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Inflammatory Demyelinating Diseases of the Central Nervous System

Inflammatory Demyelinating Diseases of the Central Nervous System

ORIGINAL ARTICLES

Copyright © 2009, Barrow Neurological Institute

Inflammatory Demyelinating Diseases of the Central emyelinating diseases can be di - Roberto Bomprezzi, MD , PhD Dvided into disorders that affect the Denise Campagnolo, MD CNS and disorders that cause the loss of in the PNS. Depending on their The CNS can be affected by several immunologically mediated diseases that origin, these diseases can be divided into manifest with demyelination and neuronal damage. Advances in the under - two categories. The first, demyelinating standing of the pathophysiology of those diseases have translated into significant conditions, are related to inflammato - improvements in treatments. This article discusses the characteristic features of ry, toxic, or metabolic causes. The sec - some of the demyelinating diseases of the CNS based on recent updates. This ond, dysmyelinating processes, are most - article reviews the basic underlying mechanisms of, key pathological findings, di - ly of a genetic nature, and involve the agnostic approaches, and potential therapies for ADEM, AHL, neuromyelitis op - progressive loss of myelin or its failure to tica, and MS. In addition, a review of the fundamental concepts of form. are presented. Although only a few CNS disorders are characterized by primary inflamma - Key Words: acute disseminated , acute hemorrhagic tory changes, their overall incidence is leukoencephalitis, demyelination, multiple sclerosis, neuromyelitis optica relatively high (Table 1). Included are illnesses such as the vasculitides in which affects the vessel walls, causing ischemic damage to the brain parenchyma (Table 2). Conversely, some disorders are caused by immune cells that penetrate the blood-brain barrier and in - duce an inflammatory reaction. Local - ization of this reaction inside the CNS is responsible for the demyelination. Despite many biomedical advances, the etiological mechanisms that under - lie these diseases are not yet understood. The exception is infectious whose pathogenesis is well defined. The localizes in the brain and deter - mines mobilization of peripheral blood cells, resulting in perivenular clustering of inflammatory cells and areas of de - myelination. This update reviews ac - quired conditions related to idiopathic inflammatory diseases that result in the Abbreviations Used: ADEM, acute disseminated encephalomyelitis; loss of myelin. AHL, acute hemorrhagic leukoencephalitis; CNS, ; CSF, ; IL, interleukin; MR, magnetic resonance; MS, mul - tiple sclerosis; PNS, peripheral nervous system Basics of Immunology The immune system has evolved over Division of , Barrow Neurological Institute, St. Joseph’s Hospital and Medical Center, Phoenix, Arizona millions of years, and its level of com -

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Table 1. Inflammatory Table 2. Features of CNS Vasculitides Diseases of the CNS Primary Angiitis of CNS Secondary Causes of CNS Vasculitis ADEM Small and medium-sized leptomeningeal Infection (viral, bacterial, fungal cortical arteries; less frequently, veins and rickettsial, mycoplasmal, proto- AHL (rare form of severe ADEM, distin- venules zoal) guished only by presence of hemor- rhages and more aggressive course) Segmental granulomatous infiltrate of Systemic vasculitis Site-restricted acute inflammatory de- arterioles, side-by-side with polyarteritis-type myelinating diseases necrotizing vasculitis and normal arterioles. Connective tissue disease Cerebellitis Foreign body and Langhans’ giant cells. Transverse Fibrinoid necrosis of the vessel wall, Sarcoidosis thrombosis, stenosis, and Brain stem encephalitis Drug-associated (sympatho- Optic Multiple microaneurysms, characteristic of mimetics, drugs of abuse) Multiple sclerosis vasculitis on abdominal or renal angiograms, distinctly rare in CNS Neuromyelitis optica or Devic’s disease CNS sarcoidosis Paraneoplastic encephalitis to the type of response to be mounted must engage with high-affinity (see below). antigens, and co-stimulatory molecules Toll-like receptors are highly con - on the surface of the antigen-presenting served throughout all species. They tar - cells must be expressed. At this point the get structural components of microor - immune response acquires specificity and ganisms, known as pathogen-associated long-lasting immune memory from the plexity has increased in parallel with the molecular patterns, which are essential clonal expansion of bothT- and B-cells. evolution of organisms. Humans likely for the survival of microbes and . No longer naïve, theT- can possess one of the most advanced forms Targeting those antigens is strategic be - transform into memory cells. Alterna - of immune systems. As is common, cause they cannot be changed by infec - tively, they can expand and give rise to however, increased complexity also in - tious agents; thus, selectivity is ensured. specificT-helper cells if expressing CD4 creases the risk of related complications. To date 12 different toll-like receptors molecules or become cytotoxic effector Both autoimmune diseases and have been identified in mammals, and T-cells if expressing CD8 molecules. represent derangements of normal im - distinct, relatively specific ligands have Similarly, B-lymphocytes proliferate and mune function that manifest as the loss been associated with the various sub- mature into plasmacytes that produce cir - of regulation of extremely intricate ma - types. Some of these receptors are extra - culating and eventually un - chinery. cellular while others are bound to endo - dergo . The immune system of mammals has somes and require internalization of the Two mutually exclusive profiles of cy - two branches—the innate and the ac - antigen for pattern recognition. 