Editorial introductions
Current Opinion in Neurology was launched in 1988. It is one of a successful series of review journals whose unique format is designed to provide a systematic and critical assessment of the literature as presented in the many primary journals. The field of neurology is divided into 14 sections that are reviewed once a year. Each section is assigned a Section Editor, a leading authority in the area, who identifies the most important topics at that time. Here we are pleased to introduce the Journal’s Section Editors for this issue.
Section Editors Peter Goadsby
Peter Goadsby obtained his basic medical degree and training at the University of New South Wales, Australia. His neurology training was done under the supervision of Professor James W. Lance in Sydney. After postdoctoral work in New York with Don Reis at Cornell, with Jacques Seylaz in Paris and post-graduate neurology training at Queen Square in London working with late Professors C David Marsden and W Ian McDonald, he returned to the University of New South Wales, and the Prince of Wales Hospital, Sydney as a consultant neurologist and was promoted to Associate Professor. He was appointed a Wellcome Senior Research Fellow at the Institute of Neurology, University College London in 1995, and this was renewed in 2000. He was Professor of Clinical Neurology and Honorary Consultant Neurologist at the National Hospital for Neurology and Neurosurgery, Queen Square, and the Hospital for Sick Children, Great Ormond St, London. He is now Professor of Neurology in the Department of Neurology, University of California, San Francisco His major research interests are in the basic mechanisms of head pain in both experimental settings and in the clinical context of headache. The work of the Headache Group involves human imaging and electrophysiological studies in primary
headache, as well as experimental studies of trigeminovascular nociception. We aim to understand what parts of the brain drive and modulate headache syndromes, and how those might be modified by treatment. Wendy Ziai
Dr Wendy Ziai is Assistant Professor in the Department of Neurology at the Johns Hopkins University in Baltimore, Maryland. She received her medical degree at Queen’s University in Canada and completed residency training in Neurology at the University of Calgary. She came to the Johns Hopkins Hospital for a fellowship in Neurocritical Care where she was appointed then after in the Departments of Neurology, Anesthesiology and Critical Care Medicine. She also obtained a Masters in Public Health at the Johns Hopkins Bloomberg School of Public Health. Dr Ziai’s clinical and research activities encompass several aspects of acute neurological disease including central nervous system and nosocomial infections in the Neurocritical Care Unit, and treatments for intracerebral and in particular intraventricular hemorrhage. She has published a number of reviews and book chapters on the critical care approach to central nervous system infection and is currently involved in the national ‘‘Positive Deviance’’ MRSA Prevention Partnership, committed to prevention of multi-drug resistant microbial infections in American hospitals. Dr Ziai serves on the Board of Directors of the Neurocritical Care Society since November 2006. She is involved as a member of several committees of an international study of clot lysis for intraventricular hemorrhage using intraventricular rt-PA. The Johns Hopkins Hospital is a major referral center for investigation and management of encephalitis. The Encephalitis Center is dedicated to providing specialty care and diagnosis for patients with acute inflammatory and infectious conditions of the central nervous system and is currently developing experimental neuroprotective strategies for use in clinical trials.
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Editorial introductions
Renaud Du Pasquier
After medical studies and residency performed at the University Hospital of Geneva, Renaud A. Du Pasquier, M.D., obtained his Swiss board certification in Internal Medicine and Neurology. In 1999, he moved to Boston where he made a post-doc in neuroimmunology/neurovirology at the Beth Israel Deaconess Medical Center, Harvard Medical School. Under the mentorship of Dr Igor Koralnik and Dr Norman Letvin, head of the Division of Viral Pathogenesis, he studied the cellular immune response against JC virus (JCV), the
agent of progressive multifocal leukoencephalopathy (PML). His research demonstrated the importance of JCV-specific CD8R T lymphocytes in containing the virus and conditioning the prognosis of PML. In 2004, he moved to the Lausanne University Hospital (Centre Hospitalier Universitaire Vaudois, CHUV) where he established his laboratory in a joint-venture between the Divisions of Neurology and Immunology. As an assistant professor, he is currently pursuing his research on PML, in particular in the context of the cases associated with natalizumab in multiple sclerosis patients, but also the possible role of Epstein-Barr as a trigger of multiple sclerosis, or still the new features of HIV-associated cognitive disorders in the highly active anti-retroviral therapies era. The clinical part of his activity is devoted to patients with inflammatory diseases of the nervous system. It is thank to the commitment of these patients that Renaud A. Du Pasquier and his colleagues can gather samples for their research.
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EDITORIAL
A promenade along the stream of demyelination Renaud A. Du Pasquier Service of Neurology, Department of Clinical Neurosciences and Service of Immunology, Department of Medicine, University Hospital of Lausanne, Lausanne, Switzerland Correspondence to Renaud A. Du Pasquier, MD, Assistant Professor, Service of Neurology, Department of Clinical Neurosciences and Service of Immunology, Department of Medicine, University Hospital of Lausanne (CHUV), 1011 Lausanne, Switzerland E-mail:
[email protected] Current Opinion in Neurology 2010, 23:203–204
To try to decipher the pathogenesis of multiple sclerosis (MS) is a little like trying to catch a trout with bare hands in a stream: each time one thinks that one has gotten it, it vanishes, and despite the fact that there are many fishermen (and women) in this stream, the trout is very slippery and does not surrender. Indeed, with the cause of MS still not having been discovered, this field of research is regularly subject to bursts of enthusiasm followed by some disappointment when things turn out to be more complicated than initially thought. The role of cytokines in MS is particularly illustrative of this situation. Such as vividly pointed out by Codarri et al. (pp. 000–000) in this issue of Current Opinion in Neurology, many promising discoveries pertaining to the role of cytokines in experimental autoimmune encephalomyelitis, an animal model of MS, have been ‘lost in translation’ when applied to humans. Is that to say that animal research is useless in the field of MS? Certainly not. As emphasized by these authors, it rather calls for a very careful preclinical evaluation of candidate treatments, such as cytokine-interfering drugs, before introducing them in clinical trials. Another important take-home message of their review is that negative findings should absolutely be published swiftly since they can prevent other researchers from wasting time and money in useless experiments. In addition to allowing establishment of the diagnosis of MS even after a single relapse, that is at the stage of clinically isolated syndrome [1], MRI is a particularly suitable and useful tool to gain an insight into the physiopathology of MS. In this issue, Filippi and Rocca (pp. 000–000) review the recent developments of this technique and demonstrate that ‘novel MR approaches highlight previously unrecognized or neglected aspects of MS pathophysiology’. One can add that the combination of ‘wet lab’ research and MRI analyses is an approach that will be increasingly used to study the pathogenesis of MS [2]. 1350-7540 ß 2010 Wolters Kluwer Health | Lippincott Williams & Wilkins
Although it is still in its research stages, stem cell transplantation in MS offers hope for MS patients. Whereas autologous hematopoietic stem cell transplantation addresses ‘only’ the inflammatory component of MS, mesenchymal stem cells not only have immunomodulatory properties but also provide a neuroprotective effect. Interestingly, this effect does not seem to be due to transdifferentiation of mesenchymal stem cells into neurons, but rather to bystander effects, such as rescuing neurons from apoptosis, promoting neurite outgrowth, and producing several trophic factors. These complex issues are comprehensively reviewed by Uccelli and Mancardi (pp. 000–000). In the arsenal of new immunomodulatory therapies, monoclonal antibodies occupy a place of choice. In a few years, these drugs have brought substantial improvement for patients with auto-immune diseases including rheumatoid arthritis, psoriasis, Crohn’s disease, and, of course, MS. Each monoclonal antibody targets a precise step in the broad cascade of the immune response. Thus, based on this knowledge, it was assumed that one would easily predict their putative side effects. Yet, after some years of use, it has become clear that treatment with monoclonal antibodies can lead to unexpected side effects. In this issue, Lysandropoulos and Du Pasquier (pp. 000–000) focus on the demyelinating side effects of some monoclonal antibodies. In addition to trying to sort out facts from hypotheses, the authors emphasize the need for neurologists to become familiar with this new field, located at the interface of neurology, immunology and infectious diseases. Even if MS is the most frequent cause of demyelination, there is a very broad list of other causes, among which are leukodystrophies with late disease onset. It is probably reasonable to state that most neurologists are only poorly familiar with this group of diseases. Yet, some leukodystrophies can pose difficult differential diagnosis with MS, in particular the rare but important to know adultonset autosomal dominant leukodystrophy. It is the merit of Ko¨hler (pp. 000–000) to provide a synthetic and updated review of this group of heterogeneous diseases and to show how most recent therapies such as enzyme replacement or cell-based therapies could change their prognosis. Last but not least, we must not forget that myelin is a major component of the peripheral nervous system. DOI:10.1097/WCO.0b013e328339d15d
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204 Demyelinating diseases
Tracy and Dyck (pp. 000–000) review the demyelinating polyneuropathies, focusing on the investigations and treatments of chronic inflammatory demyelinating polyradiculoneuropathies. In this field too, new treatments such as monoclonal antibodies are proposed, but their cost–benefit must be cautiously weighted.
along a stream in which evanescent but fascinating fishes swim together.
1
Polman CH, Reingold SC, Edan G, et al. Diagnostic criteria for multiple sclerosis: 2005 revisions to the ‘McDonald Criteria’. Ann Neurol 2005; 58:840–846.
It is our hope that this issue of Current Opinion in Neurology will be of interest to the reader and will guide his/her way
2
Zivadinov R, Zorzon M, Weinstock-Guttman B, et al. Epstein–Barr virus is associated with gray matter atrophy in multiple sclerosis. J Neurol Neurosurg Psychiatry 2009; 80:620–625.
References
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Cytokine networks in multiple sclerosis: lost in translation Laura Codarri, Adriano Fontana and Burkhard Becher Department of Pathology, Institute of Experimental Immunology, University Hospital of Zurich, Zurich, Switzerland Correspondence to Professor Burkhard Becher, Department of Pathology, Institute of Experimental Immunology, University Hospital of Zurich, Zurich, Switzerland Tel: +41446353701; e-mail:
[email protected] Current Opinion in Neurology 2010, 23:205–211
Purpose of review This review will discuss aspects of cytokine networks in neuroinflammatory diseases and attempt to provide some explanation for our failures and successes in translating preclinical data to benefit patients with multiple sclerosis (MS). We will discuss innate cytokines such as tumor necrosis factor a and interferon (IFN) b and will then go on to cover recent findings on the role of interleukin-23 and the so-called TH17 cells and how they are implicated in the pathogenesis of neuroinflammation. Recent findings Even though IFN-b has been used for the treatment of MS for many years, it is only recently that the mechanistic underpinnings of the IFN-b-mediated immune modulation was discovered in preclinical models. The timeline is at odds with the idea that preclinical data should shape the design of therapeutic strategies in the clinic. Conversely, the discovery of the so-called TH17 cells and their association with neuroinflammation has broken the dogma that IFN-g-producing TH1 cells have the exclusive capacity to invade and destroy the central nervous system tissue. So why then did a clinical trial targeting the TH17-promoting cytokine interleukin-23 fail? Summary Preclinical studies using the animal models for MS have yielded promising results, but unfortunately the translation into the clinic is often disappointing. The reason for this may be the complex nature of the pathogenesis of autoimmune neuroinflammation, but more often an oversimplified interpretation of preclinical observations appears to hinder our progress. Keywords cytokines, experimental autoimmune encephalomyelitis, innate immunity, multiple sclerosis, T helper cells Curr Opin Neurol 23:205–211 ß 2010 Wolters Kluwer Health | Lippincott Williams & Wilkins 1350-7540
Introduction Multiple sclerosis (MS) is widely held to be mediated by the action of inflammatory lymphocytes, which invade the central nervous system (CNS) to initiate tissue damage and neurological impairment. The cause remains unresolved, but autoimmune-driven processes are believed to initiate/ maintain the disease. It is clear that a major contributor of inflammation is the fact that activated leukocytes invade the ‘tissue’ and deliver soluble mediators such as vasoactive substances and cytokines. Cytokines are polypeptides comprising a large and heterogeneous family of soluble factors produced by different cell types. They are predominantly produced by immune cells, but many other cell types including cells resident in the nervous system stroma are also able to secrete cytokines. During inflammation, cytokines permit cells to communicate between one another and to instruct cell development and function. Antigen-presenting cells (APCs) are key players during both the initiation and progression of an inflammatory 1350-7540 ß 2010 Wolters Kluwer Health | Lippincott Williams & Wilkins
autoimmune response as seen in MS. APCs not only provide the T cells with their cognate antigen but also determine the faith of T cells and the ensuing immune response by creating a particular cytokine milieu. T cells can then in turn independently maintain their designated function and/or polarization to a large extent through cytokines in an autocrine manner. Recent advances in the characterization of pathogenic T cells led to the identification of different cytokine signatures associated with T-cell subsets. Researchers have made much progress in understanding these complex communication networks and are in the process of translating this ‘molecular language’ into our language. Specifically interfering with commands such as ‘kill’ or ‘destroy’ and to instead instruct ‘tolerate’ or ‘stop’ is the goal of therapeutic strategies that modulate cytokine-mediated communication. Cytokines are fundamental in the pathogenesis of inflammatory diseases such as MS, and to unravel the roles of individual cytokines in this disease we rely on experimental models. When we use the term preclinical here, we mean primarily the animal model for MS, experimental autoimmune encephalomyelitis DOI:10.1097/WCO.0b013e3283391feb
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(EAE), and we have picked some examples, which outline the complex networks and the challenges of translation, rather than providing an all-encompassing overview of the state-of-the-art.
Innate immunity and ‘early’ cytokines Although autoimmune diseases are obviously mediated by the actions of adaptive immune cells targeting self-antigen in tissues, the innate immune system plays a key role in the initiation and propagation of tissue inflammation. Here, we will discuss the state-ofthe-art regarding the involvement of typical ‘innate’ cytokines such as tumour necrosis factor alpha (TNFa), interleukin (IL)-6 and type I interferons (IFNs), which can be found abundantly in virtually every inflamed tissue. TNF-a is a prototypical pro-inflammatory mediator, which is produced by a variety of cell types including T cells, astrocytes, macrophages and microglia [1,2]. A TNF-a response is generally elicited very early during infection and inflammation. There is plenty of evidence to suspect a role of TNF-a in the pathogenesis of MS. For instance, autopsy material from MS patients revealed elevated levels of TNF-a within active lesions of the CNS [3]. TNF-a is also present in higher amounts in the serum and the cerebrospinal fluid (CSF) of MS patients compared with healthy donors and also correlates with the severity of the lesions and disease progression [4,5]. These strong implications of TNF-a in the pathophysiology of MS led to the successful TNF-a pathway manipulation in the mouse model of MS [6,7]. A TNF-a receptor 1 (TNFR1)dependent demyelinating role of TNF-a is also suggested in transgenic mice that express the cytokine in glial precursor cells or astrocytes [8]. However, the hope to use TNF-a blockers to treat MS patients was not fulfilled in clinical trials. In fact, patients treated with lenercept (a recombinant soluble TNFR1 fusion protein) suffered significantly more exacerbations compared with pretreatment and placebo controls [9]. Moreover, new-onset MS-like demyelinating lesions developed in the course of treatment with soluble TNFR2 fusion protein (etanercept) or anti-TNF-a antibodies (infliximab) in patients with rheumatoid arthritis [10]. Both biologicals have been claimed to give rise to various forms of demyelinating neuropathies [11]. An explanation for the failure of lenercept in MS may be provided by data from EAE experiments performed after the clinical trials. Even though blockade of TNF-a in EAE has proved to be efficacious, mice lacking the TNFa gene show that its function in EAE development is redundant [12,13]. A beneficial role of TNF-a has also been described [14], and signalling through TNFR2 mediates proliferation of immature oligodendrocytes
that may indicate that TNF-a is involved in repair processes [15]. IL-6, another acute phase reaction cytokine, is secreted by activated T cells and macrophages and has not only pro-inflammatory but also anti-inflammatory properties. IL-6 became recently a potential interesting therapeutic target for autoimmune disease after the discovery that IL6-deficient mice were fully resistant to EAE [16,17]. At the time of this finding, it was believed that those mice were disease-resistant because of a shift in the T-cell responses from TH1 to TH2, and IL-6 was then believed to modulate the TH1/TH2 balance (discussed below). Recently, IL-6 has been shown to play a key role in the generation of TH17 cells [18,19], and its importance in the autoimmune disease has been correlated with the presence of this novel T-helper cell subset. We will discuss the involvement of T cell-derived cytokines in the inflammatory cascade below. Since their first characterization in 1957 as protective molecules against RNA viruses, the functions of type 1 IFNs have enlarged considerably and comprise regulation of the immune response and inflammation, control of tumour growth and angiogenesis. Studies [20,21] in EAE show type 1 IFNs to suppress immune-mediated demyelination. Furthermore, IFNb gene knockout mice are much more susceptible to EAE [22]. In line with these observations, treatment of relapsing–remitting MS with subcutaneous IFN-b injection has been found to reduce the frequency and severity of clinical relapses, and to decrease the progression of disability and the development of new lesions [23–25]. The mechanism by which type 1 IFN ameliorates MS and EAE was largely unknown until recently. Prinz et al. [26] established that type 1 IFNs primarily act on myeloid cells and that engagement of the specific type 1 IFN receptor on CNS resident cells, T and B cells had no bearing on the clinical development of EAE in transgenic mice. It is likely that the same is true for humans. Hence, the preclinical findings regarding the mechanism by which IFN-b inhibits EAE will be guiding the improvement of IFN-b-mediated immune modulation in the future. In summary, even though there is strong evidence that TNF-a and IL-6 are involved in the pathogenesis of MS and EAE, they may not only play a detrimental role and we need to be careful in our interpretations of the available data. The clinical experience with type 1 IFNs over the years confirms its therapeutic, but modest, effects. Given the fact that these innate cytokines are vital for the function of host defence, it will be crucial to balance any protective potential with the increased risk of infection and malignancies when antagonists are therapeutically administered in a chronic fashion.
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Immune-deviation, the TH1/TH2 paradigm Twenty years ago, Mosmann et al. [27] proposed a model to segregate TH cells based on their cytokine signature into TH1 and TH2 subsets. Subsequently, on the basis of experimental data, a simplistic paradigm of ‘good and evil’ was drawn, in which TH1 cells represented the pathogenic subset while TH2 the protective one. The differentiation of T cells into one or the other subset is dependent upon the cytokine milieu during the antigen presentation. The APC-derived factors, IL-12 and IL-18, are master-regulators in polarization of TH1 cells to secrete IL-2, TNF-a and IFN-g supporting direct cellmediated immunity against intracellular pathogens [27,28]. Conversely, TH2 cells develop after priming in an environment rich in IL-4, IL-10 and transforming growth factor-beta (TGF-b) and produce IL-4, IL-5, IL-10 and IL-13, which promote humoral immunity [27]. On the basis of the fact that TH1 cells were found to be associated with exacerbations in autoimmune disease, whereas TH2 cells were associated with protection, the shift of TH1 cells towards TH2 cells was an attractive therapeutic strategy. This strategy became later known as ‘immune deviation’ [29].
rendered EAE-resistant mice susceptible to EAE [39] and promoted spontaneous relapses in EAE susceptible mice [40]. Finally, abrogation of IFN-g or IFN-g receptor expression converted EAE-resistant mice to a hypersusceptible phenotype [41–43]. All these findings collectively suggest protective effects of IFN-g in EAE. In humans, administration of IFN-g to MS patients caused worsening of disease [44]. One explanation is that IFN-g increases major histocompatibility class (MHC) class II molecule expression and thereby promotes antigen presentation. It also augments MHC class I proteins on the cell surface and thereby favours the generation of cytotoxic T cells. Moreover, IFN-g not only induces relapses but also possibly prevents remyelination [45] by interfering with the mobilization of oligodendrocyte precursors [46]. In the light of these data, treatment of MS patients with IFN-g seems heroic. It is likely that the pleiotrophic functions of IFN-g are not exerted at once, but that IFN-g function may differ drastically depending on the spatial and temporal release during disease development.
From TH1 to TH22: one cytokine one lineage? Immune deviation was a trend, and several approved and not-approved drugs were demonstrated to impact the TH1/2 balance including IFN-b [30]. For instance glatiramer acetate, a mixture of random sequences of four amino acids, fumaric acid, unsaturated dicarboxylic acids and laquinimod, a novel synthetic compound, act on the TH1/TH2 balance in favour of the TH2 polarized phenotype [31–34]. It remains unclear, however, whether the change in T-cell polarization is the cause of the therapeutic effect or merely the result of decreased inflammation due to an unrelated mechanism. Animal models predicted an amelioration of the disease when IL-4, a powerful TH2 cytokine, was administered by inducing a skewing of pathogenic TH1 cells towards protective TH2 cells [35]. Based on preclinical data obtained later, the concept that ‘TH1!TH2’ immune deviation is a potent means to combat MS had to be revised. In fact, in some animal experiments, the TH2 cytokine IL-10 had no effect or even worsened the chronic relapsing EAE [36]. Also, depending on the model system, an overt and overactive TH2 response has been shown to lead to the formation of a humoral response that worsened significantly the disease development [37]. Additional observations against this oversimplification of pathogenic versus protective T helper cells were made in a transgenic animal model in which the expression of the TH1 cytokine IFN-g within the CNS prevented the development of demyelination, axonal damage and thereby reduced the clinical symptoms [38]. An anti-inflammatory role of IFN-g has also been suggested from experiments using neutralizing anti-IFN-g antibodies that
IL-12 is one of the two essential cytokines responsible for the polarization of the TH1 subset, and it is composed of heterodimeric subunits called p40 and p35. Mice deficient in IL-12p40 not only fail to generate TH1 cells but are also completely resistant to EAE. In addition, adoptive transfer recipients treated with neutralizing anti-p40 antibodies at the time of transfer or at disease onset were protected or recovered from the disease [47], while treatment of mice with IL-12 mostly exacerbated EAE [48]. In line with these experimental observations, elevated levels of IL-12 were detectable in CSF and lesions of MS patients. Moreover, there was a correlation between the development of active lesions and the increase in IL-12p40 mRNA levels [49]. Later, it became clear that IL-12 was mistaken for its sister cytokine IL-23. Both IL-23 and IL-12 share a common p40 subunit, which pairs with a different second subunit (p35 for IL-12 and p19 for IL-23) [50]. After the discovery of IL-23, it was found that IL-12p35-deficient mice are not EAE resistant but are even hypersusceptible [51–53]. These findings completely dismissed any detrimental function of IL-12 in autoimmune inflammation while highlighting the fundamental and nonredundant role of IL-23 finally proven by the deletion of the p19 subunit [54]. Subsequently, IL-23 was revealed to be an essential factor for the expansion and survival of a novel effector cell subset coined TH17, after its cytokine signature IL-17A [55], and the lack of functional TH17 cells in IL-23-deficient mice cells was presumed to be the reason of their disease resistance [56,57].
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208 Demyelinating diseases
TH17 cells also produce other cytokines such as IL-17F, IL-6, TNF-a, IL-22 and IL-21. Murine TH17 cells originate, similar to inducible regulatory T cells (Tregs), from naive CD4 T cells after cognate antigen presentation in a tissue culture environment rich in TGF-b and IL-6 or IL-21 [18]. The presence of IL-6 or IL-21 inhibits the expression of Foxp3 driven by TGF-b [58] and instead induces the upregulation of IL-23R and the expression of the transcription factor RORgt, a key regulator of TH17 differentiation [59]. IL-23 plays a fundamental role in vivo in the generation/maintenance of TH17 cells and in their encephalotropism [60,61]. In fact, T cells deficient in the portion of the receptor that binds IL-12 and IL-23 p40 subunit are unable to secrete IL-17 and do not infiltrate the CNS [61]. Despite the clear link between IL-23, pathogenicity and TH17 polarization, neutralization of IL-17A via antibodies or soluble receptors did not consistently improve EAE symptoms and disease kinetics [62]. Moreover, mice deficient in IL-17A were still EAE susceptible and show only a milder clinical course of disease [63,64]. Also, mice lacking IL-17F and IL-17A were still susceptible to the disease [63]. Comparable results were observed when IL-22, another TH17 cytokine, was deleted and IL-22-deficient mice were still fully susceptible to EAE [65]. IL-21 was reported to be essential for TH17 differentiation, and mice deficient in IL-21 were shown to be resistant to EAE [66]. Others, however, could not confirm this finding and showed that the development of EAE is not at all affected in IL-21R and IL-21-deficient mice [67]. It is relatively safe to conclude that although IL-23 remains vital for EAE development, neither TH17 cells nor their cytokine signatures are essential for the disease development [68]. In other words, even though the TH1/TH2 paradigm of autoimmune disease cannot be universally applied, the newly emerged TH17 cell has not provided us with an integrative unifying theory for the observed phenomena in mice. Ever since TH17 cells were coined, researchers felt that if a T cell makes a certain cytokine, this cytokine would be a hallmark molecule representing the T helper cell lineage [69]. This has led to the ‘discovery’ of TH9 and TH22 cells producing IL-9 and IL-22, respectively. Although IL-22 has no apparent function in EAE pathogenesis [65], the case of IL-9 is slightly more complex. One group showed that IL-9R-deficient mice have lower TH17 responses in the CNS and less mast cells in the lymph nodes [70,71], whereas another group described an increased disease development caused by less suppressive Tregs. A recent report claims encephalitogenic potential of TH9 cells that could transfer EAE with comparable severity but distinct pathological phenotypes [72]. It is difficult to say whether these new T-cell
subsets, which are usually polarized under very specific in-vitro conditions, have any physiological or pathological function at all. In vivo, there appears to be a great potential for ‘plasticity’ [73–75]. It is most likely that the T helper cells produce a set of cytokines based on their cognate antigen, the microenvironment and the duration/strength of the immune response. Probably, multiple effector T cells are actually generated in a different gradient of cytokines, and that these cells give rise to the heterogeneous pathologies seen in inflammatory diseases such as MS. In EAE, everyone appears to agree that IL-23 is a notredundant requirement for the generation of an encephalitogenic immune response. So, why not just target IL-23 in MS patients? On the basis of the importance of IL-12/23 p40 in EAE, ustekinumab, an antihuman p40 antibody, was used in a phase II clinical trial of relapsing– remitting MS [76]. During the clinical trial, even though the antibody was well tolerated, ustekinumab did not show any significant therapeutic benefit in the treated versus the control group. In contrast, patients suffering from psoriasis, an inflammatory skin disorder also strongly linked to IL-23 and TH17 cells, benefited greatly from ustekinumab. There are a few possible explanations for the failure of this study: (1) There is strong evidence that IL-23 produced within the CNS is a critical factor in the pathogenesis of EAE [77]. The large size of the antibody molecule may impede its passage through the blood–brain barrier [78] and thus not deliver it where it would have the desired therapeutic effect [79]. (2) It is likely that ustekinumab would have been more effective as a very early treatment on a group with an early disease stage or clinically isolated syndrome, but ineffective in advanced stages, as previously observed in marmosets [80]. As data from animal experiments suggest that IL-12/IL-23 p40 cytokines have a greater involvement in the generation and expansion of autoreactive T cells, it is possible that the window for treatment intervention with ustekinumab might have already passed once the patients were enrolled. (3) The immunopathogenesis of MS is heterogeneous because of the lack of biomarkers useful to identify disease subtypes. In this case, any possible therapeutic effect could be masked by inter-patients differences. This is a problem not only to this clinical trial but also for every neurologist seeking to make a decision about the best therapeutic strategy for his/ her individual patient. (4) Due to the immunization in the EAE model, preclinical work focuses primarily on CD4þ T cells as the protocol biases the system towards activation in this pathway. In humans, however, there is strong evidence that CD8þ T cells are important effector
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Cytokine networks in multiple sclerosis Codarri et al. 209
cells in MS [81]. Targeting p40 only affects TH1/ TH17 cells but not encephalitogenic CD8 T cells (Tosevsky et al., manuscript in preparation). This would mean that IL-23 may be critical for the development of EAE, but patients in whom T helper cells play a less prominent role are not likely to benefit from targeting IL-23. (5) Finally, although p40 neutralization could on one hand be beneficial by blocking the IL-23 pathway, on the other hand, as it also blocks IL-12, it could annihilate any regulatory/positive effect of IL-12. The take-home message from this clinical trial is clearly that we need to fully understand every aspect of the therapeutic intervention and to use additional preclinical models to predict any efficacious or detrimental effect in patients suffering from MS [82].
References and recommended reading Papers of particular interest, published within the annual period of review, have been highlighted as: of special interest of outstanding interest Additional references related to this topic can also be found in the Current World Literature section in this issue (pp. 325–327). 1
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Conclusion An alternative approach to modulating cytokine therapy is to target adhesion molecules on effector T cells involved in the migration through the blood–brain barrier, such as natalizumab, or to target cell-specific depletion such as rituximab and alemtuzumab. These new biologicals were highly effective in reducing inflammatory brain lesions and clinical relapses [83,84]. Unfortunately, these immunosuppressive agents also impair immunosurveillance or lead to a profound disturbance of the immunoregulatory networks with dramatic side effects [85,86]. But interfering systemically with cytokines does not necessarily present a superior approach as it too may lead to completely unexpected adverse effects. We must stress again that the challenge to translate preclinical data into the clinic not only requires intelligent trial design. It is perhaps more important to take the reported successes in preclinical models with a grain of salt. In this current climate of publication policies, it happens only rarely that the failures (negative data) are being reported. This ‘positive publication bias’ may have caused more damage than good when analysing the translation of preclinical data to clinical trials in stroke patients [87]. Concerted efforts should be made to design larger and more comprehensive preclinical trials (even multicenter) and to place immunologists, neuroscientists and clinical specialists at one table to prevent any ‘loss during translation’.
Acknowledgements This work was supported by the Swiss National Science Foundation (B.B.), the National Center for Competence in Research (NCCRNeuro), the Swiss MS-Society (B.B.), the U.S.-National MS Society (B.B.), an unrestricted grant by Merck-Serono-Geneva (B.B.), and a Fellowship grant by the Forschungskredit of the University of Zurich (L.C.). A.F. is Hertie Senior Research Professor Neuroscience 2009 of the Gemeinnu¨tzige Hertie-Stiftung. The authors declare that they do not have any conflict of interests.
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Novel MRI approaches to assess patients with multiple sclerosis Massimo Filippi and Maria A. Rocca Neuroimaging Research Unit, Institute of Experimental Neurology, Division of Neuroscience, Scientific Institute and University Hospital San Raffaele, Milan, Italy Correspondence to Dr Massimo Filippi, Neuroimaging Research Unit, Institute of Experimental Neurology, Division of Neuroscience, Scientific Institute and University Hospital San Raffaele, Via Olgettina, 60, 20132 Milan, Italy Tel: +39 02 26433033; fax: +39 02 26435972; e-mail:
[email protected] Current Opinion in Neurology 2010, 23:212–217
Purpose of review This review summarizes novel MRI approaches for the investigation of lesion burden and understanding of the pathophysiology of multiple sclerosis (MS). Recent findings Recent technical advances are improving our ability to detect and define the nature of focal lesions and ‘diffuse’ tissue damage in MS as well as the functional consequences of such structural abnormalities. New contrast agents allow to monitor the pluriformity of MS inflammation. Double inversion recovery sequences enable us to detect and monitor the evolution of MS lesions in the cortex. High and ultra-high field scanners are improving imaging of MS-related abnormalities at an unprecedented resolution. Furthermore, this new generation of scanners has the potential to ameliorate structural and functional MR studies of the disease. All of this has contributed, and is likely to continue to contribute, to the definition of the factors associated with the development of irreversible disability in MS. Finally, new analysis methods have allowed to track regional disease-related changes and are resulting in an increased correlation between MRI and clinical deficits. Summary Novel MR approaches highlighted previously unrecognized or neglected aspects of MS pathophysiology, which are likely to improve our understanding of the heterogeneous clinical manifestations of this condition. Keywords analysis methods, double inversion recovery, high field, iron, magnetic resonance imaging, multiple sclerosis, permeability, plasticity, regional assessment, ultrasmall particles of iron oxide Curr Opin Neurol 23:212–217 ß 2010 Wolters Kluwer Health | Lippincott Williams & Wilkins 1350-7540
From its first introduction in the clinical arena [1], magnetic resonance imaging (MRI) appeared as a valuable tool to investigate multiple sclerosis (MS). This was mainly due to its high sensitivity for detecting focal abnormalities in the central nervous system (CNS) of these patients. The effort spent during the past three decades to explore the many potentialities of this instrument has led to the achievement of undisputable milestones, such as the inclusion of MRI findings in the diagnostic criteria for MS (which allows an early diagnosis to be reached) [2], and the identification of MRI markers to monitor the evolution of the disease both in clinical practice and in the context of treatment trials.
MR spectroscopy (1H-MRS)] have been used to study the structural CNS changes associated with this condition and are being progressively moved from a research setting to clinical practice. These techniques have the great advantage of being more specific towards the heterogeneous pathological substrates of the disease than conventional MRI. In addition, they also allow to quantify and monitor the extent of damage not only in lesions but also in normal-appearing tissues. Finally, the development of new analysis approaches to assess functional MRI (fMRI) data is disclosing, at an unprecedented pace, the mechanisms of cortical reorganization following the accrual of tissue damage, which have the potential to limit its clinical consequences.
In addition to conventional MRI [which includes dualecho, fast fluid-attenuated inversion recovery (FLAIR), and T1-weighted imaging with and without gadolinium (Gd) administration], several quantitative MR techniques [including magnetization transfer MRI, diffusion-weighted and diffusion tensor MRI, and proton
Since MRI technology continues to unfold in a seemingly limitless way, new techniques are being currently developed and applied. The most promising of these are presented here and their contributions to the improvement of our understanding of the disease pathophysiology are discussed.
Introduction
1350-7540 ß 2010 Wolters Kluwer Health | Lippincott Williams & Wilkins
DOI:10.1097/WCO.0b013e32833787b0
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Novel MRI approaches to assess patients with MS Filippi and Rocca 213
New contrast agents The injection of Gd and the identification of enhancing lesions on T1-weighted scans is the present more powerful MR approach to detect MS inflammatory changes. Such an approach allows the detection of areas with an increased blood–brain barrier permeability. More recently, new MRI contrast agents composed of iron particles, known as ultrasmall particles of iron oxide (USPIO) or super-paramagnetic iron particles of oxide (SPIO), have been used to detect the presence of macrophages in ‘active’ MS lesions [3]. In relapsing remitting MS (RRMS) patients, it has been shown that some lesions may enhance only with Gd, others only with USPIO, and others with both [3]. In addition, the same lesions can change their enhancing pattern over time [3]. These findings indicate that new contrasts might provide pieces of information complementary to that offered by Gd-enhancing MRI scans, with the potential to depict the pluriformity of the MS inflammatory process. The potential of USPIO to detect the cellular component of ‘diffuse’ MS disease has also been explored recently by measuring T1 relaxation time changes in the normal-appearing white matter (NAWM) following its administration [4].
Double inversion recovery sequences and cortical lesions In MS, cortical lesions have been described from the earliest pathological studies [5], but are typically not seen on conventional MRI scans [6]. The development and application of double inversion recovery (DIR – i.e. two inversion times are used to suppress the signal from both white matter and cerebrospinal fluid) sequences have markedly improved the sensitivity of MRI to detect such lesions in vivo (a gain of 538% has been reported vs. the use of T2-weighted spin-echo sequences) [7]. Cortical lesions have been detected in all the major MS clinical phenotypes, including patients with clinically isolated syndromes (CIS) suggestive of MS [8–10]. Remarkably, cortical lesions are more frequently seen in patients with secondary progressive MS than in those with CIS or RRMS [8], whereas in patients with benign MS they are fewer than in those with early RRMS [9]. Lesions have also been visualized in the hippocampus [11]. Recent longitudinal studies have shown that new cortical lesions continue to form in patients with early RRMS [9], and in those with the progressive disease phenotypes over 1 to 2-year periods of follow-up [10,12,13,14]. All of this suggests that cortical lesions might contribute to the accumulation of irreversible disability in MS. This notion is supported by the demonstration of an association between cortical lesion burden and progression of disability over the subsequent 2 [10] and 3 [12] years in patients with different disease phenotypes, as well as
between cortical lesion burden and the severity of cognitive impairment in patients with relapse-onset MS [14,15]. The ability of MRI to visualize cortical lesions is still suboptimal. Indeed, DIR imaging allows to classify, on average, as intracortical only 4.6% of the overall number of gray matter lesions [8] in contrast to a figure of 59% reported by pathological studies [16]. As a consequence, a set of new strategies has been proposed to improve the detection and allow a reliable classification of these lesions, including the use of a single-slab 3D DIR sequence [17], and the combination of DIR with other sequences, such as phase-sensitive inversion recovery [18] and 3D magnetization-prepared rapid acquisition with gradient echo [19]. A better in-vivo understanding of the pathological substrates of cortical lesions is likely to be achieved via the combination of DIR sequences with quantitative MR techniques, such as diffusion tensor MRI [20].
High-field MRI Magnet field strengths higher than 1.5 Tesla (T) improve image resolution, signal-to-noise ratio and chemical shift. In patients with established MS, this has resulted in an increased detection of T2-visible brain [21], but not spinal cord [22], lesions at 3.0 T compared with at 1.5 T. Remarkably, the use of DIR imaging at 3.0 T has led to a higher detection of infratentorial lesions compared with FLAIR and T2-weighted sequences in patients with both CIS and established MS [23]. So far, only one study has assessed the performance of the MRI diagnostic criteria for MS at 1.5 and 3.0 T. In CIS patients, despite an increased lesion detection, 3.0 T imaging led to very little gain in terms of showing the presence of spatial lesion dissemination [24].
Ultra-high field MRI The future of MRI is likely to reside in the use of ultra-high field scanners. A few preliminary studies performed at 7.0 T [25,26–28] showed the ability of MRI to depict the morphological characteristics of MS lesions in the white matter and gray matter at a resolution which resembles that of pathological assessment. In 12 patients with established MS, there were 97 white matter lesions detected on 1.5 T vs. 126 lesions at 7.0 T [28]. Kangarlu et al. [27] compared MR images of brain samples from newly deceased MS patients obtained at 8.0 and 1.5 T, and showed that cortical lesions, invisible on MRI scans at 1.5 T, were clearly seen at 8.0 T. More recently, using a 7.0 T scanner, Mainero et al. [26] identified 199 cortical lesions in 16 MS patients. Three major lesion patterns were identified (type I: leukocortical; type II: intracortical, and types III/IV: subpial
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214 Demyelinating diseases
extending partly or completely through the cortical layers). These studies [25,26–28] also allowed a better definition of the relationship between demyelinating lesions and the deep venous system to be achieved, and showed in-vivo that MS plaques are centered around the microvasculature. In addition, ultra-high field MRI has the potential to improve quantitative, metabolic and fMRI studies of MS. A recent 1H-MRS study at 7.0 T [29] was able to quantify the concentration of glutathione, a marker of oxidative status, in the NAWM and gray matter from healthy controls and MS patients. In healthy controls, the concentration of glutathione was higher in the gray matter than the white matter, and MS patients had a significant reduction of glutathione concentration in macroscopic lesions and the gray matter, but not in the NAWM, when compared to healthy individuals, which is consistent with a diminished protection against free radicals.
Perfusion MRI Magnetic resonance imaging can be used to assess brain tissue perfusion in vivo using either exogenous tracers (e.g. Gd chelates) or endogenous arterial water [arterial spin labeling (ASL)]. Chronic MS lesions are characterized by a decreased perfusion, whereas Gd-enhancing lesions typically show an increased perfusion. A widespread hypoperfusion in the NAWM as well as in cortical and deep gray matter of patients with relapsing remitting and progressive MS has also been shown [30]. Such changes have been correlated with clinical disability [31] and neuropsychological impairment [32]. Recently, perfusion abnormalities have also been detected in the NAWM, but not in the gray matter, from CIS patients [33], suggesting that tissue perfusion decreases might begin in the NAWM.
relation (MFC) (use of asymmetric spin-echoes to measure the influence of MR signaling by magnetic field inhomogeneity), and susceptibility-weighted imaging (SWI) (3D, high-resolution, flow compensated gradient echo sequences that use magnitude and phase data to enhance information on local tissue susceptibility), are likely to improve our ability to detect iron deposition. Basal ganglia transverse relaxation rate (R2) values were found to be higher in RRMS than in CIS patients [38]. T2’ values, which reflect the relation of local deoxyhemoglobin to oxyhemoglobin and thus the fraction of oxygen extraction, were significantly lower in the deep gray matter nuclei from MS patients compared with healthy individuals, presumably because of a high iron concentration in the former individuals [39]. In contrast, R2 values were significantly increased in patient NAWM than in controls, probably as a consequence of a reduced tissue metabolism [39]. Using a 3.0 T scanner, MFC in the deep gray matter was found to be significantly increased in RRMS patients and to correlate with T2 visible lesions and neuropsychological abnormalities [40]. Two studies, at 4.0 T [41] and 4.7 T [42], demonstrated that the use of phase and magnitude SWI can contribute to identify additional (from 18 to 47%) lesions, that are not visible on T2weighted images. SWI has also been applied to assess cerebral venous oxygen level changes in RRMS patients and showed a significantly reduced visibility of the venous vasculature in the periventricular white matter [43]. Finally, using phase imaging at 7.0 T, Hammond et al. [25] found an increased local field shift, caused by magnetic susceptibility-shifted compounds such as iron, in the deep gray matter nuclei of MS patients compared to healthy individuals, which was correlated with disease duration.
Plasticity Magnetic resonance techniques to image iron deposition Iron deposition is likely to be associated to neurodegeneration and contribute to MS pathogenesis by promoting oxidative damage. Abnormal iron deposition is thought to be the substrate of T2 hypointense areas and reduced T2 relaxation time seen in the basal ganglia, thalamus, dentate nucleus, and cortical regions seen in the majority of MS clinical phenotypes [34], including patients with benign MS (BMS) [35] and those with CIS suggestive of MS [36]. Gray matter T2 hypointensity was found to be correlated with the severity of clinical disability and cognitive impairment in patients with MS [34], as well as with clinical progression [37]. At 3.0 T or more, T2 and other imaging approaches, such as T2, T2’ or T2-rho relaxometry, magnetic field cor-
Technical advances in methods of analysis have allowed, on the one hand, to study the function of relatively small CNS structures, and, on the other, to obtain estimates of the activations and synchrony between brain areas. An increased activation of the cervical spinal cord has been demonstrated in all the major MS clinical phenotypes and has been related to the severity of clinical disability and the extent of tissue damage to this structure [44,45]. Abnormal effective connectivity within the motor [46] and the cognitive [47] networks has been shown in patients with RRMS [46] and BMS [47]. On the contrary, no such changes have been detected in patients with pediatric MS [48]. More recently, the use of measures of abnormal effective connectivity has been shown to be feasible in the context of multicenter studies [49]. These data suggest that assessing fMRI changes in MS patients might shed light
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Novel MRI approaches to assess patients with MS Filippi and Rocca 215
on the mechanisms responsible for the accumulation of irreversible clinical deficits.
Combined analysis of different magnetic resonance techniques The combination of different MR modalities, sensitive toward different aspects of MS disease, is likely to improve our understanding of the mechanisms responsible for the accumulation of fixed neurological deficits in this disease. Damage to the optic radiations measured using diffusion tensor MRI was related with retinal nerve fiber layer thickness and visual impairment in patients with relapsing remitting and progressive MS [50]. In RRMS patients, corticospinal tract (CST) damage, measured using diffusion tensor MRI tractography, was associated with an altered effective connectivity of the motor network [46]. In BMS patients a correlation between diffusivity changes of the corpus callosum and an abnormal interhemispheric effective connectivity during the performance of attention-related tasks was shown [47]. Diffusion tensor MRI abnormalities of transcallosal white matter pathways connecting the primary motor cortices have been correlated with changes of low-frequency blood oxygen level dependent fluctuations [51]. By combining cortical thickness measurements with T2 lesion load burden, an increase of white matter lesion volume was found to be correlated with impairment of both global and local topological organization of brain structural networks [52]. This provides evidence that a disconnection of brain areas may play a role in the pathophysiology of MS.
New analysis methods Additional important achievements have been obtained from the development and application of new methods to analyze MR data. Lesions
Novel approaches to the analysis of macroscopic visible lesions include the assessment of their regional distribution using lesion probability maps [53], the use of timeseries modeling of MR imaging intensity to study dynamic pixel-wise signal changes related to lesion evolution [54], and the use of subtraction approaches to display lesion changes over time [55]. Chen et al. [56] used a voxel-based analysis of magnetization transfer MRI scans to track demyelination and remyelination in individual MS lesions. Topographical distribution of normal-appearing white matter damage
Using a voxel-based approach, a recent study [53] showed that patients with RRMS and BMS differ in term of topographical distribution of white matter damage, whereas no between-group differences were found when
the overall extent of white matter diffusivity changes was assessed using a histogram-based approach. Tract-based spatial statistics (TBSS) is a technique that allows voxelwise analysis of multipatients’ diffusion tensor MRI data. Using such a technique, compared to healthy controls, MS patients had reduced fractional anisotropy values in several white matter fiber bundles, which were related to deficits of specific cognitive domains [14,57]. Regional damage can also be assessed by means of diffusion tensor MRI tractography methods, which allow to segment clinically eloquent white matter pathways. A diffusion tensor MRI tractography study showed that CIS patients with motor impairment have increased mean diffusivity in the CST compared to patients without pyramidal symptoms [58]. In patients with RRMS, corpus callosum diffusivity values were found to be associated with the level of cognitive performance [59]. Using a magnetization transfer weighted approach, a study showed that signal abnormalities in the dorsal and lateral columns of the spinal cord are correlated with vibration sensation and strength, respectively [60]. Topographical distribution of gray matter damage
The use of voxel-wise approaches has allowed to define the distribution of gray matter abnormalities in MS, thus improving the correlation with disease clinical manifestations. Voxel-based morphometry (VBM) studies have shown consistently that the patterns of regional gray matter loss differ among patients with the major disease clinical phenotypes [53]. In CIS patients, gray matter atrophy involves the thalamus, hypothalamus, putamen and caudate nucleus [61], whereas in RRMS patients cortical atrophy, which affects preferentially the fronto-temporal lobes, is typically detected [62]. In these latter patients, cortical volume reduction over 1 year was correlated to white matter lesion progression [62]. Compared to controls, BMS patients have a reduced gray matter volume in the subcortical and frontoparietal regions [63]. In comparison with BMS patients, those with secondary progressive MS (SPMS) have a significant gray matter loss in the cerebellum [63]. Patients with pediatric MS experience gray matter atrophy in the thalamus only, with sparing of the cortex and other deep gray matter nuclei [64], suggesting that the overall amount of tissue damage in pediatric MS is modest in comparison with the adult forms of the disease. Voxel-wise analysis of magnetization transfer and diffusion tensor MRI data can also be used to assess intrinsic gray matter damage. Khaleeli et al. [65] showed, in primary progressive MS patients, a significant correlation between decrease of magnetization transfer ratio (MTR) values of cortical motor areas and the Expanded Disability Status Scale (EDSS) scores, as well as between MTR values in cortical cognitive areas and the Paced Auditory Serial Addition Task scores. Similarly, using a voxel-based
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216 Demyelinating diseases
analysis of diffusion tensor MRI maps, Ceccarelli et al. [66] showed diffusivity abnormalities of brain areas associated with motor and cognitive functions in primary progressive MS (PPMS).
Conclusion The development and application of novel MR techniques of acquisition and postprocessing have resulted in an improved understanding of MS pathophysiology. This technical advancement has allowed to disclose additional factors, previously unrecognized or neglected, which are likely to contribute to the accumulation of irreversible clinical deficits in this condition. Nevertheless, at least some of the novel MR approaches discussed here are in their infancy and several issues are still to be resolved (such as those related to their optimization and standardization across centers) to move them from a research setting to daily-life clinical practice.
References and recommended reading Papers of particular interest, published within the annual period of review, have been highlighted as: of special interest of outstanding interest Additional references related to this topic can also be found in the Current World Literature section in this issue (pp. 328–329). 1
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Stem cell transplantation in multiple sclerosis Antonio Uccellia,b,c and Gianluigi Mancardia,b a Department of Neurosciences, Ophthalmology and Genetics, bCenter of Excellence for Biomedical Research, University of Genoa, Genoa and cAdvanced Biotechnology Center (ABC), Genoa, Italy
Correspondence to Antonio Uccelli, MD, Department of Neurosciences, Ophthalmology and Genetics, University of Genoa, Via De Toni 5, 16132 Genoa, Italy Tel: +39 0103537028; e-mail:
[email protected] [email protected] Current Opinion in Neurology 2010, 23:218–225
Purpose of review The recent advances in our understanding of stem cell biology, the availability of innovative techniques that allow large-scale acquisition of stem cells, and the increasing pressure from the multiple sclerosis (MS) patient community seeking tissue repair strategies have launched stem cell treatments as one of the most exciting and difficult challenges in the MS field. Here, we provide an overview of the current status of stem cell research in MS focusing on secured actuality, reasonable hopes and unrealistic myths. Recent findings Results obtained from small clinical studies with transplantation of autologous hematopoietic stem cells have demonstrated that this procedure is feasible and possibly effective in severe forms of MS but tackles exclusively inflammation without affecting tissue regeneration. Results from preclinical studies with other adult stem cells such as mesenchymal stem cells and neural precursor cells have shown that they may be a powerful tool to regulate pathogenic immune response and foster tissue repair through bystander mechanisms with limited cell replacement. However, the clinical translation of these results still requires careful evaluation. Conclusion Current experimental evidence suggests that the sound clinical exploitation of stem cells for MS may lead to novel strategies aimed at blocking uncontrolled inflammation, protecting neurons and promoting remyelination but not at restoring the chronically deranged neural network responsible for irreversible disability typical of the late phase of MS. Keywords autoimmunity, experimental autoimmune encephalomyelitis, multiple sclerosis, stem cells, transplantation Curr Opin Neurol 23:218–225 ß 2010 Wolters Kluwer Health | Lippincott Williams & Wilkins 1350-7540
Introduction In the last few years, the extraordinary progress in our understanding of adult stem cell biology has led to major advances in the field of cell therapy, allowing us to translate our basic knowledge about different kinds of stem cells into therapeutic strategies aimed at treating neurological diseases such as multiple sclerosis (MS). Although autologous hematopoietic stem cell transplantation (AHSCT) has now been proven to be a powerful, although risky, therapy for some forms of MS, other stem cell types have gained attention as potential future therapeutic options for MS. However, experimental data have posed us with an unforeseen scenario. As most scientists moved into the stem cell arena due to an unmet need for therapies for tissue repair, current evidence suggests that stem cells that have been proven to ameliorate symptoms and protect neural cells in experimental autoimmune encephalomyelitis (EAE), a model of MS, also have a limited, if any, capacity for transdifferentiating into neural cells, but may foster tissue 1350-7540 ß 2010 Wolters Kluwer Health | Lippincott Williams & Wilkins
protection and repair through unexpected mechanisms of action.
Autologous hematopoietic stem cells for the treatment of autoimmunity AHSCT has been proposed for severe autoimmune disorders unresponsive to conventional treatments [1] based on results from experimental models [2]. AHSCT procedure consists of mobilization from the bone marrow of peripheral blood stem cells (PBSCs) usually with cyclophosphamide in combination with granulocyte-colony stimulating factor. PBSCs expressing the surface antigen CD34 are collected by leukapheresis and cryopreserved. The graft can be manipulated with a positive selection of CD34þ cells or a negative depletion of T cells, in order to eliminate autoreactive clones. The patient is then treated with the conditioning regimen, usually with high-dose cytotoxic agents such as BEAM (BCNU, carmustine, etoposide, cytosine–arabinoside and melphalan), total body irradiation (TBI) or other various combinations of DOI:10.1097/WCO.0b013e328338b7ed
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SCT in multiple sclerosis Uccelli and Mancardi 219
cytotoxic agents. The conditioning regimens are usually classified as high-intensity (TBI or any busulphan-containing protocol), medium-intensity (BEAM, carmustine and cyclophosphamide) or low-intensity regimens (cyclophosphamide alone or fludarabine-based schemes). The cryopreserved graft is then re-infused into the patient and antithymocyte globulin (ATG) is administered in order to eradicate self-reactive T cells. After a period of aplasia of 2–3 weeks, engraftment occurs. The rationale of the procedure relies on intense immunosuppression aimed at destroying autoreactive cells and the subsequent immune reconstitution that is associated with profound qualitative changes of the immune repertoire.
