boy with word-blindness who can spell the separate letters, is a trouble" (Kerr, 1897). Hinshelwood's examination of these two boys in 1900 started him on a course of study which ended only shortly before his death, when he consolidated his work in his book "Congenital Word-Blindness" (Hinshelwood, 1917). He was the major player in the field of congenital, or as it is now known, developmental dyslexia for nearly two decades (Hinshelwood 1900; 1902a,b; 1904a,b; 1907; 1911; 1912; 1917). It was he who first postulated that the disorder was due to faulty development of the specific cerebral area which deals with the visual memory of words and letters, namely the left angular gyrus and its associated fibres, and his concept is as valid today as when he first stated it (Hinshelwood, 1904b). He pointed out that: "We are apt to forget that we see with our brains as well as our eyes... the brain contributes quite as much to each visual act as the eye itself, and there are many visual defects, where the eye is

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perfectly healthy and where the lesion lies in the cerebral centres of vision" (Hinshelwood, 1899b). All the main features of the disorder were delineated by Hinshelwood: first, the fact that it is associated with normal or above average intelligence, and sometimes with markedly above average mathematical ability. Secondly, that boys and girls are affected: he reported ten boys and two girls, similar as he said, to the 81% predominance in males seen by his contemporaries (Hinshelwood, 1917). For many years dyslexia was thought to be commoner in boys but the incidence is now established as similar in the two sexes (Shaywitz, 1998). It may have been weighted originally because of the greater importance then attached to boys' education. He drew attention to the familial and hereditary nature of the disorder and he stressed the value of a kind and humane approach to these children, based on individual instruction. This was most important he wrote, because otherwise: "these children may be harshly treated as imbeciles or incorrigibles and either neglected or flogged for a defect for which they are in no wise responsible" (Hinshelwood, 1890). It is sad to record that after his death his work fell into obscurity. The idea that an anatomical lesion was responsible was treated with scorn and functional, educational or psychological hypotheses abounded. Macdonald Critchley, an acknowledged authority (1964, 1970, 1986) defined dyslexia as follows: "a learning disability which initially shows itself by difficulty in learning to read, and later by erratic spelling and lack of facility in manipulating written as opposed to spoken words. The condition is cognitive in essence, and usually genetically determined. It is not due to intellectual inadequacy or to lack of sociocultural opportunity, or to faults in the technique of teaching, or to emotional factors, or to any known structural brain defect. It probably represents a specific maturational defect which tends to lessen as the child grows older" (Critchley, 1986, my bold italics).

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Even now, the definition of the disorder includes no reference to a structural abnormality: "Developmental dyslexia is characterised by an unexpected difficulty in children and adults who otherwise possess the intelligence, motivation and schooling considered necessary for accurate and fluent reading" (Shaywitz, 1998). It has now been proved, however, that dyslexia is not a developmental lag (Shaywitz, 1998) but shows incontrovertible evidence of an anatomical lesion (Drake, 1968; Galaburda and Kemper, 1979; Geschwind and Behan 1984; Geschwind and Galaburda, 1987c). It is therefore time to vindicate Hinshelwood and establish forever his true place in the study of developmental dyslexia.

DEVELOPMENTAL DYSLEXIA Developmental dyslexia, defined simply as an unexpected difficulty in reading in children who otherwise possess the necessary intelligence, motivation and schooling, is the most common neurobehavioural disorder affecting children, with prevalence rates ranging from 5 to 17.5% (Shaywitz, 1998). Early work suggested that dyslexia affected boys more often than girls but recent data indicates similar incidence in the two sexes (Shaywitz et ah, 1990, Shaywitz, 1998). Longitudinal studies, both prospective and retrospective, show that dyslexia is a persistent chronic condition, which lasts throughout life and is not a transient defect in maturation (Shaywitz, 1998). It is familial and hereditary. A family history is one of the most important risk factors with up to 65% of children who have a parent with dyslexia reported to have the disorder. 40% of siblings of affected persons are dyslexic and from 27-49% of their parents. Family linkage studies suggest involvement of loci on chromosomes 6 and 15 (Shaywitz, 1998). A phonologic model of reading, in which the process is divided into two parts, has been helpful in trying to understand the basic lesion. The first part consists of decoding the words and the second, of comprehension. In dyslexia, it is considered that there is difficulty in decoding, i.e. an inability

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to segment the written word into its phonologic elements and so identify it. This is a specific difficulty, not associated with any other cerebral problems. Comprehension is intact, along with all the other higher cognitive functions (Shaywitz, 1998). Oral instruction, for instance, presents no problems at all, as Hinshelwood frequently mentioned. The Study of Acquired Dyslexia It was the study of acquired dyslexia which led to identification of the congenital form and it was Hinshelwood's series of papers on the former which provided the first analyses in the English language literature. When he started his work he had to spend considerable time looking for previous references because the condition had attracted very little attention in Britain or the USA (Hinshelwood, 1895). Almost all studies up to then had been done by French and German workers. A most striking, personal account was given by Professor Lordat of Montpellier who described what had happened to him suddenly in 1843: "Whilst retaining the memory of the significance of words heard, I had lost that of their visible signs. Syntax had disappeared along with the words; the alphabet alone was left to me .... When I wished to glance over the book which I was reading when my malady overcame me, I found it impossible to read the title. I shall not speak to you of my despair, you can imagine it After several weeks of profound sadness and resignation, I discovered whilst looking from a distance at the back of one of the volumes in my library, that I was reading accurately the title "Hippocratis Opera ". This discovery caused me to shed tears of joy" (reported in Critchley, 1964). Other French and German contributions (reviewed in Critchley, 1964) followed. Kussmaul (1877) coined the term "word-blindness" (wortblindheit) and demonstrated that word-blindness is an isolated clinical condition: "a complete text-blindness may exist, although the power of sight, the intellect and the powers of speech are intact"

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while Professor Berlin (1897) used "dyslexia", in his monograph on clinical and autopsy findings in a similar case. The first British case was reported by Sir William Broadbent, describing a man admitted to St Mary's Hospital, in London, after a minor street accident. He could not follow the signs to the Casualty Department because, since a mild stroke the previous year, he could not understand written words, although he could see them. Shortly afterwards, he had a fatal cerebrovascular accident and at autopsy, as well as a recent lesion, an old infarct in the left angular and supramarginal gyri was found. It was this which was considered significant by Broadbent (1872). When Hinshelwood published his first major article in 1895, Broadbent wrote to him to draw attention to this description (Broadbent, 1896). Hinshelwood's article on "Word-blindness and visual memory" in 1895 was followed by several others and a book "Letter-Word-, and MindBlindness" published in 1899 (Hinshelwood, 1895, 1896a,b; 1898; 1899a,b; Hinshelwood, McPhail and Ferguson, 1904). The first case he described presented at Glasgow Eye Infirmary since, as Hinshelwood stressed, these patients were always under the impression that they had developed something wrong with their eyes. This was a 58-year-old teacher of French and German who awoke one morning to find he could not read the exercise which a pupil had given him to correct. He was so puzzled he called in his wife to ask her to read it — which she did without the slightest difficulty — but he still could not. His visual acuity was unimpaired and he could see all the letters plainly and distinctly but made the most absurd mistakes in naming them. He could write fluently and with ease to dictation but then could not read what he had written. However, he could read instantly and correctly the number at the top of the page. He also had a right homonymous hemianopia of which he was unaware (Hinshelwood, 1899b). He remained under Hinshelwood's care after his stroke and, when he died suddenly nine years later, his brain was made available for examination. Hinshelwood and his colleagues found a large, old, triangular infarct: "limited by the calcarine fissure internally and by the third temporal gyrus externally, with its apex at the occipital pole; the cortex of the cuneus (above the posterior calcarine fissure and

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between it and the parieto-occipital fissure) appears altogether normal, though the fibres — in the roof of the posterior horn of the lateral ventricle—passing to and from the cuneus must necessarily have been encroached up by the great dilatation of that cavity, while this same cause must have interfered, to a large extent, with all the fibres connected to what remained of the occipital cortex (including the tract usually described as the optic radiation), and also with the fibres ascending to the left angular gyrus from the left and right primary visual centres at the calcarine fissures. When the clinical symptoms are taken in conjunction with the existence of a lesion completely destroying both the cortex and the fibres of the infracalcarine area (while the cuneus remained apparently normal), we must conclude that the greater part at least of the visual centre lay in this case, distinctly below the level of the calcarine fissure" (Hinshelwood, McPhail and Ferguson, 1904). Hinshelwood was confident that there was an anatomical basis for wordblindness, especially when he compared this case to one of Dejerine's in which the anatomic lesion was very similar (Fig. 1) (Dejerine 1891; 1892 and discussed in Hinshelwood, 1904). He postulated that destruction of the cortical area dealing with letter and word-memory, or of its communicating fibres, in the left cerebral hemisphere occurred. He and Dejerine localized the lesion to the left cerebral hemisphere because all their patients had a right homonymous hemianopsia: by chance, they all appear to have been right-handed. By 1899, Hinshelwood had seen five cases of pure acquired dyslexia himself as well as various other types of letter-, word-, mind-blindness, word-deafness, motor aphasia or verbal amnesia and had studied reports of nine others. He was ideally placed to recognise and define developmental dyslexia. Identification of Developmental Dyslexia There is no doubt that the accurate clinical descriptions of acquired dyslexia made by Hinshelwood formed the basis for the discovery of the

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OCCIPITAL CORTEX Fig. 1. Hinshelwood's modification of Dejerine's diagram in a case of acquired dyslexia, to illustrate the effect of the lesion on the visual memory centre.

developmental, or as it was known originally, congenital form. Dr. Morgan, reporting the first case in a short letter to the British Medical Journal (1896) acknowledged this completely. Hinshelwood went on to demonstrate his mastery of the field by publishing no less than eight papers on congenital word-blindness before summarising all his views in "Congenital WordBlindness", the book he published two years before his death (Hinshelwood 1900; 1902a,b; 1904a,b; 1907; 1911; 1912; 1917). Naturally, he was disappointed that he was not the first to recognise developmental dyslexia, as shown by the following statement in one of these papers: "I have never claimed to have reported the first case of congenital word-blindness, but I do claim that this paper published in 1900

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was the first attempt in medical literature to analyse and explain the symptoms in detail, to place the diagnosis on a scientific basis and to show that the difficulties encountered in teaching these children to read could be overcome by patient and persistent training" (Hinshelwood, 1907). The first paper he wrote on developmental dyslexia (Hinshelwood, 1900), concerned four cases — two of his own, the one described very briefly by Morgan in his letter to the British Medical Journal (1896) and one under the care of Dr. Bastian. These cases were the prototypes and the characteristic features were refined in the ensuing articles i.e. an 11-year-old boy, whose teachers had finally given up the attempt to teach him to read, brought to the ophthalmologist for visual tests. For the first three or four years at school, the defect was not recognised because the boy had a very good memory and learnt his lessons by heart. Thus, whenever it came to his turn to read, he was able to disguise the fact that he was unable to do so. He could repeat the letters of the alphabet by heart but recognised only a few by sight, and those with uncertainty. He named other visual objects without difficulty. He could recognise figures easily and do mental arithmetic with no problems. He seemed quite as intelligent as his brothers and sisters and could learn from oral instruction with ease. The excellence of the auditory memory in these boys was documented by Hinshelwood in a pleasant anecdote about his first case: he asked the father and son to call later at his house for a consultation, writing down the address on the envelope. Just before the appointment was due, the father realised he had lost the address but the boy immediately repeated it correctly, having heard Hinshelwood say it once only. Hinshelwood recommended individual instruction with constant but short periods of practice for these children. In this case, by six weeks later, the boy could recognise many letters, although not all and still no words. Hinshelwood concluded that the visual memory for words and letters was congenitally defective in these children and, based on his studies of acquired dyslexia, he postulated that a specific cerebral area — the angular and supramarginal gyri on the left side of the brain — was involved. He suggested originally that word-blindness could result from disease, injury

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at birth or defective development of this area but, after studying familial and hereditary cases, concluded that faulty development was the cause (Hinshelwood, 1907). The fact that the condition could be familial was drawn to Hinshelwood's attention by a report from Dr. CJ Thomas, the Assistant Medical Officer of London County Council in 1905 (cited in Critchley, 1964) and he reported an affected family himself shortly afterwards, in which the youngest four boys of a family of 11 children were involved (Hinshelwood, 1907). They were brought to him by the headmaster of Calderwood School, on the south side of Glasgow, who had no difficulty in teaching the first seven in the family, but then encountered these four. They had been at the school from seven to nine years and the story was similar in each case: an intelligent boy who after all this time could not read even the childrens' First Primer. He knew most of the letters of the alphabet but could not recognise more than a few simple words and those only by spelling them out loud — without this aid, he could not even recognise them. He could learn anything easily on oral instruction and could name all visual objects. A feature on which Hinshelwood laid stress, was that these boys, like the others he saw, read figures fluently and progressed well in mathematics. After the boys left school, their progress in reading was nil or very poor.

MAIN EVENTS OF HINSHELWOOD'S LIFE James Hinshelwood was born in Glasgow in 1859 and graduated from Glasgow University with an M.A. in 1880 and MB CM in 1884. He had an excellent undergraduate career, winning the Junior and Senior Arnott Prizes, in addition to medals in Anatomy and Surgery. He obtained an MD "With Commendation" in 1889 for his thesis on "Syphilitic Disease of the Nervous System" and proceeded to Fellow of the Royal Faculty of Physicians and Surgeons in 1896. His first job was that of resident surgeon at the North Riding Infirmary, Middlesborough. He then returned to Glasgow to become assistant to Professor McColl Anderson at the Western Infirmary. He had a reputation as a careful, enthusiastic and inspiring teacher and he and his surgical

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colleagues gave a very successful lecture course each year to 150 students. He left the Western Infirmary in 1891 to join the staff of the newly established Glasgow Eye Infirmary, only the second such institution to be set up in Britain, 20 years after Moorfields Eye Hospital. He became an acknowledged expert on the cerebral causes of visual defects, publishing in the medical journals and attending national and international meetings — including the 12th International Medical Congress in Moscow. His health, however, was never very good and he had to retire in 1914 to the South of France at the age of 55 years. He attracted many tributes at this time and his portrait was taken (Fig. 2). He completed his work on congenital word-blindness in retirement and died in 1919, survived by his second wife and the daughter of his first wife. The Obituary Notice which appeared at that time stated that "his

Fig. 2. Portrait of James Hinshelwood, at the time of his retirement from the Glasgow Eye Infirmary.

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character may be summed up as earnestness, coupled with capability; and he had the good fortune to have this recognised early in his professional career".

AFTER HINSHELWOOD Functional Defects as the Basis for Dyslexia It is disappointing to record that the concept of an anatomical defect so ably put forward by Hinshelwood fell out of favour after his death and functional or psychological abnormalities were proposed. Samuel Orton, Director of the Greene County Mental Clinical in Iowa, exerted an enormous influence from this time. He had discovered 15 children whose only mental abnormality was that they could not read, among a series of obviously retarded children. The first was a 16-year-old boy who told him "Mother says there is something funny about me, because if you read anything to me, I get it right away but if I read it myself I couldn't get it" (cited in Critchley, 1964). Orton's interest was aroused and he travelled to England to put the problem before the leading neurologist of the time, Henry Head, who had in fact retired. Orton believed that normally, during early visual education, storage of memory images of letters and words takes place in both hemispheres with external visual stimuli radiating equally into both. He postulated that the process of learning to read entails the removal of the confusing mirrorimaging of the non-dominant hemisphere which is in reverse order, and the selection of those images which are in correct orientation and sequence. He proposed that, in cases of reading disability, there is an incomplete elision of the memory patterns in the non-dominant hemisphere. He concluded that in congenital dyslexia, there is a physiological state of ambiguous cerebral dominance, what might be called a faulty patterning of brain function. For this defect, he proposed "strephosymbolia", a difficult term which has never caught on (Orton, 1925). He pointed out that the children could sometimes read the text better in a mirror or upside down, and they often stuttered and were left-handed. He thought they could be exceptionally clumsy: Hinshelwood had not found this and it is likely that

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he was correct because later studies by Geschwind documented an unusual number of dyslexics in competition level sports (Geschwind, 1982). Others suggested there was a maturational lag, a slower than normal differentiation in the brain in these children, not a structural defect but a functional one. This implied that the dyslexic could grow out of his/her disability and achieve success or even distinction later on, a so-called "late bloomer". Hans Christian Anderson has been quoted as such a case, as discussed by Critchley (1964) who reported that he was a very poor scholar, especially weak at reading and arithmetic and never mastering the art of spelling, with numerous errors in his manuscripts of a type which strongly suggests a dyslexic background. Critchley himself made an intensive study of congenital dyslexia, summarising his views in "Developmental Dyslexia" (1964) and "The Dyslexic Child" (1970). His writings exerted an enormous influence for many years. At the end of all his work, however, Critchley concluded wrongly that a specific maturational defect, and not an anatomical lesion, was the cause. The Demonstration of Anatomical Asymmetry and the Anatomic Basis of Dyslexia It was the work of Geschwind which led workers back to an anatomic basis for the disorder (Geschwind and Levitsky, 1968). It had been readily accepted for many years that the brain is functionally asymmetrical, e.g. the left hemisphere usually controls language and manual skills while the right hemisphere is more involved with spatial and musical abilities, attention and aspects of emotion. Geschwind showed that these features are based on anatomical asymmetry, i.e. the phenomenon called lateralisation. One of the areas of the brain which is obviously asymmetrical, larger on the left than on the right in the majority, is the upper surface of the posterior portion of the temporal lobe, the region known as the planum temporale (pt). This area forms a large part of the temporal speech region of Wernicke, and thus its asymmetry may account for the fact that speech is located in the left hemisphere in the majority of humans. Anatomical differences between the left and right hemispheres appear to be a fundamental feature of cerebral development throughout the animal

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kingdom (Geschwind and Galaburda, 1987b). In humans, asymmetry is detectable in the foetus as early as the 31 st week of gestation. The basic pattern appears to be one of left hemisphere enlargement in the regions of handedness and language with the left pt reaching up to ten times the size of the right. The right pt, however, develops more rapidly than the left and its differentiation is complete first. Geschwind and Galaburda (1987a) postulated therefore, that it is less subject to the effects of injurious influences during foetal life and is less likely to show disturbances in cytoarchitectonic structure than the left. They pointed out that minor abnormalities on the left are associated with normal right hemispheres, but lesions of the right hemisphere are almost certain to be associated with lesions on the left. Similarly, since the female brain matures before the male, dyslexia may be more common in males, although this is controversial (Shaywitz, 1998). In their provocative and highly stimulating work, these authors went on to propose that minor cerebral abnormalities may be commoner than previously supposed and, when present, associated with superior talents (Geschwind and Galaburda, 1987b,c). Although major abnormalities are pathological, associated with mental defects and epilepsy, it is a paradoxical possibility that minor malformations might lead to distinctly superior capacities in certain areas. This could occur because slow growth within certain areas of the hemispghere is likely to result in enlargement of other cortical regions, including the homologous contralateral area and adjacent, unaffected regions. Therefore, even when there is growth retardation, migration abnormalities and resultant learning disorders, high talents might exist as a result of compensatory enlargement of other cortical regions. This is Geschwind's concept of the pathology of superiority. He and his co-workers documented other associations with dyslexia, including lefthandedness and stuttering, in addition to biological features such as certain immune abnormalities (Geschwind and Behan, 1982; 1984). All this work was based on solid anatomical findings to which the development of cytoarchitectonics was crucial. Cytoarchitectonics is the study of microscopic neuroanatomy and refers to the characteristic arrangements of neurones in different structures which distinguish them from their neighbours, i.e. cell size and packing density, the presence of

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particular cell types and the arrangement of neurones into layers and columns of specific widths and densities. Individual architectonic areas differ in connections and physiology and probably form specific functional units (Geschwind and Galaburda, 1987b). The first brain from a dyslexic patient was examined by Drake (1968) who reported an excessive number of neurones in the subcortical white matter, especially in the parietal region, but no size differences between the two hemispheres. It was the second case, reported by Galaburda and Kemper (1979) which yielded the more interesting findings. They studied microscopic neuroanatomical lesions and their lateralisation. The findings were: (1) a large area of micropolygyria in the left pt and posterior third of the superior temporal gyrus, (2) clusters of neurones in layer one of the cortex especially in the superior temporal gyrus and (3) abnormal primitive layering and primitive neurones in numerous perisylvian and pericingulate areas. These abnormalities were only present on the left. A third case of dyslexia revealed similar findings: primitive left hemisphere cortical differentiation and frank cortical dysplasias, especially in the perisylvian cortex, and clusters of neurones in layer one. The left hemisphere was affected much more than the right. The fourth and fifth cases described again revealed cortical dysplasia and ectopies in the temporal lobes, more striking on the left side (Geschwind and Galaburda, 1987c). Geschwind postulated that retarded growth of the left hemisphere was playing a major role, accompanied by enlargement of adjacent cortical regions and the homologous contralateral areas. He suggested that this could explain the appearance of unusual abilities in many cases of dyslexia and stuttering as well as the common occurrence of superior right hemisphere function in dyslexics and their families. It is worth recording that both Albert Einstein and Thomas Edison were dyslexics. This exciting work underlines how correct Hinshelwood was in all his writings on developmental dyslexia: his view that it was an anatomical abnormality is fully supported and the stress he always placed on the fact that these are bright, intelligent children has been explained in a way he could not have imagined.

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Acknowledgements My gratitude is due to Professor Peter Behan for helpful discussions and to the Barclay Trust of Glasgow University, to both of whom I am much indebted.

References Behan, W.M.H. and Behan, P.O. (1989). James Hinshelwood and word blindness. In: Neuroscience Across the Centuries (ed. F.C. Rose) London: Smith-Gordon, pp. 185-196. Berlin, R. (1887). Eine besondere art der Wortblindheit (Dyslexia). Wiesbaden: JF Bergmann. Broadbent, W. (1872). Cerebral mechanisms of speech and thought. Trans. Roy. Med. Chirurg. Soc. 55, 145-194. Broadbent, W (1896). Note on Dr. Hinshelwood's communication on word-blindness and visual memory. Lancet 1, 18. Critchley, M. (1964). Developmental Dyslexia. Wm Heinemann Medical Books Ltd. Critchley, M. (1970). The Dyslexia Child. 2nd edition. William Heinemann Medical Books Ltd. Critchley, M. (1986). Developmental dyslexia: A brief overview. In: The Citadel of the Senses and Other Essays (ed. M. Critchley) Raven Press, pp. 240-247. Dejerine, J. (1891). Sur un cas de cecite verbale avec agraphie, suivi d'autopsie. Memoires de la Societe Biologique 3, 197-201. Dejerine, J. (1892). Contribution a l'etude anatomico-pathologique et clinique des differents varietes de cecite verbale. Memoires de la Societe Biologique 4, 61-90. Drake, W.E. (1968). Clinical and pathological findings in a child with a developmental learning disability. J. Learning Disabilities 1, 486-502. Galaburda, A.M. and Kemper, T.L. (1979). Cytoarchitectonic abnormalities in developmental dyslexia: A case study. Ann. Neurol. 32, 13-30. Geschwind, N. and Behan, P.O. (1982). Left-handedness: Association with immune disease, migraine and developmental learning disorder. Proc. Natl. Acad. Sci. USA 79, 5097-5100. Geschwind, N. and Behan, P.O. (1984). Laterality, hormones and immunity. In: Cerebral Dominance: The Biological Foundations (eds. N. Geschwind and A. Galaburda) Harvard University Press, pp. 211 -224.

James Hinshelwood (1859-1919) and Developmental Dyslexia 75 Geschwind, N. and Galaburda, A.M. (1987a). A theory of lateralization. In: Cerebral Lateralization. Biological Dominance, Associations, and Pathology. MIT Press, pp. 10-15. Geschwind, N. and Galaburda, A.M. (1987b). Asymmetry of the human brain, ibid. pp. 20-47. Geschwind, N. and Galaburda, A.M. (1987c). Pathology of asymmetry in developmental learning disorders, ibid. pp. 58-66. Geschwind N and Levitsky, W. (1968). Human brain: Left-right asymmetries in temporal speech region. Science 161, 186-187. Hinshelwood, J. (1895). Word-blindness and visual memory. Lancet 2, 1564-1570. Hinshelwood, J. (1896a). A case of dyslexia: A peculiar form of word-blindness. Lancet 2, 1451-1454. Hinshelwood, J. (1896b). The visual memory for words and figures. Br. Med. J. 2, 1543-1544. Hinshelwood, J. (1898). A case of "word" without "letter"-blindness. Lancet 1, 422-444. Hinshelwood, J. (1899a). "Letter" without "word" blindness. Lancet 1, 83-86. Hinshelwood, J. (1899b). Letter-, Word-, and Mind-blindness. HK Lewis. Hinshelwood, J. (1900). Congenital word-blindness. Lancet 1, 1506-1508. Hinshelwood, J. (1902a). Four cases of word-blindness. Lancet 2, 358-363. Hinshelwood, J. (1902b). Congenital word-blindness, with reports of two cases. Ophthalmic Review 21, 91-99. Hinshelwood, J. (1904a). A case of congenital word-blindness. Ophthalmoscope 11, 399-405. Hinshelwood, J. (1904b). A case of congenital word-blindness. Br. Med. J. 2, 1303-1304. Hinshelwood, J. (1907). Four cases of congenital word-blindness occurring in the same family. Br. Med. J. 2, 1229-1232. Hinshelwood, J. (1911). Two cases of hereditary congenital word-blindness. Br. Med. J. 1, 608-609. Hinshelwood, J. (1912). The treatment of word-blindness, acquired and congenital. Br. Med. J. 2, 1033-1035. Hinshelwood, J. (1917). Congenital Word-Blindness. HK Lewis. Hinshelwood, J., McPhail, A. and Ferguson, A.R. (1904) A case of word-blindness with right homonymous hemianopsia. Br. Med. J. 2, 1304-1307. Kerr, J. (1987). School hygiene in its mental, moral and physical aspects. Howard Medal Prize Essay. J. Roy. Statistical. Soc. 60, 613-680.

76 W. M. H. Behan Kussmaul, A. (1877). Die Storungen der Sprache. Ziemssen's Cyclopaedia, Vol. XIV, FCW Vogel. Morgan, W.P. (1896) A case of congenital word-blindness. Br. Med. J. 2, 1378. Orton, S.T. (1925). "Word-blindness" in schoolchildren. Arch. Neurol. Psychiatry. 14, 581-615. Orton, S.T. (1937). Reading, Writing and Speech Problems in Children. Chapman and Hall. Shaywitz, S.E. (1998). Dyslexia. N. Engl. J. Med. 338, 307-312. Shaywitz, S.E., Shaywitz, B.A., Fletcher, J.M. and Escobar, M.B. (1990). Prevalence of reading disability in boys and girls: Results of the Connecticut Longitudinal Study. JAMA 264, 998-1002.

TWENTIEH CENTURY NEUROLOGY The British Contribution €> 2001 by Imperial College Press

Chapter 6

WILFRED HARMS (1869-1960) Eric Nieman

Wilfred John Harris (Fig. 1) was born in 1869 in Madras where his father was Professor of Midwifery and Diseases of Women and Children. He was sent home to be educated at Sherborne and later at University College School, and then at Cambridge University where he obtained a 2nd in the

Fig. 1. Reproduced with permission from AV Services, Imperial College School of Medicine at St. Mary's, London, W2 1PG. 77

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Natural Sciences Tripos in 1891, winning a scholarship to St. Mary's Hospital, Paddington for the clinical course. He passed the Cambridge MB in 1894, and after resident appointments at St. Mary's, spent two years "on the house" at the National Hospital, Queen Square, where he was RMO in 1895 (followed immediately by Purves Stewart and James Collier). This was at a time when such luminaries as Bastian, Jackson, and Gowers were still on the Staff. He obtained the London MRCP in 1896 and his Cambridge MD in 1898. After leaving Queen Square he returned to St. Mary's where he was successively medical tutor, registrar, and in 1904 Casualty physician. He was elected to the staff of the Maida Vale Hospital for the Paralysed and Epileptic in 1902. In the 1903 prospectus of the hospital he is described as Assistant Physician to Outpatients (with a Thursday afternoon clinic at 2pm) as well as being Registrar (the Registrar, there was only one), and with rooms in Queen Anne St. (hospital appointments were, of course, unpaid in those days). In 1905 he was still physician to Out-patients but no longer Registrar. By 1912 he was full Physician with charge of beds, and had moved to Wimpole St. In 1905, he was appointed Assistant Physician and Physician to Out-patients at St. Mary's Hospital. Since 1899, in addition to other duties, as medical tutor, he had been electro-therapeutics officer at St. Mary's, and was in charge of the Electric department until 1907. In 1903 he applied to the Board of Governors for permission to run the Electric department as an Out-patient clinic for nervous diseases. This request was initially refused, but was granted in 1907 when a department for Neurology was formally established and Wilfred Harris was appointed Lecturer in Neurology. This was the first department of Neurology in an undergraduate hospital. St. Mary's was followed closely in this by Guy's Hospital who appointed Arthur Hertz, later Sir Arthur Hurst to run their Department of Nervous Diseases. It may seem strange that an electrical department should transmute into a department of neurology! This becomes clearer when one realises that most neurological disorders (as well as psychiatric conditions such as hysteria and neurasthenia), were treated electrically. From his expertise in running the electrical department, Wilfred Harris wrote a book entitled "Electrical Treatment" which was published in 1908. The list of conditions

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treated either by the faradic or the galvanic current, or by sinusoidal baths, was considerable, and included neuritis and neuralgia, convulsive tic, hemiplegia, disseminated sclerosis, tabes dorsalis, laryngeal paralysis, Bell's palsy (treated in this way until fairly recently), and spasmodic torticollis. The last of these (now regarded as a focal motor dystonia), was then thought to be of hysterical origin, as was writer's cramp and other dystonic conditions. As readers of the Pat Barker trilogy (of which the third volume "The Ghost Road" won the Booker Prize for 1996) will know, electrical treatment was used in the management of "shell-shock" in the 1914-1918 War. In this context I think that Pat Barker was less than fair to Lewis Yealland. She depicts him as a stern, authoritarian, and rather senior figure, treating wounded soldiers by means of electrical torture. In fact, Yealland was "on the house" at the time, running the electrical department at Queen Square as the most junior member of the Staff (just as Harris had done as St. Mary's), and treating hysterical paralysis according to accepted methods. During the war Harris had the territorial rank of an PvAMC captain at the third London General Hospital in Wandsworth and also at Maida Vale. Through the kindness of Steve Wilson, archivist of the National Hospital, I have been able to see Harris' Maida Vale case-notes for 1916. He admitted six soldiers with shell-shock; the four milder cases were treated with rest, sedation with potassium bromide, and exercise (and all recovered within two months). The other two, who had muscular paralysis, were treated with the sinusoidal current (and made incomplete recoveries). Harris wrote a book (one of the Oxford War Primers) in 1915, entitled "War Injury and Shock", and this book also makes it clear that shell-shock, or war neurosis as it is now called, was treated electrically only if there were clinical features of hysterical paralysis. Early in his career, Harris became interested in neuralgia and particularly in the treatment of trigeminal neuralgia by alcohol injection into the Gasserian ganglion. Schloesser, in 1907, was the first to report the treatment of trigeminal neuralgia by the injection of alcohol into the peripheral branches of the nerve. But the first suggestion of the possibility of injecting alcohol into the ganglion without a surgical incision was made in 1909 by Wilfred Harris. The main deterrent to this procedure is the possibility of

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causing multiple cranial nerve palsies if the alcohol were to gain access to the free CSF spaces at the base of the brain. Before treating his first patient in 1910 he perfected the precise and delicate technique by injecting the cadaver with methylene blue, and he realised the care needed to avoid spread of the dye (and therefore the alcohol) into the cavernous sinus or even the ventral surface of the pons. Between 1909 and 1910 he injected hundreds of cadavers in this way. His first Gasserian ganglion injection with alcohol in an actual patient was carried out in November 1910, producing complete anaesthesia and pain relief which lasted until the patient's death 27 years later. He described his meticulous technique in a paper in the Lancet in 1912, and he continued to use the same technique until he was in his eighties when he flew to South Africa to inject a patient. Harris's method, as it was called, relied on surface markings and technical skill and was used by others, including McArdle and Penman into the 1970s. It was only improved upon in the 1960s by G.F. Swann, with three modifications. He used a short-acting anaesthetic, Brietal, when he inserted the needle, he then injected a drop of Myodil under radiological screen control, and injected a dilute solution of phenol, rather than alcohol, thereby achieving pain control without skin anaesthesia. However Wilfred Harris's skill in injection was, by all accounts, remarkable. At the International Congress of Neurology at Queen Square in 1935, he gave a demonstration of injecting selectively the fibres of the second division alone within the ganglion. In 1940 he published in Brain a paper analysing 1433 cases of paroxysmal trigeminal neuralgia and the end-results of gasserian ganglion injection (all performed by himself). Byron Stookey and Joseph Ransohoff in their book on "Trigeminal Neuralgia — Its History and Treatment", comment on this paper that "in his skillful hands, differential destruction of gasserian ganglion cells supplying various divisions was achieved. Few can repeat this feat, nor does it seem feasible to the surgeon as he sees the ganglion fully exposed at operation". My own interest in Wilfred Harris began at Queen Square in 1959 when the late Louis Hurwitz and I studied and reported 50 patients with cluster headches, of whom 11 had experienced transient oculo-sympathetic paralysis. On reviewing the literature we learned that the condition had been given

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its first clear description in 1926 by Harris in his book "Neuritis and Neuralgia", and that he had coined the term "Migrainous Neuralgia". Many other names had been given to "this particular variety of headache", as Symonds called it, and it was not until 1952 that Kunkle suggested the term "cluster headache". In 1959 Bickerstaff suggested confusion would be avoided and due tribute paid by referring to the condition as Harris's neuralgia, and the suggestion was endorsed by Symonds, but this name did not catch on. It is interesting that not only Symonds and Bickerstaff in their papers should refer to the 1926 book as containing Harris's first description of the condition, but Harris himself in a later paper makes the same claim. Perhaps he had forgotten that he first mentioned and described similar cases in a paper read to the Neurological Section of the Royal Society of Medicine in November 1921, and reported in the Proceedings of the RSM in 1922. In this paper he talked about "supra-orbital neuralgia", but mentioned the periodicity of the pain, sometimes occurring at the same time each day, and for the same duration. He also stated: "Perhaps the majority of these supra-orbital neuralgias are migrainous in type", and also "In some patients this migrainous neuralgia is limited to the temple". In the discussion following Harris's paper, Dr S.A. Kinnier Wilson "referred to the description in Dr Harris's paper of certain patients whose pains came on at certain times of the day. These cases presented very interesting problems from a theoretical point of view. The view he himself took was that such cases were essentially psychogenic. He did not believe that any factor except one of that nature could produce the occurrence of pain over the same period of hours each day". "Wilfred Harris in replying to the point raised by Dr Wilson as to the periodicity of the pain, would not subscribe to the opinion that the periodicity meant psychalgia. Periodic pain was familiar to many of them in other connexions. Moreover the pain in this case had an anatomical distribution, and, contrary to the usual results in psychalgia, injection of the ganglion produced almost complete relief". It is also ironic that Kinnier Wilson should use the term "psychalgia", as this also was a term invented by Harris to describe what we would now call "atypical facial pain". Presumably Kinnier Wilson's views did not alter with time. There is no mention in his compendious two volume text-book

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of migrainous neuralgia, nor any of its synonyms, and in spite of 48 references to other work of Wilfred Harris in the index. Before leaving the subject of precedence in the description of this condition, I should mention that Harris, at the beginning of a paper in the Lancet in 1940, states that "Since 1912 I have used the term migrainous neuralgia to describe..." (and then repeats the clinical description). Harris elaborated on the treatment of migrainous neuralgia by ganglion injection in his 1926 book "Neuritis and Neuralgia" and again in his 1936 book "The Facial Neuralgias". Although perhaps not as successful as in trigeminal neuralgia, it was the only effective treatment at all until Symonds recommended the use of ergotamine. This was followed later by methysergide, and more recently by sumatriptan. During the 1920s and 1930s Harris's professional life was divided between his appointments at Maida Vale and St. Mary's and his private practice. His appointment at St. Mary's was as a Physician; indeed in the early twenties he was Director of the Medical Unit before a professor was appointed. His clinical work there, however, was devoted entirely to neurology. He was regarded by students and junior doctors as a rather austere, patrician figure, and I have a number of letters from retired St. Mary's consultants (now in their eighties) describing him as aloof, difficult, awesome, severe on junior staff, and sometimes on patients. He was obsessive about punctuality and woe betide anyone who turned up late for a ward round or a demonstration. He had retired at age 65 in 1935, but his successor, Denis Brinton, joined the RAF in 1940. Harris came back, lived in at St. Mary's, and did his old jobs at both St. Mary's and Maida Vale, retiring finally in 1945 at the age of 75. After the war, at the age of 80, he was invited by Denis Brinton, by now Dean, to give a series of twelve o'clock clinical demonstrations. I was told by Dr Tom Kemp, that on the first occasion he demonstrated brilliantly a patient with a myopathy. Denny Brinton (no doubt busy as Dean), came in halfway, and Harris did not fail to comment on his lateness. Another letter mentioned that "he was much regarded for neurological accuracy and teaching, but was irascible and demanding, and somewhat the terror of his juniors. The HP on duty had to be Casualty physician, and the morning you had to be in Casualty

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and with him at the same time was difficult! His forte was trigeminal injection for neuralgia, done in the ward, and requiring an elaborate preparation by a nervous Sister and an immobile and cooperative patient. Harris would shout at a patient who moved, and would slap his face in rage". "No-one I think doubted his ability, but he was not much loved". However, when I wrote to Macdonald Critchley in February 1997, he was surprised at these descriptions of Harris whom he had first met in 1923 when he was RMO at Maida Vale, and whom he had always held in affection and great admiration. He wrote, "He was, perhaps, quick-tempered, but I never found him to be obnoxious or unplesant and was surprised to read in your letter that some of your correspondents found him severe and authoritarian. That was not the man I knew; at the most I would say that at times, he could be brusque. Do you think that some other people's memories might be coloured by the fact that he was a Victorian and may have appeared to non-intimated to be rather patrician?" He goes on to write: "When the time came for us neurologists to consider forming an Association of British Neurologists, there was no doubt that Wilfred Harris ought to have the honour of being our Founder-President". Peter Robinson in his Presidential address at the 50th anniversary meeting of the ABN has given a graphic account of the formation of the Association. In addition to Wilfred Harris as President, the other officers elected were Kinnier Wilson as Treasurer, and Gordon Holmes as Secretary. The first meeting of the Association of British Neurologists (ABN) took place on Friday and Saturday, 5 and 6 May, 1933, in the Medical Society of London with Wilfred Harris in the chair. Eleven papers were read, by, amongst others, C.P. Symonds and J.G. Greenfield, Douglas McAlpine, E.D. Adrian, Gordon Holmes, and Derek Denny-Brown. Harris did not read a paper himself, but he took part in the discussion of almost all of the papers. Other honours received by Harris were the Presidencies of the Neurological Section of the Royal Society of Medicine, and of the British branch of the International League against Epilepsy. After his retirement in 1935, and before his wartime return, he published, in 1939, a book entitled "The Morphology of the Brachial Plexus". This was a remarkable book, not least because it was the fruit of nearly 40

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years' work. This investigation of the different forms of the brachial plexus met with in all varieties of animals and birds, from fishes to Man, took its origin in 1902 when Harris went to the Zoo Prosectorium to ask to be allowed to dissect the plexus of a monkey, in order to trace the different components of the fifth cervical nerve, with a view to a possible anastomosis operation on a young child with a localised poliomyelitic paralysis of the deltoid and spinati muscles. At this time he was working in Victor Horsley's laboratory in University College, and took the opportunity of stimulating the fifth and sixth cervical nerves in two macaque monkeys with the faradic current, after removing the skin of the forearm and hand and carefully exposing the tendons of the flexor and extensor muscles at the wrist. By this means the muscles supplied by these two nerves were accurately determined. Later, and particularly after retiring from St. Mary's in 1935, he returned to the systematic study of the anatomy of the brachial plexus. The text and illustrations of this book start with toads, frogs, and the giant salamander, and continue with turtles, crocodiles, monitors and lizards. Birds include ostriches, eagles, pelicans, cranes and humming birds. The mammals range from duckbills, spiny anteaters, various marsupials, a three-toed sloth and a hairy armadillo; to a porpoise, bats, and many exotic rodents. Larger mammals include one adult lion and two lion cubs, a giant panda, and a Malayan bear. He also dissected a variety of primates and (under the heading Homo sapiens), 26 adult and 4 foetal plexuses. The description of each subject is accompanied by his own drawing of its brachial plexus. This important study of comparative anatomy had a practical clinical value, as in this book Harris was the first to describe, and appreciate the importance of, the pre-fixed and post-fixed plexus. He was well-known in the Zoo in other respects. He had always been interested in the physiology and pathology of vision. He wrote an important paper in the Lancet in 1935 entitled "Vision and its disturbances in relation to cerebral lesions", and in his eighties he wrote a paper in the British Medical Journal, entitled "Evolution of binocular and stereoscopic vision in man and animals", and another paper on "The fifth and seventh cranial nerves in relation to the nervous mechanism of taste sensation". Until a few years before his

Wilfred Harris (1869-1960) 85 death at the age of ninety he was investigating the optic tracts of the chameleon and the octopus. In the pantheon of British neurologists of the first half of the twentieth century, the name of Wilfred Harris has perhaps not been so well-known as some others, such as Head, Holmes, Kinnier Wilson, Riddoch, Symonds, or Walshe. I hope I have said enough to indicate that he was in the same league (and in the premier division). He was regarded throughout his career as a distinguished clinician and teacher, and he was honoured by his peers by becoming the first President of the ABN. Above all, he was a pioneer, an innovator, and for all of that time, a tireless investigator. References 1. Harris, W. (1908). Electrical Treatment. Cassell and Co. 2. Harris, W. (1915). Nerve Injuries and Shock. Oxford War Primers. Henry Frowde, OUP/Hodder and Stoughton. 3. Schloesser, K. (1907). Erfahrungen in der Neuralgiebehandlung mit Alcoholeinspritzungen. Klin. Wchnschr. 44, 533-534. 4. Harris, W. (1909). The alcohol injection treatment for neuralgia and spasm. Lancet 1, 1310-1313. 5. Harris, W. (1912). Alcohol injection of the gasserian ganglion for trigeminal neuralgia. Lancet 1, 218-223. 6. Harris, W. (1940). An analysis of 1433 cases of paroxysmal trigeminal neuralgia (trigeminal-tic) and the end-results of gasserian alcohol injection. Brain 63, 209-224. 7. Nieman, EA. and Hurwitz, L.J. (1961). Ocular sympathetic palsy in periodic migrainous neuralgia. J. Neurol. Neurosurg. Psychiat. 24, 369-373. 8. Harris, W. (1921). Proc. Roy. Soc. Med. 14, 4. 9. Harris, W. (1926). Neuritis and Neuralgia. Oxford University Press. 10. Harris, W. (1936). Ciliary (migrainous) neuralgia and its treatment. Brit. Med. J. 1, 457. 11. Harris, W. (1937). The Facial Neuralgias. Oxford Medical Publications. 12. Harris, W. (1939). The Morphology of the Brachial Plexus. Oxford University Press. 13. Bickerstaff, E.R. (1959). The periodic migrainous neuralgia of Wilfred Harris. Lancet 1, 1069-1071.

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14. Symonds, C.P. (1956). A particular variety of headache. Brain 79, 217-230. 15. Harris, W. (1952). The fifth and seventh cranial nerves in relation to the nervous mechanism of taste sensation. Brit. Med. J. 1, 831-836. 16. Harris, W. (1953). The evolution of binocular and stereoscopic vision in man and other animals. Brit. Med. J. 2, 297-301.

TWENTIEH CENTURY NEUROLOGY The British Contribution © 2001 by Imperial College Press

Chapter 7

SIR GORDON HOLMES (1876-1965) tWilder Penfield

Gordon Morgan Holmes was born in Ireland, the son of Gordon Holmes of Castlebellingham, Co. Louth. He came to be one of the world's great neurologists — an investigator, teacher, clinician and editor. It is not easy to decide in which role he made his most important contribution. He became a scientist first and a practising physician afterwards. He matriculated at Trinity College, Dublin — a tall, broad-shouldered boy with black hair, athletic and brilliant. Having won a scholarship, he graduated, BA, at 21. He qualified in medicine, and at 23 left Dublin, on the Stewart Scholarship in Nervous and Mental Diseases, for two years of graduate work abroad. At Frankfurt-am-Main he found an excellent opportunity to study the histology of the nervous system under Karl Weigert, and neuro-anatomy under the famous Ludwig Edinger. Edinger soon made Holmes an instructor in his university course of neuroanatomy and, in the end, urged him warmly to remain in Germany as his assistant. But, in 1901, aged 25, Holmes decided to return to Ireland. On his way through London, he heard of a vacancy as house physician in the National Hospital for Nervous Diseases, Queen Square. He applied for it and was accepted. At this time, there were two outstanding world centres for neurological study: Paris, where leadership was to be found in the Salpetriere, and London tdeceased 87

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with its National Hospital. Young Holmes moved up from house physician to resident medical officer. Then in 1904, a new post was created in the hospital and Holmes was asked to become pathologist and director of research. It was a great opportunity and he was ready for it. Five years later, in 1909, he accepted an appointment as honorary physician to the National Hospital. In 1912, he turned over the Laboratory of Pathology to S.A. Kinnier Wilson who was, in turn, followed, in 1914, by a permanent pathologist, J.G. Greenfield. Holmes had become a restless, indefatigable investigator and this was the time for the pathological and physiological analysis which was to pave the way for more adequate therapy. The physicians of this hospital brought their independent skills and differing genius to this neurological centre, long called the National Hospital for the Paralysed and Epileptic. Advancing up the ladder of seniority on the Staff, they served patients without remuneration and conducted graduate teaching, like the early Greeks, without university organisation. When Gordon Holmes entered the clinical field, with his knowledge of anatomy and neuropathology, he proceeded to make of neurological examination a relatively exact science. At the same time, like Gowers and Jackson, he collected and recorded his observations of patients with neurological lesions. From 1901 to 1911, his publications dealt in general with neuropathology and neuroanatomy. By 1911 he had turned to clinical neurophysiology, working with Henry Head, a neurologist of great vision and originality at the London Hospital. They studied the role of the human cerebral cortex in sensory perception, using the critical, sometimes quantitative, methods devised by Head. Holmes applied these tests with scrupulous exactitude. The formidable study which followed {Brain, 1911) showed that the optic thalamus was "the seat of physiological processes which underlie crude sensations of contact, heat and cold", while the cortex had to do with the more discriminative aspects of sensation. With the onset of the World War in 1914, Holmes went into service at once as Consulting Neurologist to the British Army. His Goulstonian lecture on The Spinal Injuries of Warfare in 1914 {Brit. Med. J. ii, 1915, 769, 215,

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855) showed how quickly he had changed the focus of his attention. A brilliant series of publications followed which dealt with the function of man's cerebellum and the effect of cortical lesions on vision and on somatic sensation. In conjunction with the surgeon, Percy Sargent, Holmes made various studies of battle casualties that involved the nervous system. At the end of the war in 1918, aged 42, Gordon Holmes was married to Rosalie Jobson, the daughter of the late Brigade surgeon, W. Jobson — a charming young woman with a Scottish accent and an unfailing sense of humour. She had studied at Oxford and had later qualified as a member of the medical profession (MRCS, LRCP, 1914). They found a house, 9 Wimpole Street, large enough for their home and consulting rooms. Here, three daughters were born to them (Kathleen, Rosalie and Elizabeth). In 1919 and 1920, with F.M.R. Walshe, he wrote a textbook — a chapter in Nelson's Loose Leaf Medicine, An Introduction to the Diseases of the Nervous System. Beginning in 1922 and continuing until 1937, he was Editor of Brain, following Sir Henry Head in this highly influential editorial post. He was elected to Fellowship of the Royal Society in 1933. In 1939 came the Second World War. Holmes was sixty three, but carried on with an ever increasing professional load. In 1935 he was President of the Second International Congress of Neurology when it met in London and, in 1951, was knighted. His contributions to the physiology of the cerebral cortex, thalamus and cerebellum of man were important and the role he played as critic and editor was of great value. But his contribution as a teacher of teachers was outstanding. "He was without a peer among clinical teachers". Sir Gordon rarely referred to his own philosophy of life. But in 1934 he did so, when the Montreal Neurological Institute was founded. He came to the Opening Exercises as a principal speaker. "The student of neurology", he said, "must equip himself with that intellectual honesty and independence which refuse to submit to authority or to be controlled by preconception.... But on the other hand, he must have the courage to formulate, when ready to do so, observations into hypotheses or rational generalisations, for, as Francis Bacon has told us, truth can emerge sooner from error than from confusion".