2 tokines can be induced by the dendrit - quired. Innate immunity provides the Once detect and inter - ic cells and macrophages when they first first line of defense against infectious nalize a foreign antigen, they migrate encounter pathogens: Th1 and Th2. agents that penetrate the physical barri - away from the site of infection to the re - Th1 is characterized by the production er of the skin or mucosa. A limited num - gional lymph nodes. There, the repre - of -gamma and tumor necro - ber of germline-encoded pattern-recog - sentative cells of the acquired immune sis factor-alpha. TheTh2 profile follows nition receptors initiate an immune system interact with antigens. 38 The anti - the secretion of IL4 and IL13. The clas - response that becomes increasingly spe - gens are processed by professional antigen- sic paradigm dictates that bacterial in - cific as acquired immunity develops. 2 presenting cells, namely macrophages, fections evoke a Th1 type of immune Macrophages and dendritic cells, the pri - dendritic cells, and B-lymphocytes. In response while parasitic infections are mary units of innate immunity, exploit the context of the major histocompati - more likely to produce theTh2 type of several families of pattern-recognition bility complex class I or II molecules, the . Recently, a third profile, receptors, such as toll-like receptors or antigens are then presented to the CD8- Th17, has been recognized. 32 On stim - nucleotide-oligomerization domain-like and CD4-positive lymphocytes, respec - ulation by IL-23, a pro-inflammatory receptors, to discern pathogens from self- tively. 13 produced by activated CD4 constituents.These cells have the role of For lymphocytes to become activat- cells, the helper T-cells start producing instructing the acquired immune system ed, two events are required. TheirT-cell IL-17, which is a critical inducer of in -

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flammation in MS and equivalent ani - Acute Disseminated certain degree of degeneracy ensure the mal models. 37 Encephalomyelitis ability to interact with a previously un - Activated lymphocytes sustain the ADEM is characterized by a multifo - known antigen. However, those aspects pro-inflammatory response by express - cal, monophasic involvement of the CNS also enable unexpected recognition of ing the necessary surface adhesion mol - in children or young adults and tends to self. This principle is supported by a few ecules that allow transmigration through resolve without sequelae. cases in which acute demyelinating in - blood vessels, penetration of tissue, and flammatory polyneuropathy andADEM 4 sensitization to chemokines. Subse - Etiology have manifested simultaneously. With quently, counterbalanced anti-inflam - ADEM has etiological relationships even stronger evidence than forADEM, matory and pro-apoptotic signals, me - to infections, and many agents have been acute demyelinating inflammatory poly - diated by regulatory cells secreting IL-10 implicated. In some series, infection has neuropathy has been shown to derive and tumor growth factor-beta, are re - preceded the development of the neu - from mechanisms of cross-immunity be - sponsible for the termination of inflam - rological manifestations of the disease by tween a pathogen and gangliosides pre - mation. days to weeks about 75% of the cases. 29 sent in peripheral . 42 Not surpris - A subset of circulating lymphocytes, In early descriptions, ADEM was linked ingly, multiple simultaneous antigens of known as natural killer cells, has been to rabies and smallpox . The the CNS and PNS may be targeted. identified as part of the innate immune elimination of neural tissue from duck system. Their contribution to the regu - embryos as a contaminant in these vac - Pathology lation of an immune response is slowly cines has dramatically decreased the The main features ofADEM can be being defined. 21 They have the ability number of postvaccination cases. Nev - summarized in scattered areas of in - to generate aTh1 orTh2 profile. More ertheless, naturally occurring infections flammation involving the brain and importantly, they appear to have a role as predispose individuals to develop the dis - . It is primarily a white mat - suppressor cells. Hence, they are key ease as evidenced by the high prevalence ter disease, but limited gray matter can players in regulating immune responses. ofADEM in areas where are en - be observed in both the cortex and Another subtype of regulatory cells demic. . In affected areas, periven - that is a fundamental player in any im - A possible mechanism leading to ular infiltration of mononuclear cells, mune response has been identified. ADEM is molecular mimicry. The ex - consisting of abundant lymphocytes and These cells are CD4+ lymphocytes that pected immune response that provides monocytes, leads to demyelination and co-express high levels of CD25 (the clearance of an infection is subsequently . 