Neuropathology Article

Neuropathology of Multiple Sclerosis

ince the first clinico-pathological descriptions of almost 2 to 1. Incidence of MS varies by geographical loca- multiple sclerosis (MS), neuropathologists, neurolo- tion, the more industrialised countries showing the highest Sgists, immunologists, geneticists and scientists have figures. It remains unclear whether this altered incidence rep- worked together in an attempt to clarify the pathogenesis resents an environmental influence, genetic difference or sim- of this enigmatic disease. Multiple sclerosis is a complex ply is the result of variable surveillance. The natural history of condition and there is no consensus as to whether it rep- MS is usually characterised by progressive neurological dete- resents a single disease or a series of diseases with a com- rioration. Physical disability is the rule. A considerable num- mon final pathway. For this reason systematic pathologi- ber of affected individuals also experience cognitive dysfunc- cal analysis of brains affected by demyelination is still tion in the course of the disease although cognitive disability important to provide new insight into the pathogenesis of at onset is rare. Patients with MS exhibit different patterns of Federico Roncaroli qualified as a the disease. This review is the result of experience gained disease activity. About 80-85% have a relapsing–remitting Histopathologist in Italy and is now from examining brains donated by patients with MS to course and a considerable number develop secondary pro- Clinical Senior Lecturer in Neuro- the UK Multiple Sclerosis Tissue Bank (UKMSTB) at the gression with or without occasional relapses. About 10% of pathology at the Department of Neuropathology, Imperial College Imperial College of London. patients exhibit primary progressive MS. The least common of London. He is one of the refer- form is progressive relapsing MS, a variant where the disease ring neuropathologists of the UK Brief historical overview is progressive from the onset with acute relapses. Multiple Sclerosis Tissue Bank. Descriptions of cases of putative MS date back as early as the Middle Ages but it was in the 19th century when doc- Neuropathology Correspondence to: tors definitively recognised MS as a distinct disease. The Macroscopic findings: At external examination, brains Federico Roncaroli, MD, first pathological report was published by Jean-Martin affected by MS can look normal or show variable degrees University Department of Charcot, Professor of Neurology at the University of Paris of atrophy. In many cases, plaques are visible on the exter- Neuropathology, Division of Neuroscience and 2 in 1868 in the Leçons du mardi. He examined a young nal surface of the optic pathways, brainstem and spinal Mental Health, woman who presented with tremor, slurred speech and cord. In atrophic brains, the lateral ventricles in particular Imperial College of London, abnormal eye movements. When she died, Charcot had appear dilated due to loss of volume of the centrum semi- Charing Cross Campus, the chance to study her brain and document the charac- ovale. Severe hydrocephalus is observed in 5-10% of cases. St. Dunstans Road, London, W6 8RP. teristic scars he termed ‘plaques’ coining the definition of On sections, plaques appear as sharply demarcated and Email: [email protected] ‘la sclerose en plaques’. He also delineated the clinical diag- slightly depressed areas varying in colour. Fresh plaques nostic criteria with the triad of nystagmus, intention are pink due to hyperaemia induced by inflammation or tremor and scanning speech which, though not specific, white to yellowish due to lipid breakdown; chronic are still helpful in recognising the disease. In 1916 James Dawson at the University of Edinburgh wrote the first Table 1: Spectrum of Demyelinating Diseases detailed microscopic description of the brains of MS patients, documenting perivascular inflammation and Demyelination due to infectious agents - Progressive multifocal leukoencephalopathy myelin disruption. Since this time, MS research has grown - Subacute sclerosing panencephalitis relentlessly with the discovery of abnormalities in spinal fluid in 1919, the discovery of oligodendrocytes made by Metabolic disorders of myelin Ranvier in 1928 and with the observation in animal mod- - Metachromatic leukodystrophy els in 1935 that injection of brain tissue produces an MS- - Globoid cell leukodystrophy like illness, called experimental allergic encephalomyelitis. - Pelizaeus-Merzbacher disease