TWENTIEH CENTURY NEUROLOGY The British Contribution © 2001 by Imperial College Press

Chapter 8 SIR GORDON HOLMES: A PERSONAL REMINISCENCE t Macdonald Critchley

I first met Gordon Holmes in 1923, on going to the National Hospital, an experience which was like entering the Valley of the Kings at Luxor (because of the ghosts of Brown-Sequard, Ferrier, Beevor, Batten, Marcus Gunn, William Fergusson and Felix Semon). And yet some of the dead seemed still to be living — Hughlings Jackson, William Gowers, and Victor Horsley — an eerie, awesome feeling, as though they were looking over one's shoulder. But here the metaphor ceases. Unlike the Valley of the Kings, there were still — striding through the halls — very much alive and in the flesh — giants. Chief among these was the Colossus, physical as well as intellectual, of Gordon Holmes who shone brightest among the galaxy of stars. It was my privilege to have been his house physician for nearly two years — which implies that I was his apprentice, his disciple, his oblate, and maid-of-all-work. He must have been 47 years old at that time but to me he might have been any age for he seemed ageless, already an institution, a living legend. I had previously been warned by one of my chiefs at Great Ormond Street that I would find Gordon Holmes to be a man who was "tempestuous... tdeceased This paper has been published in Macdonald Critchley's book of essays entitled "The Divine Banquet of the Brain" (1979), New York: Raven Press. 91

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volcanic". I did. He was surrounded by a coterie of brilliant postgraduate students, mainly from Canada, Australia and the USA, all of whom were destined to become pioneers of clinical neurology in their own countries. A big man in stature, brusque, demanding Gordon Holmes trained us like a Sergeant Major in the Brigade of Guards or the Royal Marines and we were keen and willing recruits. He made exorbitant demands upon us, exacting the utmost accuracy and dedication, and he got it, willingly. How junior hospital doctors of today would have fared, I tremble to think, but they probably would have been flung out, since we were expected to be on duty 24 hours a day. Our work might entail travel into remote parts of the country to follow-up cases in which the chief was particularly interested. I recall a case of pituitary basophilism — long before Cushing had described it — and I had to visit the patient in his home in the Midlands after he had left hospital. Once Gordon Holmes ordered me to a remote farmhouse in rural Essex to perform a drawing-room autopsy on a patient of his with a brain tumour. Often I was dispatched to libraries to look up obscure references, chiefly in German. All these chores we took in our stride for we were only too proud to carry out our master's wishes. Like so many myopes, Gordon Holmes was a meticulous, obsessional observer. All who worked with him recall the mannerism whereby he would abruptly snatch off his eye-glasses, on one side only, in order to peer closely at a sheet of paper. Moreover, he was a scrupulous recorder of observed data, and had no time for woolly thinking, any speculation notions. He examined every patient from top to toe, taking no short-cuts. Even a parkinsonian was subjected to the most rigorous sensory testing, though the diagnosis had of course been obvious to him right from the start. Only once did I know him make a spot diagnosis, when — to his disgust — he identified in a flash a so-called syringomyeliac whom I had spent many hours in working up, as a leper, as indeed she was. His clinical technique was thorough, and many would have said rough, even terrifying, yet so warm-hearted was he that he never could understand why he was regarded as a bully. Not to the patient, who was just bewildered — but to any student or house physician guilty of slipshod work. I have seen him tear up the case notes and scatter them across the ward;

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and to throw on the deck his percussion hammer or his king-size tuning fork. He could coax physical signs out of a patient like a Paganini on the violin. Perhaps it is still not yet generally realised that every neurologist alive today — wherever he works — is unconsciously utilising the routine clinical examination propagated, perfected and perpetuated by Gordon Holmes. It was a sheer delight to watch him evoking one physical sign after another in a patient with, say, tabes — a common disorder in my young days. Like some violent conjurer, he would demonstrate the typical zones of hypalgesia, and we used to say that one of the hallmarks of a tabetic was Holmes' pin left in situ, at the tip of the nose of an uncomplaining patient, perhaps with an adjacent tiny trickle of blood. As a colleague Gordon Holmes was exciting. He rarely put in an appearance at medical committees; his few angry attendances were like war-drums announcing an impending battle over some issue which evoked the tornado of his feelings. He was not endowed with wit or any broad sense of humour. Rarely did he smile and I cannot recall him giving vent to anything like a belly-laugh. Towards other members of the staff he had mixed feelings. Some, he just brushed aside as though they did not exist. A few of them blossomed in the warmth of his affection and esteem. Among these few were the neuropathologist, Godwin Greenfield, who was, incidentally, the most likeable man I have ever met. Here too was his dapper neurosurgical colleague, Sir Percy Sargent — "Pretty Percy" — as he was called at St Thomas'. Sargent had worked side by side with Gordon Holmes behind the front line in France during the First World War and mutual respect had grown up. Percy Sargent was the only one who could pull Holmes' leg and tease him and Holmes would take it. At the same time, Sargent would never venture to operate without Holmes standing over him and indicating on the skull with his finger-tip, the precise site of the underlying tumour. Francis Walshe, a junior colleague, was a young man whom Holmes admired and respected, and to whom he would always listen seriously. The one-sided feud with Kinnier Wilson cannot be glossed over. Students who came to Queen Square found themselves in a modern Verona, with the

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Montagues and the Capulets at war. They had to align themselves either with the Kinnier Wilson clique or with the camarilla of Holmes. Never could they do both. Wilson was a vain and touchy man, jealous of Holmes, and he would ostracize anyone who strayed into the other camp. Holmes, for his part, couldn't care less and simply ignored his colleague. Outside Queen Square, Holmes had a number of cronies, like Bolton the gastroenterologist; the centenarian Sir Thomas Barlowe — who had been Queen Victoria's doctor; and Hume of Newcastle, whose son became the Abbott of Ampleforth and later elevated to the Archbishopric of Westminster. Abroad, Holmes' favourites included Wilder Penfield, Patrick of Chicago, Otto Foerster and, most of all, Brouwer of Amsterdam, a giant of a man, very like Holmes in many respects. He had an admiration for Dandy but certainly none at all for Cushing... . I have referred to his apparent lack of humour but perhaps I should qualify this. He used to tell me how, when he worked on cortical sensory impairment with Henry Head (a most unlikely alliance, by the way), experience taught him that two types of patient had to be rejected as test subjects: (1) School teachers, who could never give a plain "yes" or "no" but only rambling, parenthetical, introspective, wordy replies; and (2) Scotsmen, who too would never answer "yea" or "nay", suspecting that there might be a catch in the question. When I ceased to be his house physician and was either a registrar or a junior colleague, I would often come face to face with him and his cortege in the corridor. He would always halt, seize me violently by the collar or the shoulder and bellow at me "what are you doing these days? What are you working at? If only you would go out less at night and keep away from cinemas, you might get somewhere". This was his form of blustering, benevolent and humorous encouragement. Others have written about Holmes' major contributions to our neurological lore, visual, sensory or cerebellar (see preceding and following chapters). Visual included the cortical representation of the macula, and the subtler concepts of visual inattention and visual disorientation. As to the sensory system, Holmes never referred to epicritic or protopathic. He always alluded to the instrumentalities — light touch, pin prick, two-point

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discrimination, localisation of touch. The rich symptomatology of cerebellar defect was Holmes' very own province. Holmes came to London from the laboratories of Edinger and Weigert, fluent in German and highly conversant with the intricate anatomy of the nervous system. These were two valuable qualifications which today are not fashionable. He fitted perfectly into the heady atmosphere of Queen Square, where he developed an abounding and perpetual admiration for his chiefs, especially Jackson and Gowers. Goodness knows, the latter was an oddity for, despite his genius, he was an indifferent judge of character or of aptitude. He advised Purves Stewart to take up skins and become a dermatologist, Wilfred Harris to be a surgeon, and Stanley Barnes to get lost in the provinces. Not content with this, Gowers advised Holmes to devote himself to academic anatomy; perhaps he did not welcome such a powerful figure too close to the throne. Though a very great man, conscious of his qualities, Holmes was modest to a fault. Accorded many of the academic prizes of the Royal College of Physicians, he was not concerned with the inner workings of the College. He was one of the last of the clinicians to be elected to the Royal Society. Many awards came to him but he did not, however, receive public recognition until late in life, for he had never been one to tread the corridors of power or to defer to the high priests of dispensation. He was not a diner-out or a fashionable physician. Some of us junior neurologists were bold enough, more than once, to beard the panjandrums of patronage in their dens, to protest. We were told gently, but firmly, what indeed we had already guessed; Holmes had never guarded his tongue, nor had he gone out of his way to refrain from treading on the toes of the touchy. All came right in the end, however. The time came, too, when we mooted the idea of a portrait, and there was no dearth of eager supporters from all over the world. The snag was, would we ever get Holmes, the unassuming statesman, to agree. And even if we did, would he have the patience to sit still and refrain from fidgeting? Again, all came right in the end. Our only regret is that the portrait was not painted earlier, when he was a heavily built, robust man, and not a victim of flatulent dyspepsia. He

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carried around with him a box of sodamints into which he would periodically dip, with benefit, benefit that was obvious to us all. Not long afterwards he became afflicted with a severe gastric problem and he must have lost 40 or 50 lbs in weight. Though he changed considerably in bulk, he did not change his tailor, and thereafter his clothes hung on him like the skin of an elephant. My remarks so far have been anecdotal and not the data on which a future historian will find when he thumbs through obituaries and biographies, and for this reason I think they are appropriate for they give some idea of a great man in his entirety. Havelock Ellis put this over well when he said: "To describe the birth and growth of a great man as he was in his real nature, physical and psychical, as a grape cluster on the tree of life, and not as a drop of alcohol in the vat of civilisation — that is biography. The biographer is the biologist of this new life, to whom we come to learn the origin of this tremendous energy, the forces that gave it impetus, and that drove it into one channel rather than another." Holmes was one of the past generation of clinicians who advanced knowledge in their chosen field, without any outside assistance, financial or otherwise. Not only did he never have a department, he was not even afforded the privacy of a room or office in his hospital. Head, Gowers, Jackson were in the same predicament. Their researches had to be carried out in the open wards, and at home working far into the night. Apart from his original Stewart Research Scholarship to Germany from Trinity College, Dublin, he never received a penny-piece for his work. This is not to say he was not afforded opportunities. Although the University of London did not recognise his hospitals, to my knowledge he received offers of Chairs at Johns Hopkins and also one of the Regius Chairs in Physics, both of which he turned down. As Editor of "Brain", his approach was unusual and, I am grateful to say, stimulating. You sent him a paper and later, you would be invited to his home and, after dinner, he would go over the whole text with you, sentence by sentence, word by word. With his ruthless blue pencil he would

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erase every adjective which was merely decorative; every "very", every "etc." were terms which he pointed out had no place in scientific papers. Whenever he came to an elaborate, complicated sentence, allusive and abstract in nature, he would jerk to a halt and demand "just what are you trying to say?" When you replied, somewhat aggrieved, in a word or two, giving him the gist of your nebulous thinking, he would at once proclaim "why the devil didn't you say so?" and out would go your purple patch, your flight of fancy, your probing into the higher ether. He was just as ruthless with your illustrations. Ruler in hand, he would demand what the microphotograph was really intended to show. With diffident forefinger you would point to a sorry-looking astrocyte in the centre, and out would go the pictorial background, leaving the offending structure conspicuous but naked as Godiva. I learned so much at his editorial chair that I can faithfully say that whichever command I possess of the Queen's English is due to my one and only teacher of style, Gordon Holmes. In his down-to-earth attitude Holmes had no time for neurotics and hysterics and less than none for the pagan gods of psychoanalysis. When Holmes took over the beds from Aldren Turner senior, on his retirement, I became his house physician. In the ward there was a blonde bombshell of 21, with mild tension headaches, pretty as a picture. She was as plump as a partridge for the year before she had been the Daily Mirror Bathing Beauty Queen. The first time I took Holmes round, he stopped at the foot of the bed and asked "Who's this woman?" I explained, whereupon he jerked his thumb towards the door and said "get rid of her!" Of course, I did nothing of the sort for she was useful in keeping up the morale of us house officers. A week later, he came round and said "I thought I told you to get that woman out of here". Another week passed. On this occasion I got the Sister of the ward to hide the patient in the bathroom during the ward-round. Standing at the foot of the empty bed, Holmes paused then said to me "Look here, my boy, either she leaves the hospital or you do — and I don't care which". If so far I have given the impression of Gordon Holmes as a kind of ogre, I have failed to depict the man in all his plenitude. To paraphrase somewhat what Penfield wrote: "Although he appeared to be a martinet, he

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possessed a heart of Irish gold". If he liked you he ould go to great lengths to help you. It was a delight to see him at his home with his gentle, charming lady wife. At times he would visit the wards along with his three lovely, boisterous, dimpling daughters. He was devoted to them and so proud when all three joined the Women's Forces during the war. Outside neurology, Holmes had three passionate interests, hard-hitting golf, vigorous gardening, and a considerable knowledge of Gothic architecture. As far as I can determine, he was not interested in painting, literature, the theatre, or music — in this way resembling Hughlings Jackson. I have said little enough about Holmes as a neurologist but later chapters will complete the picture. It is conventional to finish with a quotation and I have sought something appropriate from one who in many ways strongly resembled Gordon Holmes. I refer to Dr Samuel Johnson, also a burly man, a great man, a legendary figure. Holmes had none of his eccentricities or multiple tics, but he was very, very reminiscent of Johnson, who in 1795 wrote: "The life that is devoted to knowledge passes silently away and is very little diversified by events. To talk in public, to think in solitude, to read and to hear, to inquire and answer inquiries, is the business of a scholar. He wanders about the world without pomp, and is neither known nor valued but by men like himself."

TWENTIEH CENTURY NEUROLOGY The British Contribution © 2001 by Imperial College Press

Chapter 9

GORDON HOLMES' WORK ON SENSATION AND HIS ASSOCIATION WITH HENRY HEAD "^Ronald Henson

Gordon Holmes' work on sensation is essentially contained in three papers; first, the celebrated "Sensory Disturbances from Cerebral Lesions", the fruit of his collaboration with Henry Head; second, "A case of lesion of the optic thalamus with autopsy" (Head and Holmes, 1911); and third, "Disorders of Sensation Produced by Cortical Lesions" (Holmes, 1927). The case report of the patient who died with a thalamic lesion is a model of its kind and noteworthy for the fact that Holmes performed the post mortem examination besides making the neuropathological study. Holmes' major contribution to our knowledge of sensation stems from the 1911 publication with Head, for his 1927 paper is largely a reiteration and justification of the pre-war collaborative study. There is no precise information how Head and Holmes came to be associated. Head was fifteen years the senior but had failed to gain election to the staff of Queen Square, where Holmes was already an assistant physician when their work together began in 1909. Critchley has suggested to me that they met in the small London neurological world of those days and mutual scientific interest furnished the link between them.

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Holmes already had many publications to his credit, while Head, after his early work on respiration with Hering in Prague, had studied visceral pain and zoster in the 1890s and proceeded to his well-known later work on the effects of nerve section and the grouping to different impulses in the spinal cord with Rivers and Thompson, respectively. According to Holmes the working association continued until 1914 when the First World War intervened and their paths diverged; Holmes crossed the channel to work with the British Expeditionary Force, while Head remained in London as civilian consultant to the Empire Hospital for Officers in Vincent Square. Shortly after the war Head developed symptoms of Parkinsonism, the signs of this are evident in a drawing of him by Sir William Rothenstein in my possession, and he retired from The London in 1919. The partnership, but not the friendship, was broken, for Holmes continued to visit Head during his long illness. The clinical studies on which the 1911 "Sensory Disturbances from Cerebral Lesions" was based were mostly conducted at Queen Square, as Head testified and Walshe observed, but there were also Sunday morning sessions in Sister's room at The London. There have been few essays in detailed clinical observation to compare with that of Head and Holmes. According to Holmes (1927), Head started the investigation with the question: "What qualities of sensation are localisable in the cerebral cortex?". As their conclusions were to be based on the results of clinical examination, a high degree of accuracy was required. They wrote: "...The value of our work depends entirely on the trustworthiness of the methods used in our investigations... they stand midway between the rough and ready tests of the clinician and the elaborate methods of the psychological investigator.... Our aim has been to employ a series of tests which give reassurable results, without, at the same time, exhausting the patient or demanding any but the smallest amount of introspection" (Appendix I, p. 192). They continued: "We have always attempted to analyse composite forms of sensation into their simplest components. The tests are suitable for ordinary clinical purposes... they extended from five to ten hours in several sittings... and in many instances much longer". The tests were not only detailed but wide in scope. Both stimulus and response were carefully measured and recorded. New or modified methods

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of stimulation were introduced for testing appreciation of light touch, pressure touch and pain. The capacity to localise was examined in two ways. Sandpaper and the Graham-Brown aesthesiometer were employed to determine the appreciation of roughness, and thermal sense was investigated with silver tubes of standard diameter containing water of known temperature. There were twenty groups of tests in all, beginning with light touch, roughly tested by cotton wool and then in detail by Von Frey's hairs, through measured passive movements of the digits and counting the dots on dominoes to final evaluation of the response of the glans penis to measured pinprick. Appendix II of the paper contains lengthy reports on individual patients examined. Head and Holmes attempted, in their own words, "to present a coherent account of the mechanism of sensation". From their observations of lesions of the spinal cord and brainstem they concluded that sensations entered consciousness at the thalamus. They noted overloading of sensation with feeling tone in 24 cases of thalamic lesion and continued "The essential organ of the thalamus is the centre of consciousness for certain elements of sensation... it responds to all stimuli capable of evoking either pleasure or discomfort... . The feeling tone of somatic or visceral sensation is the product of thalamic activity... . These functions are influenced by the coincident activity of the cortical centres. The loss of this control due to lesions of the cortex is responsible for the features of the thalamic syndrome, including thalamic pain". As to cortical functions, they stated that "impulses (going there) underlie postural recognition and appreciation of passive movement... including judging differences in weights in unsupported hands", they also subserve tactile differences and appreciation except roughness and contact... spatial discrimination, on which recognition of size and shape depend, localisation, and identification of "those degrees of temperature which necessitate comparison with previous thermal experiences". They went on to propound the idea of the schema — "We are always building up a postural model of ourselves which constantly changes by means of perceptual alterations" — and they quoted the case of a man who

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lost his phantom limb following a stroke. They continued "anything which participates in the conscious movement of our bodies is added to the model of ourselves and becomes part of these schemata (a woman's power of localisation may extend to the feather in her hat)". And again "The sensory cortex is also the storehouse of past impressions. These may rise into consciousness as images, but more often, as in the case of spatial impression, remain outside central consciousness. Here they form organised models of ourselves which may be termed "schemata". Such schemata modify the impressions produced by incoming sensory impulses in such a way that the final sensations of position, or of locality, rise into consciousness charged with a relation to something that has happened before. Destruction of such schemata by a lesion of the cortex renders impossible all recognition of posture or of the locality of a stimulated spot in the affected part of the body". Head and Holmes also concluded "that the cerebral cortex is the organ by which we are able to focus attention upon the changes evoked by sensory impulses". From their observations on patients with cortical lesions they concluded that such damage "produces an effect upon sensation of a different order from that found at any lower level of the nervous system. All those defects, which may occur when a normal person is under examination with psychophysical tests, are present in a grossly exaggerated form. Those defects, which we ordinarily attribute to want of attention, are raised to a degree unknown in the normal human being. But the patient's power of general attention has not been lowered in such cases.... Records from the sound side show that the phenomena of defective attention are confined to the abnormal parts. A portion only of the patient has, as it were, become untrustworthy". The historic work concludes with a consideration of the inter-relation of the optic thalamus and the cortex in the production of sensation. They said "these two centres of consciousness are not co-equal and independent. Under normal conditions the activity of the thalamic centre, though of a different nature, is dominated by that of the cortex..." and finally "our view of the sensory mechanism put forward in this paper explains many of the facts already recognised both by psychologists and clinicians. It enables us to

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understand how integration can occur at all afferent levels of the nervous system, and makes development possible even in the individual. The aim of human evolution is the domination of feeling and instinct by discriminative mental activities". This seminal neurological communication did not receive universal acclaim, and Holmes (1927) felt it necessary to meet some criticisms when he spoke at the joint London meeting of American and British neurologists. He generously acknowledged that the ideas belonged to Head. He reaffirmed the value of the tests he and Head had employed, they offered no difficulties to patients, "provided they were not pathologically dull". His further studies on "men with gunshot wounds of the cortex both during and after the war" confirmed the joint earlier findings and conclusions "...There can be no difficulty in confirming the general truth of Head's conclusions, though further investigation may modify or add to them". Perhaps we should recall that the 1911 paper provided a new approach to the problem of sensation — to quote Holmes again "many clinicians had studied the sensory alterations associated with cerebral disease... but the majority were satisfied with determining the state of cutaneous and deep sensibility... or correlating with an anatomical lesion, a hemianaesthesia or a more restricted or a local loss". Head and Holmes brought light to this area of neurological darkness and provided a general theory of the role of the cortex in sensation which still stands, although modified us Holmes foresaw. Holmes' 1927 paper includes the added bonus of his observations on the distribution of sensory disturbance of cortical origin and the sensory zone of the cerebral cortex. These sections still repay study. What were the parts played by the two authors of this neurological classic? It has been said that Head provided the ideas and Holmes' the accurate observation and anatomical and physiological sense. While there may be truth in this observation, it belittles the contribution of each, to my mind. The experienced student of Head can identify points where his style shows through. There is the example of the feather in the lady's hat as an extension of her body schema; and, again, the patient who became more amorous after his thalamic lesion, "which had rendered the right half of his body more responsive to pleasant and unpleasant stimuli...", this man said

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"I crave to place my right hand on the soft skin of a woman. It's my right hand that wants the consolation...". This is vintage Head, the neurologist with a leaning towards tactile aesthetics. Less frivolously, we have the teleology of the statement on the aim of evolution, and this reads as authentic Harry (Head). The absence of any mention of Head's general theory of sensation, although this had not been fully developed at the time, strikes me as significant. I suspect that Holmes' restraining hand was at work here, holding back his brilliant, speculative colleague. Of course, Head had long since demonstrated his worth both as laboratory and clinical research worker, but his penchant for enthusiastic speculation is well documented. To me, "Sensory Disturbances from Cerebral Lesions" represents a remarkable marriage of minds and skills — and I believe it is best read in that way. The association of dissimilar partners in scientific and artistic endeavours is a common phenomenon. In the arts, the partnership of the author and composer of English Singspiel, Gilbert and Sullivan, is an extreme example. Head and Holmes were totally dissimilar in many ways, including physique and temperament. They came from different backgrounds. Head was born in Stamford Hill, then a fashionable suburb, and educated at Charterhouse and Trinity. Characteristically, the family home was decorated by William Morris, but the local decorator and his men refused to mix the colours which Morris prescribed, so the great man did most of the work himself. This event was typical Head history. At Cambridge his friends included D'Arcy Thompson, W.R. Sorley, A.N. Whitehead, William Bateson and Arthur Paley. At Harry's 21st birthday party, Whitehead proposed the health of the Universe and responded to the toast, the unknown quantity. In later years, Head was closely associated with the Georgian poets; Siegfred Sassoon and Robert Nichols were his patients. He had eclectic interests, but particularly literature and music. The only artistic pursuit which Head and Holmes shared was ecclesiastical architecture of the Gothic period; but I believe they shared other things, apart from their German training, neurological interests, and the later distinctions and awards which came to eminent physicians. They

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were both general physicians. They were both excellent teachers, long revered by their students and assistants. Both were warm-hearted, though Head more openly so, and generous of their time and talents. What did they think of each other? Holmes' 1927 paper and Royal Society biographical memoir leave us in no doubt, for he wrote generously and warmly of his colleague; indeed he has left us a picture of those spacious pre-1914-1918 days; days perhaps more suited to their research; days before the wind of change had begun to blow strongly and a different social order obtained. Unfortunately, I have been unable to trace any written account of Head's feelings about Holmes, but I have no personal doubt that he regarded Holmes as highly as Holmes regarded him.

TWENTIEH CENTURY NEUROLOGY The British Contribution © 2001 by Imperial College Press

Chapter 10 LOOKING AND SEEING — GORDON HOLMES' 1936 JOHN MALLET PURSER LECTURE REVISITED Christopher Kennard

In 1936, Gordon Holmes, then in his 60th year, returned to his alma mater, Trinity College, Dublin to deliver the sixth John Mallet Purser Lecture (Holmes, 1936). Holmes, then recognised as one of the leading clinical neurologists of his day, had obviously been greatly influenced by Purser when a student in his formative years, especially with Purser's insistence on basic principles, and these Holmes returned to time and again. Two years earlier, when delivering the Foundation Address at the opening of the Montreal Neurological Institute, Holmes espoused several principles which governed his studies. Firstly, accurate observation, examining all phenomena associated with the question. Secondly, the ability to describe facts accurately and completely, yet simply and concisely. Thirdly, intellectual honesty and independence with a refusal to submit to authority or be controlled by preconception. Finally, he was suspicious of conclusions reached too hastily or too easily, yet he was prepared to formulate observations into hypotheses or generalisations when ready to do so. These principles, to which he adhered throughout his career, are admirably exemplified in his studies in the field of visual function which commenced when he was sent to the Front as a Medical Officer in the First World War. Here, he performed a meticulous analysis of several hundred soldiers with gunshot wounds to the occipital and parietal lobes. 107

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Without the benefits of modern day brain scanners, Holmes carefully recorded the wound of entry and of exit in these soldiers to determine the path of the bullet, and so localise the likely site of cortical damage using craniometric assessment. It is remarkable that using this technique Holmes, the German neuropsychologist Walter Poppelreuter working on the opposing German side, and a few years earlier the young Japanese ophthalmologist Tatsuji Inouye studying brain-injured soldiers in the Russo-Japanese War, should all have realised that the misfortunes of war could be put to valuable purpose in the scientific pursuit and understanding of visual function. However, Holmes was well aware of the shortcomings of this type of clinical approach: "the clinician must accept the conditions as they occur; he cannot arrange for them to happen as the (laboratory) experimentalist may do, nor can he at will repeat the experiment which disease (or the bullet in the current discussion) has performed". So it was that Holmes observed two groups of brain-injured patients, one group in whom "the eyes tend to remain fixed spasmodically on any point in central vision and cannot be moved from it by will, or even by the intervention of reflexes which normally lead to their deviation"; the other in whom "the patient is unable to maintain fixation accurately though ocular movements are intact". It was this complementary series of observations, one in which the function of fixation is exaggerated and the other in which it is lost or diminished, which formed the basis of Holme's lecture. In it he was fulfilling the last principle which he had espoused, that of "hypothesis and generalisation". Looking, the placement or maintenance of the image of an object of regard on the fovea by contraction of extraocular muscles, is a necessary requisite for any animal which has a specialised region of the retina to provide high visual acuity with which "to see". Evolution has led to the development of several types of eye movements involved in looking. Firstly, there are those which redirect gaze, which include rapid conjugate eye movements, called saccades, and vergence movements for objects moved toward or away from the observer. Secondly, there is a need to maintain fixation of the object of regard if the object itself moves, when the pursuit system is used, and if the subject's head moves, in which case the vestibulo-ocular and/or optokinetic reflexes operate.

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By the 1930s, at the time of Holmes' lecture, there was already a sizeable body of knowledge concerning the location of neural centres involved in eye movements. A variety of experimental studies using neuro-anatomical methods and neurophysiological techniques such as ablation and electrical stimulation in animals, and ablation studies in man using naturally occurring diseases, such as infarction and tumours, had all helped to define a system of oculomotor related neural centres. We would today call such systems neural networks, each involved in the generation of a different type of eye movement. In the search for functional localisation within the cerebral hemispheres the use of patients with focal lesions was paramount, with Broca's description of an aphasic patient some 70 years earlier the primary exemplar. Yet Holmes was well aware of its interpretative problems, as valid today as they were then: "...occasionally disease abolishes one or more functions and leaves a simpler state for investigation... it is essential to realise that the condition produced by such experimental disease is not merely due to loss of one or more components of normal function, for the activity of structures which remain intact are disordered as a result of their isolation from the rest of the functioning organ". Holmes was concerned with fixation of the eyes and the ability to maintain gaze on an object whether it is at rest or in movement. He described in his lecture how in one patient a series of strokes had resulted in "a pure reflex machine". He could make little in the way of voluntary movements, for example, contract his facial muscles to command, yet he smiled appropriately. On the oculomotor front he was unable to look to the left, right, up or down to command, yet his eyes would deviate in the direction of an unexpected sound. If, however, he fixated a point he could follow it if moved in any direction, and his eyes moved appropriately in response to passive head turning. This patient, therefore, showed a loss of willed or voluntary saccadic eye movements with retention of pursuit and vestibulo-ocular reflex movements. Of particular interest to Holmes was the observation that the patient kept his eyes deviated, despite his effort to return them to the primary position, so long as he maintained fixation of the object. As soon as fixation was broken, either by blinking or by Holmes placing a screen in front of his face, his eyes immediately returned to the primary position.

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Holmes then went on to describe a group of patients who had clinical oculomotor signs which were almost the converse of this patient. When asked to look at a laterally located object these patients would accurately move their eyes toward it, but almost immediately their eyes started to drift back toward the primary position. A similar disturbance was observed during pursuit of a moving object in these patients. The observations made by Holmes in these two contrasting groups of patients led to a number of conclusions which I will discuss in the light of current knowledge. The first is the apparent separation of the higher neural control for voluntary versus reflexive saccades. Many experiments have been reported in the past decade attempting to define the higher neural control mechanisms which generate these two types of saccades. In particular several new behavioural paradigms have evolved to provide insights into a number of the cognitive processes, such as short term memory, prediction, response inhibition and motor planning, which are involved in saccade generation. Of particular relevance to Holmes' interest in visual fixation mechanisms are two recent studies. In a study of brain damaged patients, whose use is as valid today as it was in the early part of this century albeit with the caveats already discussed, Paus and his colleagues studied fixation mechanisms in a group of patients with circumscribed frontal lobe lesions (Paus et al., 1991). No longer needing to trace bullet paths to determine cortical localisation, modern day scanners provide very precise anatomical localisation of damaged tissue in vivo, a possibility only dreamt of by Holmes. In accord with Holmes' recognition of the importance of fixation "by its means objects of interest are held in distinct vision and our eyes are prevented without conscious effort, from wandering from the work on which we are engaged", they examined a group of 35 patients and tested the stability of central gaze fixation in two oculomotor tasks requiring the suppression of reflexive saccades triggered by the sudden appearance of novel, peripheral visual stimuli. The basis of the two tasks was to vary the attention load at the point of fixation. In one task a meaningless central stimuli was presented and the subjects were instructed to simply gaze at this stimulus. In contrast the second task was far more demanding of attention since meaningful

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central stimuli were represented in the shape of animals, and the subject had to categorise them into wild or domesticated animals by the appropriate press of two keys. By overlapping the location of the lesions on templates of the brain, 3 distinct groups of patients could be defined — those with ventrolateral, dorsolateral and medial lesions — and their responses compared. The lesioned patients were able to suppress reflexive saccades to the same degree as normal aged matched control subjects in the relatively nonattention demanding simple fixation task. Thus lesions of the frontal lobe do not affect reactivity to extraneous stimuli per se; however, when broken down into separate lesion groups one group, those with ventrolateral lesions in the left frontal lobe, made more reflexive saccades directed to the contralateral hemifield. In the second task where categorisation of stimuli at fixation was demanded, two patterns of abnormality in suppression of reflexive saccades was found. Firstly, a bi-directional deficit was noted in the ventrolateral group, and secondly a unidirectional deficit in suppression of responses to stimuli in the contralateral hemifield was observed in the medial group. Interestingly, no significant impairment was found in the dorsolateral group. This is somewhat surprising in view of the second experiment to be described using functional brain imaging. We have now entered the most exciting era in the history of our exploration of brain function in man. Not only have modern scanners allowed us access to unparallelled anatomical images of brain structure, but now the techniques of positron emission tomography (PET), functional magnetic resonance imaging, and the recording of event-related electrical brain potentials are revealing whole networks of neural centres involved in a variety of cognitive, sensory and motor tasks. In one such study, using PET, we wished to compare the neural activation during the generation of reflexive and voluntary saccades compared with fixation (Anderson et al., 1994). Following the injection of a radioactively labelled tracer, in this instance water labelled with oxygen-15, normal subjects performed the appropriate saccadic tasks and changes in regional cerebral blood flow (rCBF) were measured. Since increased neuronal activity leads to local increases in cerebral blood flow, the site of neuronal excitation can be

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determined. A number of different cortical areas were found to be activated during saccades, including in the frontal lobe, the frontal eye fields, supplementary motor area and dorsolateral prefrontal cortex, the latter two areas were predominately activated during voluntary saccades. In addition, activity was detected in the posterior parietal lobe. When we compared saccade generation with a fixation task similar to Paus's first paradigm, significant activation was observed in left ventromedial and ventrolateral areas of the frontal lobe, supporting the conclusions drawn from lesion patients. All these observations provide support for the idea of functional heterogeneity of the frontal lobe and its involvement in the physiology of ocular fixation. However, are these examples of patients, with a disordered maintenance of fixation due to their inability to suppress saccades to novel stimuli, representative of patients with what Holmes described as "an inability to maintain fixation accurately though the ocular movements are intact"? In fact what Holmes appeared to have been describing were patients with partial gaze palsies due to cortical damage. It is not uncommon to observe that patients shortly after an acute stroke may have a deviation of gaze directed to the ipsilesional side, and an inability to move their eyes into the contralesional hemifield. Usually within 7-10 days the eyes have returned to the primary position, but although such patients can make horizontal saccades, maintenance of fixation is impaired and the eyes drift back toward the primary position. The most likely explanation is that when the frontal eye field is damaged by a unilateral stroke the remaining intact frontal eye field functions unopposed leading to tonic eye deviation. Because there are parallel circuits involved in saccade generation, for example, a direct pathway from the posterior parietal lobe to the brainstem saccadic generators, these gradually take over the lost function of the frontal eye field. However, these purported adoptive changes are still hypothesised and have not been proven by experimental observation. Turning to the other patient described by Holmes in his lecture — the patient who according to Holmes had a "spasm of fixation". This patient once fixating an object, could not generate a saccade unless fixation was broken either by a blink or by temporarily obscuring the object. This would now be termed an acquired ocular motor apraxia, and had been called

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"psychic paralysis of gaze" by Balint in the case he reported in 1909 (Balint, 1909). This patient also had an inability at any given time to interpret the totality of a picture scene despite preservation of the ability to comprehend individual portions of the whole, which Balint called "a spatial disorder of attention" and Holmes called "visual disorientation". To make up the triad of defects Balint also observed optic ataxia. Post-mortem examination showed that this patient had bilateral and nearly symmetrical lesions of the posterior parietal lobe, upper temporal lobe and occipital lobe. Holmes argued that his patient's "spasm of fixation" was a "release phenomenon", describing how "the physiological mechanism of the normal reflex has become overactive owing to the absence of inhibitory impulses from more highly evolved centres which normally control it and subordinate it to the well being of the body as a whole". Holmes did not draw attention to a defect in visual attention that his patient most probably exhibited. This could well have, at least partly, explained the "spasm of fixation". Current views describe how an active release mechanism for fixation is required, followed by a shift of attention to the planned object of regard which all occur prior to the onset of a saccade. Arguments still abound as to the anatomical and physiological basis for these pre-saccadic processes, but undoubtedly they reside largely in the posterior parietal cortex. This was presumably the location of the lesions in patients described by Holmes although he did suggest that the location was "in the cortex of the brain within, or in the immediate proximity of, the area concerned in visual perception, that is the cortex in the lips and on the walls of the calcarine fissure". Modern views would locate this further forward in the parietal lobe. In conclusion, Holmes, clearly influenced by the teachings of Hughlings Jackson, was therefore also a believer in hierarchical systems within the nervous system and considered that his observations were a good example of this. At a time when reform of the House of Lords is being contemplated in the United Kingdom, Holmes analogy of the nervous system with parliamentary democracy is rather apt: "the higher centres can be, in fact, compared to the second chamber of the legislature which is capable of action on its own, but its chief function is to prevent an assembly representative of many and diverse interests, but less well informed of

114 C. Kennard all the bearings and of the facts of the situation and, therefore, less discriminative, from reacting to every impulse of the moment". References Anderson, T.J., Jenkins, I.H., Brooks, D.J. et al. (1994). Cortical control of saccades and fixation in man: A PET study. Brain 111, 1073-1084. Balint, R. (1909). Seelenlahmung des "Schauens", optische Ataxie, raumliche Stoning der Aufmerksamkeit. Monatschrift fur Psychiatrie und Neurologie 25, 51-181. Holmes, G. (1936). Looking and seeing: Movements and fixation of the eyes. Irish. J. Med. Sci. 129, 565-576. Paus, T., Kalina, M., Patockova, L. et al. (1991). Medial versus lateral frontal lobe lesions and differential impairment of central-gaze fixation maintenance in man. Brain 114, 2051-2067.

TWENTIEH CENTURY NEUROLOGY The British Contribution © 2001 by Imperial College Press

Chapter 11

KINNIER WILSON AND HIS BOOKS (1878-1937) Bryan Ashworth & Ernest Jellinek

Born in New Jersey in 1878, of Scots-Irish descent, Samuel A. Kinnier Wilson was trained in Edinburgh. After periods in Germany with Flechsig and with Marie and Babinski in Paris, he rose on the staffs of King's College Hospital and Queen Square in London during the first decade of this century. At King's he was the first British physician to confine his practice to neurology. When aged 30, he wrote a magisterial discussion of apraxia and (Freud's) agnosia in Brain, and four years later produced a classical clinical and pathological account of hepato-lenticular degeneration. This seminal study of the first treatable metabolic disease of the brain also greatly advanced knowledge of the extra-pyramidal system: its successful treatment came ten years after Wilson's death. Wilson's knowledge of neurology was encyclopaedic and included the French and German literature: it led to the posthumous publication of his great single-author, 1830-page text — the highly readable reference "Bible" of neurology up to 1937. The substrate was his library of 1500 books and reprints, some bequeathed to him by Hughlings Jackson and David Ferrier, which was recently given to The Royal College of Physicians of Edinburgh (R.C.P.E.) by the Caims Library at Oxford: a treasure trove of famous and obscure items, many from the borderlands with psychiatry. For relaxation, he indulged in tennis and fishing. He enjoyed visits to the music hall and French liqueurs. In 1934, when the Moncrief-Arnott 115

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chair of Clinical Medicine in Edinburgh became vacant, Wilson expressed an interest. He was advised not to apply. One of the great teachers of the first third of this century, Wilson was deemed Olympian by Webb Haymaker, pompous by Denny-Brown, but extolled as kind and humorous by Foster Kennedy. Wilson was a great personality, and his contemporaries felt strongly about him one way or another. The few letters to his mother in the R.C.P.E. collection suggest a nice and open relationship when he wrote to her about his various London appointments and of his engagement to the daughter of the Edinburgh Physician, Alexander Bruce (1854-1911). Dr. Bruce had neurological interests: he had translated Oppenheim's great German textbook (first edition 1884) and suffered a breakdown as a result. He was on the editorial Board of Brain from 1906, and his son Ninian was to become the editor of Wilson's great text. Foster Kennedy (1937) who had been a fellow resident at Queen Square in an obituary notice spoke of "a personality a little unlike his times, a stylist but no pedant... his sense of humour played puckishly, he would joke and laugh at his own gravity, too sensitive for inner gaiety." He died aged 59, shortly before his expected election to the Royal Society for which he had been proposed by Sherrington and Adrian. The editorial obituary in the Lancet (1937) is broadly sympathetic and eulogistic, but noticed an absence of facile social graces. Macdonald Critchley (a colleague at Queen Square and King's College Hospital) added fulsome paragraphs "he wrote easily and clearly... his keen sense of humour rare in one so witty..." But by 1979, Critchley was more outspoken "never a modest man he was soon referring to his own syndrome as Wilson's disease like everyone else. At the same time he poured bitter scorn upon the vague entity pseudosclerosis which had been described by Westphal and Strumpell which sat too close to his discovery to be comfortable". (But in the same book, Critchley renames the Kleine-Levin syndrome the Kleine-Levin-Critchley syndrome). Queen Square, according to Critchley, was divided at that time into followers of Kinnier Wilson or Gordon Holmes, like the Montagues and the Capulets in Romeo and Juliet. Critchley still extolled Kinnier Wilson's superb teaching performances but now wrote "like most neurologists he was very vain about his ability to

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put pen to paper but it is doubtful whether his prose was as distinguished as he thought it was... he was not popular, touchy and opinionated, his vanity almost childish. "Dr. Brown" I have heard him say, is a very sound man he thinks well of me". Could it have been a successful leg-pull? Wilson was a friend of Charlie Chaplin with whom he once stayed in Hollywood. As a famous demonstrator of cases at Queen Square, he was able to fabricate a physical sign. He also stressed the use of rhythmical tapping of the glabella which resulted in blinking. In the normal person the blinking soon ceased but in those with extrapyramidal disease it continued. This came to be known as Wilson's sign. In 1920, Wilson founded the Journal of Neurology and Psychopathology and became its editor. Later, the title was changed to Neurology, Neurosurgery, and Psychiatry. He was in the habit of referring to this as "my journal". It came to be known as the "green rag". In 1933, the Association of British Neurologists was formed and Wilson became the Treasurer. His early death precluded his election as President.

APRAXIA Wilson's paper entitled "A contribution to the study of apraxia with a review of the literature" in 1908 is a tour de force from a 30-year-old registrar: he followed the German expositions by Pick (1892) and Liepmann (1900). The latter defined apraxia in lieu of "motor asymbolia" as a different entity from the descriptions of apraxia coupled with agnosia in the earlier literature. Agnosia, in turn, had been coined as a new term by Freud in 1891. Wilson duly stressed the existence of pure apraxia, without any agnosia, as a cortical or subcortical disorder, with or without involvement of the corpus callosum. There were usually associated findings such as perseveration. Wilson also published a short monograph on aphasia in 1926 which was regarded by Sir Charles Symonds (1970) as the best essay on the subject yet written.

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WILSON'S DISEASE Wilson himself credited the Berlin physician F.T. Frerichs with the first clinical account in his text on diseases of the liver (1857, English translation 1860) — a case of juvenile cirrhosis with progressive neurological troubles (Table 1). Wilson next listed Gowers' (1888) brother and sister with "tetanoid chorea" (which he included in his own series). Despite Homen's (1892) attribution of fatal neurological diseases and cavitation of the basal ganglia, linked with cirrhosis in three siblings in a family of 11 to "Lues hereditaria tarda", Wilson rightly accepted them as cases of his disease; likewise a boy at St. Bartholomews' Hospital reported by Ormerod in 1890. Wilson included the Barts picture of a brain slice in his own study, as well as the full family history. In the Addendum to his great 200-page paper, Wilson mentions the very important study by Fleischer, also of 1912 (vide infra), only to condemn the term pseudosclerosis, without naming Westphal and Strumpell, or mentioning the corneal ring. Actually Westphal in 1883 had described an absence of plaques in two patients who were thought to have multiple sclerosis because they had (Charcot's) intention tremor as a feature of their lethal neurological disease: hence his term pseudosclerosis. He had not observed any gross brain changes at post-mortem. Von Strumpell, a great physician and author of a textbook of medicine which went to more than 30 editions, published three negative post-mortem cases of "pseudosclerosis", in 1898 and another in 1899 of a man who had cirrhosis but also had the distorted nose of tertiary syphilis. However, the term pseudosclerosis stuck in the German literature, and came to be applied to the very significant sufferer in whom the corneal ring was first noted by Kayser in 1902, although labelled at first as having multiple sclerosis. A second ophthalmologist, B. Fleischer of Tubingen published the same case after his death in 1909, in 1912, together with another autopsy case and a live sufferer — all three with Kayser-Fleischer rings. Fleischer's work ignored any familial features but stressed the possibility of heavy metal deposits in liver, brain, and cornea on account of the pigment granules he found in cells, in particular the possibility of

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Table 1. Major research contributions to Wilson's disease. Extrapyr. Disease Frerichs 1861

+

Westphal 1883

+

Familial

C.N.S. Pathology

Cirrhosis

Corneal Ring

Toxic/ Metabolic

Copper

Decoppering

+

(+)

von Strumpell 1888/9 Gowers 1888 Ormerod 1890

(+)

Homen 1890 Fleischer 1909/12 Wilson 1911/12 Bramwell 1916 Haurowitz 1930 Glazebrook 1945 Mandelbrote 1948 Cumings 1948/5! Denny-Brown 1951

(+)

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argyria: his chemical analyses were inconclusive. He mooted a general metabolic disease like haemochromatosis. Rumpel (1913), reporting on the same autopsy case of Fleischer, found raised levels of copper (but also of silver and antimony). Spielmeyer in 1920 declared peudosclerosis and Wilson's disease the same entity in a neuropathological review. Liithy in 1931 had reviewed about 120 cases in the literature, and added one of his own with silver and/or copper deposits. But in the previous year, there had been a definitive biochemical finding from Haurowitz (1930) in Prague of greatly raised copper in liver and basal ganglia in two sufferers of Wilson's disease who also had corneal rings. Abnormal blood copper studies in the disease were found in Edinburgh by Glazebrook (1945). Swayback in sheep in Australia stimulated copper studies in demyelinating and other diseases of the central nervous system in R.A. Peters' laboratory in Oxford where British Anti-Lewisite (BAL) had been discovered. Mandelbrote et al. (1948) described without comment very abnormal copper values, untreated, and after treatment with BAL, in a solitary case of Wilson's disease, in an otherwise normal survey of various neurological diseases. A specific study of copper in Wilson's disease by Cumings at Queen Square published in January 1951, was the first to describe the beneficial effect of "decoppering" by BAL, and was followed by similar results in Boston in December 1951 (Denny-Brown and Porter). "Decoppering" with penicillamine (Walshe, 1956; Walshe and Yealland, 1993) proved more tolerable and successful. This historical review of Wilson's disease supplements an earlier one by Walshe (1976) with changes in emphasis, particularly on the importance of Fleischer's study in 1912. More recent developments in cytogenetics have been summarised by Anita Harding (1993). In 1912, Wilson submitted an MD thesis to Edinburgh University on this disease and was awarded a gold medal. This work was published in Brain and filled a complete issue of that journal. It was entitled "Progressive lenticular degeneration: A familial nervous disease associated with cirrhosis of the liver". He noted that the condition was rare and described it as an

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extrapyramidal motor disease. Wilson reviewed reports of isolated similar cases and reported four of his own, with autopsies on three of them. Two of the patients were brothers and a search of the records at Queen Square revealed two similar cases. On hearing of the death of one of his patients in Switzerland, Wilson at once took the train to Zurich and was present at the autopsy. It confirmed that both cirrhosis of the liver and degeneration of the basal ganglia were present. This finding of cirrhosis caused Wilson to be overcome by emotion as it supported his previous observations. All four of his cases showed cirrhosis of the liver and the autopsies revealed degenerative changes in the putamen and globus pallidus. He described the clinical features in detail. They included tremor, dysarthria, dysphagia, muscular rigidity, docility, and a mild psychosis. Wilson also deduced some physiological conclusions. The corpus striatum exerted a steadying influence on the corticospinal system. He thought that the tremor was due to involvement of the lenticulo-rubro-spinal system. He also stated that the disease was not hereditary, but its autosomal recessive pattern of inheritance was identified later, and much more recently an abnormality of chromosome 13 was defined. In the cases he reported Wilson did not identify the Kayser-Fleisher ring (due to a deposit of copper in the deep layer of the cornea) (Kayser, 1902) which is now recognised as an almost invariable finding when neurological manifestations are present. Even in his textbook, Wilson referred to it as "highly inconstant" despite the use of the slit lamp. He conceded the possibility of familial cirrhosis without neurological signs (Bramwell, 1916) but deplored the use of the term "abdominal Wilson's disease". With treatment of the neurological condition, the corneal ring disappears over a period of months but therapy has to be continued indefinitely (Walshe, 1976; 1996).

T H E M O T O R SYSTEM Wilson showed a great interest in disorders of movement. He was particularly concerned with the interactions of the basal ganglia and the corticospinal

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tract or, as he described it, between the old motor system and the new. His approach in this, as in all his papers, was systematic, with a clear separation of anatomical, physiological, and clinical features. His conclusions were presented to the American Neurological Association at its meeting in Boston in 1923. The spinal cord was the oldest part of the motor system and capable of integrated movement under the influence of proprioception at segmental level. These spinal movements could be activated from the meso-encephalo-pontine centres, which in turn were isolated from the cortex and responsible for postural control. Disease involving these centres had different effects from involvement of the corticospinal tract, and Wilson referred to this as the extrapyramidal system. Activity of the corticospinal pathway could overcome postural control. This discussion was supported by a detailed and critical review of experimental work and was published (Wilson, 1928).

THE EPILEPSIES Wilson introduced this term to emphasise the clinical variation in patients diagnosed as having epilepsy. He pointed out that fit and convulsion were not synonymous. In trying to classify the epilepsies he was influenced by Hughlings Jackson's statement that there are as many forms of epilepsy as there are discharging lesions. He defined three clinical categories of epilepsy: motor, sensory, and psychical, and discussed in detail the manifestations of temporal lobe (uncinate) epilepsy and dreamy states. In a consideration of narcolepsy he accepted Gelineau's description of a sleep disorder, with or without loss of muscle tone, under the influence of emotion. After a detailed review of the continental literature, the mechanism remained unclear. Occasionally, there was an association with epilepsy. Although the symptoms of epilepsy and narcolepsy were sometimes similar, this did not mean that the mechanism was the same. This review formed the Harveian lecture to the Harveian Society of London and was reprinted in Modern Problems in Neurology (1928).

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LIBRARY Wilson's remarkable collection of more than 1500 books, many more reprints, and a few personal papers has recently found its way from the Cairns Library in Oxford to the Library of the R.C.P.E. Many of the books and reprints must have been bequeathed by his eminent predecessors at King's College Hospital, and the National Hospital Queen Square: Hughlings Jackson, Sir William Gowers and Sir David Ferrier, to judge by dedications in many of the items, going back to the second half of the 19th century and even earlier. Much must have been acquired by himself, and even more are review copies sent to the Lancet and to Wilson's own journal. Early works include Parsons' Croonian orations (1746), J.A. Wilson on Spasms (1843), Sir Charles Bell (1844), Gowers' copy of Abercrombie (1836). Most of the neurological classics are in English, French and German by contemporaries: Adrian, Bailey, Babinski, Batten, Bramwell, Charcot, Cushing, Dandy, Duchenne, Economo, Foerster, Goldstein, Gowers, Head, Horsley, Marie, Weir Mitchell, Moniz, Mott, Olivecrona, Pavlov, Penfield, Pick, Richet, Romberg, Sherrington, Elliot Smith and many others. Many of the review copies are uncut, e.g. Sicard's first description of contrast radiography with Lipiodol, or Bastian's "Hysterical Paralysis" with a dedication to Wilson. Wilson's more personal books include James Mackenzie's "Pulse" given to him by Byrom Bramwell in 1903 on completion of his House Physicianship. There are many "borderline" books on witchcraft, Mormonism, sleep and dreams, and shell-shock, indicating his special interests. Whatever the limits of Wilson's clinical practice, his library includes much psychology and psychiatry, as would have been customary in the undivided French and German neurology and psychiatry of his time. There is much by and about Sigmund Freud. The most interesting items are two bound volumes of reprints ("Monographs") by Hughlings Jackson, some dedicated to Wilson, and a further set of 24 similar "Monographs" started by Ferrier — with the earliest reprint dated 1865 — by various authors deemed important, and continued by Wilson until 1913. The vast collection of unbound and mostly later

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reprints is filed by subject — presumably for the compilation of Wilson's "Neurology". The R.C.P. Library in Edinburgh also has Ninian Bruce's own collection. On several occasions Macdonald Critchley referred to a notebook in which Wilson recorded comments of Hughlings Jackson. A search of his library and that of Ninian Bruce has not revealed it.

