Demyelinating Diseases

Demyelinating Diseases 415

Demyelinating Diseases A Javed and B G W Arnason, University of Chicago, Chicago, IL, USA ã 2009 Published by Elsevier Ltd.

Introduction The demyelinating diseases are important because of their frequency and the disability that they cause. Common to all is a patchy destruction of myelin sheaths, usually secondary to an inflammatory response. Myelin loss occurs in other conditions: examples include (1) genetically determined defects in myelin metabolism, (2) toxin exposures, and (3) infections of oligodendrocytes, the myelin producing cells of the central nervous system (CNS). These entities are usually not classified as demyelinating diseases. The demyelinating diseases can be divided into those affecting CNS myelin and those affecting peripheral nervous system myelin. CNS diseases include multiple sclerosis (MS), acute disseminated encephalomyelitis (ADEM), neuromyelitis optı´ca ((NMO) Devic’s disease), and acute necrotizing hemorrhagic encephalomyelitis (ANHE). Peripheral nervous system diseases include acute inflammatory demyelinating polyradiculoneuropathy, chronic inflammatory demyelinating polyradiculoneuropathy, anti-myelinassociated glycoprotein (MAG) neuropathy, and POEMS syndrome (so named due to polyneuropathy, organomegaly, endocrinopathy, M protein, and skin changes). The major demyelinating diseases are considered here, with emphasis directed toward mechanisms of disease causation and to treatments directed against them.

CNS Demyelinating Diseases Multiple Sclerosis

MS presents with recurrent attacks of focal neurological disorder involving brain, spinal cord, and optic nerves. Disease usually begins in young adults. In the United States, one person in 500 has this disease by age 50. During episodes of relapsing–remitting MS, neurologic deficits worsen over a period of several days to 3– 4 weeks, after which they remit. Remission may be complete after early attacks but more often is incomplete, and as relapses accumulate, stepwise progression leads to increasing deficit. In 15% of cases the illness manifests as a slowly progressive disease, socalled primary progressive MS. This is particularly likely when onset begins after age 40. In cases with earlier onset, and after multiple relapses over many

years, the disease usually transitions into a slowly but continuously progressive worsening of motor deficit called secondary progressive MS. The cause of MS is unknown, but there is agreement that abnormal immune system function characterizes the disease. Evidence for this is summarized in the following discussion. Certain histocompatibility antigen alleles are overrepresented in MS. Notable is the DR2 allele of the HLA histcombatibility complex. Possession of DR2 increases risk for MS fourfold. Many diseases are associated with histocompatibility abnormalities. Such diseases usually have (1) a chronic or recrudescent course, (2) a moderate tendency to be inherited that does not obey classical Mendelian rules, (3) an inflammatory component, and (4) an infectious or autoimmune basis in almost all instances in which cause is known. The first three features apply to MS. By analogy, the fourth likely applies as well. Twenty percent of MS patients have a first- or second-degree blood relative with the disease. This could reflect genetic endowment, a shared environmental factor, or some combination of the two. Concordance for MS in identical twins approximates 25% and for siblings, 1–3%. Thus, there must be a strong genetically determined propensity to develop the disease, but there must also be some environmental initiator. The genetic component includes histocompatibility, but almost surely additional genetically determined characteristics, at present unknown, are involved. All attempts to identify the environmental factor that sets MS in motion have failed. Most researchers believe it will prove to be an infectious agent. One candidate is the Epstein–Barr virus that causes infectious mononucleosis. All MS patients have serologic evidence of prior infection with this virus at time of diagnosis. MS is most common in north Europeans and in those whose forebears were north Europeans. MS is almost unknown among blacks in Africa. Among African Americans who develop MS, there is an increased representation of the HLA-DR2 allele, an uncommon allele among blacks in Africa. Thus, the propensity of African Americans to develop MS, and its rarity among blacks in Africa, may reflect both genetic and environmental differences. MS is uncommon in China and India. MS remains uncommon among descendents of Chinese immigrants to America, but not among descendents of immigrants from India, again indicating both regional environmental factors and genetic endowment as determinants for development of MS. MS lesions consist of foci of demyelination, known as plaques, in CNS white matter. The earliest lesions