Definition of multiple sclerosis Peroxisomal disorders affecting myelin Multiple sclerosis belongs to the complex group of disor- - Generalised peroxisomal disorders ders of the central nervous system characterised by - Cerebrohepatorenal (Zellweger) syndrome destruction of myelin (Table 1). Given the clinical and - Infantile Refsum disease (phytanic acid storage) pathological heterogeneity of MS, there is no conclusive - Neonatal adrenoleukodystrophy definition of the disease and the one suggested by Poser11 - Hyperpipecolic acidemia of an “inflammatory demyelinating disease of the central Single peroxisomal enzyme deficiencies with widespread pathology nervous system in which the particular myelinoclastic - Thiolase deficiency sequence, regardless of the clinical course and the pheno- - Acyl-CoA oxidase deficiency typic manifestation is determined by the individual - Rhizomelic chondrodysplasia endowment and which results in a pathognomonically - Single peroxisomal enzyme deficiencies with more restricted pathology unique lesion, the sharp-edge plaque” emphasises the fact - Adrenoleukodystrophy complex that we can only be descriptive. As stated, multiple sclero- .- Diseases of unknown aetiology sis is a heterogeneous pathological condition and the dif- ferent variants reported so far (Table 2) most likely repre- Multiple sclerosis sent separate entities rather than different phenotypic Acute disseminated encephalomyelitis expressions of the same disease. Fibrinoid leukodystrophy (Alexander disease) Epidemiology and clinical features Multiple sclerosis is a common disease worldwide and one of Table 2: Clinicopathological Variants of Multiple Sclerosis the leading causes of disability in Western Europe and the United States. It has been estimated that it affects more than Relapsing remitting course/Secondary progressive 2.5 million individuals with a prevalence varying between 5 Primary progressive and 119 per 100,000 in the United States. In the United Progressive relapsing Kingdom, MS affects about 85,000 individuals. The age of Acute Multiple Sclerosis or Marburg Variant onset is broad and ranges between 10 and 60 years, with a Neuromyelitis Optica or Devic’s Disease peak between 20 and 40 years and a mean of 32 years. There Balo’s Concentric Sclerosis is a predominance in females with a ratio of female/males of Myelinoclastic Diffuse Sclerosis or Schilder’s Disease

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plaques are grey–tan and firm in consistency the spinal cord, areas of myelin loss can be Consensus of classification of plaques due to marked gliosis. The number and distrib- peripheral or central. Plaques usually do not The structural pathology and immunopathology ution of plaques vary from cases to case but in at exceed 1.5 cm and often appear to be subpial. In of MS was discussed in an interdisciplinary forum least two-thirds of brains there is an equal dis- cases with long duration, the spinal cord is held in Vienna in 1998 under the patronage of the tribution of demyelination in the cerebral hemi- atrophic and on cross section the architecture is International Federation of Multiple Sclerosis spheres, spinal cord and optic pathways (Figure effaced in that there is no clear distinction 1). As a rule, plaques are not restricted to any between white and grey matter. anatomical zone, do not follow specific vascular General histological features: The vast a territories, are not related to any neuroanatom- majority of cases of MS show a mild non-specif- ical tract or system, and are not associated with ic leptomeningeal inflammatory infiltrate com- any defined neurotransmitter (Figure 2a).5 In posed of mature lymphocytes and often plasma the cerebral hemispheres, lesions usually involve cells. Histological features of plaques vary the white matter around the lateral ventricles according to the stage of demyelination and and often the lesions show continuity from the degree of activity. Commonly, plaques are classi- frontal to the occipital lobes. The borders of the fied as acute, chronic active, inactive and, when areas of myelin loss are convex at the beginning remyelination occurs they are termed shadow of the process and become finger-like as plaques. At the UKMSTB, we have adopted a demyelination proceeds following parenchymal slightly different terminology to define active and sub-ependymal veins (Dawson’s fingers). plaques and we prefer to distinguish those with Juxta-cortical plaques are also commonly seen. early activity from those with late changes based They appear smaller than white matter plaques on the number of macrophages, distribution and b and often extend to the lower part of the corti- extent of microglial activation, degree of reactive cal ribbon. Isolated cortical plaques are rare and astrocytosis and severity of demyelination. difficult to see on macroscopic inspection. Criteria are essentially those suggested by the Demyelinating areas in the brainstem are often consensus meeting held in Vienna in 1998.7 subpial and visible on the anterior aspect of Chronic active and inactive plaques: pons (Figure 2b) and medulla or subependymal Activity is determined by the presence of foamy affecting the floor of the fourth ventricle. In sec- macrophages containing fragments of myelin. tions of the brain