Child Neurology
7th Edition

Many investigators consider a viral infection to be the most likely environmental factor explaining the pathogenesis of MS. Indirect evidence supporting this theory comes from the particular distribution of the disease, with areas of high and low risk; serologic studies; isolation of viral proteins and genomic material from the brain of patients with MS; and different viral experimental models causing CNS lesions similar to MS pathology. Viruses probably related to MS include herpesvirus (in particular herpes human type 6), Epstein-Barr virus, paramyxovirus, and retrovirus. The recently discovered human endogenous retrovirus (HERV)-W family has an extracellular particle, named HSRV, that is associated to MS. Recent studies have shown that CSF levels of MSRV are related to the degree of CNS inflammation, and, even if this were an epiphenomenon, it could be used as a clinical prognostic marker of early MS (88).

It is generally accepted that in addition to an early viral infection, there must be an autoimmune reaction that attacks some of the components of the myelin (2,88,90). Most patients exhibit T-cell reactivity to a number of myelin antigens, suggesting that by the time a patient develops clinical MS there has been epitope spreading with reactivity to multiple myelin epitopes (90). T cells that can react against myelin antigens are normally present in the immune system. These cells escaped thymic mechanisms of control such as clonal deletion.

A nontolerant, peripherally activated CD4+ T cell recognizes its autoantigen within the CNS parenchyma in the context of class II MHC molecules expressed by both local glial antigen-presenting cells (88) and dendritic cells (91), which commit T cells toward a Th1 phenotype. Activated Th1 cells cause myelin disruption and the release of new potential CNS autoantigens.

Secreted proinflammatory cytokines, such as IFN-γ and TNF-α, and chemokines recruit additional nonspecific inflammatory cells and specific antimyelin antibody–forming B cells, which exacerbate tissue injury (88,92,93). Finally, the apoptotic clearance of T cells and their conversion toward a Th2 phenotype modulates the outcome of the lesion (94). Additional cells are necessary for the development of typical MS lesions, such as the cytotoxic CD8+ cells, which show a more prominent clonal expansion within MS plaques and correlate better than CD4+ cells with the extent of acute axonal injury (95,96).

The cascade of inflammatory events that culminates in demyelination of axons depends on the peripheral activation of T lymphocytes (97). Interactions of lymphocytes with the vascular endothelium are required for lymphocyte trafficking into the CNS (2). Adhesion molecules play a critical role in this process and are pivotal in lymphocytes infiltrating the CNS through the BBB (98). One such molecule is the intercellular adhesion molecule-1 (ICAM-1), a glycoprotein that interacts with many α₂-integrins such as lymphocyte function–associated antigen-1 (LFA-1) on T cells and CD11b/CD18 on monocytes (99,100). Other adhesion molecules mediating the interactions between lymphocytes and endothelial cells are very late antigen 4/vascular cell adhesion molecule-1 (VCAM-1), L-selectin (on lymphocytes) and E-selectin (on endothelial cells) (101,102).

Genetic factors have also been postulated to be contributors to the pathogenesis of MS, based on different studies. Prevalence rates for MS among first-degree relatives of individuals with MS are approximately 20-fold greater than those of other individuals from the same region (53). The risk of developing MS in the general population of 1 in 1,000 increases to 20 to 40 in 1,000 for first-degree relatives (87). In a pediatric series of 44 children with MS, 10 (23%) had a positive family history of MS in a first-degree relative (1 child), a second-degree relative (5 children), or their extended family (4 children). This is very similar to the 15% to 20% rate of a positive family history reported in an adult MS series (77). Identical twins have a 25% to 35% concordance rate for MS, as compared to 0.5% for offspring (possibly much higher for daughters of mothers with MS), 0.6% for parents, 1.2% for siblings, and 2% to 4% for dizygotic twins (87,103,104).

Guided by the considerations related to the presumptive immunopathogenesis of the disease, candidate gene searches have been focused on genes of the T cell–mediated immune response and of myelin proteins. Negative results have been found for the genes for T-cell receptor-α,
complement, chemokine receptors, interferons, other cytokine receptors, and the cytotoxic T-lymphocyte antigen 4 (CTL4), a gene located in the HLA class I region (88,103). There is a highly significant association of MS with HLA-DR2 and a weaker association with HLA-A3 and B7 in whites. Other candidates such as HLA class II have yielded positive results, especially when subtyped into HLA DRB1*1501, DQA*0102, and DQB1*0602 extended haplotype, although the estimated relative risk is only 2 to 4 (77,103,105). HLA-DR15 has been specifically associated with an earlier onset of MS in a large study of more than 900 patients (106).

Recent analysis of markers of microsatellite polymorphisms in populations of different sizes and ethnicities identified chromosome regions of interest in MS susceptibility: chromosome 6 within the MHC and chromosomes 3q21–q24, 18p11, and 17q22–q24; a later meta-analysis, however, indicated the highest consensus evidence for linkage at 17p11 (107). All studies are concordant with the conclusion that HLA contributes, although modestly, to overall susceptibility and that a relatively large number of other MHC and non-HMC genes with individually small epistatic effects may be responsible for predisposition to MS. This implies a number of genes with interacting effects and suggests a polygenic inheritance of the disease. For example, the ApoE4 haplotype is also a genetic factor determining MS severity; these patients have a twofold higher likelihood of developing “black holes” on MRI and have an approximately fivefold greater rate of brain atrophy (108,109). It is probable that the expression of the implicated genes depends on environmental factors (88,103).

In summary, there is credence in the long-standing tenet of MS pathogenesis that the disease is produced by an environmental agent acting on a genetically susceptible individual in whom there are impaired immune responses.

The external appearance of the brain in patients with MS may be unremarkable. In the chronic cases, signs of atrophy with widening of sulci and slight enlargement of the ventricular system can be observed. When sectioning the brain, it is possible to identify firm, gray lesions on the surface of the brainstem, spinal cord, and optic nerves and multiple plaques of variable diameter in the white matter (118). Inflammatory demyelinating lesions are typically disseminated throughout the neuraxis, but are more frequently encountered in certain anatomic sites relating to recognizable patterns of neurologic semiology. Although the distribution of the plaques varies among patients, the preferential locations are: periventricular white matter, floor of the aqueduct and fourth ventricle (brain stem), cerebellar peduncles, cervical spinal cord, and optic nerves (Fig. 8.1).