36 The appearance is that of ac- alpha chain of the IL-2 receptor) mol - directed toward self-components with tive plaque-like lesions. Microscopical - ecules on their surface, and they are antigenic similarities to epitopes of the ly, larger lesions may be indistinguish - characterized by the production of the infecting . 3 Well after able from the acute plaques associated transcription factor FoxP3. FoxP3 clearance of the latter when no microor - with MS. is a reliable marker of regulatoryT-cells. ganisms can be isolated from the patient, A reduction in the number of circulat - the inflammatory response localizes in - Clinical Presentation ing FoxP3-positive cells results in un - side the CNS where it generates simul - A prodromal phase of several days of controlled immune responses and auto - taneous, multifocal areas of inflamma- malaise, fever, , and skin rashes is immunity, whereas the induction of tion. Both laboratory and clinical data common. In about half of the cases, fever antigen-specific FoxP3-positive cells support the concept of a postinfection is a presenting symptom. Other consti - maintains peripheral tolerance. 9 immune response directed against anti - tutional symptoms such as nausea, vom - The innate immune system has the gens of the CNS, and many antigens have iting, , and a stiff neck are asso - ability to mount a response to a foreign been implicated as targets. 36 That infec - ciated with the acute stage of the illness. antigen or to ignore a self-antigen. The tions from a large variety of pathogens, The multifocal neurological signs that milieu of cytokines produced sets the including widespread bacteria, viruses, follow tend to develop a few days to sev - stage for the type and intensity of the rickettsias, and even parasites, are poten - eral weeks after the acute infectious actions affected by adaptive immunity. tial triggering factors suggests the in - episode. Once triggered, the onset of the Thus, innate immunity has been impli - volvement of a common, multifaceted CNS disorder is usually within several cated in by virtue of its mechanism. In other words, many dif- hours. The neurological manifestations ability to initiate the misdirected im - ferent antigens in have peak within a few days. mune response that will remain dysreg - the potential of inducing cross-reactivity The most common neurological ulated at the level of the adaptive im - to self-constituents. manifestations are motor signs (, mune system. 15 Numerous mechanisms In fact,T-cells that can react to self are ), cranial abnormalities are set to control an autoreactive pro - part of a healthy immune system. The (vision and gaze impairment, facial weak - cess. Failure at any step results in an au - stochastic nature of the maturation of the ness), sensory problems, alteration of con - toimmune disease. T-cell receptor in T-lymphocytes and a sciousness (varying from lethargy to

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coma), and . The simultaneous protein in the CSF seems to be propor - nating diseases of the CNS who failed to or closely spaced appearance of neuro - tional to the extent of the disease. This respond to steroids improved after un - logical signs reflects the diffuse and mul - finding, which reflects the massive myelin dergoing . 39 It is still un - tifocal involvement of the CNS, includ - destruction induced by the inflamma - clear whether the clearance of antigens ing the spinal cord. The severity of the tion, is a constant in the aggressive de - and immune complexes is responsible for neurological manifestations varies. The myelinating disease AHL. the effectiveness of plasmapheresis. How - diagnosis is often overlooked because the MR imaging is instrumental to the ever, its established efficacy in the treat - patients are young and otherwise healthy. diagnosis of ADEM. Invariably, these ment of other -mediated dis - Their ability to compensate for their neu - studies show multifocal signal alterations eases, such as Guillain-Barré syndrome, a rological deficits masks the symptoms. of the and demyelinating diseases of the PNS, sup - Presentations such as coma and subse - and often of the basal ganglia and spinal ports this view. quent also occur. cord. The lesions have a confluent ap - After the acute stage, the disease grad - pearance, and their size varies. Typically, ually improves within a few weeks. signals onT2-weighted and fluid-atten - Acute Hemorrhagic Most cases resolve completely in 2 to 6 uated inversion recovery sequences are Leukoencephalitis months. The outcome and rate of re - hyperintense, reflecting increased water AHL is considered to be at the end of covery can be influenced by therapy. content (i.e., vasogenic edema, demyeli - the spectrum of ADEM. In fact, these Sometimes, however, the disease pro - nation, or both). MR imaging is a sen - two disease entities are part of a contin - gresses and neurological deficits persist sitive method for following the evolution uum with overlapping clinical and patho - despite treatment. ADEM is typically of the lesions associated with ADEM. logical features. monophasic; that is, once it resolves it Complete resolution of the radiological does not recur. Whether a recurrence of picture correlates with clinical recovery Pathology ADEM should be considered progres - of function. Similar to ADEM, AHL is associated sion to MS is still debated. with multiple areas of inflammation that Therapy involve the white matter of both hemi - Diagnosis The inflammatory nature of ADEM spheres. 