Autologous hematopoietic stem cell transplantation in multiple sclerosis: clinical outcome More than 400 MS cases have been reported so far in the European Bone Marrow Transplantation database. However, although no phase III clinical trial has been completed yet, a series [3] of small phase I/II studies have been reported. Despite the concerns regarding different protocols and disease forms treated, 60–70% of patients after 3 years and 50–60% after 6–8 years do not progress from transplantation [4]. In a recent study [5], 50 MS patients were treated with BEAM and ATG followed by AHSCT at different disease phases with Expanded Disability Status Scale (EDSS) ranging from 1.5 (‘early AHSCT’) to 8.0 (‘salvage AHSCT’). The procedure was well tolerated and effective and 62% of patients improved at least 0.5 points on EDSS, particularly when AHSCT was performed in young individuals. Progression-free survival at 6 years was 72%. The Canadian MS BMT Study Group [6] treated 17 aggressive MS patients with a high-intensity conditioning regimen (busulphan and cyclophosphamide) with ex-vivo and in-vivo T-cell depletion. These patients had a favorable outcome, with 75% progression-free survival at 3 years, without any relapse or new MRI lesions nearly 5 years after treatment [6]. The retrospective analysis of transplanted patients data performed in 2002 [7] and 2006 [4], did not show any difference in disability progression between high and intermediate-intensity regimens, whereas a correlation was observed for transplant-related mortality (TRM; 6 and 5.3%, respectively) and regimens including busulphan. Although TRM has been reported to decrease to 1.3% in a recent analysis [3], most likely as a result of better patient selection and improved experience of the transplanting centers, low-intensity treatments, with minimal myelotoxic effects, have been proposed [8]. In a recent study, 21 young, relapsing– remitting MS (RRMS) patients with mild disability and short disease duration were treated using a low-intensity conditioning regimen (cyclophosphamide 200 mg/kg followed by alemtuzumab or ATG). After 3 years, 81%
of patients improved by at least 1 point on EDSS and 62% were disease free. Modest toxicity was reported and 23% of patients relapsed after 6–16 months. Recently, in an open-label study [9], the effect of low-intensity (cyclophosphamide and rabbit ATG) and medium-intensity (BEAM and horse ATG) regimens was addressed. Regardless of a similar clinical outcome, individuals treated with cyclophosphamide and rabbit ATG displayed significantly less toxicity as compared with those treated with BEAM and ATG. AHSCT has also been reported to have a significantly positive impact on rapidly evolving, ‘malignant’ MS refractory to conventional treatments [10]. In a small cohort of young patients with RRMS presenting with high number of relapses per year and high EDSS, AHSCT was able to halt disease progression and reverse disability [11]. Overall, these studies confirm that AHSCT is more effective in very active, young RRMS individuals with a short disease history.
Autologous hematopoietic stem cell transplantation-related changes of the immune repertoire The restoration of immune tolerance following AHSCT is characterized by a profound renewal of the T-cell repertoire mainly due to the expansion of naive CD4þ T cells of recent thymic origin [12]. This study [12] suggests for the first time that AHSCT results in the induction of a new immune system less prone to selfreactivity. Although self-reactive T cells may persist after transplantation [13,14], they do not seem to arise from mobilized HSC-enriched graft [15]. Thus, some peripheral or central nervous system (CNS) infiltrating T and B-cell clones may survive the conditioning regimen, as demonstrated by the persistence of oligoclonal bands in the cerebrospinal fluid of most patients and high levels of soluble CD27, a marker of lymphocyte activation, after AHSCT [16].
Future perspective for autologous hematopoietic stem cell transplantation in multiple sclerosis At the present time, a few studies on AHSCT in severe forms of MS are ongoing, including ASTIMS (Autologous Stem cell Transplantation International Multiple Sclerosis), a European Union-based phase II study comparing the effect of AHSCT versus mitoxantrone, which has been recently stopped for the insufficient accrual of patients, the Halt-MS study, a US trial, investigating the effect of BEAM, ATG and CD34þ cell selection in RRMS or progressive–relapsing MS patients and the ‘Stem Cell Therapy for Patients with MS Failing Interferon’ randomized clinical trial in the United States
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220 Demyelinating diseases
enrolling inflammatory patients with the aim of comparing transplantation of unmanipulated autologous PBSCs using a conditioning regimen of cyclophosphamide and ATG versus US Food and Drug Administration-approved MS therapies. The scientific community interested in AHSCT for MS met recently in Florence on 19–20 November 2009, discussing the possible design of a two-arm study focusing on young rapidly deteriorating patients refractory to standard therapies and with clinical and MRI signs of disease activity. Patients will be randomized to an intermediate intensity regimen or the best available treatment, with the possibility to crossover into the other study arm in case of continuing disease activity. Although the clinical effectiveness of AHSCT compared with conventional therapies is still debated, a recent analysis [17] of cost effectiveness of AHSCT versus mitoxantrone in secondary progressive MS suggests that the probability of AHSCT being cost effective, when TRM is low, depends on the achievement of a long enough disease stabilization (10 years).
Mesenchymal stem cells definition Multipotential stromal precursor cells were first isolated from the bone marrow, as the common ancestors of mesenchymal tissues such as cartilage, fat, bone and other connective tissues [18], and commonly termed as mesenchymal stem cells (MSCs). Many other tissues have been reported to be the source of MSCs, more recently the vasculature being a source of perivascular cells with the phenotype of MSCs [19,20]. The study [19] demonstrates that bone marrow stem cells capable of giving rise to the complete hematopoietic microenvironment reside exclusively in a small fraction of perivascular cells. However, such a conventional view of marrow stromal cell plasticity was challenged by several studies reporting their capability to also differentiate into cells from unrelated germ lineages including neural cells [21,22]. This heterogeneity is reflected by a complex transcriptome encoding a wide array of proteins involved in a large number of diverse biological processes that are likely to result in some unexpected therapeutic features [23].
Mesenchymal stem cells display immunomodulatory properties Several reports have demonstrated in the last few years that MSCs are endowed with a robust regulatory effect on many cells of innate and adaptive immunity [24]. MSCs were first demonstrated to inhibit in-vitro proliferation of T cells [25,26] and this was later demonstrated to be the result of an inhibition of T-cell division [27]. More recently, it has become clear that the immunoregulatory features of MSCs are elicited by inflammatory cytokines, mainly interferon-gamma and tumor necrosis factor-
alpha, resulting in the production of species-specific immunosuppressive factors, namely indoleamine 2,3 dioxygenase in humans and nitric oxide in mice [28]. The in-vivo translation of these results were achieved when the intravenous (i.v.) injection of MSCs into EAE mice led to the striking inhibition of proliferation of ex-vivo isolated lymph node T cells [29]. B lymphocytes are also the target of MSCs immunosuppressive activity. In fact, MSCs can inhibit in-vitro proliferation of B cells, differentiation to plasma cells and production of antibodies [30–32]. Similarly to what was observed for T cells, i.v. MSCs administration in EAEaffected mice resulted in the inhibition of the production of immunoglobulins specific for the encephalitogenic myelin antigen proteolipid protein [33]. Interestingly, the suppression of immunoglobulin production was recently demonstrated to depend on the effect of a variant of the MSC-derived chemokine (C–C motif) ligand 2 (CCL2), which is proteolytically degraded by matrix metalloproteinases secreted by MSCs themselves [34]. A third cell type significantly affected by the interaction with MSCs is the dendritic cell. MSCs can spoil dendritic cell in-vitro maturation resulting in an impaired secretion of interleukin (IL)-12 [35] and increased production of IL-10 [36]. MSC-induced immature dendritic cells do not upregulate major histocompatibility complex and costimulatory molecules and poorly present antigens to naive T cells [37]. These findings suggest that the net effect of MSCs on adaptive immunity is the consequence of a direct inhibition on T and B lymphocytes but also of an impaired ability of MSC-affected immature dendritic cells to properly instruct T cells, which, in turn, could also affect the capacity of T cells to provide help to B cells [24].
Are mesenchymal stem cells neuroprotective? The original observation that MSCs can transdifferentiate into neurons [21,22] in vitro and, upon in-vivo administration, acquire some markers of neural cells [38] is currently a matter of controversy, as the marker analysis alone may well be due to an aberrant expression [39,40]. Since then, in-vitro MSC neuronal differentiation has been achieved by treatment with trophic factors [41] and also by genetic manipulation [42]. Although the exploitation of ‘in-vitro neuralized’ MSCs appears a promising strategy for the treatment of neurodegenerative diseases, it is not known whether in-vitro transdifferentiation would result in the loss of other therapeutic properties such as immunoregulatory features, thus hampering their use in MS. On the contrary, current evidence from EAE suggest that in-vivo administration of in-vitro expanded undifferentiated MSCs does not result in a substantial
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SCT in multiple sclerosis Uccelli and Mancardi 221
CNS engraftment and acquisition of a neural phenotype [33,34,43,44,45]. Regardless of the limited evidence of transdifferentiation by histological analysis, there is no clear experimental confirmation that MSC-derived neuronal cells are able, when transplanted in vivo, to correctly integrate among neural networks as functional neurons. However, MSCs could act on neural cells through other modalities that may lead to tissue repair. For example, MSCs have been demonstrated in vitro to rescue neurons from apoptosis [46,47] and promote neurite outgrowth [48]. It has also been demonstrated that MSCs are able to produce a wide variety of trophic factors, cytokines, chemokines and antioxidant molecules, resulting in increased neuronal survival [34,49,50,51]. Moreover, some secreted proteins could trigger host brain plasticity, thereby inducing endogenous precursor proliferation that, in turn, may lead to neurogenesis [52] and oligodendrogenesis [44,53,54].
Administration of mesenchymal stem cells improves experimental autoimmune encephalomyelitis Clinical interest in EAE was sparked by the hope that MSCs could, on the one hand halt the autoimmune attack on the CNS and, on the other hand, repair injured tissue. Preclinical studies demonstrated that this hypothesis was correct but also that MSCs were clinically effective when cells were given early, before the onset of the chronic phase of disease, sustained by irreversible damage of the nervous system. Unexpectedly, pioneer experimental work demonstrated that a striking clinical effect was achieved in EAE by i.v. administration of either syngeneic (mouse) [29] or xenogeneic (human) [55] MSCs. In fact, i.v. administration resulted in the induction of peripheral immune tolerance leading to the inhibition of pathogenic T and B-cell reactivity [29,33]. Many other groups have now confirmed that MSCs can ameliorate EAE in different animal models when injected intravenously [43,44,45], intraventricularly [56] and even intraperitoneally [34]. Although no clear evidence of neural transdifferentiation was obtained in most of these studies [33,34,43,44], MSCs administration was sufficient to decrease axonal loss and improve neuronal survival [33,56,57], as well as to induce oligodendrocytes proliferation and remyelination [44]. These findings support the concept that MSCs are likely to foster CNS repair, acting as tolerogenic cells, elicited by inflammatory cues, on autoimmune cells and as bioactive providers of trophic and antiapoptotic factors leading to neuroprotection [51,58].
Clinical experience with mesenchymal stem cells in multiple sclerosis MSCs have been utilized in a few studies with limited numbers of patients and also as single-case, uncontrolled
treatment by many patients obtaining yet unproven stem cell therapies, a phenomenon known as ‘stem cell tourism’ [59]. Despite the fact that allogeneic MSCs have been shown to be well tolerated and effective in treating graft versus host disease (GVHD) [60], autologous MSCs from MS individuals share almost identical functional properties with those from healthy individuals [61] and, therefore, have been preferred thus far for clinical exploitation in MS. In pioneer studies, the administration of autologous MSCs, either i.v. or intrathecal, was well tolerated and, despite the lack of a proper clinical design to address efficacy, exhibited some beneficial effect on clinical and MRI parameters [62,63,64]. In order to avoid the proliferation of numerous small studies utilizing MSCs for the treatment of MS, a consensus [65] on their utilization was recently published by a panel of experts, setting the stage for an international phase II clinical trial. The consensus recognized that, at this stage, current evidence supports the i.v. administration of autologous MSCs as inhibitors of the autoimmune response in patients continuing to show inflammatory activity despite attempts to treat with immunomodulatory agents, and proof of principle of MSC biological activity on validated parameters such as MRI metrics should be achieved before testing their ability to promote tissue repair.
Neural stem cells definition Neural precursor/stem cells (NPCs) can be detected in the developing and adult CNS as a heterogeneous population of proliferating, self-renewing and multipotent cells, with the ability to differentiate toward different neuroectodermal cell lineages [66,67]. In the study [67], the authors describe that the therapeutic features of NPCs were based mainly on bystander mechanisms. In the adult CNS, at least two distinct areas, the subventricular zone of the lateral ventricles and the subgranular zone of the hippocampal dentate gyrus, have been demonstrated to contain multipotent progenitors of neural cells and, therefore, have been named CNS germinal neurogenic niches [68]. Within the neurogenic niches, NPCs are a restricted and diverse population of progenitors whose behavior is regulated by a specialized microenvironment leading to the generation of different types of neurons [69]. It has been demonstrated that endogenous NPCs residing in the germinal niches are mobilized to demyelinated periventricular lesions by inflammatory cues occurring during EAE and proliferate, giving rise to neural cells [70]. Similarly, it has been shown that activation of early glial precursors from germinal niches occurs in MS, wherein they could give rise to oligodendrocyte precursors [71]. However, the intrinsic CNS ability of undergoing self-repair is impaired during MS due to microenvironmental cues [72] that could be directly dependent on molecules associated with
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222 Demyelinating diseases
inflammation [67], due to a dysregulation of embryogenetic pathways [73], or both.
Therapeutic plasticity of neural precursor/ stem cells Although NPCs are the natural progenitors of neural cells, and NPCs-based therapies have been fairly regarded as a source for newly formed CNS cells [74], recent experimental data have shown that they display unexpected therapeutic plasticity, which mostly relies on diverse bystander effects [67]. A seminal study [75] demonstrated that i.v. or intraventricular administration of NPCs in mice with EAE led to their engraftment into demyelinating lesions and to some level of differentiation into nervous cells, including oligodendrocyte progenitors actively remyelinating axons. Despite this early report, most studies have shown very low neural differentiation of transplanted NPCs. Conversely, it was reported that systemically injected NPCs ameliorate EAE through anti-inflammatory and neuroprotective mechanisms [76,77]. These bystander mechanisms occur through the engraftment of i.v. transplanted NPCs in the perivascular area of inflamed CNS vessels where they form atypical ectopic niches and release neurotrophins, immunomodulatory molecules and factors inhibiting the formation of glial scar [67]. Recent evidence shows that i.v.
injected NPCs also display regulatory functions of the immune response within peripheral lymphoid organs through the inhibition of myelin-specific peripheral T cells [78] and an impairment of dendritic cell functions through a bone morphogenetic protein 4-dependent mechanism [79]. The study [78] shows that NPCs display also the ability to regulate autoreactive immune cells in the peripheral blood. Moreover, a recent study [80] has shown that intraventricularly transplanted NPCs could lead also to the induction of endogenous neurogenesis, as demonstrated by a mitogenic effect on host oligodendrocyte precursors. Although the clinical translation of these preclinical studies is under scrutiny, it has been demonstrated that human NPCs can be safely administered intravenously in nonhuman primates with EAE and result in the successful amelioration of symptoms and disease mainly through immunoregulatory mechanisms [81].
Other (stem) cells for the treatment of multiple sclerosis Other types of myelin-forming cells have been transplanted into rodents affected by experimental CNS demyelination [72]. For example, transplantation of oligodendrocyte progenitor cells into demyelinated lesions inside the spinal cord leads to extensive remyelination
Figure 1 The mechanisms involved in the therapeutic plasticity of adult stem cells for multiple sclerosis are depicted
HSC, hematopoietic stem cell; MSC, mesenchymal stem cell; NPC, neural precursor cell.
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SCT in multiple sclerosis Uccelli and Mancardi 223
[82]. Similar results have been obtained following the transplantation of Schwann cells [83], olfactory ensheathing cells [84] and also embryonic stem cells (ESCs) [85]. Interestingly, it has recently been shown that in-vitro differentiation of ESCs to multipotent neural progenitors ameliorates EAE but results in the loss of their capacity of remyelinate upon in-vivo transplantation [86]. Several concerns arise from these approaches. In particular, lineage-restricted myelinogenic cells show limited growth and expansion characteristics in vitro and, following in-vivo transplantation, induce scarce remyelination, often due to environmental cues limiting precursor differentiation and proliferation and their limited ability to spread far from the transplantation site [72]. Further, the use of ESCs is restricted by ethical and technical concerns about source of cells and the intrinsic risk of tumor formation. On the basis of these considerations, such strategies require further studies before their clinical exploitation for the treatment of MS.
Conclusion To date, the only ‘stem cells’ that can be considered a therapeutic option for MS are AHSCs, whose administration, however, must be mainly considered as a rescue therapy following intense immune suppression with cytotoxic drugs and may, at best, lead to an immune system less prone to autoimmunity (Fig. 1). Thus, in this case, ‘stemness’ per se does not represent a therapeutic opportunity for CNS repair. Other adult stem cells are likely to provide a realistic opportunity for remyelination and axon reorganization due to their therapeutic plasticity. It is noteworthy that results from the administration of adult stem cells in preclinical models of MS moved from almost opposite starting points to end up with some common therapeutic features, although occurring through complex and different mechanisms of action. In fact, NPCs were first described as cells giving rise to newly formed neural cells capable of remyelinating [75], then were shown to provide pleiotropic neuroprotective factors in situ [77] and, more recently, to also display a regulatory effect on the autoimmune response [78] and induce endogenous neurogenesis [80]. In contrast, MSCs were first demonstrated to induce peripheral tolerance to myelin antigens [29] and then to be capable of protecting neural cells through paracrine mechanisms [50] and even inducing local oligodendrocyte precursor proliferation [44]. Thus, a common signature defines the therapeutic plasticity of adult stem cells based on shared bystander activities, namely immunomodulation, neuroprotection and induction of endogenous neurogenesis (Fig. 1).
Acknowledgements A.U. received financial support for research, honoraria for consultation or speaking at meetings from Genetech, Roche, Allergan, Merck-
Serono and Sanofi-Aventis. G.M. received financial support for research, honoraria for consultation or speaking at meetings from Bayer-Schering, Biogen-Idec, Sanofi-Aventis and Merck-Serono. Some of the results discussed here were obtained from research supported by grants from the Fondazione Italiana Sclerosi Multipla (A.U. and G.L.M.), the Italian Ministry of Health (Ricerca Finalizzata) (A.U. and G.L.M.), the Italian Ministry of the University and Scientific Research (A.U. and G.L.M.), the ‘Progetto LIMONTE’ (A.U.) and the Fondazione CARIGE (A.U. and G.L.M.). There are no conflicts of interest.
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EDITORIAL REVIEW
Demyelination as a complication of new immunomodulatory treatments Andreas P. Lysandropoulosa and Renaud A. Du Pasquiera,b a Service of Neurology, Department of Clinical Neurosciences and bService of Immunology and Allergy, Department of Internal Medicine, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland
Correspondence to Renaud A. Du Pasquier, MD, Service of Neurology and Service of Immunology and Allergy, Centre Hospitalier Universitaire Vaudois (CHUV), BH-10, Rue du Bugnon 46, 1011 Lausanne, Switzerland Tel: +41 21 314 1228; fax: +41 21 314 1256; e-mail:
[email protected] Current Opinion in Neurology 2010, 23:226–233
Purpose of review This review discusses demyelinating events of the nervous system that have been associated with new immunomodulatory treatments, in particular monoclonal antibodies (mAbs). Recent findings Natalizumab, a mAb targeting the a-4 integrins, which is efficient in relapsing–remitting multiple sclerosis, has been associated with progressive multifocal leukoencephalopathy (PML). We will review the putative mechanisms linking natalizumab with JC virus, the agent of PML. Efalizumab, a mAb targeting a member of the integrin family, CD11a, was approved for the treatment of psoriasis, but had to be withdrawn in 2009 because of the occurrence of three cases of PML. Rituximab, an antiCD20 mAb, is used in different neoplastic and autoimmune diseases and may soon enter the pharmacopeia of multiple sclerosis. It has been suggested that rituximab is a risk factor for PML; however, evidence of such a link is unclear. Antitumor necrosis factor-alpha agents are used in several autoimmune diseases. Several cases of demyelinating events of the nervous system have been reported, prompting a heightened surveillance of treated patients. Recent data are reassuring, suggesting that the incidence of such events is relatively low. Summary Neurologists must become familiar with neurological complications of new immunomodulatory treatments, a field situated at the interface of neurology, immunology and infection. Keywords antitumor necrosis factor-alpha agents, demyelination, efalizumab, mAbs, multiple sclerosis, natalizumab, progressive multifocal leukoencephalopathy, rituximab Curr Opin Neurol 23:226–233 ß 2010 Wolters Kluwer Health | Lippincott Williams & Wilkins 1350-7540
Introduction New immunomodulatory molecules are being developed at a fast pace and are of great benefit for patients suffering from a large spectrum of disease, in particular autoimmune diseases. Among these new drugs, monoclonal antibodies (mAbs) are on the front line. Developed by Kohler and Milstein [1], the first mAbs, grown from hybridomas that produced antibodies from other species, proved to be highly immunogenic. As molecular biology progressed, chimeric and then humanized mAbs that greatly reduced the amount of foreign antibody sequences were developed [2]. mAbs are elaborated to target a precise immunological mechanism, which confers their specificity. Nevertheless, the onset of demyelinating disease, for example, progressive multifocal leukoencephalopathy (PML), in some mAbs-treated patients suggests that the mechanism of action of these drugs is not fully understood. It is important 1350-7540 ß 2010 Wolters Kluwer Health | Lippincott Williams & Wilkins
that neurologists become familiar with not only the new immunomodulatory treatments that are used as treatment for neurological disease, for example, multiple sclerosis (MS), but also those that have other indications but may have neurological demyelinating side effects.
Progressive multifocal leukoencephalopathy PML is a rare but severe viral infection of the brain, which causes demyelination by lytic infection of the oligodendrocytes [3]. PML was initially described in patients with hematological malignancies, mostly lymphoproliferative diseases, but since the 1980s, more than 80% of all cases occur in AIDS patients [4]. Despite the use of highly active antiretroviral therapies (HAARTs), the incidence of PML has not decreased as much as other central nervous system (CNS) opportunistic infections [5]. DOI:10.1097/WCO.0b013e3283398c96
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PML, which is caused by the polyoma JC virus (JCV), usually occurs in the context of severe immunosuppression, but rarely has been described in patients with minimal or occult immunosuppression [6]. The seroprevalence of immunoglobulin (Ig)G specific to JCV, in healthy blood donors, is 50% at the age of 20–29 years and rises to 68% at the age of 50–59 years [7]. IgM having never been detected in PML patients, this disease is considered to be due to reactivation of JCV rather than primo infection. JCV DNA is detected in the urine of 20–30% of healthy individuals, suggesting that the kidney is a site of latency [7]. However, JCV harvested from the urine does not infect human glial cells, and the DNA sequences of the regulatory region (the region that determines JCV replication) are different from the ones that are recovered from JCV found in the brain in cases of PML [8]. These findings suggest that the virus staying in the kidneys is not neurotropic. By contrast, JCV DNA harvested from the bone marrow, another presumed site of latency, displays sequences that are close to those in PML lesions [9,10]. In the latter compartment, JCV infects preferentially hematopoietic precursors CD34þ and B cells and uses these cells to migrate to the brain. This migration usually occurs in cases of severely decreased cellular immune competence, as even a low number of JCV VP1 (VP1 being the major capsid protein) or the virus-specific cytotoxic CD8þ T cells seems to be sufficient to maintain the virus in its latency sites [11]. Although the CNS is not considered as a primary latent site, a recent report has put this notion into question. Indeed, JCV DNA, but not full virions, was detected in oligodendrocytes and astrocytes of non-PML patients [12]. Interestingly, the neurotropism of JCV is wider than previously thought; following initial description in 2003 [13], further reports have confirmed that JCV is able to productively infect neurons of the internal granule cell layer of the cerebellum [14–17], a condition coined JCV granule cell neuronopathy [14]. Owing to the natalizumab-related PML cases, the neurological community is now more aware of this disease, the reason why we will only shortly review its clinical aspects and invite the interested reader to refer to recent reviews [4]. The diagnosis of PML remains difficult, especially in MS patients, as both diseases are leukoencephalopathies. Cognitive impairments or behavioral changes are often the heralding symptoms of PML [10,18]. Ensuing neurological deficits are typically corticospinal syndrome with motor weakness, visual disturbances due to hemianopsia and, somewhat less frequently, sensitive disorders, cerebellar ataxia, seizures and so on. Contrasting with MS, optic neuritis or spinal cord involvement is exceedingly rare. T2-weighted or fluid-attenuated inversion recovery are the best sequences to identify PML lesions on brain
MRI. Contrasting with MS, PML lesions are usually diffuse, mainly subcortical, rarely involving the periventricular area [19]. However, at the beginning, PML lesions can be unique and discrete [20]. Lesions edges are ill defined, tend to spare the cortical ribbon, destroy the U-fibers and grow asymmetrically. The posterior fossa is frequently involved [19]. Except in the context of immune reconstitution inflammatory syndrome (IRIS), PML lesions do not enhance after contrast administration and there is no mass effect. Nowadays, the diagnosis of PML rests on the detection of JCV DNA in the cerebrospinal fluid (CSF). Quantitative PCR (qPCR) techniques in experimental laboratories allow the detection of 10 copies/ml of viral DNA [21,22]. This assay is very specific (98%), and its sensitivity is reported to exceed 90% [23]. However, in practice, the sensitivity is often lower, which may be due to suboptimal processing of the sample (delay in bringing it to the laboratory, CSF kept at room temperature instead of cold, and so on). In cases of strong suspicion of PML despite repeated negative JCV DNA PCR in the CSF, brain biopsy is warranted if permitted by localization of the lesion. In HIV-negative immunosuppressed patients with PML, the only proven therapy is to relieve the immunosuppression, which is unfortunately often impossible. This fact explains why the prognosis of PML in this category of patients is grim, 10% of them surviving more than 1 year. In AIDS/PML patients, however, the prognosis is better, as HAART has raised the 1-year survival rate from 10% to more than 50% [24]. JCV uses the 5HT2A serotoninergic receptor to enter glial cells [25]. Some case reports [26– 28] have proposed that drugs, such as mirtazapine, that use the same receptor may compete with JCV for this receptor and hence decrease glial cells infection; however, a reappraisal of the effect of this drug has shown no antiviral activity at therapeutic doses [29]. Mefloquine, an antimalarial drug, has recently demonstrated an in-vitro inhibiting effect on JCV, even at relatively low doses [29]. A randomized multicentrer trial has been launched to assess the effect of mefloquine on JCV DNA levels (http://clinicaltrials.gov/ct2/show/NCT00746941).
Natalizumab Natalizumab, marketed under the name of Tysabri (Biogen Idec/Elan), is a humanized mAb, which binds to the a chain of a4b1 and a4b7 integrins that are expressed at the cell surface of hematopoietic cells [30]. Binding of natalizumab to a4b1 integrins prevents firm adhesion and diapedesis of activated lymphocytes through the blood– brain barrier (BBB) [31]. In one phase III study, the AFFIRM study (Natalizumab Safety and Efficacy in Relapsing–Remitting Multiple
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228 Demyelinating diseases
Sclerosis) [32], this drug has been shown to decrease the annual relapse rate at 1 year by 68% and the risk of sustained disability progression over 2 years by 42% as compared with placebo. In another phase III trial, the SENTINEL study (The Safety and Efficacy of Natalizumab in Combination with Interferon Beta-1a in Patients with Relapsing–Remitting Multiple Sclerosis), the combination therapy of interferon-beta 1a (IFNb1a) and natalizumab was associated with a lower annualized rate of relapse over a 2-year period than was IFNb1a alone (0.34 vs. 0.75, P < 0.001) and with fewer new or enlarging lesions on T2-weighted MRI (0.9 vs. 5.4, P < 0.001) [33]. As the blockade of a4b7 integrins prevents activated lymphocytes from crossing the epithelium of the intestinal barrier, natalizumab has been approved for the treatment of mild-to-moderate Crohn’s disease with evidence of inflammation in the United States [34]. Unfortunately, the efficacy of this drug was overshadowed by the occurrence of PML in two MS patients in the SENTINEL studies [33,35,36] and one patient in the Crohn study [37]. Thus, in 2005, Biogen Idec (Cambridge, Massachusetts, USA) and Elan (Gainesville, Georgia, USA) voluntarily suspended its marketing. After a large assessment of clinical, MRI and laboratory data of patients who had received natalizumab [19], the health authorities of the USA and Europe allowed this drug to go back on the market, provided that there would be a close postmarketing surveillance. Although there are some nuances between countries, this drug can now be given only in monotherapy and either as a first intention in aggressive relapsing–remitting multiple sclerosis (RRMS) or as a second intention in patients who failed on conventional immunomodulatory drugs, that is, IFNb or glatiramer acetate [38]. As of 9 February 2010, there had been 35 cases of PML in MS patients treated with natalizumab in monotherapy, with an overall incidence of PML of 0.52 (0.36–0.73) per 1000 natalizumab-treated patients. The incidence seems to be the highest after 2 years of infusion, being 1.29 per 1000 natalizumabtreated patients (0.84–1.91) and somewhat decreasing at later time points. At the time of writing this manuscript, two cases out of the 35 had been published and the interval between natalizumab onset and PML was 12 [18] and 14 months [20]. As natalizumab has not been consistently associated with opportunistic infections other than PML, this drug cannot be considered as a classical immunosuppressant [33]. Thus, there must be a specific mechanism that causes PML in rare patients. Deciphering this mechanism would be of great help to identify those patients at risk. By binding to integrins of CD34þ hematopoietic precursor cells, natalizumab prevents them from attaching to vascular cell adhesion molecule in the sinusoid of
the bone marrow and thus forces them to migrate out of the bone marrow [39]. Yet, an increase in CD34þ cells in peripheral blood is evident shortly after natalizumab injection [40,41]. Knowing that the bone marrow is a latency site of JCV, it has been hypothesized that cells purged from the bone marrow may carry JCV with them [42]. Consistent with this hypothesis, JCV DNA was detected by qPCR in the plasma of three of 15 (20%) and the peripheral blood mononuclear cells (PBMCs) of nine of 15 (60%) natalizumab-treated patients after 18 months of treatment. However, in studies from different groups totalling more than 2000 patients with MS, some of them being treated for up to 2 years, detection of JCV was exceedingly rare in the plasma and never present in the PBMCs [19,43,44,45,46,47]. Of note, there was no case of PML in any of these studies. Interestingly, the JCV-specific T-cell response seems to increase on natalizumab [45,48], which in itself may be a good thing, considering that such cells have been associated with containment of JCV [49]. Since T cells specific not only for JCV but also for other viral and myelin antigens seem to be increased at the same time points in natalizumab-treated patients, one can hypothesize that there is trapping of antigen-specific activated T cells in the peripheral blood [45]. Thus, a mechanism to explain the occurrence of PML in some natalizumab-treated patients is the so-called ‘double-edged sword’ theory: by blocking the BBB and thus by preventing autoimmune T cells from reaching the brain, natalizumab is very efficient, but, by doing so, this drug may also impair the immune surveillance against foreign antigens such as JCV [50,51]. Indeed, this drug decreases dramatically the number of dendritic and CD4þ T cells in the cerebral perivascular space [52] as well as B cells and T cells in the CSF for more than 6 months [53]. Yet, JCV-specific CD8þ cytotoxic T lymphocytes can be detected in the CSF of patients recovering from PML, suggesting that the protective effect of these JCV-specific CD8þ cytotoxic T cells is mediated at the CNS level [54]. Nevertheless, how would JCV reach the brain if precisely the BBB is blocked [55]? One has to postulate that either a very small number of JCV-infected cells are sufficient to bring JCV into the CNS or that JCV can freely cross the BBB, which has not been demonstrated so far. A third possibility is that JCV is already present in the brain of some individuals before natalizumab treatment. Supporting the latter hypothesis, authors have detected JCV DNA fragments in normal brain tissue [12]. Thus, it is conceivable that diminished immune surveillance plays a role in the natalizumabassociated cases of PML. However, if a decreased immune surveillance is an important feature of natalizumab, why don’t we see more often other opportunistic infections of the brain than PML? Indeed, so far, there has been ‘only’ one case each of fatal herpetic encephalitis, varicella zoster
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Demyelination and immunomodulatory treatments Lysandropoulos and Pasquier 229
virus (VZV) acute retinal necrosis, VZV encephalomyelitis [56] and ocular toxoplasmosis [57]. A patient with primary CNS lymphoma (PCNSL) was also recently reported [58]; however, the latter tumor was Epstein–Barr virus negative, which implies that this PCNSL was not due to immunosuppression and thus puts the causative role of natalizumab into question [59]. Clearly, more studies are warranted to elucidate why natalizumab is rarely but consistently associated with PML.
Management of natalizumab-associated progressive multifocal leukoencephalopathy As soon as PML is suspected, natalizumab should be stopped and plasma exchanges (PLEXs), with or without immunoabsorption, instituted. Five PLEXs have been shown to decrease natalizumab below 1 mg/ml in the plasma, a concentration that was associated with less than 50% of a-4 integrin saturation [60]. However, a consequence of this treatment is the so-called IRIS [61]. By rapidly restoring the capacity of T cells to cross the BBB, there can be a massive infiltration of PML lesions by activated T cells [62], likely including JCV-specific cytotoxic T lymphocytes [63]. Even if, ultimately, the most important factor for a favorable outcome of PML is immune reconstitution, in the case of IRIS, there can be a transient worsening of the symptoms due to the massive inflammation. On brain MRI, this is reflected by contrast enhancement and mass effect. In such cases, corticosteroids, sometimes at high doses, are warranted [20,62]. But, altogether, natalizumab-treated patients who develop PML seem to have a better outcome than other HIV-negative patients who develop PML (Biogen Idec/Elan Medical Information Services). Some authors found a rebound effect after natalizumab treatment, but, in these studies [64,65], this drug was given only for 2–3 months. Contrasting with these findings, Stuve et al. [66] found that 23 patients from AFFIRM and SENTINEL studies who had received natalizumab for about 30 months did not experience any clinical, immunological or MRI rebound 14 months after natalizumab cessation. As noted in an accompanying editorial, these findings are encouraging as they suggest that in patients who have been treated for a prolonged period, it is unlikely that there will be a sudden rebound [67]. However, it is important to notice that patients who were enrolled in AFFIRM and SENTINEL studies had a less active form of MS than patients who are currently on natalizumab.
Efalizumab and progressive multifocal leukoencephalopathy Efalizumab is a recombinant humanized mAb directed against CD11a, a component of leukocytes function-
associated antigen-1 chain (LFA1). LFA1 plays a critical role in allowing these leukocytes to egress from the peripheral circulation into sites of inflammation. Thus, inhibition of LFA1 reduces the recruitment of effector cells, thereby quelling the inflammatory responses [68]. Efalizumab was approved by the US Food and Drug Administration for the treatment of moderate-to-severe plaque psoriasis in 2003. Three out of 48 000 psoriasis patients treated with efalizumab had PML. All three had received efalizumab as monotherapy for longer than 3 years [69]. A fourth patient developed progressive neurologic symptoms and died of an unknown cause, raising the possibility that he also had PML (US Department of Health and Human Services, 2009). On 8 April 2009, Genentech (South San Francisco, California, USA) announced a phased voluntary withdrawal of efalizumab from the market based on its association with PML. Interestingly, as natalizumab, efalizumab is directed against members of the integrin family, which raises the question whether there may be a relationship between anti-integrins agents and JCV/ PML.
Rituximab Rituximab is a chimeric mouse–human anti-CD20 mAb that depletes mature circulating B lymphocytes in the blood, and apparently also in the CNS [70]. It is approved for CD20-positive B-cell non-Hodgkin’s lymphoma, untreated chronic lymphocytic leukemia (in the EU) and as a second-line treatment for rheumatoid arthritis (RA) [71]. Its mode of action may be based on the decrease not only of the humoral immune response but also of the cellular one due to dimished help provided by B cells to T cells [72]. Rituximab has also shown a strong efficacy in some severe cases of RRMS [73]. In a 48-week phase II trial [74], RRMS patients on rituximab (n ¼ 69) had significantly less active lesions on brain MRI and fewer relapses as compared with placebo group. Fewer new gadoliniumenhancing or T2 lesions and an apparent reduction in relapses were also observed compared with the year before therapy in a 72-week, open-label phase I trial in which patients received two courses of rituximab therapy 6 months apart for a total dose of 4000 mg [75]. In addition, the use of rituximab has been advocated in neuromyelitis optica [76,77]. Rituximab has been incriminated as being responsible of PML. However, this relation of causality is unclear. In a recent work, Carson et al. [10] reported 57 cases of PML in patients treated with rituximab either for lymphoma/leukemia (52) or for autoimmune diseases (5), the latter group including two patients with
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230 Demyelinating diseases
systemic lupus erythematosous (SLE). However, rituximab was always associated with other immunosuppressive treatments. Rituximab is not recommended for SLE, nevertheless, at least 8000 SLE patients have been treated with this drug and two of them developed PML [71]. Conversely, there have been so far 30 cases of PML reported in SLE patients who had never received rituximab. Thus, on the basis of these data, it seems that SLE rather than rituximab may be a trigger of PML [78]. Of note, no case of PML has been reported so far in MS patients treated with rituximab [74]. Nevertheless, these reassuring data are mitigated by the findings of Goldberg et al. [79], who followed 338 adult lymphoma patients with autologous peripheral blood stem cell transplantation. Two hundred and seventysix of them received a conditioning regimen consisting of carmustine, etoposide, cytarabine and cyclophosphamide and had no infectious complications, whereas among the 62 patients who received the same conditioning regimen and rituximab, two patients developed PML, another had a cytomegalovirus (CMV) pneumonitis and a fourth one a CMV retinitis [79]. Preliminary data suggest that there may be a reactivation of JCV in a few rituximab-treated patients with concomitant immunosuppressive drugs who have a very efficient suppression of B and T lymphocytes [80], but additional studies are warranted to confirm this hypothesis. For the time being, in Europe and in the USA, the manufacturer in collaboration with the respective health agencies proposes a patient alert card mentioning the risk of PML for patients on rituximab [71].
unexpected increase of MS relapses in the treatment group as compared with placebo [86]. Since then, additional anti-TNFa drugs have been developed, including the fusion protein etanercept and the mAbs adalimumab and infliximab. These are recognized treatments for RA, psoriatic arthritis, ankylosing spondylitis and Crohn’s disease. In 2006, the Study Group on Autoimmune Diseases (GEAS) of the Spanish Society of Internal Medicine created the BIOGEAS project, a multicenter study devoted to collecting data on the use of biological agents in adult patients with systemic autoimmune diseases [87]. Up to July 2009, 175 cases of demyelinating CNS processes after starting anti-TNFa therapies have been reported, including optic neuritis in 123, MS or MS-like (sensory disturbances, motor weakness, ataxia and so on) in 55 and others (e.g. cognitive dysfunction) in five. Eight patients presented with optic neuritis and MS-like episodes. The majority of cases occurred between 1 month and 1 year after initiation of the biological agent. Forty-four patients on anti-TNFa also presented with demyelination of the peripheral nervous system, including Guillain–Barre´ syndrome in 20, multifocal motor neuropathy with conduction block in 11, chronic inflammatory demyelinating polyradiculoneuropathy in six, axonal polyneuropathy in five and Lewis–Summer syndrome in two patients [88].
Antitumour necrosing factor-alpha and multiple sclerosis
The mechanism by which anti-TNFa medications would trigger demyelination remains unexplained. It has been hypothesized that exposure to anti-TNFa might, between other effects, increase survival of autoreactive peripheral T cells penetrating the CNS, produce proinflammatory cytokines such as IFNg and cause demyelination [89–91]. It has even been suggested that these episodes of demyelination could correspond to aborted PML [92].
There are conflicting data in the literature as to whether anti-TNFa treatment could worsen demyelination or even cause demyelination. TNFa is thought to play a significant role in the pathophysiological mechanism of several inflammatory diseases such as RA, Crohn’s disease, ankylosing spondylitis, inflammatory bowel diseases and MS [81]. High levels of TNFa have been found in plaques and in CSF of MS patients [82]. In chronic progressive MS, CSF levels of TNFa correlate with disability and the rate of neurological deterioration [83]. In experimental autoimmune encephalomyelitis, an animal model of MS, administration of anti-TNFa therapy improves the outcome of the disease [84]. On the basis of these findings, anti-TNFa treatment was advocated for MS patients. However, van Oosten et al. [85] first reported an increased immunological and MRI activity in two MS patients treated with the antiTNFa antibody cA2. Then, lenercept, a TNFa inhibitor, was administered to RR-MS patients, but led to an
However, tempering these alarming data, members of the BIOGEAS project conducted a meta-analysis [88] of randomized control trials and postmarketing studies and found that these demyelinating events were rare, ranging between 0.05 and 0.20% of anti-TNFa-treated patients. Finally, and interestingly, the failure of lenercept can be viewed differently with the current knowledge about anti-TNFa treatments; in addition to its worsening effect in MS patients, lenercept failed to be effective in patients with RA [93], which stands in sharp contrast with the high efficacy of infliximab, a more recent anti-TNFa mAb, when given to RA patients [94]. Thus, it is currently hypothesized that it was not the biological action of lenercept – that is, its anti-TNFa properties – which was responsible for paradoxical worsening of MS or RA, but rather a toxicity linked to the molecule itself or the presence of antilenercept antibodies [95].
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Demyelination and immunomodulatory treatments Lysandropoulos and Pasquier 231
Nevertheless, because of the concern that anti-TNFa treatment may trigger or worsen demyelination in some patients, a baseline brain MRI is recommended prior to the initiation of anti-TNFa treatment [95]. It has been suggested that MS patients should not be treated with TNFa inhibitors [88]. As for the demyelinating events of the peripheral nervous system on anti-TNFa treatment, it is not established that their incidence is different from the one in the general population [96].
Conclusion mAbs are very promising agents for autoimmune diseases and for MS. Nevertheless, mAbs can be accompanied by rare, but definite (at least for natalizumab and efalizumab), serious adverse demyelinating effects such as PML. Thus, postmarketing surveillance is necessary to gather information on long-term efficacy of these mAbs and on identification and management of their side effects. At the same time, neurologists must follow the indication of these mAbs and be aware of their potential demyelinating side effects. If patients are correctly informed about the potential risks of these treatments and are followed closely by informed neurologists, demyelinating side effects can be diagnosed early and thus clinical prognosis improved.
Acknowledgements This work was made possible by a grant from the Swiss National Foundation (#PP00B3-124893), a grant from the Swiss Society for Multiple Sclerosis and the Biaggi Foundation to Remote Area Development Program.
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There were no conflicts of interest.
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55 Hartung HP. New cases of progressive multifocal leukoencephalopathy after treatment with natalizumab. Lancet Neurol 2009; 8:28–31. 56 Berger JR, Houff S. Opportunistic infections and other risks with newer multiple sclerosis therapies. Ann Neurol 2009; 65:367–377. A nice review. 57 Zecca C, Nessi F, Bernasconi E, Gobbi C. Ocular toxoplasmosis during natalizumab treatment. Neurology 2009; 73:1418–1419. 58 Schweikert A, Kremer M, Ringel F, et al. Primary central nervous system lymphoma in a patient treated with natalizumab. Ann Neurol 2009; 66:403– 406. 59 DeAngelis LM. Natalizumab: a double-edged sword? Ann Neurol 2009; 66:262–263. 60 Khatri BO, Man S, Giovannoni G, et al. Effect of plasma exchange in accelerating natalizumab clearance and restoring leukocyte function. Neurology 2009; 72:402–409. This study establishes the usefulness of PLEXs in accelerating the removal of natalizumab from the blood of treated patients. 61 Tan K, Roda R, Ostrow L, et al. PML-IRIS in patients with HIV infection: clinical manifestations and treatment with steroids. Neurology 2009; 72:1458– 1464. 62 Du Pasquier RA, Koralnik IJ. Inflammatory reaction in progressive multifocal leukoencephalopathy: harmful or beneficial? J Neurovirol 2003; 9 (Suppl 1):25–31. 63 Wuthrich C, Kesari S, Kim WK, et al. Characterization of lymphocytic infiltrates in progressive multifocal leukoencephalopathy: co-localization of CD8(þ) T cells with JCV-infected glial cells. J Neurovirol 2006; 12:116– 128. 64 Tubridy N, Behan PO, Capildeo R, et al. The effect of antialpha4 integrin antibody on brain lesion activity in MS. The UK Antegren Study Group. Neurology 1999; 53:466–472. 65 Vellinga MM, Castelijns JA, Barkhof F, et al. Postwithdrawal rebound increase in T2 lesional activity in natalizumab-treated MS patients. Neurology 2008; 70:1150–1151. 66 Stuve O, Cravens PD, Frohman EM, et al. Immunologic, clinical, and radiologic status 14 months after cessation of natalizumab therapy. Neurology 2009; 72:396–401. 67 Schiess N, Calabresi PA. Natalizumab: bound to rebound? Neurology 2009; 72:392–393. 68 Molloy ES, Calabrese LH. Therapy: Targeted but not trouble-free: efalizumab and PML. Nat Rev Rheumatol 2009; 5:418–419. 69 Korman BD, Tyler KL, Korman NJ. Progressive multifocal leukoencephalopathy, efalizumab, and immunosuppression: a cautionary tale for dermatologists. Arch Dermatol 2009; 145:937–942. 70 Martin Mdel P, Cravens PD, Winger R, et al. Depletion of B lymphocytes from cerebral perivascular spaces by rituximab. Arch Neurol 2009; 66:1016– 1020. 71 Carson KR, Focosi D, Major EO, et al. Monoclonal antibody-associated progressive multifocal leucoencephalopathy in patients treated with rituximab, natalizumab, and efalizumab: a Review from the Research on Adverse Drug Events and Reports (RADAR) Project. Lancet Oncol 2009; 10:816–824. An important review on this topic. 72 Cross AH, Stark JL, Lauber J, et al. Rituximab reduces B cells and T cells in cerebrospinal fluid of multiple sclerosis patients. J Neuroimmunol 2006; 180:63–70. 73 Stuve O, Leussink VI, Frohlich R, et al. Long-term B-lymphocyte depletion with rituximab in patients with relapsing-remitting multiple sclerosis. Arch Neurol 2009; 66:259–261. 74 Hauser SL, Waubant E, Arnold DL, et al. B-cell depletion with rituximab in relapsing-remitting multiple sclerosis. N Engl J Med 2008; 358:676–688.
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Leukodystrophies with late disease onset: an update Wolfgang Ko¨hler Fachkrankenhaus Hubertusburg, Klinik fu¨r Neurologie und Neurologische Intensivmedizin, Wermsdorf, Germany Correspondence to Wolfgang Ko¨hler, Fachkrankenhaus Hubertusburg, Klinik fu¨r Neurologie und Neurologische Intensivmedizin, D-04779 Wermsdorf, Germany Tel: +49 34364 62356; fax: +49 34364 62632; e-mail:
[email protected] Current Opinion in Neurology 2010, 23:234–241
Purpose of review Knowledge of the metabolic and genetic basis of known and previously unknown leukodystrophies is constantly increasing, opening new treatment options such as enzyme replacement or cell-based therapies. This brief review highlights some recent work, particularly emphasizing results from studies in adulthood leukodystrophies. Recent findings Evidence from recent studies suggests increasing importance of metabolic dysfunctions, for example, in peroxisomal lipid metabolism or energy homeostasis, influencing axonal integrity and oligodendrocyte function and leading to white matter demyelination. In addition, diagnostic and therapeutic progress in metachromatic leukodystrophy, X-linked adrenoleukodystrophy, Krabbe diseases and other rare leukodystrophies with late onset are summarized. Summary Better understanding of leukodystrophies in neurological routine practice is of crucial importance for differentiating between other white matter diseases such as toxic, inflammatory or vascular leukoencephalopathies. Many leukodystrophies are particularly important to recognize because specific treatments already exist or are currently under investigation. The article also provides an overview of currently known leukodystrophies in adulthood. Keywords enzyme replacement, gene therapy, hematopoietic stem cell transplantation, inborn error of metabolism, leukodystrophy Curr Opin Neurol 23:234–241 ß 2010 Wolters Kluwer Health | Lippincott Williams & Wilkins 1350-7540
Introduction Leukodystrophies are genetically determined, chronic progressive white matter disorders with a variable pathogenetic background and a great diversity of clinical and paraclinical findings. Abnormalities in cerebral white matter are frequently detected by MRI in routine diagnostic procedures associated with a great variety of possible causes including multiple acquired causes and late-onset leukoencephalopathies caused by inborn errors of metabolism (IEM). Recent developments are related to increasing expertise in genotypic and phenotypic differentiation of leukodystrophies in children and adults. Sophisticated diagnostic strategies and, more importantly, advanced knowledge of biochemical and genetic background open new therapeutic opportunities with respect to metabolic treatments and gene therapy approaches.
General developments in diagnosis, treatment and understanding of leukodystrophies The interplay of myelin formation and degradation, inflammation, axonal loss and IEM is not understood 1350-7540 ß 2010 Wolters Kluwer Health | Lippincott Williams & Wilkins
widely. Recent results from experimental animal studies provided unexpected insight into the role of oligodendrocytes in supporting long-term axonal function and survival, neuroinflammation and central nervous system (CNS) demyelination [1,2]. Lack of expression of glia-specific proteins, including 20 ,30 -cyclic nucleotide 3’-phosphodiesterase (CNP), proteolipid protein (PLP) and myelin-associated glycoprotein (MAG), as well as defective peroxisomal functions causes progressive axon degeneration and inflammatory demyelination, both of which contribute to a variety of CNS diseases such as inflammatory leukodystrophies and multiple sclerosis (MS) [3,4]. These studies provide a deeper understanding of gene functions involved in hypomyelinating or demyelinating leukodystrophies and the role of glial cells in myelin formation and white matter homeostasis. In the light of substantial improvement in therapeutic efforts, such as enzyme replacement therapy or stem cell treatment, early diagnosis of the underlying IEM appears to be crucial, in both well known and previously undiagnosed leukodystrophies. As diagnoses are frequently missed in adult patients, special efforts are being undertaken to improve clinical awareness [5,6,7] and diagnostic algorithms in adulthood leukodystrophies [8]. DOI:10.1097/WCO.0b013e328338313a
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Leukodystrophies with late disease onset Ko¨hler
MRI and neurophysiological pattern recognition [8,9,10], characterization of clinical phenotypes and enhancing genetic techniques has been shown to be effective tools for optimizing diagnostic safety.
Recent developments in known leukodystrophies Increasing availability of effective treatments in specific diseases urges the need for newborn screening. As an example, detection and treatment of adrenal insufficiency in early infancy may be life-saving in X-linked adrenoleukodystrophy (X-ALD) [11], as well as early treatment with bone marrow transplantation in XALD; thus, optimized new and well tolerated newborn screening methods have been achieved [12].
Metachromatic leukodystrophy Metachromatic leukodystrophy (MLD) is an autosomal recessive neurodegenerative lysosomal disease characterized by accumulation of sulfatides, extensive white matter damage and loss of both cognitive and motor functions [13]. Its incidence is estimated to be 1 : 40 000. In vivo, the catabolism of sulfatide requires both the enzyme arylsulfatase A (ASA) and a specific sphingolipid activator protein, saposin-B, encoded by the PSAP gene. ASA activity is deficient in the classical forms of MLD with mutations in the ARSA gene, but exceedingly rare cases of MLD are due to saposin-B deficiency [14–17]. The disease manifests itself with a broad spectrum of clinical variants. During adulthood, two main clinical presentations with different genetic but identical biochemical background are described, presenting as spino-cerebellar ataxia or psychosis [18]. The correlation between MLD mutations, residual enzymatic activity associated with the mutated alleles [19] and patients’ phenotype is well established [20] and of particular relevance for patients’ prognostic evaluation, presymptomatic management and patient selection for emerging treatments. Results from hematopoietic stem cell transplantation (HSCT) have been inconclusive in MLD; however, subsets of patients may benefit from HSCT [21,22, 23]. Further improvement may be expected from new transplantation strategies using a gene therapy approach with genetically modified autologous hematopoietic stem cells or encapsulated baby hamster kidney (BHK) cells [24] that can express supraphysiological levels of ASA, thus serving as a quantitatively more effective source of functional enzyme than normal donor cells when transplanted in patients with MLD [21]. Another new approach is the treatment with pluripotent neural stem cells (NSCs). After transplanting NSCs in ARSA-deficient mice brain, the cells acquired not oligodendrocyte but
235
astrocyte cell type, with improved ASA activity and a significant amelioration of neurological deficits [25]. In addition, signs of enzyme cross-correction between transplanted and host cells were found. The success of any cell therapy approach depends on its ability to deliver sufficient amounts of gene across the blood–brain barrier to achieve distribution of the deficient enzyme throughout the brain. Intracerebral injection of a viral vector encoding human ARSA corrects the biochemical, neuropathological and behavioral abnormalities in mice and large animals [26]; however, the procedure may be too invasive in humans and not sufficient to improve enzyme levels throughout the whole brain. Alternatively, an intrathecal injection of adeno-associated viral vector serotype 1 (AAV1) was tested [27], followed by a widespread distribution of ASA activity and a significant reduction of sulfatide content in ARSA knockout mice, suggesting a useful alternative approach. Enzyme replacement therapy (ERT) has been developed recently for MLD [28,29], and a phase III trial is ongoing in late infantile MLD variants (www.Clincal Trials.gov). Recurrent intravenous treatment with the lacking enzyme significantly reduces sulfatide storage in MLD mice in a dose-dependent manner; however, the blood–brain barrier limits the access of the recombinant product to the nervous tissues. Furthermore, ERT with ASA depends on N-linked oligosaccharidemediated delivery of intravenously injected recombinant enzyme to the lysosomes of patient cells that may widely vary depending on the composition of the oligosaccharide and other secondary conditions [30].