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consist of minute pervenular foci within white matter. Over time these accumulate, enlarge, and coalesce to form plaques of considerable size, many of which abut the lateral ventricles. Axons coursing through regions where myelin has been lost are relatively but not completely spared, at least initially, although they are denuded of their insulation. Naked axons may continue to conduct nerve impulses, albeit imperfectly. Stripped axons can cease functioning when sustained effort is attempted, or if body temperature is elevated. Fatigue on effort, and worsening of deficits with fever, are characteristics of MS. Active MS plaques contain T lymphocytes. These can be subdivided into two major categories known as CD4 and CD8 cells. CD4 and CD8 are surface proteins that facilitate interactions between T cell receptors and antigenic peptides and antigen-presenting cells such as macrophages. Antigenic peptides recognized by T cells are contained within clefts of major histocompatibility complex proteins expressed on the surfaces of antigen-presenting cells. CD4 cells recognize peptide fragments presented by class II histocompatibility alleles. CD8 cells recognize fragments presented by class I alleles. DR2, overrepresented in MS, is a class II allele, indicating a major role for CD4 cells in lesion formation in the early stages of the disease. CD4 cells can be further subdivided into T helper Th1 and Th2 subtypes. Th1 cells are responsible for delayed-type hypersensitivity responses. They secrete numerous cytokines (signaling proteins of the immune system), notably interleukin-2 (a stimulator of T cell proliferation), interferon-g (an activator of macrophages), and lymphotoxin. The latter two proteins can damage oligodendrocytes. Elevated numbers of interferon-g-secreting cells are detected in the blood during MS attacks and in MS plaques when disease is active. Interferon-g, together with interleukin-2, activates macrophages that then secrete tumor necrosis factor, a protein which shares with interferon-g and lymphotoxin the ability to damage oligodendrocytes. There is a yin-yang between Th1- and Th2-type T cells. Preferential activation of Th2-type T cells inhibits Th1 cells, and in this way may be protective in MS. Activation of Th2-type T cells is one goal of MS therapy. MS plaques also contain macrophages. Macrophages often predominate within plaques even early on, and invariably predominate once disease has become progressive . Macrophages lack immunological specificity but can be armed to attack tissues under the influence of cytokines released by T cells, or by antibodies (immunoglobulins) released by B cells. Cytokines clearly activate macrophages during MS attacks. Antibodies may further facilitate macrophage activation during MS attacks and are,

in all probability, the main activator of macrophages in progressive forms of MS. Thus, macrophages are the final vectors of myelin destruction throughout the course of MS. They also scavenge debris. CD8 cells can be subdivided into cytotoxic cells and immunoregulatory (suppressor) cells. CD8 cells are found within MS plaques, but whether they are cytotoxic, have suppressor function, or both, has not been established. Interferon-b activates cytotoxic T cells yet protects MS patients (see later), making a role for cytotoxic T cells in MS problematic. In contrast, the function of circulating CD8 suppressor T cells, as measured by several tissue culture assays, is grossly deficient when MS is active, and treatment with interferon-b (a drug approved for treatment of MS) restores circulating suppressor T cell function to near normal levels in relapsing–remitting MS patients. Interferon-b also inhibits production of interferon-g, lymphotoxin, and tumor necrosis factor, at least in vitro. While the details of the immune response during MS relapses are imperfectly worked out, one possible scenario is as follows: failed regulatory T cell function (Th2 cells, CD8 cells, or both) permits reactivation of Th1 cells with specificity for an unknown brain antigen or antigens; the Th1 cells then stimulate macrophages, which attack and destroy myelin and oligodendrocytes. Restoration of regulatory cell function ends the relapse. The disease produced by MS has prompted development of therapies directed toward correcting the immune system abnormalities. Interferon-b, an agent approved for the treatment of relapsing–remitting MS, reduces MS attack frequency by 35–55%. In addition to activating CD8 suppressor cell function, and hence inhibition of proinflammatory cytokine production, Interferon-b also inhibits T cell entry into the CNS. Glatiramer acetate, another approved drug for treatment of MS, reduces MS attack frequency by 30%. It has been proposed that it activates regulatory CD8-type T cells, and promotes Th2 cell development. Natalizumab, a third class of drug, is recommended for treatment of relapsing– remitting MS patients who fail to respond to other therapies. Natalizumab drastically curtails T cell trafficking into the CNS. Trials with other agents are ongoing. A set of diseases that share numerous clinical and pathologic features with MS can be induced in laboratory animals. These diseases are known collectively as experimental autoimmune encephalomyelitis (EAE). They are induced by immunization with any of several CNS myelin proteins. The most commonly employed are myelin basic protein (MBP), proteolipid protein (PLP), and myelin oligodendrocyte protein