36 As observed in cases ofADEM, Routine laboratory tests may dem - renders it susceptible to treatment with demyelination, edema, and mononuclear onstrate elevation of indices of inflam - the anti-inflammatory therapy of choice: cell infiltration are present microscopi - mation such as the erythrocyte sedimen - steroids. High-doses of intravenous for - cally. In AHL, however, the lesion is also tation rate and level of C-reactive protein. mulations of glucocorticosteroids are the contaminated by various degrees of hem - In peripheral blood the white cell count widely accepted standard of treatment for orrhage. Tissue necrosis often follows in may be increased with lymphocytic pre - ADEM. Besides case series supporting areas with the most pronounced hemor - dominance. Classically, however, no path - the beneficial effects of steroids, their ef - rhage. A distinctive feature ofAHL is the ogen can be isolated as the neurological ficacy has been tested in a limited num - presence of polymorphonucleate cells symptoms develop. Preceding infections ber of controlled clinical trials. The con - scattered around the lesions. The cells with Epstein-Barr virus, herpes, cyto - sensus is that steroids speed the rate of likely act as scavengers of the debris asso - megalovirus, measles, varicella, mycoplas - recovery and improve outcomes. ciated with the massive destruction of the ma, streptococcus, chlamydia, and rick - The mechanism of action underlying tissues. ettsia have been reported. 36 the use of steroids for the treatment of The CSF shows more consistent ab - acute demyelinating CNS diseases is par - Clinical Features normalities than the blood tests. Occa - tially elucidated. Steroids appear to help The clinical manifestations of AHL sionally, however, the CSF is normal. The repair the blood-brain barrier, thus lim - are the same as those described for total levels of protein and cell counts in iting penetration of the CNS by the cir - ADEM, including prodromic symptoms the CSF, again with lymphocytic pre - culating cells. Moreover, steroids induce of an infectious disease followed by the dominance, are high. The indices of im - apoptosis of the activated lymphocytes, appearance of meningismus, encepha - munoglobulin intrathecal synthesis are thus limiting the recruitment of inflam - lopathy, and focal neurological signs. positive. On immunoelectrophoresis, matory cells into the CNS and shorten - Large demyelinated regions are often as - oligoclonal bands corresponding to im - ing the perpetration of the immune re - sociated with massive edema and hem - munoglobulins that migrate to form dis - sponse. orrhagic contamination. The appearance crete bands, which are present only in the Plasmapheresis may be used as an ad - of these aggressive lesions on MR imag - CSF specimen and not in the serum, are junctive or alternative to steroids. How - ing is often indistinguishable from that of sometimes detected in ADEM. These ever, this aggressive measure is associated primary CNS tumors. A is some - bands are usually present in MS and also with potential side effects and should be times required to confirm the diagnosis. may be found in chronic viral infections. reserved for severe cases. In one series, pa - Considering the level of dysfunction and Elevation of the levels of myelin basic tients with acute inflammatory demyeli - neurological deficits characteristic of the

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acute stages of AHL, the degree of re - underlying demyelination are thought to associated with a dramatic reduction in covery is usually remarkable. Again, prog - include the cascade of inflammatory the rate at the 1-year follow-up nostic factors are related to the extent of events that follows activation of comple - point. 12 When the B-cell count was re - CNS involvement and therapeutic in - ment as well as glutamate toxicity and stored to normal values 6 to 12 months tervention. neuronal death from the loss of regula - after the first dose, a subsequent dose was tion of the ionic microenvironment. 6 administered. Given the overall rarity of Therapy the disease, a direct comparison with AHL is treated in the same way as Clinical Features other therapies is unlikely to be possible. ADEM. Given the severity of AHL, Neuromyelitis optica is more com - Based on the current understanding of however, prompt initiation of steroids and mon in young adults of Asian and Afri- the pathophysiology of neuromyelitis op - early consideration of plasmapheresis are can descent than in Caucasians. It is as - tica, the effectiveness of com - recommended. sociated with severe recurrent attacks of pared to the general immune suppression , affecting one or both eyes. obtained with makes The attacks unpredictably precede or fol - biologically. Experts in the field Neuromyelitis Optica low episodes of longitudinally extended now recommend rituximab as a first-line Typically, neuromyelitis optica mani - . The severity of the agent for neuromyelitis optica. 