Globoid cell leukodystrophy (Krabbe disease) Krabbe disease is an autosomal recessive neurometabolic disorder caused by the deficiency of galactocerebrosidase (GALC) activity, with an estimated incidence rate of 1 : 100 000. The enzyme defect results in the accumulation of psychosine, which leads to oligodendrocyte apoptosis, induction of gliosis and expression of proinflammatory cytokines and inducible nitric oxide synthase in astrocytes of the CNS [31]. In addition, recent studies revealed a psychosine-induced energy depletion in oligodendrocytes and astrocytes resulting in increased lipid biosynthesis [32], a phenomenon that may also participate in the disruption of the structure of lipid rafts in oligodendrocyte membranes and neurons [33]. Inflammatory cells and increased levels of cytokines and chemokines are present in the CNS and may play a significant role in the pathogenesis of the disease. The gene coding for GALC is localized on chromosome 14q31. A number of clinical phenotypes from early
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236 Demyelinating diseases
infantile to adolescent adult can be distinguished with phenotype–genotype correlation lacking, resulting in a progressive demyelinating disease of the CNS and peripheral nervous system. Clinical symptoms in early-onset variants show rapid and severe mental and motor deterioration, seizures and visual failure leading to vegetative state and death within month to 3 years. Later-onset forms progress more slowly with spastic paraparesis, hemiparesis, visual problems and cerebellar ataxia. Adult onset with polyneuropathy and psychosis is rare but possible.
pathy. As the various phenotypes frequently co-occur within the same family, involvement of disease modifier genes has been proposed; however, environmental factors like head trauma may also contribute [41]. In the search for disease modifier genes or other cofactors, recent studies highlight a putative role of polymorphisms within the methionine metabolism [42], which is of high importance, both, as a major methyl group donor for brain myelination and for oxidative stress control via a glutathione peroxidase system.
Signal abnormalities in MR are characteristic, showing deep white matter, cerebellar and long tract involvement [34,35] and cerebral atrophy. In addition, the combination of both enlargement and enhancement of multiple cranial nerves in conjunction with unusual cystic lesions adjacent to the frontal horns of the lateral ventricles has been reported [36].
Accumulation of VLCFAs is a general finding in all XALD phenotypes, but their pathogenetic importance remains to be elucidated. However, an increasing number of studies point out the deleterious effects of elevated VLCFA, such as direct toxic effects of VLCFA on glial cells and neurons from rat hippocampus in culture [43], increased pro-inflammatory secretion of effector molecules in X-ALD lymphoblasts [44], enhanced production of nitric oxide, reactive oxygen species and pro-inflammatory cytokines in VLCFA-accumulated macrophages [45], increased cytokine expression in X-ALD astrocytes [46], widespread microglial activation and apoptosis induced by lysophosphatidylcholine (C24 : 0) injection in mice brain [47] and a VLCFAdependent defective antioxidant response [48,49]. Normalization of elevated VLCFA plasma levels, therefore, continues to be a therapeutic target in X-ALD patients despite missing results from controlled clinical trials [50].
HSCT is the only available treatment for infants with early infantile Krabbe disease. Most transplanted patients show a better outcome compared with the expected clinical course from natural history cohorts but eventually develop motor and language deterioration in many cases despite treatment [37]. New treatment options are urgently warranted concomitant with upcoming results from newborn screening programs [38]. Recent animal studies in twitcher mice highlight the importance of the gene therapy approach with intracerebrally administered genetically modified neural progenitor cells leading to an increased enzyme activity in oligodendrocytes, correction of astrocytic gliosis and providing evidence for remyelination [39]. As inflammatory mechanisms are known to be involved in brain disorder in globoid cell leukodystrophy (GLD), additional anti-inflammatory treatment strategies are investigated in GLD mice, suggesting a possible role of such treatments in combination with HSCT [40].
X-linked adrenoleukodystrophy X-ALD is a neurodegenerative disorder characterized by progressive demyelination within the CNS, adrenal insufficiency and a pathognomonic accumulation of saturated very long chain fatty acids (VLCFAs) in plasma and tissues. The disease is likely the most frequent leukodystrophy with incidence rates of 1 27 000–1 : 40 000. X-ALD is caused by mutations in the ABCD1 gene that leads to loss of function of a peroxisomal membrane protein whose putative role is the transport of VLCFAs into the peroxisome for degradation by beta-oxidation. The clinical presentation ranges from a severe childhood cerebral form (CCALD), which is rapidly progressive and associated with an inflammatory response in the brain white matter, to a slowly progressive adult adrenomyeloneuropathy (AMN) variant, which presents with distal axonopathy in spinal cord tracts and peripheral neuro-
In addition, increasing evidence shows that oxidative damage is an important pathogenetic component causing neurodegeneration in X-ALD similar to in a growing number of other neurodegenerative disorders. In this context, peroxisomes are no longer regarded as autonomous but more likely as interactive organelles involved in numerous metabolic pathways including beta-oxidation of fatty acids and the metabolism of reactive oxygen species [51,52]. Dysfunction of peroxisomes may, therefore, contribute in part to white matter disease [53,54]. Recent diagnostic progress had been made with MR spectroscopy at 7 T scanners showing global elevated myo-inositol-to-creatine ratios correlating with the severity clinical phenotypes [55] and in the detection of long tract involvement in AMN phenotype using quantitative magnetization transfer techniques [56]. Although previous studies with Lorenzo’s oil provided evidence for some preventive effects in asymptomatic boys and noncerebral X-ALD variants, normalization of VLCFA plasmas levels is not fully preventive from the onset of inflammatory cerebral demyelination and the progression of neurodegeneration. In-vitro experiments demonstrate that ABCD2, a close homologue to the
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Gene
Low C27-steroid 26-hydoxylase, high cholesterol Low folate, methionine, high homocysteine, methylmalonic aciduria Organic aciduria (depending on the metabolic defect)
Autosomal recessive
Autosomal recessive
Homocysteine remethylation defects Methylenetetrahydrofolate (MTHFR) deficiency Cobalmin C deficiency Organic acidurias Glutaric aciduria type I 1-2-OH-Glutaric aciduria 3-HMG-CoA lyase deficiency 3-Methyl-glutaconic aciduria type I
b-Hexosaminidase
HEXA, 15q23–q24
CYP27A1, 2q33–qter
b-Mannosidase b-Galactosidase
MANBA, 4q22–25 GLB1, 3p21.33
Gangliosidosis (GM1-type 3, GM2)
Cerebrotendinose xanthomatose (CTX)
a-Mannosidase
MAN2B1, 19 p13.2–q12
Mannosidosis (a,b)
Iron depletion, lysosomal lipid storage Urin-free sialic acid Low fatty aldehyde dehydrogenase
a-Galactosidase A
GLA, Xq22
MCOLN1, 19p13.3–p13.2 SLC17A5, 6q14–q15 ALDH3A2, 17p11.12
Galactocerebrosidase
GALC, 14q31
Mucolipidosis, type IV Sialuria (Salla disease) Sjo¨gren–Larsson syndrome
Arylsulfatase A, urin sulfatides elevated Saposin B, urine sulfatides elevated
ARSA, 22q13.31-qter PSAP, 10q22.1
VLCFA
Biochemical defect
Metachromatic leukodystrophy (MLD) With arylsulfatase A deficiency With activator defect Globoid cell leukodystrophy (GLD, Morbus Krabbe) Fabry’s disease
Leukodystrophies with known inborn errors of metabolism X-chromosomal adrenoleukodystrophy (X-ALD) ABCD1, Xq28 Adrenomyeloneuropathy (AMN) Adult cerebral X-ALD (ACALD)
Disease
[83]
[83]
[82]
[79] [80] [81]
[78]
[76] [77]
[75]
[74]
Reference
(continued overleaf )
AMN: spastic paraparesis, sensory and autonomic dysfunctions ACALD: behavioral changes, dementia, seizures, optic atrophy, hearing loss, spasticity Psychosis, slowly progressive spasticity, ataxia, dystonia, dementia and polyneuropathy Spastic paraparesis, visual disturbances and polyneuropathy Burning pain, angiokeratomas, corneal opacifications, strokes, cardial and renal dysfunction Immune deficiency, facial and skeletal abnormalities, hearing impairment, seizures and intellectual disability Spinocerebellar ataxia Dystonia, akinetic-rigid parkinsonism, short statue, skeletal dysplasia Ataxia, dysarthria, deafness, weakness and dementia Visual disturbances, mental retardation Ataxia, progressive dementia, visceromegaly Mental retardation, spastic paraparesis, macula dystrophy and ichthyosis Spastic paraparesis, ataxia, dementia, tendon, diarrhea, cataract and xanthomata Psychosis (also as transient episodes of confusion and coma), depression, cognitive deficits, spastic paraparesis, strokes and polyneuropathy Variable signs (macrocephalia, cognitive deficits, epilepsia, supranuclear gaze palsy, optic atrophy, spasticity)
Main symptoms
Table 1 Gene, locus, biochemical defect and leading symptoms of currently known leukodystrophies with exclusive or possible adulthood presentation
Leukodystrophies with late disease onset Ko¨hler 237
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[86] [87] [88]
[89,90]
Very slow progressive spasticity and dementia, dystonia, ataxia and seizures Dementia, bladder dysfunction, upper and lower motor neuron disease and parkinsonism Transient stroke like episodes and dementia
Bulbar signs, palatal myoclonus, cerebellar ataxia, urinary disturbance and spastic paraparesis
MLC1, 22q13.33 GBE, 3p14 NOTCH3, 19p13.2–p13.1
GFAP, 17q21, NDUFV1, 11q13
deficient ABCD1, exhibits a high degree of functional redundancy on the catabolism of VLCFA. Although ABCD2 function is not associated with specific phenotypes [57], activation of ABCD2 is able to prevent X-ALD-related neurodegeneration in mice [58]. Further studies with compounds overexpressing ABCD2 function, such as thyromimetics [59,60], are needed to confirm previous results in vivo. A second therapeutic target is currently focusing on regenerative aspects. Viral vectors engineered to produce insulin-like growth factor-1 or neurotrophin-3 were administered into the cerebrospinal fluid (CSF) of an X-ALD mouse model resulting in significant effects on neurodegeneration [61].
References for further reading are given for leukodystrophies that are not described in detail in the article.
[85] Slowly progressive spastic paraparesis, ataxia and dementia DARS2, 1q25.1
[84] metabolism EIF2B1-5 LMNB1, 5q23.3–q31.1 Autosomal dominant or sporadic
Leukodystrophies without a known inborn error of Vanishing white matter disease (VWMD) Autosomal dominant leukodystrophy (ADLD) Adult-onset leukoencephalopathy with axonal spheroids and pigmented glia Hereditary diffuse leukoencephalopathy with axonal spheroids (HDLS) Familial pigmentary orthochromatic leukodystrophy (POLD) Leukencephalopathy with brainstem and spinal cord involvement and elevated lactate (LBSL) Megalencephalic leukodystrophy with cysts (MLC-1) Adult polyglucosan body disease (APBD) Cerebral autosomal dominant arteriopathy with subcortical infarcts and leuko-encephalopathy (CADASIL) Alexander’s disease
Progressive spasticity, ataxia and dementia Slowly progressive spasticity and ataxia Memory disturbances, mood disorders, epilepsia, spasticity. More rapid progression in POLD
Gene Disease
Table 1 (continued )
Biochemical defect
Main symptoms
Reference
238 Demyelinating diseases
Up to now, allogeneic HSCT is the only promising treatment in cerebral inflammatory X-ALD variants, provided that it can be performed at an early stage of the disease. The long-term benefits of HSCT in X-ALD are mediated by the replacement of brain microglial cells derived from donor bone marrow myelo-monocytic cells. In contrast to a generally high mortality rate in untreated patients with cerebral inflammatory disease, HSCT is able to halt X-ALD progression in more than half of the treated patients [62]; however, human leukocyte antigen (HLA)-matched donors are not always available and procedure-related toxicity is high. A recent study reported results from a hematopoietic stem cell gene therapy approach using an ex-vivo lentivirus-mediated transfer of the ABCD1 gene into CD34þ cells from two boys with cerebral X-ALD [63]. ABCD1 protein was stably expressed in 9–14% of granulocytes, monocytes, T and B cells and bone marrow progenitors in both patients throughout the 24–30 months of follow-up, respectively. The clinical results were comparable to that achieved by allogeneic HSCT, showing halted cerebral demyelination beginning 14–16 months after the transplantation.
Advances in other leukodystrophies and overview Recent work highlights the clinical and genetic heterogeneity in eIF2B-related disorders including vanishing white matter disease and ovarioleukodystrophy [64, 65–67] with onset of symptoms at all ages, indicating that the disease most likely is widely underestimated. Neurological features are dominated by cerebellar ataxia and spasticity with relatively preserved mental abilities. Brain MRI shows abnormal increased T2 signal of the cerebral white matter and cystic degeneration, best seen in FLAIR sequences. A reduced asialotransferrin-totransferrin ratio in the CSF appears to be highly sensitive and specific to identify patients with likely eIF2B-related disorder for mutation analysis [68].
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Leukodystrophies with late disease onset Ko¨hler
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Adult-onset autosomal dominant leukodystrophy (ADLD) is a rare but important differential diagnosis mimicking MS. A relapsing course is possible with spastic paraparesis, cranial nerve dysfunction and autonomic dysfunctions. Ataxia and cognitive disturbances are seen less frequently. Familial occurrence of progressive neurological illness suggestive of chronic MS is also highly suspicious of ADLD. The autonomic symptoms, which involve bowel and bladder regulation and orthostatic hypotension, may be the earliest changes. Patchy white matter lesions with frontal preponderance, involvement of cerebellar peduncles and spinal cord atrophy [69] are characteristic MRI features. The gene defect has been localized on chromosome 5q23, frequently as a lamin B1 gene (LMNB1) duplication [70,71].
and Krabbe disease. Finally, hematopoietic stem cell gene therapy in X-ALD appears to be a very promising treatment strategy that clearly warrants further clinical trials in X-ALD and other life-threatening leukodystrophies.
Adult-onset leukodystrophy with neuroaxonal spheroids usually commenced with behavioral changes, progressive dementing illness and epilepsy and with impaired neurological functions later in the clinical course. Axonal degeneration, myelin loss, lipid laden or pigmented macrophages, gliosis and axonal spheroids are the pathological hallmarks [72]. MRI revealed bilateral, symmetric T2 hyperintense and T1 hypointense white matter abnormalities predominantly involving the frontal lobe in most patients. Two distinct entities with an autosomal dominant pattern of inheritance as well as sporadic cases had been described: hereditary diffuse leukoencephalopathy with axonal spheroids (HDLS) and familial pigmentary orthochromatic leukodystrophy (POLD), both showing a considerable overlap in their morphologic findings, suggesting that these diseases may all be part of the same disease spectrum [73].
1
Growing numbers of genetically defined or yet undefined leukodystrophies with possible or exclusive late disease onset are reported (Table 1), underlining an urgent need for further research in adulthood leukodystrophies. Most but not all leukodystrophies are combined with inborn errors of metabolism, which sometimes provides the essential diagnostic clue [74–76,77,78,79,80,81–90].
Conclusion
Acknowledgements This work was supported in part by the German Federal Ministry of Education and Research grant 01GM0641 (German Leukodystrophy Network, LEUKONET, www.leukonet.de).
References and recommended reading Papers of particular interest, published within the annual period of review, have been highlighted as: of special interest of outstanding interest Additional references related to this topic can also be found in the Current World Literature section in this issue (pp. 331–332). Kassmann CM, Lappe-Siefke C, Baes M, et al. Axonal loss and neuroinflammation caused by peroxisome-deficient oligodendrocytes. Nat Genet 2007; 39:969–976.
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Cell therapies such as bone marrow transplantation have been successfully established in cerebral X-ALD, MLD
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Investigations and treatment of chronic inflammatory demyelinating polyradiculoneuropathy and other inflammatory demyelinating polyneuropathies Jennifer A. Tracy and P. James B. Dyck Department of Neurology, Mayo Clinic, Rochester, Minnesota, USA Correspondence to P. James B. Dyck, Department of Neurology, Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USA E-mail:
[email protected] Current Opinion in Neurology 2010, 23:242–248
Purpose of review The evaluation of demyelinating polyneuropathies and the data for treatment of inflammatory demyelinating peripheral neuropathies, particularly chronic inflammatory demyelinating polyradiculoneuropathy (CIDP), will be discussed. Recent findings A large clinical trial showed short and long-term efficacy of intravenous immunoglobulin (IVIG) for the treatment of CIDP and the US Food and Drug Administration approved the use of IVIG (Gamunex) as a treatment for CIDP. Recent trials for other agents for CIDP treatment have not proved as promising, with a large study of methotrexate failing to show significant benefit. There are recent cases of monoclonal antibodies (e.g. rituximab, alemtuzumab) showing benefit in patients with CIDP, but the side effect profiles can be worrisome. Summary Clinical history, neurological exam, spinal fluid examination, and electrophysiological evaluation remain mainstays for the diagnosis of demyelinating inflammatory polyradiculoneuropathy. Genetic testing and nerve biopsy are important diagnostic tools in some patients. Potential treatments for immune-mediated demyelinating polyradiculoneuropathies are varied, with the authors generally favoring IVIG and/or corticosteroids as first-line agents. Plasma exchange can be helpful in selected patients. Data for efficacy of other oral immunomodulatory agents are based primarily on case reports and case series, and have not been uniformly positive. The use of monoclonal antibodies (particularly rituximab) may have promise, but further research needs to be done, and the risks need to be carefully considered. Keywords chronic inflammatory demyelinating polyradiculoneuropathy, CIDP, intravenous immunoglobulin, peripheral neuropathy Curr Opin Neurol 23:242–248 ß 2010 Wolters Kluwer Health | Lippincott Williams & Wilkins 1350-7540
Introduction There is a wide range of causes for demyelinating polyneuropathies, and the underlying pathophysiology is very important for appropriate diagnosis, treatment, and prognostication. Inherited demyelinating polyneuropathies, such as hereditary motor and sensory neuropathy type 1 (HMSN1), and hereditary motor and sensory neuropathy type 3 (HMSN3, Dejerine-Sottas) do not respond to immune therapy and so need to be recognized. The diagnosis of acquired demyelinating polyneuropathies is of particular interest, because of the potential treatable nature of these diseases. The classic syndromes are acute inflammatory demyelinating polyradiculoneuropathy (AIDP, Guillain-Barre´ syndrome) and chronic inflammatory demyelinating polyradiculoneuropathy (CIDP), 1350-7540 ß 2010 Wolters Kluwer Health | Lippincott Williams & Wilkins
but many variants have been described, including MillerFisher syndrome, Lewis Sumner syndrome (focal or multifocal forms of CIDP), chronic inflammatory demyelinating mononeuropathy (CIDM), chronic inflammatory sensory polyradiculopathy (CISP), chronic ataxic neuropathy with ophthalmoplegia, monoclonal protein, and disialosyl antibodies (CANOMAD), other demyelinating neuropathies associated with the presence of monoclonal proteins [monoclonal gammopathy of undetermined significance (MGUS)-associated neuropathy, anti-myelin-associated glycoprotein (MAG) neuropathy, lymphoma-associated neuropathy], and possibly neuropathies associated with diabetes mellitus and multifocal motor neuropathy (MMN). Drug or infection-induced demyelinating neuropathies also need to be considered. We will review the investigations required for an accurate assessment of DOI:10.1097/WCO.0b013e3283394203
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Demyelinating polyneuropathies Tracy and Dyck 243
demyelinating neuropathy, and evidence for the efficacy of treatment. Given the scope of the topic, we will focus our review of treatment options primarily on CIDP.
Investigations The investigation of a demyelinating neuropathy begins with a careful history and physical examination. Important clues to an inherited cause include early onset and slow progression of symptoms/signs, a long history of ‘weak ankles’ with multiple sprains, symmetric findings, lack of or minimal positive sensory findings, a family history, either of known neuropathy or of ‘inverted champagne bottle legs’, high arches and hammertoes. The presence of late onset, rapid progression, focal onset and/or progression, preceding infection and/or immunization, and lack of family history suggests an acquired cause. A history of co-existing diseases and medications is necessary. The presence or absence of prior response to immunomodulatory therapy is important to ascertain. Findings on physical examination consistent with a protracted course (hammertoes, high arches, thin calves) are supportive of an inherited cause, but are not specific for this. Evaluations include nerve conduction studies/electromyography, cerebrospinal fluid (CSF) examination, complete blood count, electrolytes (including fasting glucose), monoclonal protein study, human immunodeficiency virus (HIV) testing, rheumatologic testing, and genetic testing. CSF analysis usually shows a cyto-albuminologic dissociation, with elevated protein with minimal or absent pleocytosis, in CIDP more than in inherited demyelinating polyradiculoneuropathies. Increased CSF white blood cell count is suggestive of an infectious cause, an alternative inflammatory cause (such as sarcoidosis), or of an underlying malignant process such as lymphoma. Cultures and cytology can be helpful in making these distinctions, and CT and/or PET scanning of the body may help reveal diagnostic abnormalities. The presence of a monoclonal protein in the blood (or urine) should initiate hematologic work-up for the presence of lymphoma, osteosclerotic myeloma and Castleman’s disease (in association with POEMS syndrome: polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, skin changes), MGUS, or other specific hematological abnormality. In some situations, testing for anti-MAG antibodies may be of utility. Rheumatologic testing may suggest the presence of an associated connective tissue disease. Genetic testing is commercially available for several known causes of inherited demyelinating polyneuropathy including abnormalities in PMP-22, myelin protein zero, EGR2, LITAF, and connexin-32 [1]. Classic electrodiagnostic features of demyelination include prolonged distal/peak motor and sensory latencies, prolonged F-wave latencies, temporal dispersion, and
conduction block. Uniform slowing of nerve conduction is suggestive of an inherited demyelinating polyneuropathy [2–4]. The presence of nonuniform slowing of nerve conduction, temporal dispersion and conduction block is felt to occur more frequently in acquired demyelinating polyneuropathies [2,3] but can also be seen in inherited disorders [5]. Mutations in connexin-32 have been reported to be associated with heterogeneous motor nerve conduction slowing between nerves in females [6]. Hereditary neuropathy with liability to pressure palsies, although usually easy to distinguish from these other disorders on electrophysiologic criteria, can also show conduction block as well as prolonged distal latencies. More recently, it has been suggested that the determination of terminal latency index (TLI) can help distinguish between anti-MAG neuropathy and HMSN1 [7]. There are several published recommended criteria for the diagnosis of CIDP [8–11] but no universally adopted consensus. It has been argued that the published criteria, although useful for research purposes, may be too rigid for clinical practice, and may exclude many patients with CIDP [12]. Nerve biopsy may be useful in selected patients for whom the diagnosis of an inherited or acquired demyelinating neuropathy is in question, and can often be helpful in the diagnoses of unexpected abnormalities such as sarcoidosis and vasculitis. There are limitations to nerve biopsies in these cases; as CIDP is often motor and proximal predominant, a sural nerve biopsy may fail to show diagnostic pathological changes. In addition, the major diagnostic changes are sometimes seen on teased fiber evaluations, which are not routinely performed at many institutions. Characteristic findings for CIDP, if present, include increased rates of segmental demyelination and remyelination on teased fiber evaluation, the presence of thinly myelinated fibers or ‘naked axons’ (lacking a surrounding myelin sheath), onion bulbs, and increased inflammation. A recent study by the authors showed that the pattern of onion bulb distribution can be predictive of acquired versus inherited cause, with a mixed pattern of onion bulbs (onion bulbs interspersed with normally myelinated axons) more predictive of an acquired cause, and a generalized pattern (all or nearly all axons in the specimen surrounded by onion bulbs) more predictive of an inherited demyelinating polyneuropathy [13]. In some cases, when the neuropathic process is focal and does not involve easily biopsied sensory nerves, and when there are focal findings on neuroimaging (including abnormal T2 signal, focal nerve enlargement, and/or contrast enhancement), fascicular biopsies of more proximal nerves, sometimes motor, have been performed. These biopsies require access to radiologists and surgeons with particular skill in interpreting magnetic resonance imaging (usually 3 Tesla) of peripheral nerve, and in
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244 Demyelinating diseases
performing these biopsies with attention to removing a limited number of affected fascicles. A fascicular biopsy of motor nerve introduces the risk of causing a new motor deficit, and is only suitable for a limited subset of patients.
of IVIG-treated patients, and 88% of oral immunosuppressant-treated patients had improved strength. The typical intravenous methylprednisolone dosing used in this study was 1000 mg/day for 3–5 consecutive days, followed by 1000 mg weekly for the next month, with variable tapering after that point [16].
Treatment
Whereas corticosteroids can be beneficial in patients with CIDP, side effect management must be aggressive. We recommend calcium and vitamin D supplementation, weight-bearing exercise, and bisphosphonates for patients on long-term therapy [17]. In addition patients with long-term steroid use should receive Pneumocystis carinii prophylaxis. Fasting blood sugar and electrolytes should be monitored. Corticosteroids can have other untoward side effects (e.g. elevated blood pressure, cataracts), and close partnership between the neurologist and primary care doctor is necessary to make sure side effects are adequately controlled.
The judicious use of physical therapy and assistive devices such as ankle–foot orthoses, canes and safety measures in and outside the home are of the utmost importance for all patients with peripheral neuropathy, whatever the type. These will not be discussed further here, nor will we focus on the primary treatment of malignancy, infection or associated hematologic or rheumatologic diseases associated with demyelinating neuropathies. Our treatment discussion will focus upon the immunomodulatory agents used for the treatment of acquired demyelinating neuropathies, with our primary focus on CIDP.
Intravenous immunoglobulin Corticosteroids
Corticosteroids (typically oral prednisone) have been used extensively for the treatment of CIDP. These are clearly useful agents for many patients, though the literature for its efficacy is actually quite limited. A trial of 28 patients with CIDP treated with 3 months of oral prednisone showed small improvements in neurological disability and muscle strength [14]. In a prospective study of 10 CIDP patients treated with oral methylprednisolone, 500 mg weekly for 3 months, with subsequent dose adjustments based on clinical judgment, 6/9 patients who completed the study went into remission, after a mean of 27 months of treatment, with continued remission being achieved for a mean of 29 months (though none of the patients achieving remission had relapsed at the end of the study). The mean dose at 1 year was 316 mg/week of oral methylprednisolone. The median weight increased from 190 pounds before treatment to 215 pounds by 1 year after treatment, and over 3 years time, 5/9 patients had evidence of osteoporotic bone density loss on dualenergy X-ray absorptiometry scans [15]. These studies provide evidence of efficacy of oral corticosteroids in patients with CIDP, but there are concerns about the long-term tolerability of these medications. One potential strategy for dealing with this problem has been to use intravenous corticosteroids for disease management. A retrospective study of 39 patients who received primary treatment with oral prednisone or cyclosporine, versus treatment with intravenous methylprednisolone or intravenous immunoglobulin (IVIG) showed no statistically significant difference in the increase of strength attained in patients in each of those three categories. By the end of the analysis, 81% of intravenous methylprednisolone-treated patients, 86%
In a double-blind, placebo-controlled trial of IVIG (5 days) versus placebo in 28 patients, 4/15 patients in the IVIG group improved, as did 3/13 in the placebo group, with no statistically significant differences between the groups [18]. Subsequent trials with more patients and longer periods of treatment have, however, shown more promising results. A trial of 20 patients treated with IVIG or plasma exchange showed that they were both effective in CIDP [19]. Another study treated 30 patients with either IVIG (0.4 g/kg/day 5 days) or placebo and found statistically significant improvements in the IVIG-treated patients in neurological disability score, clinical grade, and grip strength [20]. A randomized double-blind trial of IVIG in 53 CIDP patients treated them with either 1 g/kg IVIG on days 1, 2, and 21, versus placebo, with evaluation of effect on muscle strength using a scale called the average muscle score (AMS). There were statistically significant improvements in AMS in the treated group at a day 42 follow-up; 11/30 patients treated with IVIG showed improvement on the Hughes’ functional disability scale by at least one functional grade. The most common side effect in this group was headache (67 versus 44% in the placebo group) [21]. That same year, a randomized double-blind cross-over trial of CIDP patients with 6 weeks of oral prednisolone (60 mg tapering down to 10 mg daily) versus IVIG (2 g/kg, over 1–2 days) showed improvements in disability score with both treatments, but no significant difference between groups [22]. Hughes et al. [23] published results of a large doubleblinded, placebo-controlled trial of the use of IVIG in CIDP patients. This trial included a short-term follow-up period, with a cross-over period for nonresponders, and an
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Demyelinating polyneuropathies Tracy and Dyck 245
extension phase for responders; 117 patients were included in the trial. The treatment group received a loading dose of 2 g/kg IVIG over 2–4 days, followed by maintenance infusions of 1 g/kg over 1–2 days every 3 weeks, for up to 24 weeks; the placebo group received albumin infusions. At the end of 24 weeks, 54% of the patients treated with IVIG and 21% of patients treated with placebo showed an improved INCAT disability score (the difference between groups was statistically significant). During the 24-week extension phase of the trial, patients treated with IVIG had a 13% probability of relapse compared to 45% of the patients treated with placebo. The most common side effects reported for the IVIG-treated patients were headache (32% patients), pyrexia (13% patients), and hypertension (9% patients). This large trial was very helpful in providing evidence for the efficacy of IVIG, and the US Food and Drug Administration (FDA) approved the use of IVIG (Gamunex) for the treatment of CIDP in late 2008. Plasma exchange
In 1986, Dyck et al. [24] performed a prospective trial of plasmapheresis treatment in patients with CIDP; 15 were treated with plasma exchanges and 14 received sham exchange over a 3-week period. Patients treated with plasma exchange had significant improvements in combined nerve conduction measurements compared with untreated patients. Hahn et al. [25] treated 18 CIDP patients with plasmapheresis in a cross-over double blind trial; 80% of the 15 patients who completed the trial showed significant improvement with plasma exchange. Of note, 8 of the 12 patients who showed a treatment response to plasma exchange had relapse within 2 weeks of the conclusion of treatment. Determining electrophysiologic parameters of response to plasma exchange has been difficult, with one study showing significant improvements in proximal ulnar M-wave amplitudes and areas with plasma exchange [26].
insufficient to detect significant responses [28]. Pentland et al. [29] described five patients with relapsing inflammatory polyneuropathy, four of whom had sustained improvement with the use of azathioprine (the maximum azathioprine dose used in this study was 300 mg/day), though some (if not all) patients were on concurrent corticosteroids or adrenocorticotropic hormone at the time of improvement. The authors also noted that the fifth patient was able to replace his corticosteroids with azathioprine. Dalakas and Engel [30] have also reported on a benefit of azathioprine in three of four steroidunresponsive patients. Mycophenolate mofetil
Mowzoon et al. [31] reported on two patients with CIDP, one with an associated monoclonal protein, and the other with diabetes mellitus, with good initial clinical response to mycophenolate mofetil. Umapathi and Hughes [32] described five patients (four with CIDP, one with multifocal motor neuropathy), unresponsive to other immunomodulatory treatment modalities, who were treated with mycophenolate mofetil, with a target dose of 1000 mg twice a day; the median treatment period was 5 months. Two of the CIDP patients were felt to have a minimal response to mycophenolate (one was treated for 11 months and the other for 5 months), though both patients discontinued the medication, one because of diarrhea, and one because ‘he did not feel better’ despite an increase in his Medical Research Council (MRC) score. Chaudhry et al. [33] reported improvements in strength in one of three CIDP patients treated with mycophenolate. Another trial of mycophenolate in immune-mediated neuropathies included 13 CIDP patients, and there were no significant improvements in MRC strength scores, sensory scores, or Rankin disability score, though three of the CIDP patients were individually felt to have some clinical improvements [34]. Methotrexate
Dyck et al. [19] treated 20 patients with either IVIG (0.4 g/kg weekly 3 weeks, then 0.2 g/kg weekly 3 weeks) or plasma exchange (twice a week for 3 weeks, then weekly for 3 weeks); there was then a washout period and a cross-over to the alternate treatment. Whereas patients in both groups showed significant improvements, there was no significant difference in outcomes between the IVIG and plasma exchange treatments. Azathioprine
A single randomized controlled trial of 27 patients comparing treatment with prednisone versus treatment with prednisone and azathioprine failed to show a significant outcome difference between the two groups [27], though the treatment period was only 9 months and there has been criticism that the dose (2 mg/kg/day) may have been
A retrospective study of 10 patients with CIDP treated with methotrexate (10–15 mg weekly doses), all of whom had previously been treated with at least two other immunomodulatory agents, showed improvement of MRC score by at least 2 points in 7 patients, leading the authors to suggest that a randomized controlled trial should be initiated [35]. A multicenter trial of 60 patients, all of whom were concurrently using corticosteroids or IVIG, treated patients with either placebo or methotrexate (7.5 mg weekly 4 weeks, then 10 mg weekly 4 weeks, and then 15 mg weekly for 32 weeks) used a primary endpoint of 20% reduction in mean weekly dose of either concurrent corticosteroid use or IVIG use by the end of the trial. Overall tolerance of methotrexate was good; lymphopenia occurred in 37% of the methotrexate group versus 18% in the placebo group. There was a significantly higher infection rate in the placebo group
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246 Demyelinating diseases
(34%) than in the methotrexate group (14%) and a higher rate of mouth ulcers in the placebo group (16%) than in the methotrexate group (0%). No serious adverse events in either group was felt to be drug-related. Unfortunately, there was no significant difference in primary outcome between the methotrexate and the placebo group. The authors speculate that the lack of response could potentially have been due to either inadequate drug dosage or treatment duration, though they point out that the dose used in their trial was equal to that used in trials showing efficacy in autoimmune rheumatologic diseases [36]. A recent case report [37] described a 63-year-old patient with treatment-refractory CIDP, with a dramatic response with the use of weekly methotrexate. Cyclosporine
Barnett et al. [38] retrospectively reviewed 19 patients with treatment-refractory CIDP who were treated with cyclosporine A, and found that in the group with progressive CIDP, mean disability scores decreased, and in the relapsing group, the mean annual incidence of relapse decreased. Mahattanakul et al. [39] reported on eight patients with CIDP treated with cyclosporine A, for whom treatment was felt to be successful in three. Matsuda et al. [40] treated seven patients with refractory CIDP with cyclosporine A (titrated to plasma trough concentration 100–150 ng/ml) and found that grip strength was significantly increased, and modified Rankin and INCAT disability scores were significantly decreased; all had subjective symptom improvement. Cyclophosphamide
Good et al. [41] retrospectively reviewed the cases of 15 patients with CIDP treated with intravenous cyclophosphamide monthly for up to 6 months, and found that 11 of these patients had a complete remission, and 12 ‘returned to routine work’. All of the patients had drug-induced leukopenia, which normalized after 2–3 weeks; other complications reported included nausea, lightheadedness, headache, rash, alopecia, and reduction in hematocrit. The authors note that the best patient outcomes occurred when the disease had been present less than 10 months by the time of treatment. Brannagan et al. [42] treated four patients with CIDP and partial resistance to other therapies, with high-dose cyclophosphamide (200 mg/kg divided over 4 days), and all had improvement in strength and functional status. All patients received forced diuresis as well as mesna. Complications included neutropenic fever, reversible renal insufficiency, congestive heart failure, and Escherichia coli bacteremia, among others. Stem cell transplantation
Remenyi et al. [43] reported on a patient with CIDP with good response to allogeneic hematopoietic stem cell transplantation. Vermeulen and Van Oers [44] reported on a CIDP patient with good response to autologous stem
cell transplantation. However, they later reported that the same patient had a relapse 5 years after receiving his transplant, and he started treatment with IVIG [45]. Axelson et al. [46] described a severely affected CIDP patient who responded well to high-dose cyclophosphamide and autologous stem cell transplantation, and after relapse, responded to repeat treatment. Oyama et al. [47] described a treatment-refractory CIDP patient who responded well to nonmyeloablative autologous hematopoietic stem cell transplantation, with no exacerbations over a 22-month follow-up period. Rituximab and other monoclonal antibodies
Rituximab is a monoclonal antibody which targets the B-cell antigen, CD20, and has been used for the treatment of various types of autoimmune disease; recent attention has been given to its possible role in CIDP, particularly in patients in whom there is evidence of a significant antibody-mediated cause. Briani et al. [48] reported significant clinical improvement in a patient with an IgM kappa monoclonal protein and CIDP. Individual studies have also shown efficacy of rituximab in patients with CIDP and associated idiopathic thrombocytopenic purpura [49], Evans syndrome [50], sulfoglucuronyl paragloboside (SGPG) IgM antibodies [51], and diabetes mellitus [52]. A small trial was performed, with two patients with CIDP, two with MMN, one with anti-MAG neuropathy, and one with Sjo¨gren’s associated neuropathy, all of whom required the chronic use of IVIG. All patients received at least 4 weekly doses of rituximab at 375 mg/ m2, and the primary endpoint was reduction in IVIG dosage by 25% at 1 year after therapy. Only two patients were considered to be responders by this criterion (one with Sjo¨gren’s and the other with MMN); one of the CIDP patients had no change in overall IVIG dose and the other had increasing need for IVIG during the trial [53]. Renaud et al. [54] reported on nine patients with antiMAG antibody associated peripheral neuropathy treated with rituximab, and noted clinical improvement in six, though in all patients peripheral blood B-cell count was below the level of detection. Pestronk et al. [55] reported on 21 patients with neuropathy with associated serum IgM antibodies, treated with rituximab, and found that 18 had an improvement in strength of at least 12% of normal. Niermeijer et al. [56] prospectively treated 17 patients with severe MGUS-associated neuropathies (16 with demyelinating neuropathies) with rituximab and only 2/17 met the primary outcome of a one point or greater improvement on the Overall Disability Sum Score (ODSS), though there was an improvement of 5% or greater improvement of the distal summated MRC score in 4 and in the sensory summated score in 9. Of note, the patient with the greatest improvement on the ODSS was the single patient defined as having an axonal neuropathy.
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Demyelinating polyneuropathies Tracy and Dyck 247
Etanercept (25 mg twice per week) was given to 10 refractory CIDP patients and 3 were felt to have ‘significant improvement’, whereas 3 others showed ‘possible improvement’ [57]. However, cases of CIDP have been reported associated with the use of antitumor necrosis factor antibody use (etanercept, infliximab) [58]. There is a single case report of a 19-year-old woman with CIDP, with frequent relapses, who, whereas responsive to IVIG, did not respond to corticosteroids, and had only a partial response to azathioprine, who was treated with alemtuzumab – a monoclonal antibody to the CD52 antigen (which leads to decreases in T and B lymphocytes and monocytes). She appeared to have some clinical benefit, but did have subsequent relapses which required further IVIG treatments [59]. Alemtuzumab is currently approved by the FDA for treatment for B-cell chronic lymphocytic leukemia, and most of the neurologic experience and interest in this treatment has been for its potential benefit in multiple sclerosis [60]. Though there is evidence for its efficacy, there is potential risk, with one large trial showing 23% developing autoimmune thyroid disease and 3% developing immune thrombocytopenic purpura [61].
limited, and the side effect profile is worrisome, and the authors are not currently using this agent for their CIDP patients.
References and recommended reading Papers of particular interest, published within the annual period of review, have been highlighted as: of special interest of outstanding interest Additional references related to this topic can also be found in the Current World Literature section in this issue (pp. 332–333). 1
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Lewis RA, Sumner AJ. The electrodiagnostic distinctions between chronic familial and acquired demyelinative neuropathies. Neurology 1982; 32:592– 596.
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Conclusion The diagnosis of demyelinating neuropathy is usually straightforward based on history, physical and electrophysiological findings, but the next step, identifying whether a treatable neuropathy exists, has more pitfalls. The lack of clear consensus criteria for the diagnosis of CIDP makes the situation more complex, as well as limitations in commercial genetic testing for suspected inherited neuropathies. A search for underlying disease, such as diabetes mellitus, hematological malignancy, and HIV, is necessary to assess whether treatment should be focused solely on the underlying neuropathic process or on a more diffuse disorder. Once a diagnosis of CIDP is established, careful evaluation of the risks and benefits of each potential treatment should be considered for an individual patient. The authors generally use IVIG and/or corticosteroid treatments (often intravenous) as first-line agents, unless there are contraindications to their use, and the FDA has recently approved IVIG (Gamunex) for the treatment of CIDP. If corticosteroids are not able to be weaned over time (as in most cases), a steroid-sparing agent is generally added. There is not good head-to-head data of the oral steroid-sparing agents, and the choice is usually based on side effect profile and the patient’s coexisting medical conditions. Monoclonal antibodies such as rituximab have shown benefit in individual patients, but the authors are not presently using these as first-line agents in patients with CIDP (and no monoclonal protein), and encourage controlled clinical trials. The data for alemtuzumab is extremely
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48 Briani C, Zara G, Zambello R, et al. Rituximab-responsive CIDP. Eur J Neurol 2004; 11:788. 49 Benedetti L, Franciotta D, Beronio A, et al. Rituximab efficacy in CIDP associated with idiopathic thrombocytopenic purpura. Muscle Nerve 2008; 38:1076–1077. Shows improvement in CIDP patient with use of rituximab. 50 Knecht H, Baumberger M, Tobon A, et al. Sustained remission of CIDP associated with Evans syndrome. Neurology 2004; 63:730–732. 51 Gono T, Matsuda M, Shimojima Y, et al. Rituximab therapy in chronic inflammatory demyelinating polyradiculoneuropathy with anti-SGPG IgM antibody. J Clin Neurosci 2006; 13:683–687. 52 Munch C, Anagnostou P, Meyer R, et al. Rituximab in chronic inflammatory demyelinating polyneuropathy associated with diabetes mellitus. J Neurolog Sci 2007; 256:100–102. 53 Gorson KC, Natarajan N, Ropper AH, et al. Rituximab treatment in patients with IVIg-dependent immune polyneuropathy: a prospective pilot trial. Muscle Nerve 2007; 35:66–69. 54 Renaud S, Gregor M, Fuhr P, et al. Rituximab in the treatment of polyneuropathy associated with anti-MAG antibodies. Muscle Nerve 2003; 27:611–615. 55 Pestronk A, Florence J, Miller T, et al. Treatment of IgM antibody associated polyneuropathies using rituximab. J Neurol Neurosurg Psychiatry 2003; 74:485–489. 56 Niermeijer JMF, Eurelings M, Lokhorst HL, et al. Rituximab for polyneuropathy with IgM monoclonal gammopathy. J Neurol Neurosurg Psychiatry 2009; 80:1036–1039. Shows response to rituximab in a minority of treated patients. 57 Chin RL, Sherman WH, Sander HW, et al. Etanercept (Enbrel) therapy for chronic inflammatory demyelinating polyneuropathy. J Neurolog Sci 2003; 210:19–21. 58 Richez C, Blanco P, Lagueny A, et al. Neuropathy resembling CIDP in patients receiving tumor necrosis factor-alpha blockers. Neurology 2005; 64:468–470. 59 Hirst C, Raasch S, Llewelyn G, et al. Remission of chronic inflammatory demyelinating polyneuropathy after alemtuzumab (Campath 1H). J Neurol Neurosurg Psychiatry 2006; 77:800–802. 60 Rieckmann P. Concepts of induction and escalation therapy in multiple sclerosis. J Neurolog Sci 2009; 227 (Suppl 1):S42–S45. Reviews strategies of using intensive immomodulatory therapy early on versus stepwise progression of agents in multiple sclerosis, with particular attention to the potential uses of alemtuzumab. 61 CAMMS223 Trial Investigators. Coles AJ, Compston DA, et al. Alemtuzumab vs. interferon beta-1a in early multiple sclerosis. N Engl J Med 2008; 359:1786–1801. Discusses efficacy of alemtuzumab in multiple sclerosis, and also addresses the risks of induction of other autoimmune disease, provides good background for possible considerations to extrapolate to the possible use of this agent for inflammatory peripheral nerve disease.
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Recent developments in pediatric headache Andrew D. Hershey Department of Pediatrics, Division of Neurology, Cincinnati Children’s Hospital Medical Center, University of Cincinnati, College of Medicine, Cincinnati, Ohio, USA Correspondence to Andrew D. Hershey, MD, PhD, Director, Headache Center, Division of Neurology, MLC #2015, 3333 Burnet Avenue, Cincinnati, OH 45229-3039, USA Tel: +1 513 636 4222; fax: +1 513 535 1888; e-mail:
[email protected] Current Opinion in Neurology 2010, 23:249–253
Purpose of review This review will focus on some of the recent findings in pediatric headache including headache characteristics, epidemiology, comorbid associations and treatment updates. Recent findings Pediatric headache remains a frequent health problem for children and their families, yet there remain many gaps in our knowledge. This review will broadly address some of the recent findings and highlight the gaps in our understanding and treatment of pediatric headache. There will be a focus on pediatric migraine as this has been the best characterized and studied. Summary Our understanding of pediatric headache is improving with increased recognition of the characteristics and associated symptomology. This should further guide the individualized treatment approaches for improved outcome and reduction of progression into adulthood. Keywords adolescent headache, migraine, pediatric headache Curr Opin Neurol 23:249–253 ß 2010 Wolters Kluwer Health | Lippincott Williams & Wilkins 1350-7540
Introduction Headache is a frequent health complaint of children and adolescents. Due to its episodic nature in otherwise healthy individuals, it is often under-recognized and ignored by patients, parents and practitioners. Headaches can be either primary, such as migraine and tension-type headache (TTH), or secondary. The first step in the evaluation and management of pediatric headaches is determining this primary vs. secondary cause. Secondary headaches by definition have a cause and effect association with a specific etiology, whereas primary headaches are intrinsic to the nervous system. For pediatric secondary headaches, there remain many gaps in the specificity and sensitivity of this recognition, although it should be expected that the adult based criteria should be equivalent. The identification of primary vs. secondary headaches can be confusing in patients with a primary headache and an exacerbation by a secondary cause (e.g. posttraumatic headache in a patient with migraine). If the headaches are recurrent and episodic they are more likely to represent primary headache disorders, especially if they do not respond to the treatment of the secondary cause. Appropriate and early recognition of primary vs. secondary headaches should be expected to result in improved response and outcome, minimizing the impact of the primary headaches and disability. 1350-7540 ß 2010 Wolters Kluwer Health | Lippincott Williams & Wilkins
The most common types of primary headaches seen in children are migraine and TTH, with migraine having the greatest impact on a child’s quality of life and disability. Although both primary headaches can impact a child’s and family’s lives, migraine is more frequently brought to the attention of parents and primary care providers, school nurses and practitioners. It can become a chronic, disabling disorder that leads to reduced involvement in school, home and social activities. When it starts in childhood and adolescence, pediatricians and primary care providers are in an important position to influence the progression of the migraine and prevent long-term suffering and change the quality of life of these individuals. TTHs are even less will recognized as they are often not brought to medical attention unless they start to become highly frequent or impact a child’s life. Therefore, primary care providers including patients may not even be aware of its presence. The impact of TTH and the progression has been much less described, but early intervention can presumably alter the trajectory of TTH.
Epidemiology Bille reported the first extensive study of pediatric migraine epidemiology in 1962 [1]. This study established the basis of pediatric headache prevalence, recognizing that by age 15 nearly 75% of children will report DOI:10.1097/WCO.0b013e3283391888
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having had a significant headache. Migraine was reported in 3.9% of children age 7–15 years, which increased from 1.7% in 7 year olds to 5.3% in 15 year olds. Recent epidemiology studies have utilized the International Classification of Headache Disorders, 2nd edition (ICHD-II) [2]. These studies have shown the frequency of migraine varies slightly from country to country and region to region, but overall remains a common disorder. Some of the more recent epidemiology studies have confirmed the geographically wide-spread occurrence of headache in children. This includes studies in Istanbul, Turkey where 46.2% of children age 5–13 years old (mean 8.2 2.4 years) had reported having a significant headache, with 3.4% of these children having migraine and an additional 8.7% having probable migraine [3]. A separate study from Turkey compared the prevalence of migraine and TTH using ICHD-II criteria, finding that of 2384 adolescents (14–18 years old), migraine was more common than TTH (21.3 vs. 5.1%) [4]. When the ICHDII criteria of number of headaches and duration of the headaches were excluded this prevalence was even higher (29.9 and 15.0%, respectively). An Italian study of 11, 13 and 15 year old adolescents found that 40% reported having at least one headache a week [5]. Additional epidemiology studies from Thailand [6], Germany [7], and Turkey [8] have reported similar findings. One area that is in need of further study is the epidemiology of late adolescents to young adulthood. This transition time appears to represent the time of the greatest increase in presentation of the migraine phenotype [9]. One study found that up to 28% of 15–19 year olds had migraine with 19% having only migraine without aura and 9% having migraine with aura [10]. Further research into this area of rapid increase in prevalence and potential ways to modify the rate of this increase have great potential in improving the outcome of adolescents and young adults with headache.
Evaluation of pediatric headache The ICHD-II can be used both clinically to help with the diagnosis of headache as well as to serve as the basis for further research in headaches. A key component of ICHD-II is the separation of primary headaches (intrinsic to the nervous system) and secondary headaches (directly attributable to another cause). This has been aided by the recent suggestion to unify the cause and effect including the temporal relationship and response to treatment of secondary headaches [11]. The ICHD-II can serve as a guide in the initial evaluation of a patient with headache in the development of questionnaires and structured
interviews [12]. Incorporation of the child’s responses with parental interpretation in such an approach has been shown to be very sensitive and specific for the diagnosis of pediatric headache [13]. The first ICHD was criticized for the incompleteness in diagnosing pediatric migraine. ICHD-II addressed these issues in footnotes for migraine without aura resulting in an improvement in the specificity and sensitivity [14– 17]. The footnotes recognize that childhood migraine tends to be shorter duration (down to 1 h with diary confirmation), that sleep should be included as part of the duration, that the location is more likely bilateral (typically frontal temporal), and that photophobia and phonophobia could be inferred by the parents and care providers based on the child’s actions. One additional footnote commented that if the location was exclusively occipital then additional work-up was warranted. In tertiary headache clinics it has been found that ICHDII could be improved by eliminating the lower time requirement, describing the location as focal (in contrast to a diffuse headache pain), and modification of the associated symptoms [14]. Even with these modifications there remained children that clinically had migraine but did not meet the criteria, suggesting the need for further refinement of the criteria. One such area is the examination of associated symptoms. Although only occurring in a quarter of children with migraine, the presence of osmophobia appears to be very sensitive and specific for separating migraine from TTH [18]. Another characteristic that needs further investigation in pediatric headache is the role and development of cutaneous allodynia [19]. In young children it is often difficult to obtain accurate responses to this semi-structured approach and parental responses are guided by their own experiences. To overcome this limitation children’s drawings fill in the verbal gap and have been demonstrated to be both sensitive and specific in their diagnosis of pediatric headaches [20,21]. In the examination of 124 children’s drawings (32.2% migraine, 37.9% TTH and 29.8% other headaches), specific identifying features were detected and suggested to be used as a standard for the analysis of children’s headaches drawings [22]. The examination of a child with headaches should include a general examination and neurological examination as well as a comprehensive headache examination [23]. This has been described in detail and extends the neurological examination to examine for neck tenderness and stability, the stability of the temporomandibular joint, sinus and facial tenderness including peripheral nerve tenderness and general cranial palpation.