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(MOG). The pathogenesis of most forms of EAE is a T-cell-mediated delayed hypersensitivity response directed against the individual proteins used to immunize the animals. The T cells responsible for the activation of macrophages that eventuates in myelin destruction during EAE are analogous to human Th1-type T cells, suggesting that T cells of this lineage are the prime movers in acute attacks of MS as well. Antibodies directed against proteins expressed on the myelin surface contribute to the demyelination seen in subacute and progressive forms of EAE, suggesting, by analogy, an ancillary role for antibodies in early MS and a substantial role, possibly a dominant one, in progressive MS. That antibodies are likely to have a major role in the axonal damage of progressive MS is supported by the observation that T cell ablation has minimal effect on progressive motor disability once MS has evolved into its progressive form. T cells from animals with EAE proliferate when exposed to MBP, PLP, or MOG, depending on the protein used to induce disease. T cells from MS patients seldom proliferate when exposed to these same proteins, or at least to no greater extent than do T cells from controls, so that an immune response directed against them is unlikely to be implicated in MS. Nonetheless, given the similarities between EAE and MS, it is possible that there may be some unique antigen against which an immune response is directed in MS. None has been found with certainty to date despite assiduous search. This could mean that the EAE models provide a false lead. Alternatively, and more likely, the antigen (or antigens) for MS simply awaits discovery. Mature oligodendrocytes are depleted in MS plaques. For this reason some have proposed that the immune attack in MS may be directed against oligodendrocytes rather than against their product, myelin, inasmuch as compromised oligodendrocytes might be expected to divest themselves of their myelin. Remyelination can follow myelin loss. This occurs to a more limited extent in MS than in other demyelinating processes. Preoligodendrocytes, the precursors of oligodendrocytes, are responsible for remyelination in the human brain. A substantial pool of them is present in the adult brain. During the events that eventuate in remyelination, preoligodendrocytes mature to become oligodendrocytes. Curiously, preoligodendrocytes are present in substantial numbers in MS plaques that are depleted of mature oligodendrocytes, yet remyelination fails. What prevents preoligodendrocytes from repairing myelin in MS is unknown. Spinal fluid of MS patients contains immunoglobulin G (IgG) in increased amount, a finding that provides useful corroborating evidence when a diagnosis of MS is suspected. Spinal fluid IgG from MS patients,

subjected to isoelectric focusing, exhibits oligoclonal banding. Oligoclonal bands bespeak expansion of specific B cell clones that produce monoclonal (i.e., single antigen-specific) antibodies within the brain, the basis for which is not understood. Much of the monoclonal antibody made in the brain in MS is irrelevant to disease pathogenesis. This does not negate the possibility that some may be directed against MSrelevant antigens, yet undiscovered. Spinal fluid in MS contains T cells. Many are activated even when disease seems quiescent (i.e., during clinical remissions). The activated cells belong to the delayed hypersensitivity response–effector cell lineage. The data point to more persistent disease activity than is apparent clinically. Similarly, when magnetic resonance imaging (MRI) scans are obtained monthly, gadolinium-positive lesions are detected in five scans obtained between overt MS attacks for every gadolinium-positive scan obtained during a relapse. Gadolinium transport into the CNS is a marker for disease activity. The finding again indicates that the illness is far more active than it appears to be clinically, and supports the strategy of continuous long-term immunomodulatory treatment for the illness. To sum up, immune mechanisms are implicated in MS, but no disease-specific antigen against which an immune-mediated attack is directed has been proved to be the cause. Similarly, attempts to implicate a virus in disease pathogenesis have failed. Yet, immunomodulatory therapies favorably affect the long-term course of MS. Acute Disseminated Encephalomyelitis