24 fests with recurrent episodes of optic neu - episodes is characteristic of the disease. In terms of the management of acute ritis and transverse myelitis. The condi - Invariably, disability follows the acute , plasmapheresis is the treatment tion was referred to as optical-spinal MS, events. Complete blindness and quadri - of choice. To maximize the chances of re - and this disease was long considered a plegia from spinal cord disease often re - covery, it should be instituted at the ear - variant of MS. Only recently has it been sult from the recurrent attacks; a slow pro - liest signs of an acute attack. defined as a distinct entity. gression with gradual decline in function is not part of the disease process. 41 Pathology Multiple Sclerosis The pathogenesis of neuromyelitis Diagnosis MS is the prototype of the inflamma - optica is primarily inflammatory in re - The diagnostic criteria for neuro my - tory demyelinating diseases of the CNS. sponse to an autoimmune attack on elitis optica have recently been modified Although its characteristic clinical and components of the CNS. 40 Only in the to include the presence of the neuromy - pathological features were first described last few years has the potential role of IgG elitis optica-IgG in the serum as one of more than a century ago, its pathology is directed against the extracellular domain the key findings. 18 In case series, the sen - still incompletely understood. The ac - of the water channel in the CNS been sitivity of the antibodies has ranged from cepted notion is that the early stages of recognized. Serum from patients with 60 to 70%, while specificity has ranged MS are initiated by an autoimmune at - neuromyelitis optica contains a comple - from 90 to 99%. 24 Other criteria that tack against components of the myelin in ment-fixating IgG that selectively binds support the diagnosis of neuromyelitis the CNS. In most cases the attacks man - to aquaporin-4, which is the most abun - optica entail optical-spinal involvement ifest as recurrent episodes of clinical re - dant water channel in the CNS. It is ex - with the presence of elongated spinal lapses and spontaneous remissions. The pressed as a transmembrane tetrameric cord lesions that typically stretch beyond ultimate common pathway for the dis - protein in the end-feet of that three contiguous vertebral bodies. Find - ease is a degenerative process that leads contact , interneuronal synap - ings on MR imaging of the brain are not to permanent disability. tic junctions, and ventricular ependyma. typical of MS. There, it functions as a major regulator Pathology and Pathogenesis of bidirectional water flux between brain Therapy The literature on MS and its pathol - and spinal fluid. Until recently the conventional ther - ogy is massive. Only an overview of re - The pattern o f lesions in patients with apy for neuromyelitis optica was based cent advances follows. neuromyelitis optica tends to coincide on such as cyclophospha - The cardinal pathological features of with the normal distribution of aqua - mide, , , or my - MS reside in the progressive accumula - porin-4 in the CNS, 33 and there is strong cophenolate. However, these treatments tion of areas of demyelination that tend evidence of the pathogenicity of the anti- fail to control the disease. Severe disabil - to be distributed in the periventricular aquaporin-4 antibodies. Several studies ity and death are common outcomes of white matter and become confluent over have demonstrated early loss of aquapor - this illness. time. Under the microscope the de - in-4 in lesions from neuromyelitis opti - Expectations are high that rituximab myelinating plaques may show, depend - ca. 24 No direct attack on oligodendro - may help prevent the attacks. This mono- ing on their stage, different degrees of cytes is thought to be part of the immune clonal antibody is selective for the CD-20 myelin loss, more or less abundant in - response, at least in the early stages of the antigen and acts by depletion of B-cells. flammatory infiltration of lymphocytes process. The hypothetical mechanisms In an open-label study, this therapy was and macrophages that are predominant -

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ly clustered around the venules, and re - finding is unexpected because in animal cess related to the deep, subcortical pa - active that replaces the as models MS can be transferred via the thology. 7 Rather, it represents primary they die. transfection of activatedT-cells. Conse - damage, which remains a poorly under - The classic description of MS as a dis - quently,T-cells have been considered the stood part of the disease. ease of the white matter has been chal - major players in the pathogenesis of MS. lenged by increasing evidence of exten - PerhapsT-cells have the ability to initiate Clinical Features sive involvement of cortical and gray a process that proceeds through an inter - Considering the potential for a ran - matter structures. 