TEXTBOOK Wilson planned his magnum opus and gathered material over many years. It was almost complete at the time of his death and then edited for publication by Ninian Bruce in 1940. A second edition in three volumes, also edited by Bruce, appeared in 1954 and included a section by Russell Brain on aphasia. The original edition in two volumes covered 1838 pages and included 276 figures and 16 plates. It was dedicated to Byrom Bramwell and Alexander Bruce. Whereas Gowers in his textbook had used an anatomical classification, Wilson grouped the diseases under etiological headings. The ten sections covered infective diseases, toxic conditions, degenerative disorders, vascular, tumour, metabolic, and congenital. Diseases of uncertain nature included epilepsy, narcolepsy, migraine, myasthenia, and tetany. A final chapter with the heading "Neuroses" covered Gilles de la Tourette syndrome, muscular spasm, myotonia, torticollis, and some occupational disorders. The clinical descriptions are detailed and valuable. Infections are described at length and particularly the neurological complications of specific fevers. The manifestations of syphilis take up 114 pages. Intoxications and metallic poisoning are included. Tumours are reported at length and the histology classified. Only 18 pages are devoted to paralysis agitans but 25 to a detailed review of progressive lenticular degeneration. The book was reviewed by Edwin Bramwell in the British Medical Journal. He discussed the classification, referred to the admirable clinical descriptions and noted the extensive bibliography. He concluded: "Neurology is the most complete account of the diseases of the nervous system in the English language; as a work of reference it is unique in our literature and

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indispensable". It remains as the last comprehensive review of neurology by a single author. References Bramwell, B. (1916). Familial cirrhosis of the liver... suggested relationship to Wilson's progressive degeneration of the lenticular nucleus. Edin. Med. J. 17, 90-99. Bramwell, E. (1940). Review of Kinnier Wilson's Neurology. Br. Med. J. 1, 529. Bruce, A. (1911). English Translation of 5 th Edition of Oppenheim's Handbook of Neurology. 2 Volumes. Schulze, Edinburgh. Critchley, M. (1937). Obituary notice S.A.K. Wilson. Lancet 1, 1254. Critchley, M. (1979). The Divine Banquet of the Brain. Raven Press, New York. Cumings, J.N. (1951). The effects of BAL in hepatolenticular degeneration. Brain 74, 10-22. Denny-Brown, D. (1953) on K.W.'s personality: Quoted by Haymaker loc. cit. Denny-Brown, D. and Porter, H. (1951). The effect of BAL (2,3 dimercaptopropranol) on hepato-lenticular degeneration (Wilson's disease). N. Eng. J. Med. 245, 917-925. Fleischer, B. (1903). Zwei weitere Falle von grunlicher Verfarbung der Kornea. Klin. Mbl. Augenheilk 41, 489-491. Fleischer, B. (1909). Hornhautverfarbung als Symptom einer Allgemeinkrankheit. Munch. Med. Wschr. 56, 1120-1123. Fleischer, B. (1912). Pseudosklerose nahestehende Krankheit, Pigmentierung, Hornhaut, Lebercirrhose. Dtsch. Z. Nervenheilk 44, 179-201. Frerichs, F.T. (1861). A Clinical Treatise on Diseases of the Liver. Trans. C. Murchison Vol. 2. New Sydenham Society, London, pp. 60-62. Freud, S. (1891). Zur Auffassung der Aphasien. Leipzig & Wien, Deuticke. Glazebrook, A.J. (1945). Wilson's disease. Edin. Med. J. 52, 83-87. Gowers, W.R. (1888). Diseases of the Nervous System. Vol. 2. Churchill, London. p. 656. Harding, A. (1993). In: Brain's Diseases of the Nervous System. 10th edn. (ed. J.N. Walton). Oxford University Press. Haymaker, W. (1953). The Founders of Neurology. Blackwell, Oxford. Haurowitz, F. (1930). Ueber eine Anomalie des Kupferstoffwechsels. Hoppe-Seylers Z. Physiol Chemie 190, 72-74.

126 B. Ashworth & E. Jellinek Homen, E.A. (1892). Lues hereditaria tarda. Arch. Psych. Nervenheilk 24, 191-238. Kayser, B. (1902). Ueber einen Fall von angeborener griinlichen Verfarbung der Kornea. Klin. MM. Augenheilk 40(ii), 22-25. Kennedy, F. (1937). Obituary. Arch. Neur. Psychiat. Chic. 38, 388-389. Liepmann, H.K. (1900). Das Krankenbild der Apraxie. Mschr. Psychiat. Neurol. 8, 15-44, 102-132 and 182-197. Liithy, F. (1931). Ueber die hepatolenticulare. Degeneration Dtsch. Z. Nervenheilk. 123, 101-181. Mackenzie, J. (1902). The Study of the Pulse. Pentland, Edinburgh. Mandelbrote, B.M., Stanier, M.W., Thompson, R.H.S. and Thruston, M.N. (1948). Studies on copper metabolism in demyelinating diseases of the central nervous system. Brain 71, 212-228. Obituaries (1937). Brit. Med. J. 1, 1094-1095; Lancet 1, 1253-1254. Ormerod, J.A. (1890). Cirrhosis in a boy with obscure and fatal nervous symptoms St. Bartholomews' Hospital Reports 26, 57-68. Pick, A. (1892). Beitrage Storungen der Sprache. Arch. Psych. 23, 896-918. Rumpel, A. (1913). Bedeurung der Leberveranderungen und der Pigmentierungen bei Pseudosklerose (Westphal-Strumpell). Dtsch. Z. Nervenheilk 49, 54-73. Spielmeyer, W. (1920). Histopathol... Wilson's Krankheit... Pseudosklerose. Zschr. ges Neurol. Psychiat. 57, 312-351. von Striimpell (1898). Spastische Pseudosklerose. Dtsch. Z. Nervenheilk 12, 115-149. von Striimpell (1899). Spastische Pseudosklerose. ibid. 14, 348-355. Symonds (1970). Studies in Neurology. Oxford University Press, London, p. 3. Walshe, J.M. (1956). Penicillamine, a new oral therapy for Wilson's disease. Am. J. Med. 21, 487-495. Walshe, J.M. (1976). Wilson's disease, in Handbook of Clinical Neurology. Vol. 27 (eds. Vinken et al.) Elsevier, Amsterdam, pp. 379-414. Walshe, J.M. (1996). Treatment of Wilson's disease — The historical background. Quart. J. Med. 89, 553-555. Walshe, J.M. and Yealland, M. (1993). Chelation treatment of neurological Wilson's disease. Quart. J. Med. 86, 197-204. Wilson, S.A.K. (1908). A contribution to the study of apraxia with a review of the literature. Brain 31, 164-216. Wilson, S.A.K. (1912). Progressive lenticular degeneration. Brain 34, 295-509.

Kinnier Wilson and His Books (1878-1937) 127 Wilson, S.A.K. (1926). Aphasia. Psyche Miniature Series 2. Kegan Paul, London. Wilson, S.A.K. (1928). Modern Problems in Neurology. Arnold, London. Wilson, S.A.K. (1940). Neurology. 2 volumes (ed. N. Bruce) Arnold, London. Wilson, S.A.K. (1954/55). Neurology. 2nd edn. 3 volumes (ed. N. Bruce) Butterworth, London.

Bibliography Scheinberg, I.H. and Sternlieb, I. (1984). Wilson's disease. In: Major Problems in Internal Medicine. Vol. 23 (ed. L.H. Smith) Philadelphia: W.B. Saunders.

TWENTIEH CENTURY NEUROLOGY The British Contribution © 2001 by Imperial College Press

Chapter 12

MOVEMENT DISORDERS Kalyan B. Bhattacharyya

SYDENHAM'S CHOREA In 1686, Thomas Sydenham (1624-1689) wrote an account of "chorea minor", a frequent complication of rheumatic fever in those days and this is in all probability, the first documented evidence of any description of movement disorders from the United Kingdom.1 Sydenham had initially been at Oxford but left higher academic pursuits for the cause of Oliver Cromwell's Puritans to overthrow the monarchy of Charles Stuart in 1649. He later returned to Oxford and was elected a Fellow of All Souls College. Known as the English Hippocrates, he is universally recognised as the "father of clinical medicine". He was a close associate of the political philosopher, John Locke, another Puritan. A wellknown painting depicts the garishly dressed John Locke, standing at a distance and watching his friend examine a semi-recumbent subject, touching tenderly his forehead. He wrote his account in Latin but a verbatim English translation was subjoined to the paper by Pechy in 1696 that appears in the celebrated textbook by Kinnier Wilson.2 It reads: "Chorea Sancti Viti' is a sort of Convulsion, which chiefly invades Boys and Girls from ten Years of age to Puberty; firstly, it shews itself by a certain Lameness, or rather Instability of one of the Legs which the patient drags after him like a Fool; afterwards, it appears in the Hand of the same side, which he 129

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that is affected with the disease, can by no means keep in the same Posture for one Moment... If a cup of Drink be put into his Hand, he represents a thousand gestures, like Jugglers, before he brings it to his Mouth; for whereas he cannot carry it to his Mouth in a Right line, his Hand being drawn hither and thither by the Convulsions, he turns it suddenly into his Mouth and drinks it greedily, as if the poor Wretch designed only to make Sport. " This brilliant clinical description was, not generally agreed upon. Cullen, for instance, thought in 1785 that the "convulsive disease of Sydenham" encompassed both "diverse states mimicking the gesticulations of ludicrous antics of a stage clown" and the "convulsive agitations of the body with the retention of consciousness, as described by Limmaeus" and that the two conditions were synonymous.3

PARKINSON'S DISEASE Medical literature teems with eponyms, no matter whether the famed paediatric cardiologist Nadas approved of its use or not.4 However, one eponymous disease that is likely to stand the most ruthless grind of time even if all others are expunged, is the one described by James Parkinson. Born in 1755 and working at 1 Hoxton Square in the district of London, James Parkinson dabbled in different directions. Appointed as the warden of the Surgeon's Company that replaced the Barber's Company in 1745 (later, succeeded in 1800 by the Royal College of Surgeons), James Parkinson turned into a political reformer, a vociferous campaigner for social welfare, a radical political pamphleteer writing under the pseudonym "Old Hubert" and a member of various secret societies,5 as he was possibly enthused by the spirit of the French revolution. Parkinson had an abiding compulsion to write and his contribution to the scientific and medical literature had been extraordinary. His books entitled "Philosophy of Physique" and "Philosophical Enquiries" were published in 1780. Amongst his remarkable works, "Organic Remains of a

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Former World" consisted of three volumes and "Chemical Pocket Book" ran into five editions. His medical works included "Some accounts of the effect of lightning", "A case of diseased appendix" — one of the first accounts of appendicitis,6 "Typhoid fever" "Hydrophobia", "Hints on the improvement of trusses" and "Gout", a disease that he and his father suffered from. He further wrote for many journals on the conditions he came across in his medical practice as well as the ones he happened to observe as the medical assistant of the Royal Humane Society.5'7 His magnum opus, published in 1817 was "An Essay on the Shaking Palsy"10 which ran into five chapters and spanned 66 pages. His description of the condition has entered into the classics of the medical literature. Here are some excerpts: "...so slight and imperceptible are the first inroads of this malady, and so extremely slow its progress, that it rarely happens that the patient can form any recollection of the precise period of its commencement. The first symptoms perceived are a slight sense of weakness, with a proneness to trembling... seldom in less than twelve months or more, the morbid influence is felt in some other parts... after a few more months the patient is found to be less strict than usual in preserving an upright posture... in a few months this limb becomes agitated by similar tremblings, and suffers a similar loss of power. ...as the disease proceeds, ...employments are accomplished with considerable difficulty... . Walking becomes a task which cannot be performed without considerable attention. The legs arenot raised to that height, ...so that utmost care is necessary to prevent frequent falls. ...writing can now be hardly accomplished; ...propensity to lean forward becomes invincible,... being at the same time, irresistibly impelled to take much quicker and shorter steps, and thereby to adopt unwillingly a running pace. ...The power of conveying the food to the mouth is at length so much impeded that he is obliged to consent to be fed by

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others. As the disease proceeds towards its last stage, the trunk is almost permanently bowed, ...and the tremulous agitation becomes violent... . The power of articulation is lost. The urine and faeces are passed involuntarily... and other marks of extreme exhaustion, announce the wished-for release. " If he was lacking in fool-proof accuracy, it was in his claim that the senses and the intellect were all along maintained, that the tremor was more severe in sleep and that rigidity escaped his attention as examination of muscle tone as a clinical method was non-existent at that time. But these shortcomings can easily be ignored considering his momentous outpourings in this primitive period of medical sciences. The present-day medical textbooks add only a bare minimum extra to this account and that indicates the intense perspicacity of James Parkinson. Parkinson drew his inference from observing only six subjects. He followed one to the terminal stage of his illness, casually encountered two others in the streets of London, followed up one more for two weeks while he was treating him for an abscess, saw one "at a distance" who had been walking at "running pace" accompanied by a helper and the last was of considerable clinical interest as his tremor improved following a stroke. The first case he described and, with the greatest detail, could now well be called "multisystem atrophy".10 Parkinson, in his naivete, considered that the seat of this illness was in the medulla or the upper cervical cord. He concluded his article with an appeal to "those who humanely employ anatomical examination in detecting the causes of and nature of diseases".'1 No verified portrait of James Parkinson is on record, even in the National Portrait Gallery or at the Royal College of Surgeons, where he was a member, and the nearest image of his physique can be obtained from an account by his friend, Gideon Mantell, who writes that he was "rather below the middle stature with an energetic, intelligent and pleasing countenance and of mild and courteous manners, readily imparting information on his favourite subjects.7 The leading medical journals of his time like the MedicoChirurgical Review, The London Medical and Physical Journal and the London Medical Repository did not publish an obituary of this outstanding clinician.

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Indeed, James Parkinson was a colourful personality. One can learn about his multifaceted life from the exhaustive accounts by Jefferson,8 Morris,7 Jewesbury12 and Rowntree.13 It is interesting to note in a recent review by Elan D. Louis14 that Parkinson received very little recognition in his own country untill JeanMartin Charcot, at the Salpetriere, assigned the eponym in 1888 to this entity. Sanders however, in 1865 suggested an alternative name "paralysis agitans" for this condition.15 Elliotson, Marshall Hall, Thompson, Paget and others16"19 either reiterated what was already described by Parkinson or made incidental passing remarks on this condition. Furthermore, some British physicians described conditions which nowadays would be classified as other entities, e.g. those by Gowry, Green and Reynolds, 20-22 a detailed account of which is given in the excellent article by Louis. In 1898, Purves-Stewart, working as a senior house physician at the National Hospital for the Paralysed and Epileptic, Queen Square, London (and later to be knighted) gave an account of paralysis agitans "with a new symptom".23 In his study of twenty eight patients in two years, he observed five subjects with the phenomenon of the toes being flexed spontaneously, forcing the patient to stop for a minute or two till the cramp disappeared so that he could resume walking. He further noticed that this happened to all the toes except the great toe which on the contrary, was "hyperextended". This is the first description of the "striatal toe" that is now universally recognised as an accompaniment of Parkinson's disease. Purves-Stewart later in collaboration with Worster-Draught, wrote a book in 1906 entitled, "The Diagnosis of Nervous Diseases". Though not studded with gems of clinical description or magnificent personal accounts as they appear in Sir William Gower's and Kinnier Wilson's textbooks, nevertheless it makes easy reading. Helen Dimsdale,24 working in Maida Vale and inspired by her teacher Russell Brain, studied the changing profile of Parkinsonism in the 20th century. She reported on 320 cases altogether, 100 each in the period from 1900 to 1919, 1920 to 1930 and one hundred and twenty cases from 1931 to 1942. Her work was possible to a large extent, as she herself mentions, due to her access to the clinical records of Russell Brain. She observed that the majority in the first group suffered from paralysis agitans, where

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mental changes, oculomotor problems and sialorrhoea were uncommon. In the second group, weakness of convergence was commoner as were mental changes, sleep disturbances and sialorrhoea; rigidity was also a prominent feature. These differences were readily explainable by the outbreak of encephalitis lethargica shortly before. The third group was found to have almost similar number of cases of paralysis agitans and post-encephalitic parkinsonism. Ineidentally, Denny-Brown, who in all estimation should be regarded as a British neurologist, in spite of his initial training and frequent attachments outside the territory of the United Kingdom,25 preferred to dismiss in his monograph that Lewy bodies were incidental, did not consider that the lesion in Parkinsonism lay in the substantia nigra and insisted that the loss of corticospinal fibres was the answer to the problem.26 One is only left to wonder how even the best minds may falter at the seemingly obvious!

WEST'S SYNDROME W.J. West brought to light the myoclonic jerks in the condition named after him in a letter to the Editor in Lancet in 1841. He observed the manifestations in his own child whom he took to such eminent physicians as Sir Charles Bell and Dr. Locock who had witnessed the signs in their large practice. Sir Charles, from the peculiar bowing of the limbs, preferred to call it "salaam convulsion".27

TOURETTE'S SYNDROME Gilles de la Tourette, working in the Salpetriere Hospital, Paris in the 19th century described the condition that now bears his name. But Dr. Samuel Johnson (1709-1784), the famous lexicographer, author and a phenomenal personality, suffered from this condition long before it was described in the medical literature. It was suggested not by a neurologist but by Dr. Johnson's friend and biographer, James Boswell.28 While Dr. Johnson was a student at Pembroke College, Oxford, his professors and friends marvelled at his

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extraordinary intellectual gifts but were, at the same time, shocked to observe the uncouth mannerisms and bizarre gestures for which he himself was often embarassed. His appetite was ravenous and he seemed to mutter ceaselessly at times. Sometimes he would form compulsive habits, like touching every lamp-post in the streets of London while walking through and plunge into bouts of depression. They all do suggest that Dr. Johnson suffered from Tourette syndrome along with its accompaniments, obsessivecompulsive traits and depression. But they were all glossed over for a man who, after all, thrived best in the company of Goldsmith the poet, Gibbon the historian, Burke the parliamentarian, Garrick the actor and, of course, Boswell the lawyer.29

MEIGE'S SYNDROME Henri Meige of Paris gave such a good account of the dystonic spasms of facial muscles that the condition is named after him. Some of the paintings of Pieter Breughel the Elder in the 16th century also depict a similar kind of face. But, for reasons that are not clear, the paintings of such British artists of the Distortive School as Stanley Spencer and William Blake, who also painted distorted faces are not recognised as witnessing and describing this condition which remains an unexplained omission.30

WILLIAM GOWERS AND GORDON HOLMES ON MOVEMENT DISORDERS One of the most magnetic personalities at Queen Square in the late 19th century was Sir William Richard Gowers (1845-1915) (Fig. 1). Appointed as the first Registrar at the National Hospital in 1870, he achieved world-wide fame for his magnificant clinical descriptions and his book "Manual of Diseases of the Nervous System, (Vol. I, 1886 and Vol. II, 1888)". Universally acclaimed as the best book on Neurology, it is affectionately dubbed as "The Bible of Neurology".31 The volumes shine with brilliant clinical accounts based essentially upon his personal experience and neatly drawn

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Fig. 1. William Gowers (1845-1915). Reproduced from "Queen Square and the National Hospital". A.G. Bishop & Sons Ltd, Orpington, Kent, 1960. (Reproduced with permission from Institute of Neurology, Queen Square, London.)

illustrations by Gowers himself. Such was the meticulous care Gowers exercised in the preparation of this book that "it is rumoured that when in doubt, he would consult his own manual".31 As a matter of fact, the opening page of his book reads "The illustrations of which the source is not stated, are original, and part of the copyright of the book".32 It will be inappropriate to assign William Gowers a place in the field of movement disorders alone; his canvas was wider and ran the entire gamut of clinical neurology. However, in his "A Lecture on Abiotrophy", delivered at the National Hospital on February 21, 1902, he considered paralysis agitans in his speech and said "...when the failure is early, it is often due only to a defect in vitality, a defect which seems to be inherent, the tendency thereto inborn. We do not indeed, apply the word "death " to this

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slow decay of these elements, we speak of degeneration... an essential failure of vitality. " Gowers coined the term, albeit hesitantly, "abiotrophy" for this slow decay of cells. The concept of "apoptosis" is a relatively new one and sells well; but the genius of Gowers could envision such a phenomenon about one hundred years ago. And there, while bringing paralysis agitans in its ambit he wrote "...Another senile malady, paralysis agitans must be referred to as vital failure in some cerebral motor functions... . It formerly seemed to me like a degeneration peculiar in kind, such as we are reminded of by that which causes the hair to become from lack of pigment though growth still is luxuriant and presents a contrast with the degeneration which causes blindness... paralysis agitans generally runs without any adequate cause and must be regarded as a pure effect of a special defect in vitality — as a form of 'abiosis'?3" Gowers confirmed Charcot's observation that head and face tremor are rarely seen in Parkinson's disease.34 "... Usually the head is free from tremor except as may be communicated to it from distant oscillations?5" I found it mentioned that Gowers did not publish in Brain as he disliked the editor who responded with a rave review of his textbook that offended Gowers.36 Going through the reference cited above I could not find any reference to Gowers at all.37 This discrepancy remains unexplained and, I suppose, calls for clarification. Sir Gordon Holmes, often bracketed in the same class with Hughlings Jackson as an outstanding neurological exponent of the world38 and being labelled as probably, if not certainly, the greatest British neurologist of the century,39 described what was then called "rubral tremor".40 In two of the subjects he studied, the pathology was in the brain stem that involved many structures including the red nucleus and the superior cerebellar peduncle.

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Fig. 2. Kinnier Wilson (1878-1937). Reproduced from "Queen Square and the National Hospital". A.G. Bishop & Sons Ltd, Orpington, Kent, 1960. (Reproduced with permission from Institute of Neurology, Queen Square, London.)

Holmes, in spite of his awareness that such tremors were found in experimental models due to lesions in the cerebellar outflow tracts, expressed uncertainty about the possible role of the red nucleus in the genesis of such tremors. Subsequent studies failed to show relevance of the rubral lesions in these situations, and in a way the term "rubral tremor" remains, a misnomer.41

W I L S O N ' S DISEASE Samuel Alexander Kinnier Wilson's contribution to movement disorders is enormous. He (Fig. 2) was born in 1878 and spent the major part of his life at the National Hospital and in 1912, while still a registrar there, published in Brain what was his thesis for MD, an account of a condition, that now bears his name.42 He wrote in his famed book

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"My monograph of 1912 described a disease unknown to the medical literature at that time. It contained references to six old, previously obscure cases... and recorded four of my own, in three of which autopsy revealed typical lenticular lesions, as well as cirrhosis of liver.43 " Gowers however, in 1888, wrote in his book that "A case was recently under my care that presented symptoms intermediate between those of chorea and of tetany. ...A brother was said to have died from some affection similar to that from which this child was suffering. There was a history of three other relations having suffered from maladies resembling chorea.44 " Wilson acknowledged this description by Gowers, and also touched upon the works by Ormerod and Homen on similar kinds of illnesses in his book.45,46 He however, came down heavily upon Westphal who in 1883 had published two cases of vague symptomatology, having little in common except tremor, which he described as "pseudosclerosis".47 He further repudiated this view supported by Strumpell48 in 1898 when he tried to revive the entity "pseudosclerosis" in support of Westphal. He wrote "Plainly these cases of Westphal and Strumpell are so heterogeneous as to be useless for the extraction of any specific clinico-pathological entity therefrom. ...In not one of these cases... was allusion made to cirrhosis of the liver, for the simple reason that it did not occur." And then, with characteristic authority he continues... "The term "hepatolenticular degeneration " proposed by Hall in 1921 is pathologically suitable; it had, however, been suggested long before, in 1912, and though I did not then adopt it owing to the absence of liver symptoms in life, it is a good alternative to the original.49"

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He gives an account of the Kayser-Fleischer ring50 and concludes the matter of diagnosing the condition as "To anyone familiar with its symptomatology the affection must appear so characteristic that he may well think it a morbus sui generis. It offers features that are almost unique.51" Kinnier Wilson coined the term "extrapyramidal system" though this was later replaced by "basal ganglia" as a better alternative. In his Croonian lectures in 1925 he concluded that "the basal ganglia situated in the base of the brain still, to a large extent, retain the characteristics of basements — viz. "darkness" suggesting thereby the mysteries that still surround this area of the brain".52 He was the first "pure" neurologist in the United Kingdom and had rather hostile relations with his colleagues. He was the editor of the British Journal of Neurology before founding the Journal of Neurology, Neurosurgery and Psychiatry, the first volume of which appeared soon after his death. Likewise, he did not live to see the publication of his extraordinarily lucid and educative textbook in 1940.53 He was quick to recognise that the condition Morvan's chorea was "neither chorea nor myoclonus" and regarded it as "a meaningless term except as synonymous for flickering contractures of muscles". Its nosology is yet uncertain, but true to the wisdom of Kinnier Wilson, it may represent generalised myokimia as a toxic effect of gold therapy or simply, benign calf muscle fasciculation.54 Apparently, as his photograph suggests, he was endowed with an imperious personality. However, he was not short of a witty remark when he stated that a choreic child is punished thrice before her condition is recognised — once for general fidgetiness, once for breaking the crockery and once for making faces at her grandmother.1

CONTEMPORARIES Writing on contemporaries is invidious, yet this essay will remain far from being complete if I do not mention at least some of the present-day luminaries, whose sterling works set high standards. Amongst many illustrious contemporaries, I cannot help but mention Charles David Marsden

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Fig. 3. Charles David Marsden (1938-1998). Reproduced from Brit. Med. J. 1998, 317, 1661. (Reproduced with permission.)

(Fig. 3) first, who in the words of J.B. Foster, is the "leader of the young academic school of British neurology".55 Marsden's research contribution to movement disorders had been phenomenal as could be witnessed from the number of publications he had to his credit till 1989 in the special supplement of Journal of Neurology, Neurosurgery and Psychiatry when he relinquished the editorship of the Journal. This stupendous outpouring of research activities could perhaps be attributed in his own words, to his being "stepped sideways from the mainstream of medical education into the research laboratory to try to discover why the substantia nigra was black".52 Indeed, his training in physiology of the nervous system, coupled with his interest in clinical neurology has made him ignore hardly any aspect of movement disorders, in the basic sciences or their clinical application, where he has not left behind an indelible stamp of authority. He was elected a Fellow of the

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Royal Society at the age of 45. Apart from editing Brain and the Journal of Neurology, Neurosurgery and Psychiatry among others for long periods, he had been the founding editor of the journal Movement Disorders. The "The Mysterious Motor Functions of the Basal Ganglia: The Robert Wartenburg Lecture" delivered in the annual meeting of the American Academy of Neurology in 1982 remains a classic.52 His works on the physiology of human movement with Merton his mentor, and Morton in the early seventies stand out as startlingly original. They contended that the human stretch reflex was cortical rather than spinal and adduced evidence to support this view. They further advanced explanation as to why the clinical assessment of muscle tone can at times be at variance with the state of the tendon jerk, as for instance, in Holmes-Adie syndrome.56 He lent his own thumb for experiment to prove that muscular movements are under the control of a "servo", including an automatic gain compensation for altered load, for use. 57 ' 58 He further defined myoclonus in clinical terms,59 identified blepharospasm and writers' cramp as focal forms of dystonia,60'61 reported Parkinsonism in twins,62 distinguished between simple and dystonic writers' cramp,62 subclassified essential tremor into four types63; among others, (mostly while moving in King's College, London in collaboration with David Parks) and this small slice of his scientific contribution provides at least a glimpse of the diversity and compass of his intellect. His later works centered around the intricacies of the pathophysiology, clinical features and management strategies of various movement disorders. Sadly, he left us a few years ago. A.J. Lees, the current editor of the journal Movement Disorders has worked on the pathology of substantia nigra, sometimes in collaboration with W.R.G. Gibb. They opined that in conditions other than Parkinson's disease, the prevalence of Lewy bodies in the central nervous system increased from 3.8% to 12.8% between the sixth and the ninth decade and suggested that these cases of incidental Lewy body disease might indicate presymptomatic cases of Parkinson's disease.64 In another elegantly conducted work, they observed that in six control subjects the pars compacta nerve cells in the ventrolateral substantia nigra contained less melanin than in the dorsomedial area. This was in consonance with what was observed

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in Parkinson's disease where, in addition, the ventral tier showed very few surviving cells or, in incidental nigral Lewy body disease, where this selective degeneration progressed from the ventral to the dorsal area. They further observed that this did not happen in ageing or with the administration of MPTP, thus adducing arguments to support the hypothesis that Parkinson's disease is not merely a phenomenon of apoptosis and that the MPTP theory still had a few loose ends.65 Along with David Marsden he was instrumental in establishing the Parkinson's Disease Brain Bank in the United Kingdom. Niall Quinn, who now heads the movement disorders unit in Queen Square, London is a comparatively young man but has done pioneering work on Parkinsonism and multiple system atrophy. His article, "Multiple system atrophy — The nature of the beast" is a testimony to his erudition.66 The "cold hands sign in multiple-system atrophy", published recently,67 seems to be a useful clinical sign for diagnosing the condition. In the 1980s A.H.V. Schapira's masterly work to include Parkinson's disease within the area of mitochondrial neurological diseases deserves special mention. He demonstrated, along with Cooper, Dexter, Jenner, Clarke and Marsden, deficiency of Complex I in the substantia nigra of Parkinsonian subjects that provided a link between the idiopathic variety of the disease and the much-vaunted MPTP model. 68 ' 69 They proposed that MPP + selectively inhibits Complex I and this calls for cell death by a decrease in ATP and an inordinate deficiency of Complex I, with the preservation of normal concentration of Complexes II-IV — an important observation, a biochemical defect that was found exclusive to the substantia nigra.70 Other references worthy of mention include Gerald Stern's "Prognosis in Parkinson's Disease" which glitters with historical details.71 Sir Roger Bannister and Michael Trimble have contributed much to the understanding of the autonomic changes and psychiatric aspects of movement disorders.72,73 Frankel's study on the use of apomorphine for off-period dyskinesia in Parkinson's disease is an important work,74 and Findley's works on essential tremor has been substantially comprehensive75'76 (I was most amused to learn that Robert Boyle, the English chemist of the 17th century gave an account of a diurnal variety of tremor that was relieved by drinking a cup of chocolate liquor77). Halliday and Marsden provided new insights into

144 K. B. Bhattacharyya

Fig. 4. Macdonald Critchley (1900-1998). Reproduced from World Neurology, the newsletter of the World Federation of Neurology 1997, 12(4). (Reproduced with permission.)

the electro-physiological phenomena of myoclonus78'79 and John Pearce's monograph on Parkinson's disease makes lucid reading.80 Peter Jenner's works on some of the biochemical aspects of Parkinson's disease, in collaboration with David Marsden are worth attention.81'82 F. Clifford Rose brought out volumes based on International Symposia on Parkinson's disease.83,84 These excellent books contain chapters, contributed by experts on Parkinson's disease and one reads with interest the chapter written by M. Swallow85 that music may help people with Parkinson's disease or the one by Daniel Rogers on bradyphrenia.86 Recently, Ray Chaudhuri et ah, in collaboration with the present author from India and others from the Caribbean countries, have highlighted differences in the clinical presentations and response to treatment in Indian and Afro-Caribbean immigrants to the UK on one hand and in their native countries on the other hand, suggesting thereby the possible role of ethnicity, dietary and environmental factors in their genesis.87

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MACDONALD CRITCHLEY — THE GENTLE COLOSSUS It is with definite intention that I desisted from taking up Macdonald Critchley (Fig. 4) in my discussion. This giant of a neurologist passed away only recently at the age of ninety seven and there is no end to discussion about the formidable knowledge, demeanour, diction and eloquence of this most distinctive personality. Although his primary interest lay in dementia and aphasia, his contribution to arteriosclerotic parkinsonism is a landmark. His masterly paper published in Brain in 1929 reads88: "...Hitherto scant attention has been paid to the occurrence of Parkinsonism among the syndromes of cerebro-vascular disease. It is the object of this paper to emphasize the importance of this syndrome as being one of the most frequent objective manifestations of a protean disease. It is not essential to find the Parkinsonian syndrome in its entirety in cerebral arteriosclerosis. Incomplete forms are more common..." Though in recent times with the advent of newer radio-imaging techniques this condition is disputed (Niall Quinn terms it "arteriosclerotic pseudoparkinsonism"89), Critchley remains firm on his convictions, albeit with subtle change in emphasis as he later wrote90: "In 1929, my paper on arteriosclerotic parkinsonism... attracted no little attention and this expression passed smoothly into the currency of neurology. However, since the significance of dopamine began to unfold... some went so far as to express the view that it was an imaginary disorder... . I am well aware that there are mythical maladies of the nervous system... but arteriosclerotic Parkinsonism, I strongly submit, does not belong to that category." Critchley also gave a comprehensive account of essential tremor. He noted that a dose of alcohol temporarily abolished the tremor but warned against its potential addictive properties. He wrote that when alcohol was used for this condition,

146 K. B. Bhattacharyya "appeared only too often to have served as an excuse for habits of intemperance.91" An excellent account of the life and works of Macdonald Critchley could be obtained from the obituary written by two of his students, W.I. McDonald and F. Clifford Rose. 92 ' 93 He was the Founding President of the World Federation of Neurology94 and the Founder Chairman of its Research Group in the History of Neurosciences92 and in this context, I would like to conclude by paying a very humble tribute to this splendid personality and great master of clinical neurology. * This work is dedicated to the memory of Charles David Marsden, the "Master of Movement Disorders". References 1. Pryse-Philips, W. (ed.) (1995). Companion to Clinical Neurology. Little Brown & Company, p. 835. 2. Wilson, S.A.K. (1940) in ChapterXX, Sydenham's Chorea in "Neurology". Edward Arnold & Co, London. Vol. I, pp. 605-606. 3. Cullen. (1940). Synopsis, 1785. Cited in Wilson S.A.K. in Chapter XX, Sydenham s Chorea in "Neurology". Edward Arnold & Co, London. Vol. I, p. 606. 4. Carson, P. (1969). Cardiac Diagnosis. McGraw-Hill Kogakusha Ltd. p. 257. 5. Pearce, J.M.S. (1996). A brief history of Parkinson's disease. Journal of Association of Neuroscientists of Eastern India 2, 94-99. 6. Shepherd, J.A. Lancet (1954), ii, 299. Quoted in Morris A.D. James Parkinson, Born April 11, 1755. Lancet (1955), 269, 761-763. 7. Morris, A.D. (1989). In: James Parkinson: His Life and Times (ed. F.C. Rose), Binkhauser: Boston. 8. Jefferson, M. (1973). James Parkinson (1755-1824). Aspects of the history of Parkinson's disease. B.M.J. 2, 601-604. 9. Parkinson, J. (1817). An Essay on the Shaking Palsy. Sherwood, Neely and Jones, London. 10. Pryse-Phillips, W. (ed.) (1955). Companion to Clinical Neurology. Little Brown & Company, p. 660.

Movement Disorders 147 11. Duvoisin, R.C. (1992). A brief history of Parkinsonism. In: Neurologic Clinics 10(2), pp. 301-316. 12. Jewesbury, E.C.O. (1970). British Journal of Hospital Medicine 4, 825. 13. Rowntree, L.G. (1912). Bulletin of the Johns Hopkins Hospital 23, 33. 14. Louis, E.D. (1997). The Shaking Palsy, The first forty-five years; a journey through the British literature. Mov. Disord. 12(6), 1068-1072. 15. Sanders, W.R. (1965). Case of an unusual form of nervous disease, dystaxia or pseudo-paralysis agitans, with remarks. Edin. Med. J. 10, 987-997. 16. Paget, G.E. (1855). Case of involuntary tendency to fall precipitately forwards: With remarks. Med. Times Gaz. 10, 178-180. 17. Elliotson, J. (1930). Clinical lecture on paralysis agitans. Lancet 1, 119-123. 18. Hall, M. (1838). Lectures on the theory and practice of medicine. Lancet 2, 41. 19. Thompson, J.B. (1842). "Chorea sancti viti" with cases and observations. Lancet 1, 616-618. 20. Gowry, T.C. (1831). Case of paralysis agitans intermitteus. Lancet 2, 651. 21. Green, H. (1844). Cases of nervous tremors in children. Prov. Med. J. 178. 22. Reynolds, J.R. (1859). Report of a case of paralysis agitans removed by continuous galvanic current. Lancet 2, 558-559. 23. Stewart, P. (1898). Paralysis agitans; with an account of a new symptom. Lancet 12, 1258-1260. 24. Dimsdale, H. (1946). Changes in Parkinsonian syndrome in the twentieth century (From Maida Vale Hospital for Nervous Diseases). Q. J. Med. 15, 155-170. 25. Pryse-Philips, W. (ed.) (1995). Companion to Clinical Neurology. Little Brown & Company, pp. 243-244. 26. Denny-Brown, D. (1992). The basal ganglia and their relation to disorders of movement. Oxford, Oxford University Press. 1962, 41. Cited in Neurologic Clinics 10(2), 308. 27. West, W.J. (1841). On a peculiar form of infantile convulsion. Lancet 1, 724-725. 28. Pryse-Philips, W. (ed.) (1995). Companion to Clinical Neurology. Little Brown & Company, p. 466. 29. Pringle, P. (1966). 101 Great Lives. Ward, Lock and Company Limited, London and Melbourne, pp. 129-131. 30. Pryse-Philips, W. (ed.) (1995). Companion to Clinical Neurology. Little Brown & Company, p. 529. 31. Cited in Queen Square and the National Hospital: 1860-1960 (1960). Edward Arnold, London.

148 K. B. Bhattacharyya 32. Gowers, W.R. (1886). A Manual of the Diseases of the Nervous System. Vol. I. London. J & A Churchill, 11, New Burlington Street. 33. Gowers, W.R. (1902). A lecture on abiotrophy. Lancet i, 1003-1007. 34. Pearce, J.M.S. (1996). A brief history of Parkinson's disease. Journal of Association of Neuroscientists of Eastern India 2, 97. 35. Gowers, W.R. (1902). A lecture on abiotrophy. Lancet i, 593. 36. Pryse-Philips, W. (ed.) (1995). Companion to Clinical Neurology. Little Brown & Company, p. 371. 37. Henson, R.A. (1978). The editors of brain. Practitioner 221, 639-644. 38. Pryse-Philips, W. (ed.) (1995). Companion to Clinical Neurology. Little Brown & Company, p. 419. 39. Henson, R.A. (1978). The editors of brain. Practitioner 221, 644. 40. Holmes, G.M. (1904). On certain tremors in organic cerebral lesions. Brain 27, 325-375. 41. Handbook of Clinical Neurology, eds. Pierre Vinken, George W. Bruiyn & Harold L. Klawans. Extra-pyramidal Disorders. Revised Series 5. 1986, Vol. 49, pp. 587-588. 42. Wilson, S.A.K. (1912). Progressive lenticular degeneration: A familial nervous disease associated with cirrhosis of liver. Brain 34, 295-509. 43. Wilson, S.A.K. (1940). Neurology. Edward Arnold, London. 2, p. 806. 44. Gowers, W.R. (1888). Tetanoid chorea. In Manual of Diseases of the Nervous System. London. J & K Churchill. 11, New Burlington Street, Vol. II, p. 656. 45. Ormerod. (1940). Case of cirrhosis of the liver in a boy with obscure and fatal nervous symptoms. Quoted in Wilson, S.A.K. Neurology. Edward Arnold, London. 2, p. 806. 46. Homen. (1940). Peculiar Disease occurring in three members of a family in the form of a progressive dementia, probably Lues hereditaria tarda. Quoted in Wilson, S.A.K. Neurology. Edward Arnold, London. 2, p. 806. 47. Westphal. (1940). Quoted in Wilson, S.A.K. Neurology. Edward Arnold, London. 2, p. 807. 48. Strumpell. (1940). Quoted in Wilson, S.A.K. Neurology. Edward Arnold, London. 2, p. 807. 49. Wilson, S.A.K. (1940). Neurology. Edward Arnold, London. 2, p. 809. 50. Wilson, S.A.K. (1940). Neurology. Edward Arnold, London. 2, p. 820. 51. Wilson, S.A.K. (1940). Neurology. Edward Arnold, London. 2, p. 829. 52. Marsden, CD. (1982). The mysterious motor functions of the basal ganglia: The Robert Wartenburg. Lecture. Neurology 32, 514-539.

Movement Disorders 149 53. Pryse-Philips, W. (ed.) (1995). Companion to Clinical Neurology. Little Brown & Company, p. 914. 54. Pryse-Philips, W. (ed.) (1995). Companion to Clinical Neurology. Little Brown & Company, p. 556. 55. Foster, J.B. (1989). Foreword to J. Neurol. Neurosurg. Psychiatry 1, (sp. suppl), 1. 56. Marsden, CD., Merton, P.A. and Morton, H.B. (1973). Is the human stretch reflex cortical, rather than spinal? Lancet i, 759-761. 57. Marsden, CD., Merton, P.A. and Morton, H.B. Is the human stretch reflex cortical, rather than spinal? 58. Marsden, CD., Merton, P.A. and Morton, H.B. Is the human stretch reflex cortical, rather than spinal? 59. Marsden, CD., Hallet, M. and Fahn, S. (1982). The nosology and pathophysiology of myoclonus. In: Movement Disorder (eds. C D . Marsden and S. Fahn) Butterworths, London, pp. 196-248. 60. Marsden, CD. (1976). Blepharospasm — Oromandibular dystonic syndrome (Brueghel's syndrome). J. Neurol. Neurosurg. Psychiatry 39, 1204-1209. 61. Sheely, M.P. and Marsden, CD. (1982). Writer's cramp — A focal distonia. Brain 105, 461-480. 62. Marsden, CD. (1987). Parkinson's disease in twins. J. Neurol. Neurosurg. Psychiatry 50, 105-106. 63. Marsden, CD., Obeso, J.A. and Rothwell, J.C (1983). Benign essential tremor is not a single entity. In: Current Concepts of Parkinson s Disease and Related Disorders (ed. M.D. Yahr) Excerpta Medica, Amsterdam. pp. 31-46. 64. Gibb, W.R.G. and Lees, A.J. (1988). The relevance of the Lewy body to the pathogenesis of ideopathic Parkinson's disease. J. Neurol. Neurosurg. Psychiatry 51, 745-752. 65. Gibb, W.R.G. and Lees, A.J. (1991). Anatomy, pigmentation, ventral and dorsal subpopulations of the substantia nigra, and differential cell death in Parkinson's disease. J. Neurol. Neurosurg. Psychiatry 54, 388-396. 66. Quinn, N.P. (1989). Multiple system atrophy — The nature of the beast. J. Neurol. Neurosurg. Psychiatry (sp. suppl.), 78-79. 67. Klein, C , Brown, R., Wenning, G. and Quinn, N. (1997). The "cold hands sign" in multiple system atrophy. Mov. Disord. 12, 514-518. 68. Schapira, A.H.V., Cooper, J.M., Dexter, D., Jenner, P., Clarke, J.B. and Marsden, CD. (1989). Mitochondrial Complex I deficiency in Parkinson's disease. Lancet i, 1269.

150 K. B. Bhattacharyya 69. Schapira, A.H.V., Cooper, J.M., Dexter, D., Jenner, P., Clarke, J.B. and Marsden, CD. (1989). Mitochondrial Complex I deficiency in Parkinson's disease. Lancet i, 1269. 70. Schapira, A.H.V., Mann, V.M., Cooper, J.M. et al. (1992). Anatomic and disease specificity of NADH CoQ reductase (Complex I) deficiency in Parkinson's disease. Quoted in AHV Schapira. The spectrum of mitochondrial neurological disease. In Recent Advances in Clinical Neurology, No. 7 (ed. C. Kennard) Churchill Livingstone, London, pp. 129-153. 71. Stern, G. (1995). Prognosis in Parkinson's disease. In Movement Disorders 2 (eds. CD. Marsden and S. Fahn) Butterworth Heinemann Ltd. pp. 91-98. 72. Bannister, R. and Oppeneheimer, D. (1995). Parkinsonism and autonomic failure. Stern, G. prognosis in Parkinson's disease. In: Movement Disorders 2 (eds. CD. Marsden and S. Fahn) Butterworth-Heinemann Ltd. pp. 174-190. 73. Trimble, M.K. and Robertson, M.M. (1995). The psychopathology of tics. Stern, G. prognosis in Parkinson's disease. In: Movement Disorders 2 (eds. CD. Marsden and S. Fahn) Butterworth-Heinemann Ltd. pp. 406-422. 74. Frankel, J.P., Lees, A.J., Kempster, P.A. and Stern, G.M. (1990). Subcutaneous apomorphine in the treatment of Parkinson's disease. J. Neurol. Neurosurg. Psychiatry 53, 96-101. 75. Findley, L.J., Cleeves, L. and Calzetti, S. (1985). Primidone in essential tremor of the hands and head: A double blind controlled clinical study. J. Neurol. Neurosurg. Psychiatry 48, 911-915. 76. Findley, L.J. and Cleeves, L. (1985). Phenobarbitone in essential tremor. Neurology 35, 1784-1787. 77. Pryse-Philips, W. (ed.) (1995). Companion to Clinical Neurology. Little Brown & Company, p. 114. 78. Halliday, A.M. (1967). The electrophysiological study of myoclonus in man. Brain 90, 241-284. 79. Halliday, A.M. (1967). Cerebral evoked potentials in familial progressive myoclonic epilepsy. Journal of the Royal College of Physicians 1, 123-134. 80. Pearce, J.M.S. (1992). Parkinson's Disease and Its Management. Oxford University Press. 81. Jenner, P., Elliot, P.N.C, Clow, A., Reavill, C. and Marsden, CD. (1978). A comparison of in vitro dopamine receptor antagonism produced by substitute benzamide drugs. Journal of Pharmacy and Pharmacology 30, 46-48.

Movement Disorders 151 82. Jenner, P. and Marsden, C D . (1995). Interpretation of radio-active ligand binding to cerebral dopamine receptors. In: Movement Disorders 1 (eds. CD. Marsden and S. Fahn) Butterworth-Heinemann Ltd. pp. 356-368. 83. Rose, F.C. (1987). Parkinson's Disease. John Libby & Company Ltd. London, England. 84. Rose, F.C and Capildeo, R. (1981). Research Progress in Parkinson s Disease. Pitman, Tunbridge Wells. 85. Swallow, M. (1987). Can music help people with Parkinson's disease? In: Parkinson's Disease (ed. F.C. Rose) John Libby & Company Ltd. London, England, pp. 109-112. 86. Rogers, D. (1987). Bradyphrenia. In Parkinson's Disease (ed. F.C. Rose) John Libby & Company Ltd. London, England, pp. 99-102. 87. Ray Chaudhuri, K., Hu, T.M. and Brookes, D.J. (2000). A typical parkinsonism in Afro-Caribbean and Indian origin immigrants to the UK. Mor. Disord. 15(1), 18-23. 88. Critchley, M. (1920). Arteriosclerotic Parkinsonism. Brain 52, 23-83. 89. Quinn, N. (1995). Parkinsonism — Recognition and differential diagnosis. B.M.J. 310, 447-452. 90. Critchely, M. (1986). The Citadel of the Senses. Raven Press, New York. 91. Critchley, M. (1949). Observations on essential (heredofamilial) tremor. Brain 72, 113-139. 92. McDonald, W.I. Queen Square Alumnus Association. Newsletter No. 14, January 1998. 93. Rose, F.C. (1997). The Newsletter of the World Federation of Neurology 12(4), 10. 94. Toole, J.F. (1998). The Newsletter of the World Federation of Neurology 13(1), 3.

TWENTIEH CENTURY NEUROLOGY The British Contribution © 2001 by Imperial College Press

Chapter 13

KERNICTERUS Beryl Corner

Jaundice in the first week of life is a common occurrence. Slight yellow coloration of the skin is often first noticed on the second or third day, increases up to the fourth or fifth day, involves the mucous membranes and conjunctivae and then gradually fades and, in mature infants, usually clears early in the second week. The urine and faeces remain of normal colour. The term "physiological" has been applied to this condition and, traditionally, midwives treated it by purging, often with mercury aperients. Rarely, a more serious disorder has been described as icterus gravis neonatorum in which jaundice is sometimes present at birth with yellow staining of amniotic fluid, or develops during the first day and rapidly becomes worse, resulting in death on the fourth to sixth days in a high proportion of cases with abnormal neurological signs. Hampson (1928; 1929) showed a mortality rate of 80%, with choreo-athetosis or spastic paraplegia in survivors. In 1903, Schmorl described post-mortem findings of nuclear jaundice in some infants dying in the first week and named this condition kernicterus. Subsequently, a few reports suggested that morbid reactions took place between the mother and her foetus. Ottenberg (1923) suggested that icterus gravis neonatorum was due to accidental placental transfusion of incompatible blood. Diamond, Blackfan and Baty (1932) in Boston, USA, linked icterus gravis with two other serious disorders in the newborn infant: hydrops foetalis which usually resulted in still-birth or first day death or severe anaemia 153

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present at birth and rapidly worsening. Since the common factor in these three clinical syndromes was a great increase of erythroblasts in the circulating blood, they named the disorder erythroblastosis foetalis. In 1934, Parsons and Hawksley, and Hawksley and Lightwood, again suggested that a haemolytic agent was the cause of this disease and Parsons (1947) recommended that it should be named haemolytic disease of the newborn, which is the name used today. The aetiology of this disease only became clear when Wiener and Peters (1940), and Landsteiner and Wiener (1940), identified the Rhesus blood group genotypes. Studies that followed confirmed that foeto-maternal isoimmunisation with Rh (Levine et al,, 1941; Tovey, 1945) and also ABO and rarer blood groups, Fell, Duffy, Lewis, was responsible for the haemolytic process which often began in the foetus (Baar, 1946). Diagnosis was confirmed by the Coombs test on the infants' red blood cells which detected maternal Rh antibodies (Coombs, Mourant and Race, 1945). Treatment of the first cases in which Rh immunisation was detected was by simple transfusion with Rh negative blood and, by this means, mortality was reduced by 26% and some cases of kernicterus probably prevented (Tovey and Corner, 1947). A great advance was the development of replacement blood transfusion in USA (Wallerstein, 1947) which aimed to remove 80% of the infant's blood over two hours and hence a high proportion of Rh antibodies and affected red cells, so halting the haemolytic process, and replacing the blood with donor Rh-negative blood. This rapidly became standard treatment and prevented kernicterus when performed adequately, which involved very frequent monitoring of bilirubin, as often as 4 - 6 hourly sometimes, and repetition of the exchange procedure, occasionally up to three times. Subsequently isoimmunisation with ABO and other blood groups was identified and similar treatment was used. Continued research over the next 20 years led to the universal adoption of antenatal testing for foeto-maternal blood group incompatibility and presence of antibodies, and eventually development of prophylactic antiRh immunisation for women at risk (Clarke, 1970). Thus by the 1970s, kernicterus due to foeto-maternal isoimmunisation became rare in all those places where adequate maternal and newborn care services existed.