stem, plaques are rounded and Staining properties of myelin debris change often cross the midline. Cerebellar involvement with time and become PAS-positive. Active is less frequent and at gross examination, plaques are characterised by progressive plaques involving folia are not recognisable. In destruction of myelin which appears to be stripped off by macrophages (Figure 3a), vari- a b able perivascular inflammatory infiltrate most- ly composed of T-lymphocytes, prominent reactive astrocytosis, and a variable degree of activation of microglial cells. Axons are often c swollen and wavy indicating damage and some- times appear interrupted with the formation of spheroids (Figure 3b). Active myelin destruc- tion can occur in normal white matter or in remyelinated lesion as in Figure 3c. Oligodendrocytes are usually preserved or slightly reduced in newly demyelinating lesions Fig 1: This axial T1-weighted MR-scan shows several whereas they often appear to be increased in brightly hyperintense periventricular and white matter number when demyelination involves a plaques (a). One subcortical plaque is seen after remyelinated plaque. As mentioned before, we administration of paramagnetic contrast (b). consider as early active plaques those lesions in which myelin loss is still incomplete, myelin Fig 3: Early active demyelination with many macrophages a debris can be seen within macrophages when and reactive astrocytes (a, LFB/PAS), the inset shows stained using Luxol fast blue (LFB) and in macrophages with cytoplasm filled with myelin debris which reactive astrocytosis predominates. In (LFB/PAS); Bielschowsky stain demonstrates axonal spheroids within the same plaque (b, Bielschowsky); these plaques, reactive astrocytes feature atypi- reactivation is seen at the edge of this plaque (c, LFB/PAS- cal nuclei and sometimes undergo mitotic divi- MHC class II antigen). sion. In contrast, late active plaques are those with nearly complete disappearance of myelin sheaths, PAS-positive myelin debris and less prominent reactive astrocytosis (Figure 4). Chronic inactive plaques are easily seen in con- ventional haematoxylin-eosin and Luxol-fast blue stains. They appear as sharply demarcated areas of discolouration with dense fibrillary Fig 2: Plaques appear as gliosis, loss of oligodendrocytes and few grey-pink and yellow irregular lesions (a). microglial cells (Figure 5a). A few macrophages containing PAS-positive old products of myelin The anterior aspect of degradation can also be seen, particularly at the the pons shows several edge of the lesion. Vessels typically are sur- confluent plaques (b). rounded by an empty space and their walls appear to be damaged. Chronic inactive Fig 4: A late active plaque with complete loss of myelin and plaques are also characterised by marked reduc- several macrophages containing PAS-positive products of b tion of axonal density (Figure 5b-5c). myelin degradation (LFB/PAS).

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a bc prominent. Aware that the process of demyeli- nation is a continuum and classifications are always artificial, we prefer to designate as acute plaques only those white matter changes with mild activation of microglia, ie. a few activated microglial cells but lacking definite activation of the immune system. Our position is in keep- ing with the interesting observation published by Barnett and Prineas on the early white mat- ter changes in a case of relapsing-remitting MS.1 This study suggested that the inflammato- ry response is secondary to the initial event of Fig 5: Inactive plaques are characterised by sharp margins and low celllularity (a, LFB/PAS). There is considerable reduction apoptotic death of oligodendrocytes. of axons (b, LFB/PAS – c, Bielschowsky). Oligodendrocyte death causes a series of tissue responses including activation of resident Societies and the National Multiple Sclerosis patient and only conversion from pattern I into microglia that remove the dying oligodendro- Societies of the United States and Canada. Fully pattern II was seen to be possible. cytes before frank myelin pathology. As part of aware of the heterogeneity of MS, neuropatholo- Pattern I: This pattern is characterised by T- the apoptotic pathway, activated complement is gists, clinical neurologists, neuroradiologists and lymphocytes and microglia and macrophages deposited on myelin sheaths and, within days, immunologists attempted to clarify pathological alone without deposition of immunoglobulins myelin appears vacuolated. The vacuolated and changes seen in MS. Observations gathered in this throughout the lesion and no deposition of complement-positive myelin attracts mono- multidisciplinary review and the conclusions were complement components. Demyelination is cytes that begin phagocytosis. When phagocy- published in a review article7 and now represent a perivenular and there is loss of all types of tosis takes