ADEM, a rare disease, is an acute multifocal demyelinating process that follows an infectious illness. Formerly, ADEM occurred particularly often in children with measles. Nowadays the illness most often follows a nondescript viral infectious illness. Although encountered in adults, most cases occur in children. Children seldom get MS, indicating that ADEM constitutes a distinct entity. ADEM occurs throughout the world, and may even be more common in less developed countries where MS is rare, than in developed ones where MS is common. In ADEM, the white matter of the brain and spinal cord is peppered with multiple foci of acute demyelination of varying size. The foci contain T cells and macrophages and most, sometimes all, are simultaneously gadolinium positive on MRI scanning. The illness is usually monophasic; recurrences after a delay are uncommon, although recrudescences may be encountered when glucocorticoid treatment (see later) is abbreviated. In animals, an acute monophasic form of EAE, with T cell sensitivity to MBP, mimics the human

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disease. Sensitivity of lymphocytes to MBP, and antibodies to MBP, have been demonstrated in ADEM, and the disease is a reasonably faithful human counterpart of acute monophasic MBP-induced EAE. Animals, recovered from acute monophasic EAE, are refractory to attempts to induce recurrences. Refractoriness is believed to reflect expansion, in recovered animals, of MBP-specific suppressor cells that damp down any future response to MBP. In MS, unlike the situation in ADEM, recurrences are the rule. Perhaps failed suppressor cell function favors these recurrences – that is, if a means to persistently augment suppressor function were at hand, MS relapses might be prevented. ADEM begins abruptly and evolves rapidly. Headache and delirium at onset that give way to lethargy and coma are common in childhood cases, less so in adults. Seizures are not infrequent, particularly in children. Later, multiple focal signs emerge, flaccid paralysis of the limbs and brain stem signs being particularly common. The symptoms observed at the onset of ADEM are associated with inflammation alone. The multiple focal findings that follow coincide with onset of demyelination. In former times, mortality was 20%, with 50% of survivors having residual deficits. The prognosis has subsequently become much more favorable. Treatment of choice is high-dose glucocorticoid administered systemically for several days, followed by an extended oral glucocorticord taper over 6–8 weeks. Controlled trials are lacking, but recrudescences are fewer when this regimen is employed than when it is not, strongly suggesting a benefit from glucocorticoid treatment, as might be expected for a T-cell-mediated process. Remyelination during recovery from ADEM is more extensive than that seen in MS, and the majority of patients recover completely. MRI scanning during the acute phase reveals subcortical white-matter lesions with fuzzy margins, some quite large, with, unlike the situation in MS, periventricular sparing. Follow-up MRIs often reveal complete resolution of prior lesions and, again unlike MS, no new ones. The spinal fluid often shows a florid lymphocytosis at disease onset. Neuromyelitis Optica (Devic’s Disease)

NMO is an uncommon inflammatory disease in which inflammation, restricted to the optic nerves and spinal cord, occurs either sequentially or simultaneously. There has been debate regarding the etiology of this entity given its topographical specificity. Until recently NMO was usually viewed as an MS variant. NMO has features that permit it to be set apart from MS or ADEM (Table 1).The clinical course is