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Involvement of paediatricians in newborn care developed in the United Kingdom in the 1940s especially for the care of the premature infant who was defined for statistical purposes as "An infant who weighs 2500 grams or less at birth regardless of the period of gestation" (League of Nations, Geneva, 1937). This definition was adopted in 1938 in Great Britain. The mortality rate of premature babies was believed to be as high as 50%, but the cause of death was often ill-defined and little was known about morbidity. In 1945, Bristol Corporation Public Health Authority decided to establish a paediatric service for all premature babies born in the City of Bristol, which subsequently involved the surrounding area and covered a population of approximately one million people. A few very small babies were admitted after birth from elsewhere in the South Western region of England. In 1946 a small unit for premature babies was opened at Southmead Hospital, Bristol where there were then 130 obstetric beds with service provided by the University of Bristol academic Department of Obstetrics. Over the next six years, the Premature Baby Service expanded rapidly and included a second unit at Bristol Maternity Hospital (developed in 1948 as a teaching hospital of the United Bristol Hospitals). Every premature baby born in the catchment area was included in the service which provided care in hospital, an emergency flying squad, domiciliary neonatal care and after-care, a human milk bank, follow-up clinics, two special cubiclised wards for transfer of sick or infected babies or readmission after discharge (Neale, Corner and Hartley, 1952). The techniques of care were originally based on those described by Hess in Chicago (1923 and 1949) and Mary Crosse in Birmingham (1945) with special emphasis on the training of medical, midwifery and nursing personnel. A new feature was the frequent timed recording of clinical observations of the appearance and behaviour of the babies on the same chart as details of feeds and treatment given, as well as the customary recording of temperature, pulse and respiration rates. This was a forerunner of modern intensive care. From these records, it was possible to identify clinical syndromes and their progression which were peculiar to these babies and which had not been fully described previously. These included some specific respiratory disorders and severe jaundice which might lead to

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kemicterus. Thus, kemicterus of prematurity was recognised as a specific clinical condition. For the first four years, admissions to the unit were restricted to the smaller babies weighing 1750 grams or less at birth, owing to the limited accommodation. Singleton births of such low weight could normally be assumed to be of less than 35 weeks gestation. The mortality rate was fairly high without the modem equipment for physiological support and controlled environmental temperature and humidity with ventilators and incubators. A detailed post-mortem was done for almost all deaths and non-macerated stillbirths by a senior lecturer from Bristol University Department of Pathology (R. Aidin). Very limited laboratory space did not permit the holding of most brains and tissues for fixation in formalin so all brains were cut wet in the post-mortem room. It was then noted that bright yellow staining of some areas of grey matter were seen in babies who had died with jaundice, but this yellow colour faded after fixation in formalin for a few weeks, an observation which led to a study of neonatal kemicterus in premature babies that appeared to be a new entity without blood group isoimmunisation. Up till this time, it was believed that kemicterus was always due to abnormal haemolysis causing hyperbilirubinaemia (Wiener and Brody, 1946) although Parsons (1947) mentioned two cases without evident Rh isoimmunisation. De Bruyne and Van Creveld (1948) considered that neonatal sepsis with haemolytic disease was important and Blackwood (1949) supported this view. Claireaux (1950) suggested that anoxia resulting from the severe anaemia which occurred in some cases of haemolytic disease increased the brain cell permeability to bilirubin but failed to demonstrate this histologically in first-week deaths. In 1948, this study of neonatal kemicterus began at Southmead Hospital, Bristol (Aidin, Comer and Tovey, 1950). A total of 239 post-mortem examinations were made on infants dying in the neonatal period of whom 144 were premature. There were 14 proved cases of haemolytic disease of which ten showed kemicterus. Haemolytic disease had been excluded in 24 premature babies, all of whom showed typical kemicterus, and also one baby weighing 6 lbs. 8 ozs. at birth. The blood of all the mothers was fully screened for blood group antibodies and found negative.

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The appearance of the wet brains macroscopically in these 25 cases was indistinguishable from kernicterus due to haemolytic disease. The distribution of the yellow staining was variable and the intensity from pale lemon yellow to deep orange. In all cases, the cornu ammonis and the subthalamic nucleus showed staining and, in many, there was staining of the nuclei in the thalamus, midbrain and medulla, as well as in the floor of the 4th ventricle. In no case was there evidence of biliary obstruction, or clinical or histological evidence of sepsis. 10 cases showed no other abnormality. A variety of pathology was found in the remainder including lung lesions such as patchy atelectasis, and small pulmonary haemorrhages and one with a tentorial tear. There was no evidence of liver pathology. Laryngeal swabs and histology confirmed absence of infection. Following this post-mortem finding of kernicterus in premature babies without any evidence of isoimmunisation, an analysis of the clinical records showed a striking similarity, thus establishing a new clinical syndrome. Cases occurred throughout the weight range, the smallest infant weighed 2 lbs. 8 ozs.

CLINICAL FEATURES Jaundice in very premature infants is often observed on the second day of life and deepens rapidly by the fourth day and in the most immature infants the intensity of jaundice increases up to the eighth day. In many infants there are initial difficulties such as respiratory distress syndrome or frequent apnoeic attacks from which recovery has occurred. The first indication of brain damage is often reluctance to suck so that gavage feeding may be necessary in previously bottle-fed infants. An expressionless face with staring eyes and head retraction are often seen, as is eye rolling with the eyes tending to remain in the "setting sun" sign. Changes in muscle tone vary from rigidity with extended back and limbs and hands tightly clenched, to generalised hypotonicity which develops terminally in all patients. Abnormalities of respiratory pattern may precede or dominate other signs, especially episodes of apnoeic attacks which may be severe and prolonged and more markedly periodic respiration than occurs normally in

158 B. Corner

immature infants. Occasional vomiting is an early sign which may result in dehydration but persistent effortless vomiting of yellow and sometimes blood stained fluid is often a terminal event. Thermolability may be marked with a tendency to terminal hyperpyrexia. A decrease in the intensity of skin jaundice is sometimes preterminal. In severe cases death occurs 24 hours after the onset of signs but is so common on the sixth day of life that when first observed kernicterus was often named as "sixth day disease". In mild cases symptoms persist for four or five days followed by gradual recovery with return to satisfactory progress but sequelae of athetoid cerebral palsy with or without deafness may be recognised within the first six months of life in some survivors.

INCIDENCE In the years 1948 to 1954 inclusive, there were 70 deaths from kernicterus of prematurity among a total of 25 279 live births in Bristol. Isoimmunisation and infection were excluded and post-mortems carried out on all cases. The mortality rate was 3.7 per 1000 live births. A simultaneous study of 2599 premature babies followed up found 37 cases of cerebral palsy of whom ten were survivors of kernicterus of prematurity (Corner, 1958). Similar findings were reported by other workers (Zuelzer and Mudgett, 1950; Govan and Scott, 1953). Crosse, Meyer and Gerrard (1955) in Birmingham noted an incidence of kernicterus of prematurity of 4.1% of all admissions to their premature baby units. In a survey of all post-mortem reports of infants in the Boston Lying In Hospital, USA, during the years 1948-1954, only three cases of kernicterus without isoimmunisation could be found in 483 autopsies performed (Corner, Berry and Neale, 1960).

POST-MORTEM FINDINGS Neurohistology of the brain showed extensive neuronal cell damage in the areas which had been noted to be stained yellow in the wet brains at autopsy (Corner, 1955). Areas of maximum cell death were seen in the subthalamic

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nucleus, the hippocampal gyrus, especially the cornu ammonis, the inferior olives and the dentate nucleus. In the worst areas there was complete loss of normal cells. The cerebral cortex and other areas of the brain appeared normal. No abnormalities were found in the other systems and in particular there was no evidence of liver disease unlike some cases of haemolytic disease of the newborn where occasionally inspissated bile was noted or hepatic cell damage (Dunn, 1963).

AETIOLOGY These observations in newborn infants stimulated investigation into bilirubin metabolism and particularly the factors involved in brain cell damage by unconjugated hyperbilirubinaemia. Bilirubin is derived from the haem of red cells which undergo lysis in the reticulo-endothelial system. In the newborn infant the red cell count is high at birth with a greater proportion of cells containing foetal haemoglobin which break down rapidly when exposed to the higher blood oxygen levels than are present in the foetus. The level of foetal haemoglobin decreases proportionally to the degree of maturity so that the erythrocyte life span in the newborn maybe only 70 to 90 days in the most immature as compared with the normal adult 120 days. The load of released lipid-soluble bilirubin is transported to the liver cells where conjugation takes place by enzyme activity to water-soluble bilirubin glucuronides which are excreted in bile and urine. Studies on normal bilirubin levels in all newborn infants but especially premature infants were difficult to make at that time owing to the inadequacy of biochemical techniques and lack of micromethods. In the mature newborn infant the level of unconjugated bilirubin in cord blood is approximately 2 mg/dl, This rises to a mean peak of 6 mg/dl by the fifth day, gradually falling to the normal adult level of 1 mg/dl by the 10th day. Mild physiological jaundice is visible in the skin when the level reaches 4-5 mg/dl which occurs in about half of all newborn infants. In premature infants peak levels may reach 10-12 mg/dl by the fifth day and may be slower to fall (Billing et al, 1954).

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Transport of unconjugated bilirubin in plasma is by loose binding with albumin on two sites; one molecule binds two molecules of bilirubin. In premature infants plasma albumin is decreased which may be a factor in release of bilirubin to brain cells and is also of great importance when other substances compete for albumin binding. The toxicity of unconjugated bilirubin was established experimentally by Kiister and Krings (1950) and subsequently high levels in premature babies were shown to be associated with kernicterus (Lathe and Walker, 1957; Day, 1954; Waters and Britton, 1955). The inhibition of bilirubin conjugation by hypoxia, hypothermia, dehydration, hypoglycaemia and acidosis which all occur commonly in premature babies was also noted (Crosse et al., 1955) and the role of various chemicals which compete for albumin binding is important. These included sulphasoxazole and novobiocin (Silverman et al., 1957; Hargreaves and Holton, 1962). Laurance (1955) noted the increased incidence of severe jaundice when synthetic Vitamin K (Synkavit) was given intramuscularly in the first two days of life as a routine in a nursery for premature infants and this started a great deal of research (Allison, 1955; Bound and Telfer, 1956; Meyer and Angus, 1956). The effect of Synkavit appears to be dose related although there is evidence that some synthetic Vitamin K analogues may be less toxic (Allison et al, 1956; Corner, Berry and Neale, 1960). The action of large doses of synthetic Vitamin K intramuscularly appears to be due to increased haemolysis of red cells as a result of glutathione inhibition. It has also been suggested that the blood brain barrier may be reduced by inadequate oxygenation. The exact mechanism of the toxic action of this substance is still uncertain. These important observations concerning synthetic Vitamin K have had a considerable impact on the routine care of newborn infants. For the prevention of early neonatal haemorrhage, it is now recommended that a single 1-mg intramuscular injection of phytomenadione (Konakion) be given shortly after birth and this is followed by oral administration for the first week. Other causes of jaundice with unconjugated hyperbilirubinaemia include the common occurrence of jaundice in the breast-fed infant which usually does not reach a peak until 10-14 days and may persist up to 6 weeks. It is thought that this is due to inhibition of glucuronyl transferase activity

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by a steroid in the milk, probably pregnane-3a-2p-diol. The jaundice clears quickly on cessation of breast feeding and is not severe enough to cause kernicterus (Newman and Gross, 1963; Arthur, Bevan and Holton, 1966). Some inherited disorders are of importance. Ethnic groups of Mediterranean and Far Eastern origin, Sephardic Jews, Thais and Chinese have glucose 6phosphate dehydrogenase (G6PD) deficiency in the red cells which manifests itself in the newborn as jaundice and is much more common in male infants. There is great variability between the different ethnic groups and infection increases the probability of haemolysis. A 10% risk of kernicterus has been reported in affected infants in Greece. The administration of synthetic Vitamin K, sulpha drugs, and novobiocin should be avoided in these ethnic groups and testing for G6PD is advised soon after birth (Doxiadis, Fessas and Valaes, 1961). There are other very rare types of congenital inherited enzyme deficiencies in the newborn, notably Crigler-Najjer disease which causes a high level of hyperbilirubinaemia and Gilbert's disease. Kernicterus can occur in both these conditions which are due to deficiency of liver transferases of conjugation for bilirubin. Treatment with phototherapy given early may reduce the hyperbilirubinaemia below the toxic level which is usually regarded as 20 mg/dl (Crigler and Najjir, 1952).

PREVENTION AND TREATMENT Kernicterus is generally a preventable condition and the careful monitoring of the newborn infant for yellow discoloration of the skin is now a part of routine care. Jaundice in the first day of life is always abnormal and requires urgent investigation, particularly for evidence of haemolytic disease of the newborn or some other haemolytic disorder. The treatment of haemolytic disease by replacement blood transfusion to remove antibodies has been extremely successful but is time consuming and not entirely without risk. Initially, there were problems in establishing the critical level of plasma unconjugated bilirubin and there was considerable difference between laboratories as to the critical level at which treatment became essential.

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Levels differed from 18-30 mg/dl but the rate of rise in the level was an important consideration so that frequent monitoring as often as 4 - 8 hourly became essential with repetition of the procedure as necessary. In very immature infants a level of 15 mg/dl was regarded as critical but for more mature infants the average accepted has been 20 mg/dl. In 1955, this treatment came into use to treat hyperbilirubinaemia in premature babies without evidence of isoimmunisation in order to reduce the plasma levels of unconjugated bilirubin and has proved very successful in the prevention of death and kernicterus in survivors (Corner, 1958). Lathe (1955) observed that the yellow colour faded in 24 hours from blood serum left in test tubes in bright sunlight and this led to phototherapy to reduce the level of unconjugated bilirubin passing through the newborn infant's skin. Cremer, Perryman and Richards (1958) introduced the irradiation of newborn infant's skin with blue light of wavelength 420-460 m\i. The serum unconjugated bilirubin level is significantly reduced, the mechanism being the production of water-soluble pyrroles which are rapidly excreted in bile and urine and do not bind to albumin or enter nerve cells. It has therefore become customary to expose all jaundiced newborn infants to phototherapy for up to four hours repeated two or three times in 24 hours for up to five days when the serum bilirubin level rises to 10 mg/dl. When it is not possible to get frequently repeated blood bilirubin estimations, a Perspex icterometer applied to the infant's skin gives a very useful estimate (Gossett, 1960). Phototherapy appears to be harmless provided care is taken to protect the infant's eyes from exposure to the light by the use of appropriate screening goggles.

LONG-TERM FOLLOW-UP OF NEONATAL JAUNDICE A number of follow-up studies have been done on low birth weight babies with neonatal jaundice. Kiister and Dortman (1958) studied tissue cultures and found that at bilirubin levels of 20 mg/dl damage to nerve cells begins and at 40 mg/dl most of the cells are killed. McDonald (1967) found spastic

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diplegia and deafness at the age of 6-8 years among 1066 children with a birth weight of 1800 grams or less who had been jaundiced, especially those with gestational age less than 31 weeks but there was no lowering of IQ in those children who had been jaundiced but had no clinical neurological abnormality. Culley et al. (1970) found no lowered intelligence in jaundiced babies with serum bilirubin below 20 mg/dl.

CONCLUSION Jaundice in the newborn baby is a sign which, although common, should always be regarded seriously. In premature babies, it is likely to occur more frequently and be of more serious consequence. So-called physiological jaundice is due to an increase in the circulating unconjugated bilirubin caused by excess of bilirubin production over the capacity of the liver glucuronyl transferase system to excrete it into bile as conjugated bilirubin. Depression of the conjugating enzyme system by various factors which are particularly common in premature babies, hypoxia, dehydration, acidosis, and hypoglycaemia, raises the level of plasma bilirubin. When binding to plasma albumin for transport is inadequate, the unconjugated bilirubin enters brain cells in areas which are likely to be most mature and metabolically active for the maturity of the infant, that is, the basal ganglia, hippocampal gyrus and nuclei in the medulla, and can result in cell death. The critical serum level at which the toxic action occurs is 20-25 mg/dl or less in very premature babies. The mortality is high in prematures with bilirubin above this level. In full term babies who survive, levels over 30 mg/dl are associated with athetoid cerebral palsy and deafness. Prevention of kernicterus necessitates monitoring of jaundiced newborn babies and lowering of plasma bilirubin when critical levels are reached by replacement blood transfusion or, in mild cases, treatment with phototherapy, and avoidance of all drugs which compete for albumin binding in plasma. Drugs which stimulate maturation of enzyme systems have been advocated, especially phenobarbitone, but there are difficulties in their routine use for premature babies, so they are not normally advised (Conney, 1967; Behrman and Fisher, 1970).

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References Aidin, R., Corner, B. and Tovey, G. (1950). Kernicterus and prematurity. Lancet 1, 1153. Allison, A.C. (1955). Danger of Vitamin K in newborn. Lancet 1, 669. Allison, A.C, Moore, T. and Sharman, I.M. (1956). Haemolysis and haemoglobinuria in Vitamin E deficient rats after injection of Vitamin K substitutes. Br. J. Haematol. 2, 197-204. Arthur, L.J.H., Bevan, B.R. and Holton, J.B. (1966). Neonatal hyperbilirubinaemia and breast feeding. Devel. Med. Child. Neurol. 8, 279-284. Baar, H.S. (1946). Post-mortem examination of newborn infants. Br. Med. Bull. 4, 178-188. Behrman, R.E. and Fisher, D.E. (1970). Phenobarbital for neonatal jaundice. Pediatrics 76, 945-948. Billing, B.H., Cole, P.G. and Lathe, G.H. (1954). Increased plasma bilirubin in newborn infants in relation to birth weight. Br. Med. J. ii, 1263-1285. Blackwood, W. (1949). In: Atlas of Neuropathology. Edinburgh. Bound, J.P. and Telfer, T.P. (1956). Effect of Vitamin K dosage on plasma bilirubin levels in premature infants. Lancet 1, 720-722. Claireaux, A. (1950). Haemolytic disease of the newborn. Arch. Dis. Childh. 25, 61-80. Clarke, C.A. (1970). Preventing Rhesus babies. The Liverpool Research and Followup. Arch. Dis. Childh. 64, 1734-1740. Conney, A.H. (1967). Pharmacological implications of microsomal enzyme induction. Pharmac. Rev. 19, 37. Coombs, R.R.A., Mourant, A.E. and Race, R.R. (1946). In vitro iso-sensitisation of red cells in babies with haemolytic disease. Lancet 1, 264. Corner, B. (1947). The Rhesus factors II Haemolytic disease of the newborn. Bristol Medico-Chirurgical J. LXIV, 74-80. Corner, B. (1955). Kernicterus and prematurity (Abstract). Am. J. Dis. Child. 90, 520. Corner, B. (1958). Hyperbilirubinaemia in premature infants treated by exchange blood transfusion. Proc. Roy. Soc. Med. 51(2), 1019-1022. Corner, B. (1958). Hyperbilirubinaemia in premature infants treated by exchange blood transfusion. Proc. Roy. Soc. Med. 51(12), 1019-1022. Corner, B., Berry, E. and Neale, A.V (1960). Hyperbilirubinaemia in premature infants and the effect of synthetic Vitamin K. Lancet 1, 715-717.

Kernicterus 165 Cremer, R.J., Perryman, RW. and Richards, D.H. (1958). Influence of light on the hyperbilirubinaemia of infants. Lancet 1, 1094-1097. Crigler, J.F. and Najjar, V.A. (1952). Congenital nonhaemolytic jaundice with kernicterus. A new clinical entity. Pediatrics 10, 169. Crosse, V.M. (1945). The Premature Baby. Churchill. Crosse, V.M., Meyer, T.C. and Gerrard, J.W. (1955). Kernicterus and prematurity. Arch. Dis. Childh. 30, 501-508. Culley, R, Powell, J., Waterhouse, D. and Wood, B. (1970). Sequelae of neonatal jaundice. Br. Med. J. 3, 383-386. Day, R.L. (1954). Inhibition of brain respiration in vitro by bilirubin. Reversal of inhibition by various means. Proc. Soc. Exper. Biol. Med. N.I. 85, 261-264. De Bruyne, J.L. and Van Creveld, S. (1948). On the cause of nuclear jaundice in neonatal sepsis with jaundice. Arch. Dis. Childh. 23, 84-89. Diamond, L.K., Blackfan, H.D. and Baty, J.M. (1932). Erythroblastosis and its association with universal oedema of the foetus, icterus gravis neonatorum and anaemia of the newborn. Pediatrics 1, 269. Doxiadis, S.A., Fessus, P.H. and Valaes, T. (1961). Glucose 6-phosphate dehydrogenase deficiency. Lancet i, 297-301. Dunn, P.M. (1963). Obstructive jaundice and haemolytic disease of the newborn. Arch. Dis. Childh. 38, 54. Gossett, I.H. (1960). A perspex icterometer for neonates. Lancet 1, 87-88. Govan, A.D.T. and Scott, J.M. (1953). Kernicterus and prematurity. Lancet 1, 611-614. Hampson, A.C. (1928). Jaundice of the newly born with special reference to physiological jaundice and grave familial jaundice. Guy's Hospital Reports 78, 199-218. Hampson, A.C. (1929). Grave familial jaundice of the newborn. Lancet 1, 429-432. Hargreaves, T. and Holton, J.B. (1962). Jaundice of the newborn due to novobiocin. Lancet 1, 839. Hawksley, J.C. and Lightwood, R. (1934). A contribution to the study of erythroblastosis: Icterus gravis neonatorum. Quarterly J. Med. 3, 155. Hess, J.H. and Lundeen, R.N. (1922) and (1949). The Premature Infant. J.B. Lippincott Co. Kuster, E. and Krings, H. (1950). Blood destruction and cerebral damage in haemolytic disease of the newborn. Z. Kinderheilk. 67, 503.

166 B. Corner Kuster, F. and Dortmann, A. (1958). Dtsch. Med. Wschr. 83, 1193. Landsteiner, K. and Wiener, A.S. (1940). Studies on an agglutin (Rh) in human blood reacting with anti-Rhesus sera and with human antibodies. J. Exp. Med. 74, 309. Lathe, G.H. and Walker, M. (1957). Enzyme defect in neonatal jaundice and Gunn's strain of neonatal rats. Biochem. J. 67, 9. Laurance, B.M. (1955). Danger of Vitamin K analogues to the newborn. Lancet 1, 819. Levine, P., Katzin, E.M. and Burnham, L. (1941). Isoimmunisation in pregnancy. Its possible bearing on etiology of erythroblastosis foetalis. J. Am. Med. Assoc. 116, 825. McDonald, A. (1967). Children of very low birth weight. MEIU Research Monograph. No. 1. Heinemann. Meyer, T.C. and Angus, J. (1956). The effect of large doses of Synkavit in the newborn. Arch. Dis. Childh. 31, 212-215. Neale, A.V., Corner, B. and Hartley, G. (1951). The Care of the Premature Baby in the Bristol Area. A Symposium. Bristol Printers Ltd. Newman, O.J. and Gross, S. (1963). Hyperbilirubinaemia in breastfed infants. Pediatrics 32, 985. Ottenberg, R. (1923). Etiology of eclampsia. J. Am. Med. Assoc. 81, 295. Parsons, L.G. and Hawksley, J.C. (1933). Studies in the anaemias of infancy and childhood. Arch. Dis. Childh. VIII-IX, 159-187. Parsons, L.G. (1947). The clinician and the Rh factor. Lancet 1, 815-820. Schmorl, G. (1903). Zur Kenntis des Ikterus Neonatorum. Verhand. Dtsch. Path. Ges. 66, 109-115. Silverman, W.A., Anderson, D.H., Blanc, W.A. and Crozier, D.N. (1956). A difference in mortality rate and incidence of kernicterus among premature babies allotted to antibacterial prophylactic regimes. Pediatrics 18, 614-624. Tovey, G.H. (1945). Hetero-specific blood group factors and their role in prevention of haemolytic disease of the newborn. J. Path. Bad. 57, 275. Tovey, G.H. (1947). The Rhesus factors I. Serology. Bristol Medico-Chirurgical J. LXIV, 68-73. Wallerstein, H. (1947). Substitution transfusion. New treatment for erythroblastosis foetalis. Am. J. Dis. Child. 73(1), 19. Waters, W.J. and Britton, H. A. (1955). Bilirubin encephalophathy. Pediatrics 15, 45-61.

Kemicterus 167 Wiener, A.S. and Peters, H.R. (1940). Haemolytic reactions following transfusion of homologous groups. Ann. Int. Med. XIII, 2306-2322. Wiener, A.S. and Brody, M. (1946). Pathogenesis of kemicterus. Science 103, 570. Zuelzer, W.W. and Mudget, R.J. (1950). Kemicterus. Pediatrics 6, 452-474.

TWENTIEH CENTURY NEUROLOGY The British Contribution © 2001 by Imperial College Press

Chapter 14 THE WATERSHED OF NEUROSURGERY J.R. Heron

"Hughlings Jackson's motto was "Error is preferable to Confusion ", Sir William Broadbent s "Chaos is preferable to Error", and hence they had many discussions... " On 27 November 1934, Wilfred Trotter FRS addressed the Royal Society of Medicine under the title "A Landmark in Modern Neurology". Central to this communication was the recording of Sir Rickman Godlee's operation performed at the National Hospital for Epilepsy and Paralysis on 25 November 1884. This decisive act of neurosurgical intervention was the outcome of the advances in neurology and neurophysiology led by such figures as Hughlings Jackson and Ferrier in this country and is indicative of the adventurous approach which was to be adopted and which owed so much to the control of infection resulting from the contributions of Joseph Lister and Louis Pasteur. Trotter detailed this early brain operation on Henderson, a native of Dumfries, aged 25 years, who had symptoms of Jacksonian epilepsy affecting the left side of the face and tongue, left hand and arm, accompanied with occasional attacks of loss of consciousness. On 3 November 1884, Henderson was admitted to the Hospital for Epilepsy and Paralysis with a left hemiparesis and the signs and symptoms of raised intracranial pressure. The clinical diagnosis of tumour of limited size involving the cortex of the brain situated at the middle part of the 169

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right fissure of Rolando was made. At operation on 25 November the ascending parietal convolution was exposed and incised. A tumour was disclosed at a depth of an eighth of an inch. The tumour which was encapsulated was enucleated piecemeal and proved to be a glioma. Postoperative recovery was satisfactory. There was residual hemiparesis, central symptoms were relieved and the patient became conscious and fully responsive. Trotter summarised the importance of this case in saying: "It had proved for the first time without the least external abnormality of the skull to point the way (that) a focal lesion of the brain substance could be found and could be removed by operation, leaving the general functions of the brain unimpaired". Despite the successful surgical outcome, infection of the wound occurred and over the next four weeks the patient's condition deteriorated and he died. Those present at the operation were Rickman John Godlee, Hughes Bennett, Ferrier and Hughlings Jackson. Godlee had been on the staff of University College Hospital for seven years and was to remain there for a further 30 years. Among his contemporaries on the staff at University College was Victor Horsley, seven years junior to Godlee. Horsley was soon to record successful neurosurgical operations and in 1887 was credited as the first surgeon to remove an accurately localised spinal tumour. Godlee was the nephew of Joseph Lister and it was apt that he should have applied the new antiseptic practices to neurosurgery. He was an excellent anatomist and in the circumstances the diagnosis with Hughes Bennett of the lesion as near the central cortex of the right hemisphere, on clinical grounds, leading to exploration and extraction of the tumour was an early crossing of the Rubicon (which in this chapter represents) the dura mater. This operation and those approximately contemporary with it were carried out at a time when surgery was emerging from the dark period of post-operative morbidity and mortality due to sepsis. Surgical techniques were sophisticated but pain, infection and blood loss marred the excellent technical skills of competent, anatomically exact and swift operating surgeons. One must recall that Louis Pasteur (1843-1910) had only lately overturned the mythology of spontaneous generation, and Koch was in the preliminary stages of founding the speciality of bacteriology. There was a complete absence of the pharmacological advances ushered in by antibiotics

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and of the investigative technology of the 20th century. The discovery of X-rays by Rontgen (1895) was imminent. The ophthalmoscope invented by Helmholtz in 1851 was limited in general use but had firm advocates in Hughlings Jackson and later Clifford Albutt and Gowers. Diagnostic lumbar puncture did not become available until 1885 when Corning1 introduced this in spinal anaesthesia and local medication of the cord; its use was also reported by Quincke in Germany in the treatment of hydrocephalus in 18912 and Essex-Wynter in the treatment of tuberculous meningitis (1891).3 It should be recorded however that John Hilton, President of the Royal College of Surgeons and Surgeon to Guy's Hospital and Professor of Anatomy, had reported between 1860 and 1862 [see Lectures on Rest and Pain. Hilton. Edited by Jacobson (1892)] important anatomical and physiological observations on the action of the cerebrospinal fluid and confirmed the aqueduct occlusion in internal hydrocephalus at the aperture of Magendie described in 1842. These observations were succinct and may well be referred back to when the mechanisms of brain stem death and infant cot death syndrome is finally elucidated. The additional techniques of investigation now commonplace — arteriography, encephalography and the generations of scanning techniques lay hidden in the future. The problem was to bridge the gulf between clinical medicine and applied science. To better appreciate the background at this watershed period it should be remembered that until the second half of the 19th century in Britain, the profession of nursing was in embryo and it was not until 1860 that Florence Nightingale, replete from her experiences in the Crimean War, was able to establish a School of Nursing at St. Thomas' Hospital. Lytton Strachey in his book "Eminent Victorians"4 describes, with no doubt a degree of exaggeration, the prior state of nursing. "A nurse meant then a coarse old woman, always ignorant, usually dirty, often brutal, a Mrs Gamp, in bunched-up sordid garments, tippling at the brandy bottle or indulging in worse irregularities". At the Radcliffe Infirmary in Oxford in the 1850s the salary of a nurse was £5 a year, and there was no distinction between a nurse and a domestic servant. The working day was 12 hours long and at night normally one nurse was in charge of the hundred bedded hospital. It is against this background that one must appreciate the true nature of the

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watershed that took place in surgery and in neurosurgery in the second half of the 19th century. It was the operative challenge of the clinical diagnosis, craniotomy, splitting of the dura, entering the substance of the brain and safe removal of the lesion which placed neurosurgery at the beginning of a scientific revolution that flowered in the 20th century.

CEREBRAL ABSCESS Local operative treatment for cerebral abscess had been considered for some years before Godlee's operation. This related principally to drainage of the external ear and debridement in head injury and compound fractures of the skull. The dural barrier remained. William Withie Gull, physician to Guy's Hospital, studied and wrote extensively on abscess of the brain in the 1857 Guy's Hospital Reports (Volume 3, 1857, page 261) and in "Reynolds System of Medicine" (Volume 2, 1869) he wrote further on this subject with Henry Sutton.5 In this last publication (1868), he analysed 76 cerebral abscesses, all with fatal outcome, and in each instance postmortem evidence as to the site and aetiology is reported. Skull trephining was carried out in a very small proportion of these where fracture of the skull had taken place. Drainage in each case was superficial. In the 11 years between these two major publications, Gull was unwilling or unable to make the imaginative decision, despite extensive familiarity with the problem of abscess, to advise entry to the brain for drainage of the abscess. He states (1857) "Even where abscess follows injury to the scalp, it is not so entirely under the external wound as to make us sure of evacuating the pus by an incision". He quotes the fascinating and signal case, "Detmold's case", notorious from the doubts as to its veracity and goes on to say "Though life was not ultimately saved, it was prolonged by the surgical interference and for a time consciousness and reason were quite restored. It might be of the highest importance in a similar case if only this could be affected". Detmold's case was in fact verified and published in the American Journal of Medical Science in January of 1850 and in the Archives of

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Pathological Anatomy and Physiology in Germany in 1857. The case described in detail a healthy man of 40 years who sustained a compound fracture of the left frontal bone in 1849. He later developed symptoms of pressure which were relieved by removing some pieces of loose bone from the wound. He subsequently developed headache and drowsiness leading to stupor and it was decided by Dr. Detmold to attempt to evacuate the pus. On 13 September 1849 scarring of the dura was dissected and an incision made into the brain one inch in length and half an inch in depth. A large quantity of pus flowed and the patient recovered consciousness and answered distinctly that he felt better. Following an excellent immediate recovery, he developed symptoms indicating raised intracranial pressure with convulsion. Five weeks after the first operation, a further incision into the brain was made and at the second attempt to a depth of four and a half inches in the direction of the lateral ventricle. It was concluded that the abscess had opened into the ventricle, which was incised and further pus was removed. The patient died seven weeks after the first opening of the abscess. Gull in 1868 comments on Dr. Hughlings Jackson's recognition of changes of optic neuritis in the retina in raised intracranial pressure from cerebral abscess and other forms of cerebral disease. In discussing Jackson's views on therapeutics of brain abscess, he accedes to the guiding principles of obviating the precipitating cause: free exit for discharge in chronic disease of the ear or nose, the importance of rest, simple diet and quiet life and finally in cases where abscess follows injury to the head, surgical interference must be considered. The principle in such cases is a mechanical one, namely to reach the abscess and evacuate its contents if that be thought advisable; experience has but little to commend it. These statements do not diminish the significant contribution made by Gull but do emphasise the time interval occupied between the genesis of a radical and important new concept and its general acceptance. Precedence in the field is not however overriding and I would refer to a neglected contribution by La Peyronie (1708) who systematically collected evidence from surgeons on the effects of wounds and diseases in the head. He commented that large quantities of cerebral cortex were often carried away or consumed by disease without loss of faculties. Not only did La

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Peyronie employ systematic observations but also experiment: in one case the removal of an abscess the size of an egg opened a cavity reaching to the corpus callosum, which relieved of its burden returned its owner to consciousness. By alternately filling and emptying the cavity of water from the syringe, it was found that the condition of the sufferer could be controlled at will. "Voila" he concludes, 'Tame installee dans le corps calleux".6 This is a very French statement and an elegant expression of deductive reasoning.

SIR WILLIAM MACEWEN Sir William Macewen in Glasgow established secure foundations for successful neurosurgery. As a student he had been influenced by Lister and followed him onto the surgical staff of the Glasgow Royal Infirmary. He worked with specially self designed instruments, and later introduced chromic cat gut; his attitude to sepsis was obsessional. Among the many advances he introduced were transplantation of bone for the repair of skull defects; in addition to his neurosurgical achievements he was attributed the first pneumonectomy and the treatment of aortic aneurysm by induction of thrombosis using percutaneous technique. Like his London, European and American colleagues he was basing his neurosurgery on localisation of intracranial lesions from advancing knowledge in neurological function provided by the studies of Broca (1861), Hughlings Jackson (1869), Fritsch and Hitzig (1870), Sir David Ferrier (1873) and, in America, Weir Mitchell and William Keen. He operated successfully on subdural haematoma {British Medical Journal 1879, 2, 10-22) and on intracranial tumour {Glasgow Medical Journal 1879, 12, 2-10). As Professor of Surgery at the Glasgow Royal Infirmary be published "pyogenic infective diseases of the brain and spinal cord". The debt to Macewen was recognised, later, by Harvey Cushing who said of him: "To Macewen belongs the distinction of having been the chief pioneer in craniocerebral surgery". Macewen made an important address published in the British Medical Journal, August 11, 1888 which he introduced by stating that the efforts of surgeons that have gone before were chiefly directed to the superficial parts of the skull and its membranes

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and were exclusively confined to the results of injury. Their operations were simple, undertaken for the most part upon the primitive evidence of direct visual and tactile observations. The function of the brain inspired fear because of its intimate association with the seat of life. It was held in awe as "the mysterious dome of thought". He went on to say that it was not a lack of boldness or dexterity that determined reluctance to deal with brain lesions. Knowledge from postmortem findings showed that cerebral lesions could easily have been reached had localisation been known in life. He commented on inhibition of surgery because of the inflammatory process which could prove fatal in intervention. He also commented on the brain being regarded as a dark continent in which the path leading to a particular diseased area was in a sense "groping in the dark". It was this possibility of positive harmfulness that had delayed active interference and made the trephine almost an obsolete instrument. Such was the state of cranial surgery as Macewen saw it until the rationalised changes to which he himself contributed so much in the 1870s. By his acknowledged skills, by application of Lister's principles in the wards of the Glasgow Royal Infirmary and the experience gained, Macewen became confirmed in his conviction that not only compound fractures of the skull but large osseous defects in the cranial vault with extensive loss of cerebral substance were amenable to treatment. These beliefs in conjunction with his physiological knowledge allowed for accurate localisation and successful neurosurgical intervention. He proceeded with accurate localisation of an abscess in Broca's area in 1876; intracranial subdural haematoma in the lower part of the fissure of Rolando; tumour of the dura mater pressing on the frontal lobe (1879), this patient lived and was able to work for 8 years after removal of the tumour and autopsy showed no recurrence of the tumour. He further describes localisation of cerebral abscess in the temporo-sphenoidal lobe, intracranial effusion in the temporo-sphenoidal lobe and discusses in detail current aspects of cerebral surgery. He then describes operations for the relief of paraplegia caused by pressure on the spinal cord and lists six cases of removal of posterior arches of vertebrae in the treatment of spinal compression. He concludes by saying that such operations are beginning to

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be practised by others and credits Victor Horsley with the first successful case of similar operative treatment for the removal of a small tumour of the theca diagnosed by Gowers.

VICTOR HORSLEY (1857-1916) Victor Horsley's singular contributions to neurosurgery are fully appreciated by this audience and are to be the subject of the next chapter (Professor J.B. Lyons). Osier has said of him "Better than any man of his generation Victor Horsley upheld the tradition of experimental physiologist and practical surgeon in a degree unequalled since John Hunter". With others such as Beevor, Schafer, Mott, Gotch and indeed Macewen, his was a brilliant achievement. Osier also commented that it was a pity that the fragmented organisation of London provided no abiding home in the shape of a great physiological institute for a man of Horsley's genius. At the British Medical Association meeting in Brighton (1886), Charcot congratulated Horsley saying that not only had English surgeons cut out tumours of the brain but here was a case in which epilepsy had been cured by operative measures. Hughlings Jackson was likewise warm in his praise of Victor Horsley. At this 54th annual meeting Horsley outlined in great detail the surgical preparations of the patient, anaesthesia, steps to avoid sepsis, the technique of craniotomy and the treatment of the dura mater and brain. He presented three cases of his own and supplied photographs. An account of these operations was also sent by way of Professor Thuring of Brooklyn to the New York surgeons. The cases described by Horsley included, excision of a cortical brain scar and thickened dura in a 22-year-old man at the National Hospital, a patient of Hughlings Jackson and Ferrier. This patient had serial Jacksonian attacks and status epilepsy, but was "fit free" when reviewed at six months post-operatively. He further reported removal of a tuberculoma causing serial focal fits, located in the frontal and parietal convolutions. This was based on his physiological work on cortical stimulating techniques, early pioneering work in this field. The third patient was experiencing serial partial seizures as a

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consequence of a previous head injury. The dura was freely opened and a cystic cavity found at the precise diagnostic site and the cystic cavity drained. Suffice it to say that Victor Horsley's contributions were many in relation to focal epilepsy, pituitary adenomata and gasserectomy for trigeminal neuralgia. This last contribution resulted from experimental work carried out at the Brown Animal Sanitary Institute of which Victor Horsley was Professor Superintendent from 1884 to 1900. This institution was destroyed in an air raid in 1944. It is significant to record that of the 12 patients operated on for pituitary adenoma taken from the files of the National Hospital, Queen Square, and his private files, 8 recovered and 4 died. This surgical intervention was based on experimental work on 54 animals, the results of which were presented to the Physiological Society in March 1914. Horsley's contributions are legendary. His family background is also deserving of further papers. For the purposes of this short communication it is significant to simply emphasise that any evaluation of these distinguished pioneers in neurosurgery is not designed to indicate precedence of individual genius but to record the general renaissance at this watershed in the neurosciences. I therefore conclude with a few anecdotes, designed with a gentle irony, which question the cult of a personality. Harvey Cushing in a diary note 5 July 1900 7 makes the following statement "He (Harvey Cushing) found Horsley living in seemingly great confusion: dictating letters during breakfast to a male secretary; patting dogs between letters; and operating like a wild man". H. Cushing gave him a reprint of his paper on the Gasserian ganglion, whereupon Horsley said he would show him how to do a case, as reported in the following chapter. His initial reaction to Horsley as a surgeon softened as he came to know him better "as a man". Sir Geoffrey Jefferson first saw Cushing operating at the Brigham Hospital in Boston on 29 April 1924.8 He commented "Well, I've seen the great man do a laminectomy and tomorrow he is to do a pituitary so I am in luck... He pottered about on odds and ends for a long time. He seems to be very indefinite and his staff never seem to know quite when he will do anything". Again in 1953, 14 years after Cushing's death, he

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wrote of him that he was "Charming, tiresome, petty, and admirable all by turns... the great qualities very heavily outweighed the others. A good talker, but a bad listener...". My last quotation, appropriately by Macewen is "Let us remember that the same phenomena by which we are now able to recognise cerebral lesions and locate them in precise areas were exhibited by patients who came under the eye of our surgical predecessors, some of whom must have the album of their memory filled with such impressions, yet they saw not their import. They were so hampered by the inculcated physiological dogma of the time that their true significance never dawned on them. The facts were reflected from their brain as objects from a mirror and no more". References 1. Corning, J.L. (1885). Spinal anaesthesia and local medication of the cord. N. Y. Med. J. xiii, 483-485. 2. Quincke, H. (1891). Ueber Hydrocephalus. Verhandlungen des Congresses fur innere Medicin. Vol. X. Wiesbaden: Bergman, pp. 321-340. 3. Wynter, W.E. (1891). Four cases of tubercular meningitis in which paracentesis of the theca vertebralis was performed for the relief of fluid pressure. Lancet I, 981-982. 4. Lytton Strachey. Eminent Victorians. Penguin Books 1948. 131. 5. A Collection of The Published Writings of Sir William Gull. London. The New Sydenham Society 1894, pp. 3-85. 6. Diderot and D'Alembert (1751). Encycledie ou Dictionnaire raisonne des Sciences, des Arts et des Metiers. Paris, Vol. 1, 341. 7. Fulton, J.F. and Thomas, C.C. (1946). Harvey Cushing. A Biography. pp. 163-167. 8. Schurr, P.H. (1997). So That Was Life. A Biography of Sir Geoffrey Jefferson. Royal Society of Medicine Press Ltd. pp. 136-137.

TWENTIEH CENTURY NEUROLOGY The British Contribution © 2001 by Imperial College Press

Chapter 15

SIR VICTOR HORSLEY (1857-1916) REVISITED John B. Lyons

INTRODUCTION Biography is an art calling for research and impartial assessment, but the process is one in which bias is inherent. Who would spend months or years writing about a "life" without the spur of hate or hero-worship to drive him, usually the latter? There is a possibility that the informed reader will redress the delicate balance painlessly, but reviewers, too, are open to bias and if an author's claims seem excessive they can chasten him. I learned this by experience. When my biography of Sir Victor Horsley1 was published in London 30 years ago, a review copy was sent to A. Earl Walker who was irked that Horsley had been referred to as "the father of neurosurgery", a parentage that from his viewpoint surely was Cushing's. Gilbert Horrax (Cushing's first assistant), Ernest Sachs and others were my witnesses for Horsley as "the father of neurosurgery", but the claim was obnoxious to Walker who said that as a father of neurosurgery Horsley was a very sterile parent. I felt devastated. My hero, resting by the Tigris (in a grave that was "forever England"), had been demeaned. In my maturity (or beyond it) I can smile at the criticism. Walker's comment was unworthy, not to say snide. He was comparing different periods, almost different generations. He was being unhistorical.

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Today I shall be more careful. I shall parcel neurosurgery into four phases: (a) (b) (c) (d)

Instinctive Informed Improved Organised

To illustrate the first of these phases, I shall select Sylvester O'Halloran (1728-1807) of Limerick in Ireland, author of A New Treatise on External Injuries of the Head (1793). Perusal of this book leaves one in no doubt that O'Halloran, who had studied in London, Paris and Leyden, was a conservative and reflective surgeon, unwilling to resort to facile trepanation, a widely favoured but highly dangerous method of treatment. He had a clear concept of concussion, and of compression of the brain by depressed fractures or effusions of blood and pus. Cerebral compression required surgical intervention, which should be avoided in concussion.2 The second phase, with which I am principally concerned, was informed by advances in neuroanatomy, neurophysiology and cerebral localisation; its leading figures in the United Kingdom in the 1880s were Macewen, Rickman Godlee and Victor Horsley. Others, e.g. Francesco Durante (1844-1934) and Fedor Krause (1856-39), worked effectively in Europe. The improvements of the third phase are said to have resulted from Cushing's application of Halstead's operative techniques, and the availability of X-rays and blood transfusion, but were really the predictable evolution of a process which once started was bound to gain momentum and refinement. The benefits of the fourth phase are long since evident in the United Kingdom, where Jefferson, Dott and MacConnell of Dublin were founders of the Society of British Neurosurgeons and, with Cairns, exemplars of Cushing's stern discipline. Since 1948 the British National Health Service has striven to provide an even spread of neurosurgical facilities.

BIOGRAPHY The infant born in London to Rosamund (nee Haden), wife of John Calcott Horsley, A.R.A., on 14 April 1857, was named Victor at the suggestion of

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Queen Victoria whose baby girl (Princess Beatrice) arrived on the same day. Victor Alexander Haden Horsley was the third son (he was to have three sisters and a fourth brother) in a family with a broad cultural background. William Horsley, an organist and composer, Victor's grandfather, married Elizabeth Calcott, daughter of a colleague. Their eldest son, John Calcott Horsley, an artist, is credited with the creation of the first Christmas card. Sir Seymour Haden, FRCS, Victor's uncle, founded the Royal Society of Painter-Etchers. An aunt, Mary Horsley, married Isambard Kingdom Brunei.3 While he was still little, Victor's parents moved with their family to Kent where they had acquired Willesley, a spacious house outside Cranbrook. Growing through boyhood he enjoyed country pursuits, attended Cranbrook Grammar School and planned to become a cavalry officer. When his father demurred, protesting that he could not support a military career, Victor accepted medicine as an alternative option, insisting that he would be a surgeon. He matriculated at London University in 1874. The Horsleys returned to London in the following year and lived at 1 High Row, Kensington Gravel Pits (now 128, Church Street, Kensington), from which Victor attended the medical school at University College Hospital (UCH). He was surgical dresser to John Marshall, and clinical clerk to H. Charlton Bastian who may have been the first to interest him in the nervous system, and with whom while still a student he wrote his first scientific paper. Gowers, too, was a vital influence; Horsley carried out anatomical studies which the former used in his monograph on the spinal cord. In November 1880, Victor Horsley took the MRCS; at the university "finals" in 1881, he was awarded a gold medal in surgery. Meanwhile working as house-surgeon at UCH, he devoted much of his spare time to research, acting as his own guinea-pig. A year in Germany was followed by promotion to surgical registrar, and two years later to a position as assistant surgeon to UCH. He became FRCS in 1883 and was elected to the staff of the National Hospital, Queen Square, three years later. By the end of his first year there he had done eleven intra-cranial operations with only one death.

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He also held the appointment of Superintendent of the Brown Animal Sanatory Institution (from 1883), and his experimental research led to his election as FRS at twenty-nine; it resulted, too, in conflict with antivivisectionists. The removal in 1887 of a spinal tumour (which Osier spoke of as "the most brilliant operation in the whole history of surgery") constitutes a surgical epic deserving to be recalled in detail. The 42 year old patient, Captain Gilbey, had experienced an Odyssey of suffering. His tribulations began in 1884 when his wife was fatally injured in a carriage accident. Gilbey on that occasion had wrenched his back but escaped more serious injury. Subsequently he attributed a backache to the accident, and on visiting his doctor was told there was nothing much amiss. During the next two years business affairs took him to China, France, and Constantinople, where doctors ascribed his symptoms variously to intercostal neuralgia, aneurysm, and neurosis. When his legs became numb and paralysed, his consequent emotional distress attracted disproportionate attention. The waters at Aix-la-Chapelle proved unavailing; a course of Weir Mitchell treatment was mooted, but, through the fortunate intervention of a family friend, Dr. W.R. Gowers was consulted. His diagnosis of spinal tumour ordinarily amounted to a death sentence. On this occasion, however, the diagnostician was determined to challenge fate. He advised surgical treatment, insisting that his radical suggestion be submitted to a second opinion. A consultation was arranged with Sir William Jenner, Gowers' former teacher, who concurred in the diagnosis, sanctioning the unprecedented therapy, but adding an unencouraging rider — "provided the patient clearly understood that a perfectly successful result was no more than a possibility". Horsley operated at the National Hospital on 9 June 1887 but when he exposed the cord it appeared perfectly normal. He palpated it, and probed with a curved needle around the anterior surface without detecting a tumour. He removed another lamina at either end of the wound with a negative result. In his account of the case in the Medico-Chirurgical Transactions, Horsley remarked: "At this juncture it appeared as if sufficient had been done...". His words concealed the dismay he must have felt, and which the onlookers in the theatre must have shared. Was Gowers' diagnosis incorrect?