place, foamy macrophages dominate sort of guideline for the pathological diagnosis. myelin protein. Pathological changes occur the pathological picture. All participants emphasised the importance of simultaneously in all plaques. It has been sug- combining neuropathology with neuroim- gested that demyelination and tissue injury is The issue of axonal damage munology and neuroimaging in elucidating the mediated by the cytotoxic effect of T-lympho- Although early observations by Charcot and pathogenesis, dynamics and mechanisms of cytes and activated phagocytes. Marburg mentioned axonal damage as a rele- demyelination. It was agreed that: pathogenesis Pattern II: This is the most common pattern. vant component of MS pathology, for decades of lesions in MS is complex and not merely a T- Pathologically similar to pattern I, it shows plaques have generally been considered to be cell mediated response. Axonal degeneration plaques with well-defined margins, perivascu- areas of demyelination with preservation or lit- occurs to a significant extent and is clinically rel- lar cuffs of lymphocytes and simultaneous loss tle disruption of neuropil.4 Features of damage evant; the regenerative potential is more pro- of myelin with myelin degradation products in such as wavy axons and axonal spheroids were nounced than previously recognised, with abun- macrophages. Dissolving myelin sheaths are known to occur in MS plaques but have usual- dant spontaneous remyelination in early stages of coated with immunoglobulins and activated ly been dismissed as an epiphenomenon of the disease and some oligodendrocyte progenitor complement and antibodies against compo- demyelination with no clinical relevance. It was cells remaining in chronic sclerotic lesions. All nents of the myelin sheath appear to be only recently that axonal damage and axonal participants finally agreed that neuropathological involved in demyelination. This pattern is asso- loss emerged as important for explaining per- studies should be performed on well-staged and ciated with shadow plaques indicating that manent irreversible neurological disability of defined material because this will give the essen- remyelination may occur. patients with MS. Recent studies have indicated tial basis for defining the mechanisms of tissue Pattern III: Activation of macrophages and that small fibres are more vulnerable and that damage and the structural correlates of MRI microglia is less pronounced than in patterns I significant axonal loss occurs not only within abnormalities. This latter is also the remit of the and II and the destruction of myelin sheaths plaques but also around demyelinating areas UKMSTB. Most important was the attempt of a does not strictly follow the distribution of and even in histologically normal white mat- more precise definition of ongoing demyelinat- inflammatory cells. Plaques are not centred on ter.5,13 Long pathways such as the pyramidal ing activity based on the presence within veins and venules and are characterised by ill- tracts and the dorsal columns of the spinal cord macrophages of degradation products of minor defined margins, preferential loss of myelin- are those most heavily affected. Multiple myelin proteins rather than on the activity of the associated glycoprotein relative to other myelin episodes of demyelination over the course of inflammatory process. The following different proteins such as MBP and proteolipid protein the disease and subclinical attacks may cause stages have therefore been delineated: i) Plaques and no deposition of IgG. Preservation of a rim permanent injury that leads to progressive with inflammation and macrophages containing of myelin around inflamed vessels is common. axonal destruction and eventually to neuron early myelin debris identified by their reactivity Typically, there is marked loss of oligodendro- loss due to Wallerian degeneration. Damage of for LFB or myelin proteins; ii) Plaques with cytes at the border of demyelination. nerve fibres appears to be more extensive dur- inflammation in the absence of early myelin Pattern IV: The inflammatory reaction of ing the first year from onset and the number of degradation products in macrophages; iii) pattern IV is similar to that described for pat- acutely injured axons decreases with disease Plaques with early myelin degradation products tern I but it is associated with a more extensive duration longer than 10 years. The anatomical in the absence of perivascular infiltrates and iv) demyelination, and death of oligodendroglial correlate of axon loss is atrophy, which increas- Plaques without inflammatory infiltrates and cells. Tissue damage is likely to be determined es along with disease progression and involves absent early myelin degradation products. by a genetic susceptibility of the target tissue for white and grey matter of the cerebral hemi- immune mediated injury. spheres, brain stem and posterior sensory