Distinctive anatomic correlates are encountered in certain variants, such as the neuromyelitis optica or Devic type. Even though in the cerebral hemispheres the lesions have a periventricular predilection, an important proportion of lesions can be observed in other locations of central white matter and the gray–white matter junction (119,120,121). Lesions involving convolutional white matter typically spare the U fibers. There are instances in which white matter lesions extend into the contiguous cortex gray matter or deep gray nuclei (basal ganglia and thalami) (119,120). Subpial and intracortical plaque formation has been described and may represent an important correlate of neurologic disability (56). Exceptionally, large, spherical, tumor-like lesions are encountered (122), but such lesions are most commonly seen in conjunction with myelinoclastic diffuse sclerosis (Schilder disease) (see later discussion).

The MS plaques can be classified into four categories encompassing cellular changes that reflect disease activity or quiescence:

Occasionally, the lesions are so severe that they evolve into cysts. It is classic to observe in the same patient lesions in different stages of progression.

There are two integral components of MS lesions, perivascular inflammation and demyelination. It has long been hypothesized that inflammatory demyelination is the result of immune-mediated responses to myelin antigens in the myelin sheaths of axons and/or at the level of myelin-forming oligodendrocytes (95,110,119). Destruction of myelin and oligodendrocytes is not uniform in MS plaques (111,119). The morphogenesis of plaques is not fully understood, although circumstantial evidence points to early inflammatory damage of the BBB and infiltration by monocytes and lymphocytes, predominantly T cells (58,95,110,119). BBB disruption signals the onset of clinical symptoms, but a correlation between symptoms and inflammatory demyelination is not clear-cut.

Four distinct pathogenetic patterns of demyelination (I through IV) have been proposed (113). The first two focus on the concept that inflammation causes demyelination by direct and/or indirect mechanisms. Lymphocytes contribute to the pathologic process through cellular- and humoral-mediated immunologic responses (presumptive direct mechanisms) or by production of lymphokines and cytokines (indirect mechanisms). It follows then that patterns I and II exhibit remarkable similarities to either T cell–mediated or T cell plus antibody–mediated autoimmune encephalomyelitis (113). Monocytes/macrophages contribute to the demyelinating process in a twofold manner. First, through their traditional phagocytic role, cells of the monocyte/macrophage lineage, including hematogenously derived and activated resident microglia of the CNS, are potent effectors of axonal myelin and oligodendrocyte damage (58). Monocytes contribute to demyelination by way of production of cytokines, nitric oxide, and proteases and/or by directly targeting oligodendrocytes at the border of MS lesions (58,101,119). Activated CNS resident microglia play a role in the early stages of demyelination through cell-to-cell contact interactions with myelin internodes of the axons at the edges of active and chronic active MS lesions (58,119).

The other two patterns (III and IV) are consistent with a primary oligodendrocyte pathology (dystrophy) reminiscent of direct viral- or toxin-induced demyelination as opposed to bona fide autoimmune mechanisms (113). Over the years, various theories have been brought forward concerning the nature of oligodendrocyte damage in MS lesions. It is believed that this damage is incurred through a variety of immunologic mechanisms, including anti-MOG antibodies, cytokines produced by monocytes/macrophages and lymphocytes, T cell–mediated injury, immunoglobulins and components of activated complement, apoptosis, and a variety of other cytotoxic factors (58,114,115,129,130). In pattern III there is loss of myelin proteins in the distalmost (periaxonal) cell processes of oligodendrocytes, which is associated with apoptotic cell death (114,130,131). This mechanism has been previously defined as “distal” or “dying-back” oligodendrogliopathy (132) and is akin to oligodendroglial injury incurred during early hypoxic-ischemic demyelination of the white matter (130). In pattern IV there is cell death of oligodendrocytes in the white matter near active lesions (113). In this regard, it has been shown that activated monocytes/microglia expressing VCAM-1 selectively target oligodendrocytes at the border of MS lesions (101).

Axonal damage in the form of axonal swellings (dystrophic neurites) and transections has emerged as a major component of the disease (55,57,58,133,134). Axonal injury correlates with certain parameters of functional MR imaging (reduction of N-acetylaspartate) and certain patterns of neurologic disability in MS (15,114,126,135). Axonal pathology, evidenced by immunohistochemical staining for amyloid precursor protein (APP) in postmortem specimens, is more prominent in active MS lesions than in chronic inactive plaques (15).

Hypoxic-ischemic damage is an important but somewhat underrated aspect of MS neuropathology. Inflammatory damage of the vessel wall, endothelium, and BBB by T cells and monocyes (111,136,137,138) resembles the injury caused by angiocentric T-cell infiltrates in human immunodeficiency virus-1 (HIV-1)–associated CNS disease in children (139). The latter, compounded by edema and disturbance of the cerebral microcirculation, may impart damage to myelin, axons, and oligodendrocytes.

Disturbances in oxidative metabolism in MS reminiscent of hypoxia-ischemia may result from vascular factors (i.e., vascular inflammation) and/or the release of toxic metabolites associated with hypoxia-ischemia (130,140). Interestingly, overt ischemic damage has been demonstrated in severe cases of acute MS of the Marburg type, Baló concentric sclerosis, and neuromyelitis optica (141,142,143). It is hypothesized that certain active MS lesions may represent a form of “sublethal” hypoxic injury reminiscent of an ischemic white matter penumbra. Evidence of hypoxia-like metabolic tissue injury in MS due to the liberation of excitotoxins, reactive oxygen species, and nitric oxide lends further credence to this postulate (50,130,144,145,146).

In summary, current understanding of neuropathogenetic mechanisms in MS supports the hypothesis that white matter demyelination, axonal damage, dendritic transection, and apoptotic loss of neurons in the cerebral cortex contribute to neurologic dysfunction in MS patients (56).

Immunologic abnormalities can be found both in the serum and the CSF. Dysfunction of cellular immunity is represented by an increase in the circulating CD4+ T-helper/inducer to CD8+ T-suppressor/cytotoxic cell ratio during MS relapses (53,162,163). Molecular markers of apoptosis (i.e., regulator CD95, caspases 8 and 10), and cytokine IL-10 and TNF-α in peripheral blood mononuclear cells correlate inversely with new MRI inflammatory activity, indicating that the CD95-dependent pathway plays a complex role in the regulation of survival of activated immune cells in MS (164).