27,30 Based on series of action with B-cells and macrophages. An dom distribution of the demyelinating brain and postmortem exami - increasing body of evidence indicates that plaques in the brain and spinal cord, it is nations from MS patients, 19 four distinct the regulatory mechanisms via CD4 and not surprising that the presentation of types of have been charac - CD8 suppressor cells are deficient in MS MS is as variable as its course. Studies terized: (1) a high degree of mononucle - patients. on the frequency of symptoms have ar cell infiltration, (2) elevated levels of The roles of genetic background and found that sensory complaints occur in antibodies, (3) elevated levels of comple - environmental factors in MS are slowly about 30% of the cases, motor and co - ment staining, and (4) loss of oligoden - being elucidated. HHV-6 and more so ordination issues occur in another third drocytes without significant inflamma - Epstein-Barr virus, which has the ability of patients, and polysymptomatic pre - tion. These observations suggested that to remain dormant in infected B-cells, sentations are most commonly encoun - demyelination may result from alterna - have been considered potential candi - tered. 26 Optic neuritis, a characteristic tive or partially coexistent mechanisms dates as initiators of an immune response manifestation of MS, occurs in about and that the triggering factors may be dis - that at later stages may evolve into a self- 20% of patients. However, the most fre - tinct for different cases. Findings from a sustained autoimmune process. 34 Vita - quently reported symptom is , recent report of brain of patients min D, another environmental agent, has which likely results from diffuse cere - in the progressive phase of MS are con - been implicated by epidemiological data, bral injury rather than from a few focal sistent with this notion. Only a subset of but conclusive evidence of its role in au - lesions. Such diffuse injuries may cor - patients was found to have germinal B- toimmunity is lacking. An ongoing Phase relate with the abnormalities detected cell follicles localized in the meninges. 20 II clinical trial on the benefits of high on MR imaging. 35 That demyelinating plaques were de - doses of vitamin D has thus far proven The variability and unpredictability of tected in the subpial regions near the safe, and efficacy data are awaited. the disease have spurred several investi - meningeal follicles is indicative of their That the penetration of activated in - gations aimed at identifying markers that pathogenetic role. Characteristically, the flammatory cells in the CNS is patho - would distinguish a benign course from absence of lymphocytic infiltration in the genic represents a long-standing acqui - an aggressive one. Clinically, the number corresponding underlying areas of de - sition in MS. In fact, more than a century of clinical relapses in the early stages of myelination is suggestive of a humorally ago, pathologists noted this relationship, disease correlates with later disease pro - mediated insult. and it is universally accepted that MS is gression. However, the number of lesions For many years, the participation of an immune-mediated disease. Howev - detected on MR imaging remains the B-cells in the pathogenesis of MS has er, the link between inflammation and most reliable measure of long-term dis - been considered of secondary impor - degeneration is only now being ex - ability. 1 Ten to 15% of patients have a be - tance despite the established presence of plored. A growing number of investiga - nign form of the disease and do not de - immunoglobulins in the form of oligo - tions using MR techniques have pro - velop major disability, but loss of function clonal bands in the CSF. Although the vided evidence that even at the earliest is unrelenting in most cases. The prima - definitive meaning of the oligoclonal stages of disease, a much more diffuse in - ry progressive form of MS more fre - bands is unknown, some evidence fa - sult to the brain can be detected. At the quently affects males who are 10 to 15 vors the significance of a humoral re- time that MS first manifests, oligoden - years older than the average patient at the sponse to viral antigens in the pathogen - drocytes, even in the normal-appearing onset of MS. This form is characterized esis of MS. 10 Interestingly, the same white matter, are already affected by by steady neurological deterioration oligoclonal bands continue to be detect - pathological changes. 27 In a correlation without much inflammation. 28 ed in MS patients at least 3 years after between MR imaging and postmortem treatment with the histopathology, the extent of cortical and Diagnosis anti-CD52 or after a bone marrow trans - subpial demyelination was independent To diagnose MS a combination of plant of autologous stem cells when the of the white matter burden of lesions. clinical features and laboratory and ra - inflammatory component of the disease That is, the degree of axonal and gray diological criteria must be met. In 2001 has been shut off dramatically. The re - matter loss was disproportionate to the new diagnostic criteria for MS were pro - sults of the clinical trial on rituximab amount of disease noted in the white posed to include MR imaging to dem - strongly support a major role for B-cells matter. This finding suggests that gray onstrate the required dissemination in in maintaining disease activity. 16 This matter damage is not a degenerative pro - space and time. 25 Barkhof et al. delineat -