monophasic in one of five of instances. Four-fifths of patients have recurrent bouts of inflammation involving the spinal cord and/or the optic nerves. These relapses are reminiscent of relapsing–remitting MS. In patients with monophasic NMO, visual and motor involvement is severe initially, but recovery, although delayed, is usually substantial. In contrast, patients with relapsing disease have less severe involvement initially, but as attacks accumulate progressive disability follows. Disability can become devastating, with total blindness and complete motor paralysis sometimes being the end result. There is a 30% incidence of respiratory failure, usually fatal, in recurrent NMO due to upper cervical cord and medullary function compromise. Respiratory failure is rare in MS or in ADEM. NMO lesions have unique features. Spinal cord lesions exhibit prominent vascular fibrosis and hyalinization. Spinal cord NMO lesions involve gray as well as white matter and there may be prominent necrosis, cavitation, and axonal loss. Extensive demyelination is seen, as is extensive oligodendrocyte loss. Lesions in the spinal cord tend to be centrally located in NMO rather than peripheral (i.e., restricted to white matter), as is the case in MS. NMO lesions, seen on MRI scans of the spinal cord, span a greater longitudinal extent than do the spinal cord lesions of MS. Macrophages predominate; T cells are rare. Distinct to NMO is prominent infiltration of neutrophils, eosinophils, and ringlike perivascular deposits of immunoglobulin M (IgM) and IgG. Complement products are also seen in NMO lesions. The incidence of other autoimmune diseases in NMO is 15-fold increased over that in the general population. Frequent associations are with Sjo¨gren’s disease, systemic lupus erythematosus, rheumatoid arthritis, mixed connective tissue disease, and myasthenia gravis. Evidence pointing to other autoimmune processes may be subtle. Rare associations of NMO with tuberculosis, cancer (especially small-cell lung carcinoma), and lymphoma have been described. An IgG antibody specific for NMO has been discovered. The antibody has a sensitivity of 73%, a specificity of 91%, and permits a clear distinction to be made between NMO and MS. The antibody is directed against aquaporin 4, a water channel protein expressed in astrocyte foot processes. NMO patients fail to respond to standard MS therapies. Acute attacks are typically treated with high-dose systemic glucocorticoids plus courses of plasmapheresis or of intravenous immunoglobulin. Pulse treatments with plasmapheresis or with intravenous immunoglobulin given every 4–6 weeks, and/or long-term maintenance on an immunosuppressive drug such as azathioprine, methotrexate, or mycophenolate

Demyelinating Diseases 419 Table 1 Features of the major CNS demyelinating diseases Feature

NMO

Multiple sclerosis

ADEM

Median age of onset (years) Sex ratio (F:M) Ethnicity Clinical course Monophasic Relapsing Primary progressive MRI features Brain white-matter lesions

40 8:1 (relapsing) " Incidence in non-Caucasians

30 2:1 (relapsing) Primarily Caucasian

15 1:1 All populations at risk

20% 80% NA

NA 85% initially 15%

>95% <5% NA

Absent at onset Longitudinally extensive Unilateral or bilateral with poor recovery

Oval, usually perpendicular to ventricles Punctate Usually unilateral with good recovery

Large, disseminated, seldom periventricular Variable Unilateral or bilateral with good recovery

""" Lymphocytes, neutrophils

" Lymphocytes

Elevated Usually absent

Typically normal >90% present

"" Lymphocytes, occcasionally neutrophils elevated Usually absent

Necrosis Necrosis, demyelination

Limited demyelination Demyelination

Limited demyelination Demyelination, edema

þþþ þ/ þþ þþþ þþþ þþ 30–50%

þþþ þþþ None None Variable Variable Infrequent

þþþ þþþ None Rare Variable Variable Not seen

Relapse related

Independent of relapses

Relapse related

Spinal cord lesions Optic nerve lesions Cerebrospinal fluid findings White blood cell count Total protein Oligoclonal bands Pathology Gray matter White matter Lesion immunopathology Macrophages T cells Eosinophils Neutrophils Antibodies Complement Coexisting autoimmune diseases Disability progression

NMO, Neuromyelitis optica; ADEM, acute disseminated encephalomyelitis.

mofetil, have been given in attempts to lessen the likelihood of future relapses. Rituximab has been used recently in recurrent NMO prophylaxis. Rituximab, a monoclonal antibody directed against the CD20 protein expressed on the surface of B cells, potently depletes B cell number and lessens antibody production. Acute Necrotizing Hemorrhagic Encephalomyelitis

ANHE is a rare disease that resembles ADEM save for its apoplectiform onset and unique pathologic features. There is massive destruction of white matter to the point of liquefaction, and the lesions are flecked with multiple small hemorrhages. As in ADEM, regions of tissue damage contain lymphocytes and macrophages, but, additionally, necrotic vessels. Polymorphonuclear cells infiltrate regions of necrosis and are found in spinal fluid, as are red blood cells. A model for ANHE can be induced by giving endotoxin to animals about to develop acute EAE. This ‘double hit’ superimposes a Shwartzman reaction

onto the animal model for ADEM. A few cases of ANHE complicating MS have been reported.