CSF abnormalities in MS patients are characteristic, although neither specific nor pathognomomic. During the acute phase of demyelination there is lymphocytic pleocytosis of variable degree (30% to 70%), not generally exceeding 50 cells/mm³ (65,71,165,166). Dysfunction of the humoral immunity is a consistent finding in patients with MS and is represented by the almost universal presence in the CSF of (a) detectable oligoclonal immunoglobulins by electrophoresis, (b) elevated rates of synthesis and concentrations
in the CSF of intrathecally generated immunoglobulin G (IgG) and IgM with varied or unknown epitopic specificity, and (c) increased levels of immunoglobulin components such as kappa chains (53,65,71,165,166,167,168,169). The finding of oligoclonal bands (OCB) of IgG present in the CSF and absent in blood has been described in 65% to 95% of adult patients with MS (33,166,170,171). The reported frequency of OCB in children with MS is variable, which is probably a reflection of the different methodologies used (172). With the isoelectric approach followed by inmunofixation, Tenembaum and colleagues (82,83) detected positive CSF OCB in 27 of 51 (53%) children with MS. The detection rates for the three clinical forms, EIMS, DIMS, and JMS, were, respectively, 46%, 38%, and 64%. Recently, the serum analysis of antimyelin antibodies, notably anti-MOG and anti-MBP, has been shown to be relatively effective in predicting the progression of isolated demyelinating syndromes to full blown MS (173). Rejdak and collaborators (174) reported increased CSF levels of nitric oxide metabolites (nitrite and nitrate levels) in adult MS patients, which correlated with clinical and MRI progression of the disease over a 3-year follow-up. Sueoka and colleagues (175) found selective CSF synthesis of antibodies against ribonucleoprotein B1 in adults with relapsing-remitting MS, suggesting that they could be a disease marker for MS.

Neurophysiologic studies are not specific. The electroencephalogram (EEG) can show changes corresponding to the epilepsy diagnosed in some patients (148,158,160). Aphasic status epilepticus, epilepsia partialis continua, and periodic lateralized epileptiform discharges have been reported (176,177,178). Prolonged treatment with corticosteroids induces changes of the sleep EEG in MS patients similar to the changes observed in patients with an acute depressive episode (179). Evoked potentials (EPs) provide information about dissemination of demyelinating disease within the CNS (77). Visual and somatosensory EPs can demonstrate a second lesion (180). Although their usefulness in pediatric MS has yet to be formally evaluated, abnormalities in visual and somatosensory EPs have been demonstrated (68) and are likely to be of similar diagnostic significance as in adult MS patients (181,182,183).

Brain and spinal cord MRI are the neuroimaging modalities of choice for evaluating children with demyelinating disorders in general and MS in particular. The typical MRI lesions described in adult patients with relapsing-remitting MS are round or oval plaques, bright or hyperintense on T2-weighted, proton density, and fluid-attenuated inversion recovery (FLAIR) images. They are
variable in number and distributed in the white matter of the centrum semiovale, adjacent to the ventricles, and in the corpus callosum, brainstem, cerebellum, optic nerves, and spinal cord (118,181). These lesions are perpendicular to the lateral ventricles, are usually small (less than 5 mm), and show an incomplete, nonuniform enhancement with gadolinium. In the experience of one of us (S.N.T.) the cerebral images of patients with juvenile MS are not different from this classic description at the time of the initial presentation or during relapses (82,83) (Fig. 8.2A).

In contrast, brain MRIs performed during the initial demyelinating episode in children younger than 10 years of age show large multifocal demyelinating plaques with a tendency to coalesce (Fig. 8.2B) in 80% of cases (83), a finding that is somewhat underrated (72). These lesions can have a tumefactive (tumor-like) appearance with variable mass effect. Usually these can be differentiated from tumors by the lesser amount of edema around the lesions frequently (but not invariably) in association with other typical, smaller lesions (184) (Fig. 8.2C). That said, there are reported cases of infantile MS with a solitary plaque associated with perilesional edema (185). The enhancement with gadolinium can be helpful for establishing this difference because the demyelinating plaque usually shows an enhancement pattern of incomplete “hoop” or “open ring” (186). Up to 15% of patients with juvenile MS may have tumefactive lesions on the MRI at the time of the initial attack. The presence of “black holes” on unenhanced T1-weighted images and signs of brain atrophy, like widened subarachnoid spaces, ventriculomegaly, and thinning of the corpus callosum, have not been frequently described in the pediatric literature, but these findings are clearly seen in children with secondarily progressive clinical forms of MS (82).

The MRI images observed in children with an initial attack of EIMS or DIMS recall the images of patients with ADEM (187,188). Characteristic lesions are large and disseminated in the subcortical white matter, but also in the cortex and deep gray nuclei, without the distribution and morphology observed in juvenile and adult MS. As a rule, only if subsequent studies at the time of clinical follow-up or relapses show new lesions that enhance with gadolinium can the diagnosis of MS can confirmed (161,189,190). With this in mind, it should be recognized that ADEM can be accompanied usually by one or several episodes of relapse (biphasic or multiphasic ADEM) (161,189,190), but successive MRIs will reveal active lesions only in the context of a concomitant clinical attack; in other words, “subclinical” or “silent” lesions exhibiting active MRI changes (that are typical of MS) are not seen in ADEM (188,191).

According to the new guidelines from the International Panel on the Diagnosis of MS, (161,192), in certain clinical situations, MRI lesions must fulfill the diagnostic criteria of space dissemination, which include three of the following four: (a) one gadolinium-enhancing lesion or nine T2 hyperintense lesions if there is no gadolinium enhancement, (b) at least one infratentorial lesion, (c) at least one juxtacortical lesion, and (d) at least three periventricular lesions. One spinal cord lesion can be substituted for one brain lesion (161). However, these criteria may not apply as well to the pediatric MS population. Children with MS appear to have fewer white matter lesions at the time of their MS diagnosis than do newly diagnosed adults. Moreover, because myelinogenesis is incomplete in childhood, this may influence lesion appearance, size, and distribution within the CNS. Further studies are necessary to develop MRI diagnostic criteria that are validated in the pediatric MS population (193).