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ed the typical features of MS on MR im - treatment (Table 4). The hope for a cure aging (Table 3). 5 Table 3. Barkhof MR is promising. Application of the proposed criteria Imaging Criteria for MS and have enhances diagnostic accuracy. Nonethe - Patients been investigated extensively even in ran - less, several neurological conditions, such domized clinical trials comparing med - as other autoimmune and infectious dis - Nine supratentorial lesions or one ications. The efficacy of these prepara - eases, are difficult to distinguish from MS -enhancing lesion tions appears to be equivalent. The only on the basis of MR imaging alone. Oc - At least one infratentorial lesion exception is a 2-year study that showed casionally, even patients with small vessel that the interferon beta-1a administered may have signal At least one juxtacortical lesion once a week had an intermediate effect abnormalities on MR imaging that re - At least three periventricular lesions between high-dose interferon and a pla - semble demyelination. Consequently, cebo. 43 The choice of which medication only a comprehensive evaluation allows to use involves considerations of logistics a correct diagnosis. In this context, CSF and tolerability. Side effects are of prima - testing becomes important. It has a pre - adjunctive method for the diagnosis of ry importance when choosing among dictive value independent of MR imag - MS and is considered an important these agents. The risks and benefits favor ing, particularly at the onset of the dis - outcome measure for therapeutic clin - initiating therapy at the earliest manifes - ease, for the so-called clinically isolated ical trials. tations of the disease. In fact, data repli - syndrome. This term is used to identify The finding of a clinically silent but cated in several studies and reviewed in a a clinical event that has characteristics of progressively destructive process is paral - meta-analysis 11 support the view that a demyelinating episode, such as trans - leled by an increasing body of evidence early modulation of disease activity im - verse myelitis or optic neuritis, but MS from MR imaging that shows that sig - proves clinical and radiological outcomes cannot be formally diagnosed. Oligo - nal abnormalities can be detected early to a level that cannot be reached by a pla - clonal bands identified by immunoelec - in the of MS patients. cebo-control group. trophoresis in the CSF and not in the Both cortical and deep gray matter are The mechanisms of action of inter - serum of patients with clinically isolated clearly affected and account for brain at - feron have been the objective of intense syndrome have a sensitivity of about 90% rophy. Sophisticated MR imaging tech - investigations. Its positive effects in MS and a specificity of 96% for predicting niques, such as MR spectroscopy, mag - appear to be mediated by multiple ac - conversion to clinically definite MS. 23 netization transfer, and diffusion tensor tions, including repair of the blood-brain The visual pathway is selectively af - imaging, combined with stronger mag - barrier and switching the cytokine pro - fected in MS patients. Consequently, nets (7 or 8Tesla scanners are now used file away from Th1. 22 Of relevance to the characteristic delay in visual evoked for research), have helped improve the clinical practice is the difference in prep - potentials has made this test part of the specificity of the signal from demyelinat - aration of the various interferons. The diagnostic armamentarium. An even ing lesions and have revealed previously first manufactured interferon was beta- more reliable method, ocular coher - unsuspected aspects of the disease. How - 1b. It contains a substitution of serine ence tomography, provides information ever, until these methods become avail - with cysteine at position 17. The inter - about the integrity of the optic fibers at able for routine practice, it remains im - feron beta-1a has the same sequence as the level of the optic disc. This test re - portant to screen for alternative diagnoses the natural product, including the glyco - lies on a harmless infrared laser beam that mimic MS based on their appear - sylated side chain, which renders the lat - projected through the dilated pupil. In ance on MR imaging. Furthermore, ter slightly less immunogenic. The im - less than 1 minute it measures the thick - evaluations to rule out vasculitides, sar - munogenicity has clinical implications ness of the nerve fibers at the optic disc. coidosis, and cerebrovascular disease re - for the production of neutralizing anti- A decrease in the nerve fiber layer cor - main necessary. interferon antibodies that can occur in responds to axonal loss, which appears MS patients treated with interferons. At to be a sensitive reflection of Therapy high titers the effect of the medication is damage. Ocular coherence tomogra - In parallel with an improved under - lost. Several reports indicate that the neu - phy supports ongoing, subclinical, slow - standing of the pathogenesis of MS, its tralizing antibodies may disappear over ly progressive loss of neural tissue in the treatment is also evolving rapidly. The time despite continuation of therapy. The optic nerve, even in the absence of a dis - first disease-modifying agent was intro - current recommendation is to discon - crete clinical attack on the nerve. This duced about 15 years ago. Since then the tinue interferon therapy when the neu - loss appears to correlate directly with number of drugs available for treatment tralizing antibodies are detected at a titer the gradual development of brain atro - has increased steadily. More important - greater than 1:100. 17 phy invariably observed in the advanced ly, several other medications in Phase II The mechanisms of action underly - stages of MS. 14 For its objectivity, ocu - and III clinical trials have already shown ing glatiramer acetate are far from un - lar coherence tomography is now an greater efficacy than currently available derstood. This compound is composed