tracts Patterns of demyelination and corticospinal tracts of the spinal cord. In a seminal study published in 2000,8 The acute plaques Atrophy is most severe in primary and sec- Lucchinetti et al. proposed a new approach to The definition of an acute plaque is challenging ondary progressive disease and may indicate MS that substantially changed the current because it implies a definition of early stages of the conversion from a relapsing remitting interpretation of the disease. Their pathological demyelination. The terminology appears con- course into secondary progression. The irre- examination of active lesions led to the recogni- fusing because the term ‘acute’ is used to versible secondary progressive stage begins tion of four different patterns of demyelination, describe subtle lesions of the white matter char- when axonal injury reaches a threshold. The all sharing a qualitatively and quantitatively acterised by oedema and initial myelin frag- mechanisms of axonal degeneration are incom- similar response of T-lymphocytes and mentation and lesions in which the inflamma- pletely understood. It seems that axonal loss macrophages. Each pattern appeared to be the tory component, active myelin phagocytosis might depend on several causes including same in all of the lesions examined in a single and reactive astrocytes are already present and direct effects through the loss of trophic influ-

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ences from oligodendrocytes, as a consequence presence of mild gliosis, corpora amylacea and a months from onset. Such an acute course may be of sustained demyelination-induced conduc- few macrophages containing products of myelin evident from the beginning or develop in the set- tion block, and indirectly through the increased breakdown at the periphery of the lesion may be ting of otherwise classical chronic MS. The few vulnerability of the exposed axons to noxious helpful. Regeneration of central myelin is some- patients that survive the acute phase then show a agents. times accompanied by invasion of Schwann cells relapsing remitting course. In Marburg disease, migrating from the root entry or exit zones of demyelination usually begins in the hemispheres Cortical involvement peripheral nerves. In many instances, recurrent or in the brainstem. Distribution of the lesions is Multiple sclerosis is not only a disease of the demyelination may occur at the edge of shadow indistinguishable from classical MS, but unlike white matter. It is not uncommon to find juxta- plaques causing enlargement of the lesion. classical MS, myelin loss occurs simultaneously in cortical plaques with extension to the lower layers Episodes of myelin breakdown in shadow all affected areas. On histological grounds, lesions of the grey matter. Some cases show isolated cor- plaques eventually lead to gliosis with tissue are similar to those of classical MS although they tical plaques and are characterised by predomi- scarring so that further remyelination can no may contain more inflammatory infiltrates and nant cortical involvement.5,12 Cortical plaques are longer occur. For this reason, recovery of myelin appear more destructive. The margins of the hardly recognisable at macroscopic examination becomes less effective with disease progression lesions are often indistinct and myelin breakdown particularly when the brains are fixed. Cortical so that post-mortem examination of brains may be patchy or incomplete. Reactive astrocytes demyelination can occur anywhere and plaques from patients with long standing disease hardly are scattered; oligodendroglial cells usually appear usually range in size between a few millimetres ever reveals shadow plaques. to be considerably reduced in the acute lesions and 1 cm. Grey matter involvement can be hard- although there is no evidence of their death and ly visible at microscopic examination using histo- Clinico-Pathological variants of multiple they increase in older lesions, indicating regenera- chemical stains because the cortex contains much sclerosis tion. Axonal damage is prominent. less myelin and inflammatory cells and microglia Relapsing remitting type: Relapsing remit- Balo-type concentric sclerosis: Described by are much less abundant in cortical demyelination ting type is the commonest variant of MS. It is Joseph Balo in 1928 as ‘Encephalitis periaxialis than the white matter counterpart (Figures 6a- characterised by periods of exacerbation with a concentrica’ and then characterised by Courville 6b). Immunohistochemical stains to identify variable amount of improvement between in 1970, this disease is aggressive and often leads gliosis, macrophages and microglial infiltrates, attacks. The pathology of typical relapsing to death in weeks to months. The age of onset and anti-myelin antibodies are therefore helpful remitting MS consists of disseminated plaques of ranges between the first and the fifth