MRI and MR spectroscopy (MRS) in patients with MS for less than 5 years shows brain atrophy and loss of axonal integrity. Although the exact mechanisms underlying CNS atrophy in MS patients are largely unknown, evidence exists that atrophy may be secondary to the repeated effects of inflammatory demyelination, axonal injury, including dystrophic changes and frank axonal transection, wallerian degeneration, and neuronal loss (56,194,195).

Although routine MRI is the mainstay of diagnosis of MS, there is increasing interest in using quantitative MRI methods to better understand pathology in gray matter and normal-appearing white matter. Magnetization-transfer MRI and diffusion-weighted MRI are techniques that provide additional useful information about the process of demyelination and remyelination in MS (196). In addition, functional neuroimaging studies like MRS, functional MRI (fMRI), single photon emission computed tomography (SPECT), and positron emission tomography (PET) allow a better study of the CNS dysfunction secondary to the pathologic changes of the disease (194,196).

MRS of the cerebral demyelinating plaques in children shows a spectrum of alterations with reduction of N-acetylaspartate (NAA) and creatine and increase of choline and myo-inositol compared with age-specific controls (71,197). MRS in adults with MS may also show elevation of lactate in the acute demyelinating plaque, but this finding has not been reported in children (74). The white matter adjacent to the plaques that has a normal appearance on MRI has a normal metabolic pattern on MRS, but the adjacent gray matter usually shows a decrease in NAA (197). These data are similar to the findings in adult patients, and are the consequence of neuronal, including axonal, injury in addition to myelin damage that occurs early as a result of repeated inflammatory demyelinating insults (194,196).

fMRI is being used in clinical research to study the neuronal mechanisms that underlie CNS function and to define abnormal patterns of brain activation that arise from

disease (196,198). A changed pattern of cortical activation, mainly characterized by increased activation of the contralateral primary sensorimotor cortex, has been found in MS patients with clinically isolated syndromes when they do a simple motor task (199). A strong correlation has also been found between the extent of activation of the contralateral primary sensory motor cortex and the reduction of the whole-brain NAA concentration, which suggests that functional cortical reorganization might contribute to the maintenance of normal cortical function in the early stages of MS. Increased activation of several sensorimotor areas, mainly in the cerebral hemisphere ipsilateral to the extremity used to do the task, has also been reported in patients with early MS and preceded by an episode of hemiparesis (200). In patients with similar characteristics but with optic neuritis as their first clinical manifestation, sensorimotor areas mainly located in the contralateral cerebral hemisphere were recruited (201). Abnormal brain activation of the prefrontal/frontal lobe has been demonstrated in MS patients with fMRI during specific tasks; the dysfunction normalizes with rivastigmine, a central cholinesterase inhibitor (202).

New functional MRI techniques are being developed to study in vivo CNS diseases at a molecular level (194). Experimental studies with Theiler murine encephalomyelitis virus have investigated MRI techniques using antibodies linked to superparamagnetic particles directed against immune-specific immune determinants. This allows selective imaging of CD4+ T cells, CD8+ T cells, and Mac1+ cells in the CNS (203). Being able to monitor dynamically the activity of specific classes of inflammatory cells in MS will provide an important way of understanding the evolution of pathology and the effects of interventions (194).

In a study of 17 MS patients, ^99mTc-D,L-hexamethylpropylene amine oxime (99m Tc-HmPAO) SPECT showed reduced ratios of regional to whole-brain activity in the frontal lobes and left temporal lobe (204). A relationship was found between left temporal lobe abnormality and deficit in verbal fluency and verbal memory. SPECT is also useful in evaluating MS patients with depressive disorders (205) and in establishing the differential diagnosis of tumor-like lesions (206).

PET studies have demonstrated that global and regional cortical glucose metabolism is significantly reduced in MS patients compared with normal controls. Such a decrease correlates with number of relapses, total lesion area on MRI, and cognitive dysfunction, indicating that MRI white lesion burden causes deterioration of cortical cerebral neural function (207,208,209). Hypometabolism is widespread, including the cerebral cortex (frontal, parietal, occipital), supratentorial white matter (parietal), and infratentorial structures (pons) (208,210). Using a radioligand for the peripheral benzodiazepine receptor, PET has allowed the visualization of microglia and its involvement in the inflammatory processes causing MS (211).

Neuroimaging techniques will continue to develop in the future to provide not only more accurate diagnosis of MS, but also important prognostic information (194,196).

On anatomic examination of the sectioned brain, the most striking alteration is the grossly discernible demyelination of the central hemispheric white matter. Typically, the plaques are fewer and larger than in classical MS and their deep location with sparing of the U fibers at the gray–white junction serves as a topographic distinguishing feature from ADEM. Remarkably, even in the most severely affected white matter with near total loss of myelin, a narrow band of subcortical, convolutional white matter is usually spared (Fig. 8.3). The lesions are most common in the frontal and posterior parietal/occipital lobes, but can involve any part of the cerebral hemispheres, brain stem, cerebellum, and spinal cord (119).

Histopathologically, the lesions are indistinguishable from active inflammatory demyelinating lesions of MS (262) or ADEM, although there is a distinctive tendency for central necrosis and cavitation especially within larger lesions (119). Histologic sections of the gross specimen confirm the presence of an inflammatory demyelinating process. As a rule in autopsy cases, lesions are of the same age. When they are extensive, multifocal, and confluent they are typically characterized by massive accumulations of foamy or myelin-laden macrophages imperceptibly merging with hypertrophic reactive astrocytes. The former are highlighted by immunohistochemistry using macrophage markers such HAM-56 and CD68, whereas the latter are delineated by robust staining for glial fibrillary acidic protein (GFAP) (50). Focal perivascular mononuclear, lymphocytic-monocytic infiltrates are present.

The pathogenesis of MDS is unknown, but it likely involves similar immunopathogenetic mechanisms to those of MS. As indicated in the discussion of MS pathogenesis, an inflammatory-type oxidative stress injury marked by increased expression of iNOS and nitrotyrosine has also been reported in cases of MDS (50).

The illness tends to present in children between the ages of 4 and 13 years, although it can be seen in adolescents and adults (53). Onset is often subacute and presents with some combination of headache, lethargy, behavioral
and cognitive disturbances, personality changes, progressive clumsiness, and ataxia. Most cases exhibit hemiparesis or asymmetric double hemiparesis, variously combined with aphasia, visual disturbances, dysarthria, oropharyngeal dysfunction, bilateral pyramidal signs, ataxia, or pseudobulbar manifestations (271,273,274,275,276). Elevated intracranial pressure with papilledema is occasionally encountered. Unlike ADEM, there is usually no history of prodromal illness or fever (53).