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Recent developments in pediatric headache Hershey 251
The impact of the headache on a child’s life must be part of the evaluation including an assessment of quality of life and disability. A recent review of the literature found 33 studies addressing this question and the tools for assessing the impact and found that headaches had a significant impact on both the child’s and the parents’ lives [24]. For quality of life one of the widely administered tools for pediatrics and adolescents is PedsQL 4.0 [25]. For disability, multiple tools have been developed for adults (i.e. MIDAS, HIT-6), PedMIDAS has been developed for children and adolescents [26,27]. In a study from Taiwan, PedMIDAS was administered to 3963 middle school children and it was found that, although TTH was the most common headache (27.6%), PedMIDAS identified that disability was much higher in children with migraine (11.2%) and probable migraine (12.2%), with a higher risk of depression, increased severity and increased frequency in the migraine group [28]. When an abnormality is found in the history or examination, neuroimaging must be considered. Collaboration between the American Academy of Neurology, Child Neurology Society and the American Headache Society has established guidelines for the use of neuroimaging in childhood headaches [29]. These guidelines found that the neurological examination is the most sensitive test to identify the need for neuroimaging. These guidelines also found that exclusively occipital headaches warranted further evaluation. An MRI study is the most sensitivity test to identify structural abnormalities and should be the preferred neuroimaging test, and should be sufficient in most cases to identify these secondary causes [30]. If there are clinical and physical findings present suggestive of a vascular component, additional imaging techniques such as magnetic resonance angiography may be added.
suspicion of a secondary headache, whereas what is really happening is that a primary headache is being modified by these comorbid conditions. A determination of this role may help with the understanding of the underlying pathophysiological basis of migraine and these additional conditions. Some of the conditions that have been suggested to have a comorbid relationship with migraine include asthma and allergic disorders [31,32], obesity [33,34], epilepsy [35–38], sleep disorders [39–44], and psychological/emotional disorders [45–47]. Some recent studies of comorbid condition identification have focused on obesity, with the increasing worldwide rate of obesity and its psychological impact. For obesity, children with a BMI percentile at the extremes (<5th percentile and >95th percentile) and children at risk of obesity (85th to 95th percentile) had a higher likelihood of increased frequency of headaches and disability, with children moving toward normalization of their BMI demonstrating a greater degree of improvement in their headaches [33]. The impact of psychological factors is a complicated role with mixed findings [48]. Of particular concern is the impact of school phobia and anxiety contributing to headache frequency [49] and an increased risk of suicidal ideation in adolescents with migraine [50].
Treatment The treatment of pediatric headache includes both pharmacological acute and preventive strategies, and biobehavioral intervention. The goal of treatment should be addressed at each visit, with an overall goal to minimize the impact of both the individual attacks with return to normal function, headache-free as soon as possible and the overall reduction of headache attacks. In a recent study of 151 children (10.4 3.2 years old), these approaches were addressed in less than half the patients [51].
Comorbid conditions Oftentimes in the evaluation of a child with headache there is the identification of additional diseases and conditions. These conditions may be independent from the headache or may be intrinsic to the headache expression. Further study into this interaction is needed, but it is clear that many of these conditions can complicate migraine diagnosis and influence management choices, overall outcome and response. Examples of treatment choice adjustments are using antiepileptic medications in patients with seizures, antidepressant medications when there is depression, anxiety or emotional disorders, or adjusting the medication based on side effects such as appetite reduction and biobehavioral features, or a balanced diet and exercise when obesity is present. The commonality of many of the conditions suggested to be associated with headaches may confuse the cause and
Acute treatment
Acute treatment should result in consistent response with minimal side effects and quick return to normal function. Guidelines have been developed and treatments meeting these goals have been identified [52]. In general, two groups emerged – nonsteroidal anti-inflammatory medications (NSAIDs) and triptans. Additional studies have added to this literature, but the general principles remain that NSAIDs (especially ibuprofen) are effective when used early in the attacks at an adequate dose (7.5 to 10.0 mg/kg/dose) and that triptans are effective when the NSAIDs are not completely effective, especially during the more severe attacks [53]. The most recent advancement in the area of acute treatment is the approval of almotriptan by the US Food and Drug Administration for the treatment of adolescent
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headaches. This was based on a randomized, doubleblind, placebo controlled trial of almotriptan in 866 adolescents (age 12–17), which found a 2-h pain-relief rate that was significantly higher for all doses of almotriptan – 6.25 mg (71.8%), 12.5 mg (72.9%) and 25 mg (66.7%) compared with placebo (55.3%) [54].
feasibility of using a CD-ROM to teach this behavioral therapy [68]. The Internet can also be used to teach cognitive behavioral training, with a positive benefit demonstrated [69]. Biobehavioral approaches may be especially effective in younger children [70].
One caution in acute treatment is the avoidance of medication overuse. In general, nonspecific analgesics should be limited to less than 2–3 times per week, while limiting migraine specific agents to less than 6 times per month.
Conclusion
Preventive treatment
When the headaches are frequent (more than once a week) or disabling (PedMIDAS score above 30 – Grade III or IV), preventive treatment should be considered with the goal to reduce the headache frequency to less than 1 to 2 per month and the disability for at least 4 to 6 months. Agents that have been used for pediatric migraine prevention include antidepressant medications, including amitriptyline [12], antihypertensive medications, including propranolol [55–57], antihistamine/ antiserotonergic medications, including cyproheptadine [58], and antiepileptic medications including valproic acid [59] and topiramate [60]. The most recent controlled studies have focused on the antiepileptic medications. These include a double-blind, placebo controlled study of 100 mg topiramate divided twice a day in 44 children with migraine (headache frequency reduction from 16.14 9.35 days per month to 4.27 1.95 days vs. placebo of 13.38 7.78 to 7.48 5.94 days per month) [61]. In addition, in a randomized, double-blind placebo controlled study, a 100 mg daily dose divided into twice a day dosing in 103 adolescents (age 12–17 year) demonstrated topiramate to be statistically superior to placebo (median headache frequency reduction in the last 12-weeks of treatment of 72.2% vs. 44.4%) [62]. In an open-label study of divalproate there was a significant reduction in headache frequency [63,64], whereas a comparative study of topiramate and valproic acid found both medications to be effective in decreasing the frequency, severity, duration and PedMIDAS score at a similar rate [65]. Biobehavioral therapy
Biobehavioral therapy, or the incorporation of adherence, education, lifestyle adjustment, and coping skills, is also essential to the management of pediatric migraine [66]. The study of these techniques is limited. A study using telephone-assisted behavioral therapy demonstrated an improvement in 34 adolescents after 3 and 8-month periods [67]. A separate study has begun to address the
Pediatric headache and its transition into young adulthood remains a significant problem. Advances in the understanding of the epidemiology may help understand this progression, whereas characterization of the disease phenotypes may help better understanding of the pathophysiology and risk of progression. Further research into this process should help improve the management of headache in this age range and overall improve the outcome of patients into their adulthood.
References and recommended reading Papers of particular interest, published within the annual period of review, have been highlighted as: of special interest of outstanding interest Additional references related to this topic can also be found in the Current World Literature section in this issue (p. 334). 1
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New therapeutic developments in chronic migraine Brigitte V. Lovell and Michael J. Marmura Department of Neurology, Thomas Jefferson University, Philadelphia, Pennsylvania, USA Correspondence to Brigitte V. Lovell, Department of Neurology, Thomas Jefferson University, 111 South 11th Street, Suite 8130, Gibbon Building, Philadelphia, PA 19107, USA Tel: +1 215 955 1956; e-mail:
[email protected] Current Opinion in Neurology 2010, 23:254–258
Purpose of review Chronic migraine is a common cause of chronic daily headache, which is often refractory to standard treatment. New research has increased our understanding of this disorder and its treatment. This review focuses on recent clinical trials and advances in our understanding of migraine pathophysiology. Recent findings Migraine research has traditionally focused on the more common episodic form of the disorder, but recent clinical trials have started to focus on chronic migraine or chronic daily headache. Topiramate, onabotulinum toxin type A, gabapentin, petasites and tizanidine are among the agents that appear to be effective in the treatment of chronic migraine. New acute medications including an inhaled form of dihydroergotamine will soon be available and neuromodulatory procedures such as occipital nerve stimulation may be effective for the most disabled patients. In the past few years, other studies have shed light on potential risk factors for chronic migraine such as medication-overuse headache, temporomandibular disorders, obstructive sleep apnea and obesity. Summary This review explains advances in the treatment of chronic migraine, a common disorder seen in neurological practice. These new advances in preventive treatment and a better understanding of its risk factors will allow clinicians to better identify individuals at greatest risk and prevent the development of chronic migraine. Keywords abortive therapy, chronic migraine, preventive therapy Curr Opin Neurol 23:254–258 ß 2010 Wolters Kluwer Health | Lippincott Williams & Wilkins 1350-7540
Introduction Chronic migraine is defined as either tension-type and/or migraine headache that occurs more often than 15 days a month for more than three months. Eight of these headache days must meet the criteria for migraine without aura and last more than 4 h [1,2]. Chronic migraine is a common and disabling disorder that makes up a large percentage of new visits to headache centers [3], usually develops in individuals who previously experienced episodic migraine and is the most common cause of chronic daily headache (CDH). About 3% of those with episodic migraine progress to chronic migraine in a given year [4]. Chronic migraine was previously called ‘transformed migraine’. In most patients with chronic migraine,migrainesgradually increase in frequency until they become daily or almost daily over a period of months or years [5,6]. The majority of those with chronic migraine are women and population data suggest a prevalence rate between 2 and 4% [7]. Risk factors for the development of chronic migraine appear to include acute medication overuse, obesity, caffeine intake and stress [8,9]. To date, most migraine research studies, including clinical trials, have focused on episodic migraine. Chronic 1350-7540 ß 2010 Wolters Kluwer Health | Lippincott Williams & Wilkins
migraine sufferers have higher Migraine Disability Assessment (MIDAS) scores, more lost productivity time, greater direct medical costs and greater co-morbidities compared with episodic migraineurs [10]. Triptans, the mainstay of treatment for patients with episodic migraine, are less effective after the pain is already severe [8] and overuse of acute pain medication may lead to treatment refractoriness and medication-overuse headache (MOH) [11]. Migraine is a common neurologic disorder with a prevalence of 1.3–2.4% in population-based studies [12]. New treatments are needed for patients with frequent or daily headache, such as chronic migraine. The ultimate goal should be allowing chronic migraine to revert back to episodic migraine, or preventing the development of chronic migraine in the first place, suggesting that preventive therapy is essential.
Chronic migraine: advances in preventive therapy Most clinical medication trials in migraine prophylaxis have studied episodic migraine, but it appears that many of the agents that treat episodic migraine are also useful in chronic migraine. Some studies focus on chronic migraine DOI:10.1097/WCO.0b013e3283396d6b
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Therapeutic developments in chronic migraine Lovell and Marmura
and others on CDH, chronic migraine being very common. Medications that appear effective in the treatment of either chronic migraine or CDH include topiramate, onabotulinumtoxin A, gabapentin, tizanidine, amitriptyline and fluoxetine [13]. Preventive therapy is indicated in all patients with chronic migraine and populationbased surveys suggest that migraine prophylaxis is extremely underutilized; only 3–13% of migraine patients use prophylactic medication [14]. Preventive therapy may make acute medication more effective [15] or improve long-term outcomes in those with frequent headache [16]. Topiramate is one of the best studied medications for the treatment of migraine, and recent studies have confirmed its effectiveness in the treatment of chronic migraine. Its effectiveness may be due to augmentation of the GABAA receptor, modulation of sodium channels, glutamate receptor antagonism, carbonic anhydrase protein kinase inhibition, possible serotonin activity or alteration of neuroinflammatory factors [17]. A recent double-blind, placebo-controlled, multicenter clinical trial of 306 patients demonstrated that the use of topiramate 100 mg per day improved measures such as headache severity, nausea, photophobia, phonophobia and multiple measures of quality of life without serious adverse events [18,19]. In patients who continued to take acute medications for pain, topiramate was equally effective in patients with or without medication overuse headache, (MOH) [20]. This suggests that preventive therapy may be effective for the treatment of chronic migraine patients with MOH even without detoxification. Onabotulinumtoxin A (BTX) is a form of botulinum toxin type A, which has been studied in the treatment of multiple pain disorders including headache. BTX is a neurotoxin that reversibly blocks presynaptic acetylcholine release. Its effectiveness in pain disorders is probably due to inhibition of the release of neurotransmitters, such as substance P and calcitonin gene-related peptide (CGRP), and effects on muscle spasm and nerve transmission [21,22]. BTX may inhibit peripheral sensitization, which prevents the progression to central sensitization [23,24]. Despite positive open-label studies and case reports, BTX has not proven to be effective for many patients with chronic tension-type headache or episodic migraine based on double-blind placebo-controlled trials. These results could have been confounded by a high placebo response rate [25,26]. There is increasing evidence, however, that BTX is effective in the treatment of chronic migraine and CDH. In initial studies, BTX appeared to reduce headache days in patients with CDH using 105–260 units in a fixed site or modified follow-the-pain
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pattern [27]. More recently, a large multicenter randomized, double-blind, placebo-controlled trial of more than 1300 patients with chronic migraine demonstrated significant reductions in headache symptoms, frequency, disability and triptan utilization along with improvements in measures of health-related quality of life [28]. Compared with other preventive treatments, BTX has a rapid onset of action (less than 2 weeks) with few serious adverse events and does not require daily medication use or titration. A separate study comparing topiramate 100–200 mg per day and BTX up to 200 units found that both effectively treated chronic migraine and decreased acute pain medication use, although BTX users had fewer adverse events [29]. Gabapentin at a dosage of 2400 mg per day was evaluated in a 21-week, multicenter, cross-over trial in 133 patients with CDH. Gabapentin was associated with a 9% improvement in headache-free rate. Adverse events included dizziness, somnolence, nausea and ataxia [30]. Pregabalin also appears to be effective for the treatment of chronic migraine [31]. Tizanidine is a muscle relaxant and an alpha-2 adrenergic agonist. Tizanidine 24 mg per day decreased the baseline headache index to 2.6 and the reduction headache index went down to 1.5 in patients with CDH when compared with placebo. Participants used tizanidine as an adjunct to other preventive medications. Somnolence, dry mouth and dizziness, along with asthenia, were among the reported adverse events [32]. Fluoxetine, a selective serotonin reuptake inhibitor, was evaluated in 64 participants with CDH and 58 with episodic migraine. After 3 months of up to 40 mg per day, participants taking fluoxetine had 1.57 fewer headache days per week compared with controls who had 1.12 headache-free days per week [33]. In another study, zonisamide lowered headache days per month from 20.7 to 18.0 after being on an average dose of 337.9 mg for nearly 190 days for 33 patients with episodic migraine or chronic migraine. Many of these patients had failed many other preventive treatments [34]. Memantine (MEM) is a noncompetitive antagonist at glutamergic N-methyl-D-aspartate (NMDA) receptors. The NMDA receptor is a potential new target in chronic pain disorders including migraine, which some feel is a disorder of brain hyperexcitability [35,36]. Thirty-eight participants who had failed at least one standard migraine preventive medication were given MEM 10–20 mg per day in an open-label pilot study. Over 71% of participants had chronic migraine. After 3 months, the mean number of severe headache days was reduced from 7.8 at baseline to 3.2 at 3 months. MIDAS scores after 3 months were
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256 Headache
reduced from 54.9 to 36.6. Common MEM adverse events included somnolence, asthenia and mood changes [37]. MEM may be a useful off-label preventive treatment in chronic migraine patients who fail traditional management.
disorder. Chronic migraine patients are at a high risk for MOH and the relationship between acute medication use and treatment refractoriness is becoming clearer. Although many medications, including triptans, pose a risk of MOH, frequent opioid use appears to be a robust risk factor for the development of chronic migraine [48].
Terminating the attacks
Population-based studies suggest obesity may also be a risk factor for chronic migraine. Obese individuals, defined as those with a BMI greater than 30 kg/m2, have a five times greater chance of developing CDH as compared to individuals with a normal weight. Individuals within the BMI bracket of 25–29 kg/m2 had three times the risk of developing chronic migraine [9] Metabolic syndrome [49] and obstructive sleep apnea also appear to be risk factors for migraine. Individuals with chronic migraine may be more likely to have reduced physical activity due to pain and may take daily medications that contribute to weight gain.
Acute treatments are necessary for most migraine sufferers. Two new sumatriptan formulations are or will soon be available for acute migraine treatment. Sumavel Dose Pro (Zogenix) is a needle-free, injectable sumatriptan. This medication offers rapid absorption and distribution, with efficacy similar to traditional sumatriptan injections [38,39]. Zelrix (NuPathe), a sumatriptan transdermal patch, avoids delayed gastric emptying and first-pass metabolism, has sustained delivery and fewer adverse events, and will soon be available [40]. Dihydroergotamine (DHE) is highly effective in the treatment of chronic migraine, but this drug has low oral bioavailability. MAP004, (Levadex; MAP Pharmaceuticals, Mountain View, California, USA), is an inhaled form of DHE that will soon be available with efficacy similar to intravenous (i.v.) DHE with fewer adverse events [41,42]. Peripheral procedures such as occipital nerve blocks (ONBs) or trigger point injections are a promising rescue treatment for migraine and may be effective in MOH and chronic migraine. Frequent injections may decrease disability and headaches days and ONBs may be particularly useful in individuals with allodynia [43]. Tobin and Flitman [44] reported that 56% of analgesic overuse headache patients had a positive response to ONBs. In a single blinded randomized controlled trial of chronic migraine patients, ONBs with triamcinolone combined with lidocaine was not superior to lidocaine alone [45]. Occipital nerve stimulation (ONS) is a surgical procedure for refractory headache including chronic migraine. A 60% improvement was seen in 17 patients with CDH after ONS including two with chronic migraine. Lead migration and infection were common problems after ONS replacement in earlier studies, but did not occur in this study [46]. Calcitonin gene related peptide (CGRP) is important in migraine, and CGRP antagonists appear effective in the acute treatment of migraine. In a large phase III clinical trial, telcagepant 300 mg demonstrated similar efficacy to zolmitriptan with fewer adverse events [47].
Temporomandibular (TMD) joint disorders may also predispose individuals to chronic migraine. The annual incidence rate of TMD is 6.5% [50]. CDH patients and migraineurs experience TMD at higher rates than those without headache, suggesting that TMD and migraine are comorbid conditions [51]. Roughly 27% of patients with headache report jaw pain [51]. Patients with TMD should be treated, which may decrease the risk of chronic migraine [52]. An interdisciplinary approach is recommended. The biological differences explaining the clinical difference between episodic migraine and chronic migraine are unclear, but it is suspected that individuals with chronic migraine have increased cortical hyperexcitability [53] and central sensitization. Cutaneous allodynia, the perception of pain when a nonnoxious stimulus is applied to normal skin, is a marker for central sensitization in migraine and is common in chronic migraine, especially in older patients [54]. Chronic migraine patients have lower pain thresholds when compared to individuals with episodic migraine [55]. Free radical formation then develops within the periaqueductal gray matter and neuronal injury and iron deposition may also result from consistent migraine attacks [56]. Increased migraine frequency and aura appear to predispose individuals to white-matter lesions in the posterior circulation infarcts [57]. The effect of preventive treatment in changing the biology of the disorder and the relative contribution of these biomarkers to the development of chronic migraine remains unclear.
Chronic migraine pathophysiology: new insights
Conclusion
Much of the new research in regards to chronic migraine has focused on risk factors for the development of the
Chronic migraine is a highly disabling disorder that dramatically affects quality of life. Preventive treatments
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Therapeutic developments in chronic migraine Lovell and Marmura
are the mainstay of treatment, and new studies suggest that many are effective. New acute treatments for those who do not improve with available therapy will improve outcomes. Ultimately, however, we need to gain a better understanding of why patients ‘transform’ clinically from episodic migraine to chronic migraine and what can be done to reverse the course of the disease.
Acknowledgements B.V.L. does not have any known or suspected conflicts of interest with regard to the subject matter of this manuscript. M.J.M. is on the Cephalon speaker’s bureau and has received research grants from Merck and Glaxo Smith Kline.
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What have we learnt from triggering migraine? Henrik W. Schytza, Guus G. Schoonmanb and Messoud Ashinaa a
Danish Headache Center and Department of Neurology, Glostrup Hospital, Faculty of Health Sciences, University of Copenhagen, Glostrup, Denmark and bLeiden University Medical Centre, Department of Neurology, Leiden, the Netherlands Correspondence to Messoud Ashina, Danish Headache Center and Department of Neurology, Glostrup Hospital, University of Copenhagen, Faculty of Health Sciences, Nordre Ringvej 57, DK-2600 Glostrup, Copenhagen, Denmark Tel: +45 43 23 30 33; e-mail:
[email protected], www.danishheadachecenter.com Current Opinion in Neurology 2010, 23:259–265
Purpose of review This review presents what we have learnt from triggering migraine. Recent findings Experimental studies have shown that glyceryl trinitrate (GTN), calcitonin gene-related peptide (CGRP), pituitary adenylate cyclase activating polypeptide-38 (PACAP38) and prostaglandin I2 (PGI2) induce migraine-like attacks in migraine suffers indistinguishable from their spontaneous attacks. These studies point to two key pathways to play an important role in migraine pathophysiology: cyclic guanosine monophosphate (cGMP) and cyclic adenosine monophosphate (cAMP). At present, no valid experimental model exists to reproduce aura episodes in migraine with aura patients. Familiar hemiplegic migraine patients seem to be less sensitive to GTN and CGRP provocation compared with common types of migraine. Advances in recent imaging studies suggest neuronal mechanisms to be behind migraine attacks. The experimental headache models have resulted in development and an ongoing search of new migraine targets. Summary Human models of migraine offer unique possibilities to study mechanisms responsible for different migraine subtypes and to explore the mechanisms of action of existing and future antimigraine drugs. Adding advanced imaging techniques to the models may lead to a better understanding of the complex events that constitutes a migraine attack and thereby more targeted ways of intervention. Keywords human models of migraine, migraine treatment, signaling molecules Curr Opin Neurol 23:259–265 ß 2010 Wolters Kluwer Health | Lippincott Williams & Wilkins 1350-7540
Introduction The episodic and unpredictable nature of spontaneous migraine attacks results in various logistic challenges when attempting to study the neurobiology of migraine under controlled conditions. Spontaneous migraine attacks are, despite their seemingly spontaneous nature, well known to be provoked by various natural triggers, such as stress, food and hormone variation [1]. A powerful method to study migraine pathophysiology is using pharmacological triggers to induce migraine attacks in humans (Fig. 1). The pharmacologically induced migraine attacks are indistinguishable in clinical phenotype from spontaneous migraine, including triptan response [2]. This review will summarize human models of migraine with a particular focus on what we have learnt from triggering migraine attacks.
Glyceryl trinitrate model of migraine The first anecdotal evidence of headache response to glyceryl trinitrate (GTN), a prodrug for nitric oxide, dates back to 1847 when Ascanio Sobrero, an Italian chemist who synthesized GTN, warned ‘great precaution should 1350-7540 ß 2010 Wolters Kluwer Health | Lippincott Williams & Wilkins
be used, for a very minute quantity put upon the tongue produces a violent headache for several hours’ [3]. One hundred and fifty years later the Copenhagen Headache Research Group developed, through systematic and extensive studies, a GTN model of migraine [4]. In particular, Thomsen et al. [5] demonstrated that 80% of migraine without aura patients developed a delayed headache fulfilling International Headache Society (IHS) criteria for migraine peaking 5 h after the end of the infusion compared with 10% after placebo. Later, other groups have reproduced these data showing GTN infusion as a valid model of triggering migraine attacks [6,7] (Table 1) [5–8,9,10–14,15,16,17,18,19]. The exact neurobiological mechanisms of GTN induced migraine like attacks are not fully clarified [20,21]. The GTN serve as a vasodilator because it is converted to nitric oxide in the body. Nitric oxide is highly lipid soluble and easily penetrates membranes including the blood–brain barrier. Thus, nitric oxide may trigger migraine through peripheral and/or central modulation of the brain. The question is whether peripheral production of nitric oxide may provoke migraine attacks. Schytz et al. [22,23] tested this hypothesis by examining DOI:10.1097/WCO.0b013e328337b884
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260 Headache Figure 1 Experimental design of a human model of migraine
Patients with migraine or healthy volunteers are randomly allocated to receive intravenous infusion (20 min) of ‘target substance’ or placebo (isotonic saline) in a double-blind, crossover design. Headache intensity is recorded on a verbal rating scale from 0 to 10 (0, no headache; 1, a very mild headache (including a feeling of pressing or throbbing); 5, moderate headache; 10, worst imaginable headache). The following haemodynamic variables are recorded at intervals: mean velocity of blood flow in the middle cerebral artery by transcranial Doppler with hand-held probes; diameter of the frontal branch of the superficial temporal artery by a high-resolution ultrasonography unit. Heart rate and blood pressure are measured continuously throughout the study. The individuals are asked to complete a headache diary every hour until 10 h after discharge. The diary includes headache characteristics and accompanying symptoms necessary to classify migraine. Reprinted from Olesen et al. [62] with permission from Wiley–Blackwell.
an acetylcholine analogue, carbachol, known to induce peripheral endothelial nitric oxide production, in healthy volunteers and migraineurs. These studies have shown that carbachol triggers immediate mild headache similar to GTN infusion but no migraine-like attacks [22,23]. The failed attempt to provoke migraine attacks could be due to an insufficient carbachol dose limited by systemic side effects [23]. In support of central mechanisms Afridi et al. [24] reported brainstem activation of the dorsal lateral pons ipsilateral to the pain side during GTN induced migraine attacks. However, delayed brainstem activation might be related to activation of the pain modulatory system. At present, there is no firm evidence implicating a direct central modulation in humans by GTN. Nitric oxide activates intracellular soluble guanylate cyclase and catalyzes the formation of cyclic guanosine monophosphate (cGMP). To test whether the second
messenger system is involved in GTN induced migraine attacks, Kruuse et al. [11] examined sildenafil, a selective inhibitor of phosphodiesterase 5 (PDE5), which is the major enzyme responsible for the breakdown of cGMP. The authors [11] demonstrated that sildenafil induced migraine-like attacks in 83% of migraine patients. Interestingly, in contrast to GTN studies, migraine-like attacks were reported without immediate dilatation of intracranial and extracranial arteries. This study suggested that migraine might be provoked by upregulation of intracellular cGMP and triggered without immediate vasodilatation. In view of the potentially important role of nitric oxide in migraine, surprisingly few therapeutic studies have been performed with nitric oxide synthase (NOS) inhibitors. Lassen et al. [25] investigated whether a nonselective NOS inhibitor, N(G)-mono-methyl-Larginine (L-NMMA), might have antimigraine effects.
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Table 1 Percentages of patients reporting migraine-like attacks in experimental studies Compound
Migraine
Dose
GTN
MA
10 mg/kg IV
MO
0.9 mg SL 10 mg/kg IV
FHM
0.9 mg SL 10 mg/kg IV
MO MO MA MO FHM MO MO MO MO
100 mg PO 10 mg/kg IV 30 mg IV 40 mg IV 30 mg IV 568 mg/kg IV 200 pmol/kg IV 200 pmol/kg IV 0.25 mg/kg IV
Sildenafil Histamine CGRP Dipyridamole VIP PACAP38 PGI2
Number of individuals
Migraine-like attacks (%)
Aura (%)
12 21 22 23 10 168 8 8 12 20 14 9 9 10 12 12 12
50 67 41 83 80 82 25 13 83 70 57 67 22 50 0 66 50
0 10 14 0 0 0 0 0 0 0 29 0 0 0 0 0 0
Reference [8] [6] [7] [6] [5] [7] [9] [10] [11] [12] [13] [14] [15] [16] [17] [18] [19]
CGRP, calcitonin gene-related peptide; FHM, familial hemiplegic migraine; GTN, glyceryl trinitrate; IV, intravenous; MA, migraine with aura; MO, migraine without aura; PACAP38, pituitary adenylate cyclase activating polypeptide-38; PGI2, Prostaglandin I2; PO, per oral; SL, sublingual; VIP, vasoactive intestinal peptide.
This proof of concept study demonstrated that NOS inhibition is effective in treating spontaneous migraine attacks. Recently, the pharmaceutical industry has introduced selective NOS inhibitors. Inducible NOS (iNOS) inhibitors (www.clinicaltrials.gov: NCT00242866) and neuronal NOS (nNOS) inhibitors (www.clinicaltrials.gov: NCT00920686) are currently undergoing phase II clinical trials.
Calcitonin gene-related peptide model of migraine In 1988 Goadsby et al. [26] reported how thermocoagulation of the trigeminal ganglion lead to CGRP release into the extracerebral circulation of humans. This was the first report of CGRP involvement in the trigeminovascular reflex. The importance of CGRP in migraine became later firmly established when Lassen et al. [14] conducted a double-blind crossover study, where CGRP or placebo was infused for 20 min in 12 migraine without aura patients. Following CGRP infusion 67% experienced migraine-like attacks compared with only one after placebo. A recent study by Hansen et al. [13] revealed that CGRP induced migraine without aura attacks in 57% of migraine with aura patients. Mechanisms responsible for CGRP induced migraine attacks are unknown. CGRP receptor activation leads to increased cyclic adenosine monophosphate (cAMP) levels [27]. Cilostazol, an inhibitor of PDE3, is known to increase intracellular cAMP. To test the hypothesis that activation of cAMP pathway plays a role in generation of head pain, Birk et al. [28] examined cilostazol in 12 healthy individuals. The study showed that 92% developed headache, out of which 18% had migraine-like features, such as pulsating pain quality and aggravation by physical activity. Interestingly, none of the partici-
pants had family history of migraine. These data suggest that the cAMP pathway may play an important role in initiating head pain and migraine. The migraine generating properties of CGRP stimulated interest in CGRP antagonism as a potential antimigraine drug target. The first proof of concept study showed that olcegepant, a selective CGRP antagonist, was effective in treating acute migraine attacks [29]. Later, a phase II trial demonstrated that a novel oral CGRP receptor antagonist, telcagepant, was effective and generally well tolerated for the acute treatment of migraine [30].
Pituitary adenylate cyclase activating polypeptide model of migraine Pituitary adenylate cyclase activating polypeptide (PACAP) plays an important role in neural and hormonal regulation of systemic circulation [31]. Immunohistochemical studies have demonstrated that PACAP is distributed in human sensory [32] and parasympathetic nerve ganglia [33] with perivascular nerve fiber projections. PACAP has been found to co-exist with vasoactive intestinal peptide (VIP) [34], which belongs to the secretin-glucagon peptide family. The VPAC1 and VPAC2 receptors bind both PACAP and VIP ligands with similar affinities, whereas the PACAP type 1 (PAC1) receptor preferentially binds PACAP [35]. The headache eliciting effect of VIP and PACAP38, the most predominant PACAP form [31], have been systematically studied in healthy volunteers [18,36] and in patients with migraine without aura [17,18]. These studies have shown that the systemic administration of VIP induces only a very mild and short lasting immediate headache both in healthy individuals [36] and migraineurs [17]. However, the most interesting part of the
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262 Headache
studies was that despite marked immediate vasodilatation none of migraine sufferers reported delayed migraine like attacks after VIP. Hence, VIP is the first vasoactive substance found not to induce migraine. Infusion of PACAP38 induced vasodilatation of a similar magnitude to VIP, but longer lasting. In contrast to VIP, PACAP38 infusion induced migraine attacks in 58% of migraine without aura patients [18]. Given that VIP infusion does not cause migraine, the shared VPAC1 and VPAC2 receptors are unlikely to be involved in PACAP38-induced migraine. Thus, migraine induction by PACAP38 might be caused by selective activation of the PAC1 receptor. Interestingly, PACAP38, VIP and CGRP share the cAMP intracellular signalling pathway, but only CGRP and PACAP38 provoke migraine attacks. At present, there is no firm evidence implicating the PAC1 receptor in migraine pathophysiology and there are no available VIP/ PACAP receptor antagonists for human use.
Prostaglandin-induced migraine Prostaglandins are important mediators of pain and inflammation and considerable evidence implicates their involvement in the pathogenesis of migraine. Prostanoid concentrations are elevated ictally in saliva and the internal jugular vein in migraineurs [37,38]. Wienecke et al. [39–41] have systematically investigated the headache-eliciting effects of prostaglandin I2 (PGI2), prostaglandin E2 (PGE2) and prostaglandin D2 (PGD2) in healthy volunteers. These studies have shown that all prostanoids induce headache associated with vasodilatation [39–41]. The effects of PGI2 have also been explored in migraine without aura patients [19]. In this study, 75% of the migraineurs reported their headache to mimic a spontaneous migraine attack during and within an hour after the end of PGI2 infusion. Interestingly, in contrast to delayed nitric oxide, CGRP and PACAP38 migraine attacks, PGI2 seems to initiate migraine symptoms in relation to infusion [19]. This suggests that PGI2 might have modulatory effects in the late course of spontaneous migraine. There are various prostaglandin receptors with different physiological functions. Of special interest is the EP-4 receptor, which can lead to intracellular increase in cAMP. Currently, a pharmaceutical company is investigating if EP-4 receptor antagonist can prevent the PGE2-induced headache in a phase I trial (www.clinicaltrials.gov: NCT00957983).
Human models of migraine in familial hemiplegic migraine Familial hemiplegic migraine (FHM) is an autosomal dominant migraine subtype that typically includes hemiparesis during the aura phase [42]. The identification of the mutated FHM genes [43–45] stimulated interest to explore the link between genotype and phenotype [46].
The range of disease phenotypes produced by alleles at FHM (type 1, 2 and 3) loci is quite broad, and the phenotypic spectrum includes seizures and ataxia as well as migraine. Clinical similarities of aura and migraine pain suggest that FHM may serve as a valid model for migraine with and without aura [46]. Using pharmacological triggers Hansen et al. [9,10,15] have made the first attempt to explore the relationship between genotype and neurobiological pathways involved in migraine. In a series of studies, patients with FHM-1 and FHM-2 received intravenous infusion of GTN and CGRP and in contrast to common types of migraine only 13–25% of FHM patients reported migraine-like attacks [9,10,15]. These data raise the question whether FHM does not share the same pathophysiological trait in the majority of patients with and without aura. In support, recent neurophysiological data suggested normal or more pronounced interictal habituation in FHM patients compared with controls [47]. This is in contrast to the common form of migraine characterized interictally by habituation deficits [48]. Provocation studies have also shown that the few FHM patients reporting migraine-like attacks after pharmacological provocation tended to be those who also had attacks of migraine with aura and/or migraine without aura [49]. Interestingly, another recent study in FHM patients without known mutations reported that GTN triggered more migraine-like attacks in FHM patients with coexisting nonhemiplegic migraine [50]. Arguments in favor of a shared pathophysiological trait between FHM and the common types of migraine state that the clinical phenotype of aura symptoms in FHM and migraine with aura suggests a common putative pathogenic mechanism for aura such as cortical spreading depression. Furthermore, migraine is a heterogeneous condition and provocation studies demonstrated that 20–50% of patients with common types of migraine do not develop migraine-like attacks after GTN (Table 1). In addition, low baseline attack frequency in FHM might have caused a low GTN response although in migraine with aura no relation between response and attack frequency was found [51]. It could also be argued that migraine aura and the pain including associated features may be determined by another gene or genes [52]. In conclusion, it seems that the majority of FHM patients are not hypertensive to pharmacological triggers such as GTN and CGRP and the available data demonstrate that experimental headache models might have a potential to explore possible links between genetic mutations and neurobiological pathways.
Human models of migraine and brain imaging Both the aura and headache phase of a spontaneous migraine attack have been studied with different imaging
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modalities. Blood oxygen level-dependent (BOLD) imaging during exercise induced migraine aura showed spreading suppression of activity suggesting cortical spreading depression [53]. During the headache phase, positron emission tomography (PET) showed several areas of activation including the brainstem [24,54]. Perfusion weighted imaging in a series of 14 migraine attacks without aura did not show significant haemodynamic changes in microvasculature [55].
clinical reports of aura triggered by visual stimuli and vigorous physical activity in a few migraine with aura patients [54,61]. However, given that relatively few migraine with aura patients experience aura during provocation studies with GTN and CGRP, aura episodes might be due to experimental stress. In conclusion, so far no valid experimental model exists to reproduce aura episodes in migraine with aura patients.
Imaging studies using pharmacological triggers (mainly GTN) have initially focused on vasodilatation, as most of the known triggering substances are vasoactive. GTN is a strong vasodilatator of cranial arteries. Magnetic resonance angiography (MRA) studies showed a diameter increase up to 35% of both intracranial and extracranial arteries during infusion of GTN [21,56]. However, during the infusion of GTN patients did not have migrainous headache [21]. Approximately 5 h after the infusion 75% of migraine patients developed a delayed migraine attack without any vasodilation [21]. Pure vasodilation of cranial arteries does not seem to trigger migraine or cause migraine headache. These findings are supported by the fact that a strong vasodilator, VIP, does not trigger migraine attacks [17].
Human models of migraine as a tool to investigate the mechanism of action of drugs
Recent imaging studies have shifted from a vascular towards a neuronal mechanism of action. GTN and CGRP have been shown to activate the trigeminal nucleus caudalis in animal models [57,58]. In humans GTN infusion has been shown to activate areas in the dorsal lateral pons during a triggered migraine attack, lateralized to the side of pain [24]. Future studies could combine pharmacological triggers with new imaging and neurophysiological techniques. For instance functional MRI in combination with GTN could provide information on brainstem activation in trigeminal nucleus caudalis during a triggered attack [59].
Human models of migraine aura Migraine aura is likely to be caused by cortical spreading depression (CSD) [54,56,60]. Attempts have been made to trigger aura in migraineurs using human models of migraine. Using GTN, Christiansen et al. [8] demonstrated that 50% of the patients suffering exclusively from migraine with aura developed migraine headache with associated symptoms, but none of them developed migraine aura. Afridi et al. [6] reported that one out of 21 patients with migraine with aura had an aura triggered on two separate occasions by GTN, and one only during the second session. Following sublingual GTN provocation, Sances et al. [7] reported that 3/22 (14%) developed a visual aura. Interestingly, Hansen et al. [13] infused CGRP in 14 migraine with aura patients and reported that 4/14 (29%) developed aura. There are also two
Currently, only the triptans are designed and specifically have effect as acute treatment for spontaneous migraine attacks [62], but their exact mode of action is still unresolved [63]. Preventive migraine treatments are used for various disorders, such as hypertension, epilepsy and depression, but their antimigraine effect has been detected by chance and not by neurobiological considerations [64]. The experimental models of migraine/headache may be a helpful method to explore relevant neurobiological mechanisms of existing antimigraine drugs. The effect of sumatriptan on GTN induced headache has been examined in several studies [65,66]. In a double blind cross over study Iversen and Olesen [2] injected sumatriptan 6 mg or placebo subcutaneously in 10 healthy individuals, followed by GTN infusion. This study demonstrated that sumatriptan reduced the GTN induced immediate headache and aborted cranial dilatation. Another study by Schmetterer et al. [65] confirmed the efficacy of sumatriptan to prevent GTN induced headache and dilatation of the middle cerebral artery. A recent study [67] tested the effect of zolmitriptan and aspirin after 140 min infusion of GTN (0.125 mg/ kg/min) in healthy volunteers. Both drugs were administrated 20 min after start of infusion. The study showed no effect on aspirin or zolmitriptan, and the authors suggested that nitric oxide might work later in the cascade of events that lead to headache than the antimigraine drugs. Discrepancy between triptan response in previous [2] and present [67] studies is likely due to different administration route and drug timing in relation to GTN infusion. Tvedskov et al. [68] introduced for the first time the GTN model of migraine to test the effect of valproate, a well known prophylactic drug in migraine treatment. This study showed that pretreatment with valproate was better than placebo in preventing GTN-induced migraine. In another study Tvedskov et al. [69] observed no effect of the prophylactic drug propranolol on GTN-induced headache and migraine. Recently, Tfelt-Hansen et al. [70] explored the effect of 15 migraine without aura patients pretreated with 150 mg of prednisolone or placebo followed by GTN infusion in a double-blind
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264 Headache
placebo-controlled study. Pretreatment with prednisolone did not reduce the immediate GTN-induced headache or inhibit the frequency of delayed headache. However, the intensity of delayed GTN-induced headache was significantly decreased compared with placebo. The GTN may induce delayed inflammatory response, which can be suppressed by prednisolone. In support, Reuter et al. [71] reported macrophage inducible NOS (iNOS) mRNA upregulation in the dura mater 4–6 h after GTN infusion in an experimental rat model. The time of development is correlated to delayed migraine attacks after GNT in migraineurs. Taken together, studies in healthy volunteers and migraineurs demonstrated that the GTN model of migraine might represent a powerful tool for preclinical testing of antimigraine drugs and thereby contribute to better understanding the mechanism of action of existing and future migraine therapies.
Conclusion Human models of migraine offer unique possibilities to study mechanisms responsible for different migraine subtypes and to explore the mechanisms of action of existing and future antimigraine drugs. Furthermore, these models have played an important role in preclinical migraine research leading to the identification of new principally different targets in the treatment of migraine attacks. New additions to the model, such as advanced imaging methods, may lead to a better understanding of the complex events that constitute a migraine attack, and possibly better and more targeted ways of intervention. At present, the GTN model of migraine represents a powerful tool for preclinical testing of antimigraine drugs.
Acknowledgement We thank Dr J.M.H. for his valuable comments on the human models of migraine in familial hemiplegic migraine. There was no conflict of interests. The present work was supported by the Lundbeck Foundation as part of the Lundbeck Foundation Center for Neurovascular Signalling (LUCENS).
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An update on the blood vessel in migraine K.C. Brennan and Andrew Charles Department of Neurology, David Geffen School of Medicine at UCLA, California, USA Correspondence to K.C. Brennan, 635 Charles E. Young Drive South, Neuroscience Research Building, Room 555a, Los Angeles, CA 90095, USA Tel: +1 310 206 7226; e-mail:
[email protected] Current Opinion in Neurology 2010, 23:266–274
Purpose of review The cranial blood vessel is considered an integral player in the pathophysiology of migraine, but its perceived role has been subject to much discussion and controversy over the years. We will discuss the evolution in our scientific understanding of cranial blood vessels (primarily arteries) in migraine. Recent findings Recent developments have clarified the role of cranial blood vessels in the trigeminovascular system and in cortical spreading depression. An underlying theme is the intimate relation between vascular activity and neural function, and we will emphasize the various roles of the blood vessel that go beyond delivering blood. We conclude that migraine cannot be understood, either from a research or clinical point of view, without an understanding of the vascular derangements that accompany it. Summary Migraine is accompanied by significant derangements in vascular function that may represent important targets for investigation and treatment. Keywords artery, constriction, cortical spreading depression, dilation, migraine, trigeminovascular Curr Opin Neurol 23:266–274 ß 2010 Wolters Kluwer Health | Lippincott Williams & Wilkins 1350-7540
Introduction Most physicians have been trained to think of migraine as a ‘vascular headache’, despite the fact that the original ‘vascular hypothesis’ of migraine has been challenged by extensive basic science and clinical evidence. Recent studies have focused to a greater extent on alterations in brain excitability in migraine patients, and debates have characterized migraine in a polarized fashion as either a primarily neural disorder or a primarily vascular disorder. This dichotomy between vascular and neural mechanisms of migraine is simplistic and artificial. Migraine is a complex, multisystem disorder, and blood vessels are quite literally intertwined with all other mediators of migraine pathophysiology. It is important to consider the vessels not as isolated conduits for blood, but rather as complex and heterogeneous components of networks, that are capable of bidirectional signaling with the surrounding parenchyma. In conjunction with perivascular neurons and glial cells, blood vessels are capable of actively detecting and responding to changes in the environment. They are thus ideally placed, both anatomically and physiologically, to exert an influence on migraine.
Vascular physiology in a nutshell Significant differences in the structure and regulation of blood vessels underlie their different physiological roles, as well as their potential roles in migraine. 1350-7540 ß 2010 Wolters Kluwer Health | Lippincott Williams & Wilkins
Arteries and arterioles consist of an endothelium and basement membrane lining the inner vessel wall (intima), a smooth muscle layer (media), which mediates contraction and dilation, and a connective tissue layer (adventitia) in contact with surrounding tissue. The artery is innervated (primarily by fibers whose cell bodies are outside the brain) in two main layers: within the vessel wall (myoneural synapses), and in the adventitial layer (sensory nerve endings) [1]. Within the brain parenchyma, the adventitial layer is in contact with astrocyte foot processes, and may also be contacted by parenchymal neuronal processes [2]. Capillaries consist of monolayers of endothelial cells with attached pericytes (cells with contractile filaments that may mediate constriction and dilation). Veins lack the media layer and vasomotor innervation of arteries, and serve as capacitance vessels that dilate passively with increased volume. Venous sinuses are formed from layers of dura, and function similarly to veins, but have dense sensory innervation [3,4]. It is important to recognize that blood vessels (especially arteries) are differentially regulated along their length. The large arteries of the circle of Willis are much more densely innervated with sensory and autonomic fibers than more distant branches. And as large surface vessels beget vertical penetrator arteries, there is a reduction in innervation, and most likely a change in locus of control DOI:10.1097/WCO.0b013e32833821c1
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Update on the blood vessel in migraine Brennan and Charles 267
from peripheral to more local neural and astrocytic mechanisms [2,3,5] (Fig. 1). Arterial motility and regulation
Ultimately, arterial constriction and dilation are mediated by either contraction or relaxation of actin and myosin filaments in smooth muscle cells. A bewildering array of mediators and signaling pathways converge on this common final behavior (Table 1) [3,6,7,8–15]. Constriction or dilation can be induced by arterial contents (blood), the artery wall itself (locally and from a distance), perivascular astrocytes and neurons, and sympathetic, parasympathetic, and sensory nerve terminals in the artery wall. The multilayered regulation is consistent with an obviously critical function.
Localized changes in an artery can be transmitted along its length by intrinsic conduction mechanisms. These conduction mechanisms may involve changes in membrane potential and intracellular calcium as well as purinergic receptor-mediated signaling, in layers of gap junctionally coupled smooth muscle cells or endothelial cells [16]. Conducted dilation has been shown to occur during cortical spreading depression (CSD), the presumed physiological correlate of the migraine aura [17], and in this setting may transmit vascular signals ahead of the slowly propagated wave of neuronal and glial depolarization. Neurovascular coupling is the process by which neural activity calls up an appropriate blood supply to meet
Figure 1 The varied regulation of the cerebral artery
Schematic shows a cortical surface artery, with its penetrator branches and arterioles in the cortex itself. The surface vessel is heavily innervated by sensory fibers from the trigeminal ganglion (TG), parasympathetic fibers from the sphenopalatine and otic ganglia (SPG/OG), and sympathetic fibers from the superior cervical ganglion (SCG). Peripheral innervation trails off as arteries enter the cortex, and regulation switches primarily to more local mechanisms. Inset: the ‘neurovascular unit’ consists of astrocytes which contact local neurons as well as arterioles (via their end-feet). Neurovascular coupling is mediated by the astrocyte, which transduces signals from neural activity (glutamate, Kþ) either directly or indirectly onto the vessel, causing dilation and increased blood flow. Interneurons have been shown to contact vessels directly, though the significance of these contacts is debated. Finally, ascending projections from brainstem nuclei can modulate cortical arterial diameter (note that they can also do this through effects on the trigeminal, parasympathetic, and sympathetic nerves that contact surface vessels). The differential regulation of cerebral vessels is highly relevant to migraine: cortical surface vessels are likely conduits for migraine-associated pain; and parenchymal microvessels are in close apposition to the neurons involved in cortical migraine phenomena. 5HT, serotonin; ACh, acetylcholine; CGRP, calcitonin gene-related peptide; GABA, g-amino butyric acid; glu, glutamate; NA, norepinephrine; NKA, neurokinin A; NOS, nitric oxide synthase; NPY, neuropeptide Y; PACAP, pituitary adenylate cyclase activating peptide; PNS, peripheral nervous system; SOM, somatostatin; SP, substance P; VIP, vasoactive intestinal peptide. Reproduced with permission from [2].
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268 Headache Table 1 The regulators of cerebral arterial function (a partial list)
Constriction
Mediator
Effector(s)
Source/location
Comments
Caþþ
L-type Caþþ channel; ryanodine receptor
Extracellular; endoplasmic reticulum
Membrane voltage (Vm)
L-type Caþþ channel
Endothelin-1 (ET-1)a
Endothelin-A receptor (ETA-R)
Perivascular nerves, astrocyte foot processes. Endothelium? Endothelium, brain parenchyma. Perivascular nerves?
Norepinephrine (NE)a (NPY, ATP co-released)a
a-1 adrenoreceptor, (NE); P2X purinergic receptor (ATP) 20-HETEa (via epoxygenase), thromboxane A2a (via cyclooxygenase)
Sympathetic nerves (superior cervical ganglion)
Serotonin (5-HT)a
5HT1b/d/f (to Gi/o proteins) 5HT2a (to Gq/11 proteins)
Platelets, mast cells, raphe nuclei, sympathetic nerves?
Transmural pressure
Transient receptor potential (TRP) channels via cation entry? Reactive oxygen species Vm
Endothelium? Vascular smooth muscle cell (VSMC)? Subarachnoid hemorrhage Spreading depression, stroke, tissue injury (generally Kþ above 20 mM) Hyperoxia
Caþþ entry, and release from internal stores mediates excitation–contraction coupling in smooth muscle cells. Depolarization of smooth muscle cells causes constriction via Caþþ-mediated mechanisms. Relevant to intrinsic tone, also activated by tissue injury. Activation of ETA-R increases [Caþþ]i via G-protein coupled mechanisms. Increases in intracellular Caþþ via phospholipase C (NE, NPY); Naþ and Caþþ entry (ATP). AA diffuses to vascular smooth muscle cell (VSMC) and is converted to 20-HETE. 20-HETE constricts by inhibiting VSMC BKCaþþ channels, activating L-type Caþþ channels, and inhibiting NO production. 5HT1b/d activity may constrict via AA derivatives. 5HT2a activity constricts via [Caþþ]i elevation. Stretch results in depolarization, constriction.
Arachidonic acid (AA) derivatives (eicosanoids)
Hemoglobin (Hb) Kþa,b
Dilation
a,b
O2a,b
Superoxide anion (O2-) ?
Kþa
KCaþþ, KATP, KIR, K(v)
Vm
Endothelium-derived hyperpolarizing factor (EDHF) (likely H2O2) cGMP, myosin light chain phosphatase
Nitric oxide (NO)a
NO inactivates myosin light chain kinase via guanylate cyclase and myosin light chain phosphatase. Dilation via NO and inhibition of NE constriction. Dilation via NO. Stretch results in hyperpolarization, dilation. A2A receptor reduces L-type Caþþ channel activity via tyrosine phosphatase; adenosine can activate GIRK channels, cause hyperpolarization. 5HT1b/d activity dilates via NO, EDHF. Most studies show that the net 5HT1b/d effect is constriction (see above). CGRP binding activates KATP channel, hyperpolarizes VSMC (NO production also increased). NK1 activation increases NO production.
PAC1, VPAC1,2 receptors KCaþþ, KATP, Cl- channels Adenosine A2A receptor, L-type Caþþ channel; GIRK channel
Parasympathetic nerves Endothelium? VSMC? Conversion from ATP, other purines extracellularly and intracellularly.
Serotonin (5-HT)a
5HT1b/d/f (to Gi/o proteins)
Platelets, mast cells raphe nuclei?
Calcitonin gene-related peptide (CGRP)a
CRLR/RAMP1
Trigeminal nerves
Substance P (SP)a, Neurokinin A (NKA)a Arachidonic acid (AA) derivatives (eicosanoids) Glutamatea
Neurokinin 1 (NK1) receptor
Trigeminal nerves
Histamine
Mechanical
Endothelial cells, parasympathetic nerves (from pterygopalatine ganglion, otic ganglion) Parasympathetic nerves
NO, inhibition of NE release
a
a
PGE2
Metabotropic glutamate receptor (mGluR); AA derivatives. KCaþþ activation, NO, EDHF H1, H2 receptors
O2- generated in hyperoxic conditions may inactivate NO. Kþ efflux hyperpolarizes VSMC membrane, allows dilation. EDHF activates KCaþþ channels.
VIP, PACAPa Transmural pressure Adenosinea
a
Hb scavenges NO, impeding dilation. Membrane depolarization opens voltage gated Caþþ channels.
Neural, astrocytic activity, other mediators (see below) Endothelial cells
Acetylcholine (Ach)a
Bradykinin
Sensation Nociceptive
Astrocytes (generate AA via phospholipase A2)
Astrocyte (generates AA via phospholipase A2) Astrocyte Venular endothelium Mast cells, endothelial cells, smooth muscle cells, glia? Circulation, brain parenchyma? Circulation
Estradiola (progesterone)a
NO, EDHF, BKCaþþ
Angiotensin II
AT1,2 receptors
CO2
Multiple, including acid sensing ion channels
Circulation
Hþ, Kþ, CGRP, stretch?, cytokines? others? Constriction, dilation, traction, perfusion pressure
TRPV1 receptor, CRLR/RAMP1, others?
Trigeminal ganglion
Stretch receptors (TRP family?)
Trigeminal ganglion, vessel wall
Activation of Kþ channels hyperpolarizes VSMC (may also increase NO production). Activation of mGluR on astrocyte increases AA derivative (EET) release. Kþ efflux, EDHF hyperpolarizes VSMC, NO relaxes. H1 effects via G-protein and phospholipase C; H2 effects via myosin light chain kinase. Kþ efflux, EDHF hyperpolarizes VSMC, NO relaxes. AT receptor activation increases VSMC Caþþ levels favoring constriction Dilation via cholinergic mechanisms. Trigeminal afferent activation increases TNC activity, also antidromic release (trigeminovascular reflex). May form component of nociceptive response, also response to blood pressure (autoregulation).