decade and for a correct assessment of cortical pathology. different ages. Plaques can be found wherever there are no clinical findings that distinguish this Cortical pathology in MS has been carefully there is central myelin. Lesions range from acute variant from other types of MS. Some cases with investigated in recent studies by Kidd et al3 and plaques to early and late active and chronic inac- Balo-type lesions may improve and develop a Peterson et al.10 These authors studied 112 corti- tive plaques. Although plaques can appear any- typical relapsing remitting MS. The striking and cal lesions identified in 50 patients with MS and where, the periventricular white matter, optic diagnostic pathological feature is the presence of suggested a classification of cortical plaques, the nerves, spinal cord, and juxtacortical areas are alternating bands of demyelinated white matter type 1 being contiguous with subcortical lesions, the commonest sites. The majority of patients with bands of preserved or regenerated myelin. type 2 small, usually perivascular lesions con- then develop secondary progressive MS. These concentric lesions always involve the cere- fined to the cortex, and type 3 extending from the Secondary progressive: Change from relaps- bral hemispheres, most commonly the frontal cortical surface to layer 3 or 4 of the cortex. In ing remitting to secondary progressive MS usu- lobe, and may range from one to several centime- grey matter plaques, demyelination is accompa- ally occurs in patients in their 40s or early 50s tres in diameter. They can be spherical or irregu- nied by mild microglial activation. Cortical after many years of disease. Clinically, the sec- lar. Histological examination suggests that the pathology seems to play an important role in MS ondary progressive course is marked by slowly lesions expand over weeks or months by progres- and cortical lesions may account for many of the ascending paralysis or rarely by progressive sive addition of bands of myelin breakdown. The cognitive changes occurring in the later stages of ataxia. Pathological examination demonstrates demyelinated areas exhibit axonal preservation, the disease. loss of axons in the spinal cord with cord atro- absence of oligodendroglial cells, and variable ab phy. Many plaques are chronic inactive and inflammatory infiltrates. There is currently no only a few appear to be active plaques. A feature anatomical, immunohistochemical, vascular or of secondary progressive MS is also degenera- immunological explanation for the remarkable tion of multiple individual nerve fibres, which development of concentric, alternating bands of is likely to be the result of inadequate supply of demyelination and white matter preservation. transported materials. Demyelination of indi- Neuromyelitis optica of Devic: In 1894, vidual fibres could be the substrate for the slow- Eugene Devic reported the case of a 45-year-old ly progressive ascending paralysis. woman who presented with intractable headache, Primary progressive: The primary progres- depression and generalised weakness. The illness sive form of the disease accounts for about 10% progressed with urinary retention and complete of cases of MS and usually occurs in older paraplegia and eventually with complete bilateral patients. Onset is insidious and progression is blindness whereas the depression and headache constant. Disability affects primarily the spinal resolved with time. Pathological examination cord without exacerbations or remissions. demonstrated demyelinating and necrotising Fig 6: This coronal cut shows a cortical plaque at the base of the superior frontal sulcus (a); A cortical plaque is seen Pathologically, lesions in primary progressive lesions of both white and grey matter limited to with LFB/PAS (b). MS feature T-lymphocytes and macrophages but the spinal cord and optic nerves. This patient and there is no deposition of IgG and complement. A another 16 reported in Europe and the United Remyelination hallmark of this variant is death of oligodendro- States were studied in the doctoral thesis of Remyelination is commonly seen in cases of cytes, which occurs in the white matter adjacent Fernand Gault ‘De la neuromyélite optique aiguë’ relapsing-remitting MS. Defined as shadow to areas of demyelination with the simultaneous in the same year and published by Devic. In his plaques, areas of myelin recovery appear as loss of various myelin proteins. paper, Devic named the disorder ‘neuro-myélite plaque-like lesions where myelin stains weakly, Marburg’s type: This disease was first optique’ or ‘neuroptico-myélite’ as a clinical type, cellularity is increased due to an increased num- described by Otto Marburg in 1906. Marburg or rather a syndrome and suggested a relationship ber of oligodendrocytes and progenitor cells documented a few cases presenting with a short with an acute form of MS. It was Acchiote who and myelin sheaths appear to be thinner than and fulminant course and showing extensive proposed in 1907 to define neuromyelitis optica normal and of relatively uniform thickness. Less myelin destruction. Clinically, Marburg disease is as Devic’s disease. Devic’s type MS is an acute ill- commonly, recovery of myelin is nearly com- an acute, severe and progressive condition with no ness characterised by optic neuritis and transverse plete and shadow plaques are indistinguishable relapsing–remitting course. The illness progresses myelitis, which occur within a short time of each from normal white matter. In these cases, the relentlessly and often leads to death within other and with little or no involvement of other