Peripheral Nervous System Demyelinating Diseases Demyelination in the peripheral nervous system may be caused by immune mechanisms that involve T celland macrophage-mediated mechanisms, by antimyelin antibodies, or by cytokines released at a distance from nerves. Mixed mechanisms are also seen. Examples are presented in the following sections. Guillain–Barre´ Syndromes

Demyelinating and axonal forms of Guillain–Barre´ syndromes are recognized. The demyelinating form, often designated as acute inflammatory demyelinating neuropathy (AIDP), predominates in North America, Europe, and Australia. Axonal forms predominate in other countries, most notably in China. Annual frequency of AIDP is 1.5 persons per 100 000 across all

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age groups, so that one person in 1000 will contract this illness at some point over their lifetime. AIDP follows an acute infectious illness in two-thirds of patients. Some 10% of cases follow infection with cytomegalovirus, another 5% follow Epstein–Barr virus infection (both are herpes viruses). Some 20–30% of cases follow infection with Campylobacter jejeuni, a bacterium that causes diarrhea. An additional 5% of cases follow infection with Mycoplasma pneumoniae. This agent can also incite a concurrent ADEM to give a mixed CNS and peripheral nervous system presentation. Weakness, leading to frank paralysis, that requires respiratory support in 20% of AIDP cases evolves subacutely over several days for up to 4 weeks; 5% of patients succumb and the rest recover, usually completely, although 15% have residual disability. AIDP is usually monophasic. Relapses occur months or years later in fewer than 5% of cases. Pathologic examination reveals peripheral nerve infiltration with lymphocytes and monocytes/macrophages. The latter strip myelin to leave denuded axons. Segmental demyelination occurs throughout the peripheral nervous system but more so in nerve roots and distal nerve terminals. Remyelination, which can be extensive, correlates with relatively rapid restoration of function. In severe cases axons may be interrupted, followed by either slow regrowth once the inflammatory process has ceased, and hence delayed restoration of function, or no regrowth and permanent deficit. Complement deposition on the surface of Schwann cells is seen early on, suggesting a potential role for antibody directed against a myelin antigen that remains unknown. It is also likely that nerve-invading CD4-type T cells instruct macrophages to attack myelin. In cases with a protracted course, a late-stage role for CD8-type cytotoxic T cells has also been proposed. Courses of either plasmapheresis or of intravenous gamma globulin have been shown, in controlled clinical trials, to provide substantial benefit in AIDP. Animal models that mimic AIDP with varying degrees of fidelity exist. Experimental autoimmune neuritis (EAN) is an acute inflammatory neuritis induced by immunization with proteins of peripheral nerve myelin. T cells from such animals proliferate when challenged with myelin proteins and the disease can be transferred to naive recipients with T cells from EAN donors, indicating that EAN is mediated largely by T cells. EAN mimics the histological and clinical features of AIDP, yet sensitivity of T cells from AIDP patients to myelin proteins can be shown in only a minority of cases. The axonal forms of the Guillain–Barre´ syndrome are characterized by purely motor involvement (acute

motor axonal neuropathy, or AMAN), a mixed motor and sensory neuropathy (acute sensorimotor axonal neuropathy, or ASMAN), and the Miller Fisher syndrome, in which oculomotor paralysis, ataxia, and areflexia are cardinal features. These illnesses are mediated by antibodies to gangliosides situated on axonal membranes. Most cases follow infections with C. jejeuni. The antibodies are directed against oligosaccharides of the Campylobacter bacterium, but cross-react, because of molecular mimicry, with peripheral nerve gangliosides. In AMAN, antibodies to anti-GM1/anti-GD1a gangliosides are the rule, whereas in the Miller Fisher syndrome antibodies to GQ1b ganglioside are usually detected. GM1 is enriched at nodes of Ranvier and at motor nerve terminals. Deposition of antibodies and of complement at these sites explains motor nerve functional compromise. GQ1b is enriched in extraocular nerves so that anti-GQ1b antibodies preferentially localize to extraocular nerves in the Miller Fisher syndrome. The axonal forms of the Guillain– Barre´ syndrome involve nerve impulse conduction block when mild, and irreversible axonal transection when severe. They are not demyelinating. Nonetheless, the finding that antiganglioside antibodies cause paralysis has led to speculation that AIDP may likewise be mediated by antibodies directed against some substance expressed on the surface of peripheral nerve myelin. The issue remains open. Chronic Inflammatory Demyelinating Neuropathy