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Was the intrepid operation ill-advised? Horsley may be pardoned if he wavered at that moment. "At this juncture it appeared as if sufficient had been done, but I was very unwilling to leave the matter undecided, and my friend Mr Ballance being strongly of the opinion that further exposure of the cord was indicated I determined to explore further if the state of the patient warranted me in doing so". He eventually located and removed an almond-shaped tumour (fibro-myxoma) at the level of the third and fourth dorsal roots on the left side. Within five days Gilbey had some return of sensation, and on the 13th day he moved a leg. He went on to make a full recovery and survived for twenty years.4

FAMILY MATTERS Victor Horsley married Eldred Bramwell in 1887 and they had three children, Siward, Oswald and Pamela. From 1891 they lived at 25 Cavendish Square, previously occupied by C.B. Radcliffe, and before him by the redoubtable C.E. Brown-Sequard. Mrs Pamela Robinson (nee Horsley) whom I interviewed when writing my biography of her father told me of the sad, and highly ironic, situation that presented when her brother Siward developed epilepsy. The inadequate therapy then available failed to control the seizures. An operation was deemed to be necessary. Horsley, convinced that none of his colleagues had his own extensive experience of the surgical treatment of convulsive attacks, decided to do the operation himself. It went off uneventfully, and at first it appeared a success. But to the family's distress the improvement was temporary. Seizures recurred again and again. Despite this reason for unmerited self-reproach, Horsley's reputation was spreading. His visitors in 1900 included a young American, Harvey Cushing, with a letter of introduction from "Popsy" Welch. By invitation Cushing came to breakfast at Cavendish Square and found a great deal going on of which I shall have more to say later. He was rather put off by this and expressed his feelings in a letter to his father: "I am a little disappointed in Victor Horsley. His place is in the laboratory doubtless. I have seen him do

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some interesting things, however — neurological mostly.... The technique of all these men is execrable from our standpoint and they must have many septic wounds".5 How serious Gushing was in his approach to Horsley is open to question. Having found in Kocher of Berne a teacher and friend, Halstead's interest in British surgeons (other than Lister) was minimal. His disciple may have had his sights really set on Kocher, but in the event Gushing accepted projects in Kronecker's and Sherrington's laboratories. Horsley was knighted in 1902. In the last decade of his life, one is more aware of Sir Victor's campaign against alcohol, his medico-political activities and support of National Health Insurance, than of brain surgery. His logical mind recognised the importance of social change: this was not a matter of Christian charity, for in fundamental beliefs he was agnostic. He did, however, persist with research and lecturing. His Linacre lecture

Fig. 1. Colonel Sir Victor Horsley, FRS, FRCS.

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(1909) was a tour de force based on 25 years study of the motor cortex. Earlier he had carried out extensive research to correlate raised inracranial pressure, cerebral circulation and systemic blood-pressure. He inserted a balloon into the cranial cavities to investigate the consequences of increased intra-cranial pressure, but in the opinion of Douglas Northfield the "most dramatic and notable contribution Horsley bequeathed to neurosurgery was the invention with Clarke of the stereotaxic instrument".6 Designed and constructed by Clarke; the idea was Horsley's. Through this invention Horsley has continued to influence neurosurgery directly into its "organised" phase. The late Irving S. Cooper wrote: "Although he died almost half a century before I entered neurosurgery, I have long regarded him as a true hero and one of my greatest teachers".7 When war was declared in August 1914, Sir Victor volunteered immediately. He worked at Wimereux, before being posted to Egypt and Mesopotamia (Fig. 1). He died at Amara on the Tigris on 16 July 1916.

PUPILS Horsley was not by any means the "sterile parent" Walker would have us see. His acolytes were fewer than Cushing's troupe, a series facilitated by the increasing number of residencies available in North America through Abraham Flexner's reforms, but all were important figures. He had quickly established a reputation in France, and in one of his "lecons du mardi" Charcot spoke of a patient with focal epilepsy, successfully operated on by Horsley. Babinski referred a patient with a spinal tumour to Horsley in London — as no French surgeon could deal with it, in the early twentieth century. Then when Thierry de Martel took up neurosurgery he made weekly trips to London, to watch Horsley operate.8 He credited his progress as largely due to his work with Horsley. "With Horsley [he said] I learned to operate with care and a great deal of gentleness". Horsley was one of Wilfrid Trotter's teachers. Trotter (1872-1939) succeeded him on the surgical staff staff of UCH, becoming eventually professor of surgery at University College, London, and a contributor to Choyce's System of Surgery. Samuel P.W. Black from Columbia,

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Missouri, remarking on Trotter's technical facility, and his "meticulous and gentle handling of tissue and careful haemostasis", was reminded of the Halstead school. But Trotter had mastered his operative technique in London. Horsley's influence was not confined to neurosurgery. Sir Walter Langdon Brown spoke of him as an intellectual hormone; Sir Thomas Lewis stated that when he was a student Horsley's reputation attracted him to UCH, and in Horsley's laboratory at University College Lewis found encouragement to pursue his own investigational work; George Crile of Cleveland regarded an opportunity to work in Horsley's laboratory as one of the good fortunes of his life. When Ernest Sachs graduated at Johns Hopkins in 1904, his neurologist uncle, Dr Bernard Sachs, advised him to take up neurosurgery, aware of the opportunities existing in that field, and arranged for him to train in London where at that time Horsley had the only well-established neurosurgical practice in the world. Sachs was given a letter of introduction to Sir Victor by Cushing (who cannot have thought so badly of his methods, after all). He spent the greater part of his three years in Europe, working under Horsley. Returning to the United States, he soon settled in St Louis at Washington University, becoming shortly after World War I the first professor of neurological surgery. W Jason Mixter was given a "special assignment in neurosurgery" at the Massachussetts General Hospital in 1911, in which year, newly-married, he travelled to London where in 1912 "he came under the tutelage of Victor Horsley".9 Mixter (invited by Cushing) was one of the founding members of the American Society of Neurosurgeons in 1920. On 30 September 1933, he presented with Joseph P. Barr as co-author an important paper to the New England Surgical Society — "Rupture of the Intervertebral Disc with Involvement of the Spinal Canal". After Horsley's death in Mesopotamia from an infection rapidly complicated by hyperpyrexia, there was nobody quite of his stature to replace him in London. Sir Percy Sargent and Donald Armour retained commitments in general surgery, and at the National Hospital the reins of power were in the hands of physicians. A degree of animosity seems to have existed

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between Percy Sargent and Cushing. The latter was annoyed when Gordon Holmes and Sargent published studies on suprasellar meningiomas, thus invading a province which Harvey Cushing regarded as his own. Sargent, a rapid and dextrous operator was content to leave diagnosis to neurologists. His tendency to deride Cushing's slowness irritated Bucy, who attributed it to "jealousy and envy for Cushing's accomplishments".

ASSESSMENTS Gilbert Horrax, Cushing's devoted assistant has written: "It seems to me that there can be no possible dispute to the right of Sir Victor Horsley to be called the father of neurosurgery... it was he above all who pointed the path to the advancement of this newest branch of surgery by his physiological experiments in addition to his clinical and pathological contribution. Furthermore he was the first surgeon ever to devote the bulk of his time to neurological surgery.10" Ernest Sachs, an alumnus of Johns Hopkins, wrote: "Unquestionably he was the father of neurological surgery... the first man to devote himself exclusively to this work".11 The anthropomorphic metaphor "father", rather than first or founder, seems to invite dispute, giving rise to endless argument. Has not Sir William Macewen, for instance, the right to be seen as the father of British neurosurgery? Let us, then, avoid this troublesome term and seek some other measure of distinction. Horsley's appointment as surgeon to the National Hospital, as Samuel Goldblatt reminds us, was the first ever appointment, anywhere, of a neurosurgeon — "he can legitimately be called the first neurosurgeon".12 Douglas Northfield saw Horsley's training in neurosurgery as unique — "it consisted entirely of the experience and skill acquired in the course of his experimental researches into the function of the brain and spinal cord in animals. Many of these were survival experiments demanding a high

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standard of skill and a technique which overcame the risks of infection". Before he joined the staff at Queen Square, Horsley must have done more than 100 intracranial operations on monkeys. Northfield offered the following assessment: "Horsley may be regarded with confidence as the "first" neurological surgeon, if we accept as a definition one whose main surgical interest is the central nervous system and whose neurological diagnostic ability matches his skill in surgical craftsmanship. In his later years, Horsley gave up general surgery except for private practice.13 "

ODIOUS COMPARISONS My own interest in Horsley was kindled by Sir Geoffrey Jefferson, who was still a presence at the Manchester Royal Infirmary when I worked there in the early 1950s. I availed, too, of opportunities to discuss Horsley with his younger contemporaries, Sir Arthur MacNalty and Sir Gordon Holmes, by then very senior figures. The latter who had been in both Horsley's and Cushing's operating rooms affirmed that Horsley was the better craftsman. A modern trend in the historiography of neurosurgery has been to denigrate Horsley while deifying Cushing, albeit presenting the latter with a forked tongue, if not with cloven feet. The notorious row with Dandy is a stain on his record. Even Jefferson, so benign in most respects, remarked that Cushing appeared to be "very nice and friendly, but I can see that his staff are rather uncertain of him and what my further opinion of his personality will be I cannot say".14 Offering a considered opinion later, Sir Geoffrey proclaimed Cushing's greatness, explaining that a man can "be incandescent in the scientific world, and yet have faults". Cushing was "charming, tiresome, delightful, petty, and admirable all by turns...". His combativeness was a part of his creativity. "He in the United States and Horsley in England gave neurosurgery respectability for the first time".15

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Percival Bailey (1892-1973) believed Cushing — "Pepper Pot" to his schoolmates — retained something of the same "charming, hot-tempered boy" to the end, and since Cushing attributed his own sense of superiority over Horsley to his training with Halstead, it is not inappropriate to mention that at the outset of his career, Cushing's first efforts so often ended in fatalities that Halstead is rumoured to have been uncertain as to whether he should say "poor Cushing's patients" or "Cushing's poor patients".16 Later he experienced the bad patches that dog every surgeon, and there are details of adverse results in his personal letters. June 14, 1909: "My ganglion case went badly today — 3 hours — all tied up in the scars of the previous operation. Will have to try again in a few days". June 24, 1909: "It's my turn to be depressed. I lost a little boy today with a brain tumour — most unexpectedly — and his poor people are terribly broken up. This is only one of many troubles. I never had such a lot of bad cases at one time before". There was, too, the day he tore the ophthalmic artery intracranially; the occasion when he subjected a case of subacute combined degeneration of the cord to laminectomy; the hysterical woman operated on for an imagined tic douloureux. Cushing's intervention in General Leonard Wood's mortal illness was a disaster: "The operation [reported by Hugh Cairns] was a terrible affair. It went alright for the first 5 hours but then the Chief began to blame everyone — but especially me. It seemed to me that the main causes of his behaviour was exhaustion...".17 Initially, Cairns had thought Cushing "a wonderful man", but before long the Chief's faults were listed in his letters home — they included cheating at tennis, and blaming others if anything went wrong in the operating room. "One result of this is that all his permanent assistants are absolutely devoid of initiative: so much has he felt the need of being "II Prince" (or whoever Machiavelli's man was) that he has never encouraged them beyond a certain point". Eventually, Cairns told a colleague he was buying a revolver "determined either to shoot himself or Cushing". They both survived, of course, and Cushing's beneficial influence on Cairns was lasting.

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In his Macewen lecture, Cushing paid a token tribute to British predecessors: "We merely stand on the shoulders of our predecessors and the sturdy contemporary figures of Macewen on one side and of Horsley on the other are what support the arch of modern neurological surgery". This was in 1927 when he himself was an icon. His earlier attitude to Horsley, as we have seen, was rather different. While still a student at Harvard he had first heard of the Londoner from John Wheelock Elliot of Boston, whom he assisted at two operations for brain tumours. "Jack" Elliot was full of praise for Victor Horsley, who had inspired him to take up neurosurgery. Bearing Welch's introduction, young Dr Cushing called by arrangement to 25 Cavendish Square. It was a July morning in 1900 and Horsley, as was his wont, was managing to do a number of things at the same time, having breakfast, dictating letters, and patting a dog's head. A pleasant enough scene, one would have thought, as the backdrop of a busy surgeon's domestic life, but John F. Fulton, Harvey Cushing's biographer, looked at it askance. "He found Horsley living in seemingly great confusion [wrote Fulton, drawing on material offered years later by one of Cushing's students]: dictating letters during breakfast to a male secretary; patting dogs between letters; and operating like a wild man. H. Cushing gave him a reprint of his paper on the Gasserian ganglion, whereupon Horsley said he would show him how to do a case".18 Why either Cushing, his future student, or his biographer should have found these perfectly normal matutinal activities so disturbing is difficult to understand. In the early 1930s Lady Horsley discussed her husband with Hugh Cairns, saying "how he was always doing something very intensely and could write his papers while the others were talking round about him. He went to bed early and never went out to dinner. We never asked back and gradually people got to know it".19 The operation for trigeminal neuralgia which Cushing attended on 4 July 1900 was already scheduled. It must have been perfectly routine cisAtlantic practice, at the outset of the aseptic period, for a surgeon to sterilise his instruments at home and take them to wherever he was operating, but Fulton contrives to make it seem a highly doubtful procedure.

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"Horsley dashed upstairs, had his patient under ether in five minutes, and was operating fifteen minutes after he entered the house, made a great hole in the woman's skull, pushed up the temporal lobe — blood everywhere, gauze packed into the middle fossa, the ganglion cut, the wound closed and he was out of the house less than an hour after he had entered it. This experience settled Harvey Cushing's decision to leave London; for he felt that the refinements of neurological surgery could not be learned from Horsley".20 It is likely that this passage, violent in style, and exaggerated in content, from a much publicised biography, harmed Horsley's reputation irremediably. Was it designed to do so, a set piece calculated to take Horsley down a peg? Cushing's own report on his visit to London was softened by his comment: "I found Horsley kindness itself...". And when he attended the British Medical Association meeting at Oxford in 1909 Cushing noted in his diary: "in the Anatomical Section [Gustav] Mann and Horsley on the thalamic region — very interesting talks — anatom and physiolog. Horsley is a daisy". During a visit to England with the Society of Clinical Surgery in the summer of 1910 he attended "demonstrations by Sir Victor Horsley at the National Hospital and in his old laboratory at University College". Sir Gordon Holmes, with whom I discussed Cushing's put down of Horsley, was inclined to attribute it to the arrogance of youth. It should be remembered that his criticism of the British during that early visit extended to Sherrington whom one would have thought above reproach. "He operates well for a 'physiolog' [Cushing wrote in his diary] but it seems to me much too much. I do not see how he can carry with any accuracy the great amount of experimental material he has under way.... As far as I can see, the reason why he is so much quoted is not that he has done especially big things, but that his predecessors have done them all so poorly before". "...The whole thing referable to experimental neurology much to my surprise is still in a most crude condition. The problems are still immense. S. goes at them too fast. Few notes are taken during the observations which is bad. S. says himself he has a bad memory — putters around his laboratory till after seven in the evening trying to catch up on things and then is used up and doesn't begin till ten or eleven the next day".21

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Fulton's example has encouraged others to write disparagingly of Horsley. Paul Bucy, editor of Neurosurgical Giants: Feet of Clay and Iron, accepted Cushing's evidence without question: "As Cushing had observed, Horsley was not a good technical surgeon". And this in a chapter in which Douglas Northfield had already stated: "Many of Horsley's experiments were of such delicacy that he must have possessed great dexterity, and this was confirmed by his surgical assistants". (Bucy also tells a preposterous story featuring Sir Victor sending a letter to The Times to which he had signed the name of the current Prime Minister.) Evidently, Cushing was sufficiently tactful to conceal from Horsley his actual opinion of the latter's operative skill, and over the years a cordial relationship was maintained. He praised Horsley's work on myxoedema highly, and was directly influenced by Sharpey-Schaefer's and Horsley's experiments on the pituitary. Horsley eulogised Cushing's book on head-injuries to an extent that would have delighted any author. On another occasion, Horsley asked Cushing for "another copy of your paper on your Surgical Laboratory" which he intended to send to the Vivisection Commission. Later, Horsley wrote: "I thought of you the other day & your class. If you want a cheerful exercise in the surgery of the cerebellum, I recommend the common duck, on whom we are doing some experiments at the present time, as calculated to break the proudest spirit".22 Despite this amity, however, Cushing rather spoiled a kind gesture to Hugh Cairns by introducing a gratuitous reference to Horsley in a letter to Abraham Flexner: "[Cairns] wants to devote his entire time to the furtherance of neurosurgical work in London which since Horsley's death is practically non-existent — and wasn't very much even then, though I would not want this opinion broadcasted".23 Jefferson had never actually known Horsley, but from a perusal of the latter's operation notes while preparing the Centenary Lecture, he felt he could claim that as an operator the Londoner "must have been extremely dextrous", and that he was "an extrordinarily gentle, skilful, and knowledgeable surgeon". His judgement (at such a distance) is open to question, but others closer to Sir Victor have commented in this regard.

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Sachs stated that Horsley's handling of brain tissues "was exquisite and very delicate", his knowledge of brain anatomy outstanding. MacNalty, who more than once had seen Horsley's "deft and steady hand" remove a cerebellar tumour, praised his technique. In a letter to William Sweet in January 1957, Jefferson expressed a belated admiration for his subject: "The Horsley Centenary Lecture in April has been killing me. I am now impressed by this chap. He was a wonder. Harvey Cushing did not even try to understand him. When I say that, I have to admit that I didn't either until this compulsory survey was forced on me".24 Comparing the two men in his Centenary lecture, Jefferson remarked how far their interests diverged. "Horsley's preoccupation was in the intimate structure and physiology of the nervous system. Cushing's was not, it was more practical". Horsley had his eye on the future; Cushing's was focused on present needs. "The details of operative surgery Horsley thought important, but not important enough to deserve much publication. Cushing, on the other hand was much more interested in the immediate present, in technical improvements in a field which was ripe, if mortality was to be reduced and the rate of cure raised, for a change in method. His great gifts were better canalized than Horsley's, but had he been more generous to the older man it would have been more seemly and more just". 25 Comparisons, notoriously, are odious and I shall desist from making them. Abraham Colles (1773-1843), a Dublin surgeon whose name is invoked daily in a thousand casualty departments, advised his students to be singleminded: "If you are clever in anything else but your profession [he said] do not let the world know it". Horsley subsumed politics into medicine, supported suffragettes, battled with anti-vivisectionists, and denounced alcohol. Posterity remains confused by his endeavours, and I merely ask that Sir Victor be granted the place in the sun he appears to have lost. Cushing would surely have agreed that this should be accorded. Very likely he would have been shocked to realise that his private criticisms attained world-wide circulation, to the detriment of his great predecessor. The fine concluding set-piece in Cushing's biography of Osier, places "the

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spirits of many, old and young — of former and modern times — of Linacre, Harvey, and Sydenham; of John Locke, Gesner, and Louis...", filing past the "watching-chamber".26 Horsley is given a place in the procession, a high compliment to his senior colleague by which Cushing does make amends. References 1. Lyons, J.B. (1966). The Citizen Surgeon — A Life of Sir Victor Horsley, FRS., FRCS. Peter Dawnay. 2. Lyons, J.B. (1991). Sylvester O'Halloran In: What Did I Die Of! Lilliput Press, pp. 1-12. 3. Paget, S. (1919). Sir Victor Horsley. Constable. 4. Lyons, J.B. (1967). Sir Victor Horsley. Medical History XI, 361-373. 5. Thompson, Elizabeth, H. (1961). Harvey Cushing. Collier Books. 6. Northfield, D.W.C. (1985). Sir Victor Horsley 1857-1916 In Neurosurgical Giants: Feet of Clay and Iron (ed. Paul C. Bucy) Elsevier, pp. 43-50. 7. Cooper, I.S. (1982). Sir Victor Horsley: Father of Modern Neurological Surgery In: Historical Aspects of the Neurosciences (eds. EC. Rose and W. Bynum) pp. 235-238. 8. Pecker, J. (1985). Thierry de Martel In: Neurosurgical Giants: Feet of Clay and Iron (ed. P. Bucy) Elsevier, pp. 197-202. 9. Ballantine, H.T. (1985). William Jason Mixter In: Neurological Giants: Feet of Clay and Iron (ed. P. Bucy) Elsevier, pp. 405-410. 10. Horrax, G. (1952). Neurosurgery: An Historical Sketch. C.C. Thomas. 11. Sachs, E. (1958). Victor Horsley. J. Neurosurg. 15, 240-244. 12. Goldblatt, S.H. (1997). A History of Neurosurgery. American Association of Neurological Surgeons. 13. Northfield, D.W.C. (1985). Sir Victor Horsley In: Neurosurgical Giants: Feet of Clay and Iron (ed. P. Bucy) Elsevier, p. 44. 14. Schurr, PH. (1997). So That Was Life: A Biography of Sir Geoffrey Jefferson. Royal Society of Medicine. 15. Jefferson, G. Sir (1985). Harvey Cushing 1869-1939 In: Neurosurgical Giants: Feet of Clay and Iron (ed. P. Bucy) Elsevier, pp. 51-65. 16. Thompson, E.H. (1961). Harvey Cushing. Collier Books. 17. Fraenkel, G.J. (1991). Hugh Cairns. Oxford University Press.

Sir Victor Horsley (1857-1916) Revisited 195 18. 19. 20. 21. 22. 23. 24. 25.

Fulton, J.F. (1946). Harvey Cushing A Biography. Blackwell. Fraenkel, G.J. (1991). Hugh Cairns. Oxford University Press. Fulton, J.F. (1946). Harvey Cushing A Biography. Blackwell. Fulton, J.F. (1946). Harvey Cushing A Biography. Blackwell. Thompson, E.H. (1961). Harvey Cushing. Collier Books. Fraenkel, G.J. (1991). Hugh Cairns. Oxford University Press. Schurr, P.H. (1997). So That Was Life. Royal Society of Medicine. Jefferson, G. Sir (1957). Sir Victor Horsley 1857-1916 Centenary Lecture. Br. Med. J. 1, 903-910. 26. Cushing, H. (1925). 77;e Life of Sir William Osier. Clarendon Press.

TWENTIEH CENTURY NEUROLOGY The British Contribution © 2001 by Imperial College Press

Chapter 16

NEUROSURGERY IN THE NINETEEN-TWENTIES AND THIRTIES Boleslav Lichterman

INTRODUCTION The interwar period of 1919-1939 was characterised by continuing specialisation in medicine and surgery, a process well illustrated by the development of neurosurgery in Great Britain. This chapter is focused primarily on the history of the Society of British Neurological Surgeons (SBNS), founded in London on December 2, 1926. Although valuable details of its early years are chronicled elsewhere,1,2 this work is based on systematic investigation of the SBNS archives kept at the Royal College of Surgeons of England, Lincoln Inn Fields, London, supplemented by some case reports and minute books from the archives of the Institute of Neurology, Queen Square, London.

THE FORMATION OF SBNS In the early 1920s, neurosurgery as a separate speciality, was virtually non-existent in the British Isles. Both Victor Horsley (died 1916) and William Macewen (died 1923) viewed themselves as general surgeons, who did surgical neurology on a part-time basis, but did not form a school of neurosurgery. The key figures of British neurosurgery (Geoffrey Jefferson, Hugh Cairns, Norman Dott and Patterson Ross) spent a year in Boston 197

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Fig. 1. Harvey Gushing (in the centre) flanked by James Patterson Ross of London (right) and Kenneth McKenzie of Toronto (left) (Boston, 1923). (Courtesy Sir Keith Ross Bt RD MS, FRCS)

Fig. 2. Geoffrey Jefferson. (Reprinted from: Sir Geoffrey Jefferson, Selected Papers. London: Pitman Medical Publishing Co, 1960)

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with Harvey Gushing before resolving to devote themselves to neurosurgery (Figs. 1 and 2). Jefferson wrote in Cushing's obituary3: "Many of the great pioneers have been great individualists; it falls to few to found a school Horsley and Macewen are examples of this lapse in our own country. Gushing attracted people to his clinic from all over the world; they made themselves his pupils, his disciples and his friends". Geoffrey Jefferson was a driving force in creating the Society of British Neurological Surgeons in December 1926, a society based on the Society of Neurological Surgeons, established in the United States in 1920 by Harvey Gushing.4 Jefferson began to form the future Society by sending letters in the summer of 19265 to some of his colleagues who were interested in the surgery of the nervous system. Their replies were mostly positive: "...I agree with you as to the desirability of forming an Association of Neurological Surgeons. The idea appeals to me immensely. Two meetings a year would be ample, but we ought to meet before setting dates — times to fit the majority, and the Society must be a small one. It must be as there are so few who are interested. And, for God's sake, keep it to surgeons. We don't want anyone impractical. If the idea materialises, I could submit the names of such whom

Fig. 3. Sir Charles Ballance in 1927. (SENS Archives)

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I know — whose services to Neurological surgery would be useful. The names of Trotter, Sargent and Wakeley and there are others. Only keep it small and select." (Bathe Rawling, July 19, 1926). "I need hardly say that I am most interested and will be glad to do anything I can for the proposed Society of Neurological Surgeons..." (Learmonth, September 9, 1926). The next step was to approach Sir Charles Ballance (1856-1936) [Fig. 3] who agreed to be President of the new Society. The following letters from Ballance to Jefferson from the SBNS archives cover the details of the forthcoming Society and its first meeting: September 6, 1926 ...Perhaps I am more enthusiastic about our Society than some others. It is fashionable now not to be enthusiastic about anything! I am sure the president and members of Council should change frequently. The Secretary unless he is a loafer should be semipermanent! I think I might put this before the members after our dinner. I think I will ask the Associates to the dinner also. The fact is if our Society numbered 50 or 100 it would not matter but as our number is very small 14 or 15 it is a problem to keep them together and keen. We must descend to strategy and cunning! I am to see Souttar operate tomorrow. Perhaps the new members of Council might be Souttar and Armour? I hope Souttar will be given a morning or afternoon in December. Yes, you are right "we don't want to lose them but we feel they ought to go". October 4, 1926 ...I will do all I can to aid the new Association. Circumstances make it impossible for me to invite the "first band" of members to dinner at my house on February 28: but if a number is small I might invite them to the Atheneum. I would be a purely professional and business meeting. I think the membership should be strictly limited to only those who are known to have contributed to our subject should be admitted to membership.

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I think too the meetings should be private so that work not completed could be brought forward and discussed. When I first voyaged to America I went to give the opening address at the Meeting of the American Surgical Society. (By the way, I like the word "society" better than the word "association"). The association or society there consisted of 100 members and there were 200 or 300 surgeons trying to get elected at the next vacancy. This competition was all the good for it induced many of them to do work which would increase there chances of success at the next election. I also belonged in London long years ago to a club of pathologists and physiologists whose meetings were private. I think Watson Cheyne and myself were the only surgeon members. I learnt much from these meetings and those working in some special subject often gained helpful hints from the friendly discussions that took place. How many do you propose should be at the first meeting— 10 or 12? Who do you propose to invite? This is a most important question. At the first meeting, the constitution of the Association must be settled and only a small Committee can settle this: a large Committee never does anything! I think at the meeting we should be ready with a scheme. I suggest that not more than 10 should be invited to the first meeting including ourselves! I might possibly on Friday afternoon show some experimental animals. Ferrier is still alive and is very keen. As on his work so much of present neurological surgery rests we might make him an honorary member. What do you say? October 6, 1926 Life is too short to postpone the 1 st meeting beyond November.... I think 5 or 6 of us might meet in the afternoon before the dinner to discuss the constitution of the Club and then after the dinner the final Constitution of the Club might be discussed and settled.... As far as I know no one on your list at present limits himself to neurological surgery — certainly Sargent does not. At the same time I agree we must stick to our tribe.

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November 2, 1926 The Society of Neurological surgeons will dine at the Atheneum on Thursday, December 2 at 7.30 pm. The business meeting will be on Friday, December 3 morning and afternoon.... PS. Please send when convenient a list of proposed members (+ addresses) so that I can ask them to dinner. We must limit the number or we shall form an ordinary surgical society. November 12, 1926 Sargent and I have been talking about the society all this evening... We must have nothing to do with physicians in active practice... If we submit Bylaws the meeting will not end till 2 am... By the way, ought we to have asked McConnell? Southern Ireland is no longer within the United Kingdom! November 15, 1926 ... There are so few students of Neurology who are also A.I. [?] Surgeons that I hope you will not have enough of me! I have always enjoyed meeting you. I feel very much giving up the Presidency of our new Society but I have thought a great deal about the future of the society and have talked to Sargent and two or three others. The acid test of action should be the welfare of the Society and I think (I may be wrong) that in order to keep the members of a very small Society keen and eager it is desirable to turn our capital over as quickly as possible: in other words the Society must be run not by a small group of members but by all the members. Do you not agree? Sargent said Trotter was his senior and had better be the next President. Trotter seems tired to me but I fancy it is the face which he cannot help and which is often associated with the possession of much of this worlds' goods. Would it not be well to print or type a card each year with a list of officers of the Society and its members. This could be distributed to members — it would promote a corporate feeling! E.g.

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(i) (ii) (iii) (iv) (v)

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Emeritus members Honorary members President, Treasurer, Secretaries, Members of Committee List of members List of associate members

What about the "golden roll" which I thought we might slowly collect: men who by their labours have made possible the present position of Neurological Surgery? Hughlings Jackson, Horsley, Hitzig, Macewen... etc. Anything which adds to the prestige of the Society helps to keep the society together during its early years of life. This list if collected might also be printed on the card. We want to help on the formation of neurological centres in university towns other than Manchester! November 17, 1926 Dear Jefferson, I have been thinking about the dinner programme and I should like to know your views. My idea is: (i) The dinner will be short (ii) After the King's toast I propose (a) to ask approval of the "Constitution" (b) the name of the Secretary (c) "—" Treasurer (d) somebody must propose a President (e) I propose names of Committee The Committee to draw up Bylaws etc. (the Society to consist of 15 members, to meet twice a year, subscription to be 1 guinea). (f) Honorary members or Corresponding Hon. Members ? 1 from each European country. ? 2 from America — Harvey Cushing and Frazier. Kern ought to be an Emeritus Hon. member. These questions to be left to the Committee.

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(g) Emeritus Hon. Members — Schafer, Ferrier, Sherrington, Elliot Smith and Keith. These 5 are coming to the dinner so we shall have a good send off! When the E. Hon. Members have been elected we might drink their health and thank them for becoming our Patrons? (h) Ask if shall maintain a roll of the "Glorious Dead". The names that occur to me are Broca, Fritsch, Hitzig, Hughlings Jackson, Horsley and Macewen. When the business is over J.S. thinks it would be interesting if I gave a few reminiscences of past N. Surgeons and Scientific workers. What do you say? You wish I am sure to make notes at the dinner — we must have a minute book which could be written up afterwards. I suppose some account of the meeting and the Friday programme will have to be sent to the Medical papers afterwards. November 22, 1926 ... The Constitution is all right except I think you should add the number of the executive Committee which would form a quorum: ? 3. ...Schafer, Ferrier, Sherrington, Keith and Elliot Smith are coming to the dinner. I propose to make them all speak! They are all old friends of mine and if we make them talk I fancy the dinner will be one of the most remarkable functions I have ever been at... I should strongly object to the holding of two meetings in London in this year. The object of the Society should be the promotion of centres outside London for the study and practice of Neurology. I am... too for the Society to visit clinics and laboratories abroad. You must not count on me in the future. I lost my dear wife recently after two years of dreadful illness. I am so tired and sad that I am quite unfit for anything. This coming shoe seemed to me a duty to fulfil which I could not escape. I just mention this so that you may know privately my

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difficulties — I will do all I can to further the interests of the society but for myself the future is dark and not clear. I am glad you agree that No 15. We cannot elect men to the membership of the Society because they have opened a cerebellar abscess! Not "Glorious Dead". What we want is "a roll of the illustrious dead". Schafer, Sherrington, Keith etc. would give us advice as to names. We must be careful in this matter or the roll will be a farce! ...I agree about Bylaws 13-16. In 14 instead of "Clinics" — I suggest "Hospital and Laboratories" ["Each Meeting shall be primarily a visit to Hospital and laboratories of a Member or Members"]: — we want to indicate Science as well as practice — don't you think so? ...We must not bore our distinguished guests with business! Only one reply by Jefferson to Ballance dated November 17, 1926 is preserved in the SBNS archives: "I think perhaps it would be as well to limit it [SBNS] to 15 members, but I can see that in a few years we shall probably have to extend to 20, but further enlargement beyond that are rather improbable for a long time... About the suggestions for Corresponding Members:... I fully concur on the question of Keen and Cushing and Frazier, and perhaps Elsberg and Adson6 will be good choices. " Autumn 1926 was a time of intensive correspondence between Jefferson and other potential members of the society. Here are few examples: Jefferson to Mr Donald Armour7 (October 8, 1926): "Dear Mr. Armour, You will remember that some little time ago [July 1926] I wrote to you about the formation of a Neurological Surgeons' Society. Sir Charles Ballance has consented to be our president and I think that soon we shall be able to have an inaugural

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meeting, probably in November. I enclose a list of the proposed members." Jefferson to Bankart (October 8, 1926): "We are thinking of forming a small neurological Society for surgeons only, to meet perhaps twice a year, rather on the lines of the Orthopoedic Association. We shall of course be a very select band, with Ballance as president, Sargent, Trotter, Souttar, and so forth, and we hope yourself; perhaps twelve or fourteen in all. There will probably an inaugural meeting at some date to be fixed in November... . " Jefferson to Bromley (October 8, 1926): "I think Sargent has spoken to you already about the proposed formation of a small Society of Neurological Surgeons with Ballance as president. We hope that you will be one of the original members, and will help to make it success. There is a need for such a society, as other neurological societies are heavily overloaded with physicians and we may reasonably expect to gain a good deal from mutual discussion of more practical sides of the question. " Jefferson to Learmonth (October 12, 1926): "As the Society of Neurological Surgeons is rather slow in coming into this world the meeting which was arranged for 28th October has had to be abandoned owing to Sargent's illness. He is still way on holiday, but comes back again on the 18th, when I hope to be able to get him to fix a date in November for the first meeting. " Jefferson to L. Broster (no date): "We are forming a small Neurological Society for Surgeons to discuss and forward the practical side of neurology, and

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hope that we may count on your support as one of the original members. It seems to me that we may be able to get a good deal of amusement and instruction through such a society, which will naturally be a very small one, containing at most some fifteen members to start with. " The inaugural meeting and dinner took place on December 2, 1926 at the Athenaeum. It was attended by 17 participants. The Menu of that historical dinner is carefully preserved in the SBNS "Minute Book": Grape Fruit Consomme de Volaille Filet de Sole frites Sauce Tartare Faisans rotis Salade de Saison Pommes frites Jambon braise au Champagne Epinards a la creme Compote de fruits Creme de Devonshire Merluche sur croutes Dessert Andalucia Sherry, 1815 Geisler, 1911 Dow's Port, 1890 The President's speech was delivered by Sir Charles Ballance: "I look forward for a future when a window in the skull will be made by the surgeon with the like gentleness, precision, and ease that a pane of glass is fashioned by the glazier by means of a diamond".8

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A week after, on Saturday, January 15, 1927, the following poem appeared in "The Manchester Guardian": The Obscurantist Some talk television, some trifle with Freud; Such pryings and peerings they make me annoyed: At windows in heads I am simply aghastIs privacy wholly a thing of the past? I may be old-fashioned and stupid and dull, But I don't want a window knocked into my skull, And if one were added I think you would find A man of refinement would pull down the blind. No matter how swiftly and painlessly done I won't have this "tenant's improvement begun"; No — be it a dormer, a lattice, or bay, I won't have a window whatever they say! What, have my top storey and all its affairs Arranged so that any outsider who cares Is free to peep in through my crystallised dome And note whether all of the chairs are at home? Away with such notions! No surgeon I'll fee To open so magic a casement on me, Lest wags in my window this notice should set:"With vacant possession: this attic to let." The poem is signed "Lucio", but most likely it was written by Manchester-based Jefferson. There were also speeches by emeritus honorary members: Sir David Ferrier, Sir Edward Sharpey-Schafer, Sir Arthur Keith and Professor Elliot Smith. "This the age of specialisation in medicine, and specialisation is essential to progress. Narrow specialism is to be deprecated,

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but this cannot be said of the special surgery of the nervous system" — said Ferrier.9 The society was informally called "The Nutcrackers" or "The Nut-Crackers Union".10

EATING HABITS AND HOTEL ACCOMMODATION OF BRITISH NEUROSURGEONS The Society was formed as a convival club — all menus of the meetings for several decades are preserved in the "Minutes". In his letter to Jefferson dated December 4, 1934 Sir Charles Ballance wrote: "The primary objective of the society is the advancement of science. I believe (the) social side too is of much importance. Carlyle defines the dinner as the outlook for hidden signs — the intimate act of communion —for some men that have communion in nothing else may still live to some show of brotherhood over food and wine! Social gatherings thus rub over the sharp corners of life and so the outward and visible sign by becoming inward and invisible, is recreated a spiritual form of good fellowship." Nevertheless, hospitality was prevented, as illustrated by the following correspondence: Jefferson to Dott (June 13, 1927): "The Society has adopted an unwritten law against hospitality, as it is far better for the members to be thrown together in a hotel...". Jefferson to McConnell (June 13, 1927): "It is thought best that we should have an unwritten law against hospitality. The best hotel is the Midland". Bromley invited Jefferson to stay at his place during the meeting. The answer was (November 23, 1927): "Many thanks for your kind invitation. I have already refused one, as I think we ought to stick to our unwritten law about hospitality, and stay, more or less together, in one hotel".

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T H E P R A C T I C E O F N E U R O S U G E R Y IN 1926: A C A S E OF QUEEN SQUARE The scientific meeting was held at the National Hospital, Queen Square on Friday, December 3, 1926. There were four operations performed between 9 am and 1 pm (when luncheon at the Holborn Restaurant was scheduled): suprapituitary tumour (partial removal) and parietal endothelioma (no tumour found) by Mr. Percy Sargent (cases of Dr. Gordon Holmes); cordotomy for gastric crises (case of Dr. Grainger Stewart) and acoustic neurofibroma (no tumour visible) (case of Dr. Adie) by Mr. Donald Armour. The case records of some of these cases were found in the archives of the National Hospital for Neurology and Neurosurgery, Queen Square. The first case of suprapituitary tumour (adamantinoma) was a 21-year old lady Eileen Ross (House Physician Dr. Critchley) admitted 30.11.26 because of gradual loss of sight and headaches with vomiting. Two years before the admission pains at the back of her orbits appeared. Soon after it was followed by mistiness of vision. She had to give up reading 6 months ago. In last 8 months sight has gradually diminished. On examination she was found very small and having infantile appearance, never menstruated; distinct bitemporal hemianopia. Progress Note, December 3: "Right frontal bone flap was lifted up. Lying between the olfactory and optic nerves, a bluish tumour was seen, arising out of the pituitary fossa. The tumour was incised and a quantity of yellow fluid escaped in which glistening crystals (? Cholesterin) were seen. The solid portions of the tumour were sucked away, wound sewn up as usual. Time 45 minutes. (Society of British Neurological Surgeons present)." The patient died 6.12.26. P.M. Notes: Recent right frontal bone flap operation. At the underside of the bone flap was a pad of clotted blood about an inch thick. This had not passed elsewhere and very little blood has been seen at the base of the brain.

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Fig. 4. Post-mortem specimen of suprapituitary tumour after partial removal (a case of Mr. Percy Sargent). From P.M.R. Book 9, N 68/1926. (Archives of the Institute of Neurology, Queen Square)

A tumour was found in interpeduncular region above the pituitary fossa, which was not eroded or... enlarged. The tumour passed upwards behind the optic chiasma and round underneath it to rise again in front of the chiasma below the frontal lobes. In consistence it appeared to be made up of minute cysts containing gelatinous material (Fig. 4). The pituitary itself was scarcely compressed and attached by a short stalk to the under surface of the tumour. Histologically: A typical adamantinoma.11 The second case was a 31-year-old ship's butcher Mr. George Eames admitted for the second time to the hospital because of fits preceded by a grogginess. Diminished sensation to pain in the left hand, left facial paresis. The surgery was performed on December 3: "Bone flap turned back in right parietal region. Skull was extremely thick. On opening dura the brain was seen to be under definitive tension. The cortical veins were intensely engorged, with two large vessels converging to a joint just behind the fort of Rolando. This area was inspected but nothing except a large lacuna was seen.

212 B. Lichterman Flap and wound stitched as usual. Time 50 minutes. (Society of British Neurological Surgeons present)." December 14: "Since the operation his left arm and leg (especially arm) are hemiplegic but power is steadily returning". Discharged 12.01.27. The third case was a 42-year-old Mr. William Webb, who complained of vomiting and pain in upper abdomen since autumn 1923 (fourth admission). The attacks lasted 3 days and were associated with hyperaesthesia below xiphoid and increased abdominal reflexes. They were worse at night. He has lost weight. Infection at 17 years. Irritable disposition lately. General falling off "not the man he was". Obsessions. Articulation — tends to stutter and stumble over syllables. R pupil larger than L —do not react to light but react on accomodation. Fine tremor of tongue. Analgesive bands C7-Th5, Thl0-L2. Left upper and lower limbs weaker than right. Incoordination heel knee test. Gait ataxia. Abdomen reflexes are absent. Intravenous hypertonic saline was given with relief of gastric crisis. The patient underwent surgery on December 3 and died two days thereafter. Case records were not found, but post mortem notes are available12: "Fairly wellnourished man. Recent upper thoracic cordotomy. Brain and cord removed. The cord had been split in the middle line in the upper thoracic region. There was no excessive haemorrhage round this region nor obvious oedema of the cord above or below". Diagnosis: "Tabes dorsalis. Gastric crises". The fourth case was a 64-year-old woman Mrs. Eliga Paiker, who complained on unsteadiness in walking and loss of strength in legs during 13 months. The examination revealed left facial paralysis and deafness of the left ear, and blurring of disc edges and fullness of veins of optical fundi. She was diagnosed acoustic fibroma and underwent surgery on December 3. The patient died on December 5, 1926. It also could not be found in the case book of Dr. Adie, but postmortem notes are available13: "Recent subtentorial decompression. There was some subcutaneous ecchymosis of the left side of the neck and general oedema of the neck and face. The brain was removed. It showed no macroscopic abnormality except that the meninges and blood vessels which were very much softened and everywhere covered with slight saneous exudati, stripped at once off the brain as it was removed. The condition suggested a very acute postmortem infection of the meninges. No evidence of tumour was seen on section either naked eye or

Neurosurgery in the Nineteen-Twenties and Thirties 213 histologically. But there was some meningeal exudati of small round cells and very many cocci with a few opiochaelis in this exudate". The case was diagnosed as "serous meningitis?". As we see, the results were rather discouraging: three cases out of four had fatal outcome and in at least two cases the surgery was unnecessary.

MORE MEETINGS, MORE MEMBERS Although the membership in the Society was limited to 15, the number of interested surgeons was far greater, as illustrated by the following letter from Jefferson to Rogers (January 4, 1927): "I cannot usefully send you any literature about the society, for membership is by invitation only, but naturally there is no reason why anybody should not suggest himself, as it were". The initial subsciption was one guinea, but was raised to 3 guineas next year. The second meeting in June, 1927 in Manchester was attended by Harvey Cushing. Jefferson wrote to Ballance (May 3, 1927): "...I think it would be very nice if we could get Cushing to come, though I am not particularly anxious to have him watch my attempts at operation. I think the best plan would be for you to ask him to come, if you would. He need not come for the morning operations, but I think he might possibly come for the Friday afternoon or Saturday morning". At that time neurosurgical interventions were occasionally performed by general surgeons as could be illustrated by the following letter of Calvert from Belfast to Jefferson (May 19, 1927): "I have nothing in the way of a paper to give. Unfortunately orthopaedic work has absorbed my time to the exclusion of everything else for the past two months. The only things on my list are a couple of rather interesting brain cases". Such meetings were inspiring for attending surgeons. Bathe Rawling to Jefferson (June 28, 1927): "I congratulate you on your meeting. We returned physically tired but neurologically stimulated". Calvert to Jefferson (July 14, 1927): "The meeting was easily the best that I have ever had to attend; every moment held something of interest for

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me and the heaps of new facts that I acquired have made me very keen to learn more". At the third meeting (December 1927) by-laws were changed: "The Society shall visit from time to time a foreign Neurological Clinic". And indeed, the Society became a kind of travellers club. Paris was visited several times, other places visited in the 1930s include Dublin, Amsterdam, Berlin and Breslau. Nevertheless, there was a tendency to make these meetings in Britain closed to outsiders, as illustrated by the following letter of Sargent to Jefferson, dated December 4, 1928: "I think that the meeting last week is one of the best we had. It shows how much better it is to have no outsiders admitted, for the Charing Cross meeting was, on that account alone, less enjoyable than either the Guys or the Queen Square meeting. Besides that, we are getting to know one another better". To find an appropriate case for surgery was often a big problem. "I will scour the country to find a suitable case to operate on" — wrote Bromley to Jefferson on October 17, 1928. At the meeting in November 1931, it was suggested "that the Society should publish the collected papers of Sir Victor Horsley and possibly of Sir William Macewen. After discussion it was felt that Sir W. Macewen had left a monument to his name in the form of published volumes, whilst most of Sir Victor Horsley's work was scattered in the journals. The Committee was encouraged to discuss this matter further and Mr. Wilfred Trotter was co-opted for this work. The Committee to report to the next meeting". Unfortunately, the report did not follow and Horsley's neurological papers are still waiting for their publisher. According to modern standards, neurosurgical work was not very intensive and the number of cases was small. For example, Dott wrote to Jefferson (April 11, 1932) that "it would really be quite impossible for me to come with the work going at full pressure, three or four cases a week..". The technical level of those British neurosurgeons who were not familiar with Cushing's technique might be illustrated by the following description of surgery at the 14th meeting at Queen Square (December 1933): "Mr. Julian Taylor operated and wired an osteoplastic flap on the left side for a meningioma. The bone flap was cut

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completely free and removed temporarily (after of course turning down a large skin independent flap). After dealing with bleedy points on the dura the bone was replaced without opening the dura and the case left as a first stage. Patients general condition before operation was bad but she held up well enough. Transfused.14'" The 1934 summer meeting in Edinburgh and Aberdeen is remarkable for the discussion started by Professor Learmonth: "Is Society in position to formulate guiding principles for declining to operate in certain cases of intracranial tumour?". It was continued at the next meeting in Manchester: "Professor Learmonth, of Aberdeen, opened a discussion on the selection of brain tumour cases for operation. He suggested the Society should formulate some definite conclusions regarding some cases of brain tumour which were not benefited by operation. Mr. Hugh Cairns suggested that the root of the trouble was the pathology of these tumours. We were able to-day to localise most of the cerebral tumours, but we were not able to say at present what was the pathology of these localised tumours prior to operation. Mr. Julian Taylor suggested that tumours of the left temporal lobe of the brain were really not worth operating upon, and that some cases of acoustic neuromata did not, in his opinion, justify operation. Mr. Norman Dott, of Edinburgh, suggested that tumours in the brain stem and in the basal nuclei did not justify operative interference. Mr. Patterson Ross thought also that one had to consider the possibility of secondary deposits in the brain and that these cases did not justify surgical interference in his opinion. He did not think it justifiable to operate on a blind patient who was "symptom free". The President, Mr. Geoffrey Jefferson, said that he did not think that sufficient attention was paid always to the general condition of the patient".15

FATHERHOOD DISPUTED Jefferson viewed the Society as his own creation and was quite jealous if someone else pretended for fatherhood. When Bathe Rawling resigned from the members of the society in 1935 he wrote to Jefferson:

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"I always felt that our Society was my "baby" — a delightful little lady full of precocity and development, and she is proving a healthy child. May she grow to strapping adolescence!" Jefferson's ironical comments are written across this letter by pencil: "Of course he played a minor role... in the maternity of the "baby", the child was on the way before he tried his hand (if hand is the right word)". A TRIP TO GERMANY The 22nd meeting of the Society was held at W. Tonnis' clinic in Berlin on Tuesday, Wednesday and Thursday, June 29, 30 and July 1, and at

Fig. 5. A joint meeting of British and German neurosurgical societies (Breslau, July 2 - 3 , 1937). Otfrid Foerster (sitting in the centre), G. Jefferson (fifth from the left in the front row) and N. Dott (fifth from the right in the front row). (SENS Archives.)

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Otto Foerster's clinic in Breslau, on Friday and Saturday, July 2 and 3, 1937. There were three full members of SBNS, 15 associate, honorary and corresponding members and 22 guests (Fig. 5). As Joe Pennybacker recalled: "Douglas Northfield and I travelled together and we were rather amused by serious-minded German doctors giving the Nazi salute at the beginning and at the end of their papers, and I certainly didn't realise the implication of the number of men in uniform, and of streets and public buildings bedecked with Nazi flags. But what was apparent was that small knots, of foreigners in particular, were talking in whispers, not of neurosurgery but of the coming war". Nazi neurosurgeons Tonnis, Kobcke and Chiasserini were elected Honorary Members of SBNS. In 1946 their names, as John Potter wrote, "were by unanimous resolution solemnly erased from the Society's membership". Acknowledgements The author wishes to thank Mr. Steve Wilson, an archivist from the Institute of Neurology, Queen Square, for his help in locating relevant case records and minute books, Professor David Thomas, Consultant Neurosurgeon at the Institute of Neurology, Queen Square, for providing access to the SBNS archives and Dr. Chris Lawrence from the Wellcome Institute for the History of Medicine for his critical comments on this paper. The project was generously supported by the Wellcome Trust, London, UK (grant 046223/ Z/95/Z). References 1. Pennybacker, J. (1976). Fifty Years On. The Seventh Cairns Memorial Lecture delivered at the Midland Centre for Neurosurgery and Neurology, Smethwick, on 8 October 1976, p. 12. 2. Potter, J. (1987). Six decades of the Society of British Neurological Surgeons. J. Neurol. Neurosurg. Psychiat. 50, 958-964. 3. BMJ October 21, 1939, p. 832. "We find him [Cushing] treating his patients and recording his experiences in the journals as if they had been physiological experiments on man" — noted Jefferson.