20-HETE, 20 hydroxyeicosatetraenoic acid; ATP, adenosine triphosphate; BKCaþþ, large conductance calcium activated potassium channel; [Caþþ]i, intracellular calcium; cGMP, cyclic guanosine monophosphate; CRLR, calcitonin receptor-like receptor; GIRK, G-protein coupled, inwardly rectifying potassium channel; K(v), voltage gated potassium channel; KATP, ATP-sensitive potassium channel; KCaþþ, calcium activated potassium channel; KIR, inwardly rectifying potassium channel; NPY, neuropeptide Y; PACAP, pituitary adenylate cyclase activated peptide; RAMP1, receptor activity modifying protein 1; TRP, transient receptor potential family of receptors; TRPV1, transient receptor potential (vanilloid 1); VIP, vasoactive intestinal peptide. Data from [3,6,7,8–15]. Not all references could be included for reasons of space. a A mediator or effector which has effects on vessel, perivascular nerves, astrocytes, or parenchymal neurons beyond simple constriction or dilation. See text for further detail. b Pathological.
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Update on the blood vessel in migraine Brennan and Charles 269
metabolic needs. It arises locally, with the sensation of neural activity by astrocytes, and the transmission of the astrocytic signal to the precapillary arteriole, which then dilates to increase the volume of blood delivered to the active region [18,19]. Measures of interictal neurovascular coupling appear to be normal in humans with migraine without aura [20]; however, neurovascular coupling may be disrupted in the wake of the migraine aura [21–23], and as discussed in greater detail below, it is disturbed in both animals and humans during CSD [24–26,27]. Autoregulation is a homeostatic response of cerebral arteries which keeps cerebral perfusion pressure constant in the face of a range of mean arterial pressures (from 50 to 150 mmHg). CO2 reactivity is the perfusion response to alterations in the partial pressure of CO2 in the blood (dilation to increased pCO2, constriction to decreased pCO2). In contrast to neurovascular coupling, which arises locally, autoregulation and CO2 reactivity are global responses, triggered by carotid chemo- and baroreceptors and possibly by stretch receptors in the cerebral vessels [6,28]. Autoregulation appears to be intact in both humans with aura and animals with CSD. CO2 reactivity is altered, however. It is increased interictally in migraine patients [29,30], but blunted after aura [23], and after CSD in experimental animals [31]. Sensory and paracrine function
Blood vessels are a focal point for multiple converging functional elements, including processes of sensory and autonomic neurons, astrocytes, and neurons within the brain parenchyma. Considered as a unit, these elements constitute a paracrine organ whose sensory and effector function is not limited to the vessel itself. The classic work of Wolff and Penfield showed that stimulation of cerebral blood vessels causes pain in humans, indicating that they are a primary conduit for intracranial nociceptors [32,33]. Cerebral arteries, dural arteries, and dural sinuses are densely innervated by branches of the trigeminal nerve [3,4]. The nerve fibers are primarily small diameter, unmyelinated nociceptive afferents. However, there are also larger-diameter myelinated fibers [7], which may serve for mechanosensation. The arterial wall itself may serve as a sensor: vascular smooth muscle cells express transient receptor potential (TRP) family receptors which may be involved in mechanosensation and autoregulation [6]. As detailed in Table 1, endothelial cells, smooth muscle cells, perivascular neuronal fibers, and astrocytes are all capable of release of multiple mediators. Importantly, these mediators not only modulate vascular tone, but also activate receptors on sensory neurons, on surrounding astrocytes, and potentially on surrounding neurons in the brain parenchyma [2,3,19,34,35].
Trigemino-vascular and trigemino-autonomic loops
Trigeminal stimulation, either over cerebral vessels, along the trigeminal nerve, or in the trigeminal ganglion, causes antidromic release of substance P, neurokinins, and CGRP from the afferent terminals. These mediators dilate dural and cortical surface vessels; permeabilize dural vessels leading to plasma protein extravasation; activate perivascular mast cells; and cause further depolarization of the very nerves that released them, creating a positive feedback loop. This feedback can be amplified by activation of parasympathetic efferents, an integrated response referred to as the trigeminoautonomic reflex [3,34]. Both the trigeminovascular and trigemino-autonomic reflexes can be tested (albeit indirectly) in humans [3,36,37].
Wolff’s vascular hypothesis and its downfall The original ‘vascular hypothesis’ of Harold Wolff was that the pain of migraine was due to the dilation of painsensitive cerebral vessels, and that any preceding aura was due to constriction of these vessels. The hypothesis was based on his [32] and Penfield’s [33,38] work showing that cerebral vessels were sensitive to pain, and to his demonstration that vasodilators caused, and vasoconstrictors relieved, headaches [39]. Wolff’s ideas have for the most part been refuted. Olesen et al. [21] first showed that the pain of migraine with aura actually coincided with hypoperfusion, following a brief hyperperfusion associated with the aura. Further evidence against a simplistic dilation model has come from studies of pharmacologically induced migraine. Most headachetriggering drugs exert a biphasic effect, causing an initial dilation and mild headache in nearly all subjects, and only later (after dilation has stopped) a migraine-like headache in susceptible patients. Interestingly, the initial dilation is of equal size in migraineurs and controls. With headache induced by nitroglycerin (thought to model migraine without aura), Schoonman et al. [40] detected no difference in the diameter of large cerebral and meningeal arteries during headache, despite a significant dilation immediately following nitroglycerin infusion. In addition, not all vasodilators [vasoactive intestinal peptide (VIP) [41] and ethanol [42], for example] cause headache; and not all headache-promoting agents cause vasodilation (sildenafil induces headache but no middle cerebral artery dilation [43,44]). Moreover, not all vasoconstrictors relieve headache, and in fact many vasoconstrictors cause headache: examples are cocaine [45,46], and high or chronic doses of ergots [47,48]. Perhaps most convincingly, reversible cerebral vasoconstriction syndromes and the vasospasm of subarachnoid hemorrhage are intensely painful [49,50]. These experimental and clinical observations show that vasodilation is neither necessary nor sufficient to cause the pain of migraine. However it should be
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270 Headache
noted that they do not rule out a role for vasoconstriction as an initial trigger for subsequent migraine pain.
Beyond dilation and constriction Though still popular among nonspecialists, Wolff’s vascular hypothesis is a bit of a straw man in the discussion of headache pathophysiology, as the evidence against it is strong, and for years other plausible ‘vascular hypotheses’ have been available. The trigemino-vascular/trigemino-autonomic model of headache
The underlying assumption of this robust, experimentally based model is that the vessel (artery or dural sinus), is an agent in the generation and transmission of headache pain, through its sensory, effector, and vasomotor functions. A strength of the trigemino-vascular/trigemino-autonomic (TGV/TA) model is that it directly translates to humans. The same mediators measured in experimental animals can be measured in humans [36,51], though generally surrogate measures are used. Direct electrophysiological recording from brainstem centers is not possible in humans, but indirect measures such as nociceptive blink reflex [52] and cutaneous allodynia [53,54] can be employed. The systematic testing, in humans, of substances identified in the rodent trigemino-vascular system has led to significant insights. Calcitonin gene-related peptide (CGRP), a peptide released by trigeminal nerve terminals, was identified over two decades ago as a potential mediator of headache pain [36], and CGRP inhibitors are now poised for clinical use in migraine [55]. Other trigemino-vascular mediators could also be important. Vasoactive intestinal peptide (VIP) and the related pituitary adenylate cyclase activating peptide (PACAP) are released from parasympathetic and trigeminal nerves in cranial blood vessels. Interestingly, VIP failed to elicit migraine-like attacks, even though it caused significant cranial dilation [41]. But PACAP38, the most common form of PACAP, was a potent inducer of migraine-like headaches in patients with migraine without aura [56]. These paired publications confirm that dilation per se may not be the critical step in activation of nociceptive pathways. On an important clinical note, they suggest PACAP inhibitors as migraine therapeutic agents. Whether insights gained from the TGV/TA model can be extrapolated to all types of migraine is an open question. Most induced migraines (with nitroglycerin [57], CGRP [58], and PACAP [56], for example) are similar to migraine without aura, even in patients with migraine with aura [57], calling into question whether migraine with aura (or at least the aura portion) is amenable to such study. Moreover, neither NTG nor CGRP induces either aura or migraine in familial hemiplegic migraine,
suggesting that these disorders may be biologically distinct, perhaps even from other forms of migraine with aura [59 –61]. Nevertheless, the systematic testing, in humans, of hypotheses generated using the TGV/TA model is a true example of the power of translational neuroscience, and promises great insights to come. Other recent insights using the TGV/TA model increase our knowledge of arachidonic acid derivatives (eicosanoids) in the basic mechanisms of migraine. Eicosanoids are products of enzymatic digestion of plasma membrane phospholipids, involved in both conventional neurovascular coupling [62] and the deranged neurovascular coupling that accompanies CSD [63,64]. They are also known mediators of pain and inflammation [65]. Iliff et al. [66] identified epoxyeicosatrienoic acids (EETs) as potential players in the TGV/TA system, by demonstrating the presence of EET synthetic enzymes in trigeminal and sphenopalatine ganglion neurons, and attenuating trigeminally induced cortical hyperemia with an EET antagonist. Maubach et al. [67] identified BGC20–1531, a prostanoid EP4 receptor antagonist, as a potential migraine treatment, demonstrating its ability to bind to the human EP4 receptor, and to antagonize the dilatory effects of PGE2 on human cerebral arteries. Both articles highlight the sometimes neglected role of eicosanoids in migraine, and suggest a targeted investigation of these mechanisms in migraine drug discovery. Vascular changes during cortical spreading depression
Cortical spreading depression is thought to be the physiological basis of the migraine aura, as hemodynamic events consistent with CSD have been observed during the migraine aura [21,68], and conclusive electrophysiological recordings of CSD have been made in brain injured humans [69,70]. CSD is capable of activating the trigeminal nucleus caudalis [71,72], and is thus inferred to be able to generate the pain of migraine. Finally, pharmacologically diverse medications used in migraine prophylaxis inhibit CSD [73]. Thus CSD has developed into a model system to study migraine with aura. It has long been known that stroke causes peri-infarct depolarizations, which are electrophysiologically indistinguishable from CSD [74], and the vasoconstrictor ET1 is a potent inducer of CSD, likely via ischemia [75]. Nozari et al. [76] used a mouse model of embolic infarction to demonstrate that air, latex microspheres, or cholesterol crystals could all cause CSD. Importantly, they showed a dose response to size and number of emboli, and at the lower end (either size or number) found little or no permanent ischemic damage. From this they inferred that embolization events, subclinical from a stroke point of view, could still cause CSD and thus migraine. The clinical correlation of this work, a reported
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Update on the blood vessel in migraine Brennan and Charles 271
increased rate of patent foramen ovale (PFO) in migraine, is less robust than previously thought: a population study found no association of migraine and PFO [77]. Moreover the first randomized trial of PFO closure in migraine was negative [78]. But, the physiological proof of principle is valuable, confirming that an ischemic vascular trigger of migraine with aura is possible. The migraine aura is associated with alterations in neurovascular coupling [21–23], and CSD causes significant derangements in neurovascular coupling in both animal model systems [24–26] and humans [27]. The CSD wave itself can involve a complete inversion of normal neurovascular coupling [17,27,79], which can result in tissue hypoxia [27,80]. Perhaps more relevant to migraine, the hour to 90 minutes following CSD also show disruptions in neurovascular coupling. Two recent studies expand our knowledge of this dysfunction. Piilgaard and Lauritzen [81] and Chang et al. [82] both show that in the wake of the CSD wave, there is a distinct phase of long lasting mismatch between vascular supply and demand, leading to tissue hypoxia and hemoglobin desaturation. Both also directly show a disruption of neurovascular coupling, which seems to be due to a deficient vascular response. Finally, and counterintuitively (as CSD is thought to silence the cortex), both studies show changes that might favor increased neuronal activity after CSD. Both studies underline the point that neurovascular coupling is a mutable phenomenon, whose characteristics depend on the state of the cortex. They also show that neurovascular coupling is a two-way street: vessels can affect neurons as well as vice versa. It is appealing to speculate that the dysregulation of cortical neurovascular function after CSD might help explain altered sensory processing during migraine with aura.
Questions for future research Migraine is a systemic disorder; the study of migraine is thus obligatorily a study of systems physiology. We can confidently predict that no single reductionistic model system (either in humans or animals) will be sufficient to understand the phenomenon. The way forward likely lies in pooling insights from different model systems. Critical to this is an understanding of what each model tells us, and what it does not, in the light of the vascular physiology we discussed above. Here we raise a few questions for further research, brought up by recent advances. What kind of vascular changes are we measuring in migraine patients and model systems?
A critical point in the study of vascular changes in migraine is that different techniques look at differently controlled vessels. The best evidence of perfusion changes in humans with migraine comes from techniques (PET, fMRI, scintigraphy or SPECT) that sample changes in the micro-
vasculature [21,68,83,84], a compartment structurally and functionally distinct from larger vessels [5,2]. It has been shown that the parenchymal microvascular response and the cortical surface vessel response can be dissociated in rodents [17]. Should we expect the situation to be any different in humans? It is important to understand that a change (or lack thereof) in parenchymal microvessels does not necessarily predict the behavior of larger vessels, and vice versa. As the surface vessels are heavily innervated structures that likely transmit pain signals, and the microvessels are in intimate relationship with the neurons that mediate cortical function and dysfunction, the relation of their activity to migraine phenomenology is not merely academic. On a related note, it should be emphasized that arterial diameter changes related to cortical spreading depression [17] occur in surface vessels that are not reliably accessible to 3T magnetic resonance angiography [40], even in humans. It should also be noted that the large trunk vessels normally sampled by transcranial Doppler sonography [56] and magnetic resonance angiography [40] may not be affected even during massive neurovascular events such as CSD. Again the important message is to know what we are looking at. Moving forward, it would be very helpful to sample surface vessel and parenchymal signal simultaneously in humans during induced and spontaneous migraine. This may be possible using high resolution techniques such as 7T MRI. Are the vascular changes of spreading depression really relevant to migraine pain?
Cortical spreading depression has shown great utility as a migraine model, but the evidence that it generates migraine pain is of a limited nature, and remains controversial. Different groups have had varying success in eliciting c-fos activation in the trigeminal nucleus caudalis, and it is very difficult to control for other sources of pain in head-restrained animals with cranial surgery [85,71]. Direct electrophysiological evidence of trigeminal activation would be much more conclusive than measurement of immediate early gene activation. Preliminary studies of this nature have recently been presented (Burstein R, 14th Congress of the International Headache Society, 2009). How can we explain the delay in headache after a vascular disruption or aura?
Nearly all subjects infused with nitroglycerin (or other headache-inducing agents) experience an immediate mild headache which corresponds with cranial and extracranial dilation. The migraine-like headache only occurs after a delay of 4–6 h [56,57,58]. There are also (shorter) delays involved in aura induction in migraine with aura. Elements of the xenon scintigraphy technique used in classic cerebral blood flow studies (likely vascular
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272 Headache
disruptions, as the technique involved direct infusion of tracer into the carotid circulation) appeared to induce migraine with aura, as events were much more frequent than normal after this procedure [21,22]. Delays to aura were in the range of tens of minutes. Finally, there is a tens-of-minutes delay that typically occurs between aura and the onset of migraine pain. The mechanisms of these delay phenomena, which could fundamentally alter our understanding of headache induction, are unknown. One might speculate on both local (regenerative release of mediators on the vessel until pain threshold is reached) and networked (trigemino-vascular, brainstem autonomic, and higher cortical) phenomena. Very interestingly, preliminary studies show that trigeminal activation after CSD appears to be subject to a delay of tens of minutes after the wave (Burstein R, 14th Congress of the International Headache Society, 2009). If this is the case, CSD-based models might be used to uncover the basic mechanisms of delay between aura and migraine pain. Are we neglecting constriction and hypoperfusion?
It is interesting how much emphasis is placed on craniovascular dilation or hyperperfusion, when strong experimental evidence in both humans and animals shows constriction or hypoperfusion to be equally prevalent [17,21,27,68,79,82,84]. Constriction is at least as plausible as dilation as a pain trigger; in fact CGRP and nitric oxide are released in response to constriction [3]. Of particular interest is the highly replicable hypoperfusion in humans after the migraine aura, and in animals after CSD [21,68,81,82]. Recent evidence [81,82] emphasizes the long-known disruption of neurovascular coupling after CSD, and suggests a mismatch in metabolic demand and supply. Such mismatches are potent triggers of pain in the periphery – the best-known and most extreme example is angina. Could the post-aura hypoperfusion be a pain stimulus in itself?
vasospasm and CSD [75], a common unifying hypothesis would be that these disorders share a tendency toward vasospasm which could both induce CSD and directly cause cranial pain. In this light it is interesting to note that CADASIL transgenic mouse arteries have reduced flow-induced dilation, and increased pressure-induced myogenic tone, suggestive of a tendency toward constriction [89]. Focused physiological study of human mutation carriers in these ‘pure’ vasculopathies, and generation of more mouse models, could reveal a great deal about potential vascular mechanisms of headache.
Conclusion The craniocerebral blood vessel is not just a carrier of blood: its intrinsic sensory and secretory abilities, as well as its inextricable association with perivascular nerves and astrocytes, make it an integral part of a sensory and effector network. It is multiply and variably regulated along its length, and it is bidirectionally linked with the brain in the parenchyma (through neurovascular coupling mechanisms) and in the periphery (through trigeminal and autonomic nerves). Migraine, especially migraine with aura, is consistently linked with micro or macrovascular changes during the attack. The idea that simple dilation or constriction can explain migraine pain is simplistic, but the rejection of the vessel as an agent of migraine is equally simplistic. Recent work on two key models of migraine – the trigemino-vascular model and cortical spreading depression – bears this out. Alterations in vascular function may or may not be the first derangement in a migraine attack: we would argue that the initial step can vary, with several possible pathways that lead to the generation of pain. But migraine cannot be understood without a clear understanding of the dynamic role of the blood vessel in its pathogenesis.
Acknowledgements What can we learn from the ‘pure’ vasculopathies?
Much appropriate emphasis has been placed on the mutations that confer familial hemiplegic migraine, two of which (CACNA1A and SCN1A) code for neuronal ion channels, and are thought to increase neuronal excitability [86,87]. However, there are disorders whose phenotype includes migraine that involve exclusively vascular disease. The most prominent of these is cerebral autosomal dominant arteriopathy with subcortical infartcts and leukodystrophy (CADASIL; NOTCH3 mutation). Two others are retinal vasculopathy with cerebral leukodystrophy (RVCL; TREX1 mutation) and hereditary infantile hemiparesis with retinal arterial tortuosity and leukoencephaly (HIHRATL; COL4A1 mutation) (reviewed in [88]). The mutations are diverse but a common theme of all three disorders is a structurally and functionally abnormal cerebral vasculature. Given the demonstrated ability of the endogenous vascular mediator endothelin-1 to cause
The work was supported by the National Institutes of Health (NINDS K08 NS059072 and NIH Loan Repayment Program, K.C.B.), the Larry L. Hillblom Foundation (K.C.B., A.C.), and the Migraine Research Foundation (A.C.). Neither author has any conflict of interest to declare.
References and recommended reading Papers of particular interest, published within the annual period of review, have been highlighted as: of special interest of outstanding interest Additional references related to this topic can also be found in the Current World Literature section in this issue (pp. 335–336). 1
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EDITORIAL REVIEW
Dopamine: what’s new in migraine? Annabelle R. Charbit, Simon Akerman and Peter J. Goadsby Headache Group - Department of Neurology, University of California, San Francisco, San Francisco, California, USA Correspondence to Professor Peter J. Goadsby, Headache Group–Department of Neurology, University of California, San Francisco, 1701 Divisadero St, San Francisco CA 94115, USA E-mail:
[email protected] Current Opinion in Neurology 2010, 23:275–281
Purpose of review Dopamine has been implicated in the pathophysiology of migraine, although its exact role remains unclear. Recent data offer some new perspective on a possible role for dopaminergic mechanisms in migraine. This review aims to summarize our current understanding of dopamine in migraine. Recent findings Direct application of dopamine and dopamine receptor agonists onto trigeminocervical complex neurons inhibits their activation after nociceptive stimulation. The dopaminergic A11 nucleus of the hypothalamus has been identified as the likely source of this dopamine. Recent evidence has shown that the genes for dopamine beta-hydroxylase and the dopamine transporter SLC6A3 may play a role in migraine pathophysiology, and dopamine has also been implicated in menstrual migraine. Summary Dopamine is currently considered to contribute to the pathophysiology of migraine, and dopamine receptor antagonists are prescribed in the treatment of acute migraine. Laboratory data suggest that the role of dopamine in migraine is more complex, perhaps due to the multiple receptors and levels of the brain involved in the disorder. These data suggest a reappraisal of dopaminergic therapeutic targets in migraine as our understanding of the role of this important biogenic amine is better characterized. Keywords dopamine agonists, dopamine beta-hydroxylase, dopaminergic A11 nucleus, headache, menstrual migraine, premonitory symptoms, vomiting Curr Opin Neurol 23:275–281 ß 2010 Wolters Kluwer Health | Lippincott Williams & Wilkins 1350-7540
Introduction Migraine is a complex neurological disorder affecting both peripheral and central neurotransmitter systems in various brain areas. The pathophysiology of migraine is still not completely understood, but it is generally accepted that migraine involves activation of trigeminovascular afferents [1]. These afferents excite neurons in the trigeminocervical complex (TCC), which further conveys somatosensory and visceral information from the head and orofacial structures to the hypothalamus and other higher brain areas. Additionally migraineurs often experience other sensory disturbances, alongside the pain, such as nausea, vomiting, gastrokinetic discomfort, and sensitivity to light, sound and smells. Some cases also include neurologic symptoms, the aura. The data point towards migraine being described as a dysfunction of sensory modulatory networks resulting in abnormal processing of essentially normal neural traffic.
tonin gene-related peptide (CGRP), as these are clear therapeutic targets in migraine. Triptans, 5-HT1B/1D receptor agonists, are now used routinely in the treatment of migraine, and good studies are now available with CGRP. It is generally accepted that other systems must be involved and historically dopamine has been implicated as playing some role in migraine pathophysiology. The exact role of dopamine in migraine is still somewhat unclear, with some evidence pointing to dopamine as pathogenic in migraine and other evidence pointing to dopamine as therapeutic in migraine. Here we will review the most recent advances in our understanding of the role of dopamine transmission in migraine. For a more historical overview of the role of dopamine in migraine we refer the reader to other recent reviews [2–4].
Dopamine and the pathogenesis in migraine A number of neurotransmitter systems have been implicated in migraine, most notably serotonergic and calci1350-7540 ß 2010 Wolters Kluwer Health | Lippincott Williams & Wilkins
There is evidence suggesting that dopamine may be involved in the pathogenicity of migraine. DOI:10.1097/WCO.0b013e3283378d5c
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276 Headache
Clinical markers
One of the key aspects that relate dopamine to migraine is the premonitory symptoms that present at the very beginning of an attack. Excessive yawning, nausea, vomiting and gastrokinetic disturbances are all thought to be dopamine-driven processes that help define the dopamine theory of migraine [5]. Indeed administration of the dopamine agonist apomorphine has variously found increase in yawning, nausea, vomiting and dizziness, compared to controls [6–8]. This would suggest a hypersensitivity to dopamine, and these symptoms can be reversed by D2-like receptor antagonists. More recent studies measured platelet levels of dopamine and platelet binding to D2 receptors in migraineurs, and it was found that platelet levels of dopamine were increased in migraine with and without aura [9,10], and there was also an increased binding affinity of platelet D2 receptors to dopamine, specifically in migraine without aura patients [10]. This increased binding affinity, and increased levels of dopamine in platelets, validates the argument of hypersensitivity to dopamine in migraine patients, or at the very least suggests altered dopaminergic activity at D2-like receptors. Dopamine pharmacotherapy
The other major reason for implicating dopamine in the pathogenesis of migraine is the use of D2-like receptor antagonists in the acute treatment of migraine. They have been shown to alleviate the headache component to some extent, and predominantly the migraine-associated premonitory symptoms, such as yawning, irritability, nausea, vomiting and gastrokinetic dysfunction. Prochlorpromazine, metoclopramide, droperidol, haloperidol and domperidone [11,12,13–15] have all been used successfully to treat migraine. Recently prochlorperazine was found to also be effective when administered by inhalation [16]. The mechanism by which these D2-like receptor blocking drugs alleviate headache remains to be determined, particularly as headache is not a recognized side effect of direct dopamine agonists used in the treatment of Parkinson’s disease or restless legs syndrome (RLS). It may be important to note that none of these drugs has an exclusively dopaminergic pharmacology. Premonitory symptom treatment
Interestingly, D2-like receptor blockade treated the premonitory symptoms of yawning, drowsiness, nausea, vomiting and gastrokinetic disturbances, and these are all dopamine-driven processes. D2-like receptor agonists have been shown in many studies, to induce these premonitory symptoms in people, and D2-like receptor antagonists, with their well documented antiemetic and prokinetic effects, have been shown to reverse them [6,7]. Considering all this, it seems likely that altered dopaminergic activity at D2-like receptors may have a pathophysiologic role in migraine.
Dopamine as therapeutic in migraine The headache phase of migraine is likely to be a result of activation of trigeminal afferents that project to the trigeminal nucleus and subsequently activate third-order neurons in the thalamus. Dopamine and the trigeminocervical complex
Recently evidence has emerged that dopamine may act directly on trigeminal afferents to modulate firing in the TCC. Dopamine was found to attenuate nociceptive signaling when microiontophoresed directly onto neurons in the rat TCC activated by durovascular nociceptive stimulation [17]. Immunocytochemistry has further demonstrated that D1 and D2 dopamine receptors can be identified in the rat TCC [17]. Furthermore, intravenous administration of the D2-like receptor agonist quinpirole inhibited nociceptive transmission in the rat TCC evoked by electrical stimulation of the dural vasculature and mechanical cutaneous stimulation of the ophthalmic dermatome [18]. Quinpirole crosses the blood brain barrier, and its effect is consistent with the finding that dopamine has antinociceptive properties at D2-like receptors located centrally in the TCC [17]. Moreover, intravenous administration of centrally active D2-like receptor antagonists eticlopride and remoxipride but not the peripheral only D2-like receptor antagonist domperidone, facilitated firing in the TCC evoked by both noxious and innocuous stimulations of the trigeminal nerve [18]. The facilitatory effects of these centrally active D2-like receptor antagonists on evoked firing in the TCC suggest the possible existence of a tonic dopaminergic inhibition of neuronal firing in the TCC in response to nociceptive stimuli, which is abolished when the D2like receptors are blocked. Origins of descending dopamine: the A11 nucleus
One candidate for the origin of this tonic dopaminergic modulation of neurons in the TCC is the hypothalamic A11 dopaminergic nucleus first identified by Dahlstrom and Fuxe [19] and distributed along the rostro-caudal axis, in the periventricular posterior region of the hypothalamus and the periventricular grey of the caudal thalamus. The A11 nucleus is known to send direct inhibitory projections to the spinal cord dorsal horn [20,21], and is also understood to be the sole source of dopamine in the spinal cord [22]. It was also found that the A11 dopaminergic nucleus modulates trigeminal processing, as electrical stimulation within the rat A11 nucleus led to inhibition of evoked nociceptive signaling from the TCC. This response was effectively reversed by an intravenous D2-like receptor antagonist [23]. As such it can be suggested that dopamine, possibly arising from the A11 nucleus, binds to inhibitory D2-like receptors in the dorsal horn of the TCC, and thus inhibits the rostral transmission of nociceptive signals (Fig. 1).
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Dopaminergic mechanisms in migraine Charbit et al.
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Figure 1 The A11 nucleus and the trigeminovascular system
(a) Immunofluorescent staining for tyrosine hydroxylase (TH; green) and dopamine-b-hydroxylase (DBH; red) in the A11 (50 magnification). The A11 nucleus has been located by immunohistochemical staining for dopaminergic cell bodies, using a double-staining protocol with anti-TH antibodies (TH is the enzyme involved in the first step in the synthesis of dopamine), and anti-DBH antibodies (DBH is the enzyme that catalyses the conversion of dopamine to norepinephrine). The perikarya of dopaminergic neurons can be distinguished from noradrenergic neurons by the immunohistochemical demonstration of the enzyme DBH only in the latter. The cells in the A11 nucleus stain only for TH (green) and not for DBH (red), hence confirming that these are dopaminergic neurons [23]. (b) A schematic diagram of what may be happening at the level of the A11 dopaminergic nucleus when the trigeminal system is activated: The trigeminal nerve is activated and the A11 nucleus provides inhibitory dopamine to D2-like receptors at either presynaptic first order neurons or post-synaptic second-order neurons in the TCC (original). Location of the A11 dopaminergic nucleus: interaural level; 5.52 mm [24]. , Vasoactive molecules (SP, CGRP, NKA, EAA); , Dopamine. 3v, third ventricle; DMD, dorsomedial hypothalamic nucleus dorsal part; f, fornix; ml, medial lemniscus; mt, mammillothalamic tract; Pe, periventricular hypothalamic nucleus; PH, posterior hypothalamus; PLH, lateral hypothalamus peduncular part; VM, ventromedial thalamic nucleus.
Furthermore electrical lesioning of neurons in the rat A11 nucleus led to facilitation of evoked nociceptive signaling from the TCC [23,24]. The data predict that loss of A11 function would be pro-nociceptive. The A11 nucleus is primarily known for a possible role in RLS [25,26], a sensorimotor disorder clinically characterized by uncomfortable and unpleasant sensations in the limbs [27], relieved by movement, and worsened during periods of inactivity such as sitting or lying down. Dopamine, and specifically the D2-like receptor, was identified as having an important role in this disorder when it was found that low-dose dopaminergic agonists provided relief in patients with RLS [28], whereas symptoms worsened when patients were given D2-like receptor antagonists, such as olanzapine [29]. On this background Rhode and colleagues [30] report a comorbidity of RLS and migraine. Both syndromes are more common in females,
both are affected by sleep, both are likely to co-exist with depression, both are influenced by pregnancy, both have the same regional epidemiology, that is more common in Caucasians and less common in Asians, and both are clinically influenced by drugs acting at dopamine receptors. The overlap reinforces the utility of better understanding the A11 nucleus [30]. Interestingly lesioning of rat A11 neurons also caused facilitation of firing in response to non-nociceptive (innocuous) stimulation of the trigeminal receptive field [23]. As such it has been proposed that a dysfunction in A11 neurons, that is loss of normal inhibitory tone, may be involved in the pathophysiology of sensitization [23]. It has previously been hypothesized that when trigeminal nerve activation occurring during migraine is not interrupted, peripheral sensitization progresses to
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278 Headache
central sensitization, causing cutaneous allodynia in the ipsilateral head [31]. Sensitized second-order neurons can further sensitize third-order neurons, which mediates the development of cutaneous allodynia to the contralateral head and further even beyond the cephalic region to the ipsilateral forearm [32]. A mechanism that would permit this cascade to occur would be a modulatory nucleus, such as the A11, becoming dysfunctional early in the evolution of the migraine. Dopamine inhibits firing in the TCC, by binding to D2-like receptors. The A11 nucleus is not the only group of neurons with inhibitory actions on the TCC, considering the presence of inhibitory 5HT receptors, but it may have a contributing role in preventing sensitization of second order neurons in the TCC.
Dopamine and menstrual migraine Many women with migraine report some relationship with their menstrual period, with the migraine occurring more or less at the same time each cycle. It is estimated that up to 60% of women with migraine have some menstrual influence [33]. The menstrual cycle is divided into two parts: the follicular phase, when oestrogen levels are high and progesterone levels are low, and the luteal phase, when oestrogen levels are low and progesterone levels are high. Studies comparing levels of oestrogen and progesterone in women with menstrual migraine as compared with controls have found no convincing differences, therefore research has focussed on ‘withdrawal’ of oestrogen and progesterone that occurs during the luteal phase and follicular phase, respectively, of the menstrual cycle. It has been found that withdrawal of oestrogen, that occurs during the luteal phase, is associated with increased incidence of migraine [34,35], and thereby proposed that rising levels of oestrogen may protect against migraine. Indeed this would seem to fit in with those women whose migraine occurs in the few days leading up to their period. On the contrary, it has been proposed that the rise in progesterone during the luteal phase is preventive of migraine compared with other times of the cycle, whereas the drop in progesterone at the end of the luteal phase/start of the follicular phase might trigger a migraine attack [34,36]. In terms of a possible dopaminergic role, it is interesting to note that migrainous women were shown to have increased serum levels of prolactin [37]. The secretion of prolactin from the pituitary gland is controlled by the dopaminergic tuberoinfundibular pathway, whereby progesterone stimulates the dopaminergic arcuate nucleus, which sends dopamine, via the median eminence and portal blood vessels, to inhibit the anterior pituitary gland from secreting prolactin [38]. Six patients with high
prolactin serum levels, suffering from headache, were treated with 0.5 mg of the D2-like receptor agonist cabergoline twice a week, and their headache improved within a few months [37]. It might therefore be that the increased levels of prolactin in migraineurs are due to decreased levels of, or decreased responsiveness to progesterone or dopamine. This is consistent with the hypothesis that decreased dopamine activity is pathogenic to migraine headache. Taken together one could argue that because progesterone regulates dopamine release, migraine is either triggered in the follicular phase when progesterone levels are low and the tuberoinfundibular dopamine cascade is less active, or that migraine is triggered in the luteal phase when progesterone levels should be high and the tuberoinfundibular dopamine cascade should be active, but for some reason this is altered or malfunctioning.
Dopamine genetics and migraine Some cases of migraine are thought to have a genetic cause. The most discussed genes have been the P/Q-type Ca2þ channel gene (CACNL1A), whose various mutations are thought to be responsible for familial hemiplegic migraine (FHM) and episodic ataxia type-2 (EA-2) [39–41], the gene that encodes the a2 subunit of the Naþ/Kþ ion channel, whose mutation was proposed as the cause of familial hemiplegic migraine type 2 (FHM2) [42], and a gene on the X chromosome that is held responsible for susceptibility to migraine and may provide alternate explanations for female prevalence of migraine [43,44]. Dopamine genetics have also been implicated in migraine. It was found that individuals with migraine with aura have an increased frequency of the Nco1 gene that encodes the D2 receptor, whereas those with migraine without aura showed the same frequency of the gene compared with controls [4], thereby suggesting a dopamine hypersensitivity at the D2 receptor. A more recent study found a transmission distortion in the third exon of the gene that encodes the D4 receptor, whereby this exon is transmitted 45 times in individuals with migraine without aura, as opposed to 69 times in controls, whereas in migraine with aura there is no transmission distortion [45]. Another study found a particular allele (allele 4) of the D4 receptor to be significantly overrepresented in migraine without aura compared with controls [46]. No differences have been found between migraineurs and controls in the distribution of genes encoding dopamine receptors D1, D3 and D5 [47]. Moving away from dopamine receptor genes onto other dopamine-related genes, a study examined two separate populations and found that a single-nucleotide
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Dopaminergic mechanisms in migraine Charbit et al.
polymorphism (SNP) in the promoter of the dopamine beta-hydroxylase (DBH) gene (1021C!T) was associated with migraine. Individuals with two copies of the allele T genotype had a decreased risk of migraine compared to controls in both tested populations, yet individuals with even one T allele were more likely to suffer from vomiting, compared to those with no T allele (i.e. two C alleles). It appears therefore that the TT genotype is protective against migraine and the CC genotype is protective against vomiting [48]. Indeed this polymorphism in the promoter of the DBH gene is associated with altered plasma levels of DBH, with the T allele being linked to lower plasma DBH activity (therefore increased dopamine) than the C allele [49]. This is interesting, in light of our observation on the differing roles of dopamine in migraine, that at the genetic level, more circulating dopamine appears to protect against migraine but not the premonitory symptom of vomiting, whereas less circulating dopamine appears to protect against vomiting but not migraine. A genetic association study of 10 genes from the dopaminergic system, namely COMT, DBH, DDC, DRD1, DRD2, DRD3, DRD4, DRD5, SLC6A3 and TH, in a migraine with aura case–control study found that certain alleles of the dopamine transporter gene SLC6A3 are significantly associated with migraine with aura. SLC6A3 mediates the reuptake of dopamine from the synapse and is a major regulator of dopaminergic neurotransmission [50]. Contrarily, another group pooled together eight genes involved in dopamine neurotransmission, namely DRD1, DRD2, DRD3, DRD5, DBH, COMT, SLC6A3 and TH, and found that none of these genes were involved in any genetic predisposition to migraine [51]. The impact of genetics on our understanding of migraine pathophysiology is an evolving subject due to its relative novelty in this disease system. As such there is much conflicting evidence, particularly with regard to dopamine receptor mutations. However, the most consistent relationship to dopamine genetics and migraine seems to be with DBH and dopamine transporter molecules, which might readily tie-in with a hypersensitivity to dopamine, as much of the data implies there is more dopamine at the synapse and the migraineur responds as a consequence.
Conclusion It seems the dopaminergic mechanism in migraine is twofold. On one hand dopamine is possibly involved in some of the premonitory symptoms of migraine, such as yawning, nausea, vomiting and gastrokinetic disturbances, as D2-like receptor antagonists have been effective at treating these symptoms. If we consider a genetic hypersensitivity to dopamine, then we could see how this is
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possible. On the other hand, dopamine and dopamine agonists may have a therapeutic role in the headache phase of migraine, as the descending A11 dopaminergic nucleus has been shown to have an inhibitory effect on nociceptive processing at D2-like receptors in the TCC. Finally the facilitation of non-nociceptive stimulation of the trigeminal receptive field upon lesioning of the A11 raises the question as to whether a dysfunction in the A11 inhibitory input (disinhibition) to the TCC might be responsible for the allodynia that often accompanies migraine. Migraine prophylaxis includes the use of D2-like receptor antagonists, which is relevant for treating premonitory symptoms, but not the headache phase of migraine. In practice it has not been possible to treat migraine using dopamine agonists, as is done in RLS, as migraine patients exhibited enhanced reactions to D2-like receptor agonists, mainly in the form of premonitory phase symptoms [8,52]. Migraine is a complex disorder and the role of dopamine as a potentially antinociceptive agent conflicts with its pathogenic role in the premonitory phase of this disorder. Future studies might involve the use of mutant or knockout mice specifically affecting those genes involved in dopamine neurotransmission, such as the DBH gene. Another useful approach would be the development of an animal model with aspects of both the headache and the premonitory symptoms of a migraine, since dopamine appears to affect both. Definitely there is a lot more work to do to understand fully the role of dopamine in migraine.
References and recommended reading Papers of particular interest, published within the annual period of review, have been highlighted as: of special interest of outstanding interest Additional references related to this topic can also be found in the Current World Literature section in this issue (p. 336). 1 Goadsby PJ, Charbit AR, Andreou AP, et al. Neurobiology of migraine. Neuroscience 2009; 161:327–341. This is an important review that pools together the many aspects of migraine and also highlights the recent advances in our understanding and treatment of migraine. 2
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280 Headache D’Andrea G, Granella F, Perini F, et al. Platelet levels of dopamine are increased in migraine and cluster headache. Headache 2006; 46:585– 591. This study provides a different model for understanding the relationship between dopamine and migraine, and provides direct evidence of an abnormal metabolism of dopamine in migraine, which has hitherto been lacking.
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10 Shukla R, Khanna VK, Vinod P, et al. Platelet dopamine: D2 receptor binding in patients with migraine. Cephalalgia 2009; 29:532–538. 11 Miller MA, Levsky ME, Enslow W, Rosin A. Randomized evaluation of octreotide vs. prochlorperazine for ED treatment of migraine headache. Am J Emerg Med 2009; 27:160–164. This study shows that the dopamine receptor antagonist is more potent than somatostatin in the treatment of migraine, and was particularly useful at alleviating the symptom of nausea. 12 Friedman BW, Esses D, Solorzano C, et al. A randomized controlled trial of prochlorperazine versus metoclopramide for treatment of acute migraine. Ann Emerg Med 2008; 52:399–406. A randomized controlled trial with a good sample size that compares two dopamine receptor antagonists that are both effective in the acute treatment of migraine.
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35 MacGregor EA, Frith A, Ellis J, et al. Incidence of migraine relative to menstrual cycle phases of rising and falling estrogen. Neurology 2006; 67:2154–2158. 36 Martin VT, Wernke S, Mandell K, et al. Defining the relationship between ovarian hormones and migraine headache. Headache 2005; 45:1190–1201. 37 Cavestro C, Rosatello A, Marino MP, et al. High prolactin levels as a worsening factor for migraine. J Headache Pain 2006; 7:83–89. 38 Moore KE, Lookingland KJ. Dopaminergic neuronal systems in the hypothalamus. In Kupfer DJ, editor. Psychopharmacology. The American College of Psychoneuropharmacology; 2000. pp. 1–14. 39 Nyholt DR, Lea RA, Goadsby PJ, et al. Familial typical migraine: linkage to chromosome 19p13 and evidence for genetic heterogeneity. Neurology 1998; 50:1428–1432. 40 May A, Ophoff RA, Terwindt GM, et al. Familial hemiplegic migraine locus on 19p13 is involved in the common forms of migraine with and without aura. Hum Genet 1995; 96:604–608. 41 Ophoff RA, Terwindt GM, Vergouwe MN, et al. Familial hemiplegic migraine and episodic ataxia type-2 are caused by mutations in the Ca2þ channel gene CACNL1A4. Cell 1996; 87:543–552. 42 De Fusco M, Marconi R, Silvestri L, et al. Haploinsufficiency of ATP1A2 encoding the Naþ/Kþ pump alpha2 subunit associated with familial hemiplegic migraine type 2. Nat Genet 2003; 33:192–196. 43 Nyholt DR, Curtain RP, Griffiths LR. Familial typical migraine: significant linkage and localization of a gene to Xq24-28. Hum Genet 2000; 107:18–23. 44 Nyholt DR, Dawkins JL, Brimage PJ, et al. Evidence for an X-linked genetic component in familial typical migraine. Hum Mol Genet 1998; 7:459–463. 45 de Sousa SC, Karwautz A, Wober C, et al. A dopamine D4 receptor exon 3 VNTR allele protecting against migraine without aura. Ann Neurol 2007; 61:574–578. 46 Cevoli S, Mochi M, Scapoli C, et al. A genetic association study of dopamine metabolism-related genes and chronic headache with drug abuse. Eur J Neurol 2006; 13:1009–1013. 47 Shepherd AG, Lea RA, Hutchins C, et al. Dopamine receptor genes and migraine with and without aura: an association study. Headache 2002; 42:346–351. 48 Fernandez F, Colson N, Quinlan S, et al. Association between migraine and a functional polymorphism at the dopamine beta-hydroxylase locus. Neurogenetics 2009; 10:199–208. This study brings together the many attempts at understanding the role of the polymorphisms in the promoter of the DBH gene and its connection to migraine. It also highlights again the opposing relationship of dopamine with headache and dopamine with premonitory symptoms such as vomiting. 49 Zabetian CP, Anderson GM, Buxbaum SG, et al. A quantitative-trait analysis of human plasma-dopamine beta-hydroxylase activity: evidence for a major functional polymorphism at the DBH locus. Am J Hum Genet 2001; 68:515– 522.
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Dopaminergic mechanisms in migraine Charbit et al. 50 Todt U, Netzer C, Toliat M, et al. New genetic evidence for involvement of the dopamine system in migraine with aura. Hum Genet 2009; 125:265– 279. This is a comprehensive study which analyses 10 dopamine-related genes, and provides new evidence for the involvement of the dopamine transporter gene SLC6A3 in the pathophysiology of migraine.
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51 Corominas R, Ribases M, Camina M, et al. Two-stage case-control association study of dopamine-related genes and migraine. BMC Med Genet 2009; 10:95. 52 Del Bene E, Poggioni M, De Tommasi F. Video assessment of yawning induced by sublingual apomorphine in migraine. Headache 1994; 34: 536–538.
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New approaches to neuroimaging of central nervous system inflammation Guido Stolla and Martin Bendszusb a Department of Neurology, University of Wu¨rzburg, Wu¨rzburg and bDepartment of Neuroradiology, University of Heidelberg, Heidelberg, Germany
Correspondence to Professor Dr Guido Stoll, Department of Neurology, University of Wu¨rzburg, Josef-Schneider-Str. 11, D-97080 Wu¨rzburg, Germany Tel: +49 93120123769; fax: +49 93120123489; e-mail:
[email protected] Current Opinion in Neurology 2010, 23:282–286
Purpose of review Inflammation is an important component not only in autoimmune but also in ischemic/ degenerative disorders of the central nervous system (CNS). We here review magnetic resonance imaging (MRI)-based techniques to visualize neuroinflammation in vivo. Recent findings Iron oxide particles such as superparamagnetic iron oxide (SPIO) and ultrasmall SPIO (USPIO) are phagocytosed by hematogeneous macrophages upon systemic application into the circulation and allow in-vivo tracking of infiltration to the CNS due to their paramagnetic effect by MRI in experimental CNS disorders, and also in multiple sclerosis and stroke. Thereby, the size and application scheme of the iron particles is critical for interpretation of the MRI data which in addition to neuroinflammation involves passive diffusion and intravascular trapping. Targeting of inflammatory, activationdependent enzymes such as myeloperoxidase or immune function molecules by MR contrast agents represents a molecular approach to visualize critical steps of lesion development caused by neuroinflammation. Clinical studies with Gd-DTPA in conjunction with experimental investigations employing more sensitive MR contrast agents such as gadofluorine revealed that breakdown of the blood–brain barrier and SPIO/USPIO-related macrophage infiltration occur mostly independently. Summary Cellular and targeted molecular MRI provides important insights into the dynamics of neuroinflammation. Keywords iron-contrast agent, magnetic resonance imaging, neuroinflammation Curr Opin Neurol 23:282–286 ß 2010 Wolters Kluwer Health | Lippincott Williams & Wilkins 1350-7540
Introduction Inflammation plays a pivotal role in disorders of the central nervous system (CNS). Depending on the lesion paradigm, polymorphonuclear leukocytes, T-cells, B-cells, dendritic cells, and most often macrophages infiltrate the CNS. Whereas histological analysis after biopsy gives a precise but static picture on the actual extent of inflammation within a relatively small lesion area, MRI allows follow-up of lesion development in time and space. As an important caveat, however, signal alterations on T2-weighted (T2-w) MRI reflect nonspecific proton changes caused by a variety of different processes rather than neuroinflammation. Novel imaging techniques employing cellular MR contrast agents nowadays allow specific visualization of cellular inflammation. Knowledge of active phases of cell infiltration during CNS disorders such as multiple sclerosis (MS) is important because anti-inflammatory treatments can target cell adhesion molecules and chemokines guiding cellular 1350-7540 ß 2010 Wolters Kluwer Health | Lippincott Williams & Wilkins
trafficking (reviewed in [1]). Within the last decade MR-based cellular neuroimaging has provided important insights into the complex interplay between cellular infiltration and breakdown of the blood–brain barrier (BBB). In the present review we focus on current progress in visualizing CNS inflammation by contrast-enhanced MRI. For a comprehensive overview additionally covering the older basic literature the reader is referred to a previous review [2].
Principles of cellular labelling for MRI: contrast agents and pulse sequences For in-vivo detection of cells by MRI, the cells have to be specifically marked by contrast media. The following types of MR contrast agents are available: paramagnetic compounds with lanthanide chelates, superparamagnetic iron oxide (SPIO) particles, and contrast agents containing MR-visible nuclei other than hydrogen. DOI:10.1097/WCO.0b013e328337f4b5
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New approaches to visualize neuroinflammation Stoll and Bendszus 283
Paramagnetic compounds
Lanthanide chelates like gadolinium (Gd)-DTPA, a marker for breakdown of the BBB in clinical use, shorten the T1 relaxation time, but have a weak influence on the T2 relaxation time. Gadofluorine M (Gf; Bayer Schering Pharma AG, Berlin, Germany) is a new fluorinated Gd compound that enabled labelling and in-vivo tracking of stem cells in experimental studies [3]. Moreover, Gf has unique binding properties that allow detection of disturbances of the BBB with a much higher sensitivity than Gd-DTPA on T1-w MRI [4,5]. One general disadvantage of Gd chelates is the relatively high local concentration required to achieve sufficient contrast on MRI. However, Gf features a six times higher longitudinal relaxivity than Gd-DTPA and allows detection of as few as 100–200 Gf-labelled cells on MRI. Superparamagnetic particles
Compared to Gd-containing compounds, iron oxide particles feature a more extensive shortening of T1 and T2 relaxation times. Thereby, sensitivity for iron oxide containing contrast media is much higher than for Gd compounds at comparable tissue concentrations, which enables visualization of even single iron-laden cells at clinical field strength [6,7]. In general, accumulation of iron oxide particles in tissue results in a hypointensity on T2-w and T2-w images. On T1-w images accumulation of iron oxide particles results in a hyperintensity caused by the shortening of the T1 relaxation time. The signal changes induced by iron oxide particles on T1-w and T2-w images are complex and dependent on the particle size and the compartment of the particles (i.e. extracellular/intracellular) [7]. Quantification of ironlabelled cells can be performed in vivo by multiparametric MRI if compartmentalization of iron particles is considered [8]. At clinical dosage of iron oxide particles they can induce hyperintensity on T1-w images in the absence of signal alterations on T2/T2-w images [9,10]. The lack of a signal change on T2-w images is due to concentration and cellular dependent effects [10]. In general, the terminology for iron particles is based on the size of the entire particle (for review see [11]). SPIO particles exhibit an iron core of 4–8 nm coated with a dextran layer. Since several iron oxide cores are covered by a polymer coating, these particles are referred to as polycrystalline magnetic nanoparticles. The overall particle size is 50–150 nm. In ultrasmall superparamagnetic iron oxide (USPIO) particles only one iron oxide core is covered by a polymer coating. USPIO particles feature a smaller overall particle size of approximately 10–50 nm. Upon systemic application SPIO/USPIO particles are partly phagocytosed by macrophages within the circulation. The extent of cellular labelling in relation to clearance by the reticulo-endothelial system in the
liver and spleen depends on particle size, coating, and method of delivery. When circulating macrophages are attracted to inflammatory lesions, their iron-loading can be exploited to localize them in vivo by MRI [10,12] since in tissue iron particles shorten both the T1 and T2 relaxation time. A measure for the shortening of the relaxation times is the relaxivity r (l/mmol s). Nuclei other than hydrogen
Due to the abundant concentration in tissues, hydrogen is by far the most commonly used nucleus for MRI or spectroscopy, but cellular imaging based on hydrogen is hampered by a high background signal of normal tissue. This can be overcome by using nuclei with a generally low or absent concentration in tissues like 19F, 13C or 15N. Due to natural abundance, high chemical stability and good sensitivity on MRI, 19F has most commonly been used in heteronuclear experiments. Inflammatory cell populations can be tracked in vivo after ex-vivo incubation with polyfluorinated nanoemulsions [13]. Thereby, the signal on 19F MRI is specific for the labelled cells without interference of signal from the host’s tissues. Ahrens and colleagues [14] could detect prelabelled cells after local injection by in-vivo 19F imaging at 11.7 T. Although this technique holds promise for MRI of neuroinflammation in the future, at present only one study showed inflammation in the photothrombosis lesion model in the CNS [15].
Functional consequences of cell labelling by MR contrast agents There is an ongoing debate whether SPIO/USPIO uptake changes physiological properties of labelled cells and clinical outcome in diseases. In an in-vitro study, internalization of SPIO/USPIO shifted mouse and rat macrophages towards an anti-inflammatory, less responsive phenotype by enhancing interleukin-10 (IL-10) and inhibiting tumour necrosis factor (TNF) production [16]. A recent study by Hsiao et al. [17] confirmed that SPIO uptake (Ferucarbotran) did not modify proliferation and viability of a macrophage cell line, and TNF and nitric oxide production were normal at clinically relevant SPIO concentrations, but increased at high concentrations of 100 mg Fe/ml. Scha¨fer et al. [18] reported that native mesenchymal stem cells (MSCs) ameliorated symptoms in experimental autoimmune encephalomyelitis (EAE), whereas, surprisingly, SPIO-labelled MSC led to increase in disease activity. In their study more SPIO-labelled MSC reached the CNS than nonlabelled MSC, but the reasons for the different effects remain elusive. Bone marrow stroma cells-derived neural stem cells transplanted into the striatum of rhesus monkeys after labelling in vitro with SPIO particles survived, differentiated, were incorporated in the brain without side effects and could be followed by MRI [19]. Accordingly,
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284 Inflammatory diseases and infection
ferumoxide-labelled stem cells could be tracked in a rat stroke model at 1.5 T MRI [20]. Similarly to iron oxide particles, labelling of monocytes with Gf did not result in an impairment of cell viability [21].