Chronic inflammatory demyelinating neuropathy (CIDP) may be an AIDP variant. The illness is characterized by progressive loss of motor and sensory function that evolves over many years. The process is roughly symmetrical, weakness of proximal and distal muscles predominating. Sensory dominant forms are uncommon. The onset is usually insidious without, unlike AIDP, any evident precipitating event. Some patients have a series of relapses prior to developing a progressive course. CIDP can occur at any age but is more common with advancing years. CIDP predominantly affects spinal roots, major plexuses, and proximal nerve trunks. The process is demyelinating, as readily documented by electrophysiologic testing. This reveals dispersed slowing of nerve conduction velocity. The spinal fluid protein is elevated, in keeping with leakage from damaged spinal roots. Tendon reflexes are usually lost. Histologic examination of active lesions reveals lymphocytic infiltrates, usually modest, and macrophage-mediated demyelination. Macrophages insert processes between myelin lamellae, phagocytose myelin, and denude axons. The process is morphologically

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identical to that seen in AIDP, albeit more indolent. Repair occurs to some extent as witnessed by thinned myelin and shortened internodal distances, cardinal features of successful remyelination. As the illness evolves, interruption of naked axons becomes engrafted onto the demyelinating process. Failed attempts at remyelination are evidenced by layers of Schwann cell cytoplasm separated by collagen fibers forming concentric rings, or so-called onion bulbs. The process is held to be primarily T cell mediated, but T cell reactivity to characterized myelin proteins is seldom found, and the putative antigen, or antigens, against which the T cell response is directed remains unknown. A role for antibody in CIDP has also been proposed since a small proportion of patients have antibody to the Po protein of peripheral nerve myelin. Most patients respond modestly to oral glucocorticoids when these are first given. This treatment is not helpful in AIDP. There is also evidence that intravenous IgG and plasma exchange may offer modest benefit for a time. Treatment for this condition remains unsatisfactory over the longer term. Anti-Myelin-Associated Glycoprotein Neuropathy

MAG neuropathy is a demyelinating neuropathy mediated by monoclonal IgM antibody that binds to an oligosaccharide shared by MAG, a minor myelin protein, and two glycolipids of peripheral nerve, sulfated 3-glucuronyl lactosaminyl paragloboside and sulfated 3-glucuronyl paragloboside. The clinical picture is one of a primarily sensory distal and symmetric neuropathy. IgM antibodies have low affinities, but this is compensated for by high avidities due to their pentameric structure. MAG is primarily expressed in uncompacted myelin of the periaxonal and paranodal regions and in Schmidt–Lantermann clefts. Anti-MAG antibody and complement are deposited at these sites and MAG is selectively lost. MAG is implicated in the maintenance of axonal function and its loss compromises axonal function. Anti-MAG antibodies injected into the sciatic nerves of cats cause demyelination, proving that anti-MAG antibody causes the neuropathy. A blood test for anti-MAG antibody is reliable and confirms the diagnosis. Electrophysiologic studies reveal a demyelinating process with distal accentuation of reduced conduction velocity. Treatment with antimetabolic drugs such as the purine analog fludarabine has been reported as helpful, as has rituximab, a humanized murine monoclonal antibody directed against the CD20 antigen expressed on B cells. Rituximab exerts a cytotoxic effect on B cells with, as a consequence, reduced antiMAG antibody titers.