218 B. Lichterman 4. The American society was founded by 11 members. The semiannual format of the meetings, focused on morning operative clinics conducted by the host and followed by afternoon scientific sessions, attendance by Society members and their guests, restricted access of membership — all these features were also characteristic for the new Society of British Neurological Surgeons. See: Hauber, C.H. and Philips, C.A. (1997). The evolution of organised neurological surgery in the United States. In A History of Neurosurgery (S.H. Greenblatt, ed.) pp. 529-542, AANS. 5. These letters are kept in a separate file in the archive of SBNS, currently held at the Royal College of Surgeons in London. 6. Names of American neurosurgeons. 7. Donald Armour and Percy Sargent were surgeons at the National Hospital for Paralytic and Epileptic, Queen Square, London. 8. BMJ Jan 8, 1927, p. 66. 9. BMJ Jan 8, 1927, p. 68 10. A letter from H.A. Harris to Jefferson, dated Nov 17, 1927 (SBNS archive); see also: Walshe, F.M.R (1961). Bibliographical Memoirs of Fellows of the Royal Society 7, 128. 11. Post Mortem Records. Book 9; entry 68/1926. Archive of the Institute of Neurology, Queen Square. 12. Post Mortem Records. Book 9; entry 70/1926. Archive of the Institute of Neurology, Queen Square. 13. Post Mortem Records. Book 9; entry 69/1926. Archive of the Institute of Neurology, Queen Square. 14. "Minutes...", p. 177. Sir Percy Sargent advocated fast surgery and was critical of the slow manner of Cushing's operations (see editorial note by Paul C. Bucy in "Surgical Neurology" 1976, 6(4), 210). 15. Anonym (1934). The Medical Press and Circular 5 Dec, p. 526.

TWENTIEH CENTURY NEUROLOGY The British Contribution © 2001 by Imperial College Press

Chapter 17

NEUROLATHYRISM Dan F. Cohn & Diana Paleacu

Human neurolathyrism (NL) is a self-limiting disease of the nervous system mainly affecting the upper motor neuron and causing degeneration of the distal corticospinal tract in the spinal cord which results in a spastic paraparesis (Ludolph et al., 1987). The term osteolathyrism (OL) was coined by Selye for the experimental skeletal changes in the rat, guinea pig, hamster, rabbit, monkey, cat, dog and other animals (Selye, 1957). We have known since 1985 that both conditions may appear in humans following the ingestion of the Lathyrus sativus (LS) seeds under certain nutritional and environmental conditions (Cohn, 1986). To date, NL is the only upper motor neuron disease for which the specific cause has been established: ingestion of the legume, the chickling pea (also called grass pea, LS) or related species such as Lathyrus clymenum and cicera (Spencer et al., 1984). High levels of the excitatory amino acid, beta-(N)-oxalylamino-L-alanine (BOAA), also known as beta-(N) oxalyl-L-alpha-beta-diamino-propionic acid (ODAP), found in the chickling pea is currently thought to be the responsible agent for causing NL. The grass pea or chickling pea (LS) is a hardy crop and one of the most successfully grown pulses since its yields are considerable, even with very little agricultural attention. If not for its toxicity, it would have been one of the commonest pulses with high nourishing value, containing about 22% protein, 1.5% fat and 64% carbohydrates (Spencer et al., 1984). LS, an annual legume which grows to a height of 30-60 cm, has rich foliage and flowers of varying colours. The foliage is fed to cattle and 219

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horses. In India, Ethiopia, the Near East and the Mediterranean countries, it is a winter legume, and in central and northern Europe it is grown as a summer crop. The LS seeds germinate and thrive on almost any type of soil, on very dry land, in semi-desert conditions as well as in areas with excessive rainfall. It can also endure the invasion of different pests and will grow in altitudes of up to 2000 metres. The seeds may be sown by broadcasting without any further treatment. When the first pods are ripe, the plants are uprooted, carried in bundles to the threshing floor and dried before the seeds are beaten out (Cohn and Kislev, 1987). LS thus forms an inexpensive and nourishing component of the human diet among poor people in certain overpopulated or poor countries such as India, Ethiopia, Bangladesh and others. In times of flood and drought, particularly when other crops are destroyed, the hardy chickling pea becomes a survival food for humans, cattle and horses. The legume also becomes an essential and important part of human diet in communities where meat and milk are not frequently used because of religious restrictions, taboos or periodic and accidental shortage. The seeds are ground, mixed with water and baked, or whole seeds are cooked in water and eaten in the form of soup. Thus, LS is frequently consumed, despite awareness of its deleterious results, when no other food is available (Gebre-ab et al., 1987). The earliest documentation in the western world exists in the "Book of Epidemics" by Hippocrates (460-377 BC) who wrote: "At Ainos, all men and women who ate peas continuously became impotent in the legs and that state persisted" (Hippocrates on Epidemics, 1846). The Roman writer Pliny the Elder (Gaius Plinius secundus, 23-79 AD) describes the disease and later Galen (Claudius Galenus, 130-210 AD) mentions in his writings the hunger period in Ainos and the disease acquired by the people who ate the peas as follows: "ex fame in Aeno leguminibus vescentes crura imbecillia habuere". The Greek herbalist and physician Diascorides (Pedanius Diascorides) also knew of the Lathyrus sativus pea in about 50 AD. However, only in 1671 was the baking and consumption of bread containing LS peas prohibited by Duke George of Wurttemberg. His successors in 1705 and 1714 re-established this prohibition in Germany (Cohn and Streifler, 1978). Although NL and its cause were well known in Europe, people continued to use the LS peas in their food, and major outbreaks of

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NL occurred in France (1700-1701), Algiers (1883), Russia (1892) and India (1829 and 1856). The outbreak of 1829 in India was described in detail by Sir William Henry Sleeman in the book Rambles and Recollections of an Indian Official as follows: "In 1829, the wheat and other spring crops in Saugor and surrounding villages were destroyed by severe hailstorms and rains; in 1830 they were deficient from the want of seasonable rains, and in 1831 they were destroyed by blight. During these three years, the 'teori' or what in other parts of India is called 'kesari' (L. sativus), a kind of wild vetch which, though not sown itself, is left carelessly to grow among the wheat and other grains and given in the green and dry state to cattle, remained uninjured and thrived with great luxuriance. In 1831, they reaped a rich crop of it from the blighted wheat fields and subsisted upon its grain during that and the following years, giving the stalks and leaves only to their cattle. In 1833, the sad effects of this food began to manifest themselves. The younger part of the population of this and the surrounding villages, from the age of thirty downward, began to be deprived of the use of their limbs below the waist by paralytic strokes, in all cases sudden, but in some cases more severe than others. About half the youth of this village of both sexes became affected during the years 1833-1834 and many of them have lost the use of their lower limbs entirely and are unable to move. The youth of the surrounding villages in which the 'teori' from the same causes formed the chief article of diet during the years 1831-1832 have suffered to an equal degree. Since the year 1834, no new cases have occurred, but no persons once attacked have been found to recover use of limbs affected and my tent was surrounded by great numbers of youth in different states of the disease imploring my advice and assistance under the dreadful visitation. Some of them were very fine young men of good caste and respectable families and all stated that their pains and infirmities were confined entirely to the part below their waist. They described the attack as coming on suddenly, often while the person was asleep, and without warning symptoms whatever and stated that a greater portion of young men were attacked than of young women" (Sleeman, 1844). The British botanist George Don wrote in 1831 that if flour prepared from the chickling pea is added in equal parts to barley flour, a very good

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bread can be prepared that does not cause any harm. But bread baked from the Lathyrus sativus pea alone causes spasticity in the lower limbs in people who consume such bread continuously. He also states that the syndrome generally appears suddenly without warning signs, and that although the disease is not fatal, there is thought to be no recovery from the symptoms (Don, 1831). An ancient Hindu medical text, the Bhavaprakasa, mentions the fact that "the triputa pulse causes a man to become lame and crippled and it irritates the nerves". Only at the end of the last century was the Lathyrus sativus pea prohibited as a part of the diet in Indian jails and institutions over which the government has direct control (Chopra, 1935). During World War II, an outbreak of NL occurred when LS peas were part of the diet given by the Germans to prisoners of war and in the forced labour camp in the Ukrainian town of Wapniarka. The surviving invalids have been medically followed for many years and the signs and symptoms continue to be documented (Cohn and Streifler, 1981). The name lathyrism was coined by Cantani and the name neurolathyrism (NL) for the human syndrome by Selye (Cantani, 1873; Selye, 1957). Since NL is a degenerative disease of the corticospinal tract in the thoracic region, it is very seldom that the arms are involved. Both sexes are affected with there being a preponderance of young males. The onset of the spastic lower paraparesis may be acute, subacute or insidious, and probably depends on the amount of LS consumed, the content of the neurotoxin and the premorbid condition of the individual. Signs and symptoms of NL may appear when food consumption over a period of two to six months consists of one-third to one-half of LS seeds. The presenting symptoms are usually painful muscle spasms in the lower extremities lasting seconds to minutes which are especially troublesome at night. Thereafter, urinary urgency and frequency develop and the affected people need to urinate as many as 30 to 40 times during the day. The gait becomes unstable and a spastic paraparesis of various degrees develops, a condition which remains irreversible. An excellent description of the syndrome was given by Stockman as follows: "In man the symptoms usually begin suddenly and seem often to

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be precipitated by exposure to cold and wet and fatigue, this being the reason assigned for the comparative immunity of children and elderly men. Sometimes there are prodromal sensory symptoms of pain, prickling, numbness and cramps, but most commonly the victim quite suddenly feels the legs and loins weak and heavy, the muscles are tremulous when weight is put on them, there is dragging of the legs, increased reflexes and more or less inability to walk. This may go on to a further stage of extreme spasticity and rigidity of the leg muscle; the gait becomes jerky with short steps taken on the balls of the feet and with the knees slightly flexed; ankle clonus and adductor spasm of the thigh muscles are easily excited and account for the jerky cross-legged walk, in which the limb is raised up with an effort and a heave of the corresponding shoulder; the foot is turned in with the great toe tending to scrape the ground and the heel drawn up by gastrocnemius spasm. In the slighter cases the patient can get about with or without the aid of a stick, but often the disability is very severe and he finds himself unable to walk or stand, or only able to do so with the support of one or two long sticks which he grasps high up. In extreme cases he is driven to progress on his hands and feet in a sitting posture. There may be no sensory disturbances and no muscular wasting and almost invariably the lower limbs are affected. The lesion in chronic poisoning is evidently a partial degeneration of the motor tracts in the cord. Babinski's sign is present as well as the exaggerated deep reflexes. But in many cases other symptoms have been recorded which point to a wider implication of the spinal cord. Loss of control of the bladder and rectum and impotence are quite common. Tingling, formication, lightning pains, pains around the waist, diminution of tactile sensation, complete loss of sensation to heat and pain, and marked muscular wasting have been observed. In a few cases the arms have been affected like the legs. It is said to be sometimes ushered in by convulsive movements of the upper and lower limbs and painful contraction of the muscles — apparently somewhat similar to the seizures I have described in monkeys. Early cases sometimes recover, others never" (Stockman, 1929). The spastic paraparesis of varying degree which develops in the acute stage is irreversible. The resulting gait disturbance was classified as follows; (1) A mild spastic paraparesis — non-cane stage. (2) Spastic paraparesis — one cane stage. (3) Severe spastic paraparesis — two cane stage (crutches).

224 D. F. Cohn & D. Paleacu

(4) Wheelchair stage, or crawler stage in India. The none and one cane stage invalids have a peculiar gait because their hips and knees are slightly flexed and the feet are in planar flexion. The lumbar spine and pelvis sway and the legs drag with the toes touching the ground. Some of the invalids develop a distal sensory neuropathy, and very few show involvement of the lower motor neurons (Cohn and Streifler, 1983). Osseous changes are seen, especially in the vertebrae and the long bones. Thus, the invalidity resulting from the consumption of LS is significant to this day. During the last few years an international team including neuroscientists, botanists, agronomists, biochemists, clinicians and specialists in other disciplines, the International Lathyrus Lathyrism Research Association (ILLRA) is trying to grow the grass pea with as little toxin as possible. It could then become a cheap, nourishing and safe food. In England, Professor Arthur Bell of the Neurodegenerative Disease Research Centre King's College London, the previous Director of Kew Gardens, who for many years has also been working the Lathyrus species, has succeeded in isolating different neurotoxic amino acids from this species. He, together with Professor Peter Nunn and coworkers, continues to conduct this important research (Bell, 1962; Bell and O'Donovan, 1966; Bell and Tirimanna, 1965). References Bell, E.A. (1962). Association of ninhydrin reacting compounds in the seeds of 49 species of Lathyrus. Biochem. J. 82, 225-229. Bell, E.A. and Tirimanna, A.S.L. (1965). Association of amino acids and related compounds in the seeds of 47 species of Vicia. Their taxonomic and nutritional significance. Biochem. J. 97, 104-111. Bell, E.A. and O'Donovan, J.P. (1966). The isolation of alpha and gamma oxalyl derivatives of alpha gamma diamino butyric acid from seeds of Lathyrus latifolius, and the detection of the alpha oxalyl isomer of the neurotoxic alpha amino beta oxalyl amino propionic acid which occurs with the neurotoxin in this and other species. Phytochem. Photobiol. 5, 1211-1219. Cantani, A. (1873). Latirismo (lathyrismus). Morgani. 15, 745-765. Chopra, R.N. (1935). In The British Encyclopedia of Medical Practice 7, 651.

Neurolathyrism 225 Cohn, D.F. (1986). Does human osteolathyrism exist. In Lathyrus and Lathyrism (eds. A.K. Kaul and D. Combes) Third World Medical Research Foundation. pp. 315-317. Cohn, D.F. and Kislev, M.E. (1987). Human neurolathyrism. Adler Museum Bulletin 13, 5-8. Cohn, D.F. and Streifler, M. (1978). Neurolathyrism. Historical notes. Koroth. 7, 142-152. Cohn, D.F. and Streifler, M. (1981). Human neurolathyrism, a follow-up study of 200 patients. Arch. Suisse Neurol. Neurosurg. Psychiat. 128, 151-163. Cohn, D.F. and Streifler, M. (1983). Intoxication by the chickling pea {Lathyrus sativus): Nervous system and skeletal findings. Arch. Toxicol. Suppl. 1 6, 190-193. Don, G. (1831). General System of Gardening and Botany. Vol. 4. London. Gebre-ab, T., Gabriel, Z.W., Maffi, M. et al. (1987). Neurolathyrism. A review and a report of an epidemic. Ethiop. Med. J. 16, 1-11. Hippocrates on Epidemics, Vol. 5, Book 2, Section 4, p. 126. E. Littre Publishers, Paris, 1846. Ludolph, A.C., Hugon, J., Dwivedi, M.P. et al. (1987). Studies on the etiology and pathogenesis of motor neuron disease. Brain 110, 149-165. Selye, H. (1957). Lathyrism. Rev. Canad. Biol. 16, 1-82. Sleeman, W.H. (1844). Rambles and Recollections of an Indian Official. J. Hatchard & Son, London. Spencer, P.S., Schumburg, H.H., Cohn, D.F. et al. (1984). Lathyrism: A useful model of primary lateral sclerosis. In Research Progress in Motor Neurone Disease (ed. C.F. Rose) Pitman, London, pp. 312-327. Stockman, R. (1929). Lathyrism. J. Pharmacol. Exp. Ther. 37, 43.

TWENTIEH CENTURY NEUROLOGY The British Contribution © 2001 by Imperial College Press

Chapter 18 FROM TREPONEMES TO PRIONS: THE EMERGENCE OF BRITISH NEUROPATHOLOGY Jennian Geddes

Although the genesis of modern neuropathology in Britain is probably best dated to the 1870s, it can nevertheless be seen as the outcome of an evolutionary process which had been gathering momentum from the beginning of that century. The earliest neuropathological reports were descriptions of morbid anatomy, documenting the gross appearances of diseased brain and spinal cord, the results of personal observations by general physicians. Such publications from the first half of the nineteenth century include a few notable works: an early monograph by John Cheyne dealing with apoplexy and lethargy included the first description and illustration of subarachnoid haemorrhage (1812), but the first major contribution was that of John Abercrombie, who in 1828 produced what was effectively a textbook of neuropathology, entitled Pathological and Practical Researches on Diseases of the Brain and Spinal Cord, based on his own findings in over 150 post-mortem examinations.1 Further minutely observed descriptions of common diseases of the central nervous system (CNS) were provided in atlases by Robert Hooper, whose collection of superb lithographs (1828) was based on material culled from more than 4000 autopsies2; by Robert Carswell,3 Professor of Morbid Anatomy at University College, London (1838); and by the Guy's physician, Richard Bright. The second volume of

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Bright's work, published in 1831, was devoted to the nervous system, and is remarkable for its meticulous clinicopathological correlations.4 But texts such as these were rare: generally speaking, in the first half of the nineteenth century, there were very few advances in morbid anatomy as a whole, let alone in neuropathology. Pathology was studied by the more enquiring physicians only, in their spare time: it was not until the work of the great German pathologist Rudolf Virchow became widely known in the 1850s and 1860s that morbid anatomy began to be treated as a serious scientific pursuit in its own right. Even after that, in many institutions an appointment as pathologist was merely a necessary stage in the training for a clinical career,5,6 and very few outside the universities were to choose to specialise in pathology for another 50 or 60 years. 7,8 It was the teaching of the German morbid anatomists — that disease in organs was expressed as signs or symptoms, and that gross anatomy supplemented by microscopy held the key to the understanding of disease processes — which was to give the necessary impetus to the search for

Fig. 1. In revealing the fine detail of the structure of the nervous system, the metallic impregnation techniques developed by Golgi, Cajal and Hortega provided an important stimulus to the development of neuropathology. Here, rod cells (microglia) in the cortex of a patient with GPI are demonstrated by a modification of one of Hortega's methods.

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improved histological methods. By the 1850s good quality microscopes had been developed and were widely available, but technical methods — tissue fixation, processing, embedding, sectioning and staining — had lagged behind.9 As these slowly improved during the second half of the nineteenth century, knowledge grew of the fine structure of the various tissues in health and in disease, mostly gained on sections stained with simple monochrome dyes such as carmine. The CNS, however, remained terra incognita: not only was little known about functional localisation within the brain, but the stains in general use did not distinguish the different cellular components of nervous tissue; techniques that did so would not begin to become available until Golgi published his method in 1873, and after him Marchi, Nissl, Cajal, Bielschowsky and Hortega. It was only with Cajal's metallic impregnation methods, developed over the 30 years leading up to the First World War, that the immense complexity of the microscopic structure of nervous tissue was finally appreciated (Fig. 1).

EARLY NEUROPATHOLOGY IN THE LUNATIC ASYLUMS The technical methods essential for neuropathology to develop beyond the mere description of the gross appearances of diseases of the CNS began to appear during the 1870s, and it is reasonable to date the beginning of modern neuropathology in this country from then. It was not however the physicians with an interest in morbid anatomy who took up these new tools but psychiatrists, to whom most of the advances in neurohistology of that period can be attributed. Throughout the nineteenth century, there was a remarkable increase in the population of lunatic asylums, which were rapidly being built all over the country as more suitable housing for the mentally ill than the workhouses. The total number of asylum patients grew from 1046 inmates in 1827 to about 7000 by 1850; at the end of the century the latter figure had multiplied more than ten times.10 The single most common diagnosis was general paralysis of the insane (GPI),11' n the cause for which was unknown, since the link with Treponema pallidum had not yet been made. While syphilis was known to be a venereal disease, GPI (Fig. 2) was believed to be a degenerative condition triggered by any one of a

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Fig. 2. Photograph by Dr. James Crichton-Browne of an inmate at West Riding Lunatic Asylum, suffering from general paralysis of the insane (c. 1869).

number of different causes, including "brain exhaustion, irritation, excesses in drinking, sexual excess, over-work, over-worry, syphilis or injuries55.13 There was of course no effective treatment, and the mortality rate from all causes inmost asylums approached 40%. u The more farsighted Medical Superintendents began to recognise that their institutions could be a unique

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research resource. Success in curing inmates may have been low, but there was now a population providing new opportunities for elucidating the causes of disease: autopsies could be performed, vast numbers of brains were available for examination. These could be dissected and weighed, region by region, studied under the microscope and the findings analysed according to clinical diagnosis. Structural causes for psychiatric diseases could be found. Outstanding among the asylum administrators who saw the potential for research was James Crichton-Browne (Fig. 3), who in 1866 at the age of 26 was appointed Medical Director to the West Riding Lunatic Asylum at Wakefield, in Yorkshire. Crichton-Browne's ten years there brought international renown to the asylum, principally because of the scientific work that it produced. In 1871, he set up the first laboratory at an asylum, and the following year secured the appointment of a pathologist. This

Fig. 3. James Crichton-Browne (1818-1876), instrumental in starting neuropathology in the lunatic asylums in Britain.

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achievement was hailed by Crichton-Browne as a "momentous step in the march of scientific progress in the Lunatic Asylums of this country" which would result in a "[rapid expansion of] our knowledge of brain disease, and of the means by which it may be averted or controlled".15 So began the painstaking work of documenting structural changes in the brains of patients at Wakefield, the most complete report of which summarises the findings in 1565 brains examined over an 11-year period.16 For the first time in Britain, the brain was being systematically studied microscopically as well as macroscopically: from Crichton-Browne's laboratory, Herbert Major and William Bevan-Lewis, each of whom was later to follow him as Medical Director at Wakefield, made major contributions to neurohistology. Working on the histology of the insula, Major established in 1876 that, contrary to the belief of many of the experts of the day, the human neocortex was a six-layered structure.17 Bevan-Lewis's methods for processing and staining sections of brain tissue, together with the use of the new freezing microtome that he had invented 18-21 resulted in excellent histological preparations, and he too recorded detailed new observations on cortical cytoarchitecture, particularly that of the motor cortex.22 The most outstanding research to come out of the West Riding Lunatic Asylum, however, was of course that of David Ferrier, who was invited by Crichton-Browne to work in the Wakefield laboratory, and provided with "a liberal supply of pigeons, fowls, guinea-pigs, rabbits, cats, and dogs" as experimental animals.23 And so in 1873 at the asylum, Ferrier started the pioneering experiments on cerebral physiology and pathology for which he is principally remembered, and which culminated in his book, Functions of the Brain (1876). The many honours that Ferrier received in recognition of his work included appointment in 1889 to the first Chair of neuropathology in the country, created for him at King's College Medical School. The astonishing amount of research carried out at Wakefield was disseminated in two ways. The first was by widely advertised and well-attended "medical conversazioni" organised by Crichton-Browne and held once a year at the asylum. These were academic soirees at which an invited authority gave a lecture on a topical subject, after which the audience were invited to visit the numerous stalls placed around the hall, where displays,

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exhibitions and demonstrations of neurological and psychiatric interest were to be found. Refreshments and music supplied by the asylum band ensured the popularity of these scientific events.24 The other more lasting way in which the work of the asylum was communicated was in the famous West Riding Lunatic Asylum Medical Reports, founded by Crichton-Browne in 1871, and edited by him. These reports were produced annually until 1876, and contained the first comprehensive studies of an asylum population. About half of the papers consisted of studies on brain weights, measurements and pathology; clinical reports comprised the other half. A sample from the index to Volume 4 (1874) gives the flavour of the publication: "On a case of recovery from double optic neuritis" by J. Hughlings Jackson; "Pathological illustrations of brain function" by David Ferrier; "The urinology of general paralysis" by John Merson; "On inhibition, peripheral and central" by T. Lauder Brunton; "Observations on the histology of the morbid brain" by Herbert C. Major; "Acute dementia" by J. Crichton-Browne. The Medical Reports, which ceased when Crichton-Browne left Wakefield, were to be the direct forerunners of the journal Brain, which was founded in 1879 by James Crichton-Browne, David Ferrier, John Hughlings Jackson and John Bucknill to fill the gap left by its predecessor.

MORE ASYLUM PATHOLOGY: FORD ROBERTSON AND FREDERICK MOTT The departure of Crichton-Browne did not see any decrease in scientific activity at the West Riding Lunatic Asylum, but without his leadership, his "conversazioni" and the Medical Reports, the institution no longer occupied the pre-eminent position that it once had. Pathological research in asylums was to continue, most notably at Claybury and in Scotland, but the integration of neurology, psychiatry, physiology and pathology was never again to be quite as complete as it had been at Wakefield. 1896 marks the start of neuropathological research in Scotland, the year in which Dr. Thomas Clouston, Superintendent of the Royal Edinburgh Asylum, founded the Central Pathological Laboratory of the Scottish Asylums in Edinburgh with William Ford Robertson as its first director

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and pathologist. Robertson's duties were carefully laid down: "(A) To carry on original researches upon the Pathology of Insanity; (B) To examine Pathological Material sent from the Asylums, and to furnish Reports; (C) To teach and give assistance to members of the Medical Staff of the Associated Asylums in regard to Research-work upon the Pathology of Insanity".25 Robertson wrote a number of papers on his findings in psychiatric disease which he subsequently used as the basis of his best-remembered work, A Text-Book of Pathology in Relation to Mental Diseases, published in 1900. Unlike the textbooks of the Bristol physician Edward Fox26 and Wakefield medical officer William Bevan-Lewis,27 which had been published some years earlier, Robertson's book was written specifically from a neuropathological rather than a psychiatric standpoint, and aimed to "awaken a more general interest in the study of the pathology of insanity in the asylums of this country, and assist those who are anxious to carry out original researches". Much of it covers the same topics that were investigated at Wakefield, but there are also comprehensive descriptions of microscopic changes in neurons, both in disease and under experimental conditions, most of which are beautifully illustrated in colour (Fig. 4). Focal pathological conditions — malformations, vascular lesions, tuberculomas and tumours — are reviewed as rare causes of insanity, his briefest of comments on cerebral tumours revealing no advance in the 50 years since Virchow's descriptions: "Primary tumours of the brain are, in the large majority of instances, either sarcomata or gliomata, of both of which several varieties are described".28 Asylum medical officers and pathologists around the country were beginning to teach the pathology of mental disease, through textbooks, lectures and courses, and Ford Robertson is remembered as an enthusiastic and effective teacher. Apart from his handbook for asylum medical officers, he also produced sets of microscope slides which he sent round to the other Scottish asylums, and so gradually assembled a large collection of reference material for teaching.29 It was the appointment of the physician Frederick Mott (Fig. 5) as pathologist to the London County Council (LCC) asylums the previous year however that really marks the advent of the modern neuropathologist. Working at Claybury Asylum, in purpose-built accommodation which

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Fig. 4. Pathology of the dural vessels, illustrated by Ford Robertson in his textbook (1900). The two drawings in the top left comer are normal examples; the rest of the pictures show changes in various psychiatric illnesses.

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Fig. 5. Frederick Mott (1853-1926), the first modern British neuropathologist

included a room for experimental work, chemical, bacteriological and histological laboratories, a photographic studio with facilities for demonstrations, a museum, a library and a post-mortem room (complete with cold chamber),30 Mott undertook a comprehensive programme of neuropathological research. His appointment coincided with an era of rapid expansion in experimental pathology, and his early work includes a number of papers with Charles Sherrington, who himself often used the newer neuropathological methods to assess tract degeneration in his experiments. Mott carried out seminal studies on the sensory tracts in monkeys, describing the path of the medial lemniscus and the spinothalamic tract, but with time his interests shifted entirely from physiology and anatomy to pathology. He studied the biochemistry of neuronal degeneration, particularly Wallerian degeneration and the Marchi reaction, the pathological sequelae of bilateral ligation of the carotid and vertebral arteries, and published the first description of changes in trypanosomiasis in the CNS. He wrote a number of papers on the pathology

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of various intoxications including alcohol, and gave a classic description of pellagra in 1913. His paper "Combined sclerosis with grave anaemia"31 was one of the earliest descriptions of subacute combined degeneration of the cord, although there is no mention of the characteristic gastric pathology in his case. In describing microscopic changes in the brains of patients dying in status epilepticus, Mott drew upon experimental biochemical data as a basis for speculations on the relative contributions of pyrexia and hypoxia in their pathogenesis. He also instigated a prospective study of heredity and mental disease, collecting and collating clinical details of relatives of inmates at the LCC asylums. In 1900, Mott edited the first volume of the Archives of Neurology of the London County Council. The contents list reflects the two major concerns of medical staff in the asylums — syphilis and GPI — and the volume's first 340 pages are devoted to what were still considered to be two separate diseases, two of the longest papers (158 and 77 pages, respectively) being by Mott himself. His writings on syphilis, GPI and tabes are less well-known than those of his contemporaries Nissl and Alzheimer, but he was one of the first to recognise the importance of syphilis as a major cause of paralytic dementia. Even before Hideyo Noguchi had found the spirochaete in the brains of patients with GPI (1913), Mott was arguing that prevention and early treatment of syphilis would lead to a dramatic decline in the incidence of the disease.32 He later confirmed Noguchi's findings by demonstrating the presence of T. pallidum in the majority of his brains, the first pathologist to do so in this country. The First World War provided Mott with the opportunity to study structural changes caused by shell blast injury, and in 1916 his laboratory moved from Claybury to a more central site at the new Maudsley Hospital, where he continued to work until his retirement from the LCC in 1923. An excellent discussion and evaluation of Mott's work is given by Alfred Meyer,33 and a bibliography of his principal papers can be found at the end of Webb Haymaker's biography.34 Mott was the really outstanding British neuropathologist of the first two decades of the twentieth century. Many others were studying the pathology of the nervous system at that time, but by 1900 the complex histological

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techniques necessary to visualise it, the familiarity with neuroanatomy and neurophysiology that was essential if one were to practise neuropathology, meant that "general pathologists... developed an anxiety state towards neuropathology, and a distaste for the subject that still persists".7 This "anxiety state" was to be the root cause of the historical isolation of neuropathology from general pathology, with the subject being practised independently of general pathology by clinical neurologists, psychiatrists and — latterly — neurosurgeons. A trawl through the relevant volumes of the Journal of Mental Science, the Edinburgh Medical Journal, Brain and the Journal of Pathology and Bacteriology in the early years of this century reveals a number of major neuropathological papers by clinicians, very few by pathologists: Gordon Holmes on the pathology of a familial cerebellar degeneration (1907), Kinnier Wilson on the inherited degenerative condition that came to be known as Wilson's disease (1912), James Dawson on the histology of multiple sclerosis (1916). The morbid anatomist Hubert Turnbull's papers on the pathogenesis of saccular aneurysms (1918) and on postvaccinial encephalomyelitis (1926-1929), are notable exceptions. At the West Riding Asylum Joseph Shaw Bolton had by now succeeded BevanLewis as Medical Director, and in 1914 published The Brain in Health and Disease, which after a long introduction on normal cerebral function, localisation and anatomy was principally devoted to the morbid anatomy and histopathology of senile dementia and GPL Though full of careful personal observation, it was less comprehensive than Robertson's earlier work.

NEUROSURGERY AND THE BIRTH OF MODERN CLINICAL NEUROPATHOLOGY A direct consequence of the experiments carried out at Wakefield by Ferrier, and after him by Victor Horsley at the National Hospital for the Paralysed and Epileptic, Queen Square, was that neurological surgery was now a real possibility. Surgery on the brain had been up till then restricted to traumatic injuries, where external signs such as lacerations or bruising indicated the likely site of underlying brain damage. But it was now possible to localise

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lesions for surgery on the basis of clinical symptomatology, and as a result enthusiasm for neurosurgical work grew. In 1888, the Glasgow surgeon William Macewen reported 10 intracranial operations for which he had applied the principles of cerebral localisation, including a dural tumour excised in 1879, five years before the celebrated removal of a glioma by Rickman Godlee at the Hospital for Epilepsy and Paralysis, Regent's Park (subsequently Maida Vale).35 Neurosurgery progressed rapidly. Surgical neuropathology as we know it today really started in 1884 with the description of the specimen excised by Godlee, and by 1912 the Queen Square surgeons had performed enough operations for the physician Howard Tooth to be able to report on 500 brain tumours, 258 of which had been examined histologically.36 In the 1920s Hugh Cairns, Geoffrey Jefferson and Norman Dott all went to Boston to learn neurosurgery from Harvey Cushing, and in 1926 there was sufficient enthusiasm for a group of surgeons and neurologists to form the Society of British Neurological Surgeons, David Ferrier being one of the founder members. Though the early neurosurgeons were often — through necessity — practised microscopists, they recognised the need for specialist pathologists, and the arrival of neurosurgical centres throughout the country in 1948 provided the impetus for the appointment of neuropathologists. J.G. Greenfield (Fig. 6) was appointed in 1914 to the National Hospital for the Paralysed and Epileptic, Queen Square, and so was already in post as neurosurgery developed there. Godwin Greenfield was the first full-time pathologist at the hospital, and became the father of clinical neuropathology as it is practised today. His interests were as varied as the material available to him. From his earliest years at Queen Square he supplemented his meagre pathologist's income by examining cerebrospinal fluids, and the observations from these provided the basis for a number of publications throughout his working life. With Farquhar Buzzard, one of the clinicians who preceded him as pathologist, he produced both an important paper on encephalitis lethargica (1919) and later a small textbook (1921).37 Over 100 publications were to follow this early work, on subjects as disparate as intracranial tumours, dystrophia myotonica, subacute combined degeneration of the spinal cord, disseminated sclerosis, presenile dementia, subacute sclerosing

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Fig. 6. Godwin Greenfield (1884-1958), described as "the Dean of neuropathologists" by Wilder Penfield and Webb Haymaker.

panencephalitis, post-encephalitic parkinsonism and disease of the spinal cord (a full bibliography is given in the obituaries by W.H. McMenemey and Webb Haymaker38'39). Greenfield's most substantial contributions, however, were his writings on the encephalitides, disseminated encephalomyelitis, the spinocerebellar degenerations and metachromatic leucodystrophy. After his retirement Greenfield continued his research for several years at the Institute of Neurology before taking up a post at the National Institute of Neurological Diseases and Blindness in Bethesda, Maryland, where he exercised an enormous influence on American neuropathologists, who were in the habit of describing him as "the Dean of neuropathologists".39'40 His lasting work was his second book, Neuropathology, a textbook planned by him and written with the help of four colleagues and published shortly after his sudden death in 1958.

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Fig. 7. Dorothy Russell (1895-1983) is remembered for her contributions to neuropathology, although she was also a general pathologist. As Professor of Morbid Anatomy at the London Hospital Medical College, she was the first woman to occupy a medical Chair in Western Europe.

Meanwhile, at the London Hospital in Whitechapel, Hugh Cairns had encouraged the young research pathologist Dorothy Russell (Fig. 7) to take up neuropathology in 1928. One of a small group of gifted women born in the 1890s who benefited from the new social opportunities available to them as a result of the First World War, Russell's life has recently been described.6 Like Greenfield, she developed an extraordinary range of interests in the course of her career in neuropathology (a selected bibliography is given in an obituary by her colleague and collaborator, Lucien Rubinstein41). The majority of Russell's papers, which cover almost every aspect of neuropathology, were classic descriptive studies, but she was also one of

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Fig. 8. Dorothy Russell and J.O.W. Bland were the first workers to use astrocytoma cultures to answer questions about tumour histogenesis (J. Pathol Bacteriol.,1933). The low-power picture shows one of their cultures; at higher power, the characteristic fibrillary processes reveal it to be an astrocytoma.

the first with John Bland to grow tumour cells in culture and study their properties. Her tissue culture experiments (Fig. 8) confirmed the previously disputed astrocytic nature of the pilocytic astrocytoma, and the arachnoidal origin of meningiomas. During the Second World War she was seconded to Oxford, where she worked with Hugh Cairns both at the Military Hospital for Head Injuries and at the Radcliffe Infirmary. This move provided her with an opportunity to do more experimental work on problems encountered by her neurosurgical colleagues in wartime. She investigated the effects of antiseptics on brain tissue, the way in which cerebral abscesses form and become encapsulated, the pathogenesis of post-traumatic cerebral cysts, and the effects on the brain of new materials used in cranioplasty. As with Greenfield however, Dorothy Russell's enduring legacy was a book, the first textbook of neuro-oncology, written with a younger colleague, Lucien Rubinstein. Pathology of Tumours of the Nervous System, first published

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in 1959, was a companion volume to Greenfield's Neuropathology from the same publishers, and like Greenfield's work was to be influential and highly regarded throughout the English-speaking world. The principal achievement of Russell and Rubinstein, whose work was based on a large collection of neurosurgical and autopsy material at the London Hospital, was to simplify Bailey and Cushing's classification of brain tumours, particularly the gliomas,42 and to make the subject accessible for all those involved in the diagnosis and management of patients with brain tumours. After Russell's retirement in 1960, Rubinstein moved to the United States, where he worked in tumour pathology, producing further editions of their book, the last in 1989.

EXPERIMENTAL NEUROPATHOLOGY: THE INSTITUTE OF PSYCHIATRY Greenfield and Russell were essentially descriptive neuropathologists working on their own, supporting the clinicians, bringing pathological expertise to the sort of research that clinicians had formerly done. It was less usual to see a neuropathologist working on an equal footing with clinicians as a member of a multidisciplinary research team, but an outstanding example of such an arrangement was Alfred Meyer's membership of the group at the Maudsley Hospital working on temporal lobe epilepsy. A refugee from prewar Germany, Meyer (Fig. 9) had begun his career at the instigation of Walter Spielmeyer with experimental studies on selective vulnerability in the brain in hypoxia; after his arrival in England he turned to clinicopathological studies, principally in the field of neuropsychiatry, using whole brain sections embedded in celloidin in the classic German tradition. The late 1940s saw his collaboration with Elizabeth Beck, also a refugee from Nazi Germany, on the neuropathology of frontal leucotomy, which resulted in a series of papers on the anatomy of frontal lobe connections, as well as an important monograph that critically evaluated this type of psychosurgery.43 After Murray Falconer's appointment in 1950 as neurosurgeon to the Maudsley Hospital and Director of the Guy's-Maudsley neurosurgical unit, Meyer was recruited to work on temporal lobe epilepsy.

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Fig. 9. Alfred Meyer (1895-1990) brought expertise and techniques learnt in Walter Spielmeyer's laboratory to the study of temporal lobe epilepsy at the Maudsley Hospital. (Reproduced from Neuropathol. Appl. Neurobiol. 1991, 17, 83-87)

Now with a Chair in neuropathology, he joined a group of clinicians studying the surgical treatment of seizures. The value of this collaborative approach was immense: patients were fully investigated psychologically, radiologically and by EEG before and after surgery, and Meyer, with details of these investigations available to him, was able to bring expertise acquired in Germany to the examination of the material resected. From his laboratory came a series of important publications, notably on Amnion's horn sclerosis and its role in the aetiology of temporal lobe epilepsy. Meyer's collaborative experimental work on cats with a group in Marseille under Henri Gastaut led directly to the more recent analytical studies from the Maudsley on the causal mechanisms behind these important brain lesions. The department of neuropathology at the Institute of Psychiatry under Meyer and later Peter Daniel produced a new generation of neuropathologists, including Jim Brierley, whose experimental studies on the pathogenesis of hypoxic brain damage were directly encouraged by Meyer; John Cavanagh, whose work in the field of neurotoxicology did much to elucidate the pathogenesis of toxic neuropathies and myelopathies; and Sabina Strich,

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who in common with so many others had started in psychiatry, was the first to describe diffuse traumatic damage to white matter ("DAI"). Also associated with the Institute was Nick Corsellis, who occupied the Chair of Neuropathology there for three years, having been attracted from psychiatry to do research into dementia, and who was later to develop interests in normal ageing and the sequelae of boxing and to establish the important Brain Bank at Runwell Hospital.

THE EXPANSION OF NEUROPATHOLOGY With the arrival of neurosurgery, neuropathologists were appointed in centres outside London, and neuropathology began to grow as a specialty.44 John Henry Biggart, professor of general pathology at Belfast who had started his career as an asylum neuropathologist in Edinburgh, produced a small popular basic handbook of neuropathology in 1936,45 which went to three editions. In Leeds, Charles Lumsden carried out tissue culture experiments, worked on demyelination and wrote extensively on multiple sclerosis. In Bristol, Ronald Norman who had trained as a psychiatrist and worked with mentally retarded children before turning to neuropathology, undertook the first serious studies in paediatric neuropathology in Britain. Although his clinical output covered the whole field of paediatric neuropathology, Norman retained particular interests in metabolic storage diseases, which he studied in conjunction with the neurochemist A.H. Tingey, and in the pathogenesis of perinatal brain damage. In south London Len Crome studied and described the neuropathological basis of mental subnormality with Jan Stern.46 At the National Hospital for Nervous Diseases, Maida Vale, W.H. McMenemey's main research interest was in the then unfashionable subject of the dementias, particularly Alzheimer's disease and spongiform encephalopathies, and in his laboratory Michael Kidd was the first to suggest that paired helical filaments make up neurofibrillary tangles in Alzheimer's disease (1964). Also working on dementia, Bernard Tomlinson in Newcastle joined a group of clinicians concerned with the psychiatry of old age, and collaborated with them in carrying out the first quantitative studies of multi-infarct dementia and of senile plaques.

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In Birmingham, Walter Smith, who had the first Chair of Neuropathology at the university, was one of the first to study brain biopsies taken for diagnosis in cases of dementia, and to do experimental work on neurological manifestations of metabolic disorders, while in Glasgow, the neuropathology department founded by Hume Adams rapidly established a strong research group in the Institute of Neurological Sciences, and carried out internationally acclaimed work on head injury, historically a neglected subject. In Cambridge, J.R.M. Innes, a veterinary pathologist who had also trained in medical pathology in Germany under Aschoff in 1932, turned to neuropathology after being introduced to Hortega's metallic impregnation techniques there. Innes' principal publications were on the neuropathology of distemper, swayback, and inherited cerebellar atrophies in animals, and his book Comparative Neuropathology, written with Leon Saunders,47 is a classic comparative text. Innes retained a close professional association with Godwin Greenfield and the neurologists at Queen Square as well as with Dorothy Russell, and was responsible for founding the strong tradition of comparative neuropathology that still exists at the Cambridge veterinary school.

THE NEUROPATHOLOGICAL CLUB Godwin Greenfield's career had spanned the years during which neuropathology began to be recognised as a specialty, rather than as merely applied neurology or psychiatry, and he was one of the first to regard himself as a neuropathologist. By the time he retired from Queen Square in 1949 the advent of the National Health Service had seen the establishment of neurosurgical centres throughout the country, many with neuropathologists already in post. In 1950 with a group of senior colleagues Greenfield started the Neuropathological Club, with 28 founder members. The Club served two useful purposes. It had an important educational function, allowing members of the different schools of neuropathology that had sprung up around the country the opportunity to get together to discuss problem cases, and it united those who had a major clinical commitment in neuropathology with those concerned principally with experimental work. Two years later in 1952 the first International Congress of Neuropathology was held in Rome.

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This was not to everyone's approval: the neurologist Sir Francis Walshe commented with dismay that separate international meetings for neuropathologists and neurosurgeons "[tore] the seamless garment of neurology".48 In 1962 the Club had grown sufficiently for it to become more formal, and the name was changed to the British Neuropathological Society (BNS). By 1998 there were 200 active members; in the year 2000, the Society celebrates its 50th anniversary. 1967 saw the founding of the International Society of Neuropathology, in which BNS members have played an active role, providing three of the Secretaries-General and two of the Presidents to date. In 1975 the BNS launched Neuropathology and Applied Neurobiology, which has become one of the major neuropathology journals.

THE BRITISH AND NEUROPATHOLOGY So what have been the principal British contributions to neuropathology? Any answer to that question must start with the two classic textbooks, Neuropathology by Greenfield and Pathology of Tumours of the Nervous System by Russell and Rubinstein. The former, retitled Greenfield's Neuropathology after its principal author's death, remains (in its sixth edition49) the leading English-language text on the subject. It is difficult for us today, in an era in which textbooks abound, to appreciate how new Greenfield's book was when it appeared in 1958. Nothing like it, covering the whole field of non-neoplastic neuropathology, had appeared before, and it became an immediate success. The latter, Russell and Rubinstein's book, exerted great influence on neuro-oncology for over 30 years, although less in recent years. The major reason for its prolonged popularity was that it was not an edited collection of chapters, but reflected the experience of the two original authors, with the strengths (and weaknesses) that such authorship brings to a textbook. A new sixth edition, retitled Russell and Rubinstein s Pathology of Tumors of the Nervous System, has recently been published (1998), although, unlike "Greenfield", now under American editorship. In other many specific areas of neuropathology, one can point to achievements that are clearly identifiable as British. These include elucidation of the pathogenesis and neuropathology of epileptic seizures, particularly temporal

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lobe epilepsy, from the Maudsley group; contributions to the understanding of peripheral nerve pathology, starting with J.Z. Young, particularly his wartime studies on the biology of nerve grafting carried out at the MRC unit at Oxford, and followed by others — notably John Cavanagh, P.K. Thomas and William Blackwood; pioneering work on head injury, started by Hugh Cairns in the war, and continued from the 1960s by Hume Adams' group in Glasgow; to demyelination, from James Dawson's classic histology, Lumsden's studies of experimental allergic encephalitis, and the Cambridge veterinary neuropathologists' work on mechanisms of remyelination in the nervous system; to the attempts to understand spongiform encephalopathies, including early transmission experiments and the first histological confirmation of transmission of Creutzfeldt-Jakob disease (CJD) to chimpanzees by Elizabeth Beck, culminating in work on animal and human prion diseases at the Neuropathogenesis Unit in Edinburgh, the Central Veterinary Laboratory, and the National CJD Surveillance Centre. Any selection is invidious: I have taken widely diverse themes deliberately to illustrate the variety of work undertaken.

THE FUTURE OF NEUROPATHOLOGY IN BRITAIN British neuropathology has an honourable past; has it a future? One of its strengths has been the diversity of pathways by which people have come to the subject: until recently, it was quite usual for clinicians to become neuropathologists, as we have seen, but the demands of modern training curricula now make it difficult for those without a background in general pathology to enter the specialty. This is likely to favour the assimilation of clinical neuropathology into general pathology in the UK, with the neuropathologist inevitably being replaced by a general pathologist "with an interest in" neuropathology at some centres. Such a trend is likely also to be promoted by the fact that in a cost-conscious health service, expensive subspecialties such as diagnostic neuropathology are going to be seen as dispensable — or at least ripe for economies. Politics and neuropathology have often gone hand in hand. In late nineteenth century Germany, state funding became available for the work

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Fig. 10. Spongiform change and florid amyloid plaques (centre field) are the distinctive histological features of "variant" CJD, first described in 1996 by workers at the National CJD Surveillance Centre in Edinburgh (Periodic acid Schiff stain).

of neuropathologists as concern grew over the enormous prevalence of GPI in the psychiatric hospitals. Out of this initiative came the work of people like Alzheimer and Nissl, which resulted in the pre-eminence of Germany in the field of the dementias for many years. In the second half of this century Britain has seen two serious pestilences, one a more significant public health problem than the other (at least, at the time of writing), but both of which had completely "new" neuropathology — namely, AIDS and the newer varieties of spongiform encephalopathy. In both cases, as public concern grew, central funding was rapidly made available for both descriptive and experimental neuropathology. While the spectre of asylums full of patients with "variant" CJD (Fig. 10) in the early twenty-first century still hangs over us, understanding of the condition has been greatly increased by this funding. That said, up until a few years ago our knowledge of CJD was essentially on a par with the asylum pathologists' knowledge of GPI: like them, we were studying a disease without knowing what we were studying,

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but seeking to detect patterns, identify variants, and so define the neuropathological substrate. This descriptive process is still essential: molecular genetic techniques may now have superseded many of the neuropathologist's traditional diagnostic methods, but neuropathology remains a prerequisite for such techniques, because you need a diagnostic category before you can use them. Finally, there are some hopeful signs for the specialty. International initiatives such as the Decade of the Brain, and the fact that there are now genuine possibilities of effective therapy for diverse previously incurable conditions — head injury, Alzheimer's disease, stroke and multiple sclerosis — have focussed attention back to neuropathology and ensured that research money is available. The irony is that while clinical diagnostic neuropathology may be tending to contract, experimental neuropathology actually thrives — though sadly often in the hands of neuroscientists who would not see themselves primarily as neuropathologists. Acknowledgements The author would like to thank Professor J.H. Adams, Dr. R.O. Barnard, Dr. A. Gordon, Mr. I.S. Levy, Mr. N.L.J. Montagu, Dr. A.C. Palmer and Mr. G.H. Vowles for their generous help in the preparation of this paper. A particular debt of gratitude is due to Professor J.B. Cavanagh, who answered endless questions, provided advice about the form the account should take, ideas about who or what should be included, and finally criticised the manuscript. The permission of the following to reproduce figures is gratefully acknowledged the Wellcome Institute Library, London (Fig. 2), Mrs. B. Greenfield (Fig. 6), John Wiley & Sons Ltd. (Fig. 8) and Blackwell Science Ltd. (Fig. 9). References 1. Abercrombie, J. (1828). Pathological and Practical Researches on Diseases of the Brain and Spinal Cord. Waugh and Innes. 2. Hooper, R. (1828). The Morbid Anatomy of the Human Brain. Longman, Rees, Orme, Brown and Green.