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parts of the central nervous system. Unlike chron- placed round nucleus. Histochemical stains for Mastronardi and Moscarello9 suggests an inter- ic MS, this variant appears to be common in myelin and immunohistochemistry are manda- esting and innovative pathogenetic hypothesis. Asians and Africans. It is usually monophasic tory in these cases and complete clinical infor- The authors propose that the initial degenera- although several cases have developed a relapsing mation needs to be taken into consideration tive process results from a failure to maintain remitting course. In these instances, residual before issuing the final diagnosis. adult compact myelin which becomes more lesions after attacks are more severe and more easily degradable. The decreased stability of necrotic than classical MS. On pathological The issue of pathogenesis myelin seems to depend on metabolic causes grounds, Devic’s lesions are composed of isolated The pathogenesis of MS is obscure and the his- such as the loss of positive charges on myelin or confluent areas of demyelination with tissue tory of the disease is also the history of the basic protein and changes in the microtubular destruction. Perivascular cuffing by T-lympho- many hypotheses on the causative mechanisms network of oligodendrocytes. Interestingly, the cytes is present in many cases. When the episode underlying myelin destruction. Despite the authors show that white and grey matter distant of demyelination resolves, marked atrophy and enormous body of results achieved so far, there from areas of demyelination are also affected. even cystic changes may follow. Interestingly, the are several questions that require an urgent Given the lack of a clear understanding of MS, few plaques found in the cerebral hemispheres of answer if we are to achieve the result of a cure we should be open to all interpretations and be patients with Devic’s disease are histologically for patients with MS. We are all clear that the ready to go beyond the dogma of MS being pri- similar to plaques of classical MS. Whether immune system is somehow tricked into marily an inflammatory disease. Although there is Devic’s disease represents a variant of MS or a dis- destroying central myelin but the processes that no doubt that the immune system plays a key role, tinct entity remains unclear and questions that sustain such immune-mediated damage in these two hypotheses seem intriguing and it will Devic asked at the end of his study on the reasons humans remain uncertain and the key question be important to determine if a structural impair- for such a peculiar distribution of lesions and its as to whether the immune response to myelin is ment of myelin can trigger oligodendrocyte death pathogenesis still remain unanswered. primary or secondary to another disease mech- with subsequent activation of the immune Myelinoclastic diffuse sclerosis or Schilder’s anism is still unanswered. The other, perhaps response and whether this can help explain the disease: Schilder’s disease is a controversial enti- more speculative question is about whether the clinicopathological heterogeneity of MS. ty and for a long time it has been unclear cause of MS is genuinely enigmatic or rather whether this condition fitted into the classifica- that we are merely incapable of understanding tion of MS variants. The reason for this contro- what is in front of our eyes. We entirely agree on versy was the fact that the second and third case the comment by Trapp that our eyes see only described by Paul Schilder himself respectively what our mind is prepared to comprehend.13 References 1. Barnett MH, Prineas JW. Relapsing and remitting multi- in 1913 and 1924 were most likely ple sclerosis: Pathology of newly forming lesions. Ann adrenoleukodystrophy and subacute sclerosing Fig 7: Single plaques Neurol 2004;55:458-68. panencephalitis. It is now accepted that the 14- may mimic intrinsic 2. Charcot JM. Histologie de la sclerose en plaque. Gaz tumours. This axial Hopital (Paris) 1868;41:554-66. year old female patient reported in 1912 was an T1-weighted MR-scan 11 3. Kidd D, Barkhof F, McConnell R, Algra PR, Allen IV, example of MS. The designation of Schilder’s after gadolinium Revesz T. Cortical lesions in multiple sclerosis. Brain administration disease is nowadays applied to cases with acute 1999;122:17–26. demonstrates a right bilateral demyelination of cerebral hemispheres. 