POEMS Syndrome

The POEMS syndrome, a demyelinating neuropathy, was originally described as a complication of sclerosing myeloma, an immunoglobulin-secreting plasma cell tumor. Most myelomas are osteolytic and multifocal, but 3% of them are solitary tumors that cause bone to sclerose. Fifty percent of patients with a sclerosing myeloma develop the POEMS syndrome. Radiation therapy of a sclerosing myeloma can be followed by remission of the neuropathy, indicating that some product released by the tumor causes the POEMS syndrome. Those sclerosing myelomas that cause the POEMS syndrome invariably secrete monoclonal IgG or IgA immunoglobulin into the blood. Documentation of this secretion is required for diagnosis, although the monoclonal immunoglobulin may be secreted in such miniscule amounts as to prove difficult to detect. The light chain of the IgG or IgA released by the tumor is of the l type in almost all instances. Other B cell dyscrasias can be complicated by the POEMS syndrome, including multicentric angiofollicular lymph node hyperplasia (Castelman’s disease), an entity characterized by gross lymph node hyperplasia, and polyclonal plasma cell proliferation. In cases complicated by the POEMS syndrome, focal accumulations of monoclonal plasma cells secreting IgG l are detectable, pointing to a communality with sclerosing myeloma-associated POEMS syndrome. The POEMS acronym emphasizes several of its cardinal features: polyneuropathy, the dominant clinical feature; organomegaly; endocrinopathy, most often gonadal dysfunction; M (i.e., myeloma) protein; and skin changes, including hyperpigmentation and hypertrichosis. There are additional features not described by the acronym. These are elevated intracranial pressure with or without papilledema, edema of the extremities, effusions in body cavities, and, ultimately, renal failure and/or failure of multiple other organs. The process that begins as a neuropathy ultimately becomes widespread. The neuropathy is symmetrical and begins with distal sensory abnormalities, numbness, and dysesthesias predominating. The process then ascends and weakness supervenes. Nerve conduction studies reveal evidence for both demyelination and axonal loss, as do nerve biopsies. Importantly, there is no inflammatory cell infiltrate nor is immunoglobulin deposition within nerves seen. The latter finding indicates that monoclonal IgG or IgA does not cause the neuropathy. Endoneurial blood vessels show endothelial cell hypertrophy. Endothelial cell processes extend into the lumen, reduce luminal diameter, and hence promote hypoxia. Disruption of the tight

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junctions that ordinarily join nerve endothelial cells to one another is also seen with, as a consequence, leaky vessels. Vascular endothelial growth factor (VEGF) is an angiogenic hormone. Elevated levels of VEGF are observed in the blood in POEMS syndrome and levels correlate with the tempo of worsening. VEGF levels return to normal with successful treatment of solitary myelomas by radiation, or with alkylating agents and glucocorticoids when the process is more widespread. These findings have led to the postulate that excessive VEGF production by plasma cells causes endothelial cell proliferation and leaky vessels. VEGF, acting far from its site of origin to compromise blood flow throughout the body, fits well with the multiorgan involvement seen in the later stages of the POEMS syndrome. See also: Autoimmune Autonomic Neuropathy; Axonal Injury in Demyelinating Disease and CNS Injury; Demyelination and Demyelinating Antibodies; Myelin: Molecular Architecture of CNS and PNS Myelin Sheath; Neuropathy: Peripheral; Transplantation of Myelin Forming Cells.

Further Reading Anlar B, Basaran C, Kose G, et al. (2003) Acute disseminated encephalomyelitis in children: Outcome and prognosis. Neuropediatrics 34: 194–199. Dale RC, de Sousa C, Chong WK, et al. (2000) Acute disseminated encephalomyelitis, multiphasic disseminated encephalomyelitis and multiple sclerosis in children. Brain 123: 2407–2422. Dispenzieri A, Kyle RA, Lacy MQ, et al. (2003) POEMS syndrome: Definitions and long-term outcome. Blood 101: 2496–2506. Hughes RAC, Allen D, Makowska A, et al. (2006) Pathogenesis of chronic inflammatory demyelinating polyradiculoneuropathy. Journal of the Peripheral Nervous System 11: 30–46. Keegan MB and Noseworthy JH (2002) Multiple sclerosis. Annual Review of Medicine 53: 285–302. Lennon VA, Kryzer TJ, Pittock SJ, et al. (2005) IgG marker of opticspinal multiple sclerosis binds to the aquaporin-4 water channel. Journal of Experimental Medicine 202(4): 473–477. Scarlato M, Previtali SC, Carpo M, et al. (2005) Polyneuropathy in POEMS syndrome: Role of angiogenic factors in the pathogenesis. Brain 128: 1911–1920. Steck AJ, Stadler AK, and Renaud S (2006) Anti-myelin-associated glycoprotein neuropathy. Current Opinion in Neurology 19: 458–463. Willison HJ (2005) The immunobiology of Guillain–Barre´ syndromes. Journal of the Peripheral Nervous System 10: 94–112.