From Treponemes to Prions: The Emergence of British Neuropathology 251 3. Carswell, R. (1838). Pathological Anatomy. Illustrations of the Elementary Forms of Disease. Longman, Orme, Brown, Green and Longman. 4. Bright, R. (1831). Reports of Medical Cases. Vol.11: Diseases of the Brain and Nervous System. Longman, Rees, Orme, Brown and Green. 5. Burston, J. and Timperley, W.R. (1997). The birth of hospital pathology. Biologist 44, 460-462. 6. Geddes, J.F. (1997). A portrait of "The Lady": A life of Dorothy Russell. J. Roy. Soc. Med. 90, 455-461. 7. Smith, W.T. (1974). A Legacy of the Blighted Brain. University of Birmingham. 8. Maulitz, R.C. (1987). Morbid Appearances. Cambridge University Press. 9. Bracegirdle, B. (1978). A History of Microtechnique. Heinemann. 10. Jones, K. (1991). The culture of the mental hospital. In 750 Years of British Psychiatry, 1841-1991 (eds. G.E. Berrios and H. Freeman) Gaskell. pp. 17-28. 11. Savage, G.H. (1886). Presidential address. J. Ment. Sci. 32, 313-331. 12. Thompson, M.S. (1988). The wages of sin: The problem of alcoholism and general paralysis in nineteenth-century Edinburgh. In The Anatomy of Madness. Ill: The Asylum and its Psychiatry (eds. W.F. Bynum, R. Porter and M. Shepherd) Routledge. 13. Clouston, T.S. (1883). Clinical Lectures on Mental Diseases. J&A Churchill. 14. Bynum, W.F., Porter, R. and Shepherd, M. (eds.) (1988). The Anatomy of Madness. Ill: The Asylum and its Psychiatry. Routledge. 15. Todd, J. and Ashworth, L. (1991). The West Riding asylum and James CrichtonBrowne, 1818-1876. In 750 Years of British Psychiatry, 1841-1991 (eds. G.E. Berrios and H. Freeman) Gaskell. pp. 389-418. 16. Bullen, F.S.J. (1890). An abstract of 1565 post-mortem examinations of the brain performed at the Wakefield Asylum during a period of eleven years. J. Ment. Sci. 36, 15-43. 17. Major, H.C. (1876). The histology of the Island of Reil. West Riding Lunatic Asylum Medical Reports 6, 1-10. 18. Bevan-Lewis, W. (1878). Application of freezing methods to the microscopic examination of the brain. Brain 1, 347-350. 19. Bevan-Lewis, W. (1878). On the methods of preparing, demonstrating, and examining cerebral structure in health and disease. Brain 1, 338-359. 20. Bevan-Lewis, W. (1881). On the methods of preparing, demonstrating, and examining cerebral structure in health and disease. Brain 2, 314-336; 502-515.

252 J. Geddes 21. Bevan-Lewis, W. (1882). On the methods of preparing, demonstrating, and examining cerebral structure in health and disease. Brain 5, 74-88. 22. Bevan-Lewis, W. and Clarke, H. (1878). The cortical lamination of the motor area of the brain. Proc. Roy. Soc. Lond. 27, 38-49. 23. Ferrier, D. (1873). Experimental researches in cerebral physiology and pathology. West Riding Lunatic Asylum Medical Reports 3, 30-96. 24. Todd, J. and Ashworth, L. (1973). "The House": Wakefield Asylum 1818... Wakefield Health Authority. 25. Clouston, T.S. (1897). Scheme for appointment of pathologist to the Scottish asylums. Appendix to Minutes of the Royal Medico-Psychological Association (Scottish Division). Thursday 11 March. 26. Fox, E.L. (1874). The Pathological Anatomy of the Nervous Centres. Smith, Elder & Co. 27. Bevan-Lewis, W. (1889). A Text-Book of Mental Diseases. Charles Griffin and Company. 28. Robertson, W.F. (1900). A Text-Book of Pathology in Relation to Mental Diseases. William F. Clay. 29. Henderson, D.K. (1964). The Evolution of Psychiatry in Scotland. E&S Livingstone. 30. Collins, W.J. (1900). Preface. Arch. Neurol. 1, viii-xii. 31. Mott, F.W. (1900). Combined sclerosis with grave anaemia. Arch. Neurol. 1, 377-387. 32. Anonymous. (1926). Obituary. Sir Frederick Mott, KBE, MD, FRCP, FRS, LLD. Br. Med. J. 1, 1063-1066. 33. Meyer, A. (1973). Frederick Mott, Founder of the Maudsley Laboratories. Br. J. Psychiatry 122, 497-516. 34. Haymaker, W. (ed.) (1953). The Founders of Neurology. Charles C. Thomas. 35. Davis, C.H. and Bradford, R. (1984). Biology of Brain Tumour. In Proceedings of the Second International Symposium on Biology of Brain Tumour (eds. M.D. Walker and D.G.T. Thomas) London. 36. Tooth, H.H. (1912). Some observations on the growth and survival period of intracranial tumours based on the records of 500 cases, with special reference to the pathology of the gliomata. Brain 35, 61-108. 37. Buzzard, E.F. and Greenfield, J.G. (1921). Pathology of the Nervous System. Constable and Co. 38. McMenemey, W.H. (1959). Joseph Godwin Greenfield (obituary). J. Pathol. Bacteriol. 78, 577-592.

From Treponemes to Prions: The Emergence of British Neuropathology 253 39. Haymaker, W. (1958). J. Godwin Greenfield, MD. A neuropathologist's appreciation. Arch. Neurol. Psychiatry 80, 590-596. 40. Penfield, W. (1958). J.G. Greenfield: Appreciation of the man. Arch. Neurol. Psychiatry 80, 587-589. 41. Rubinstein, L.J. and Smith, F.J. (1984). Obituary: Dorothy Stuart Russell. Neuropathol. Appl. Neurobiol. 10, 314-320. 42. Bailey, P. and Cushing, H. (1926). A Classification of the Tumors of the Glioma Group on a Histogenetic Basis. J.B. Lippincott Company. 43. Meyer, A. and Beck, E. (1954). Prefrontal Leucotomy and Related Operations: Anatomical Aspects of Success or Failure. William Ramsay Henderson Lecture, Oliver and Boyd, Edinburgh. 44. Blackwood, W. (1985). Contributions to neuropathology made in Great Britain in the first 70 years of the 20th century. Bull. Roy. Coll. Pathol. 49, 7-10. 45. Biggart, J.H. (1936). Pathology of the Nervous System. E&S Livingstone Ltd. 46. Crome, L. and Stern, J. (1967). Pathology of Mental Retardation. Churchill Livingstone. 47. Innes, J.R.M. and Saunders, L.Z. (1962). Comparative Neuropathology. Academic Press. 2nd edition. 48. Schurr, P.H. (1997). So That Was Life. Royal Society of Medicine Press Ltd. p. 301. 49. Graham, D.I. and Lantos, P.L. (eds.) (1996). Greenfield's Neuropathology. Arnold. 6th edition.

TWENTIEH CENTURY NEUROLOGY The British Contribution © 2001 by Imperial College Press

Chapter 19

MITOCHONDRIAL MYOPATHIES Hannah R. Cock & Anthony H.V. Schapira

INTRODUCTION Although it is only 19 years since the mitochondrial genome was sequenced,1 it seems appropriate to take stock since the number of mitochondrial mutations associated with the disease has increased exponentially. However, as more conditions are linked it becomes harder to explain the mechanisms that give rise to the wide range of associate clinical presentations. We are increasing our understanding of the regulation of mtDNA transcription and replication, nuclear inter-relationships and looking for other secondary factors in disease pathogenesis. As many scientists continue to work in this rapidly developing field our appreciation of the complex molecular mechanisms involved will undoubtedly expand, and ultimately allow for the development of clearer diagnostic strategies and new therapeutic approaches. Living human tissues are dependent on ATP production via oxidative metabolism, in turn reliant on the integrity of the mitochondrial respiratory chain (MRC). Abnormalities in the mitochondrial or nuclear genomes encoding proteins involved in MRC biogenesis or function can hence result in disease. This review aims to classify this group of disorders in the light of current knowledge, and cover the clinical and biochemical features of the major syndromes so far described.

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Mitochondrial Genetics Human mitochondrial DNA (mtDNA) is a closed circular molecule of 16 659 base pairs. Its complete sequence and functional assignment of the genes have been understood for some time. 1,2 MtDNA is very compact and consists almost entirely of genes encoding 22 tRNA species, a 16s and 12srRNA, and 13 polypeptides all of which contribute to the MRC. Our understanding of mtDNA replication and transcription is still expanding, but certainly involves nuclear encoded proteins. A gene free region referred to as the D-loop (displacement loop) contains the origin of heavy (H) strand replication (OHR) from where nuclear encoded DNA polymerase, imported from the cytoplasm, initiates H-strand synthesis proceeding clockwise around the circle to a second origin of replication for the light (L) strand (OHL).3 MtDNA replication occurs independent of the cell cycle and, as each cell may have several hundred copies of mtDNA, any mutation which arises may only be present in a proportion of the total cellular complement. This can lead to a cell having two (or more) populations of mtDNA — normal and mutated, a condition know as heteroplasmy. As the cell divides, the mutant and normal mtDNAs are randomly distributed to the daughter cells. This replicative segregation may cause drift of the genotype ultimately towards homoplasmy: pure mutant or pure normal mtDNA. Clearly mutations which interfere with mtDNA replication would not be expected to survive this process but other factors influencing the direction of such drift are poorly understood. Mitochondrial transcription also starts within the D-loop from two adjacent promoters, one for each strand: heavy strand promotor (HSP) and light strand promotor (LSP), resulting in one giant poly-transcript containing all the mRNAs. A nuclear product, mitochondrial transcription factor A (mtTFA), has been shown to bind to HSP and LSP and stimulate transcription in vitro,4 and it is also required for efficient replication of mtDNA.5 In addition, nuclear respiratory factors (NRF) have been identified with recognition sites both in nuclear genes with products contributing to the MRC, the mtRNase P gene and in a proximal promotor of the mtTFA gene.6 As such, NRFs have the potential to communicate nuclear regulatory events to the mitochondrial replication/transcription machinery, and could

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also feed back cytoplasmic signals relating to the cellular energy state to the nucleus.7 Once transcription has taken place many changes to the transcript are necessary before translation can occur. This requires RNAase P to cleave each tRNA from the polytranscript, poly(A)polymerase and nucleotidyl transferase activities.3 All of these are nuclear encoded, but only the mtRNAase P has so far been characterised.3 In addition, specific sequences proximal to the promoters of nuclear genes involved with the MRC, for example the ATP synthase gene, seem to act as positive or negative transcriptional factors for their respective genes. In vitro binding factors to these regions, named OXBOX and REBOX, respond to intracellular signals and external hormonal influences as well as nuclear factors, again providing a mechanism for bigenomic co-ordinate expression.9 More recently binding domains for Ets proteins, a group involved in controlling nuclear gene expression in response to cell cycle signals, have been identified within the dorsal promoter region of ATP synthase, so these may be involved in coordinating the 2 genomes in response to proliferative signals.10 Subsequent translation of the now separated 13 mRNAs takes place on mitochondrial ribosomes so an excess of rRNAs is required from each transcript in order to provide a balance. This is achieved by a mitochondrial termination factor (mTERF) which binds to mtDNA downstream of the 16s rRNA gene, within tRNA Leu(n ) resulting in a shortened transcript predominantly coding for the rRNAs. In addition to the 22 mtDNA encoded tRNAs, translation requires a set of nuclear encoded aminoacyl tRNA synthases. Here again are several probable control sites, but the precise mechanisms have yet to be elucidated. The Mitochondrial Respiratory Chain The MRC represents the means by which cellular ATP is generated through oxidative phosphorylation. It consists of five multi subunit enzyme Complexes (I-V) situated on the inner mitochondrial membrane.12 MtDNA encodes 7 of the 41 identified subunits of Complex I (NADH ubiquinone oxidoreductase), cytochrome b of Complex III (ubiquinone: cytochrome c oxidoreductase), 3 subunits (COX I, II and III) of 13 in Complex IV (cytochrome c oxidase), and 2 of 13 subunits in Complex V (ATPase).

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The remaining subunits and all of Complex II (succinate: ubiquinone oxidoreductase) are nuclearly encoded.1'2 Complexes I-IV make up the electron transport chain, oxidising mainly NADH and FADH2 and passing the electrons to the terminal acceptor oxygen, which is reduced to water. Protons are concurrently pumped into the mitochondrial intermembranous space generating an electrochemical gradient across the inner membrane. This potential energy is then utilised by Complex V to synthesise ATR Hence, normal MRC function also requires the co-ordinate expression of both nuclear and mitochondrial genomes as discussed above. Subsequently, nuclear encoded proteins, synthesised on cytoplasmic ribosomes, need to be transported into the mitochondria and then directed to the appropriate internal compartment for biosynthesis of the complete enzyme complexes.13 Initially, proteins interact with specific outer membrane proteins, directed by targeting sequences present on the precursor molecules, and then presented to a general insertion pore (GIP) which is in close apposition to the inner membrane (IM). The subsequent translocation across the IM into the mitochondrial matrix has been much studied (for review see Ref. 14). An initial driving energy dependant on the membrane potential presents the aminoterminal to the matrix space where, after cleavage of the precursor sequence, mitochondrial heat shock protein (Hsp)70 binds to it and pulls the protein across the membrane. The protein can then be transferred to Hsp 60 which mediates ATP-dependant refolding. Hsp 60 is one of a group of molecular chaperones ("chaperonins") and may also play a role in the assembly of the final multisubunit complexes though this has not yet been defined.15 Living human tissues are dependent on ATP production via oxidative metabolism, in turn reliant on the integrity of the MRC. Abnormalities in the mitochondrial or nuclear genomes encoding proteins involved in MRC biogenesis or function can hence result in disease. The purpose of the review is to classify this group of disorders in the light of current knowledge and explain some of the mechanisms that may be involved.

CLASSIFICATION OF MITOCHONDRIAL DISORDERS Mitochondrial disorders may be inborn or acquired, and can be classified according to their genetic basis, biochemical expression or clinical phenotype.

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Our increasing understanding of molecular genetics involved leads to a straightforward classification strategy on this basis, which we have chosen to use. However, it will become apparent, as different diseases and mutations are discussed in more detail, that simply having a particular mutation does not always result in the given disease, and far more complicated mechanisms are at work. Nuclear-Driven Mutations As the mitochondrial genome is so small and has been completely sequenced identifying mutations within it has been a relatively easy task. However given that the majority of MRC subunits are nuclear-encoded and, with our increasing understanding of nuclear regulatory factors, more genomic mutations causing mitochondrial disease can be expected to emerge. Protein studies have revealed deficiencies of nuclear encoded components of Complex I16 but no definitive identification of a nuclear mutation has yet been made. Compex II deficiency is relatively uncommon but in at but in at least some described cases there are reduced levels of Complex II Fe-S protein in mitochondrial preparations, with a reduction in the Rieske Fe-S protein of Complex III also apparent.17 In this case, further studies showed normal amounts of these Fe-S proteins in whole muscle homogenates suggesting that the problem was one of protein import into the mitochondrion rather than a true deficiency of the nuclear product. There has also been a case reported of multiple mitochondrial enzyme deficiencies presenting in a neonate as multisystem failure in whom a deficiency of Hsp 60 was also present, and may have been the causative defect.18 It is now clear that large rearrangements of mtDNA causing MRC dysfunction, initially described as being of sporadic mitochondrial origin (see next section) may result from nuclear defects. There are now several families described who demonstrate autosomal dominant inheritance of multiple deletions of mtDNA.19'20 Further characterisation shows that the deletions commonly all arise within the D-loop, but differ in size and frequency within and between family members. This pattern suggests a nuclear defect which either increases an intrinsic propensity of mtDNA to undergo rearrangement, or reduces the organelles' ability to detect and eliminate deleted mtDNA.21

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Defects in candidate genes have not yet been identified. Finally, in a rare fatal infantile disorder where the major problem is a reduced number of copies of mtDNA in each cell, known as mtDNA depletion,22 complementation studies have demonstrated that the defect is nuclear in origin.23 Furthermore in both yeast24 and human cells,25 a deficiency of mtTFA has been associated with mtDNA depletion but whether this is the pathogenetic event or a secondary marker is not clear. MtDNA Rearrangements Numerous mutations arising within the mitochondrial genome have now been described, and mtDNA does seem more susceptible to damage. Factors which contribute to this include the relative paucity of "redundant" DNA within the mitochondrial genome and its the lack of histones and efficient repair mechanisms.26 Combined with its proximity to the most prolific producer of free radicals within the cell in the form of the MRC,27 this makes mtDNA particularly susceptible to damage. Heteroplasmic rearrangements of mtDNA, predominantly deletions, are the most frequently encountered and most usually found in patients with CPEO (chronic progressive external ophthalmoplegia) or KSS (Kearns-Sayre syndrome). They have also been reported in those with cardiomyopathy, diabetes mellitus and Pearson's marrow-pancreas syndrome. Such cases are usually sporadic and the deletion is commonly flanked by direct repeats,28'29 possibly arising through a slip replication model.30 More recently, it has become apparent that many patients with deletions also have small duplications of mtDNA within the D-loop.31 The duplicated mtDNA includes the HSP and LSP and so results in a partial excess of replication machinery which could increase the risk of replication slippage through generation of displaced heavy strands, and lead to the formation of deleted mtDNA molecules. The same duplications have been found in lesser amounts in maternal relatives who are clinically normal and lack the deletion, and moreover in one case have been shown to disappear over time in vivo whilst the proportion of deleted mtDNA molecules increased.32 This has led to the suggestion that though the disease causing deletions are not

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inherited per se, the duplication may be maternally transmitted and be a transient intermediate in the formation of deletions.33 However duplications alone, ranging from a few bases to several kilobases, may also cause disease. MtDNA Point Mutations Missense mutations may affect coding genes for MRC subunits such as in LHON (Leber's hereditary optic neuropathy)34 and NARP (neurogenic muscle weakness, ataxia and retinitis pigmentosa).35 In these cases biochemical dysfunction of the affected complex is often demonstrable.36,37 Mutations within tRNA genes result in a more severe disruption to mitochondrial protein synthesis. Almost invariably, these are heteroplasmic and associated with significant biochemical defects. As a group they account for some of the most diverse clinical pictures, with considerable variation in expression between individuals. Typically they result in severe mitochondrial myopathies hallmarked by "ragged-red" skeletal muscle fibres on Gomori trichrome staining, and accumulation of structurally abnormal mitochondria on electron microscopy. The major disease entities causally associated with tRNA mutations are MELAS (mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes), MERRF (myoclonic epilepsy with ragged-red fibres) and MMC (maternally inherited myopathy and cardiomyopathy). Each will be discussed in more detail later on. Ribosomal RNA mutations are a more recently described phenomenon and though reportedly some rRNA heteroplasmic mutations are found with a higher incidence in patients with Alzheimer's disease,38 the only clear disease association is with non-syndromic and antibiotic induced deafness.39 Bigenomic Mutations To date, there are no diseases in which pathogenic mutations in both mitochondrial and nuclear genomes have been characterised, but this is likely to change. Although in the described Arab-Israeli family with nonsyndromic deafness40 a mitochondrial rRNA mutation has been identified,39 the inheritance through many generations is not exclusively maternal, and

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conforms best to a model involving both autosomal recessive and mitochondrial mutations. The inferred nuclear defect has yet to be identified. Furthermore in the case of LHON there is a substantial excess in male sufferers (~85%)41 despite equal numbers of females carrying the same mtDNA mutations. This is hard to account for through mitochondrial genetics alone, and one explanation would be that similarly an additional factor, perhaps X-linked, is required in order for the mtDNA mutation to cause clinical disease. Despite several attempts through linkage analysis (12,700,52,628), opinions on an X-linked factor in LHON are still divided. That some influence other than that of the associated mtDNA mutations is involved is clear.

CLINICAL AND BIOCHEMICAL FEATURES OF MITOCHONDRIAL DISEASE Mitochondrial disorders can present in a huge variety of ways. Some such as LHON seem very tissue specific, whilst others are of a more generalised nature. A family history or high blood lactate level in a patient with an undiagnosed myopathy or neurodegenerative condition may be suggestive,42 but confirmation can only be made by mtDNA analysis and/or muscle biopsy. Many of the commoner mutations such as those for LHON, MELAS or MERRF are easily screened for with polymerase chain reaction (PCR) amplification and restriction fragment length polymorphism (RFLP) analysis of blood DNA.43 Deletions may be similarly demonstrated by Southern blotting or PCR but often in dividing cells such as in blood or tissue culture the deletion is not present.44 DNA analysis may then need to be carried out on biopsy material, and microscopy of muscle samples may also reveal the presence of RRF indicative of mitochondrial dysfunction. In addition, the enzymatic activities of all of the MRC complexes can be assessed by oxygen electrode polarography or spectrophotometry and information about protein synthesis and structure can be studied on fresh or cultured samples.45 With such techniques a diagnosis of mitochondrial disease can be made confidently in the majority of patients. The following paragraphs will deal with the clinical and biochemical features of diseases associated with the

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major mitochondrial DNA and/or respiratory chain abnormalities to date, although an ever increasing number of clinical syndromes is now being described. Autosomal Dominant Deletions This late onset groups of mitochondrial disorders was first described in 1989 and is characterised by progressive external ophthalmoplegia, progressive limb weakness, bilateral cataracts and precocious death.19 Symptoms appeared in twenties with exercise intolerance and associated lactic acidosis, and RRF on muscle biopsy. In addition similar pedigrees have since been reported.46 A family with recurrent attacks of inco-ordination, drowsiness and ketoacidotic coma has also been described.20 Lactic acidosis and deficiencies predominantly affecting Complexes I and IV are the usual biochemical findings, with RRF on muscle biopsy. Mitochondrial Depletion Syndromes This quantitative defect of mtDNA was first described in 1991,22 since when several other patients have been identified. Two phenotypes can be distinguished.47 The first presents at birth with hypotonia and weakness. There may also be hepatopathy, cardiomyopathy or seizures. Death has always occurred within months. Retained mtDNA varies from 2-17% in muscle, and is associated with a corresponding decline in Complex IV activity. Other MRC activities are also low when corrected for a mitochondrial matrix enzyme, citrate synthase. The later onset form presents in the second year of life with limb weakness, respiratory failure and hypotonia, but with no evidence of multisystem disease so far. MtDNA levels in this group are reported between 14-34% of normal. Pedigree analysis suggests autosomal inheritance, certainly dominant in one family where 3 affected infants had the same father but 2 separate mothers.48 This is consistent with the experimental data showing nuclear complementation and low mtTFA as discussed in the earlier section on nuclear-driven disorders. The complementation studies involve fusion of enucleated patient cells with p°

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(mtDNA-less) cells, hence placing the mitochondria in a control nuclear environment. This resulted in restoration of MRC function whereas the reverse experiment (normal mitochondria inserted into patient cells) failed in this respect. Protein Transport Defects The two cases discussed in the Introduction in respect to defects in the import of proteins into the mitochondria show very different phenotypes. In the first17 in whom a defect in the transport of Fe-S Rieske proteins involved in Complexes II and III was suspected, the child presented at the age of 13 with a history of progressive exercise intolerance and weakness which had in fact been symptomatic since early infancy with delayed motor milestones. She had generally reduced trunk and limb muscle bulk with mild diffuse weakness, mildly myopathic electromyography, and normal creatine kinase levels. She had elevated resting and aerobic lactate levels suggestive of a mitochondrial disorder, and muscle biopsy subsequently confirmed cytochrome oxidase and succinate dehydrogenase deficient fibres, though no RRF. In contrast the patient with HSP 60 deficiency18 was dysmorphic at birth, hypotonic, had a severe lactic acidosis, dextrocardia and a persistent fetal circulation. She died after two days and post mortem showed abnormalities of brain, heart, lungs and liver. These very different clinical pictures reflect the respectively specific and generalised nature of the import defect. As further similar defects are no doubt identified even more variety is likely to be seen. Kearns-Sayre and Pearson's Marrow-Pancreas Syndrome As with many other mitochondrial disorders the spectrum of symptoms in KSS is varied, but clear diagnostic criteria have been set: CPEO, retinitis pigmentosa and onset before the age of 20 years, with any one of ataxia, heart block or elevated CSF protein.49 Short stature and deafness are common, and other features include inco-ordination, mental retardation and episodic coma. Seizures may occur but are usually associated with

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concomitant hypoparathyroidism. Preliminary investigations reveal lactic acidosis and RRF. The first reports of an association with mtDNA deletions were in 1988,50~52 since when many confirmatory series have followed. A 4977 bp deletion spanning Complexes I and IV genes as well as intervening tRNAs is found in 30-40% of cases,29,53 though over 130 types of deletions ranging from 13 to 7.6 Kb have been reported in muscle, but are rarely detectable in blood.54'55 KSS is mostly sporadic and the deletion is not transmitted so must originate in the oocyte or during early development. Typically the clinical course progresses with age, probably due to the preferential replication of the smaller deleted mtDNA molecules resulting in an increasing proportion of mutant/normal mtDNA ratios with time in non-dividing tissues such as brain and muscle.56 There is no clear correlation between the site and size of the deletion and its biochemical phenotype, but nearly all deletions include tRNA's so might be expected to affect translation of additional coding genes outside the deleted region. Deficiencies of all the MRC enzymes are commonly seen.54 Both deleted and normal mtDNA molecules are transcribed and though not surprisingly expression of the actual deleted genes is reduced, there is a compensatory increase in remaining mtDNA transcripts. In MELAS and MERRF, associated with tRNA mutations, a parallel increase in the expression of nuclear oxidative phosphorylation (OXPHOS) genes has also been documented,57 presumably through a feedback mechanism in response to impaired MRC function. In KSS, this is not the case, and it is thought that the segmental accumulation of deleted molecules that is seen within the muscle fibre fails to communicate the defect as effectively with the nucleus. Pearson's marrow-pancreas syndrome has a quite different clinical phenotype, but is discussed here as the same mtDNA deletions, in particular the common 4977 bp deletion, are seen in these children's tissues.58 Notably the deletion is easily detectable in blood and lymphocytes in contrast to KSS, but in keeping with the main clinical feature of a resistant pancytopenia, associated with exocrine pancreatic dysfunction. If the patient survives the infantile period with support, then full recovery of both these features is expected, but at least two cases have gone on to get KSS later in life.59 In

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a further case, the mother had KSS with a deletion in muscle, and her son had Pearson's syndrome, with an identical deletion in his blood cells, and subsequently recovered as the level of deletion fell.60 Hence the phenotype seems to be determined by the proportion of deleted mtDNAs in the respective tissues with an apparent selection against deleted mtDNA molecules in dividing cells such as blood, through accumulation in muscle and brain where there is high oxidative demand stimulating mitochondrial replication and low cell turnover. CPEO This is a term applied for those patients who fail to fulfil the KSS diagnostic criteria and in whom the prominent clinical feature is that of CPEO. The same deletions and biochemical features as in KSS have been described in up to 50% of patients, the remainder having largely undefined genetic defects but often sharing the MRC dysfunction and RRF demonstrable in muscle biopsies.61 LHON LHON is recognised as the commonest cause of isolated blindness in young men. It presents with subacute painless visual loss, often unilateral initially, and characterised by a peripapillary telangiectatic microangiopathy on fundoscopy in the acute phase,62 progressing to optic atrophy as acuity is lost. Typically onset is in the late teens and twenties, but cases have been reported at both extremes of age. Vascular changes may also be seen in asymptomatic family members in a milder form.63 Though some cases are sporadic the majority display strict maternal inheritance64 making the mitochondrial genome an obvious target. To date 16 mtDNA coding gene mutations have been associated with LHON. Three Complex I mutations are regarded as primary in that each has been found either in a homoplasmic or heteroplasmic state in patients and never in controls, alters a highly conserved amino acid and, despite different mtDNA backgrounds, has resulted in disease. Penetrance is incomplete with males being affected more

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than females, and the possible role of nuclear factors in this has already been covered. The 3460 bp G to A mutation in ND1, 65 11778 G to A in ND466 and 14484 T to C in ND667 account for up to 80% of LHON cases.68 The remaining secondary mutations (for review see Ref. 55) occur in combination with each other or with primary mutations and may influence clinical penetrance in the latter case. They affect highly or moderately conserved sequences in subunits of Complexes I, III and IV but are not sufficient alone to cause blindness or significant MRC dysfunction. The 15257 cytochrome b69 resembles a primary mutation in that it affects a conserved amino acid within an evolutionarily constrained region, and has been reported in families where no other LHON mutations have been found.70 However, it can also be associated with other primary mutations and, more importantly, detected in normal controls (0.4%).71 Some LHON mutations are also associated with additional neurological disease: the 14459 G to A has been demonstrated in a family with LHON and dystonia72; some patients with the 11778 mutation display features of a multiple sclerosis (MS)-like illness,73'74 and an association between the 15257 variant and an increased incidence of spinal cord and peripheral neurological symptoms has been reported.75 Biochemically the 3460 ND1 mutations is associated with a > 60% reduction in mitochondrial activity in platelets,76 white blood cells77 and cultured fibroblasts.78 The 11778, 14484 and 4160 (secondary), mutations have also been show to cause milder Complex I dysfunction in some studies,77,79 though other factors such as the inhibitory effect of smoking on platelet Complex I80 need to be take into account to interpret data reliably. However, no correlation between biochemical severity and clinical phenotype has been shown to exist.36 Others have tried to link mutation type/patterns to clinical expression in LHON. Visual recovery is reported more often in those with the 14484 as opposed to 11778 or 3460 mutations,81 and the proportion of mutant mtDNA in some cases is correlated to disease severity,82 but these factors alone cannot explain why some family members of either sex with high mutant loads remain asymptomatic. The association of LHON with MS in some cases has led to the suggestion that an abnormal immune response may be involved. A

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mitochondrial Complex I factor has been shown to be involved in a mouse histocompatibility antigen,83 and the presence of circulating antibodies to mitochondrial proteins in primary biliary cirrhosis is well recognised, though its relationship to the pathogenesis of the disease is not clear. If autoimmunity were involved in LHON it might account for certain patients developing visual failure, perhaps triggered by an environmental agent, whilst others do not. In addition, it could explain the fundal appearance at presentation and the association with CNS white matter lesions and MS. A circulating antibody to Complex I has been identified in LHON patients84 in keeping with this hypothesis, though it was also present to a lesser extent in unaffected family members. In contrast, no association between blindness and HLA type has been shown,85 which would not be typical of an autoimmune disease. NARP and Leigh's Syndrome A mutation causing a T to C or T to G transition at position 8993 of the ATPase subunit 6 gene which appears to inhibit ATP production by blocking the proton channel of the ATPase, has been clearly implicated in some though not all cases of Leigh's syndrome, a fatal infantile disorder.86 This is a multisystem disorder but the clinical picture is dominated by CNS involvement with psychomotor regression, ataxia, seizures, peripheral neuropathy, optic atrophy and brainstem dysfunction. When the proportion of mutated mtDNA falls below -90% a more benign phenotype is exhibited, known as NARP,35 and with lower percentages, yet a peripheral retinopathy may be the only manifestation. All phenotypes may appear in the same family,87 and it is one of the few diseases where there is reasonably good correlation between mutant load and clinical presentation. MELAS There has also been one report of an 11084 Complex I mutation resulting in a MELAS phenotype,88 but this is more characteristically linked to tRNA mutations. The most commonly reported is the 3243 tRNALeu mutation,89

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but a 3271 mutation in the same gene has also been documented with the MELAS phenotype.90 The pathogenicity of the 3243 mutation has been demonstrated by transfer of mutant mitochondria into control human p° cells where the defects in mitochondrial protein synthesis and of the MRC chain (Complexes I, III and IV) persisted.91 In common with other mtDNA point mutations MELAS may show maternal inheritance, though considerable clinical variation within a family is the norm. The most severely affected have normal early development but this is followed by a severe progressive encephalomyopathy with exercise intolerance, weakness, seizures and dementia, punctuated by paroxysmal stroke-like episodes. Most if not all present before the age of 40.92 In relatives, severe migrainous episodes,93 deafness94'95 or a milder myopathy96 may be the only symptoms, and to some extent this correlates with mutant load in target tissues, with a threshold of -60% above which the more classical MELAS emerges. Investigation reveals RRF in skeletal muscle and lactic acidosis; mildly elevated CSF protein may be found in 50% and a third in a 1991 series had basal ganglia calcification.97 MERRF MERRF was initially associated with the 8344 tRNALys mutation98 and in the majority of cases this holds true.99 Another mutation at position 8356 within the same gene have since come to light,100 and the MERRF phenotype has also been reported in a family with a 3256 tRNALeu mutation.101 The major clinical features include a cerebellar syndrome, generalised convulsions, myoclonus, dementia, deafness and a positive family history.102 Lateralising cortical symptoms are conspicuously absent in contrast to MELAS, but similarly clinical variation is common. The mutation is again heteroplasmic with higher mutant loads in affected tissues; futhermore there appears to be a general association between mutant load in blood and both age of onset and clinical severity.103 This can shift considerably through successive generations, presumed to be a consequence of only a few mtDNA molecules being passed to offspring through a "bottleneck" between oogenesis and embryogenesis.

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Other tRNA Diseases MMC (maternally inherited myopathy and cardiomyopathy) is also a wellcharacterised tRNA syndrome,104'105 with a mutation at position 3260 in tRNALeu, and a third mutation within the tRNALeu gene at position 3252 has been reported in one family with encephalomyopathy, diabetes mellitus, hypoparathyroidism, dementia and a pigmentary retinopathy.106 The 3243 MELAS mutation has also been reported in association with maternally inherited diabetes mellitus with107,108 and without43 deafness. Various other tRNA mutations have been described in association with myopathies (3250-tRNA Leu ) 109 and fatal infantile mitochondrial diseases affecting skeletal and/or cardiac muscle (4269 and 4317-tRNA IIe ). 110 ' m One case of CPEO had a 5730-tRNA Asn mutation not found in controls.101 Finally a new type of tRNA mutation at position 15590 (tRNAPro) has recently been identified involving the anticodon for proline and converting it to serine. The patient was a seven-year-old girl with a mild pure myopathy and RRF; the mutation was heteroplasmic at 85% in her muscle but was not found in her blood or that of her mother.112 Biochemically she had significant impairment of all MRC enzymes (Complexes I, II and IV) with mtDNA encoded subunits, and reduced Complex I and COX II proteins on immunostaining, similar to the findings in other tRNA mutations. PCR amplification of single fibres showed only those with >90% mutant mtDNA to be cytochrome oxidase negative on histochemical analysis, showing a high threshold for functional effect. A simple proline-serine substitution resulting from this anticodon swap would be expected to have serious effects on secondary and tertiary protein structure and hence MRC function at much lower mutant loads; other factors may therefore also be involved in the pathogenesis in this case.

TREATMENT OF MITOCHONDRIAL DISORDERS That these mitochondrial disorders are a comparatively new diagnostic area is reflected in the lack of specific therapies available to date. As with any neuromuscular condition general measures such as adequate explanation to

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patients, or more often their carers, and accessibility of help when required are of prime importance. General practitioners, general physicians and ancillary staff may have little knowledge in this field, so communication about the likely problems with other involved professionals is equally vital. Physiotherapy, practical aids for increasing disability and good nutrition can all contribute to good quality life. Though with other mitochondrial disorders affecting such as disorders of fatty acid oxidation specific dietary manipulations can give considerable benefit by decreasing the endogenous production of harmful metabolites, the same is not true for respiratory chain defects. Instead therapies to date rely on attempting to manipulate the metabolic pathways through cofactors and substrates. Thiamine, part of several enzymes in the tricarboxylic acid (TCA) cycle, has been given to patients with lactic acidaemia, but almost without effect except for occasional case reports in patients with Complex I or Complexes I and III defects.113 Other vitamins such as folate, nicotinamide and ascorbate have also been used with the idea that they are enzyme precursors or coenzymes involved at or near the defect (for review see Ref 114) but no consistent direct evidence for their use exists. Vitamin E and ascorbate have additional antioxidant properties which makes them appealing as a treatment in MRC dysfunction, but clinical trials are lacking. Artificial electron acceptors to bridge any defect in the electron chain such as coenzyme Q10 may be more promising. Subjective improvement in symptoms and in markers such as lactic acidaemia, CSF protein and Complex I function has been documented in KSS patients, but again the numbers are very limited.115-116 Finally genetic counselling is necessary but not that straightforward. Cases of KSS and CPEO are usually sporadic, but it would be important in any atypical patient to take an adequate family history to rule out any autosomal factor such as is seen with the familial deletions. Most point mutations are strictly maternally inherited, so it must be made clear that affected males cannot pass it on. Females however will inevitably transmit the mutation to all offspring but, as we have discussed, the lack of correlation between genotype and phenotype, coupled with the unpredictable mutant load passed on from heteroplasmic mothers, makes accurate predictions

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278 H. R. Cock & A. H. V. Schapira 74. Harding, A.E., Sweeney, M.G., Miller, D.H. et al. (1992). Occurrence of a multiple sclerosis-like illness in women who have a Leber's hereditary optic neuropathly mitochondrial DNA mutation. Brain 115, 979-989. 75. John, D.R, Smith, K.H, Savino, P.J. and Miller, N.R. (1993). Leber's hereditary optic neuropathy: Clinical manifestations of the 15257 mutation. Ophthalmology 100, 981-986. 76. Smith, P.R., Cooper, J.M., Govan, G.G., Harding, A.E. and Schapira, A.H.V. (1994). Platelet mitochondrial function in Leber's hereditary optic neuropathy. J. Neurol. Sci. Ill, 80-83. 77. Majander, A., Huoponen, K., Savontaus, M.-L., Nikoskelainen, E.K. and Wikstrom, M. (1991). Electron transfer properties of NADH: Ubiquinone reductase in the ND1/3460 and the ND4/11778 mutations of Leber hereditary optic neuroretinopathy (LHON). FEBS Lett. 292, 289-292. 78. Cock, H.R., Cooper, J.M. and Schapira, A.H.V. (1995). Nuclear complementation in Leber's hereditary optic neuropathy. Neurology 45, A294. 79. Howell, N., Kubacka, I , Xu, M. and McCullough, D.A. (1991). Leber hereditary optic neuropathy: Involvement of the mitochondrial ND1 gene and evidence for an intragenic suppressor mutation. Am. J. Hum. Genet. 48, 935-942. 80. Smith, PR., Cooper, J.M., Govan, G.G., Harding, A.E. and Schapira, A.H.V. (1993). Smoking and mitochondrial function: A model for enviromental toxins. Q. J. Med. 86, 657-660. 81. Johns, D.R., Heher, K.L., Miller, N.R. and Smith, K.H. (1993). Leber's hereditary optic neuropathy: Clinical manifestations of the 14484 mutation. Arch. Ophthalmol. Ill, 495-498. 82. Zhu, D., Economou, E.P., Antonarakis, S.E. and Maumenee, I.H. (1992). Mitochondrial DNA mutation and heteroplasmy in type I Leber hereditary optic neuropathy. Am. J. Med. Genet. 42, 173-179. 83. Loveland, B., Wang, C.-R., Yonekawa, H., Hermel, E. and Lindahl, K.F. (1990). Maternally transmitted histocompatibility antigen of mice: A hydrophobic peptide of a mitochondrially encoded protein. Cell 60, 971-980. 84. Smith, PR., Cooper, J.M., Govan, G.G., Riordan-Eva, P., Harding, A.E. and Schapira, A.H.V. (1995). Antibodies to human optic nerve in Leber's hereditary optic neuropathy. J. Neurol. Sci. 130, 134-138. 85. Yang, J.H., Lee, H.C., Lin, K.J. and Wei, YH. (1994). A specific 4977-bp deletion of mitochondrial DNA in human ageing skin. Arch. Dermatol. Res. 286, 386-390.

Mitochondrial Myopathies 279 86. Santorelli, F.M., Shanske, S., Macaya, A., De Vivo, D.C. and DiMauro, S. (1993). The mutation at nt8993 of mitochondrial DNA is a common cause of Leigh's syndrome. Ann. Neurol. 34, 827-834. 87. Ortiz, R.G., Newman, N.J., Shoffner, J.M., Kaufman, A.E., Koontz, D.A. and Wallace, D.C. (1993). Variable retinal and neurologic manifestations in patients harbouring the mitochondrial DNA 8993 mutation. Arch. Ophthalmol. Ill, 1525-1530. 88. Lertrit, P., Noer, A.S. and Jean-Francois, M.J.B. et al. (1992). A new disease related mutation for mitochondrial encephalopathy, lactic acidosis and strokelike episodes (MELAS) syndrome affects the ND4 subunit of the respiratory Complex I. Am. J. Hum. Genet. 51, 457-468. 89. Goto, Y.I., Nonaka, I. and Horai, S. (1990). A mutation in the tRNA 1 ^ 1 ™) gene associated with the MELAS subgroup of mitochondrial encephalomyopathies. Nature 348, 651-653. 90. Goto, Y.-I., Nonaka, I. and Horai, S. (1991). A new mtDNA mutation associated with mitochondrial myopathy, encephalopathy, lactic acidosis and stroke like episodes (MELAS). Biochim. Biophys. Acta 1079, 238-240. 91. Chomyn, A., Martinuzzi, A., Yoneda, M. et al. (1992). MELAS mutation in mtDNA binding site for transcription termintaion factor causes defects in protein synthesis and in respiration but no change in levels of upstream and downstream mature transcripts. Proc. Natl. Acad. Sci. USA 89, 4221-4225. 92. Ciafaloni, E., Ricci, E., Shanske, S. et al. (1992). MELAS: Clinical features, biochemistry and molecular genetics. Ann. Neurol. 31, 391-398. 93. Montagna, P., Gallassi, R., Medori, R. et al. (1988). MELAS syndrome: Characteristic migrainous and epileptic features and maternal transmission. Neurology 38, 751-754. 94. Huang, C.-C, Chen, R.-S., Chen, C.-M. et al. (1994). MELAS syndrome with mitochondrial tRNALeu(UUR) gene mutation in a Chinese family. J. Neurol. Neurosurg. Psychiatry 57, 586-589. 95. Jean-Francois, M.J.B., Lertrit, P., Berkovic, S.F. et al. (1994). Heterogenity in the phenotypic expression of the mutation in the mitochondrial tRNALeu(UUR) gene generally associated with the MELAS subset of mitochondrial encephalomyopathies. Aust. N. Z. J. Med. 24, 188-193. 96. De Vries, D., de Wijis, I., Ruitenbeek, W. et al. (1994). Extreme variability of clinical symptoms among sibs in a MELAS family correlated with heteroplasmy for the mitochondrial A3243G mutation. J. Neurol. Sci. 124, 77-82.

280 H. R. Cock & A. H. V. Schapira 97. Hirano, M., Ricci, E. and Koenigsberger, M.R. (1992). MELAS: An original case and clinical criteria for diagnosis. Neuromusc. Disord. 2, 125-135. 98. Shoffiier, J.M., Lott, M.T., Lezza, A.M.S., Seibel, P., Ballinger, S.W. and Wallace, D.C. (1990). Myoclonic epilepsy and ragged-red fibre disease (MERRF) is associated with a mitochondrial tRNALys mutation. Cell 61, 931-937. 99. Zeviani, M., Amati, P., Bresolin, N. et al. (1991). Rapid detection of the A-G 8344 mutation of mtDNA in Italian families with myoclonic epilepsy and ragged-red fibres (MERRF). Am. J. Hum. Genet. 48, 203-211. 100. Silvestri, G., Moraes, C.T., Shanske, S., Oh, S.J. and DiMauro, S. (1992). A new mtDNA mutation in the tRNALys gene associated with myoclonic epilepsy and ragged-red fibres (MERRF). Am. J. Hum. Genet. 51, 1213-1217. 101. Moraes, C.T., Ciacci, F., Bonilla, E. et al. (1993). Two novel pathogenic mitochondrial DNA mutations affecting organelle number and protein synthesis. J. Clin. Invest. 92, 2906-2915. 102. Wallace, D.C, Zheng, X., Lott, M.T. et al. (1988). Familial mitochondrial encephalomyopathy (MERRF): Genetic, pathophysiological and biochemical characterization of a mitochondrial DNA disease. Cell 55, 601-610. 103. Hammans, S.R., Sweeney, M.G., Brockington, M. et al. (1993). The mitochondrial transfer RNALys A to G(8334) mutation and the syndrome of myoclonic epilepsy with ragged-red fibres. Brain 116, 617-632. 104. Zeviani, M., Gellera, C , Antozzi, C. et al. (1991). Maternally inherited myopathy and cardiomyopathy: Association with a mutation in mitochondrial DNA tRNALeu
Mitochondrial Myopathies 281 108. van den Ouweland, J.M.W., Lamkes, H.P.J., Trembath, R.C. et al. (1994). Maternally inherited diabetes and deafness is a distinct subtype of diabetes and associates with a single point mutation in the mitochondrial tRNALeu(UUR) gene. Diabetes 43, 746-751. 109. Goto, Y.-L, Tojo, M., Tohyama, J., Horai, S. and Nonaka, I. (1992). A novel point mutation in the mitochondrial tRNALeu(UUR) gene in a family with mitochondrial myopathy. Ann. Neurol. 31, 672-675. 110. Taniike, M., Fukushima, I., Yanagihara, H. et al. (1992). Mitochondrial tRNAIIe mutation in fatal cardiomyopathy. Biochem. Biophys. Res. Commun. 186, 47-53. 111. Tanaka, M., Ino, H., Ohno, K. et al. (1990). Mitochondrial mutation in fatal infantile cardiomyopathy. Lancet 336, 1452. 112. Moraes, C.T., Ciacci, R, Bonilla, E., lonasecu, V., Schon, E.A. and DiMauro, S. (1993). A mitochondrial tRNA anticodon swap associated with a muscle disease. Nature Genet. 4, 284-288. 113. Morgan-Hughes, J.A, Hayes, D.J, Clark, J.B. and Cooper, J.M. (1984). Results of exploratory therapeutic trials. In Biochemical and Clinical Aspects of Coenzyme Q (eds. Folkers, K. et al.) Elsevier Science Publishers, Amsterdam. pp.417-424. 114. Przyrembel, H. (1987). Therapy of mitchondrial disorders. J. Inker. Metab. Dis. 10, 129-146. 115. Ogasahara, S, Nishikawa, Y, Yorifuji, S. et al. (1986). Treatment of KearnsSayre sayndrome with coenzyme Q10. Neurology 36, 45-53. 116. Shoffner, J.M, Lott, M.T, Voljavec, A.S, Soueidan, S.A, Costigan, D.A. and Wallace, D.C. (1989). Spontaneous Kearns-Sayre/chronic external opthalmoplegia plus syndrome associated with a mitochondrial DNA deletion: A slip replication model and metabolic theory. Proc. Natl. Acad. Sci. USA 86, 7952-7956.

TWENTIEH CENTURY NEUROLOGY The British Contribution © 2001 by Imperial College Press

Chapter 20

BRITISH AND AMERICAN NEUROLOGISTS MEET: LONDON, 1927 Michelle Flye & James Toole

INTRODUCTION From its earliest meetings, the American Neurological Association (ANA) actively sought international connections through a variety of means. On June 6, 1876, the council addressed the problem of "the mode of disposal of the remaining copies of the transactions". The council instructed the corresponding and recording secretaries of the ANA to "supply copies to American and foreign journals, libraries and gentlemen in the specialty".1 On June 6, 1877, the minutes mention that a report was given by the corresponding secretary that 62 copies of the transactions were "sent to foreign specialists and jounalists".2 By 1888, the practice of electing foreign neurologists and psychiatrists as honorary or associate members of the ANA was an accepted one. The 1888 "Constitution, By-laws and List of Members"3 lists eight honorary members and 12 associate members. Included among these names are: Drs. J. Hughlings Jackson, Victor Horsley, David Ferrier, H.C. Bastian, Thomas S. Dowse, W.R. Gowers and J.S. Lombard, all of London. On June 4, 1890, six names were proposed for honorary membership, causing some discussion among the members, as this would fill up all the spots available for honorary membership. Dr. Charles Dana replied "it had seemed to the council expedient to fill up the list of honorary members because the names were nearly all those of prominent Europeans and it 283

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was thought that by engaging their interest it would give greater recognition to the work of the association".4 The year 1897 marked another milestone in the ANA's history of involvement in international affairs. A letter from Dr. F.G. Roddick, president-elect of the British Medical Association (BMA), was read at the first executive session of 1897 by Dr. Moses Allen Starr. This letter invited the ANA to send a delegate to the BMA's meetings, which were scheduled in Montreal from August 31 to September 3 of that year.5 The ANA continued to add honorary and associate members and to send delegates to as many international medical conferences as possible. At the 49th Annual Meeting in 1923, a list of 19 proposals for honorary membership and three proposals for associate membership was presented in honor of the 50th Anniversary Meeting of the ANA. A committee of five was appointed to consult with the Council regarding any honorary or associate members to be elected at the 50th Anniversary Meeting. The final list of 20 nominees for honorary membership who were elected at the 1924 meeting included Dr. Sigmund Freud of Vienna, Dr. Henry Head of London and Dr. Charles S. Sherrington of Oxford. The final list of 17 nominees for associate membership who were elected at the 1924 meeting included Dr. Gordon Holmes and Sir James Purves-Stewart, both of London. These two gentlemen were instrumental later on in setting up the joint meeting between the American and British neurologists.6 Getting Together July 17, 1925 Dear Dr. Holmes: It has occurred to Dr. Frederick Tilney and myself that it is about time for us to have a combined meeting of the British and American Neurologists. The next meeting of the American Neurological Association will be held some time in May or June, 1926. The incoming president is Tilney. I am not certain whether there is a British Neurological Society but there is a Neurological Section I am certain.