4. Kornek B, Lassmann H. Axonal pathology in multiple temporal hypointense sclerosis. A historical note. Brain Pathol 1999;9:651-56. Patients may present with hemiparesis, seizures, lesion with no contrast changes in their behaviour and signs of uptake (a). 5. Herndon RM. The Pathology of Multiple Sclerosis. In: increased intracranial pressure. The course is Histologically, the Herndon RM Multiple Sclerosis: Immunology, Pathology and Pathophysiology, Demos Medical typically progressive and neurological dysfunc- lesion features high cellularity and nuclear Publishing New York, 2003;185-197. tion widespread. Pathologically, the cases diag- atypia that can be 6. Hickey WF. The pathology of multiple sclerosis: A histori- nosed as Schilder’s disease demonstrate asym- misinterpreted as an astrocytoma (b, Haematoxylin-eosin). cal perspective. J Neuroimmunol 1999;98:37-44. metrical sharp areas of extensive myelin loss 7. Lasmann H. Recent neuropathological findings in multi- predominantly affecting the cerebral hemi- ple sclerosis. J Neurol 251(suppl 4):N2-N5, 2004 8. Lucchinetti C, Bruck W, Parisi J, Scheithauer B, spheres. Involvement is often bilateral. A pecu- Rodriguez M, Lassmann H. Heterogeneity of multiple liar feature is preservation of the subcortical ‘U’ sclerosis lesions: implications for the pathogenesis of fibres although this finding is not invariable. At demyelination. Ann Neurol 2000;47:707-17. the microscopic level, changes in acute lesions 9. Mastronardi FG, Moscarello MA. Molecules affecting myelin stability: A novel hypothesis regarding the pathogene- are similar to those observed in classical MS but sis of multiple sclerosis. J Neurosci Res 2005;80:301-08. unlike the classical variant cavitation or multi- 10. Peterson JW, Bo L, Mork S, Trapp BD. Transected neuri- ple cysts are common. Older demyelinated areas ties, apoptotic neurons, and reduced inflammation in corti- feature little or no lymphocytic inflammation. cal multiple sclerosis lesions. Ann Neurol 2001;50:389-400. Axonal damage is always present and seems 11. Poser CM, Brinar VV. The nature of multiple sclerosis. Clin Neurol Neurosurg 2004;106:159-171. more severe in older parts of the lesions. 12. Prineas JW, McDonald WI, Franklin RJM. Demyelinating diseases. In:Graham DI & Lantos PL Greenfield’s Diagnosis of MS on surgical samples Conclusion Neuropathology, 7th ed Arnold London, 2002;471-550. Rarely, plaques may present as a single space- As a conclusion of this brief review, I would like 13. Trapp BD, Peterson J, Ransohoff RM, Rudick R, Mork S, occupying lesion and mimic an intrinsic brain to mention two recent studies that suggest Bo L. Axonal transection in the lesions of multiple sclero- sis. N Engl J Med 1998;338:278-85. tumour. In these instances, the differential diag- intriguing explanations of the pathogenesis of 14. Trapp BD. Pathogenesis of Multiple Sclerosis: The Eyes nosis with diffuse astrocytomas or oligoden- MS and give hope that the real cause will be Only See What the Mind Is Prepared to Comprehend. drogliomas is difficult if not impossible using revealed soon. In the first study, published in Ann Neurol 2004;55:455-57. neuroimaging studies (Figure 7a) and a biopsy the Annals of Neurology by Barnett and is often necessary. Histological examination of Prineas1 the authors observed the initial stages Acknowledgements: surgical biopsies in patients with MS is chal- of demyelination in a young patient with Dr SM Gentleman PhD – Reader in Experimental lenging and poses considerable problems of relapsing-remitting MS and suggested that for- Neuropathology, Department of Neuropathology Prof R Reynolds BSc PhD – Professor of Cellular interpretation. Active plaques are always hyper- mation of plaques begins with apoptotic death Neurobiology, Scientific Director of the UKMSTB cellular and reactive astrocytes may show severe of oligodendrocytes and that death of oligoden- Dr O Malik MD – Consultant Neurologist, Clinical Director nuclear atypia and mitotic activity (Figure 7b). droglial cells is the primary cause of inflamma- of the UKMSTB Also, macrophages may mimic neoplastic cells, tion. Activation of the immune system comes Dr R Nicholas MD – Consultant Neurologist, referring Neurologist of the UKMSTB and particularly neoplastic oligodendrocytes later, only when complement and immuno- Dr A Vora PhD – Manager of the UKMSTB because during the first stages of their activa- globulins begin accumulating on myelin Prof MB Graeber Professor of Neuropathology, University tion they feature little cytoplasm and a centrally sheaths. The other study published by Department of Neuropathology

22 I ACNR • VOLUME 5 NUMBER 2 • MAY/JUNE 2005