Neuroinflammation in central nervous system autoimmunity In clinical practice the number of hyperintense lesions on T2-w MRI is taken as a paraclinical activity marker in MS, but they represent nonspecific tissue alterations. It would be of great value to develop a MR correlate of acute inflammatory plaques which are the pathological hallmark of active MS and its animal model, EAE. Cellular MRI may add important new information beyond T2-w lesion load and Gd-DTPA enhancing lesions. As described above SPIO/USPIO particles are mainly phagocytosed by macrophages upon systemic application. Depending on the size, charge and concentration, iron oxide particles can also be spontaneously taken up by other immune cells such as T-cells [22], and used for cell tracking after ex-vivo labelling. Several recent studies further support the previous notion that SPIO/USPIO enhanced MRI allows cellular neuroimaging: Chin et al. [23] used USPIO-enhanced MRI in myelin-oligodendrocyte-glycoprotein-induced EAE to study the spatiotemporal evolution of lesions. Spinoolivo-cerebellar pathways were primarily affected by macrophage infiltration in the acute phase, whereas during the relapse phase inflammatory lesions were mainly located in the cerebellum or spinal cord/brainstem. Accordingly, Baeten et al. [24] showed that different CNS regions became hypointense on T2-w MRI during myelin basic protein-induced EAE in rats depending on the timing of USPIO application. However, there appears to be a difference in the accuracy of visualizing neuroinflammation in relation to the size of the iron oxide particles. In a photothrombotic lesion model, Oude Engberink et al. [25] could show that transfusion of SPIO-labelled monocytes led to a delayed signal loss in the lesions indicating macrophage infiltration, whereas contrast enhancement after systemic USPIO injection increased at a much earlier time point and diminished thereafter indicating at least partial passive leakage of USPIO through a defective BBB. Myeloperoxidase (MPO) is one of the most abundant enzymes secreted by inflammatory cells and, thus, may serve as a marker of macrophage inflammation. In an elegant study, Chen and colleagues [26] took advantage of a prototype MPO-activatable paramagnetic sensor. When converted by MPO in the presence of hydrogen peroxide, the sensor is radicalized and forms oligomers of higher relaxivity. In a mouse model of EAE, MPOinduced chemical changes resulted in a markedly increased signal on T1-w MRI and allowed visualization
of active lesions. Overall, MPO imaging detected more lesions and much smaller lesions than conventional T1-w and T2-w MRI. Inflammatory cells are guided by cell adhesion molecules expressed on endothelial cells and are attracted by chemokines released from injured tissue [1]. For imaging of the intercellular adhesion molecule-1 (ICAM-1) during EAE in Lewis rats, Schneider et al. [27] conjugated SPIO nanoparticles to anti-ICAM-1 antibodies. Ex-vivo MRI revealed numerous spinal cord lesions with signal loss indicative of ICAM-1 expression, and thoroughly performed control experiments with competition of excess of free anti-ICAM-1 confirmed specificity of ICAM-1 staining and imaging. An important next step would be transferring this molecular imaging approach to in-vivo MRI. In a traumatic brain injury model, in-vivo imaging of the expression of another cell adhesion molecule, E-selectin, was reported using a targeted USPIO contrast agent [28]. The imaging diagnosis of MS, a human disorder partly mimicked by EAE, is based on hyperintense lesions in typical locations on T2-w MRI (i.e. posterior fossa, paraventricular region, juxtacortical, spinal cord), and focal uptake of the extracellular contrast agent Gd-DTPA on T1-w MRI which is indicative for disruption of the BBB. Commonly, Gd-DTPA enhancement is taken as evidence for acute inflammation. In an important study, Vellinga and colleagues [10] examined 14 patients with active MS by USPIO-enhanced MRI. Overall, 188 USPIO-positive lesions (most likely reflecting macrophage infiltration) were detected, as many as 144 of which were Gd-DTPA-negative. In some of the initial USPIOpositive/Gd-DTPA-negative lesions USPIO enhancement preceded Gd-DTPA enhancement by 1 month. This study supports previous experimental data in EAE showing that macrophages can infiltrate the CNS independently from breakdown of the BBB as defined by Gd-DTPA enhancement. Interestingly, USPIO lesions persisted for up to 3 months, supporting the hypothesis that signal alterations on MRI were caused by iron-laden macrophages in tissue rather than passive diffusion of USPIO. More recently the same group reported on diffuse USPIO-related signal alterations even in normal appearing white matter of MS patients [29]. Thus, USPIO-enhanced MRI may disclose subtle and diffuse inflammatory activity in MS patients not visible on conventional T2-w MR sequences and unrelated to Gd-DTPA enhancement.
Neuroinflammation in ischemic stroke Unexpectedly, cerebral ischemia evokes an inflammatory response similar to autoimmune disorders of the CNS that on one hand contributes to early tissue damage, and
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New approaches to visualize neuroinflammation Stoll and Bendszus 285
on the other hand directs tissue remodelling. It has been shown that MR signal changes after intravenous SPIO/ USPIO injection are related to inflammatory cells at the subacute stage of focal cerebral ischemia [9,30]. This notion has recently been confirmed by Kim et al. [31] who noted signal loss in parts of the ischemic lesions at days 3 and 4 postreperfusion. However, at the initial stages after focal ischemia, SPIO/USPIO related signal alterations are difficult to interpret. In a recent study, Desestret et al. [32] used multiparametric MRI at 7T and histological techniques to match the cellular and extracellular distribution of systemically applied USPIO from 6 to 24 h after permanent middle cerebral artery occlusion (MCAO). Within the first 24 h of pMCAO, early USPIOrelated MR signal changes were mainly caused by passive diffusion of free USPIO through a defective BBB or by intravascular trapping during thrombotic vessel occlusion, but not related to macrophage infiltration. The latter observation confirms our previous results in a model of cerebral photothrombosis [33]. As an alternative approach to SPIO/USPIO-enhanced cellular MRI in stroke, Breckwoldt and colleagues [34] tracked the inflammatory response by sensing the enzyme MPO. MPO was widely distributed in ischemic brain lesions, correlated positively with infarct size and persisted for up to 3 weeks after infarction at in-vivo MRI. MPO imaging, however, could not discriminate between MPO secreted from polymorphonuclear leukocytes and macrophages/ microglia. In clinical stroke studies, application of USPIO particles resulted in hyperintense signal alterations on T1-w images and a signal loss on T2-w images [9,35]. Signal alterations were restricted to areas which exhibited a diffusion restriction on diffusion-weighted sequences, indicating acute cerebral ischemia. USPIO enhancement was less extensive than the complete ischemic damage on diffusion-weighted MRI. Overall, there was a highly variable extent and distribution of USPIO enhancement, which did not correlate to infarct size and was not related to a disturbance of the BBB. In some stroke patients, USPIO enhancement was completely absent [9,35].
numerous lesions with leakage of the BBB not exhibiting Gd-DTPA enhancement and not visible on T2-w MRI [4]. When acute macrophage infiltration as indicated by SPIO-enhanced MRI and breakdown of the BBB as assessed by Gf-enhanced MRI were directly compared in EAE, numerous lesions showed Gf enhancement, but no signal loss after SPIO application and vice versa [36]. This study strongly supports the notion that macrophage infiltration and leakage of the BBB for humoral factors are independent events. Further support comes from a recent experimental study aimed at disrupting of the BBB by focused ultrasound for enhancing drug delivery to the brain [37]. Certain parameters of sonication led to a transient BBB leakage without macrophage infiltration. Likewise, USPIO enhancement occurred in the absence of Gd-DTPA enhancement, which is a surrogate marker for a disruption of the BBB in human MS and stroke [9,10,35].
Conclusion The advent of novel MR contrast agents allowing cellular and targeted molecular imaging has provided important insights into the dynamics of neuroinflammation and its regulation by cell adhesion molecules. It became apparent that cellular infiltration revealed by SPIO/USPIOenhanced MRI is a timely restricted event in experimental and clinical CNS disorders which is often unrelated to breakdown of the BBB as indicated by Gd-DTPA enhancement on T1-w MRI. Novel cellular MR contrast agents such as polyfluorinated nanoemulsions or activatable paramagnetic sensors may help to overcome the current limitations of SPIO/USPIO-based cellular imaging.
Acknowledgements The authors declare no conflict of interest. Work in our laboratories has been supported by the Deutsche Forschungsgemeinschaft, Bonn (SFB 688 B1), the Gemeinnu¨tzige Hertie-Stiftung, Frankfurt, Main, the Interdisciplinary Center for Clinical Research, Wu¨rzburg (grant F-25) and an endowed professorship for Neuroimaging (Bayer Schering Pharma AG, Berlin) at the University of Wu¨rzburg. We thank our numerous colleagues who contributed to our own work cited in this review.
References and recommended reading The relation between neuroinflammation and blood–brain barrier disruption There is an ongoing debate whether breakdown of the BBB for soluble factors also means unrestricted access of inflammatory cells. To assess whether macrophage infiltration is linked to breakdown of the BBB, novel and more sensitive experimental contrast agents are available. As described above Gf is an amphiphilic macrocyclic Gdcomplex giving rise to bright contrast on T1-w MRI which allows imaging of widespread changes of BBB properties by far extending areas showing Gd-DTPA enhancement [5]. In EAE, Gf allowed detection of
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New drug therapies for multiple sclerosis Arturo Mangasa, Rafael Coven˜asa and Michel Geffardb a Institute of Neurosciences of Castilla y Leo´n (INCYL), Laboratory 14, Salamanca, Spain and bIMS Laboratory, ENSCPB-EPHE, Pessac, France
Correspondence to Dr Arturo Mangas, Instituto de Neurociencias de Castilla y Leo´n (INCYL), Laboratorio 14, c/ Pintor Fernando Gallego, 1, 37007-Salamanca, Spain Tel: +34 923294400 x5315; fax: +34 923294549; e-mail:
[email protected] Current Opinion in Neurology 2010, 23:287–292
Purpose of review Multiple sclerosis (MS) is an autoimmune and inflammatory disease of the central nervous system (CNS) that causes neurological disability in young adults and that to date has no cure. Until now, expensive and only partially efficacious therapies have become available. For this reason, researchers, clinicians and pharmaceutical companies are currently investigating new drugs for the treatment of MS. Here, we review the most recent data on drug candidates for MS. Recent findings In the preclinical phase, such drug candidates have shown a beneficial effect on the onset of experimental autoimmune encephalomyelitis (microtubule-stabilizing drugs, MS14, Lithium, GEMSP. . .), a decrease in CNS cell infiltrates (recombinant T cell receptor ligand, lovastatin–rolipram, ribavirin, GEMSP. . .), prevention of demyelination (lovastatin–rolipram, calpain inhibitor, lithium. . .); and a reduction of axonal loss (phenytoin, lovastatin–rolipram, calpain inhibitor). In clinical trials, drug candidates against MS have shown safety (rituximab, ustekinumab, intravenous immunoglobulin, laquinimod, BHT-3009, fumarate, chaperonin 10, GEMSP. . .), an improvement of gadolinium-enhanced lesions (protiramer, fingolimod, laquinimod, BHT-3009, fumarate, daclizumab. . .), and an improvement of the relapse rate (fingolimod, fumarate. . .). Summary Future research into MS should focus on a combination of therapies and on the development of drugs directed against the remitting and progressive phases of the disease. In this sense, MS is a very complex multifactorial disease that requires treatment able to cover all the aspects of MS and not only the anti-inflammatory aspect. Keywords autoimmune disease, demyelination, experimental autoimmune encephalomyelitis, inflammatory disease, multiple sclerosis Curr Opin Neurol 23:287–292 ß 2010 Wolters Kluwer Health | Lippincott Williams & Wilkins 1350-7540
Introduction Multiple sclerosis (MS) is an autoimmune and inflammatory disease that courses with a demyelination process, which finally produces axonal degeneration and neuronal death. This disease tends to debut in young people and generally courses over several decades. Owing to the partial efficacy of currently approved therapies, which do not arrest the disease, and in the best of cases only delay its course, it is crucial to search for new approaches. It is also essential to search for new remedies able to palliate this situation. This is because all approved therapies have focused on the inflammatory aspect of the disease and because sooner or later they must be changed or withdrawn (e.g. due to the side effects). In this sense, only the relapsing–remitting phases of MS are taken into account in already approved therapies, which have no efficacy against the primary and the secondary progress1350-7540 ß 2010 Wolters Kluwer Health | Lippincott Williams & Wilkins
ive phases of the disease. In sum, approved treatments and most new drug candidates are focused against the relapsing–remitting phases and not against the progressive phases. Adequate therapies must cure or arrest the disease and must avoid side effects, although unfortunately we are still quite far from achieving such a goal. Thus, we must look for therapies that will both treat the inflammatory aspects and also take into account other aspects of MS, such as oxidative stress, chronicity, demyelination and neuronal death. This means that a global treatment of the disease, including the progressive phases, is required. Although we are still far from finding a definitive drug for MS, the broad spectrum of action of some of the new candidates proposed suggests that in the future an adequate treatment for the disease will be reached. Here, we review the latest data on the drug candidates tested in experimental autoimmune encephalomyelitis (EAE) models and in clinical trials. DOI:10.1097/WCO.0b013e32833960f6
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288 Inflammatory diseases and infection
Drugs The studies conducted so far have been preclinical, usually tested in EAE models, in vitro, or clinical. The drugs used in clinical and preclinical studies (potassium channel blockers, sterols, statins, antibodies. . .) are quite different and exert different physiological actions. Most of them are directed against the relapsing–remitting phases, whereas only some of them (daclizumab [1], chaperonin 10 [2], fampridine [3], GEMSP [4]) have been tested in the progressive phases of MS. Many of these drugs decrease and/or delay the onset of EAE, but fail to abolish it. This, together with safety, should be taken into account before undertaking longer and expensive clinical studies. Despite this, other candidates (GEMSP [4], lithium [5]) seem to completely abolish the onset of EAE.
(5)
(6)
(7)
(8) Preclinical experimental autoimmune encephalomyelitis studies
(1) Microtubule-stabilizing drugs [6] arrest cell proliferation by stabilizing microtubules in the G2/M phase of the cell cycle. Paclitaxel and peloruside A show the same delay of onset, and in vitro inhibit T-cell proliferation (see Table 1). However, peloruside A has fewer side effects than paclitaxel. (2) Recombinant T-cell receptor ligands (RTLs) [7] inhibit the proliferation of T cells and decrease the onset of EAE, central nervous system (CNS) infiltration by leucocytes, and they also decrease interleukin (IL)-2 and IL-17 levels (Table 1). Moreover, RTLs increase the levels of IL-10, IL-13 and IL-14. (3) MS14 [8] is a herbal-marine product that decreases the onset of EAE and neuropathological damage (Table 1). Moreover, it seems that in MS patients who took this product voluntarily the MS symptoms were ameliorated and no side effects were observed. It would appear that this product acts as an antioxidant. (4) Phenytoin (Ph) [9], a sodium channel blocker, ameliorates EAE, depresses brain vascular permeability, decreases brain leucocyte infiltration and protects axons in EAE animals (Table 1). How-
(9)
(10)
(11)
ever, after the withdrawal of Ph, an exacerbation of the onset has been reported. Rabeximod modulates EAE [10], showing a doserange effect (Table 1). In vitro, this drug suppresses the release of proinflammatory cytokines, and its efficacy has been demonstrated in an arthritis model. Rabeximod is a promising drug for the treatment of autoimmune diseases. Lovastatin and rolipram combination [11]. Both drugs exert a synergic effect on EAE when suboptimal doses are combined (Table 1). This combination reduces axonal loss, attenuates CNS infiltration, and improves endothelial function. Ribavirin [12] decreases the onset of EAE (Table 1), modulates cytokine production, reduces inflammation, and decreases CNS infiltration. Probiotic lactobacilli [13] decrease the onset of EAE and have a good safety profile; no side effects or toxicity have been reported (Table 1). Calpain inhibitor [14] decreases the onset of EAE, preserves axonal morphology, and reduces the accumulation of amyloid precursor protein, the expression of Nav1.6 channels, demyelination, and inflammation (Table 1). When lithium [5] is administered before the induction of EAE, the onset of EAE is abolished, but when it is administered after the induction of EAE, it promotes the recovery of onset (Table 1). When treatment is withdrawn, the clinical score increases rapidly. On the basis of these data, those authors suggested that glycogen synthase kinase-3 (GSK3) would be a major target for future MS treatment and other CNS diseases. GEMSP [4] is a new drug candidate that was originally conceived for the secondary progressive phases form of MS. In both EAE models (acute and chronic), this new designer drug abolishes the onset of EAE, inhibits leucocyte CNS infiltration, and prevents CNS damage. No side effects have been described. Moreover, it seems that GEMSP exerts a myelin-protecting role (Table 1).
Table 1 Tabular representation of drugs and improvement imposed by them Improve Drug
Model
Microtubule stabilizing [6] RTLs [7] MS14 [8] Phenytoin [9] Rabeximod [10] Lovastatin–rolipram [11] Ribavirin [12] Lactobacilli [13] Calpain inhibitor [14] Lithium [5] GEMSP [4]
Mouse EAE Mouse EAE Mouse EAE Mouse EAE Mouse EAE Rat EAE Rat EAE Rat EAE Mouse EAE Mouse EAE Rat EAE
Delay or shorter onset þ þ þ þDay 7 þ
Decrease onset intensity þ þ þ þ þ þ þ þ þ A A
Inflammatory lesions
Infiltrates
þ þ
þ
Demyelination
þ þ
þ
þ þ
þ þ
Axonal loss
þ þ
þ þ
þ
þ þ þ
þ
A, abolish; A, abolish in pretreatment; þ, significant decrease. EAE, experimental autoimmune encephalomyelitis. White cells: no data available.
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RR RR & SP RR & SP RR, PR, PP, SP SP IIb II IIa III IIa Fumarate [25] Daclizumab [1] Chaperonin 10 [2] Fampridine [3] GEMSP [4]
257 15 50 296 22
RR RR RR IVIG [22] Laquinimod [23] BHT-3009 [24]
127 306 267 II II II
Fingolimod [20 ] Ustekinumab [21]
289
: not statistically significant, or further studies required; : some attributed to treatment, others present as well in placebo; GdE: gadolinium-enhanced lesions; i.m.: intramuscular; i.v.: intravenous; PR: progressive relapsing; PP: primary progressive; RR: relapsing–remitting; SP: secondary progressive; s.l.: sublingual. White cells: no data available.
þ
þ þ þ þ þ þ þ þ240 mg 3/day
þ240 mg 3/day þ þ 24 week 12 month 3 month 14 week 6 month
þ þ þ þ þ þ þ þ (0.6 mg/day) þ 1 year 36 week 48 week
þ þ þ þ þ þ þ þ þ þ þ þ þ30 mg/week þ 72 week 36 week 6 month, 24 month 37 week
i.v. 1g 0, 2, 24, 26 week s.c 15–30 mg/week Oral; 1.25–5 mg/day s.c. 27, 90, 180 mg/4 week or 90 mg/8 week i.v. 0.2, 0.4 mg/kg Oral; 0.3–0.6 mg/day i.m. 0.5, 1.5 mg on weeks 0, 2, 4, 8, 12, 16, . . . Oral 120 mg/day–240 mg 3/day i.v -2 mg/kg i.v. 5–10 mg/week Oral 10 mg/day Oral (s.l.) 0.75 mg/day RR RR RR RR 26 65 281; 250 249 I Pilot studies II II
Relapse rate GdEImprove Duration Route MS course Patients Trial phase
(1) Rituximab [18] is well tolerated (Table 2). The side effects are mild/moderate, and they are reduced after repeated infusions of the drug. In the future, its efficacy against MS should be addressed in other trials, including a control group. (2) In general, protiramer [19] is well tolerated. Following the administration of protiramer, the clinical data reveal that most patients (around 74%) remain relapse-free, and that gadolinium-enhanced lesions (GdE) decrease when the highest dose of the drug (30 mg/week) is administered. Side effects have been described (e.g. injection-site reaction), and all patients develop antibodies against the compound (Table 2). (3) After 24 months of treatment with oral fingolimod (FTY720) [20] (Table 2), most patients remain free from GdE (79–91%) and relapses (> 70%). As from the seventh month of treatment, side effects (mild or moderate) are more frequent. Phase III trials should further characterize the safety and tolerability of this promising new oral drug.
Drug
Clinical studies
Table 2 Tabular representation of number of patients’ time taken and drugs
(1) b-Sitosterol is a natural hypocholesterolaemic agent from plants that reduces pro-inflammatory cytokines [tumour necrsis factor (TNF)a and IL-12] and does not modify the levels of anti-inflammatory cytokines (IL-10 and IL-5) in blood mononuclear cells from MS patients [15]. (2) Glatiramer acetate induces a downmodulation of inducible nitric oxide synthase (iNOS), nitric oxide, 3nitrotyrosine and O2 in blood adherent mononuclear cells from relapsing–remitting patients. In these patients, the increase in nitric oxide and O2 in plasma levels is reduced after 3 months of glatiramer acetate treatment, remaining stabilized after 6 months of treatment. Those authors suggested that the blood levels of the earlier-mentioned molecules should be monitored. This is one of the many examples pointing to the multifactorial pathogenic processes (e.g. oxidative stress) involved in MS [16]. (3) In previous phase II trials, it has been demonstrated that alemtuzumab is highly effective in relapsing– remitting phases, although around 30% of patients develop autoimmunity. It has been demonstrated (blood samples were taken from relapsing–remitting patients) that such autoimmunity arises in patients with greater T-cell apoptosis and cell cycling in response to alemtuzumab-induced lymphocyte depletion, a phenomenon that is driven by higher levels of IL-21. The authors suggested that the level of IL-21, prior to treatment, could be of huge importance in the choice of the best candidates for therapy, thereby decreasing possible side effects. At present, this monoclonal antibody is in phase III trials [17].
Safety
In-vitro studies
Rituximab [18] Protiramer [19]
Side effects
New drug therapies for multiple sclerosis Mangas et al.
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290 Inflammatory diseases and infection
(4) The administration of ustekinumab [21] to patients with relapsing–remitting MS was withdrawn, in all dosage groups, after the 37th week of treatment due to the lack of efficacy (Table 2). (5) Intravenous immunoglobulin (IVIG) [22] treatment is well tolerated (Table 2), but at the doses used no beneficial effect is observed. (6) Laquinimod [23] is well tolerated and reduces GdE (Table 2). In MS patients, neither the relapse rate nor the relapse-free group shows a statistically significant improvement. A transient elevation of liver enzymes has been reported. At present, the study is in a phase III trial. (7) DNA vaccine (BHT-3009) [24] has demonstrated safety and tolerability (Table 2). The side effects are mild or moderate. In the last 6 months of the trial, GdE was reduced by 50% and in the entire study was 67% lower. The relapse rate and Expanded Disability Status Scale (EDSS) data were not improved significantly. (8) Oral fumarate [25], used in relapsing–remitting phases, reduces the GdE and the relapse rate (Table 2). In some patients, fumarate elicits dose-related side effects (e.g. an increase in transaminase levels). Adverse gastrointestinal events should be studied better and its safety profile warrants a long-term phase III trial. (9) Twelve patients in relapsing–remitting and three in secondary progressive phases were first treated with inteferon 1b (IFN) and then with both daclizumab [1] (Table 2) and IFN. Five and half months after the coadministration of both drugs, the patients showing a reduction greater than 75% of the contrast-enhancing lesions were treated exclusively with daclizumab, whereas the other patients continued with IFN and daclizumab. Side effects were present in 33% of patients. It should be noted that one of the three secondary progressive phases patients was a full responder to treatment, but showed hepatomegaly and generalized lymphadenopathy. (10) Chaperonin 10 (Ch10) is [2] well tolerated, and remains active up to 4 days (Table 2). Apparently, it improves GdE, but the differences are not statistically significant. No important side effects have been reported. In that study, 14 patients in secondary progressive and 36 in relapsing–remitting phases were included. (11) A phase III trial revealed that 35% of the patients treated with fampridine [3] (Table 2), a potassium channel blocker, improved their walking ability. This was associated with an improvement in selfassessed ambulatory disability. This study included patients in relapsing–remitting (62), primary progressive (31), secondary progressive (125) and progressive relapsing phases (10).
(12) GEMSP is a recently designed drug made with a mixture of functional polypeptides: fatty acids, antioxidants, free radical scavengers and amino acid linked to poly-L-lysine [4]. In a phase IIa trial, 22 secondary progressive phase patients were treated with sublingual GEMSP; 55% of them were stabilized and 18% showed a decrease in EDSS. No side effects have been described (Table 2). The clinical data demonstrated safety and tolerability. GEMSP did not elicit biological (triglycerides, creatinine. . .), haematological (red blood cell, haematocrit. . .) or hepatic (total bilirubin, enzymes) side effects. A phase IIb trial should be developed in the future. Thus, many drugs are currently being tested for MS treatment, but to date none has been able to cure the disease. Accordingly, a drug candidate or a combination of drugs for MS treatment should meet the furthermentioned requisites. It should be conceived for a multifactorial disease able to treat all the aspects of this complex disease (demyelization, axonal loss, oxidative stress. . .) and not only the inflammatory aspect, it should be directed against all the phases of MS, not only against the relapsing–remitting phases, and its action should be exerted without side effects, or at least should minimize them, in order to allow long-term treatment. In this sense, for example, the combination of lovastatin and rolipram [11] has shown a synergistic effect and shows no additional toxicity when used in combination therapy, whereas daclizumab [1], chaperonin 10 [2], fampridine [3], or GEMSP [4] have been used in the progressive phases of the disease. We consider that these strategies are the best way forwards for future approaches to the treatment of MS. This may be interesting for pharmaceutical companies owing to the unexploited field of the progressive phases. The convenience of an orally administered product in order to avoid injection site reactions should also be noted (see Table 2). Moreover, other aspects merit attention. For example, glatiramer acetate [16] seems to exert an antioxidant action and hence future studies should be carried out in patients with progressive forms, whereas the lactobacilli study [13] suggests that probiotics could be used as a complement in MS therapies. Finally, the unexpected apparent failure of some therapies (e.g. ustekinumab [21], IGIV [22]) should be considered for future studies using similar therapies.
Conclusion In the near future, more studies are required to determine the actions and the efficacy of the drugs reported here. In this sense, it would be necessary to gain better insight into the mechanisms of action of the drugs
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New drug therapies for multiple sclerosis Mangas et al.
(e.g. fampridine [3], GEMSP [4], lithium [5], MS14 [8]), to develop additional studies for the translation of the drugs (e.g. microtubule stabilizing [6], ribavirin [12]) from animal models to humans, to demonstrate/confirm the efficacy of the drugs (e.g. daclizumab [1], GEMSP [4], phenytoin [9], protiramer [19]), to demonstrate a neuroprotective role for the drugs (e.g. GEMSP [4], fumarate [25]), to demonstrate an improvement in the prevention of GdE events caused by the drugs (e.g. chaperonin 10 [2], GEMSP [4], rituximab [18]), and to demonstrate/confirm the safety/side effects of the drugs (e.g. daclizumab [1], phenytoin [9]). In sum, the broad spectrum of new drug candidates with different mechanisms of action highlights the complexity of MS, a disease of unknown aetiology that should no longer be treated merely as an inflammatory illness. Thus, therapies that take into account other aspects of the disease (oxidative stress, chronicity, demyelination and neuronal death) should have a promising future, much more so if the progressive phases are included and side effects can be excluded or minimized.
Acknowledgements This work has been supported by the Red de Terapia Celular de Castilla y Leo´n (Spain) and the Consejerı´a de Educacio´n (Junta de Castilla y Leo´n, Spain) (SA099A08). IDRPHT (Talence, France). The authors wish to thank to Nicholas Skinner for supervising the English text.
References and recommended reading Papers of particular interest, published within the annual period of review, have been highlighted as: of special interest of outstanding interest Additional references related to this topic can also be found in the Current World Literature section in this issue (pp. 336–337). Bibiana B, Howard T, Packer AN, et al. Effect of anti-CD25 antibody daclizumab in the inhibition of inflammation and stabilization of disease progression in multiple sclerosis. Arch Neurol 2009; 66:483–489. This article highlights the results on GdE in relapsing–remitting and secondary progressive phases patients. The safety profile requires in-depth studies.
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9 Black JA, Waxman SG. Phenytoin protects central axons in experimental autoimmune encephalomyelitis. J Neurol Sci 2008; 274:57–63. This article demonstrates the beneficial effects of phenytoin against the onset of EAE, infiltrates and axonal loss. This could be a drug for future use if its safety profile can be confirmed. 10 Hultqvist M, Nandakumar KS, Bjo¨rklund U, Holmdahl R. The novel small molecule drug rabeximod is effective in reducing disease severity of mouse models of autoimmune disorders. Ann Rheum Dis 2009; 68:130–135. This article underscores the effect of this small molecule on MS and rheumatoid arthritis models. 11 Paintlia AS, Paintlia MK, Singh I, Singh AK. Combined medication of lovastatin with rolipram suppresses severity of experimental autoimmune encephalomyelitis. Exp Neurol 2008; 214:168–180. This article demonstrates that the combination of lovastatin and rolipram at suboptimal doses exerts a synergic effect on EAE. This highlights the importance of combined drug strategies. 12 Lavrnja I, Stojkov D, Bjelobaba I, et al. Ribavirin ameliorates experimental autoimmune encephalomyelitis in rats and modulates cytokine production. Int Immunopharmacol 2008; 8:1282–1290. 13 Maassen CBM, Claassen E. Strain-dependent effects of probiotic lactobacilli on EAE autoimmunity. Vaccine 2008; 26:2056–2057. This article highlights the importance of probiotics in autoimmune diseases. Probiotics could be an important complement to therapies. 14 Hassen GW, Feliberti J, Kesner L, et al. Prevention of axonal injury using calpain inhibitor in chronic progressive experimental autoimmune encephalomyelitis. Brain Res 2008; 1236:206–215. This article demonstrates that a calpain inhibitor exerts several actions in the EAE model and highlights the importance of drugs acting on several targets. 15 Desai F, Ramanathan M, Fink CS, et al. Comparison of the immunomodulatory effects of the plant sterol b-sitosterol to simvastatin in peripheral blood cells from multiple sclerosis patients. Int Immunopharmacol 2009; 9:153–157. This article shows the importance of this natural hypocholaesterolaemic agent, b-sitosterol, as a modulator of cytokines in blood mononuclear cells from MS patients. 16 Iarlori C, Gambi D, Lugaresi A, et al. Reduction of free radicals in multiple sclerosis: effect of glatiramer acetate (Copaxone1). Mult Scler 2008; 14:739–748. This article highlights the importance of glatiramer acetate in the induction of a downmodulation of iNOS, nitric oxide, 3-nitrotyrosine and O2 in blood adherent mononuclear cells. 17 Jones JL, Phuah C-L, Cox AL, et al. IL-21 drives secondary autoimmunity in patients with multiple sclerosis, following therapeutic lymphocyte depletion with alemtuzumab (Campath-1H). J Clin Invest 2009; 119:2052–2061. 18 Bar-Or A, Calabresi PAJ, Arnold D, et al. Rituximab in relapsing-remitting multiple sclerosis: a 72-week, open-label, Phase I Trial. Ann Neurol 2008; 63:395–400. This article reports the clinical trial safety data of rituximab. This article is the most recently published study addressing this drug. Other data require further studies. 19 De Stefano N, Filippi M, Confavreux C, et al. The results of two multicenter, open-label studies assessing efficacy, tolerability and safety of protiramer, a high molecular weight synthetic copolymeric mixture, in patients with relapsing-remitting multiple sclerosis. Mult Scler 2009; 15:238–243. In this article, clinical trials provide evidence of the effect of protiramer on GdE. Other data require further studies.
4 Mangas A, Coven˜as R, Bodet D, et al. A new drug candidate (GEMSP) for multiple sclerosis. Curr Med Chem 2009; 16:3203–3214. This article highlights the multifactorial action of GEMSP in EAE models. This new drug did not present side effects either in animals or in humans. It is an oral drug for secondary progressive phases patients.
20 O’Connor P, Comi G, Montalban X, et al. Oral fingolimod (FTY720) in multiple sclerosis: two-year results of a phase II extension study. Neurology 2009; 72:73–79. This article highlights the efficacy of this promising new oral therapy in a two-year randomized study. Clinical phase III trials should further characterize its safety profile.
De Sarno P, Axtell RC, Raman C, et al. Lithium prevents and ameliorates experimental autoimmune encephalomyelitis. J Immunol 2008; 181:338– 345. This article underscores the importance of lithium as a new drug candidate for MS, as it does abolish the EAE onset.
21 Segal BM, Constantinescu CS, Raychaudhuri A, et al. Repeated subcutaneous injections of IL12/23 p40 neutralising antibody, ustekinumab, in patients with relapsing-remitting multiple sclerosis: a phase II, double-blind, placebo-controlled, randomised, dose-ranging study. Lancet Neurol 2008; 7:796–804.
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292 Inflammatory diseases and infection 22 Fazekas F, Lublin FD, Li D, et al. Intravenous immunoglobulin in relapsing remitting multiple sclerosis: a dose-finding trial. Neurology 2008; 71:265– 271. This study highlights the apparent lack of efficacy of IVIG at the doses used.
24 Garren H, Robinson WH MD, Krasulova E, et al. Phase 2 Trial of a DNA vaccine encoding myelin basic protein for multiple sclerosis. Ann Neurol 2008; 63:611–620. This article highlights the safety and efficacy on GdE in relapsing–remitting patients. Other data require further studies.
23 Comi G, Pulizzi A, Rovaris M, et al. Effect of laquinimod on MRI-monitored disease activity in patients with relapsing-remitting multiple sclerosis: a multicentre, randomised, double-blind, placebo-controlled phase IIb study. Lancet 2008; 371:2085–2092. This article highlights the safety and efficacy of laquinimod in relapsing–remitting patients. Other data require further studies.
25 Kappos L, Gold R, Miller DH, et al. Efficacy and safety of oral fumarate in patients with relapsing-remitting multiple sclerosis: a multicentre, randomised, doubleblind, placebo-controlled phase IIb study. Lancet 2008; 372:1463–1472. This article highlights the safety and efficacy profiles of this promising oral drug. Fumarate shows a potentially unique mode of action, and hence could be used as monotheraphy or in combination with other drugs.
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Mechanisms of cerebral edema in traumatic brain injury: therapeutic developments James J. Donkina and Robert Vinkb a
Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver BC, Canada and bThe Discipline of Anatomy and Pathology, University of Adelaide, Adelaide SA, Australia Correspondence to James Donkin, PhD, Department of Pathology and Laboratory Medicine, University of British Columbia, Child and Family Research Institute, 950 West 28th Avenue, Vancouver, BC V5Z4H4, Canada Tel: +1 604 875 2345x7146; fax: +1 604 875 3120; e-mail:
[email protected] Current Opinion in Neurology 2010, 23:293–299
Purpose of review Although a number of factors contribute to the high mortality and morbidity associated with traumatic brain injury (TBI), the development of cerebral edema with brain swelling remains the most significant predictor of outcome. The present review summarizes the most recent advances in the understanding of mechanisms associated with development of posttraumatic cerebral edema, and highlights areas of therapeutic promise. Recent findings Despite the predominance of cytotoxic (or cellular) edema in the first week after traumatic brain injury, brain swelling can only occur with addition of water to the cranial vault from the vasculature. As such, regulation of blood–brain barrier permeability has become a focus of recent research seeking to manage brain edema. Aquaporins, matrix metalloproteinases and vasoactive inflammatory agents have emerged as potential mediators of cerebral edema following traumatic brain injury. In particular, kinins (bradykinins) and tachykinins (substance P) seem to play an active physiological role in modulating blood–brain barrier permeability after trauma. Substance P neurokinin-1 receptor antagonists show particular promise as novel therapeutic agents. Summary Attenuating blood–brain barrier permeability has become a promising approach to managing brain edema and associated swelling given that increases in cranial water content can only be derived from the vasculature. Inflammation, both classical and neurogenic, offers a number of attractive targets. Keywords aquaporins, cytotoxic edema, neurogenic inflammation, neurotrauma, neurovascular unit, trauma, vasogenic edema Curr Opin Neurol 23:293–299 ß 2010 Wolters Kluwer Health | Lippincott Williams & Wilkins 1350-7540
Introduction The mechanisms associated with the development of tissue damage following traumatic brain injury (TBI) have been extensively studied over the past few decades and it has become increasingly evident that the formation of cerebral edema is one of the major factors leading to the high mortality and morbidity in affected individuals. Indeed, some studies have reported that cerebral edema may account for up to half of the mortality in all victims of TBI [1], and in younger victims of TBI, up to half of all mortality and morbidity [2]. Edema is harmful because it causes cell swelling, swelling that alters cellular metabolite concentration and therefore cellular physiology, biochemistry and function. When the swelling involves not only the cells themselves but also the tissue parenchyma, there is a rapid increase in intracranial pressure (ICP), which results in compression of blood vessels, reduced tissue blood flow, reduced oxygenation and eventually shifts tissue down pressure gradients (herniations) that may crush vital 1350-7540 ß 2010 Wolters Kluwer Health | Lippincott Williams & Wilkins
brain centres such as those involved in respiration and cardiac function. Although interventions targeting brain edema and swelling have existed for some time, therapies have not changed in over 50 years, largely because the mechanisms associated with edema development are incompletely understood. Accordingly, treatments have focussed on management of the symptoms rather than control of the mechanisms. Recently, significant progress has been made toward identifying factors that mechanistically contribute to edema formation after TBI. The present review will summarize current understanding of edema formation following TBI before considering recently identified factors that contribute to the process of edema development.
Classification of edema It has long been established that cerebral edema can be classified into two main categories, namely cytotoxic (also DOI:10.1097/WCO.0b013e328337f451
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known as cellular) edema or vasogenic edema [3]. Cytotoxic edema is characterized by an increase in water content within the intracellular compartment in response to an osmotic gradient. It is usually associated with a failure of the ATP-dependent Naþ/Kþ-pumps under conditions of energy failure typically observed in cerebral ischemia, anoxic-ischemic encephalopathy and severe TBI. This leads to an increase in cellular ionic content, an overall increase in cell osmolality and the influx of water into the cells. It is essentially a compartment shift of water in the skull, with water shifting from the extracellular to the intracellular compartment (Fig. 1). As such, cytotoxic edema of itself does not result in an increase in brain water content or brain swelling, and no rise in ICP. It does however, adversely impact on cellular function by altering intracellular metabolite concentration.
Figure 1 Schematic demonstrating cytotoxic and vasogenic cerebral edema
The inability of cytotoxic edema to cause brain swelling is not always readily apparent and is perhaps best illustrated using an example as originally described by Simard et al. [4]. If a piece of tissue is excised from a live brain, it will show all the typical signs of cytotoxic edema such as shifts in ionic and water content between the extracellular and intracellular compartments. However, over time, that excised piece of tissue will not gain ionic content, will not gain water content and will not swell. There simply is no source for the ions and water; these can only come from the vasculature. Swelling, and any associated increase in ICP, therefore requires a vascular contribution and active blood flow. A vascular contribution is the hallmark of vasogenic edema. By definition, vasogenic edema is the result of the movement of water from the vasculature to the extracellular space in response to an osmotic gradient generated by the leakage of vascular components into the brain parenchyma (Fig. 1). It is characterized by an open blood–brain barrier (BBB) typically observed in conditions such as TBI, brain tumours, infection, intracerebral hemorrhage and inflammation. Given that vasogenic edema results in an increase in brain water content, tissue swelling and an increase in ICP will be observed. Variants of these two major forms of edema have also been described for specific situations. For example, transependymal edema describes an increase in periventricular interstitial fluid due to a failure of the ependymal lining of the ventricular wall, common in obstructive or communicating hydrocephalus. Hydrostatic edema is a variant of vasogenic edema that occurs when cerebral perfusion pressure increases to a level at which autoregulatory mechanisms break down. This type of edema is observed in hypertensive encephalopathies. Finally, osmotic (or ionic) edema occurs when plasma osmolality falls below brain osmolality and there is a net movement
Cytotoxic edema is essentially a water compartment shift with no change in tissue water content or volume. In contrast, vasogenic edema increases tissue water content, leading to swelling. Tissue swelling thus requires a vascular contribution if it is to occur.
of water from the vasculature to the brain interstitial fluid in the absence of gross disruption of the BBB. Despite these distinct classifications of cerebral edema, in most clinical situations there is a combination of different types of edema depending on the disorder and time course of the disease [5].
Edema in traumatic brain injury Debate over which type of edema predominates in TBI has persisted for a number of decades. Early studies
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Mechanisms of cerebral edema in TBI Donkin and Vink 295
proposed that vasogenic edema from BBB opening was the main contributor following injury [6,7], although this conclusion was largely based on a simplistic, cryogenic model of traumatic injury that is limited in terms of replicating many of the features associated with clinical TBI. It is now recognized that TBI is a complex and heterogenous injury and more recent experimental models attempt to reproduce as many of the features of clinical TBI as possible, including associated secondary conditions such as arterial hypotension, hypoxia or ischemia. Using these more recent experimental models, a biphasic profile encompassing both vasogenic and cytotoxic components has emerged. With the aid of novel MRI techniques, vasogenic edema, as indicated by an increased water diffusion distance, was demonstrated to occur in the first few hours after TBI [8,9], followed by cytotoxic edema that developed more slowly over the next few days and persisted for up to 2 weeks [8]. These observations, based on water diffusion distance, were confirmed by BBB permeability measurements demonstrating that the barrier was open to large plasma proteins for only a few hours after TBI [10,11]. However, the BBB does not simply close after this initial opening, with recent evidence suggesting that the BBB closes gradually, with the smaller vascular components being permeable for up to 7 days after TBI [12]. What accounts for this persistent permeability is unclear, although posttraumatic alterations to the endothelial cytoskeleton promoting endothelial barrier opening have been implicated [13]. Thus, the BBB is maximally permeable at 4–6 h after TBI, before commencing to close and becoming differentially permeable to smaller molecules over a 7day period. Given the critical role that the vascular contribution plays in brain water content and ICP changes, it is clear that an understanding of BBB changes following TBI, and their contribution to edema, is essential to develop potential interventions. Considerable evidence now exists supporting that brain water content after TBI is maximal at 2–3 days after trauma [1], which is also the point at which ICP usually peaks. For brain water content and swelling to be maximal at this time point, there must still be an active vascular contribution despite the BBB being closed to large plasma molecules after 6 h. Although a second opening of the BBB has been mooted [14], such an event is not essential given the gradual closing of the barrier to smaller vascular molecules over time. We therefore propose that the initial transient opening of the BBB is associated with a brief period of ‘pure’ vasogenic edema, the presence of which would be permissive for the development of any subsequent cytotoxic edema [15]. Cytotoxic edema would indeed develop with the gradual development of cellular injury over time, and would become more prominent as more cells were affected. The intracellular shift of ions and water from the extra-
cellular compartment would then indirectly drive the entry of more ions and water from the vasculature, with this entry being facilitated by the BBB being permeable to ions and small molecules, albeit not to the larger plasma proteins commonly used to measure BBB permeability. Thus, the ‘pure’ vasogenic phase would be replaced by a mixed cytotoxic/vasogenic phase that would be dominated by the cytotoxic, or cellular, component as more cells become dysfunctional and die. Nonetheless, the driving force for the increased brain water content, brain swelling and increased ICP, would be the vascular contribution. Thus, interventions that target the vascular contribution to edema, even if the dominant edema is cellular, may be particularly effective in the management of brain swelling.
Mediators of brain edema A number of mediators have been identified that play a role in edema formation after TBI. Arguably, the most exciting recent developments include the identification of aquaporin water channels as critical participants in the development of edema, and the focus on agents that affect the BBB, and therefore the vascular contribution to brain swelling. These aspects are summarized below. Aquaporins
The identification of the water-channel proteins, aquaporins (AQPs), as a key player in the development and resolution of cerebral edema has highlighted their potential as a therapeutic target to prevent brain swelling [16– 18]. AQPs are integral membrane proteins belonging to a family that form pores in the membranes of mammalian cells [19]. Of the 13 AQPs known to exist in mammals, AQP1, AQP4 and AQP9 are highly expressed in brain [20]. AQP4 is predominately expressed in the astrocytic end foot processes in close proximity to intracerebral vessels and at the ventricular interface. AQP9 is coexpressed with AQP4 in astrocytic foot processes, whereas AQP1 is expressed in the choroid plexus epithelium and in ganglionar sensory neurons. Other AQPs have also been identified in brain, but these are expressed at much lower concentrations [20]. A number of studies have now shown that AQP4 expression is markedly altered in both experimental and clinical brain injury [5,17,21,22], and that genetic variation of the channels may influence degree of edema [23]. Similar increases in AQP1 and AQP9 after experimental TBI have been reported [24,25]. Initial studies suggested that upregulation of AQPs after brain injury promoted edema formation [16] and it was accordingly postulated that therapeutic inhibition of AQP4 would be beneficial in edema control [18]. However, it subsequently became evident that the alterations in AQP4 expression are regionally distinct and dependent on the type of edema
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[26–28]. For example, in a model of rat cerebral ischemia, inhibition of AQP4 expression was associated with reduction in edema, infarct area and an improvement in functional outcome [29,30]. Rat cerebral ischemia typically results in cytotoxic edema. In contrast, vasogenic edema induced by cold lesion injury was exacerbated in AQP4 knockout animals, suggesting that AQP4 is essential for clearance of vasogenic edema [27].
temporally and spatially associated with BBB disruption and edema formation [41,42]. Consistent with this, mice lacking the MMP-9 gene have been shown to be protected in both focal and global ischemia as well as TBI [41,43,44], with gene knockout mice having reduced BBB disruption and edema, a reduced inflammatory response, improved integrity of white matter components plus improved functional outcome.
In experimental TBI, an increase in AQP4 expression in the glia limitans was observed but a downregulation of perivascular AQP4 was noted during the early period when vasogenic edema would be present [26]. Notably, pharmacological reduction of edema formation and improved functional outcome was associated with restoration of the AQP4 channels to their normal state. The speed at which the reappearance of AQP4 channels on the perivascular glial endfeet occurred after treatment suggests that there was a posttranslational modification, perhaps involving subunit aggregation, rather than enhanced protein synthesis. Similarly, in a rat cortical contusion model, exacerbation of injury by a secondary insult involving hypoxia and hypotension led to a worsening of brain edema, which was associated with a reduction in the APQ4 expression [31]. The increased brain water content can only be attributed to a vascular component as a cytotoxic compartment shift would not increase brain water content. Thus, AQP4 upregulation is associated with the development of cytotoxic edema whereas perivascular downregulation occurs in regions experiencing vasogenic edema. Generalized inhibition of AQP4 channels may therefore not be beneficial in those conditions in which vasogenic edema plays a critical role. Indeed, AQP4 activators have the potential to facilitate the clearance of the vasogenic component of edema, whereas AQP4 inhibitors have the potential to protect the brain in cytotoxic edema.
MMP inhibitors, such as minocycline or TIMP-1, have also been shown to block BBB injury, cerebral edema and cell death in a number of experimental animal models [35,45–47]. However, recent data suggest a more biphasic role for MMPs in TBI [48], with MMPs reported to play an important role in neurogenesis, neurovascular remodeling and matrix-trophic signaling in the later stages of recovery from TBI and stroke [39,48]. Inhibition at these delayed time points may in fact worsen recovery. As such, the most challenging aspect with respect to MMP inhibitors is the timing of administration in an effort to coordinate their beneficial and detrimental effects following TBI. This balance between positive and detrimental effects has been recognized for some time in inflammation [49].
Matrix metalloproteinases
The ability of matrix metalloproteinases (MMPs) to degrade many types of extracellular matrix proteins, including the neurovascular basal lamina and tight junction proteins of the BBB, has been the subject of a number of recent TBI investigations [32–34]. MMPs are zinc-dependent endopeptidases involved in the process of tissue remodeling following various pathologic conditions. The regulation of MMP expression and activation is complex and tightly controlled, and loss of this control has been identified as potentially playing a critical role in the pathophysiology of synaptic loss and BBB breakdown in TBI, stroke and neurodegeneration [35,36–38]. MMPs, and in particular MMP-2, MMP3 and MMP-9, are upregulated following TBI [33,39,40] in which they cause acute disruption of the BBB, leading to vasogenic edema and subsequent cell death. Indeed, the upregulation of MMP-9 in particular has been
Vasoactive agents
It is well established that inflammatory, vasoactive agents can increase BBB permeability and lead to cerebral edema [50]. Recent studies in TBI have focused not only on mediators related to classical inflammation, but also those derived from neurogenic inflammation. In terms of classical inflammation, the bradykinin family of kinins has been strongly implicated in the development of edema following acute brain injury [51]. The bradykinins are formed from the cleavage of kininogen by kallikreins, with the active peptides (bradykinins and kallidin) producing their effects through two subtypes of bradykinin receptors known as B1 and B2 receptors. Following TBI in mice [52], bradykinin itself was maximally increased at 2 h after trauma whereas both the B1 and B2 receptors were significantly upregulated in the first 24 h. Despite the increase in both receptors after trauma, only B2 receptor knockout mice had significantly less edema and better functional outcomes after TBI [52], implying that B2 receptor binding may play an integral role in edema formation after trauma. Administration of a B2 receptor antagonist was subsequently shown to reduce ICP and contusion volume in a rodent focal contusion model [53], which confirmed earlier findings in other models of acute brain injury [51,54,55]. Despite these positive findings, no positive effects of the B2 antagonists have been noted in subsequent clinical trials of the compounds [56,57]. The other distinct family of kinins is the tachykinins, a group of peptide mediators that have been implicated in
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Mechanisms of cerebral edema in TBI Donkin and Vink 297
neurogenic inflammation. Neurogenic inflammation is a process that encompasses vasodilation, plasma extravasation and neuronal hypersensitivity caused by the release of neuropeptides from sensory neurons [58]. Although several neuropeptides have been implicated in neurogenic inflammation, calcitonin gene-related peptide (CGRP) has been identified as being associated with the vasodilation whereas substance P is thought to enhance plasma protein extravasation. Although few studies have suggested a role for neurogenic inflammation in edema formation following TBI [59,60], Donkin et al. [61] recently demonstrated that injury results in an elevated perivascular substance P immunoreactivity that is associated with enhanced vascular permeability and edema formation in a rodent model of moderate diffuse TBI. A similar increase in substance P immunoreactivity was also reported following mild concussive head injury [62] and reperfusion injury [63]. Subsequent studies in human TBI by the same group also reported elevated substance P immunoreactivity in human TBI [64]. Specifically, patients who had sustained traumatic head injuries, who had died within 1 week and who had undergone postmortem and detailed neuropathological examination, demonstrated an elevation in substance P immunoreactivity in cortical microvasculature. Moreover, the localization to perivascular neurons suggested that injury to the neuron may result in a localized perivascular release of neuropeptides, with a resultant increase in BBB permeability and edema formation. Notably, substance P is stored and co-released with CGRP, a potent endogenous vasodilator that potentiates edema formation in the presence of mediators of increased vascular permeability, such as substance P [65]. Thus, their combined release during neurogenic inflammation would theoretically facilitate a profound edema response. Given the increased perivascular substance P after acute injury to the brain, Donkin et al. [61] subsequently administered the substance P neurokinin-1 receptor antagonist N-acetyl-tryptophan after TBI and noted a marked attenuation of BBB permeability and subsequent edema formation. Similar findings were noted in a reperfusion model of transient ischemia [66], with highly significant reductions in edema formation as measured at 24 h after the induction of stroke. Although the results using neurokinin-1 antagonists were useful in establishing a role for substance P in brain injury, an alternative approach to establishing a more general role for neurogenic inflammation in TBI is by inhibition of central neurogenic inflammation by neuropeptide depletion. Neuropeptide depletion can be accomplished by chronic preinjury administration of the vanilloid receptor agonist capsaicin, which stimulates the release of neuropeptides from the presynaptic sensory nerve terminals to the point
of depletion. Nimmo et al. [59] used this approach to demonstrate that neuropeptide depletion results in a marked attenuation of early posttraumatic BBB permeability and any subsequent edema formation. Remarking that their study validated the assumption that vasogenic edema is permissive for cytotoxic edema formation [15], they concluded that early inhibition of neurogenic inflammation may present a novel approach to the treatment of posttraumatic edema formation.
Conclusion Although a number of factors contribute to the high mortality and morbidity associated with TBI, the development of cerebral edema with brain swelling remains the most significant predictor of outcome. Brain swelling can only occur with addition of water from the vasculature (vasogenic edema), as cytotoxic edema is essentially a compartment shift of water from the extracellular to intracellular compartment. As such, attenuating BBB permeability has increasingly become a promising approach to managing brain edema and associated swelling. AQPs, MMPs and vasoactive inflammatory agents have emerged as potential mediators of cerebral edema following TBI. Inflammation, both classical and neurogenic, offers a number of attractive targets, with the tachykinins (substance P) in particular seeming to play an active physiological role in modulating BBB permeability after trauma.