10 BARROW QUARTERLY • Vol. 24, No. 2 • 2008 Bomprezzi and Campagnolo: Inflammatory Demyelinating Diseases of the Central Nervous System

of random combinations of four amino acids present in high concentrations in Table 4. Disease-Modifying Therapies for MS human . It was de - veloped in an attempt to induce MS in a FDA-Approved Medications mouse model and was found to be pro - Interferon beta 1a: weekly intramuscular injections (Avonex) tective against the disease. Initially, it was Interferon beta 1a: subcutaneous injections three times/week (Rebif) hypothesized that a shift fromTh1 toTh2 Interferon beta 1b: subcutaneous injections every other day (Betaseron) was the main effect of glatiramer. Newer Glatiramer acetate: daily subcutaneous injections (Copaxone) data, however, do not support this theo - : monthly endovenous infusion (Tysabri) ry. Its effect appears to be much broader, Mitoxantrone: intravenous infusions every 3 to 6 months (Novantrone) including an instructive role at the level of the innate immune system. Regardless Drugs under Investigation of its mechanism of action, glatiramer re - mains a good first-line agent for MS. It is Fumarate as effective as high-dose interferons, with an overall better safety profile, given the Laquinamod potential for worsening and DNA recombinant MBP liver toxicity associated with interferons. Natalizumab, a humanized mono - cloncal antibody directed to the alpha 4 Rituxan subunit of the integrin, has lately come to the forefront for the treatment of MS. It MBP = myelin basic protein was voluntarily pulled from the market in 2006 by the manufacturing company after two patients developed progressive multifocal leukoencephalopathy. It was this therapy has again been tempered by than current regimens. Monoclonal an - then reintroduced as a second-line agent several additional cases of progressive tibodies are a particularly promising class with a policy of mandatory enrollment multifocal leukoencephalopathy report - of medications. Thanks to their high se - in a clinical registry aimed at monitor - ed in patients treated with natalizumab as lectivity, these molecules have thus far ing adverse events. Since then its safety a single agent for MS. exhibited a relatively good safety profile record has been acceptable, and its effi - Mitoxantrone is a chemotherapeu - combined with unprecedented effec - cacy has been superior to other ap - tic agent that owes its efficacy to its cy - tiveness in the treatment of MS. proved medications. Consequently in totoxicity forT- and B-cells. With more April 2008, it received approval for use as than a decade of use in MS, consider - a first-line drug for the treatment of MS able experience has been acquired with Conclusion and severe Crohn’s disease. Quenching this medication and its safety profile is Recognizing and becoming familiar the inflammation as it first manifests is well established. 8 The maximum total with some of the most commonly en - one of the key messages of the most re - lifetime dose of 140 mg is considered countered immunological disorders that cent studies on therapy for MS. Natal - below the limit for an increased risk of may affect the CNS are key to initiating izumab does so effectively given its abil - leukemia and cardiotoxicity. These con - appropriate treatment. The field of im - ity to target the adhesion molecule on ditions, however, can still occur from munology is subject to constant updates activated mononuclear cells. As an IgG1, idiosyncratic reactions. The evidence as new concepts are introduced. Hence, it does not bind complement and does for stabilization of aggressive forms of the understanding of the mechanisms not induce apoptosis in the bound cells. MS with treatment with mitoxantrone of action of the immune systems is con - It does prevent them from penetrating is robust. Mitoxantrone is still the only tinuously refreshed by new discoveries. the blood-brain barrier, thus limiting the agent recommended for the treatment Furthermore, the therapeutic options recruitment of pro-inflammatory cells of secondary progressive MS. available to treat diseases caused by into the CNS. 31 Data on patients ex - Numerous other medications are in deregulated immune responses are ex - posed to the medication for more than Phase II or III clinical trials (Table 4). Ex - panding rapidly. These options will like - 3 years have been collected, but no long- pectations for some of these therapies are ly continue to grow, and practitioners term outcome or safety data are avail - high. 8 Among the many newer drugs, will be provided with better therapies able. Therefore, the question of what is oral formulations are of particular inter - to offer patients. It is hoped that cures the best continuous long-term manage - est because they are more convenient will become available for these some - ment of MS patients treated with natal - than injectables and infusions and be - times devastating diseases in the not too izumab remains. In fact, enthusiasm for cause their overall tolerability is better distant future.

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