Recently, optic neuritis has been reported as a novel mode of presentation in Schilder disease (277)

The subacute onset of focal neurologic signs and increased intracranial pressure often suggests a space-occupying lesion, namely a brain tumor or an abscess (278,279). The CSF protein levels are usually within normal range, as is the CD4/CD8 ratio. Oligoclonal bands are detected in some cases (262,276).

Extensive hypodense areas are typically seen on computed tomography (CT). MRI shows massive involvement by either single, albeit large, or multiple areas of cerebral white matter disease consistent with demyelination. Multiple lesions in Schilder disease are characteristically bilateral, but exceptionally multiple unilateral lesions may occur (278). The typical large lesions are usually clearly visible as areas of hyperintense bright signal on T2-weighted images. Some lesions have a tumefactive (tumor-like) cystic appearance, with a peripheral rim enhancing with gadolinium (122,271,276,278,279).

The absence of significant perilesional edema, the irregular and incomplete ring enhancement, and the discrepancy between size of the lesions and the associated mass effect may help differentiate Schilder disease from a neoplastic or pyogenic process (278). As a rule, neuroimaging studies exclude the diagnosis of a tumor or abscess and point to a demyelinating process. The diagnosis of diffuse sclerosis can be made with a high degree of certainty because no other demyelinating condition can progress relatively rapidly to produce edema.

It is important to emphasize that the diagnosis of Schilder disease cannot be made unless adrenoleukodystrophy (ADL) has been ruled out by analysis of the long-chain fatty acids of plasma cholesterol esters (262,280) (see Chapter 3). ADL, which occasionally can progress relatively rapidly, can be distinguished by the presence of very long chain fatty acids in the serum. In addition, ring enhancement distinguishes the lesions of Schilder disease from the myelin abnormalities observed in ADL, which is usually found in the parieto-occipital white matter (281).

MDS must be included in the differential diagnosis in young patients with a brain tumor with atypical neuroimaging features (279,282). Many of these lesions are subjected to open craniotomy and resection because of the suspicion of tumor (278,279,282,283). Biopsy and frozen sections of these are often misinterpreted as astrocytoma. However, the inflammatory nature of the lesion dominated by macrophages, perivascular mononuclear cuffs, and reactive astrocytes is more easily recognized in paraffin-embedded material, especially with the aid of immunohistochemical markers (50,278).

Immunosuppression with corticosteroids (methylprednisolone) or with a combination of cyclophosphamide and adrenocorticotrophic hormone (ACTH) has been reported to induce rapid, often dramatic and unequivocal improvement in the majority of cases, with complete or near-complete resolution of the MRI lesions (275,276). In the series by Barth and coworkers, all 5 patients did well after corticosteroid therapy (273).

The rapid early improvement of the clinical manifestations and neuroimaging changes after administration of corticosteroids is a characteristic feature of Schilder disease. Maximal recovery may require weeks or months of treatment and can often be incomplete. The time for discontinuing steroids is not clear-cut and may be dictated by the clinical picture. It may vary from 4 to 6 months (279). The benefit of adding intravenous immunoglobulin to the regimen in patients who attained only partial response to corticosteroid therapy is uncertain (279), and more studies are needed in this regard. The precise effect of corticosteroids in achieving maximal recovery or preventing progression to MS is unclear. Although some uncertainty exists about the optimal dose, it is generally agreed that high doses should be administered intravenously for 3 to 5 days followed by an oral taper. Although the MRI appearances usually improve, abnormalities may persist for years, especially if there is necrosis or cavitation in large tumor-like lesions. In some cases surgical decompressive aspiration of large lesions may improve the recovery (284).

The majority of patients appear to experience prolonged remissions after treatment; however, occasionally there are recurrences (275). As in MS, it is important to distinguish exacerbation caused by tapering of steroids from true recurrences.

Garell and coworkers suggested that there may be two clinical subsets of the disease: (a) a self-limiting, monophasic type, in which patients do well after the first brief episode, and (b) a progressive type, which is less responsive to treatment and may result in severe neurologic deficits or death (279). It is unclear whether these apparently divergent courses in the natural history of the disease represent inherent variations in the nosologic spectrum of MDS or are the result of early or efficacious treatment. Interestingly, in Garell’s small series, consisting of only 3 patients, the patient who underwent gross full resection did considerably better than the 2 patients who were treated only medically (279).

Fatal cases of Schilder disease present as a rapidly progressive, unremitting white matter disease resembling acute MS (Marburg type), with diffuse cerebral and spinal cord involvement (50,119).

The immunopathogenesis of NMO is unclear. Inflammation plays a major role in NMO, where BBB damage and inflammatory cells prevail, although these changes can fluctuate. The lesions are mostly inflammatory at onset and may undergo necrotizing changes over time (293). Stansbury proposed in 1949 that perivascular inflammation is the initial stage in the pathogenesis of NMO lesions (294). Autopsy studies of patients with NMO have shown abnormal vasculature in the spinal cord (295). The latter may be a target for autoimmune inflammation, with participation of immunoglobulins, activated complement (C9 neoantigen), and macrophages immunoreactive for myelin proteins, including MOG; in addition, T cells and monocytes/macrophages may contribute to the myelin damage (142,286,288). Moreover, eosinophils may play a significant role in the destructive inflammatory process of NMO (142).

The most typical neuropathologic features of the lesions are demyelination associated with inflammatory necrosis, a topographic distribution restricted to the anterior part of the optic tract (optic nerve and usually the chiasm) and the spinal cord without any signs of other lesions elsewhere. The spinal lesions are located in one or several segments. They sometimes extend to the whole spinal cord, but usually are not multicentric (296). The lesions progress through a series of stages (294):

The presence of hyalinized medium-sized spinal cord arteries is very characteristic (288,291). The selective localization of NMO lesions may be explained by the vulnerability of the spinal cord and optic nerve to antibody-mediated injury due to inherent susceptibility of the BBB at these sites or less likely by the fact that the latter regions of the neuraxis may harbor anatomically restricted neural or vascular antigen(s) (142).