Acknowledgement R.V. is supported by the Neurosurgical Research Foundation, Australia. J.J.D is supported by the Alzheimer’s Society of Canada Postdoctoral Fellowship. We thank Tavik Morgenstern for the medical illustration.
References and recommended reading Papers of particular interest, published within the annual period of review, have been highlighted as: of special interest of outstanding interest Additional references related to this topic can also be found in the Current World Literature section in this issue (pp. 337–338). 1
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Update on investigation and management of postinfectious encephalitis Romain Sonnevillea, Isabelle F. Kleinb and Michel Wolffa a Department of Critical Care Medicine and Infectious Diseases and bDepartment of Radiology, BichatClaude Bernard Hospital, Universite´ Paris 7, Paris, France
Correspondence to Romain Sonneville, Department of Critical Care Medicine and Infectious Diseases, BichatClaude Bernard Hospital, Universite´ Paris 7, 46 rue Henri Huchard, 75877 Paris Cedex 18, France Tel: +33 1 40257703; fax: +33 1 40258837; e-mail:
[email protected] Current Opinion in Neurology 2010, 23:300–304
Purpose of review Encephalitis is a complex syndrome associated with significant morbidity and mortality. Despite biological and neuroimaging investigations, the cause of encephalitis remains undetermined in more than half of the cases. The aim of this review was to describe available data concerning diagnosis and treatment of postinfectious encephalitis, focusing on acute disseminated encephalomyelitis (ADEM) and acute hemorrhagic leukoencephalitis (AHLE). Recent findings The increasing availability of brain MRI studies has allowed a better delineation of diagnosis and prognosis of postinfectious central nervous system disorders. Beneficial effects of steroids and plasma exchange have been described in the most severe forms of postinfectious encephalitis, including ADEM and AHLE, but randomized controlled studies are lacking. Intravenous immunoglobulins may be of value in ADEM with peripheral nerve involvement and for patients in whom corticosteroid therapy is contraindicated. Summary Postinfectious encephalitis needs to be identified early in the management of patients with unexplained encephalitis as it represents a treatable disease. Randomized studies are needed in order to assess the potential benefit of early combined immunotherapy in ADEM. Keywords acute disseminated encephalomyelitis, acute hemorrhagic leukoencephalitis, demyelination, encephalitis, postinfectious Curr Opin Neurol 23:300–304 ß 2010 Wolters Kluwer Health | Lippincott Williams & Wilkins 1350-7540
Introduction Acute encephalitis is a complex neurological syndrome for physicians to manage and is associated with significant morbidity and mortality [1]. It is clinically characterized by the association of encephalopathy, focal deficits, seizures and fever, and usually has an infectious origin. In 2006, the California encephalitis project, which evaluated 1570 patients with encephaliti, identified an infectious causative agent in approximately 30% of cases and a postinfectious disease process in 8% of cases. Of note, no cause was identified in 63% of the patients [2]. Postinfectious encephalitis differs from acute infectious encephalitis by the usual failure to isolate infectious agents from neural tissue and by the predominance of inflammation and demyelination. The spectrum of acute demyelinating syndromes has been extensively described and diagnostic criteria have been proposed in the pediatric literature [3,4]. Recent studies suggest that adult patients with a diagnosis of acute disseminated encephalomyelitis (ADEM) or acute hemorrhagic 1350-7540 ß 2010 Wolters Kluwer Health | Lippincott Williams & Wilkins
leukoencephalitis (AHLE) can present with typical features of acute infection of the central nervous system (CNS), often preceded by a nonspecific febrile illness or vaccination [5]. The aim of this article is to give an update on the investigation and management of patients with postinfectious encephalitis, focusing on ADEM and AHLE.
Acute disseminated encephalomyelitis Acute disseminated encephalomyelitis is usually a monophasic inflammatory demyelinating disorder of the CNS that occurs within days to weeks of a viral illness or a vaccination. The preceding infection is typically a benign upper respiratory tract infection or a nonspecific febrile illness. Historically, most cases were associated with exanthematous diseases (measles, varicella and rubella). ADEM has also been described after various definite infections or vaccinations. Preceding infections consist mostly of viral agents, group A b-hemolytic streptococci and intracellular bacteria such as Mycoplasma pneumoniae DOI:10.1097/WCO.0b013e32833925ec
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[6]. ADEM is predominantly a pediatric disease, with recent studies reporting an incidence of 0.4 to 0.9 per 100 000 [7]. However, in adult patients, incidence studies are not available. The age of onset in the adult population ranges from 30 to 50 years and both sexes seem to be affected with the same frequency [5,8]. Acute disseminated encephalomyelitis is thought to be an auto-immune disease and two pathogenetic mechanisms have been advanced. The first mechanism implies the molecular mimicry phenomenon, consisting of structural homology between a pathogen and myelin proteins of the host leading to T-cell activation and specific autoimmune CNS response against the brain and spinal cord [3]. The second mechanism is the direct aggression of the CNS by a pathogen that may cause brain tissue damage and an infection-induced myelin antigen release associated with blood–brain barrier rupture [9]. This hypothesis is supported by case reports of patients that presented features of acute disseminated encephalitis following PCR-proven herpes simplex virus-1 encephalitis [10]. Recently, circulating antibodies to native myelin oligodendrocyte protein have been identified in about 40% of children with acute CNS demyelination [11]. Clinical findings
Acute disseminated encephalomyelitis is clinically characterized by the acute onset (maximal neurological deficit reached within hours to days of onset) of focal neurological signs and encephalopathy (early evidence of behavioral impairment, delirium, fluctuations of vigilance). It usually follows a minor infection or vaccination, with a latency period of 2–30 days. Patients can present with a clinical picture of severe CNS infection with impaired consciousness, fever and sometimes nuchal rigidity. Both focal and generalized seizures have been reported with an incidence ranging from 4 to 30% in adults [5]. In a patient presenting with features of encephalitis, some clinical signs should raise the suspicion of a possible acute inflammatory demyelinating process. Careful examination often discloses evidence for disseminated demyelination in the form of optic neuritis, myelitis and/ or acute polyradiculoneuropathy [12]. Optic neuritis (unilateral or bilateral) was reported with an incidence of 6% in adult patients with severe acute demyelinating disease [8]. Spinal cord lesions of myelitis are clinically characterized at the acute phase of the disease by para or tetraplegia (depending on lesion location) with deep tendon reflexes abolition and acute urinary retention [5,8]. Spinal cord symptoms have been reported with an incidence of 50–68% [5,8]. Peripheral nervous system (PNS) involvement in adult patients has been reported, with an incidence ranging from 25 to 44% [5]. All the
abovementioned symptoms and signs can be observed in the same patient within different patterns and encephalomyeloradiculitis appears to be the most frequent picture observed in adults [13]. Neuroimaging
Edematous white-matter T2 hyperintense lesions occurring at the same time is the classical picture of ADEM. Asymmetrical distributed lesions affect the central white matter and cortical gray–white junction of both cerebral hemispheres and infratentorial areas [3]. Although no specific MRI criteria have been identified, three MRI lesion patterns are generally recognized, but in all cases lesions are multifocal with a relatively small mass effect and involve mainly the supratentorial white matter: multifocal lesions of less than 5 cm, confluent multifocal lesions of more than 5 cm and multifocal lesions involving basal ganglia. Multifocal hemorrhagic and edematous lesions are seen in the Weston Hurst disease [14]. Deep gray matter (thalami and basal ganglia) involvement is reported in 15–60% of cases in adults [5], which may help differentiate ADEM from mutiple sclerosis (MS) in patients with a diagnosis of acute demyelination of the CNS [8]. Lesions are isointense or hypointense on T1 sequence. Apparent diffusion coefficient (ADC) is increased in ADEM lesions, whereas isotropic diffusion maps appear normal (consistent with vasogenic edema) [15]. Likewise, enhancement of lesions is usually absent or moderate, involving all the lesions at the same time [14]. A recent study using proton magnetic resonance spectroscopy in children with ADEM has shown major elevation of lipids and reduction in myoinositol/creatine ratio during the acute phase, followed by a reduction in lipid peak and elevation above normal in myoinositol/ creatine ratio during the chronic phase that may help early diagnosis [16]. Spinal cord involvement, consisting of focal or diffuse myelitis, is seen in up to two-thirds of patients. Few studies suggested that decreased ADC and brainstem involvement at the acute phase may be associated with a poor prognosis [15,17]. A pattern of diffuse demyelination can be seen in the most severe cases in adults, with large demyelinating lesions of the white matter extending to the corpus callosum and to the contralateral hemisphere [3,5]. However, neither lesion volume threshold nor other imaging criteria may indicate secondary deterioration. Cerebrospinal fluid
Cerebrospinal fluid (CSF) findings of ADEM patients are nonspecific and include elevated white-cell count (lymphocytic pleocytosis) with slightly increased protein levels, normal CSF glucose levels and sterile cultures. CSF examination can be strictly normal in about onethird of patients [18]. Some observations in adults
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demonstrated that neutrophils in CSF predominated in approximately one-fourth of the patients but this finding did not seem to be associated with an adverse outcome [5]. Oligoclonal bands (OCBs) analyzed with isoelectric focusing should be systematically sought in patients with a presumed diagnosis of acute demyelination of the CNS. Marchioni et al. recently described that CSF-restricted oligoclonal bands were found in 89% of MS patients and in only 10% of ADEM patients and that identical serum and CSF OCBs (‘mirror pattern’) or no OCBs were detected in 84% of ADEM patients and only 10% of MS patients. The mirror pattern observed in ADEM suggests a predominantly systemic immune activation [19].
Acute hemorrhagic leukoencephalitis Acute hemorrhagic leukoencephalitis is a rare disorder that is considered as a distinct form of postinfectious CNS disorder or may be the more severe form of ADEM. The fulminant course and the existence of hemorrhagic whitematter lesions may differentiate AHLE from ADEM. AHLE usually appears 1–20 days following a banal viral infection, mainly upper respiratory tract infection. The onset is brutal, with fever, coma, seizures and focal neurological signs. The CSF opening pressure is usually elevated and analysis shows a lymphocytic pleocytosis and up to 1000 red blood cells/ml with increased protein levels, ranging from 1 to 3 g/l. MRI lesions are consistent with hyperintensities of the white matter on both T1 and T2-weighted images, which are widespread in both hemispheres. Lesions can also affect thalami, brainstem and cerebellum [20,21]. The white-matter lesions are more often nonenhancing and accompanied by evidence of cerebral edema. Petechial hemorrhages can be seen on T2-weighted sequences in the peripheral white matter [22]. Diffusion-weighted imaging with apparent diffusion coefficient map can show restriction of diffusion within the lesions. The neuropathology of AHLE consists of inflammation and demyelination similar to ADEM together with widespread hemorrhagic lesions in the cerebral white matter. Fibrinoid necrosis of veins and arterioles and exudates in the perivascular area with intense polymorphonuclear cell infiltration and edema are also observed [12]. Some authors reported the benefit of early aggressive therapy in AHLE, with both surgical management of raised intracranial pressure and immunosuppression with cyclophosphamide. The disease is fulminant and the mortality can be as high as 70%, leaving survivors with significant sequelae [23].
specific treatment. All frequent causes of infectious encephalitis need to be excluded before concluding an acute form of postinfectious inflammatory CNS disorder. CSF should therefore be systematically screened for herpes CNS infections (PCR of Herpes simplex and Varicellazoster virus), and nonspecific tests (direct examination and CSF culture) for Mycobacterium tuberculosis and Listeria monocytogenes, in accordance with recent recommendations [24]. Of note, these four pathogens were responsible for most of the identified causes in a recent French study on encephalitis [25]. HIV infection, including seroconversion, should be ruled out at admission. Intravenous aciclovir must be immediately started while awaiting for CSF studies, together with antibiotics if any suspicion of bacterial meningitis remains [26]. If no evidence of CNS infection is found and if neuroimaging is consistent with acute inflammatory lesions, then a diagnosis of ADEM has to be considered. Many other CNS diseases can mimic ADEM: these include systemic diseases (Behc¸et’s disease, systemic lupus erythematosus, sarcoidosis), primary or secondary small-vessel CNS vasculitis, vascular, toxic or leukoencephalopathies and intracerebral malignancies, and paraneoplastic disorders of the CNS. Acute toxic encephalopathy can also mimic ADEM but it is mainly a diffuse disease with a hyperacute onset associated with elevated intracranial pressure. In young patients presenting with unexplained seizures and movement disorders, anti-N-methyl-Daspartate (NMDA) receptor encephalitis should be considered, as it represents another potential treatable cause of encephalitis in ICU patients [27]. Cerebral angiography, which is typically normal in ADEM patients, can show abnormalities in patients with moderate-vessel to large-vessel vasculitis. In all cases of unexplained encephalopathy with multifocal areas of increased signal of the CNS white matter, brain biopsy has to be considered, especially when neuroimaging and noninvasive tests (CSF PCR for organisms, CSF cytology and OCB) are unconclusive [12,28]. The immunopathology of ADEM is characterized by perivenular demyelination associated with inflammatory infiltrates dominated by lymphocytes and mononuclear cells. Lesions appear to be of similar age and evidence of inflammation can also be found in the meninges [29]. The lesions are located in the cerebral white matter, brainstem and spinal cord. Gray matter may also be involved, particularly basal ganglia, thalami and brainstem. Axons and arteries are relatively preserved [30].
Management of patients Differential diagnosis The main problem in the differential diagnosis of encephalitis is to distinguish acute viral encephalitis from postinfectious encephalitis and other causes that deserve
Patients with encephalitis are at high risk for developing serious secondary complications and general supportive measures are the cornerstone of treatment. Patients must be immediately transferred to the ICU in the case of deterioration of mental status and efforts should focus on
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avoiding raised intracranial pressure. Surgical decompression has been reported to reduce raised intracranial pressure refractory to medical management. To date, there have been no randomized, controlled trials for the treatment of ADEM in either children or adults. High-dose intravenous corticosteroids are considered as first-line therapy, alone or together with other immunomodulatory therapies, including intravenous immunoglobulin or plasma exchange. Most of the data describing treatment for ADEM are derived from case reports and small series.
postinfectious encephalomyelitis. The authors observed that steroid-resistant patients showed high prevalence of PNS damage (89%) and myelitis (95%). IVIg were effective, the clinical improvement beginning within the end of the treatment. Milder onset disability and lower CSF albumin were the predictors of IVIg response [31]. IVIg may be of value in ADEM with peripheral nerve involvement. A typical regimen consists of 0.4 g/kg per day for 5 days but rapid infusions have been reported [35,36]. Treatment with IVIg should also be considered for patients in whom corticosteroid therapy is contraindicated [28].
Steroids
Although there are no controlled studies about the dose or effectiveness of corticosteroids for ADEM and other forms of acute demyelinating disorders, high-dose steroids are now accepted and have been recommended [26]. Intravenous (i.v.) methylprednisolone pulse has been the most widely reported therapy, with a typical treatment regimen of 1 g per day, for a duration of 3–5 days [3]. Higher doses (total dose of 6–10 g) have been reported in severe forms of steroid-resistant postinfectious encephalomyelitis [5,31]. Pulses are sometimes followed by oral steroid (prednisone 1 mg/kg per day) taper for 4–6 weeks, but it might not be necessary if symptoms start to improve. The occurrence of adverse events, including hyperglycemia, hypokalemia, high blood pressure and mood disorders, should be carefully monitored at the initial phase of treatment [3]. Plasma exchange
Although there is evidence for the benefit of plasma exchange for acute life-threatening demyelination unresponsive to corticosteroids, its use in ADEM patients has been reported in only a small number of patients. A series examined the outcome following plasma exchange for 59 patients with a variety of severe CNS demyelinating diseases (10 cases of ADEM). Ninety-two per cent of the patients had been previously treated with high-dose steroids. Forty-four per cent of the patients had moderate to marked improvement following plasma exchange [32]. In this study, a mean number of seven exchanges were performed. Male sex, preserved reflexes, and early initiation of treatment (within 21 days after onset) were associated with clinical improvement. Successfully treated patients showed rapid and sustained improvement following plasma exchange [33]. In a recent study, early initiation of plasma exchange (within 15 days after onset) in acute attacks of CNS demyelination (including seven patients with ADEM) was identified as a predictor of clinical improvement at 6 months [34]. Intravenous immunoglobulins
The potential utility of intravenous immunoglobulins (IVIg) has been reported in severe steroid-resistant
Outcome Outcome of ADEM patients is usually favorable, with mortality rates less than 5% in pediatric series. In adults, mortality can be as high as 25%, especially in patients requiring ICU admission [5]. Recurrent and multiphasic forms have been reported, mainly in children. After a severe demyelinating event, up to 30% of adult patients will develop a clinically definite form of MS with recurrences of demyelinating events [8]. Criteria to evaluate the risk of evolution to MS have been identified and include atypical clinical symptoms for MS (one or more of the following: consciousness alteration, aphasia, hemiplegia, paraplegia, tetraplegia, seizure, vomiting, bilateral optic neuritis, or confusion); absence of oligoclonal bands in CSF and gray-matter involvement (basal ganglia, cortical gray matter). The presence of two of these three criteria is suggestive of ADEM disease with a positive predictive value of 97% and a negative predictive value of 75% [8]. In children, corpus callosum long-axis perpendicular lesions and periventricular lesions appear to be associated with a higher risk of MS-defining relapses. A systematic clinical and neuroimaging follow-up should be performed at 6 months in patients with postinfectious encephalitis. Serial imaging can provide evidence of lesion dissemination in time that can confirm a diagnosis of MS even in the absence of clinical relapse [4]. In ADEM, lesions should resolve or remain unchanged [9].
Conclusion Postinfectious encephalitis should be considered in all cases of unexplained encephalitis, as it represents a treatable disease. In patients with ADEM, diffuse and focal CNS signs together with PNS involvement may be present simultaneously at physical examination. Because there is no biomarker of the disease, neuroimaging play a key role in the diagnosis and needs to be performed early in the management of patients to look for evidence of multifocal acute inflammation and demyelination. Randomized controlled studies are needed in order to assess the potential benefit of early combined immunotherapy in ADEM.
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304 Inflammatory diseases and infection
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Acute encephalopathy and encephalitis caused by influenza virus infection Gefei F. Wang, Weizhong Li and Kangsheng Li Department of Microbiology and Immunology, Key Immunopathology Laboratory of Guangdong Province, Shantou University Medical College, Shantou, Guangdong, P.R. China Correspondence to Kangsheng Li, Shantou University Medical College, 22 Xinling Road, Shantou 515041, Guangdong, P.R. China Tel: +86 754 8890 0456; e-mail:
[email protected] Current Opinion in Neurology 2010, 23:305–311
Purpose of review Influenza-associated acute encephalopathy/encephalitis (IAE) is an uncommon but serious complication with high mortality and neurological sequelae. This review discusses recent progress in IAE research for a better understanding of the disease features, populations, outcomes, diagnosis, and pathogenesis. Recent findings In recent years, many IAE cases were reported from many countries, including Japan, Canada, Australia, Austria, the Netherlands, United States, Sweden, and other countries and regions. During the novel influenza A/H1N1 pandemic, many IAE cases with A/H1N1 infection in children were reported, particularly in those hospitalized with influenza infection. Pathogenesis of IAE is not fully understood but may involve viral invasion of the CNS, proinflammatory cytokines, metabolic disorders, or genetic susceptibility. An autosomal dominant viral acute necrotizing encephalopathy (ANE) was recently found to have missense mutations in the gene Ran-binding 2 (RANBP2). Another recurrent ANE case following influenza A infection was also reported in a genetically predisposed family with an RANBP2 mutation. Summary Although IAE is uncommon, compared with the high incidence of influenza infection, it is severe. However, this complication is not duly recognized by health practitioners. Recent advances highlight the threat of this complication, which will help us to have a better understanding of IAE. Keywords acute encephalopathy and encephalitis, acute necrotizing encephalopathy, influenza, influenza-associated acute encephalopathy/encephalitis Curr Opin Neurol 23:305–311 ß 2010 Wolters Kluwer Health | Lippincott Williams & Wilkins 1350-7540
Introduction Influenza-associated acute encephalopathy/encephalitis (IAE) is a central nervous system (CNS) complication with high mortality and neurological sequelae, which is a particular threat to children hospitalized with influenza infection. This complication is often not recognized by health practitioners. This review discusses recent progress in IAE research for a better understanding of the disease features, populations, outcomes, diagnosis, and pathogenesis.
Influenza and central nervous system complications Influenza virus can cause common respiratory tract infections and rarely multiorgan system disorders, resulting in mild infection, severe respiratory disease, or systemic disease and complications. Symptoms of mild influenza infection usually include fever, headache, cough, sore 1350-7540 ß 2010 Wolters Kluwer Health | Lippincott Williams & Wilkins
throat, myalgia, and sometimes diarrhea or vomiting. In general, it is usually self-limited and not serious. However, certain patients, especially children, elderly people, pregnant women, and people with certain diseases, have a higher risk of incurring pneumococcal pneumonia and CNS complications. CNS dysfunction, an important complication of influenza infection [1,2], includes IAE [3,4], febrile seizure [5], Reye’s syndrome [6,7], postinfluenza encephalitic Parkinson’s disease [1,2], and encephalitis lethargica [8,9]. Febrile seizure is common among the CNS complications with influenza infection in children and has been reported to occur in more than 20% of the children hospitalized with influenza [10]. Acute encephalopathy/encephalitis and Reye’s syndrome have similar clinical symptoms of CNS dysfunction, such as lowered consciousness [7], but unlike IAE, Reye’s syndrome involves fatty acid degeneration in the liver caused by mitochondrial failure and is characterized by low blood DOI:10.1097/WCO.0b013e328338f6c9
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306 Inflammatory diseases and infection
glucose and high blood ammonia. The interval from the onset of fever to the onset of neurological symptoms for IAE is usually 1–2 days, which is shorter than that for Reye’s syndrome [11].
Influenza-associated acute encephalopathy/ encephalitis IAE is a rapid progressive encephalopathy that usually presents in the early phase of influenza infection [1]. Because of lack of inflammation in the CNS, IAE is always named influenza-associated acute encephalopathy, which includes acute necrotizing encephalopathy (ANE) [12]. IAE is an uncommon but serious complication with high mortality and neurological sequelae. Cases of IAE during influenza epidemics have been reported mostly from Japan since 1995 [13], with a few cases from other areas, including Taiwan [14–17], North America [18–21,22, 23,24], and Europe [25–30]. Most cases involve children younger than 5 years. Both influenza A (including novel H1N1 and H5N1) and B and even C can cause this complication [15,23,28,31]. The clinical symptoms of IAE are diverse. In general, the clinical characteristics include symptoms of both flu and CNS dysfunction. Typical flu symptoms involved are fever, cough, nasal discharge, sore throat, and headache, and CNS neurological manifestations including seizure, altered or loss of consciousness, decreased cognitive processing including speech, motor paralysis or sensory loss, abnormal or delirious behavior, and change in mental status. Neurological complications may develop within several days of the first symptoms of flu [11,14,27,32,33,34,35].
Populations and outcomes of influenzaassociated acute encephalopathy The data from the Japan National Epidemiological Surveillance of Infectious Diseases in 1998–1999 influenza season [36] indicated that neurologic complications such as acute encephalitis/encephalopathy are associated with influenza virus infection, especially among young children. The Japanese Ministry of Health and Welfare performed a cross-sectional survey of influenza in all medical facilities during the 1998–1999 influenza season. Of the 217 identified IAE cases, in which diagnosis of encephalopathy was based on clinical symptoms, 179 (82.6%) were children younger than 5 years, 58 (26.7%) died, and 56 (25.8%) had neurological sequelae. There was no sex difference in prognosis and incidence [32]. Subsequent analysis of the same data by Morishima et al. [33] confirmed 148 cases of IAE, which were diagnosed on the basis of virologic analysis. One hundred twenty-
one children (81.8%) involved were less than 5 years old. The mortality rate (31.8%) and frequency of neurological sequelae (27.7%) were also high. Togashi et al. [11] also investigated the incidence of IAE in Hokkaido, Japan, during eight influenza seasons from 1994 to 2002. In each season, the peak incidence of cases coincided with the peak of the influenza epidemic; among a total of 89 cases reported, 70 (78.7%) were children (<5 years), 33 (37.1%) died, and 17 (19.1%) had neurological sequelae. Yoshikawa et al. [37] studied 20 patients with IAE during the 1997–2001 influenza seasons. Among them, five (25%) patients died and eight (40%) had neurological sequelae. They also noted that patients with coagulopathy, hepatic dysfunction, and computed tomographic abnormalities had a poor prognosis. Based on the severity of disability, the neurologic sequelae include mild sequelae and severe sequelae that require personal help for daily life activities [33]. Diverse neurologic sequelae occurred in these patients, such as impaired cognitive function, mutism, behavioral disturbances, ataxia, paralysis, dystonia, hand tremor, spasticity, and so on [29,38–40]. In recent years, IAE complication has received international recognition and concern. Similar populations and outcomes of IAE were reported from Canada [20,21], Australia [41,42,43], Austria [28], the Netherlands [29,30], United States [19,22,24,44,45], Sweden [27,46], and other countries and regions [15,17,25,26]. Review of data from 1994 to 2004 by Amin et al. [20] showed that influenza virus infection was associated with about 5% (14 of 311) of acute childhood encephalopathy/ encephalitis cases in the Hospital for Sick Children, Toronto, Canada, and 11 (78.6%) children were under 5 years old. More than 50% of patients had neurological sequelae. In addition, the prevalence of neuroimaging abnormalities was higher in children under 2 years of age. Those reports suggest that children, especially those under 5 years of age, are inclined to suffer from neurologic complications with influenza infection. Most of the patients with IAE recovered within 2–6 weeks. The serious outcomes including death and neurological sequelae could be as high as 50%.
Diagnosis of influenza-associated acute encephalopathy The diagnosis of IAE takes account of definition of both influenza infection and encephalitis/encephalopathy. Influenza infection definition is different in some reports. The cases of influenza infection included cases that met the clinical case definition (sudden onset of a fever over 398C, respiratory symptoms, myalgia, and headache) and/or laboratory-confirmed definition [32]. The latter defined influenza infection on the basis of either positive viral culture, viral antigen test, or viral RNA PCR or by
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significant increases in the titer of hemagglutination inhibition test [33]. In the report by Smidt et al. [29], a more rigorous influenza infection definition was used, including repeated isolation of influenza A virus from nasopharyngeal aspirates and seroconversion between acute and convalescent sera. In addition, serological tests of Epstein–Barr virus, cytomegalovirus, herpes simplex virus, varicella-zoster virus, mumps, measles, and Mycoplasma pneumoniae have been used to exclude other encephalopathy/encephalitis pathogens. The diagnosis of encephalitis/encephalopathy has been based on clinical symptoms and signs. Patients with meningitis, myelitis, and febrile seizure should be excluded. Neuroimaging, such as MRI and computed tomography (CT), and electroencephalographic (EEG) analyses were performed in some reports. Diffuse involvement of the cerebral cortex and diffuse brain edema were detected by neuroimaging in severe cases, and the degree of radiological change was associated with the prognosis [18,47,48]. Some (about 20–30%) of the patients, who developed severe illness and/or acute necrotizing encephalopathy, exhibited multifocal, symmetrically distributed brain lesions of the thalamus, cerebral white matter, brainstem, cerebellum, and parenchyma by CT and MRI [12,33,49,50]. Different from other encephalitides, such as Reye’s syndrome, the bilateral thalamic necrosis on neuroimaging was considered to be one of the features of IAE [12,50]. EEG abnormalities such as focal slowing or sharp waves in the frontal or temporal area, diffuse slowing, abnormal background, electrographic seizure, and generalized slow-wave activity were found in many cases [20,22,25,27]. Therefore, neuroimaging and EEG can be used to make laboratory diagnosis and predict prognosis of encephalitis/encephalopathy. In conclusion, the influenza infection should be defined by both clinical features and laboratory results. Other encephalopathy/encephalitis pathogens should be excluded. Neurological symptoms should develop usually within 2 days after the onset of flu symptoms.
Novel H1N1 and influenza-associated acute encephalopathy Neurological symptoms were reportedly associated with some cases of the novel influenza A/H1N1 infection. Neurologic complications, including encephalopathy and seizure, in children in Dallas, Texas, were reported in MMWR by the United States Centers for Disease Control and Prevention [22]. Gonzalez and Brust [24] reported a mother and her daughter in Florida presenting with an acute febrile encephalopathy. Lyon et al. [18] reported a 12-year-old girl from Texas infected with influenza A H1N1 who suffered from acute necrotizing
encephalopathy with rapid progressive neurologic deterioration. Larcombe et al. [41] reported the clinical spectrum of 43 children with A/H1N1 pandemic virus from a single Australian hospital during the peak winter influenza season of 2009 and 7% (3/43) had an encephalopathy. Therefore, IAE should still be considered a threat to children, especially the hospitalized children, in this H1N1 pandemic.
Pathogenesis of influenza-associated acute encephalopathy/encephalitis: viral invasion of central nervous system Whether the influenza virus invades the CNS or not is still controversial. Fujimoto et al. [4] reported that influenza virus RNA was detected frequently (71.4%, five positives in seven patients) in the cerebrospinal fluid (CSF) of patients who developed IAE. However, in other reports, only a small number of patients were positive for viral RNA in CSF and brain, and there was lack of inflammation in brain tissue of fatal cases [11,22,33,51]. Okumura et al. [34] reported that the clinical symptoms, laboratory data, and outcomes were not different between influenza and noninfluenza patients with ANE, suggesting that the pathogenetic mechanism of ANE is not dependent on infectious agents. Some data from animal model and in-vitro experiments however indicated that influenza virus can enter the CNS from peripheral nerves and induce encephalopathy and neuroinflammation. Vascular endothelial cells, astrocytes, and neurons can be infected and undergo induced apoptosis by influenza virus [52–54]. With regard to the pathogenesis of IAE, viral invasion of the CNS is short of direct evidence. Viral invasion of the CNS is more likely a result not a cause of disease or may contribute to the pathogenetic process in some patients.
Pathogenesis of influenza-associated acute encephalopathy/encephalitis: cytokine storm The concentrations of proinflammatory cytokines such as interleukin (IL)-6, IL-1b, tumor necrosis factor (TNF)-a, and soluble TNF receptor were reportedly elevated in the CSF and plasma of patients with IAE [55–58]. The concentrations of other cytokines/chemokines, including CXCL8/IL-8, CCL2/MCP-1, and CXCL10/IP-10, were also highly elevated both in CSF and plasma [59]. The serum IL-6 level was correlated with worse prognosis and the time course of serum IL-6 levels also reflected the clinical condition [60,61]. Serum IL-6, IL-10, TNF-a, and CSF IL-6 are part of the regulatory system of cytokines in some acute encephalopathy cases [62]. The severity of IAE is positively correlated with the concentration of proinflammatory cytokines.
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308 Inflammatory diseases and infection
In encephalopathy due to infection with other viruses, such as human herpesvirus-6 and respiratory syncytial virus, elevated levels of proinflammatory cytokines (especially IL-6) in serum and CSF are also important for predicting neurological sequelae and have been considered to mediate the pathogenesis of acute encephalopathy [63,64]. Proinflammatory cytokines, such as IL-6 and TNF-a, can induce apoptosis and injury of vascular endothelium, glial cells, and neurons, cause vascular lesions and breakdown of the blood–brain barrier (BBB), and thereby induce brain edema and damage, CNS disorders, and/or systemic symptoms [13,37,58,65–67]. Some proteins, such as cytochrome c and e-selectin, which are associated with apoptosis and vascular endothelial injury, were increased in some cases [57,67–69]. Serum cytochrome c was related to the development of severe encephalopathy in the initial phase [69]. Cytochrome c, an apoptosis marker of several organs including the cerebrum and liver, was increased under the influence of hypercytokinemia [67]. Therefore, cytokine storm is a more likely pathogenesis of IAE.
Pathogenesis of influenza-associated acute encephalopathy/encephalitis: other factors Some patients had hepatic and/or renal dysfunction, such as increased serum creatinine and aspartate transaminase, and hematuria or proteinuria, suggesting IAE is frequently associated with metabolic disorders [28,35,70,71]. Hypoprothrombinemia, disseminated intravascular coagulation (DIC), and decreased serum CD40 ligand were also reported in some cases [28,66,72,73]. Therefore, metabolic
disorders and coagulopathy might also be involved in the pathogenesis of IAE in some cases [74]. The case of a mother and her daughter presenting with an acute encephalopathy after novel influenza A (H1N1) infection suggests a genetic susceptibility to IAE [24]. Recurrent or relapsing IAE cases have been occasionally reported [25,75]. It is not clear whether patients with certain genetic backgrounds are more susceptible to IAE. Mutations in the gene Ran-binding 2 (RANBP2) have been shown to be associated with familial or recurrent viral ANE [76]. For example, an autosomal-dominant ANE was reported to have missense mutations in RANBP2 [76]. Another recurrent ANE case following influenza A infection was also reported in a genetically predisposed family with an RANBP2 mutation [75].
Pathogenesis of influenza-associated acute encephalopathy/encephalitis: in summary In summary, as indicated in Fig. 1, some patients with certain genetic backgrounds infected by certain influenza strains have disorders in proinflammatory cytokine release and hypercytokinemia. Proinflammatory cytokines could induce vascular endothelial injury and increased BBB permeability. Proinflammatory cytokines could penetrate into the CNS through a damaged BBB, induce the immunopathogenesis and apoptosis of neurons and glia, and activate glia to release more cytokines, therefore influencing the function of the CNS. In some patients, viruses could infect the CNS through the peripheral nerve or damaged BBB, thereby inducing a CNS cytokine storm, direct damage, and promotion of apoptosis of neurons and glial cells. Cytokine storm may also contribute to apoptosis of liver cells, hepatic/renal
Figure 1 The pathogenesis of influenza-associated acute encephalopathy/encephalitis
BBB, blood–brain barrier; CNS, central nervous system; DIC, disseminated intravascular coagulation.
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dysfunction, metabolic disorders, and coagulopathy and DIC, which may induce or aggravate severity of disease.
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Because IAE is induced by influenza infection, antiviral therapy using amantadine or oseltamivir phosphate is necessary. Antiviral medicine was administered in some reports and clinical conditions of some patients were gradually improved [11,12,39,77].
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Mild hypothermia therapy and anticytokine agents may be effective for severe IAE treatment. In a report by Yokota et al. [66], four children with IAE were enrolled for hypothermia treatment for the purpose of stabilizing the cytokine storm in the CNS. The children were soon cooled down to approximately 348C for 3 days, and rewarmed to normal temperature at a rate of no greater than 1.08C per day during the next 3 days. The mild hypothermia was effective for suppressing brain edema and protecting the brain from subsequent irreversible neural cell damage and systemic expansion [66]. Subsequently, treatment with a combination of mild hypothermia, anticytokine agents (high-dose methylprednisolone and ulinastatin), and amantadine was effective for two children with severe IAE [78].
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Treatment of influenza-associated acute encephalopathy/encephalitis
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Conclusion Although IAE is uncommon compared with the high incidence of influenza infection, it is severe. It is one of the recognized complications of influenza infection in children, with high mortality and neurological sequelae. Awareness and diagnosis of encephalopathy/encephalitis in the setting of influenza is important in order to provide appropriate monitoring and treatment for this lifethreatening condition.
Acknowledgements This study was supported by the National Natural Science Foundation of China (30771988, 30972766), Guangdong Natural Science Foundation (8151503102000022, 9451503102003499), Specialized Research Fund for the Doctoral Program of Higher Education (20094402110004), 211 Project of Guangdong Province (Mechanism and Prevention of Emerging Infectious Diseases), and Shantou University Medical College Research Foundation. We thank Li Rui for critical discussion and Dr William Ba-Thein and Zhang Chi for manuscript editing.
References and recommended reading Papers of particular interest, published within the annual period of review, have been highlighted as: of special interest of outstanding interest Additional references related to this topic can also be found in the Current World Literature section in this issue (p. 338). 1
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52 Wang G, Zhang J, Li W, et al. Apoptosis and proinflammatory cytokine responses of primary mouse microglia and astrocytes induced by human H1N1 and avian H5N1 influenza viruses. Cell Mol Immunol 2008; 5:113– 120. 53 Sumikoshi M, Hashimoto K, Kawasaki Y, et al. Human influenza virus infection and apoptosis induction in human vascular endothelial cells. J Med Virol 2008; 80:1072–1078. 54 Jang H, Boltz D, Sturm-Ramirez K, et al. Highly pathogenic H5N1 influenza virus can enter the central nervous system and induce neuroinflammation and neurodegeneration. Proc Natl Acad Sci U S A 2009; 106:14063– 14068. 55 Ichiyama T, Morishima T, Isumi H, et al. Analysis of cytokine levels and NF-kappaB activation in peripheral blood mononuclear cells in influenza virus-associated encephalopathy. Cytokine 2004; 27:31–37. 56 Ichiyama T, Endo S, Kaneko M, et al. Serum cytokine concentrations of influenza-associated acute necrotizing encephalopathy. Pediatr Int 2003; 45:734–736. 57 Ichiyama T, Isumi H, Ozawa H, et al. Cerebrospinal fluid and serum levels of cytokines and soluble tumor necrosis factor receptor in influenza virusassociated encephalopathy. Scand J Infect Dis 2003; 35:59–61. 58 Kawada J, Kimura H, Ito Y, et al. Systemic cytokine responses in patients with influenza-associated encephalopathy. J Infect Dis 2003; 188:690–698. 59 Lee N, Wong CK, Chan PK, et al. Acute encephalopathy associated with influenza A infection in adults. Emerg Infect Dis 16:139–142. 60 Aiba H, Mochizuki M, Kimura M, Hojo H. Predictive value of serum interleukin6 level in influenza virus-associated encephalopathy. Neurology 2001; 57:295–299. 61 Fukumoto Y, Okumura A, Hayakawa F, et al. Serum levels of cytokines and EEG findings in children with influenza associated with mild neurological complications. Brain Dev 2007; 29:425–430. 62 Ichiyama T, Suenaga N, Kajimoto M, et al. Serum and CSF levels of cytokines in acute encephalopathy following prolonged febrile seizures. Brain Dev 2008; 30:47–52. 63 Otake Y, Yamagata T, Morimoto Y, et al. Elevated CSF IL-6 in a patient with respiratory syncytial virus encephalopathy. Brain Dev 2007; 29:117– 120. 64 Ichiyama T, Ito Y, Kubota M, et al. Serum and cerebrospinal fluid levels of cytokines in acute encephalopathy associated with human herpesvirus-6 infection. Brain Dev 2009; 31:731–738. Increased cytokines in acute encephalopathy associated with influenza and other viruses provide a clue that cytokine storm is more likely a pathogenesis of acute encephalopathy. 65 Nakai Y, Itoh M, Mizuguchi M, et al. Apoptosis and microglial activation in influenza encephalopathy. Acta Neuropathol 2003; 105:233–239. 66 Yokota S, Imagawa T, Miyamae T, et al. Hypothetical pathophysiology of acute encephalopathy and encephalitis related to influenza virus infection and hypothermia therapy. Pediatr Int 2000; 42:197–203. 67 Nunoi H, Mercado MR, Mizukami T, et al. Apoptosis under hypercytokinemia is a possible pathogenesis in influenza-associated encephalopathy. Pediatr Int 2005; 47:175–179. 68 Hosoya M, Nunoi H, Aoyama M, et al. Cytochrome c and tumor necrosis factor-alpha values in serum and cerebrospinal fluid of patients with influenzaassociated encephalopathy. Pediatr Infect Dis J 2005; 24:467–470. 69 Hosoya M, Kawasaki Y, Katayose M, et al. Prognostic predictive values of serum cytochrome c, cytokines, and other laboratory measurements in acute encephalopathy with multiple organ failure. Arch Dis Child 2006; 91:469– 472. 70 Purevsuren J, Hasegawa Y, Kobayashi H, et al. Urinary organic metabolite screening of children with influenza-associated encephalopathy for inborn errors of metabolism using GC/MS. Brain Dev 2008; 30:520–526.
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Influenza-associated acute encephalopathy Wang et al. 311 73 Ichiyama T, Morishima T, Suenaga N, et al. Analysis of serum soluble CD40 ligand in patients with influenza virus-associated encephalopathy. J Neurol Sci 2005; 239:53–57. 74 Yao D, Kuwajima M, Chen Y, et al. Impaired long-chain fatty acid metabolism in mitochondria causes brain vascular invasion by a non-neurotropic epidemic influenza A virus in the newborn/suckling period: implications for influenzaassociated encephalopathy. Mol Cell Biochem 2007; 299:85–92. 75 Gika AD, Rich P, Gupta S, et al. Recurrent acute necrotizing encephalopathy following influenza A in a genetically predisposed family. Dev Med Child Neurol 2009; 52:99–102. A recurrent acute necrotizing encephalopathy case following influenza A infection was confirmed in a genetically predisposed family with an RANBP2 mutation.
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Mechanisms of injury in bacterial meningitis Joachim Gerbera and Roland Naub,c a Department of Neurology, RWTH University Hospital, Aachen, Germany, bDepartment of Geriatrics, Evangelisches Krankenhaus Go¨ttingen-Weende and c Department of Neurology, Georg-August-University, Go¨ttingen, Germany
Correspondence to Professor Dr. med. Joachim Gerber, Department of Neurology, RWTH University Hospital, Pauwelsstr. 30, 52074 Aachen, Germany Tel: +49 241 80 89601; fax: +49 241 80 82582; e-mail:
[email protected] Current Opinion in Neurology 2010, 23:312–318
Purpose of review This review describes the pathophysiology of cellular and axonal injury in bacterial meningitis. Recent findings Toll-like receptors have been recognized as important mediators for the initiation of the immune response within the central nervous system. Activation of microglial cells by bacterial products through these receptors increases their ability to phagocytose bacteria, but can also lead to destruction of neurons. The cholesterol-binding hemolysin pneumolysin has a direct toxic effect on neuronal cells. Adjuvant therapy with corticosteroids and glycerol improved the outcome of bacterial meningitis in clinical studies. Summary Brain damage in bacterial meningitis leading to long-term neurologic sequelae and death is caused by several mechanisms. Bacterial invasion and the release of bacterial compounds promote inflammation, invasion of leukocytes and stimulation of microglia. Leukocytes, macrophages and microglia release free radicals, proteases, cytokines and excitatory amino acids, finally leading to energy failure and cell death. Vasculitis, focal ischemia and brain edema subsequent to an increase in cerebrospinal fluid outflow resistance, breakdown of the blood–brain barrier and swelling of necrotic cells cause secondary brain damage. Keywords bacterial meningitis, brain edema, inflammation, neuronal damage, Toll-like-receptor Curr Opin Neurol 23:312–318 ß 2010 Wolters Kluwer Health | Lippincott Williams & Wilkins 1350-7540
Introduction Acute bacterial meningitis is a life-threatening infection requiring fast diagnosis and treatment. Even after good recovery from bacterial meningitis, neuropsychological testing revealed cognitive impairment in approximately one third of survivors [1,2]. This review is focused on pathophysiology and mechanisms involved in neuronal injury in bacterial meningitis.
Nasopharyngeal colonization, bacteremia and entering of the subarachnoid space Colonization of the mucosal membranes is an important ability of most pathogens causing community-acquired meningitis. Bacteria have several virulence factors that enable them to colonize and invade the mucosa, Streptococcus pneumoniae, for example, binds to polymeric immunoglobulin receptors of epithelial cells. The pneumococcal adherence and virulence factor A (PavA) mediates the binding to endothelial cells and modulates adherence and other factors of virulence in S. pneumoniae [3,4]. Furthermore, pneumococci are able to counteract defense mechanisms of the host. The polysaccharide 1350-7540 ß 2010 Wolters Kluwer Health | Lippincott Williams & Wilkins
capsule promotes colonization and impedes phagocytosis and the activation of the complement system, which is important to prevent bacteremia and sepsis after pneumococcal mucosal colonization [5]. Bacterial proteases are able to cleave IgA antibodies. Meningococci colonize the nasopharynx by binding to mucosal CD46 and CD66 proteins [6]. After colonization, bacteremia allows the microbes to reach the blood–brain barrier and enter the central nervous system (CNS). A high amount of bacteria circulating in the blood is thought to be necessary for the invasion of the CNS and is therefore a risk factor for developing meningitis. Usually, the blood–brain and blood–cerebrospinal fluid (CSF) barriers protect the brain and meningeal space against microbial pathogens. Some bacteria, however, have developed mechanisms to overcome this barrier. During the last years, a variety of factors have been identified contributing to the ability of the bacteria to cross the blood–brain barrier. The exact mechanism of entering the CSF, however, is as yet unclear for most organisms. DOI:10.1097/WCO.0b013e32833950dd
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Mechanisms of injury in bacterial meningitis Gerber and Nau 313
The brain endothelium is considered one important site of bacterial invasion. Laminin receptors located on brain microvascular cells have been shown to mediate adhesion of pneumocci, meningococci and Haemophilus influenzae [7]. The neuraminidase NanA of S. pneumoniae mediates adherence and invasion of human brain microvascular endothelial cells [8]. Whereas in-vitro studies suggest that transcytosis is a common way for H. influenzae, pneumococci and Escherichia coli to cross the endothelium, a paracellular way for meningococci to enter the CNS has been suggested [9]. Another factor important for Streptococcus group B bacteria to cross the microvascular endothelium is the surface-anchored serine-rich protein Srr-1 [10]. As the barrier between blood and CSF consists of the choroid plexus epithelium and the endothelium of meningeal capillaries (and not the microvascular endothelium of the brain), microbes able to reach the CSF and cause meningitis may have other strategies not elucidated, yet enabling them to cross specifically the meningeal capillaries. Evidence for bacterial invasion through the epithelium of the choroid plexus comes from experiments with Streptococcus suis [11,12]. Alternatively, local infections in the vicinity of the CNS may allow the bacteria to directly enter the CNS through the foraminae at the base of the skull or through bone defects caused by trauma or infection (e.g. cholesteatoma, mastoiditis). Within the subarachoid space, bacteria grow and release proinflammatory compounds by autolysis and secretion causing inflammation and invasion of immune cells.
Bacterial compounds as a cause of inflammation and cellular injury Bacterial compounds released after spontaneous autolysis or after initiation of antibiotic treatment increase inflammation, promote leukocyte migration into the CNS and stimulate the production of proinflammatory cytokines. Besides proinflammatory effects, some bacterial products (e.g. pneumolysin) can induce cellular death directly. Lipopolysaccharide (LPS) is known as one of the strongest inducers of inflammation and is used in experimental models of septic shock and meningitis. Teichoic and lipoteichoic acids (LTAs) composed of repetitive oligosaccharide units conjugated to phosphorylcholine are considered the most potent proinflammatory constituents of the membrane and the cell wall of S. pneumoniae, thereby promoting inflammation, leukocyte invasion and stimulation of microglia. Heat-inactivated pneumococci have been used to investigate the action of bacterial
compounds on the host. In vitro, they injure neurons cocultured with glial cells [13] and induce cellular damage in organotypic hippocampal cultures [14]. A recent study using a membrane-based slice culture system of organotypic hippocampal cultures, however, showed no direct capacity of soluble factors released from pneumococci to induce apoptotic cell death, suggesting contribution of other or additional pathways in the pathogenesis of cell death [15]. Pneumolysin is a 53 kDa cytoplasmatic hemolysin common to nearly all S. pneumoniae isolates and capable of forming transmembrane pores [16]. Pneumolysin is toxic to microvascular endothelial cells [17] and induces neuronal cell death by promoting the influx of extracellular calcium and induction of mitochondrial damage [18–20]. In astrocytes, fibroblasts and neuroblastoma cells, pneumolysin caused microtubule bundling and decreased organelle motility [21]. Pneumolysin is released by autolysis and a nonautolytic mechanism and has been shown to be localized also to the cell wall of intact pneumococci [22]. Bacterial DNA stimulates inflammation and activates genes functionally associated with the immune response and cell division [23].
Response against the microbes: the immune response and inflammatory mechanisms The defense of the host against bacterial invasion needs recognition of the microbes and activation of the immune system. Toll-like receptors (TLRs) recognize bacterial factors; activation of microglial cells and invasion of leukocytes promote inflammation by the release of free radicals and metalloproteinases (MMPs). Toll-like receptors
TLRs are central regulators of the innate immune response responding to conserved molecular patterns shared by bacteria, fungi and viruses [24], and their gene expression is upregulated in CNS infections [25]. Activation of TLRs induces the translocation of nuclear factor kappa B (NF-kB), the activation of mitogen-activated protein kinases and the transcription of genes encoding inflammatory cytokines. TLR2 interacts with lipoteichoic acids and other compounds [26]. TLR4 is activated by LPS and recognizes also pneumolysin [27]. TLR9 interacts with bacterial DNA, which – in contrast to mammalian DNA – is characterized by a high frequency of unmethylated cytosine–guanine (CpG) motifs that exert strong immunostimulatory properties. Bacterial CpG motifs of Gram-positive and Gram-negative organisms have been shown to cause septic shock [28] and cerebral inflammation [29].
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314 Inflammatory diseases and infection
Stimulation of TLRs leads not only to activation of the central signaling molecule MyD88 but also to MyD88independent processes [26,30]. The intracellular signal transducer MyD88 in TLR signaling is essential for generating an effective immune response in bacterial meningitis [31]. TLR2 is involved in the pathogenesis of pneumococcal meningitis and mediates the host responses to cell wall components of Gram-positive bacteria. TLR2-deficient mice show reduced bacterial clearing and enhanced inflammation and are more susceptible to infection with S. pneumoniae [32,33]. TLR2 deficiency is associated with enhanced tumor necrosis factor (TNF)-alpha expression [34], and treatment with an inhibitor of TNF-alpha converting enzyme (TACE) improved survival in a mouse model of pneumococcal meningitis [35]. TLR2 is also stimulated by lipoproteins in Stapyhlococcus aureus infection [36]. Recent experiments in TLR-deficient mice have shown that not only TLR2 but also TLR4 participates in the immune response of the host after S. pneumoniae infection [37]. Although TLR2 signaling mediates the immune response and inflammation in pneumococcal infection, it does not directly induce hippocampal apoptosis [38]. TLRs are essential for the host to create an effective immune response and to prevent bacterial growth. Adjuvant therapies with drugs selectively interfering with the TLR cascade (in a way to control excessive inflammation without reducing the ability of the host to phagocytose and kill) might be a promising therapy in future. Microglia
Microglial cells express a wide range of TLRs together with meningeal and paravascular macrophages and, therefore, they trigger the first events of the immune response in the CNS. Microglial cells are important for initiating the immune response and probably also for the protection of the brain and spinal cord against bacterial invasion, but they contribute also to neuronal injury. Treatment of microglia with TLR agonists of 1/2, 4 and 9 activated microglia and increased phagocytosis of bacteria [39,40]. On the contrary, stimulation of microglia via TLR9 and subsequent release of nitric oxide and TNF-alpha caused neuronal injury in cocultures with neurons [41]. Invasion of leukocytes
In bacterial meningitis, meningeal macrophages, ependymal cells, choroid plexus epithelial cells and stimulated microglia produce soluble factors that stimulate bloodderived leukocytes to enter the subarachnoid space. Circulating leukocytes are important for the host defense against bacteria, even when they have already entered
the CNS. In a murine model of S. pneumoniae meningitis, granulocyte-depleted mice died earlier than immunocompetent animals [42]. On the contrary, after migration into the CNS, leukocytes release a variety of factors [e.g. reactive oxygen species (ROS)] that contribute to vasospasm and vasculitis and are capable of damaging brain tissue. Free radicals
ROS and reactive nitrogen intermediates (e.g. nitric oxide) produced by phagocytes are important for the host defense against bacteria. Although free radicals usually are a component of the immune reaction and defense, toxic effects of these substances also cause cellular injury and death in neurons and other cells and may, therefore, promote complications and long-term deficits. Free radicals are released by granulocytes, microglia and endothelial cells, but also by the bacteria. Oxygen and nitrogen radicals promote formation of the relatively stable peroxynitrite, which has been considered a central mediator of cellular damage. These molecules mediate cell death by membrane peroxidation, breakdown of protein structure, DNA damage and subsequent activation of poly(ADP)-ribose polymerase (PARP) leading to energy depletion and cell death [43]. Nitric oxide produced by the inducible nitric oxide synthase (iNOS) mediates hippocampal caspase-3 activation and cell death [44]. Metalloproteinases
MMPs are endopeptidases that target extracellular matrix proteins as well as a number of other proteins. MMPs are released both from brain-resident cells and invading leukocytes, and they have been suggested to contribute to inflammation, blood–brain barrier dysfunction and cellular damage [45,46]. Lipoteichoic acids induce the expression of MMP-9 in rat brain astrocytes [47].