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I am writing you informally to find out whether or not it is possible to bring such a thing about. If the British Neurologists are invited do you think that they would come? We could arrange the meeting at most any time to suit you. So far as the program is concerned we can, of course, arrange that later, but our idea is to have a symposium in which both the British and the Americans would take part. I would appreciate an early reply from you. (Letter, from Dr. T.H. Weisenburg, secretary of ANA7) Though Dr. Holmes' reply to Dr. Weisenburg's letter was negative, it prompted a chain of events which led to a formal invitation from the Section of Neurology of the Royal Society of Medicine to the ANA for a "special joint meeting of the two Societies to be held in London in July 1927".8 Sir James Purves-Stewart wrote Dr. Weisenburg on the same day, requesting guidance on the disposal of the Neurological Section's one honour, the Hughlings Jackson lectureship. The lecture was traditionally given every three to four years "by the most distinguished neurologists available". Sir James Purves-Stewart and the Council of the Section of Neurology proposed to offer the lectureship to a distinguished senior member of the ANA planning to attend the joint meeting.9 Dr. Charles Dana was selected for this honour by the ANA. By December 1926, plans were already in progress for the scientific program with Dr. W.J. Adie serving as secretary of a subcommittee in charge of this aspect of the meeting. The plans for the program included readings of short papers on July 25; a "discussion on cerebellum, to be opened by American Neurological Association" and a clinical meeting on July 26; a "discussion on sensory disturbances in organic nervous disease, to be opened by the Neurological Section of the Royal Society of Medicine" and a pathological session on July 27.10 The eager anticipation with which the American Neurological Association awaited the joint meeting was reflected in official communications to members. In a letter from the secretary, Henry Alsop Riley, to members of the association, Riley wrote:

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"On account of the importance of this first Joint Meeting ever held by the American Neurological Association with the British Section of Neurology of the Royal Society of Medicine, all of the members of the American Neurological Association are urged to make a special effort to attend this Joint Meeting. The plans are already well under way and from all indications a most enthusiastic meeting is assured. (January 15, 1927)n" By March 1, 1927, travel and lodging arrangements for ANA members had been made. According to an official letter to ANA members, an agreement had been made with the Raymond and Whitcomb Company for ANA members to sail from New York on July 14 on "the HamburgAmerican liner, the "New York", a boat only recently placed in commission by the line". The "New York" was scheduled to arrive in Southampton on July 22, allowing members time to settle into either the Victoria or the Metropole Hotels in London, conveniently located near the Royal Society of Medicine, No. 1 Wimpole Street, where the meeting would be held. "More and more interest is being manifested in this initial rapprochement with the English neurologists and it is expected that the experiment will be a most enthusiastic success".12 The English neurologists continued planning the meeting and extending various offers of hospitality to the Americans, including an invitation from Dr. Edwin Bramwell to attend the Annual Meeting of the British Medical Association. Bramwell was president of the BMA's Section of Neurology at that time.13 By April 11, Dr. Adie sent the final arrangements for the scientific program to Dr. Weisenburg,14 and on July 6, an invitation from Dr. Anthony Feiling, chairman of the subcommittee in charge of social arrangements, arrived announcing a reception on July 25 and a banquet on July 28.15

THE MEETING The scientific sessions of the meeting officially began Tuesday, July 26, 1927 with presentations by both British and American neurologists, followed

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by short papers. The agenda of the meeting reveals much about mutual concerns in the neurological field at the time. On Wednesday, the Americans discussed "The Cerebellum", and on Thursday, the British discussed "Sensory Disorders of the Nervous System". A presentation of papers on pathological subjects on Thursday afternoon included "A Case of Senile Chorea" by Dr. S.A.K. Wilson of London and "Diffuse Myelitis with Optic Atrophy" by Drs. Gilbert Beck and J.G. Greenfield, both of London.16 Dr. Dana's Hughlings Jackson Address At 5 pm Dr. Dana gave the Hughlings Jackson lecture on "The History of American Neurology". Dr. Dana's lecture focused "on the origin of American neurology from my personal standpoint". Dr. Dana was uniquely qualified to give such a lecture at that time, as his career began in the early days of neurology. "My earliest recollection of American neurology was when, as an intern in Bellevue Hospital, I became possessed of a copy of Hammond's "Treatise on Nervous Diseases" of 1874", Dr. Dana stated. Though Dr. Dana credited Charcot, Erb and Kussmaul with influencing the fathers of American neurology, he also bowed to the contributions of Dr. Hughlings Jackson and other English neurologists. Dr. Dana also mentioned the view that neurology grew from the Civil War and the experiences of Drs. S. Weir Mitchell, W W Keen and William A. Hammond. However, his lecture concentrated on the four New York doctors who Dr. Dana felt were most influential in the early organised days of neurology: Dr. Edward C. Spitzka, Dr. Hammond, Dr. George M. Beard and Dr. Edward C. Seguin. With the end of the nineteenth century the storm and stress of organizing a new specialty had subsided. The American Neurological Association had been organized and the Journal of Nervous and Mental Diseases founded. The prime mover in both these activities was Dr. Jewell of Chicago, with certain local associates. American neurology in its first

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organized form originated in Chicago; we are glad to admit this, and I am pleased to be able to show a portrait of this midwestern father of our cult. Dr. Dana concluded his lecture with a call for more preventive neurology and a defense of the neurological field in general. "I believe, then, in the neural constitution as the highest type of human make-up, and I do not urge or believe that we seek to prevent neuroses by developing lymphatic and melancholic temperaments".17 Entertainment and Hospitality By all accounts, the Americans were exceedingly impressed by the hospitality of their British hosts. Thirty members of the ANA attended the joint meeting, which began at 9 pm Monday, July 25, 1927, with a reception in honor of the American neurologists. The president of the Royal Society of Medicine and his wife, Sir James and Lady Berry, were present for the reception, and Sir Purves-Stewart gave "a delightful discourse" on a little known group of monasteries in Greece titled "Mount Athos, A Survival of the Middle Ages". Music for the event was provided by Dr. Leonard E. Smith's Orchestra. The meeting ended with a banquet on Thursday, July 28, 1927. The banquet, which was hosted by the Section of Neurology of the Royal Society of Medicine, was held at the Cafe Royal "and was in every way a brilliant culmination to this first joint meeting of these two societies and served as a fitting climax to an event which has not had its equal in the annals of the American Neurological Association". Members and their spouses also reported their gratitude for the hospitality of individual members of the Section of Neurology. According to the minutes, the visiting ANA members and their spouses were entertained in the homes of the British neurologists for lunch and in the evening on each day of the meeting.18

The British and the American Neurology Meet: London 1927 289 CONCLUSION From this meeting, the Americans gained both professional and personal contacts with the English. Hoping to encourage further association between the two societies, future meetings between the two were advocated in the minutes of the joint meeting. "From (the meeting) has sprung a renewed inspiration for the advancement of our knowledge and the further cementing of the ties which link us together".19 Despite this conviction and tentative plans for a return joint meeting, these plans were later abandoned. The ANA continued to foster interest in and participate in international neurological and medical conventions. However, American neurologists did not officially meet with British neurologists until 1967, when at the invitation of the Association of British Neurologists, members of the ANA attended another joint meeting in London. References 1. American Neurological Association, Council Meeting Minutes, 1876. 2. American Neurological Association, 3rd Annual Session Minutes, 1877. 3. American Neurological Association, "Constitution, Bylaws and List of Members", 1888. 4. American Neurological Association, 16th Annual Session Minutes, 1890. 5. American Neurological Association, 23rd Annual Session Minutes, 1897. 6. American Neurological Association, 50th Annual Session Minutes, 1924. 7. Weisenburg, Theodore, H., Philadelphia, to Gordon Holmes, London, 17 June 1925, typed. American Neurological Association Archives, Wake Forest University School of Medicine, Winston-Salem, N.C. 8. Section of Neurology of the Royal Society of Medicine, London, to American Neurological Association, Philadelphia, 22 June 1926, typed and signed by James Purves-Stewart, Anthony Feiling and W.J. Adie. American Neurological Association Archives, Wake Forest University School of Medicine, WinstonSalem, N.C. 9. Purves-Stewart, James, England, to T.H. Weisenburg, Philadelphia, 22 June 1926, typed and signed. American Neurological Association Archives, Wake Forest University School of Medicine, Winston-Salem, N.C.

290 M. Flye & J. Toole 10. Adie, W.J., England, to T.H. Weisenburg, Philadelphia, 17 December 1926, typed and signed. American Neurological Association Archives, Wake Forest University School of Medicine, Winston-Salem, N.C. 11. Riley, Henry Alsop, New York, to American Neurological Association members, 15 January 1927, typed. American Neurological Association Archives, Wake Forest University School of Medicine, Winston-Salem, N.C. 12. Riley, Henry Alsop, New York, to American Neurological Association members, 1 March 1927, typed. American Neurological Association Archives, Wake Forest University School of Medicine, Winston-Salem, N.C. 13. Bramwell, Edwin, Edinburgh, to T.H. Weisenburg, Philadelphia, 6 March 1927, typed. American Neurological Association Archives, Wake Forest University School of Medicine, Winston-Salem, N.C. 14. Adie, W.J., England, to T.H. Weisenburg, Philadelphia, 11 April 1927, typed and signed. American Neurological Association Archives, Wake Forest University School of Medicine, Winston-Salem, N.C. 15. Feiling, Anthony, London, to T.H. Weisenburg, Philadelphia, 6 July 1927, typed and signed. American Neurological Association Archives, Wake Forest University School of Medicine, Winston-Salem, N.C. 16. American Neurological Association, British-American Joint Meeting Minutes, 25-27 July 1927. 17. Charles, L. Dana, Early Neurology in the United States: The Hughlings Jackson Address, Journal of the American Medical Association 90 (May 5, 1928), 1421-1424. 18. American Neurological Association, British-American Joint Meeting Minutes, 25-27 July 1927. 19. American Neurological Association, British-American Joint Meeting Minutes, 25-27 July 1927.

TWENTIEH CENTURY NEUROLOGY The British Contribution © 2001 by Imperial College Press

Chapter 21

THE INFLUENCE OF BRITISH NEUROLOGY ON HARVARD NEUROLOGY AND VICE VERSA H. Richard Tyler

Since the early 1800s a number of prominent individuals have fostered a relationship between London and Boston neurology and neuroscience schools. These men were unique and strong personalities whose goals and messages were often global in impact. In the last few decades, training, research opportunities and teaching have become the major driving forces for the present interactions.

GASPAR SPURZHEIM (1776-1832) After being forbidden to lecture in Vienna in 1802 because of the accusation that their philosophy was dangerous to morality and religion, Franz Gall and Gaspar Spurzheim left Austria in 1805. They traveled throughout Europe, giving lectures and anatomical demonstrations. Their success was phenomenal. They eventually settled in Paris in 1807, where they had the freedom to express their new ideas on brain anatomy and function. Gall was accepted by Parisian society as someone with well established "international" fame. He became a social, financial and scientific success. Spurzheim found himself in competition with Gall, and could not achieve the financial independence he wanted. In 1812, he left Paris for London, hoping to establish himself there and to improve his economic situation. He gave 291

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lectures, anatomical demonstrations, and aspired to a permanent place in English medical circles. John Warren (of Boston) who attended some of Spurzheim's anatomical lectures and demonstrations in London was impressed with the demonstrations of cerebral anatomy, but not with Spurzheim's claims concerning their philosophical meaning. In 1932, Spurzheim made a lecture tour of the United States which was very well received. He visited cities along the eastern seaboard, including Philadelphia, New York, New Haven and Boston. John Warren and other prominent local physicians welcomed him to Boston where he lectured at Harvard Medical School. He also gave a series of public lectures in Boston, which were popular and heavily attended. Warren never accepted phrenology as "scientific", but was impressed with the anatomical knowledge its proponents had developed. While in Boston, Spurzheim became acutely ill with pneumonia, and possibly typhoid, and died. He was the second person buried at the Mount Auburn Cemetery in Cambridge, Massachusetts. A large stone crypt was donated by a prominent citizen. His skull resides at the Harvard Medical School in the Warren Anatomical Museum, which also acquired most of Spurzheim's possessions from the Boston Phrenological Society when it disbanded, and they form a significant part of the Museum's permanent collection. Spurzheim brought the "science" of phrenology to the United States, where it remained a prominent, popular movement for the next 30 years. There was a large lay following and a number of phrenological societies were established.

CHARLES EDOUARD BROWN-SEQUARD (1817-1894) Brown-Sequard was born on the island of Mauritius, the son of an American merchant sea captain and a French mother. In 1838, at the age of 20, he left for Paris with his mother and attended medical school there, qualifying for his degree in 1846. As a British subject, Brown-Sequard was able to leave France in 1851 when a coup d'etat established France as an Empire, and the situation became acutely uncomfortable for ardent Republicans. He had letters of introduction, including one from Paul Broca, and traveled in the United States on an active lecture tour. In Boston, in 1853,

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he met and soon married Ellen Fletcher, a niece of Daniel Webster's wife. His professional contacts were equally successful and he made the acquaintance of Drs. H.J. Bigelow and H. Bowditch, two of Boston's most prominent physicians and faculty members of Harvard Medical School, and they sponsored a resolution of thanks following his Boston lectures. This tour led directly to the publication of his first book Experimental Research Applied to Physiology and Pathology (Brown-Sequard, 1854). He spent a short time as Professor of Physiology and Medical Jurisprudence at the Medical College of Virginia 1854-1855. In early 1858 he lectured in London at the Royal College of Surgeons and at St. Bartholomew's Hospital selling his lectures to the Lancet for 50 pounds. He wrote to his wife in France noting that his lectures were given before the largest audience ever assembled at the College and included all the medical men of distinction in London; his letters indicated that he felt he had made quiet an impact there. He received an offer from the Lancet and possibly an offer of a chair in physiology at Oxford. When the National Hospital for the Relief and Cure of the Paralysed and Epileptic at Queen Square was being organised he wrote from Paris offering himself as a candidate for the new hospital detailing his credentials. There were letters from many English physicians encouraging his appointment, including Paget, who was very supportive. On December 29, 1859 he was elected physician to the hospital and in January 1860, wrote a letter of acceptance. He was the second physician (Jabez S. Ramskill was the first) appointed to the staff of the newly established hospital. This was largely an honorary position, but private practice was allowed, and over the next four years he built a very large practice. He became a Fellow of the Royal College of Physicians and the Royal Society. He gave the Croonian lectures in 1861 to the Royal Society and the Goulstonian lectures in London to the Royal College of Physicians. In May 1862, he proposed that Hughlings Jackson be elected Assistant Physician to the National Hospital. In subsequent years, he wrote to Bowditch that he was "proud of his former student". By 1863, he was tiring of practice, which had proven very successful, and indicated he planned to resign from Queen Square. In June 1864, Harvard Medical School sought some physiologically oriented scientists to add to the practitioners who were the major teaching

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faculty of the school. Brown-Sequard was an established exponent of the "new physiology", which utilised experimentation to answer clinical problems that had arisen. The President and Fellows of Harvard College voted on June 11,1964 to "proceed to the election of a Professor of Physiology and Pathology of the Nervous System. Whereupon, ballots being given, it appeared that Dr. E. Brown-Sequard was chosen". On June 25, 1864 he wrote back "I accept most willingly this honourable appointment and will spare no effort to justify the confidence in my usefulness shown by the corporation". His appointment as Harvard's first professor of Physiology and Pathology of the Nervous System represented a deliberate attempt by the President of Harvard to introduce a new type of training in the medical school. Brown-Sequard had grandiose ideas and schemes which included building a huge physiological and pathologic institute similar to those found in Europe. It is known that he gave some lectures which were attended by students as well as local physicians. A copy of notes from one of his lectures is included in Bowditch's notebooks now at the Countway Library. While in Boston, Brown-Sequard developed severe headaches, probably of the cluster variety. Following the death of his wife, he also had a number of problems with his American in-laws, who resided in Boston. This played a significant role in his decision to resign from his position at Harvard Medical School shortly after the academic year started. He was encouraged by the dean and faculty to withdraw the resignation, and planned to initiate a lecture series again the following year, but a recurrence of his headaches led him to resign again. This time a frustrated dean and faculty accepted the resignation without further efforts to keep him. He remained in private practice in Boston (Cambridge) through 1868, taking some interest in the activities of the medical school. He lectured on "nervous forces" to the Lowell Institute of Boston in 1874. While in Boston he stayed with Louis Agassiz, at his home in Nahant, and he did some of his early rejuvenation experiments in 1875. He made a brief attempt to re-establish himself in practice in London in 1876 and in 1878. In later years he continued corresponding with his Boston friends, including James Jackson Putnam (Harvard's second professor of Neurology) and Louis Agassiz (Professor of Zoology and Geology). He returned to France in 1878 to assume a prestigious professorship in Paris as Claude Bernard's successor.

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SIR DAVID FERRIER (1843-1928) In the 1870s, Ferrier was developing his ideas of localisation of brain function. The antivivisection movement in England had severely curtailed his ability to experiment and his work had been strongly criticised by Dupuy and Goltz. Dupuy, in particular, had noted an American case in which there was no paralysis in spite of damage to the frontal motor centres. He thus became aware of the case of Phineas Gage, the "crowbar man", who had been reported initially by Harlow, and made credible by Bigelow's paper from Harvard. An iron crowbar went through Gage's skull, and despite what must have been severe brain damage, he lived with little motor or sensory disability and no aphasia. Ferrier had noted a personality change in his monkeys after frontal lobe excision and was impressed with the account of Gage's personality change after the accident. Prior to the accident, Gage was a churchgoing, responsible foreman of a railroad gang. Afterwards, he became short-tempered, irresponsible and abusive, and he could not keep a job for any period of time. Ferrier corresponded with his friend Bowditch at Harvard to clarify and define the details of the injury and the precise localisation of the lesions. He felt that some of the drawings of the skull by Harlow were not fully accurate and tried to establish that the brain lesion was purely "prefrontal" and did not affect the motor centres. He had Bowditch send photographs of the skull and then reinterpreted the nature of the lesion, and used this information to defend his ideas about the function of the frontal lobes. He subsequently presented the material Bowditch had sent him in his Goulstonian lectures in 1879 (Ferrier, 1890). He looked to Bowditch and Putnam (who had spent part of his postgraduate time in London) as leaders of American neurology and kept encouraging them to write articles for his new journal Brain, which he had established with other British neurologists, including Hughlings Jackson.

HARVEY CUSHING (1869-1939) Early in his surgical career, Harvey Cushing spent a "wanderjahr" on the continent as was fashionable at that time. In London, he was not impressed

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with the neurosurgery he encountered, and spent most of his time in England with Sherrington. As Professor of Surgery at Harvard, Cushing developed the Peter Bent Brigham Hospital's surgical service to be the prime neurosurgical centre of the world. During World War I, he was sent to Europe where he was a colonel serving with the Harvard Hospital Unit assigned to the British Expeditionary Forces. He harshly criticised a British surgeon and was placed at risk for court martial, until he was transferred to an American command. He subsequently became responsible for all neurosurgery for the American Forces. Returning to Harvard after the war, he continued training most of the most prominent neurosurgeons of the next few decades. One of his students was Hugh Cairns, who returned to London to become one of the leading British neurosurgeons before accepting a prestigious post at Oxford. Cushing carried on an extensive correspondence with Cairns who clearly regarded him as his chief and mentor. His early demise was a great loss for British neurosurgery. Cushing recommended another of his pupils, Geoffrey Jefferson, for an appointment at National Hospital. He had a very close relationship with William Osier, both before and after Osier's Oxford period, and wrote the classic biography of this great physician (Cushing, 1926; Cushing papers). Cushing established a yearly Visiting Professorship at the Peter Bent Brigham Hospital in Boston, and outstanding surgeons from all over the world came there to run his surgical service for one week. A number of senior London surgeons came to Boston in this role, and Cushing served in a similar capacity at some London hospitals. He knew most of the major surgical figures in London at that time but not all of his dealings with them were harmonious. When his Cavendish lecture in 1922 was published in Brain, a number of illustrations were left out and others reproduced badly. This upset him and he had the paper reprinted privately in Boston. Sir Thomas Lewis turned down the publication of the lecture he gave at the Medical Research Society at University College on "hyperactivation of the neurohypophysis is the basis of eclampsia", and he considered this an insult. In 1924 Cushing gave the Cameron Prize lectures which appeared in the London Hospital Gazette (1926).

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His correspondence, most of which is saved at Yale, clearly documents his intimate and friendly relations with the London surgical and neurological community (Cushing papers). He often checked facts with, or asked favours of, Greenfield, Walshe, Russell, Cairns, Henderson, Symonds and others. He contributed copies of his books to the National Hospital Library, and respected the great school of Neurology at Queen Square, which included figures like Holmes, though it is reputed that Holmes did not regard him highly as a neurologist. On at least one occasion Cushing toned down remarks which could be interpreted as critical of the clinical judgment of National Hospital physicians when he noted a specimen of brains there which he felt were examples of clinically treatable tumours. A plaster cast of his hands was bestowed to the Royal College of Surgeons where it was on public display for a long period of time.

SIR CHARLES SYMONDS (1890-1971) Sir Charles Symonds spent a year (1921) in the United States, primarily at John Hopkins in Baltimore with Adolph Meyer. He also spent two weeks with Cushing in the late summer and fall of 1921 before he returned to London to take his initial appointment at Guys Hospital. While in Boston he was assigned to the House Staff team on the Peter Bent Brigham Surgical Service. During rounds one day he suggested that one of the patients that Cushing was planning to operate on (with the diagnosis of a pituitary lesion) had a ruptured cerebral aneurysm. Despite the suggestion, Cushing operated on the patient with a pre-operative diagnosis of pituitary adenoma; at operation it was clear that Symonds' diagnosis was correct. Cushing promptly excused Symonds from further clinical responsibilities, and he was instructed to go to the library and prove that his diagnosis was not a "fluke" (Symonds, 1970). Cushing expected Symonds to review the literature and collect case material to back up his clinical diagnosis. Symonds subsequently produced the classic papers on subarachnoid hemorrhage and aneurysms based on this experience, on cases from the literature, and on his later experience (Symonds, 1923). Cushing referred to subsequent cases of aneurysmal rupture as "Symonds' syndrome".

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It must have been an impressive two weeks for Symonds, who left Cushing's service to return to Baltimore to get married. Cushing frequently chided him that he had never mentioned this reason for leaving and he (Cushing) thought that Symonds had gone to say good-bye to Adolph Meyer. Symonds regarded Cushing as one of the four major figures who influenced him strongly — carrying on a personal correspondence with him over the years and calling him "Chief (Tyler, personal correspondence). Of some interest is the fact that Sir Charles Symonds' forebears had come from Boston, and were English loyalists. With the start of the American Revolution, they had to leave Boston, going to New Brunswick, Canada. We can trace his forebears back five generations, from his father and grandfather, both physicians, to his great grandfather, a barrister, and his great-great grandfather Richard Simmonds, a legislator. He had been given 2,000 acres in New Brunswick by the Crown after resettling from Boston. The family anglicised their name from Simmonds to Symonds when his grandfather returned to London as a surgeon. One of America's greatest neurologists, S. Weir Mitchell, spent summers salmon fishing in the Restigouche River in New Brunswick — in the same area that Sir Charles Symonds' great grandfather practised law. One wonders if they ever met.

STANLEY COBB (1887-1968) Stanley Cobb, a major figure in Boston neurology, received his early training initially with Cushing, but spent time in England in late 1923, after having already established himself on the Harvard faculty as a clinician, teacher and investigator. He started his European year at Queen Square, Flexner having written to Sir Henry Head introducing Cobb. Flexner not only financed Cobb's two years abroad but he also made certain that Cobb met most of the important people in Europe. He spent five and a-half months in London, and was especially impressed with S.A.K. Wilson (1878-1937), serving as his clinical clerk. Wilson was described by Cobb as active and stimulating in the extreme — but inclined to jump too quickly into new ideas at the time. Cobb regarded Queen Square as a wonderful neurological museum. Gordon Holmes, Farquhar Buzzard and James S. Collier also

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impressed him, and he did some neuropathology with Greenfield. While in England he encountered Symonds whom he had known in Meyer's clinic in Baltimore. They both harboured similar feelings about the role and importance of psychiatry and neurology. With the help of the Rockefeller Foundation, Cobb set up a new neurological department at Harvard. This department was remarkable in its orientation and achieved a leadership role in American neurology. Epilepsy research, development of the EEG, and the discovery of Dilantin by his co-workers — Lennox, Gibbs and Merritt — quickly followed. This was the start of scientifically based American neurology. Cobb resigned as head of the department at the Boston City Hospital and subsequently followed his psychiatric interests at the Massachusetts General Hospital. He was made chairman of the search committee for the "new" Professor of the Harvard Department of Neurology (established with a Rockefeller Foundation grant) at the Boston City Hospital. They were encouraged by Conant, the president of Harvard, to get the "best in the world". Cobb turned to Sir Charles Symonds for help in identifying qualified candidates and depended significantly on Sir Charles' assessments. Derek Denny-Brown and Carmichael were the "English candidates", and F.M.R. Walshe was also initially considered. Sir Charles was instrumental in providing the evaluation which led to Denny-Brown's unanimous choice by the committee over other local and international candidates. A local committee of Boston neurologists visited London trying to abort Denny-Brown's acceptance as they strongly favoured the local candidate, Houston Merritt (who was not seriously considered by the committee). Denny-Brown often remarked that this convinced him to accept the professorship.

DEREK DENNY-BROWN (1901-1981) Derek Denny-Brown was born in New Zealand, but came to England on a Beit Fellowship to work with Sherrington at Oxford. He was awarded a doctorate in Philosophy and the Rollerton Prize for his work on postural reflexes.

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In 1928, he received a house appointment at the National Hospital, subsequently rising up through the ranks to Assistant Visiting Physician in 1935. He was also attached to Guys as Registrar and as Assistant Visiting Physician. In 1935, he left Guys to become a neurologist at St. Bartholomew's Hospital. In 1939, he was invited to accept the Chair of Neurology at Harvard Medical School. He visited Boston briefly that summer, and planned to return in the winter. However, the war intervened, and he was called to military service. Dr. Conant, the president of Harvard, was head of the National Research Council under President Roosevelt. He told Mrs. Denny-Brown that when he was in England on an official mission, during the early part of the war (1941), he met with Churchill at Roosevelt's request. Conant was able to inform Churchill of a particularly important contribution that the United States was about to make (the development of radar) which would obviously be a major help to the British war effort. After the meeting, a pleased and grateful Churchill asked if there was any personal favour he could do for him. Conant, aware that Denny-Brown had been elected to the professorship at Harvard (in 1939), but that he was unable to come to the United States because of his wartime obligations, asked Churchill if Denny-Brown could be released so that he could accept this post. Churchill turned to Lord Hawes and told him to "arrange it". Denny-Brown was subsequently called to the War Office and told he was going to be transferred to the United States, thus allowing him to accept Harvard's offer (Tyler, personal communication). He was demobilised in September 1941, retaining his commission but being liable to recall if needed. He was, in fact, recalled in April 1945. Derek Denny-Brown was a member of the Hexagon Club, on the staff at Queen Square, and an established clinician, pathologist and physiologist in London. In Boston he quickly established the Neurological Unit at the Boston City Hospital and Harvard as an important American centre for neurological training. A significant percentage of all the training programs established in the late 1940s and early 1950s, a period of rapid growth of American neurology, were headed by his students. Denny-Brown brought the English tradition and methodology into American neurology. He remarked that Gordon Holmes, his teacher, provided the analytical clinical

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background on which most present-day American clinical neurology flourished. Queen Square and English neurology, rather than French neurology, became the standard on which American neurologists would measure themselves. Denny-Brown stood as an icon for pure "neurology" rather than "neuropsychiatry", which was the American fashion of that era. He helped establish the tradition of experimental research based on clinical neurological problems and used neurophysiology (and neuropathology) as the basic research tools. Many English trainees came to work at Harvard's Neurological Service with Denny-Brown and his associate Ray Adams at the Massachusetts General Hospital, including Richard Chambers, Chris Earl, Roger Bannister, Geoffrey Rushworth, John Walton, and others. Most of the British neurologists would visit Boston when they came to the Americas. I met Lord Brain, Macdonald Critchley, F.M.R. Walshe and others when they visited Boston and the Neurological Unit. Denny-Brown also encouraged his residents to go to Queen Square for the unique clinical experience it provided. I was fortunate to be the first of Denny-Brown's residents to spend a year at the Neurological Institute. It was there that I met Holmes, Symonds, Walshe, Purves-Stewart, Carmichael, Critchley, McAlpine and many other remarkable clinicians. Denny-Brown returned to London to give the Croonian lectures in 1960 and the Sherrington memorial lecture in 1962. He was especially proud that his old chief, Gordon Holmes, came up from Suffolk to London for one of his former lectures. On the occasion that I visited Gordon Holmes in Suffolk, I asked him which of his students he was most proud of—being sure he would pick my chief Denny-Brown. Gordon Holmes' choice was O. Langworthy Hopkins — a fact that I could never relate to Denny-Brown!

NORMAN GESCHWIND (1926-1984) Norman Geschwind was the successor to Derek Denny-Brown as the James Jackson Putnam Professor of Neurology at Harvard Medical School. He had spent his early years of training in neurology at National Hospital,

302 H. R. Tyler

Queen Square, with the help of Mosley and Public Health fellowships. He was especially involved with Ian Simpson and, like many others, came under the spell of Sir Charles Symonds' whose teaching concerning aphasic patients he learned to appreciate in retrospect. There was also a large exposure to temporal lobe epilepsy with Denis Williams which was an area of major interest to him. He subsequently returned to do his "chief residency" with Denny-Brown in Boston. His early ideas on Disconnection Theory (which led the explosion in research on aphasia) were initiated while at Queen Square. He returned to Boston, continuing the tradition of Englishoriented neurological training. His roots in English neurology were always apparent, and he had many friends and collaborators in England. He trained Peter Behan (now in Glasgow, who had traced his early interest in neuroimmunology to Geschwind's influence. In 1982, Geschwind gave an address to the Royal Society of London on disorders of attention. Many other Boston neurologists have spent time at Queen Square bringing back the experiences and knowledge gained with Walshe, Symonds, Carmichael, Greenfield, Critchley and, more recently, Marsden. Similarly, Denny-Brown and Ray Adams attracted a number of English physicians who did 1-2 years of research with them at formative stages of their careers, and it has truly been a two-way street. References 1. Brown-Sequard, C.E. (1854). Experimental Research Applied to Physiology and Pathology. Balliere, New York. 2. Carmichael, A. (1833). A Memoir of the Life and Philosophy of Spurzheim. Dublin, F. Wakerman. 3. Cushing, H.C. (1926). The Life of Sir William Osier. Oxford Press, Claredon. 4. Harvey William Cushing Papers at the Yale University Library; Series I, Folder 1367, Reel 50, Box 62 Series II, 671. 5. Denny-Brown, D. Box 1, Personal Biographical Sketch Collection of Papers. Francis A. Countway Medical Library, Harvard Medical School, Boston, MA. 6. Ferrier, D. Letters to Bowditch. Rare Book Library, Francis A. Countway Medical Library, Harvard Medical School, Boston, MA. 7. Ferrier, D. (1879). The Localisation of Cerebral Disease. Being the Goulstonian Lectures of the Royal College of Physicians. NY, CP. Putnam's Son.

The Influence of British Neurology on Harvard Neurology and Vice Versa 303 8. Ferrier, D. (1890). The Croonian Lectures on Cerebral Localisation. Smith, Elder and Co. 9. Geschwind, N. (1982). Disorders of attention: A frontier in neuropsychology. Trans. R. Soc. London, Ser B 298, 173-185. 10. Meyer, A. Letters, John Hopkins Medical Archives, Baltimore, Maryland. 11. Olmstead, J.M.D. (1946). Charles Edouard Brown-Sequard. Baltimore, Johns Hopkins Press. 12. Schachter, S.C. and Devinsky, O. (1997). Behavioral Neurology and the Legacy of Norman Geschwind. Lippincott-Raven. 13. Symonds, C.P. (1923). Contributions to the clinical study of intracranial aneurysm. Guys Hospital Reports 73, 139-158. 14. Symonds, C.P. (1970). Studies in Neurology. Oxford. 15. Tyler, H.R., Tyler, K.L. (1970). Charles Edouard Brown-Sequard, Professor of Physiology and Pathology of the Nervous System at Harvard Medical School. Neurology 34, 1231-1236. 16. White, B.U. (1984). Stanley Cobb, The Francis A. Countway Library of Medicine. 17. Gowers, W.R. (1960). Queen Square and the National Hospital 1860-1960. Edward Arnold.

INDEX Abercrombie, John 227 abiotrophy 135, 136, 147 ABO 154 abscess 172-175 acidosis 160, 163 acoustic fibroma 212 acoustic neurofibroma 210 acoustic neuromata 215 acquired dyslexia 63, 65-67 acquired illiteracy 59 adamantinoma 210, 211 Adams, Hume 246, 248 Adams, Ray 301,302 Adrian, Edgar 5 Adson 205 aetiology 154, 159 Agassiz, Louis 294 albumin binding 160, 163 albumin 160, 162, 163 alcohol injection into the Gasserian ganglion 79 alcohol 145 alienist 52 ambidextrality 55, 58 America 4 American Neurological Association (ANA) 283 An Essay on the Shaking Palsy 131, 146 ANA's history 284

anatomical basis of dyslexia 71 word-blindness 65 anatomical differences 54 anti-Rh immunisation 154 antiseptic 50 aphasia 47, 51-3,57 apoptosis 136, 142 architecture of the network 52 Archives of Neurology 237 Armour, Donald 200, 205, 210, 218 arteriosclerotic parkinsonism 144, 145, 150 arteriosclerotic pseudoparkinsonism 145 associationist 47, 48 athetoid cerebral palsy 158,163 Australia 4 automatic speech 51,53 Baillarger 32, 45 Ballance, Sir Charles 5, 199, 200, 205-207, 209, 213 Bannister, Sir Roger 143, 301 basal ganglia 47, 139, 141, 148, 149 Bastian 31,33,34,45 Beck, Elizabeth 243,248 Behan, Peter 302 Bell, Sir Charles 134 Bennett, Hughes 170 Bevan-Lewis, William 232, 234

305

306

Index

Bielschowsky 229 Bigelow, H.J. 293 Biggart, John Henry 245 bilirubin conjugation 160 inhibition 160 bilirubin levels 159,162,164 Bismarck 2 Blackwood, William 248 Blake, William 135 Bland, John 242 blepharospasm 142, 148 blood brain barrier 160 blue light 162 Bolton, Joseph Shaw 238 Boston City Hospital Boston Phrenological Society 292 Boston 291-294, 296-302 Boswell, James 134 boutons terminaux 2 Bowditch, H. 293, 295, 302 Boyle, Robert 143 brain from a dyslexic patient 73 brain scar 176 brain tumour 215 brain 137,139,147,227,229,230,232-234, 238,239,242-246,251,252 Brain 133, 137, 138, 141, 144, 147, 148, 150, 227, 232, 233, 238, 245, 250-252 Brain, Lord 301 Brain, Russell 3 breast-fed infant 160 Breughel the Elder, Pieter 135 Brierley, Jim 244 Bright, Richard 227 British Journal of Neurology 139 British Medical Association (BMA) 284 British Neuropathological Society (BNS) 247 British neurosurgeons 209, 214 Broca 204

Brown Institute 177 Brown-Sequard 292 Bucknill, John 233 Buzzard, Farquhar 239, 298 Cairns, Hugh 197,215,239,241,242, 248, 296 Cajal 228,229 Cambridge University Press 6 Cambridge 2-7 Canada 4 Carlyle 209 Carmichael 299, 301, 302 Carswell, Robert 227 Cartesian theatre 56 category-specific semantic disorders 38, 45 Cavanagh, John 244, 248 Central Veterinary Laboratory 248 centres 52 cerebal localisation 3 cerebellum 47, 48, 89 cerebral abscess 172,173,175 cerebral cortex 47-52 cerebral localisation of function 2 Chambers, Richard 301 Charcot, Jean-Martin 133, 176 Cheyne, John 227 Cheyne, Watson 201 Chiasserini 217 chimpanzees 54 chorea minor 129 choreo-athetosis 153 Clarendon Press 5 Claybury Asylum 234 clinical examination 93 clinical features 157 clinical syndrome 157 Clouston, Thomas 233 Cobb, Stanley 298,303 Collier, James S. 298

Index Columbia University 3 complementary specialisation 47, 53, 54 Complex I 143, 149 Conant 299, 300 congenital word-blindness 60,66, 69,75,76 congenital 59, 60, 63, 66, 69-71, 75, 76 congenitally defective 67 conjunctivae 153 consciousness 48, 55, 56 continent 48 Coombs test 154 cordotomy 210, 212 cornu ammonis 157,159 Corsellis, Nick 245 cortex 3, 5 cortical functions 101 cortical localisation of function 47 craniotomy 172, 176 Creed 5 Creutzfeldt-Jakob disease (CJD) 248 Crichton-Browne, James 230, 231,233, 251 Crigler-Najj er disease 161 Critchley, Macdonald 144, 145, 301 critical serum level 163 Crome, Len 245 Croonian lecture 2, 3, 139, 293, 301, 303 crowbar man 295 Cullen 130, 146 Cushing, Harvey 3, 5, 174, 177, 178, 198, 199, 203, 205, 213, 217, 239, 295' Daniel, Peter 244 Dawson, James 238 de la Tourette, Gilles 134 deafness 158, 163 death 153, 155, 158, 162, 163 deep dyslexia 40 dehydration 158, 160, 163 Denny-Brown, Derek 4, 5, 142, 149, 299-301

307

Descartes 5 Dermoid 172, 173 developmental dyslexia 59, 60, 62, 65-67, 71,73,74 diagram makers 35, 36 Dimsdale, Helen 133 disconnection theory 302 distributed systems 51 Dott, Norman 197,215,239 dyslexia 59-67,70-76 dystonia 142 Earl, Chris 301 early neonatal haemorrhage 160 Eastbourne 6 Eccles 4, 5 Eccles, Jack 6 educational potential 55 electrical treatment 78, 79, 85 Elliotson 133, 146 Elsberg 205 emotion 48 empirical associationist 48 encephalitis lethargica 134 epilepsy 169, 176, 177 epileptic attack 50 equipotent 52 equipotentiality 49 erythroblastosis foetalis 154,166 erythrocyte life span 159 essential tremor 142, 143, 145, 150 ethnic groups 161 experimental animals 201 extrapyramidal system 13 9 faculty of speech 3 2 Falconer, Murray 243 familial 61,62,68 Ferrier 169, 170, 174, 176, 201, 204, 208, 209, 295, 302, 303

308

Index

Ferrier, David 2, 5, 232, 233, 239 Findley 143, 150 floor of the 4th ventricle 157 Florey 4 Foerster, Otfrid 216 foetal haemoglobin 159 foeto-maternal isoimmunisation 154 Forbes, Alexander 4 Foster, J.B. 140 Foster, Sir Michael 3 Fox, Edward 234 Frankel 143, 149 Frazier 203, 205 Fritsch 204 Fulton 4 functional imaging studies 41,44 functional imaging 52, 53 functional localisation 47, 51 Gage, Phineas 295 Gall, Franz 291 gastric crises 210,212 general paralysis of the insane (GPI) 229 Geschwind, Norman 301, 303 gestational age 163 Gibb, W.R.G. 142,299 Gifford lectures 6 Gilbert's disease 161 Glasgow Royal Infirmary 174, 175 glucose 6-phosphate dehydrogenase (G6PD) deficiency 161 glucuronyl transferase activity 160 glucuronyl transferase system 163 Godlee, Sir Rickman 169, 170, 239 golden roll 203 Golgi 2 Goltz 2,295 Goulstonian lectures 293 Gowers, Sir William Richard 135

Gowry 133, 146 Granit, Ragnar 4 Green 133, 146 Greenfield, J.G. 93, 239, 253, 297, 299, 302 Gregg, Alan 4 Gull, William Withie 172, 173, 178 haemolytic disease of the newborn 154, 159, 161, 164-166 Hall, Marshall 133 Halliday 143, 150 Harris, Wilfred 77-83, 85 Harvard Department of Neurology 299 Harvard Medical School 292-294, 300-303 Hatfield, Frances Margaret 43 hatlessness 55 Haymaker, Webb 237,240 head injuries 54 Head, Sir Henry 31,35,43,45,46,88, 89, 298 Helmholtz 171 hemisphere 47, 49-55, 57 hemispheric differences 54, 55 Henderson 169, 297 hereditary 61,62,68,75 Hexagon Club 300 higher mental functions 52 Hill, A.V. 5 Hinshelwood, James 59, 68, 69, 74 Hitzig 203,204 Holman 4 Holmes, Sir Gordon 137, 238, 297, 298, 300, 301 Homen 139, 148 Hooper, Robert 227 Horsley, Sir Victor 170, 176, 177, 179, 184, 187, 191, 194, 195, 197, 199,203, 204, 214, 238

Index Hortega 228, 229 Hospital for Epilepsy and Paralysis, Regent's Park 239 hospitality 209 hydrops foetalis 153 hypoglycaemia 160, 163 hypothermia 160 hypoxia 160, 163

Keith 198,204,205,208 kemicterus of prematurity 156,158 deaths from 158 kemicterus 153 prevention of 163 Kidd, Michael 245 Kobcke 217 Koch 170

icterus gravis neonatorum 153, 165 imperception 53, 57 incidence 158, 160, 166 inhibition 5 Innes, J.R.M. 246 Institute of Neurology, Queen Square 197, 211,217,218 Institute of Psychiatry 243, 244 international affairs 284 International Congress of Neuropathology 246 International Society of Neuropathology 247 intracranial tumour 174, 215 Ipswich 5, 6 IQ 163

la gaucherie cerebrale 50 La Peyronie 173 Langley, J.N. 2 lateralisation 71, 73 law of symmetry 50 Learmonth 200,206,215 Lees, A.J. 142 left cerebral dominance 50, 53 left hemisphere 49, 50, 52, 53, 57 Lennox 299 letter-word-, and mind-blindness 64 Lewy bodies 142 Liddell 5 Limmaeus 130 lipid-soluble bilirubin 159 Lister 169, 170, 174 liver transferases 161 Liverpool 3, 4 localisation of brain function 295 localisation 47, 49-53, 57, 58 localisationists 52, 53 Locke, John 129 Locock 134 London Hospital 241, 243 Louis, Elan D. 133 lumbar puncture 171 Lumsden, Charles 245 lunatic asylums 229, 231, 232

Jackson, Hughlings 31-33,35,45,137,169171, 174, 176, 203, 204, 233, 293, 295 jaundice 153, 155-166 Jefferson, Sir Geoffrey 133, 146, 177, 178, 197-200, 203, 205, 206, 208, 209, 213— 218,239,296 Jenner, Peter 143 Jewesbury 146 Johnson, Samuel 134 Joseph Shaw Bolton 238 Journal of Neurology, Neurosurgery and Psychiatry 140, 141 Kayser-Fleischer ring 139

309

Macewen, Sir William 174, 197, 199, 203, 204, 214, 239

310

Index

Magendie 171 Maida Vale Hospital 78 Major, Herbert 232 Mammalian Physiology; A Course of Practical Exercises 4 Man on His Nature 6 Mantell, Gideon 132 Manual of Diseases of the Nervous System 135, 147 march 50 Marchi 229, 236 Marsden, Charles David 140, 141 materialist localisationist 48 Maudsley Hospital 237, 243, 244 McAlpine 301 McDonald, W.I. 145 McGill University 5 McKenzie, Kenneth 198 McMenemey, W.H. 240 Medical College of Virginia 293 Medical Research Council of Britain 4 medulla 157, 163 Meige, Henri 135 meningioma 214 mental functions 47,51-53,56 mental 47,48,51-53,56 Merritt 299 metallic impregnation methods 229 Meyer, Alfred 237,244 midbrain 157 migrainous neuralgia 81, 82, 85 Military Hospital for Head Injuries 242 Miller 4 miming 51 modern phrenology 53 monitoring 154, 161-163 Morris 133, 146 mortality 153-156, 158, 163, 166 Morvan's chorea 140 Mott, Frederick 233, 234, 236, 252

Mount Auburn Cemetery 292 movement disorders 129,135,137,140-143, 149, 150 MPTP 142, 143 mucous membranes 153 muscle reflexes 5 muscle relaxation 5 muscle spindles 2 myoclonus 140, 142, 143, 148, 150 Nadas 130 National CJD Surveillance Centre 248, 249 National Hospital for Epilepsy and Paralysis 169 National Hospital for Nervous Diseases, Maida Vale 245 National Hospital for the Paralysed and Epileptic, Queen Square 238, 239 National Hospital 293, 296, 297, 300, 301, 303 National Hospital, Queen Square 210 neglectful 50 neuritis and neuralgia 79, 81, 82, 85 neuroanatomical lesions 73 neurohistology 158 neuroimmunology 302 Neurological Unit 300, 301 neurology 197, 202, 204, 260, 210, 211, 217,218 neuronal cell damage 158 Neuropathogenesis Unit 248 Neuropathological Club 246 Neuropathology and Applied Neurobiology 247 neuropathology 227-229,231,232, 238-241, 243-250, 253 neurophysiology 88 neurosurgery 197, 199, 210, 217, 218 neurosurgical interventions 213 neurosurgical work 214

Index New Zealand 4 newborn infant's skin 162 irradiation of 162 Newton's Principia 3 Nightingale, Florence 171 Nissl 229,237,249 Nobel Prize 4, 5 Norman, Ronald 245 novobiocin 160, 161, 165 optic thalamus 99, 102 Ormerod 139, 147 Osier, Sir William 4, 176, 296, 302 Oxford 4 - 6 Paget 133, 146, 293 paragrammatism 35, 37, 38, 45 parallel distributed network 52 paralysis agitans 133-137,146 paraplegia 175 parietal endothelioma 210 Parkinson, James 130, 132, 133, 146 Pasteur 169, 170 pathology of superiority 72 Pearce, John 143 Pechy 129 Penfield, Wilder 6 Pennybacker, Joe 217 perspex icterometer 162,165 Peter Bent Brigham Hospital 296 phenobarbitone 163 phototherapy 161, 162, 163 phrenology 49, 53, 56, 292 physical 51,52 physiological function 51 physiological jaundice 159, 163, 165 Physiological Society 2 physiological 153, 156, 159, 163, 165 physiology 2-6 phytomenadione 160

311

pineal gland 56 pituitary adenomata 177 planum temporale 71 plasma unconjugated bilirubin 161 critical level of 161 poetry 4, 6 post-encephalitic parkinsonism 134 post-mortem findings 153,158 Potter, John 217 pregnane-3a-2(3-diol 161 premature babies 155-158, 160, 162, 163 premature baby service 155 premature infant 155, 165 Princeton 4 Professor of Physiology and Pathology of the Nervous System 294, 303 pure alexia 40 Purkinje 2 Purves-Stewart 133, 301 Putnam, James Jackson 294, 301 Queen Square 293, 297, 298, 300-303 Quinn, Niall 142, 145 Ramon y Cajal 2 Rawling, Bathe 200,213,215 Rede lecture at Cambridge 6 reflex 48, 56 replacement blood transfusion 154,161,163 Reynolds 133, 146 Rh antibodies 154 Rhesus 154, 164, 166 Rhodes Scholars 4 Rio-Hortega 6 Robertson, William Ford 233 Rockefeller Foundation 4, 299 Rogers, Daniel 143 Rontgen 171 Rose, F. Clifford 143, 145 Ross, Patterson 197, 198, 215

312

Index

Rowntree 133, 146 Royal College of Surgeons of England 6, 197 Royal Society of Medicine 285, 286, 288, 289 Royal Society 2, 4 Rubinstein, Lucien 241,242 rubral tremor 137 Runwell Hospital 245 Rushworth, Geoffrey 301 Russell, Dorothy 241, 242, 246, 251, 297 salaam convulsion 134 Salpetriere Hospital 134 Sanders 133, 146 Sargent 200-202, 206, 210, 211, 214, 218 Schafer 204,205,208 Schapira, A.H.V. 143 science 205, 209 scientific research 4 Section of Neurology 285, 286, 288, 289 semantic representation 39 sensori-motor control 48 sensory aphasia 33 sensory disturbances 99, 100, 104 serous meningitis 213 servo 141 Sherrington, Charles 1-6, 204, 205, 236, 296, 299, 301 Silliman lecture 3 Simpson, Ian 302 single self 56 skull defects 174 Smith, Elliot 204,208 Smith, Walter 246 Society of British Neurological Surgeons (SBNS) 197 Society of British Neurological Surgeons 239 Society of Neurological Surgeons 199, 202, 200, 206

soul 48 Southmead Hospital, Bristol 155,156 Souttar 200, 206 spastic diplegia 162 spastic paraplegia 153 speech therapy for aphasia 42 Spencer, Stanley 135 Spielmeyer, Walter 243 spinal cord 2, 3, 5, 48, 174, 175 spinal injuries 88 Spurzheim, Gaspar 291,292,302 St. Mary's Hospital 78 St. Thomas' Hospital 2 Stanford 4 Stern, Gerald 143 Stern, Jan 245 Strachey, Lytton 171,178 striatal toe 133 Strich, Sabina 244 Strumpell 139, 148 subarachnoid hemorrhage and aneurysms 297 subdural haematoma 174,175 substantia nigra 140,142,143,149 subthalamic nucleus 157,158 sulphasoxazole 160 sunlight 162 suprapituitary tumour 210, 211 surface dyslexia 40, 46 surgical interference 215 Swallow, M. 143 Sydenham, Thomas 129 symbolic formulation and expression 35 Symonds 297-299, 301-303 Symonds' syndrome 297 synapse 3 synaptic mechanisms 5 Synkavit 160, 166 synthetic vitamin K (Synkavit) 160

Index Taylor, Julian 214,215 Textbook of Physiology 3 thalamus 88, 89, 157 The Endeavour of Jean Fernel 6 The Facial Neuralgias 82, 85 The Integrative Action of the Nervous System 3 The Morphology of the Brachial Plexus 83, 85 The Neurology of Psychotic Speech 37, 45 The Reflex Activity of the Spinal Cord 5 the Robert Wartenburg lecture 141 third frontal convolution 49, 51 Thomas, P.K. 248 Thompson 133, 146 Tingey,A.H. 245 Tomlinson, Bernard 245 Tonnis, W. 216, 217 Tooth, Howard 239 topographical agnosia 53 trigeminal neuralgia 79, 80, 82, 85, 177 Trimble, Michael 143 Trotter, Wilfred 169,170,200,202,206,214 tuberculoma 176 tumour 169, 170, 174-176 Turnbull, Hubert 238 unconjugated bilirubin 159-163 inhibition of 160 toxicity of 160 transport of 160 unconjugated hyperbilirubinaemia 159, 160 University of British Columbia 7 University of Edinburgh 6 University of Toronto 3 variant CJD 249 veterinary 246, 248 Virchow, Rudolf 2,228

313

vital 48 vitamin K analogues 160,166 volition 48 voluntary speech 51 Wakeley 200 Walshe, F.M.R. 3,297,299,301,302 Walton, John 301 War Injury and Shock 79 Warren Anatomical Museum 292 Warren, John 292 water-soluble bilirubin glucuronides 159 water-soluble pyrroles 162 Waynflete chair 4 Wesbrook, Frank 7 West Riding Lunatic Asylum Medical Reports 233,251,252 West Riding Lunatic Asylum 230-233, 251,252 West, W.J. 134 Westphal 139, 148 wet brains 157,158 Williams, Denis 302 Wilson, Kinnier 93, 94, 129, 137-140, 238 Wilson, S.A.K. 298 word-blindness and visual memory 60, 64, 74,75 word-blindness 33, 59, 60, 63-67, 69, 74-76 word-deafness 33 World War I 54 wortblindheit 63, 74 writers' cramp 142 Yale University 3 yellow staining 153,156,157 Yorkshire 5 Young, J.Z. 248