Clinically, ON attacks are generally severe and exhibit poor recovery; a minority of patients experience simultaneous bilateral ON. Myelitis attacks are often fulminant, bilateral, complete acute transverse myelitis (ATM) and accompanied by pain and a great degree of residual neurologic impairment (287,288,296). The clinical course is monophasic in about 35% of patients, where there is a single episode of ON and ATM and several years of follow-up that reveals no further exacerbations. Most patients experience a relapsing course, where ON and ATM may be many weeks or even years apart but attacks recur over the next months or years (288,297); 55% of relapses occur within the first year after the initial clinical event, 78% at 3 years, and 90% at 5 years (298).

The diagnosis is based on the typical association of ON and ATM (see Table 8.5)

The differential diagnosis with connective tissue diseases and MS may be difficult in some cases at the time of the first clinical attack. Early diagnosis and treatment are very important to reduce morbidity of NMO (288,299). Recently, Lennon and collaborators (299) described NMO-IgG, a serum autoantibody against a putative target autoantigen of NMO, associated with both the subarachnoid glia limitans and Virchow-Robin spaces and the
extracellular matrix or parenchymal-penetrating microvessels in the CNS. This antibody was detected in almost three-fourth of patients with NMO, in nearly half of those at high risk of developing NMO, and in about one-tenth of those showing ON or ATM as the initial manifestation of MS. However, it was negative in all patients with classic MS. The authors concluded that NMO-IgG is a specific marker autoantibody of NMO, which is useful for establishing a differential diagnosis with MS and for monitoring the progression of ONM and its response to treatment (299). Patients with ONM also have a high seropositivity for multiple markers of autoimmunity such as antinuclear antibody (ANA), extractable antinuclear antigen (ENA), and thyroid antibodies (288,289).

The CSF is often abnormal with mild elevation of protein and pleocytosis, including neutrophils, up to 3,000 cells/mm³. Pleocytosis can vary depending on the phase of the disease, being relevant during the acute symptomatic event(s) and normalizing during the stationary phase. Oligoclonal bands may be present, but less often than in typical MS, and, if they are present, they usually disappear in the course of the disease, contrary to what happens in MS (286,289,290,293). In patients with relapsing NMO total IgG concentration is elevated, as in MS patients, but the percentage of IgG1 and IgG1 index are increased only in patients with MS; these findings suggest less Th1 immunity in relapsing NMO and may also explain the rarity of oligoclonal bands in patients with this disease (300).

Brain MRI in NMO patients shows no focal white matter lesion suggestive of MS, whereas spinal cord MRI displays extensive cervical or thoracic confluent, longitudinally extensive lesions, usually longer than two vertebral segments. They are T1 hypointense, which distinguishes them from those described in MS, which are hyperintense in T2-weighted sequences and enhance with gadolinium (288,289,290,293).

In selected cases, leptomeningeal biopsy shows increased vascularization and thickened hyalinized vessel walls (291).

The treatment of choice for acute attacks in NMO is intravenous methylprednisolone for 5 days followed by prednisone taper. In patients refractory to corticosteroids, intravenous IVIG has been used with some success (286,288,291). Plasmapheresis, in a randomized, double-blind, crossover trial in patients with idiopathic inflammatory demyelinating disease, showed moderate or marked improvement in 6 of 10 patients with severe, corticosteroid-refractory NMO (301).

Case series of NMO patients suggest that azathioprine and prednisone may reduce relapse frequency and protect optic nerve and spinal cord function more effectively (302). The use of other immunosuppressive drugs like cyclophosphamide and mycophenolate mofetil has been limited (286,288). The role of immunotherapy with interferons or glatiramer acetate is unclear, but anecdotal evidence has been discouraging (288). Based on knowledge about the immunopathogenesis of NMO, B-cell modulators should be investigated as possible therapeutic agents (288).

The prognosis of patients with NMO has been well studied in adults, and is related to the severity and clinical course of the disease (288,289,290). In the experience of the Mayo Clinic, patients with monophasic NMO have more severe acute ON and ATM, but the long-term neurologic impairment and disability is significantly less than in patients with a relapsing course. Although 22% of them may remain legally blind at least in one eye, more than 50% recover to 20/30 visual acuity or better. Neurologic impairment is mainly related to sequelae of ATM; most patients experience at least a moderate degree of both limb weakness and sphincter dysfunction. Five-year survival in this group is 90%, and the cause of death is unrelated to NMO or its complications (288). A relapsing course of NMO is more likely to occur if patients are of female gender, are older at disease onset, and have less severe motor impairment with the first ATM attack and there is a longer interval between the first and the second attacks. The prognosis is worse in these patients: at 5 years of follow-up more than 50% will be legally blind in at least one eye. In addition, with each relapse the motor disability increases. Life expectancy is seriously affected: Almost one-third of patients die secondary to recurrent myelitis with respiratory failure and attendant medical complications. The presence of autoimmune disease, the degree of motor recovery after
the initial myelitis event, and a higher attack frequency in the first 2 years of disease all predict a shorter survival (288,292,297). Other series of patients with NMO reported similar prognostic data (289,290).

The peripheral blood counts may be within normal range, although they can also show leukocytosis with lymphocytosis. The CSF is essentially unremarkable in one-half of the patients, whereas in the other half it may show a mild to moderate pleocytosis, rarely, though, above 100 cells/mm³. Glucose is usually within normal range and protein is moderately elevated (64,188,311,312,314,315, 326,357,358).

The presence of IgG oligoclonal bands or increased IgG index in the CSF, indicating intrathecal synthesis of immunoglobulins, is a rare occurrence (311,312,313,357). In a series of 84 patients previously reported by one of us (S.N.T.), only 2 patients showed presence of oligoclonal bands; both patients had developed ADEM following HSV encephalitis (188). The finding of increased CSF MBP is an indicator of the destruction of myelin and depends on the timing of performing the spinal tap and on the extent of the demyelinating lesions and has no clinical diagnostic value. High levels of IL-6 (311) and low levels of IL-10 and TNF-α (315) have recently been reported in the CSF of ADEM patients.

A recent study by Yoshikawa and colleagues (359) found low levels of hypocretin in the CSF of ADEM patients that correlated with excessive daytime sleepiness during the course of the disease. The authors suggested that a dysfunction of hypothalamic hypocretin-peptide neurotransmission is involved in the altered state of alertness in these patients.