Morphology of neuronal cell death In the hippocampal formation, both in experimental studies and in human autopsy cases, neuronal cell death in bacterial meningitis occurs mostly as apoptosis in the dentate gyrus of the hippocampal formation and as necrosis in the neocortex and the CA1–4 region of the hippocampus. In other regions of the brain, neurons die with necrotic morphology [48–50]. The mode of cell death in the hippocampal formation depends on the strength of the noxious stimulus and may also be a hybrid form of apoptosis and necrosis. In a rat model of bacterial meningitis, S. pneumoniae caused predominantly classical apoptotic cell death in the hippocampal dentate gyrus, whereas infection with group B streptococci was associated with a caspase-3-independent cell death characterized by clusters of uniformly
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Mechanisms of injury in bacterial meningitis Gerber and Nau 315 Figure 1 Neuronal injury in bacterial meningitis
Therapeutic options Rapid and effective antibiotic therapy is mandatory in patients suffering from bacterial meningitis. Several drugs have been investigated in experimental models. Clinical studies using dexamethasone and glycerol as adjunctive therapy have been performed showing beneficial effects in bacterial meningitis. Clinical studies
As corticosteroids have a great potency to limit inflammation, their use in bacterial meningitis has been proposed early. The European study of de Gans and van de Beek [55] has shown that early treatment with dexamethasone improves the outcome in adults with community-acquired bacterial meningitis in developed countries. A recently published meta-analysis investigating data from five clinical trials, however, did not find a significant benefit of adjunctive dexamethasone therapy in bacterial meningitis [56]. Similarly, in childhood bacterial meningitis the effect of adjuvant dexamethasone is inconsistent. With the exception of H. influenzae meningitis [57], which has been almost eradicated by vaccination in many countries, there is no clear evidence for a beneficial effect of adjuvant dexamethasone therapy. In a double-blind placebo-controlled trial, oral glycerol therapy reduced neurologic sequelae in childhood bacterial meningitis [58]. Glycerol causes an increase in serum osmolality, lowers increased intracranial pressure and, thereby, enhances, probably, cerebral blood flow and oxygenation [59]. Studies in experimental models
(a) Necrotic cell death in the hippocampus and the dentate gyrus in a mouse model of pneumococcal meningitis (arrows). (b) Apoptotic neuronal cell death in the dentate gyrus of the hippocampal formation in a rabbit 24 h after infection with Streptococcus pneumoniae. DNA fragmentation is visualized by in-situ tailing. (c) Focal ischemia in the white matter (arrows) of a patient with bacterial meningitis, probably caused by vasculitis (MRI). (a and c) Reproduced with permission from [54].
shrunken cells in this region [51]. Another important feature of brain damage in bacterial meningitis is white matter injury as a consequence of small-vessel vasculitis and focal ischemia or venous thrombosis [52,53]. Brain swelling as a consequence of edema or necrosis of large areas subsequent to vasculitis and obstruction of main arteries can cause brain death particularly during the acute phase of the disease [50,54] (Fig. 1).
Various other therapies have been investigated in experimental models. Treatment with nonbacteriolytic antibiotics reduces the release of proinflammatory and toxic compounds, mortality and neuronal damage [60]. Even short pretreatment with the nonbacteriolytic rifampicin shortly followed by ceftriaxone 1 h later shows this beneficial effect [61]. Similarly, the nonbacteriolytic antibiotic daptomycin reduced CSF inflammation and brain damage [62]. Antibodies against the CD18 epitope inhibiting the invasion of leukocytes into the subarachnoid space reduce neuronal damage. Furthermore, inhibitors of MMPs and TNF-alpha-converting enzyme have been shown to decrease neocortical and hippocampal damage [48,63]. Therapeutic attempts with antioxidants have shown neuroprotective effects, but results were inconsistent, in part probably as a consequence of toxic effects of the antioxidant itself or because of a limited efficacy of the drugs used to impede neuronal cell death [64–67]. In a rat
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316 Inflammatory diseases and infection Figure 2 Pathophysiological events in bacterial meningitis
Bacteria Colonization
Penetration of mucosal membranes Bacteremia
Focal infection close to CNS
Invasion of CNS and multiplication in the subarachnoid space
Release of proinflammatory and/or toxic compounds and stimulation of the innate immune system
Glial stimulation and/or toxicity
Neuronal injury
Leukocyte invasion
Vasculitis
Increased barrier permeability
Increased CSF outflow resistance
Ischemia
Cytotoxic edema
Interstitial edema
Vasogenic edema
Summary of pathophysiological events leading to brain damage in bacterial meningitis. Bacterial invasion causes inflammation and the activation of the immune defense. Release of bacterial compounds promotes invasion of leukocytes and stimulation of microglia (by TLRs). Some microbial compounds (e.g. pneumolysin) have a direct toxic effect on cells. Leukocytes, macrophages and microglia – both essential for the fight against bacteria but also detrimental for the surrounding cells by doing so – release free radicals, proteases, cytokines (e.g. tumor necrosis factor-alpha) and excitatory amino acids, finally leading to energy failure and cell death executed by caspases. Arterial vasculitis and cerebral venous thrombosis lead to secondary ischemia and cytotoxic and vasogenic brain edema. The increase in intracranial pressure is caused partially by vasogenic and cytotoxic edema. Probably the main cause is interstitial edema and hydrocephalus subsequent to the increase in the cerebrospinal fluid (CSF) outflow resistance. Subdural empyema is a rare complication of meningitis in adults able to cause secondary injury.
model of pneumococcal meningitis, N-acetylcysteine attenuated acute and long-term hearing loss [68]. In summary, antioxidative treatment strategies remain promising with respect to modulation of the inflammatory host reaction and decrease in cell death. Other modulators of inflammation may also be useful to reduce cellular damage: the endogenous TNF-related apoptosis-inducing ligand (TRAIL) reduced inflammation and cellular damage in experimental meningitis [69]. A modifying effect on inflammation has been proposed for statins. In experimental pneumococcal meningitis, simvastatin reduced CSF leukocyte counts, whereas intracranial pressure and blood–brain barrier breakdown was not altered [70].
As TLRs are key mediator of immunity and inflammation, a novel approach is the treatment with drugs interfering with the TLR system. Intrathecal administration of the TLR2 agonist Pam(3)Cys induced CSF inflammation. Adjuvant treatment in addition to S. pneumoniae infection did not change the rate of apoptotic cell death [38]. Further experiments with TLR antagonists and agonists may be promising ways to develop better treatment strategies. Interestingly, not only cellular destruction but also proliferation of neuronal progenitor cells has been observed after bacterial meningitis [71], suggesting an endogenous potential of cell renewal in the hippocampal formation in this disease. Whether stimulation of
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Mechanisms of injury in bacterial meningitis Gerber and Nau 317
endogenous neurogenesis can be used as a therapeutic option in survivors of meningitis remains an open question.
Conclusion Neuronal damage in bacterial meningitis is caused by several mechanisms (Fig. 2), which have been identified by experimental studies during the last years. Clinically, the use of corticosteroids and glycerol has been investigated so far. Killing of the bacteria without releasing large quantities of proinflammatory products and modulation of the inflammatory cascade may further improve the outcome of this life-threatening disease.
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59 Singhi S, Ja¨rvinen A, Peltola H. Increase in serum osmolality is possible mechanism for the beneficial effects of glycerol in childhood bacterial meningitis. Pediatr Infect Dis J 2008; 27:892–896. This prospective, randomized, double-blind study suggests that the beneficial effect of glycerol in childhood meningitis is caused by an increase of serum osmolality. 60 Nau R, Wellmer A, Soto A, et al. Rifampicin reduces early mortality in experimental Streptococcus pneumoniae meningitis. J Infect Dis 1999; 179:1557–1560. 61 Spreer A, Lugert R, Stoltefaut V, et al. Short-term rifampicin pretreatment reduces inflammation and neuronal cell death in a rabbit model of bacterial meningitis. Crit Care Med 2009; 37:2253–2258. 62 Grandgirard D, Oberson K, Bu¨hlmann A, et al. Attenuation of cerebrospinal fluid inflammation by the nonbacteriolytic antibiotic daptomycin vs ceftriaxone in experimental pneumococcal meningitis. Antimicrob Agents Chemother 2010; 54:1323–1326. This study shows less inflammation and brain damage in an infant rat model of meningitis after treatment with the nonbacteriolytic antibiotic daptomycin in comparison to ceftriaxone standard therapy. 63 Meli DN, Loeffler JM, Baumann P, et al. In pneumococcal meningitis a novel water-soluble inhibitor of matrix metalloproteinases and TNF-alpha converting enzyme attenuates seizures and injury of the cerebral cortex. J Neuroimmunol 2004; 151:6–11. 64 Auer M, Pfister LA, Leppert D, et al. Effects of clinically used antioxidants in experimental pneumococcal meningitis. J Infect Dis 2000; 182:347–350. 65 Loeffler JM, Ringer R, Hablutzel M, et al. The free radical scavenger alphaphenyl-tert-butyl nitrone aggravates hippocampal apoptosis and learning deficits in experimental pneumococcal meningitis. J Infect Dis 2001; 183:247–252. 66 Gerber J, Lotz M, Ebert S, et al. Melatonin is neuroprotective in experimental Streptococcus pneumoniae meningitis. J Infect Dis 2005; 191:783–790.
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The implications of vaccines for prevention of bacterial meningitis Andrew Riordan Department of Paediatric Infectious Diseases and Immunology, Alder Hey Children’s NHS Foundation Trust, Liverpool, UK Correspondence to Andrew Riordan, Consultant in Paediatric Infectious Diseases and Immunology, Alder Hey Children’s NHS Foundation Trust, Eaton Road, Liverpool L12 2AP, UK Fax: +44 151 252 5929; e-mail:
[email protected] Current Opinion in Neurology 2010, 23:319–324
Purpose of review Conjugate vaccines now exist that can protect against some types of bacterial meningitis (Haemophilus influenzae type b, Neisseria meningitidis group C and seven serotypes of Streptococcus pneumoniae). To broaden the protection against meningitis, new vaccines are needed. This article reviews new uses of the established vaccines and the new meningitis vaccines in development. Recent findings A conjugate group A meningococcal vaccine to prevent epidemics of meningitis in Africa is about to be used widely in the ‘meningitis belt’. A ‘quadrivalent’ conjugate vaccine against meningococcal serogroups A C Y and W135 is in use in the United States. A ‘tailor-made’ group B meningococcal vaccine was successfully used to control an epidemic of meningococcal disease in New Zealand. Other group B meningococcal vaccines are in development. Despite routine vaccination against pneumococcus in the United States, this organism is still the commonest cause of meningitis. Pneumococcal vaccines need to include more serotypes to offer broader protection. Summary Great progress has been made in developing vaccines that prevent meningitis. The remaining challenges are to introduce vaccines with broad protection against meningococci and pneumococcus, develop an effective vaccine against group B meningococcus and to get these highly effective vaccines to those areas of the world that most need them. Keywords bacterial meningitis, conjugate vaccines, Haemophilus influenzae type b, Neisseria meningitidis, Streptococcus pneumoniae Curr Opin Neurol 23:319–324 ß 2010 Wolters Kluwer Health | Lippincott Williams & Wilkins 1350-7540
Introduction Bacterial meningitis is an important cause of morbidity and mortality, especially in children [1]. Children less than 2 years of age have immature immunological responses to the polysaccharide capsule of some bacteria. Children are, thus, particularly susceptible to meningitis caused by the encapsulated bacteria Haemophilus influenzae type b (Hib), Streptococcus pneumoniae and Neisseria meningitidis. Effective vaccines against these organisms could prevent many cases of meningitis. Conjugate vaccines, which combine both protein and polysaccharide antigens, can provide immunological protection for young children. However, protection may be short-lived in infants, who need booster doses at 12 months of age [2]. Conjugate vaccines exist that offer protection against disease caused by Hib and selected serogroups/serotypes of N. meningitidis and 1350-7540 ß 2010 Wolters Kluwer Health | Lippincott Williams & Wilkins
S. pneumoniae. These vaccines are not only able to prevent serious disease, but they also provide protection against asymptomatic carriage. The resulting herd immunity effects have been striking and have played an important role in the public health success of conjugate vaccination programmes [3]. The introduction of Hib, meningococcal C and sevenvalent pneumococcal conjugate vaccines has been successful in reducing meningitis in resource-rich countries [4]. These vaccines now need to become available to children in resource-limited countries. New conjugate vaccines that give broader protection against pneumococcus and meningococcus (groups A, Y and W135) have been developed and are currently in clinical trials. Attempts to produce an effective vaccine against group B meningococcus have proved more difficult. Vaccines for specific strains of group B DOI:10.1097/WCO.0b013e3283381751
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320 Inflammatory diseases and infection
meningococcus causing outbreaks have recently been developed and successfully used. Other group B vaccines based on meningococcal outer membrane proteins (OMPs) are in development. This article will review new uses of the established vaccines (e.g. Hib) and the new vaccines in development. Combining these vaccines may affect their immunogenicity, so studies of vaccine combinations will also be reviewed.
Group A meningococcal vaccines
Serogroup A meningococcus causes epidemics of meningitis, especially in the ‘meningitis belt’ of sub-Saharan Africa. A polysaccharide group A meningococcal vaccine has been available for many years. Although this vaccine is strongly protective against serogroup A meningococcal meningitis in people over 5 years of age, the protection is short-lived and the level of efficacy in young children is unknown [12]. This vaccine is used for emergency vaccination of the population during outbreaks of group A meningococcal disease in sub-Saharan Africa, but cannot provide long-term protection [13].
Haemophilus influenzae type b Hib is an important cause of meningitis in children less than 5 years of age. Overall fatality for Hib meningitis is 5%, with up to 11% of survivors having neurological sequelae. A conjugate vaccine against Hib has been shown to be well tolerated and effective against Hib disease at all ages [5]. Most usage of Hib vaccine is in resource-rich countries, such as the United States of America and Europe. In the United States, Hib is now a rare cause of bacterial meningitis in children [4]. The majority of Hib meningitis occurs in the resource-poor countries that are least able to purchase conjugate vaccines and implement routine immunization. The Global Alliance for Vaccines and Immunization (GAVI) has been developed to build consensus around vaccine policies, strategies and priorities in developing countries. GAVI aims to provide financial resources to purchase vaccines and to support the operational costs of immunization. Hib vaccine has, thus, been able to be used in some resource-poor settings. This has led to a decrease in Hib meningitis in Uganda [6], Tonga [7] and the Dominican Republic [8]. A decrease in Hib meningitis has also been reported in India, despite low vaccine coverage from mainly private providers [9]. Despite the excellent immunogenicity of Hib conjugate vaccines, Hib disease still affects a small proportion of vaccinated children; these children have inadequate production of high-quality antibody [10,11].
Neisseria meningitidis Meningococcal disease is an important public health concern worldwide, especially in sub-Saharan Africa, where it occurs as regular epidemics. Five of the 13 serogroups of N. meningitidis cause most invasive disease: A, B, C, Y and W135. Serogroup A is responsible for epidemic disease in sub-Saharan Africa and other developing countries. Serogroups B and C cause most of the infection in developed countries, particularly Europe, whereas serogroups Y and W135 are more prominent in North America.
A conjugate group A meningococcal vaccine would have the advantages of protecting young children, giving longterm protection, decreasing carriage of group A meningococcus and providing herd immunity. Such a vaccine could be given with routine childhood immunizations together with mass vaccination of 1–29-year-olds to induce herd immunity, avoiding the need for mass vaccination during outbreaks. Widespread use of such a vaccine is likely to generate herd immunity and to put an end to Group A meningococcal epidemics. A partnership between PATH and the World Health Organization hopes to eliminate meningococcal epidemics in Africa through the development, licensure, introduction and widespread use of conjugate meningococcal vaccines [14]. A meningococcal A conjugate vaccine has been developed [15], and a phase 1 study showed the vaccine was well tolerated, immunogenic and able to elicit persistent functional antibody titres in adults [16]. Those given the conjugate vaccine were more likely to develop protective antibody, have higher antibody levels and more likely to have protective antibody present at 1 year compared with those given the polysaccharide vaccine. Phase II clinical trials are underway in children in Africa [17]. For routine infant immunization against group A meningococcus, it would be logistically easier to combine this new vaccine with the routine vaccines given to African infants [diphtheria, tetanus, pertussis, hepatitis B and Hib (DTPw-HBV/Hib)]. However, combining vaccines may affect the efficacy of one or more components. A meningococcal AC conjugate vaccine has been combined with DTPw-HBV/Hib vaccine. Infants given three doses of this vaccine had similar protection and similar adverse events to those given DTPw-HBV/Hib vaccine alone [18]. The vaccine also induced bactericidal antibodies against meningococcal serogroups A and C in the majority of infants and produced immune memory [19]. However, antibody titres fell below the protective level in nearly half of the infants by the age of 12 months, suggesting that a booster dose is required at that age [20].
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Vaccines for prevention of bacterial meningitis Riordan 321
Group A C Y W135 meningococcal vaccines
The meningococcal serogroups Y and W135 cause a significant proportion of cases of meningococcal disease in North America, in contrast to Europe where most disease is due to group B. A ‘quadrivalent’ polysaccharide vaccine has been available for some time to protect against four meningococcal serogroups: A C Y and W135. However, like most polysaccharide vaccines, protection was short-lived and the vaccine was poorly immunogenic in young children. Serogroup C conjugate vaccines have become established in the immunization programmes in many countries and the first quadrivalent meningococcal vaccine, containing the polysaccharides from the serogroups A, C, Y and W135 meningococci conjugated to a protein carrier, was licensed in the United States in 2005. This vaccine is recommended for all adolescents in the United States. However, this licensed quadrivalent conjugate vaccine is poorly immunogenic in infancy, the age group most likely to get meningococcal disease [21]. Another quadrivalent conjugate meningococcal vaccine uses the diphtheria mutant CRM197 to conjugate to the polysaccharides. This vaccine is immunogenic in infants [22,23] as well as in adolescents [24] and adults [25]. This new vaccine induced higher antibody titres than the quadrivalent polysaccharide vaccine and the licensed quadrivalent conjugate vaccine [24,26,27]. Other quadrivalent meningococcal vaccines conjugated to tetanus toxoid are also more immunogenic than the polysaccharide vaccine in preschool children and adolescents [28,29]. These vaccines and others in development offer the potential to broaden population protection against meningococcal disease and decrease cases of meningitis, especially in North America.
meningococcal OMPs or outer membrane vesicles. The ideal vaccine target should be immunogenic and provide protection against a broad range of group B meningococci. Few OMPs or vesicle vaccines are able to do this. Meningococcal vesicle vaccines
Meningococci naturally produce ‘blebs’. These are small outpouchings of the outer membrane, which are released as vesicles. These outer membrane vesicles contain a number of OMPs, such as the Por A proteins, as well as endotoxin. Once the endotoxin is removed, the vesicles can be used as the basis for a vaccine. The most significant limitation for widespread use of vesicle vaccines is that the immune response is strain-specific in infants, mostly directed against the Por A protein present in the vesicle [30]. Vesicle vaccines have been successfully used to control outbreaks of group B meningococcal disease. For example, a meningococcal group B P1.7-2,4 epidemic occurred in New Zealand between 1991 and 2007. A vesicle vaccine was ‘tailor-made’ for this outbreak, by a public/private partnership between the New Zealand Ministry of Health and Chiron Vaccines [31]. The vaccine was given to people less than 20 years of age from July 2004 [32]. Previous vesicle vaccines had been poorly immunogenic in children less than 5 years of age, so this age group was carefully studied. Three doses of vaccine given to children between 16 months and 12 years of age were well tolerated and elicited a good immune response against the epidemic strain [33,34]. However, in infants, four doses were required to give antibody titres comparable to those achieved after three doses in older children [35]. Protection was strain-specific as few children given a different vesicle vaccine strain (B:15:P1.7,16) got protective antibody levels against the New Zealand strain [34].
Group B meningococcal vaccines
An effective group B meningococcal vaccine could prevent many cases of meningitis as the majority of meningococcal disease in Europe is caused by serogroup B. However, developing a group B vaccine has been very difficult as the polysaccharide capsule is not immunogenic. The serogroup B capsular polysaccharide is poorly immunogenic in humans because it is similar to carbohydrates found in foetal brain tissue. Attempts to make the group B capsular polysaccharide immunogenic by conjugation might, therefore, lead to potentially harmful autoantibodies. An effective meningococcal group B vaccine for widespread use is, therefore, still not available. Vaccine targets other than capsular polysaccharide need to be identified for group B meningococci. Strategies to develop group B meningococcal vaccines have used
Overall vaccine effectiveness was estimated to be 73% with an estimated 54 epidemic strain meningococcal cases prevented in the first 2 years of the vaccination programme [36]. A cohort analysis of New Zealand children aged 6 months to 5 years gave an estimated vaccine effectiveness of 80% [37]. These results encourage the use of ‘tailor-made’ vesicle vaccines for the control of group B meningococcal epidemics in the future. Moreover, they support the development of vesicle vaccines with additional crossprotective antigens. For example, a meningococcal vesicle vaccine has been developed to cover the circulating strains in Europe (B:4:P1.19,15 and B:4:P1.7-2,4). In adolescents, this vaccine induced an immune response against related strains (51% of individuals against strains of P1.19,15 and 66% against strains of P1.7-2,4) and
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322 Inflammatory diseases and infection
against a set of three heterologous strains (in 28–46% of individuals) [38].
and this would protect against 70% of the serotypes causing meningitis in African children [47].
An alternative vesicle vaccine has been made from the commensal bacterium Neisseria lactamica. Natural immunity to meningococcal disease in young children is associated with carriage of N. lactamica, so it was hoped that this vaccine may provide cross-protection against meningococcus. In adults, the vaccine seemed well tolerated, but only induced modest cross-reactive immunity to six strains of serogroup B N. meningitidis [39]. Further studies are awaited.
Coverage against more pneumococcal serotypes is, therefore, needed for Africa as well as North America and Europe.
Meningococcal outer membrane protein vaccines
The genome of N. meningitidis has been sequenced, allowing a new approach to vaccine development: reverse vaccinology [40,41]. This computer-based method searches the meningococcal genome for novel, surfaceexposed proteins that might be vaccine targets. On the basis of these findings, vaccines containing serogroup B recombinant protein are being developed [42]. These include Neisserial surface protein A (NspA), the adhesin NadA and the factor H-binding protein (fHbp) [43,44]. Incorporating these proteins into vesicle vaccines may improve their immunogenicity and increase the number of strains covered [45]. The results of clinical trials of these vaccines are eagerly awaited.
Streptococcus pneumoniae vaccines S. pneumoniae can cause a broad range of infections, but between 100 000 and 500 000 children less than 5 years of age die annually from pneumococcal meningitis. Pneumococcus presents a more complex problem to control by immunization as it has 91 serotypes. However, seven serotypes are responsible for up to 90% of invasive pneumococcal disease in North America (4, 6B, 9V, 14, 18C, 19F and 23F). A conjugate pneumococcal vaccine containing these seven serotypes was approved for use in American children of less than 2 years of age in February 2000 and has subsequently been introduced to many European countries. This vaccine has an efficacy against invasive pneumococcal disease caused by vaccine serotypes of 80%, 58% against all serotypes and 11% for all-cause mortality [46]. Despite widespread use of the seven-valent pneumococcal conjugate vaccine in the United States, pneumococcal meningitis is still the commonest bacterial meningitis in children, mostly due to nonvaccine serotypes [4]. S. pneumoniae is a common cause of meningitis in African children with a high case fatality (19%). In Uganda, only 43% of pneumococci causing meningitis were serotypes that are in the currently available seven-valent pneumococcal conjugate vaccine. A conjugate pneumococcal vaccine containing 13 serotypes has been developed
Combination ‘meningitis vaccines’ Recent developments have meant that a combined ‘meningitis vaccine’ protecting against all three bacterial causes might be possible. However, combining conjugate vaccines sometimes affects their immunogenicity. A combined pneumococcal, meningococcal and Hib conjugate vaccine gave lower antibody levels against Hib than if the vaccines were given separately [48]. Further studies of combination vaccines are needed.
Conclusion Great progress has been made in developing vaccines that prevent meningitis (Hib, meningococcal C, seven serotypes of penumococcus). The remaining challenges are to introduce vaccines with broad protection against meningococci and pneumococcus, develop an effective vaccine against meningococcus B and to get these highly effective vaccines to those areas of the world that most need them.
Acknowledgements Dr A.R. has received research funding and sponsorship to attend scientific meetings from Wyeth and GSK Vaccines.
References and recommended reading Papers of particular interest, published within the annual period of review, have been highlighted as: of special interest of outstanding interest Additional references related to this topic can also be found in the Current World Literature section in this issue (pp. 338–339). 1
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Nigrovic LE, Kuppermann N, Malley R, Bacterial Meningitis Study Group of the Pediatric Emergency Medicine Collaborative Research Committee of the American Academy of Pediatrics. Children with bacterial meningitis presenting to the emergency department during the pneumococcal conjugate vaccine era. Acad Emerg Med 2008; 15:522–528. This study describes the epidemiology of children presenting with bacterial meningitis in the United States, during the era of widespread Hib and pneumococcal vaccination. Causes of meningitis included S. pneumoniae (33.3% – of which 62% were due to nonvaccine serotypes), N. meningitidis (29.0%) and group B Streptococcus (18.2%). This study shows that despite the introduction of a seven-valent pneumococcal conjugate vaccine, S. pneumoniae remains the most common cause of bacterial meningitis in children in the United States, with approximately half of cases due to nonvaccine serotypes. The introduction of pneumococcal conjugate vaccines with an increased number of serotypes and broad meningococcal vaccines are needed to prevent more cases of meningitis.
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Vaccines for prevention of bacterial meningitis Riordan 323 5
Prasad K, Karlupia N. Prevention of bacterial meningitis: an overview of Cochrane systematic reviews. Respir Med 2007; 101:2037–2043.
Iriso R, Ocakacon R, Acayo JA, et al. Bacterial meningitis following introduction of Hib conjugate vaccine in northern Uganda. Ann Trop Paediatr 2008; 28:211–216. This hospital-based study found a decline in the prevalence of H. influenza meningitis after the introduction of routine Hib vaccination in Uganda. This study shows that Hib conjugate vaccine delivered through a national immunization programme is effective in reducing Hib meningitis in African children.
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Russell FM, Fakakovi T, Paasi S, et al. Reduction of meningitis and impact on under-5 pneumonia after introducing the Hib vaccine in the Kingdom of Tonga. Ann Trop Paediatr 2009; 29:111–117.
Lee EH, Corcino M, Moore A, et al. Impact of Haemophilus influenzae type b conjugate vaccine on bacterial meningitis in the Dominican Republic. Rev Panam Salud Publica 2008; 24:161–168. This hospital-based study of confirmed and probable meningitis in children less than 5 years of age found a substantially reduced incidence of both confirmed and probable bacterial meningitis, after the introduction of routine Hib vaccination in the Dominican Republic. This study shows that the impact of Hib vaccine on meningitis maybe even greater when culture negative cases are included.
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9 Verghese VP, Friberg IK, Cherian T, et al. Community effect of Haemophilus influenzae type b vaccination in India. Pediatr Infect Dis J 2009; 28:738–740. This Indian hospital-based study found a decrease in Hib meningitis cases after the introduction of Hib conjugate vaccine in the private healthcare sector, despite relatively low vaccine coverage. This study suggests that even low vaccine coverage can have a significant impact on Hib disease. 10 Lee YC, Kelly DF, Yu LM, et al. Haemophilus influenzae type b vaccine failure in children is associated with inadequate production of high-quality antibody. Clin Infect Dis 2008; 46:186–192. This study found decreased functional activity of antibody to Hib in children experiencing vaccine failure, leading to susceptibility to Hib disease. These children appear to have a defect in immunological priming, which requires further study. 11 Ladhani S, Heath PT, Ramsay ME, et al. Long-term immunological follow-up of children with Haemophilus influenzae serotype b vaccine failure in the United Kingdom. Clin Infect Dis 2009; 49:372–380. This study assessed Hib antibody levels in children who had had Hib disease despite Hib vaccination. More than one-half of the children with Hib vaccine failure had antibody concentrations below those considered to confer long-term protection. This study highlights a group of children who respond poorly to conjugate vaccines and may remain at risk of meningitis, despite immunization. 12 Patel M, Lee CK. Polysaccharide vaccines for preventing serogroup A meningococcal meningitis. Cochrane Database Syst Rev 2005:CD001093. 13 Okoko BJ, Idoko OT, Adegbola RA. Prospects and challenges with introduction of a mono-valent meningococcal conjugate vaccine in Africa. Vaccine 2009; 27:2023–2029. 14 LaForce FM, Konde K, Viviani S, Pre´ziosi MP. The meningitis vaccine project. Vaccine 2007; 25 (Suppl 1):A97–A100. 15 Lee CH, Kuo WC, Beri S, et al. Preparation and characterization of an immunogenic meningococcal group A conjugate vaccine for use in Africa. Vaccine 2009; 27:726–732. This paper describes the successful development of a conjugate meningococcal group A vaccine for use in the ‘meningitis belt’ of sub-Saharan Africa. 16 Kshirsagar N, Mur N, Thatte U, et al. Safety, immunogenicity, and antibody persistence of a new meningococcal group A conjugate vaccine in healthy Indian adults. Vaccine 2007; 25 (Suppl 1):A101–A107. 17 LaForce MF, Ravenscroft N, Djingarey M, Viviani S. Epidemic meningitis due to group A Neisseria meningitidis in the African meningitis belt: a persistent problem with an imminent solution. Vaccine 2009; 27 (Suppl 2):B13–B19. This review describes the development and clinical trials of a meningococcal A conjugate vaccine for Africa (MenAfriVac). The results of the phase II clinical trials in Africa are awaited. 18 Kerdpanich A, Warachit B, Kosuwon P, et al. Primary vaccination with a new heptavalent DTPw-HBV/Hib-Neisseria meningitidis serogroups A and C combined vaccine is well tolerated. Int J Infect Dis 2008; 12:88–97. This clinical trial showed that combining conjugate meningococcal A and C vaccines with routine infant vaccines was associated with more infants having a fever more than 398C, but not associated with more infants seeking medical advice. 19 Gatchalian S, Palestroque E, De Vleeschauwer I, et al. The development of a new heptavalent diphtheria-tetanus-whole cell pertussis-hepatitis B-Haemophilus influenzae type b-Neisseria meningitidis serogroups A and C vaccine: a randomized dose-ranging trial of the conjugate vaccine components. Int J Infect Dis 2008; 12:278–288. This clinical trial showed that combining conjugate meningococcal A and C vaccines with routine infant vaccines was well tolerated, immunogenic and did not interfere with responses to the routine vaccines. This vaccine could, thus, be used for routine immunization of infants and will also protect them against meningococcal groups A and C.
20 Hodgson A, Forgor AA, Chandramohan D, et al. A phase II, randomized study on an investigational DTPw-HBV/Hib-MenAC conjugate vaccine administered to infants in Northern Ghana. PLoS One 2008; 3:e2159. This clinical trial showed that combining conjugate meningococcal A and C vaccines with routine infant vaccines was well tolerated, immunogenic and did not interfere with responses to the routine vaccines. This vaccine could provide protection against seven important childhood diseases (including meningococcal A and C) and be of particular value in countries of the African meningitis belt. 21 Rennels M, King J Jr, Ryall R, et al. Dosage escalation, safety and immunogenicity study of four dosages of a tetravalent meningococcal polysaccharide diphtheria toxoid conjugate vaccine in infants. Pediatr Infect Dis J 2004; 23:429–435. 22 Snape MD, Perrett KP, Ford KJ, et al. Immunogenicity of a tetravalent meningococcal glycoconjugate vaccine in infants: a randomized controlled trial. JAMA 2008; 299:173–184. This trial studies the safety and immunogenicity of a new conjugate quadrivalent meningococcal vaccine (ACYW135) in infants. Three doses of vaccine gave protective antibody levels in over 90% of infants. Two doses only gave protection against serogroup A in 60% of infants. This study shows this vaccine is immunogenic in infants (unlike the previous vaccine), but that three doses are needed for high levels of protection against serogroup A. 23 Perrett KP, Snape MD, Ford KJ, et al. Immunogenicity and immune memory of a nonadjuvanted quadrivalent meningococcal glycoconjugate vaccine in infants. Pediatr Infect Dis J 2009; 28:186–193. This trial studies the safety and immunogenicity of two doses of a new conjugate quadrivalent meningococcal vaccine (ACYW135) in infants. Protective antibody levels were obtained in 80–90% of infants except against serogroup A (50%). This study shows that this new quadrivalent vaccine is immunogenic in infants, in contrast to the licensed vaccine. 24 Jackson LA, Jacobson RM, Reisinger KS, et al. A randomized trial to determine the tolerability and immunogenicity of a quadrivalent meningococcal glycoconjugate vaccine in healthy adolescents. Pediatr Infect Dis J 2009; 28:86–91. This trial compares a new conjugate quadrivalent meningococcal vaccine (ACYW135) in adolescents with the quadrivalent polysaccharide vaccine. The immunogenicity of the conjugate vaccine, measured by geometric mean titre at 1 month, was significantly greater than that of the polysaccharide vaccine for all four serogroups. The percentage of individuals with protective antibody levels 12 months after conjugate vaccine was significantly greater than that of those given polysaccharide vaccine for serogroups C, W135 and Y. This study confirms that conjugate quadrivalent meningococcal vaccines can produce better and longer lasting immunity than polysaccharide vaccine. 25 Reisinger KS, Baxter R, Block SL, et al. Quadrivalent meningococcal vaccina tion in adults: a phase III comparison of an investigational conjugate vaccine, MenACWY-CRM, with the licensed vaccine, Menactra. Clin Vaccine Immunol 2009; 16:1810–1815. This study compares the safety and immunogenicity of the Novartis quadrivalent meningococcal conjugate vaccine (ACWY) with the licensed meningococcal conjugate vaccine, Menactra. This study shows that conjugate vaccines with the same polysaccharide antigens can have different immunogenicity. 26 Black S, Klein NP, Shah J, et al. Immunogenicity and tolerability of a quad rivalent meningococcal glycoconjugate vaccine in children 2–10 years of age. Vaccine 2010; 28:657–663. This trial compares a new conjugate quadrivalent meningococcal vaccine (ACYW135) in children 2–10 years of age with the quadrivalent polysaccharide vaccine. The immunogenicity of the conjugate vaccine was greater than that of the polysaccharide vaccine at 1 and 12 months. This study confirms that conjugate quadrivalent meningococcal vaccines produce better responses than polysaccharide vaccine in young children. 27 Jackson LA, Baxter R, Reisinger K, et al., V59P13 Study Group. Phase III comparison of an investigational quadrivalent meningococcal conjugate vaccine with the licensed meningococcal ACWY conjugate vaccine in adolescents. Clin Infect Dis 2009; 49:e1–e10. This study compares the safety and immunogenicity of the Novartis quadrivalent meningococcal conjugate vaccine (ACWY) with the licensed meningococcal conjugate vaccine, Menactra. Adolescents were given a single dose of one vaccine. Antibody titres after the Novartis vaccine were higher than those after Menactra, and a greater proportion of individuals achieved bactericidal levels with the Novartis vaccine. This study shows that conjugate vaccines with the same polysaccharide antigens can have different immunogenicity. 28 Knuf M, Kieninger-Baum D, Habermehl P, et al. A dose-range study assessing immunogenicity and safety of one dose of a new candidate meningococcal serogroups A, C, W-135, Y tetanus toxoid conjugate (MenACWY-TT) vaccine administered in the second year of life and in young children. Vaccine 2010; 28:744–753. This trial compares a new conjugate quadrivalent meningococcal vaccine (ACYW135) in children 1–5 years of age with the quadrivalent polysaccharide vaccine. The immunogenicity of the conjugate vaccine was greater than that of the polysaccharide vaccine. This study confirms that conjugate quadrivalent meningococcal vaccines produce better responses than polysaccharide vaccines in young children.
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324 Inflammatory diseases and infection 29 Ostergaard L, Lebacq E, Poolman J, et al. Immunogenicity, reactogenicity and persistence of meningococcal A, C, W-135 and Y-tetanus toxoid candidate conjugate (MenACWY-TT) vaccine formulations in adolescents aged 15– 25 years. Vaccine 2009; 27:161–168. This trial compares a new conjugate quadrivalent meningococcal vaccine (ACYW135) in adolescents with the quadrivalent polysaccharide vaccine. This study did not find that conjugate quadrivalent meningococcal vaccines produced better immunity than polysaccharide vaccine in adolescents, though immunity was longer lasting for two serogroups. The study shows the importance of clinical trials in demonstrating immunogenicity of new conjugate vaccines, which may not always perform as well as expected. 30 Holst J, Martin D, Arnold R, et al. Properties and clinical performance of vaccines containing outer membrane vesicles from Neisseria meningitidis. Vaccine 2009; 27 (Suppl 2):B3–B12. 31 O’Hallahan J, McNicholas A, Galloway Y, et al. Delivering a safe and effective strain-specific vaccine to control an epidemic of group B meningococcal disease. N Z Med J 2009; 122:48–59. This paper summarizes the outcomes of the New Zealand vesicle vaccine campaign, including coverage levels achieved, evidence of vaccine effectiveness and safety and the strategies used to manage key events and risks that emerged during the campaign. 32 Lennon D, Jackson C, Wong S, et al. Fast tracking the vaccine licensure process to control an epidemic of serogroup B meningococcal disease in New Zealand. Clin Infect Dis 2009; 49:597–605. This paper describes the process of identifying the need for immunization, development of the vaccine and subsequent licensure, introduction and monitoring of the new MeNZB vaccine. 33 Wong S, Lennon D, Jackson C, et al. New Zealand epidemic strain meningococcal B outer membrane vesicle vaccine in children aged 16–24 months. Pediatr Infect Dis J 2007; 26:345–350. 34 Hosking J, Rasanathan K, Mow FC, et al. Immunogenicity, reactogenicity, and safety of a P1.7b,4 strain-specific serogroup B meningococcal vaccine given to preteens. Clin Vaccine Immunol 2007; 14:1393– 1399. 35 Wong SH, Lennon DR, Jackson CM, et al. Immunogenicity and tolerability in infants of a New Zealand epidemic strain meningococcal B outer membrane vesicle vaccine. Pediatr Infect Dis J 2009; 28:385–390. This phase II trial gave the New Zealand meningococcal B:4:P1.7-2,4 vesicle vaccine (MeNZB) with routine immunizations at 6 weeks, 3 months and 5 months of age. A fourth dose at 10 months of age was needed to produce antibody titres comparable to those achieved after three doses in older children. This study shows the difficulty of inducing immunity in infants with vesicle vaccines. 36 Kelly C, Arnold R, Galloway Y, O’Hallahan J. A prospective study of the effectiveness of the New Zealand meningococcal B vaccine. Am J Epidemiol 2007; 166:817–823. 37 Galloway Y, Stehr-Green P, McNicholas A, O’Hallahan J. Use of an observa tional cohort study to estimate the effectiveness of the New Zealand group B meningococcal vaccine in children aged under 5 years. Int J Epidemiol 2009; 38:413–418. This study included children in New Zealand who were diagnosed with laboratoryconfirmed meningococcal disease due to the epidemic strain B:4:P1.7-2,4. Compared with unvaccinated children, fully MeNZB-vaccinated children were five to six times less likely to contract epidemic strain meningococcal disease in the 2 years after vaccination. This corresponded to an estimated vaccine effectiveness of 80%. This study shows good protection against the vaccine strain of meningococcal disease even in infants; however, protection against other strains of meningococci is likely to be poor. 38 Boutriau D, Poolman J, Borrow R, et al. Immunogenicity and safety of three doses of a bivalent (B:4:p1.19,15 and B:4:p1.7-2,4) meningococcal outer membrane vesicle vaccine in healthy adolescents. Clin Vaccine Immunol 2007; 14:65–73.
39 Gorringe AR, Taylor S, Brookes C, et al. Phase I safety and immunogenicity study of a candidate meningococcal disease vaccine based on Neisseria lactamica outer membrane vesicles. Clin Vaccine Immunol 2009; 16:1113–1120. This phase I study assessed the safety and immunogenicity of a vesicle vaccine made from N. lactamica. The vaccine appeared well tolerated but only induced a weak antibody response to N. meningitidis. This vaccine needs to be more immunogenic if it is to be developed further. 40 Rinaudo CD, Telford JL, Rappuoli R, Seib KL. Vaccinology in the genome era. J Clin Invest 2009; 119:2515–2525. This review describes the use of ‘reverse vaccinology’ to rapidly identify novel vaccine antigens. 41 Pajon R, Yero D, Niebla O, et al. Identification of new meningococcal serogroup B surface antigens through a systematic analysis of neisserial genomes. Vaccine 2009; 28:532–541. This paper describes how five vaccine candidates for group B meningococci were identified by analysis of the meningococcal genome with subsequent experimental validation. 42 Giuliani MM, Adu-Bobie J, Comanducci M, et al. A universal vaccine for serogroup B meningococcus. Proc Natl Acad Sci U S A 2006; 103:10834– 10839. 43 Halperin SA, Langley JM, Smith B, et al. Phase 1 first-in-human studies of the reactogenicity and immunogenicity of a recombinant meningococcal NspA vaccine in healthy adults. Vaccine 2007; 25:450–457. 44 Beernink PT, Granoff DM. Bactericidal antibody responses induced by meningococcal recombinant chimeric factor H-binding protein vaccines. Infect Immun 2008; 76:2568–2575. This paper describes the development of an investigational vaccine, based on a recombinant chimeric meningococcal fHbp, and shows the feasibility of making a broad meningococcal vaccine from a single recombinant protein. 45 Koeberling O, Giuntini S, Seubert A, Granoff DM. Meningococcal outer membrane vesicle vaccines derived from mutant strains engineered to express factor H binding proteins from antigenic variant groups 1 and 2. Clin Vaccine Immunol 2009; 16:156–162. This study describes a meningococcal outer membrane vesicle vaccine, which was engineered to overexpress the immunogenic protein fHbp. This method may improve the immunogenicity of both vesicle vaccines and protein vaccines and lead to a group B meningococcal vaccine which protects against a broad range of subtypes. 46 Lucero MG, Dulalia VE, Nillos LT, et al. Pneumococcal conjugate vaccines for preventing vaccine-type invasive pneumococcal disease and X-ray defined pneumonia in children less than two years of age. Cochrane Database Syst Rev 2009:CD004977. This Cochrane review found that the seven-valent pneumococcal vaccine had a vaccine efficacy against invasive pneumococcal disease caused by vaccine serotypes of 80%, 58% against all serotypes and 11% for all-cause mortality. This supports the use of the vaccine and encourages development of vaccines that include more serotypes. 47 Kisakye A, Makumbi I, Nansera D, et al. Surveillance for Streptococcus pneumoniae meningitis in children aged <5 years: implications for immunization in Uganda. Clin Infect Dis 2009; 48 (Suppl 2):S153–S161. This surveillance study collected data on meningitis from three Ugandan hospitals and showed that the most common cause identified was S. pneumoniae. However, only 43% of these were serotypes that are in the available seven-valent pneumococcal conjugate vaccine, although 70% are in the proposed 13-valent pneumococcal vaccine. This study shows that pneumococcal meningitis in Africa is due to different serotypes than in North America and Europe. Conjugate pneumococcal vaccines for Africa, therefore, need different serotypes to protect most children. 48 Lagos R, Munoz A, Levine MM, et al. Immunology of combining CRM(197) conjugates for Streptococcus pneumoniae, Neisseria meningitis and Haemophilus influenzae in Chilean infants. Vaccine 2009; 27:2299–2305. This clinical trial studied three conjugate vaccines (pneumococcal, meningococcal C and Hib) mixed together as a single injection and compared them to separately administered vaccines in infants. The frequency of adverse events was similar but recipients of the combination vaccine had significantly lower geometric mean concentrations to Hib, though the percentage of individuals who achieved protective antibody levels was the same. This study shows the importance of studying combination vaccines as unexpectedly lower antibody responses can occur.
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Bibliography Current World Literature This bibliography is compiled by clinicians from the journals listed at the end of this publication. It is based on literature entered into our database between 1 February 2009 and 31 January 2010 (articles are generally added to the database about two and a half months after publication). In addition, the bibliography contains every paper annotated by reviewers; these references were obtained from a variety of bibliographic databases and published between the beginning of the review period and the time of going to press. The bibliography has been grouped into topics that relate to the reviews in this issue.
Papers considered by the reviewers to be of special interest Papers considered by the reviewers to be of outstanding interest The number in square brackets following a selected paper, e.g. [7], refers to its number in the annotated references of the corresponding review. Current Opinion in Neurology 2010, 23:325–339
Contents Demyelinating diseases 325 Cytokine networks in multiple sclerosis: lost in translation 327 Cell trafficking and the blood brain barrier 328 Novel MRI approaches to assess patients with multiple sclerosis 329 Demyelination as a complication of new immunomodulatory treatments 330 Stem cell transplantation in multiple sclerosis 331 Leukodystrophies with late disease onset: an update 332 Investigations and treatment of chronic inflammatory demyelinating polyradiculoneuropathy and other inflammatory demyelinating polyneuropathies
335 What have we learnt from triggering migraine? 335 An update on the blood vessel in migraine 336 Dopamine: whats new in migraine? Inflammatory diseases and infection 336 New approaches to neuroimaging of central nervous system inflammation 336 New drug therapies for multiple sclerosis 337 Mechanisms of cerebral edema in traumatic brain injury: therapeutic developments 338 Update on investigation and management of postinfectious encephalitis 338 Acute encephalopathy and encephalitis caused by influenza virus infection 338 Mechanisms of injury in bacterial meningitis
333 Patent foramen ovale and migraine: revisiting the association at the bench
338 The implications of vaccines for prevention of bacterial meningitis
334 Medication overuse headache- novel insights into potential mechanisms 334 Recent developments in pediatric headache
Demyelinating diseases
Berger JR, Fee DB, Nelson P, Nuovo G. Coxsackie B meningoencephalitis in a patient with acquired immunodeficiency syndrome and a multiple sclerosis-like illness. J Neurovirology 2009; 15:282–287. Bichuetti DB, Oliveira EML, Souza NA, Rivero RLM, et al. Neuromyelitis optica in Brazil: a study on clinical and prognostic factors. Multiple Sclerosis 2009; 15:613– 619. Bittner S, Meuth SG, Gobel K, Melzer N, et al. TASK1 modulates inflammation and neurodegeneration in autoimmune inflammation of the central nervous system. Brain 2009; 132:2501–2516. Bjork P, Bjork A, Vogl T, Stenstrom M, et al. Identification of Human S100A9 as a Novel Target for Treatment of Autoimmune Disease via Binding to Quinoline-3Carboxamides - art. no. e1000097. PLoS Biol 2009; 7:800–812. Blink SE, Miller SD. The Contribution of y delta T Cells to the Pathogenesis of EAE and MS [Review]. Current Molecular Medicine 2009; 9:15–22. Bo L. The histopathology of grey matter demyelination in multiple sclerosis [Review]. Acta Neurol Scand 2009; 120:51–57. Bodendiek SB, Mahieux C, Hansel W, Wulff H. 4-Phenoxybutoxy-substituted heterocycles - A structureactivity relationship study of blockers of the lymphocyte potassium channel Kv1.3. Eur J Med Chem 2009; 44:1838–1852. Brambilla R, Persaud T, Hu X, Karmally S, et al. Transgenic Inhibition of Astroglial NF-kappa B Improves Functional Outcome in Experimental Autoimmune Encephalomyelitis by Suppressing Chronic Central Nervous System Inflammation. J Immunol 2009; 182:2628–2640. Brosnan CF, John GR. Revisiting Notch in remyelination of multiple sclerosis lesions. J Clin Invest 2009; 119:10–13. Cader S, Palace J, Matthews PM. Cholinergic agonism alters cognitive processing and enhances brain functional connectivity in patients with multiple sclerosis. J Psychopharmacol 2009; 23:686–696. Carson KR, Evens AM, Richey EA, et al. Progressive multifocal leukoencephalopathy after rituximab therapy in HIVnegative patients: a report of 57 cases from the Research on Adverse Drug Events and Reports project. Blood 2009; 113:4834–4840. [85]
8th Course of the European School of Neuroimmunology From basic to clinical neuroimmunology: An introductory course Abstracts. J Neuroimmunol 2008; 203:125. Anderson JM, Patani R, Reynolds R, Nicholas R, et al. Evidence for abnormal tau phosphorylation in early aggressive multiple sclerosis. Acta Neuropathol (Berl) 2009; 117:583–589. Arjmandi A, Liu K, Dorovini-Zis K. Dendritic Cell Adhesion to Cerebral Endothelium: Role of Endothelial Cell Adhesion Molecules and Their Ligands. J Neuropathol Exp Neurol 2009; 68:300–313. Atzori M, Battistella PA, Perini P, Calabrese M, et al. Clinical and diagnostic aspects of multiple sclerosis and acute monophasic encephalomyelitis in pediatric patients: a single centre prospective study. Multiple Sclerosis 2009; 15:363–370. Baarine M, Ragot K, Genin EC, El Hajj H, et al. Peroxisomal and mitochondrial status of two murine oligodendrocytic cell lines (158N, 158JP): potential models for the study of peroxisomal disorders associated with dysmyelination processes. J Neurochem 2009; 111:119–131. Barnard AL, Chidgey AP, Bernard CC, Boyd RL. Androgen depletion increases the efficacy of bone marrow transplantation in ameliorating experimental autoimmune encephalomyelitis. Blood 2009; 113:204–213. Bebo BF, Dehghani B, Foster S, Kurniawan A, et al. Treatment with Selective Estrogen Receptor Modulators Regulates Myelin Specific T-Cells and Suppresses Experimental Autoimmune Encephalomyelitis. Glia 2009; 57:777–790. Bell E. NEUROIMMUNOLOGY Finding a way into the brain. Nat Rev Microbiol 2009; 9(6):386, 200:386. Belmar NA, Lombardo JR, Chao DT, Li O, et al. Dissociation of efficacy and cytokine release mediated by an Fc-modified anti-CD3 mAb in a chronic experimental autoimmune encephalomyelitis model. J Neuroimmunol 2009; 212:65–73.
334 New therapeutic developments in chronic migraine
Headache
# 2010 Wolters Kluwer Health | Lippincott Williams & Wilkins 1350-7540
Cytokine networks in multiple sclerosis: lost in translation Review: (pp. 205–211)
Vol 23 No 3 June 2010
Costagliola D. Central nervous system demyelinating events and hepatitis B vaccine: A new episode of the never ending French saga! [French]. Rev Epidemiol Sante Publique 2008; 56:379–381. Courtney AM, Treadaway K, Remington G, Frohman E. Multiple Sclerosis. Med Clin North Am 2009; 93:451. Coyle P, Arnason B, Hurwitz B, Lublin F. Optimizing Outcomes in Multiple Sclerosis - A Consensus Initiative. Multiple Sclerosis 2008; 14:S5–S35. Da Silva AG, Yong VW. Matrix Metalloproteinase-12 Deficiency Worsens Relapsing-Remitting Experimental Autoimmune Encephalomyelitis in Association with Cytokine and Chemokine Dysregulation. Am J Pathol 2009; 174:898– 909. Das A, Guyton MK, Butler JT, Ray SK, et al. Activation of Calpain and Caspase Pathways in Demyelination and Neurodegeneration in Animal Model of Multiple Sclerosis. CNS Neurol Disord-Drug Targets 2008; 7:313–320. Defaux A, Zurich MG, Braissant O, Honegger P, et al. Effects of the PPAR-beta agonist GW501516 in an in vitro model of brain inflammation and antibody-induced demyelination art. no. 15. J Neuroinflamm 2009:15. Donia M, Mangano K, Amoroso A, Mazzarino MC, et al. Treatment with rapamycin ameliorates clinical and histological signs of protracted relapsing experimental allergic encephalomyelitis in Dark Agouti rats and induces expansion of peripheral CD4+CD25+Foxp3+regulatory T cells. J Autoimmun 2009; 33:135–140. Dugger KJ, Zinn KR, Weaver C, Bullard DC, et al. Effector and suppressor roles for LFA-1 during the development of experimental autoimmune encephalomyelitis. J Neuroimmunol 2009; 206:22–27. Dujmovic I, Pekmezovic T, Obrenovic R, Nikolic A, et al. Cerebrospinal fluid and serum uric acid levels in patients with multiple sclerosis. Clin Chem Lab Med 2009; 47:848–853. Duncan ID, Brower A, Kondo Y, Curlee JF, et al. Extensive remyelination of the CNS leads to functional recovery. Proc Natl Acad Sci USA 2009; 106:6832–6836. Eixarch H, Espejo C, Gomez A, Mansilla MJ, et al. Tolerance Induction in Experimental Autoimmune Encephalomyelitis Using Non-myeloablative Hematopoietic Gene Therapy With Autoantigen. Mol Ther 2009; 17:897–905, 2009 May.
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