Neurophysiologic studies show nonspecific abnormalities. The EEG performed during the acute phase of the disease shows generalized or focal slowing, with high-amplitude theta and delta waves (188,311,312,326). The observed prolonged latencies in the evoked potentials are nondiagnostic because they can be seen in other acute encephalopathies. However, they correlate well with the clinical and neuroimaging data and can be useful in evaluating the course of the disease. It is important to emphasize that the evoked potentials do not reveal subclinical involvement of functional systems in ADEM, in contrast to MS (311,312).

MRI examination of the CNS is the investigation of choice for establishing the diagnosis of ADEM (64,315, 360,361), which should be suspected on the basis of the clinical history and neurologic evaluation. Demyelinating lesions are hypointense on T1 and inversion-recovery sequences and hyperintense on T2, proton density, and FLAIR images. Lesions are usually asymmetric and variable in number and size (187,213,311,312,313,326, 357,362,363). The absence of periventricular changes is one of the key features that help to distinguish ADEM from a first clinical presentation of MS (313,353). The lesions involve the deep white matter with variable compromise of the subcortical white matter of the cerebral hemispheres, cerebellum, brainstem, and spinal cord. However, cortical and deep gray matter involvement is a commonly reported finding (189,313,364). The corpus callosum is usually not
involved in ADEM; infrequently, its involvement has been reported, suggesting extensive lesion load (312,353). Lesions may not enhance after the administration of gadolinium, or, more often, may enhance in a homogeneous fashion, which indicates that they are in the same phase of progression (365,366). Different patterns of enhancement can be observed, including ring shaped, nodular, incomplete ringlike, and complete-ring shaped (367). Although multifocal or disseminated lesions are characteristic of ADEM, there have been instances with solitary CNS lesions (122,368,369).

Tenembaum and colleagues (188) developed a classification of MRI lesions in ADEM, which include the following groups: A (62%), with small demyelinating lesions (less than 5 mm) (Fig. 8.4A); B (24%) with larger demyelinating plaques (greater than 5 mm or confluent), an asymmetric distribution, and variable tumefactive effect (“pseudo-tumoral ADEM”) (Fig. 8.4B); C (12%), with additional, symmetric, bilateral thalamic involvement; and D (2%): acute hemorrhagic encephalomyelitis (HAEM) or Hurst disease, with large plaques showing some evidence of hemorrhage.

The diffusion-weighted imaging (DWI)-MRI technique adds to the diagnostic power of MRI in patients with ADEM, and may help to elucidate different overlapping phases in CNS inflammation (362,370,371,372). Diffusion tensor MRI (DT-MRI) measures diffusibility or microscopic random translational motion of molecules and water, which provides information about the orientation, size, shape, and geometry of brain structures. DT-MRI of the basal ganglia has demonstrated that patients with ADEM have a high mean diffusibility (microscopic random translational motion of molecules and water), in contrast to MS patients, suggesting that deep gray matter tissue damage occurs in ADEM patients. DT-MRI may be useful for establishing a differential diagnosis between ADEM and MS (373).

Studies with quantitative proton MR spectroscopy reveal low levels of N-acetylaspartate (NAA), without increase in choline, and elevated lactate within the regions of prolonged T2 MRI signal, which recover with normalization of clinical and MRI findings (369,371,374).

99m Tc-HmPAO SPECT studies have shown areas of hypoperfusion that are more extensive than the MRI lesions (375,376,377,378). SPECT also reflects better the clinical course than the time course of MRI abnormalities; in spite of
MRI becoming normal, SPECT detects persistent cerebral circulatory impairment probably contributing to cognitive and language deficits observed in these patients (376). Similarly, PET scan demonstrated global decreased cerebral metabolism in both hemispheric white and gray matter in a case where MRI showed a focal right frontoparietal demyelinating lesion (378).

The differential diagnosis of ADEM is broad. In patients presenting with acute changes in mental status, motor focal findings, fever, and partial seizures one is required to rule out acute viral meningoencephalitis, in particular due to HSV. It is recommended to initiate specific antiviral treatment (acyclovir) until MRI and virologic studies confirm or rule out HSV infection (53).

The cases of ADEM with large MRI lesions with variable mass effect need to be differentiated from primary cerebral tumors or Schilder disease (262,368). MRI resolution with corticosteroid treatment in patients with a monophasic disease will support the diagnosis of ADEM but this is not entirely clear-cut given the responsiveness of cases of Schilder disease to steroid treatment.

The use of MR spectroscopy can be of value in supporting the diagnosis of gliomatosis cerebri because it shows high choline/creatine and choline/NAA ratios (379). Clinical and radiologic recovery after a pulse of corticosteroids is diagnostic of demyelinating disease (ADEM or Schilder disease) as opposed to tumor.

The metabolic leukoencephalopathies, such as metachromatic leukodystrophy, Krabbe disease, and adrenoleukodystrophy, as well as mitochondrial disorders should be included in the differential diagnosis (313). However, the clinical course in these disorders is different than in ADEM.

Isolated angiitis of the CNS and macrophage activation syndromes (i.e., familial hemophagocytic lymphohistiocytosis) should also be considered in the differential diagnosis (380).

In patients with bithalamic MRI involvement one has to rule out acute necrotizing encephalopathy of childhood, which presents with a severe, acute neurologic dysfunction and bilateral thalamic necrosis with cavitation (381,382). Patients with ADEM show complete resolution of the bithalamic lesions without cerebral atrophy or gliosis (188,383,384,385). A similar neuroradiologic pattern can be observed in patients with deep cerebral venous thrombosis (386), but a careful observation of T1 and T2 MRI images in sagittal views makes it possible to rule out this condition when not showing signal changes in the deep cerebral veins and straight sinus. Infantile striatal necrosis and other forms of encephalitis involving the basal ganglia should also be considered in the differential diagnosis of patients with bilateral bright MRI signal in the caudate and lenticular nucleus (387).

Finally, the biphasic or multiphasic clinical forms of ADEM raise the issue of risk of developing MS (188,311, 312,387) (see later discussion).

Serologic evaluation for specific antibodies may be helpful in identifying a specific infectious agent (467). CSF findings vary depending on the time of lumbar puncture in the course of the disease (474). Abnormalities are found in more than half of patients and include moderate lymphocytic pleocytosis and high protein level (53,467,474). Myelin basic protein is elevated in cases of postinfectious ATM (53,463,476). IgG index may be increased (457). CSF viral studies or molecular investigations (e.g., PCR for Lyme disease) will confirm an etiologic diagnosis in some patients.

Clinical neurophysiologic studies are important in distinguishing central versus peripheral nervous system dysfunction (474). Although peripheral nerve conduction velocity is normal, compound muscle action potential amplitudes may be affected if segmental anterior-horn cells are affected. Missing F waves or prolonged F latencies, indicating root involvement, occur in Guillain-Barré syndrome and in anterior spinal artery infarction. Prolonged or absent somatosensory-evoked potentials (SEPs) in conjunction with normal sensory nerve action potentials indicate a CNS lesion, for example, in the spinal cord as in ATM (474). Magnetic motor-evoked potentials (MEPs) are not very useful in children because their absence is physiologic before 12 years (477), but they may be helpful in adolescent patients (478).

In a study of 39 adult patients with ATM, abnormal central motor conduction time to tibialis anterior was the most frequent abnormality (90%), followed by abnormal tibial SEP (77%). Central motor time to abductor digiti minimi was abnormal in 30% and median SEP in 15% of patients. Evidence of denervation on electromyography (EMG) was present in 51% of patients. MEPs and SEPs had a good correlation with motor or sensory findings, respectively (479). Unrecordable, prolonged, or normal EPs reflect the decreasing severity of spinal cord involvement. Unrecordable motor and sensory EPs may be due to necrosis, edema, and severe demyelination resulting in conduction block. The prolongation of central conduction time may be due to dispersion and/or demyelination. The normal EPs may be due to milder involvement or sparing of fast-conducting motor or sensory pathways (479). In cases of mild ATM with normal SEPs and spinal cord MRI, the diagnostic segmental EPs need to be performed to confirm the diagnosis (A.L., personal experience). Visual evoked potentials (VEPs) are useful for ruling out or ruling in MS (53).

MRI results are relatively variable and nonspecific in ATM. The value of MRI is to exclude other conditions that cause paraparesis, particularly space-occupying lesions that require emergency surgical treatment (467,474). In post–infectious/immunization ATM the most frequent findings are spinal cord swelling, longitudinal fusiform-like diffuse hyperintensities on T2-weighted images, and presence of gadolinium enhancement in a nodular, diffuse, or peripheral pattern. The lesions are solitary in more than 80% of cases and frequently extend over several vertebral segments (467,474,480,481,482). When ATM is associated with SLE, the MRI findings are similar to those found in MS, sometimes with overlap features called “lupoid sclerosis” (482). After clinical remission of ATM with residual symptoms, atrophy of the spinal cord can be found on T1-weighted images and with low intensity on T2-weighted images. Brain MRI may show clinically silent T2 bright lesions (483), the significance of which is unclear, and, as in ON, should not necessarily suggest a diagnosis of MS (53).

The first step in the algorithm of differential diagnosis of ATM is to consider whether it is idiopathic or disease associated (Table 8.6). Specific tests will confirm the diagnosis (464). Then ATM should be differentiated from other acute myelopathies such as spinal cord compression by a tumor or abscess, arteriovenous malformation, hemorrhage, stroke (myelomalacia), or radiation injury (53,472); MRI is the test of choice for clarifying the diagnosis (481,482). Tropical spastic paraparesis is a progressive myelopathy caused by HTLV-1 infection, which may produce MRI changes similar to ATM, although its neurologic progression is much slower than that of ATM (53). Sometimes MS can present with a clinical picture similar to ATM. In MS, spinal MRI is abnormal in only 5% to 12% of cases if the brain MRI is normal. In MS, spinal cord lesions rarely extend more than two vertebrae; they may be multifocal; spinal cord enlargement is rare; and MRI may show typical diagnostic high-signal T2 lesions (474). Devic disease requires the diagnosis of associated ON. The differential diagnosis of an acutely presenting Guillain-Barré syndrome (GBS) and the initial phase of ATM may be difficult in some cases. The presence of CSF albumino-cytologic dissociation and abnormal peripheral nerve conduction velocity are the keys supporting the diagnosis of GBS (484).

An antecedent acute infectious illness has been documented in approximately two-thirds of children who develop GBS (484,670,671,672,677). Most commonly, it is a respiratory tract infection or gastroenteritis. Several agents have been implicated in these infections (694,695,696,697,698,699,700,701,702). Of these, Campylobacter jejuni infection has become recognized as the most common bacterial antecedent of GBS (484,670,672,696,698,701). In various series it accounted for 23% to 41% of sporadic cases (698,701). Other responsible agents include cytomegalovirus, which has been implicated in 8% to 22% of GBS cases (696,701), and the Epstein-Barr virus, which is responsible for up to 2% to 10% of cases (696,697). Primary infection with herpes zoster has been noted in nearly 5% of childhood cases of GBS in some series (702). Other viruses implicated in the evolution of GBS are listed in Table 8.8. The chief feature shared by most of these is that they have a viral envelope. GBS has also been associated with Mycoplasma pneumoniae (703) and Haemophilus influenzae (704) infections.

Several vaccines have been related to the evolution of GBS. Of these, the best substantiated is the rabies vaccine as prepared from brain tissue and probably contaminated with myelin antigens (705,706). The swine-flu influenza vaccine, as administered in 1976 and 1977, was also responsible for numerous cases of GBS (646). Furthermore, it has been suggested that GBS is associated with other immunizations, including those for tetanus (707), polio (oral vaccine) (708), influenza (709), mumps, measles, and rubella (MMR) (710), hepatitis A (711), hepatitis B (712), and H. influenza type b (713). The most reasonable conclusion we can draw today from all available data is that a causal relationship between immunization and GBS has not convincingly been established, but cannot be excluded (672).

The association of GBS with trauma or surgical procedures purportedly precipitating stressful immunologic events is probably anecdotal (53).

There is ongoing debate as to whether the primary effector mechanism of autoimmune injury is antibody mediated, T cell driven, or both (672).

The first step in GBS immunopathogenesis is the presentation of antigen to “naive” T cells resulting in their activation. The activated T cells circulate in the bloodstream and attach to the venular endothelium of peripheral nerves. T cells need to traverse the blood–nerve barrier. They migrate through the endothelial lining to a perivascular location into the endoneurium with the participation of a pathway of adhesion molecules, including selectins and leukocyte integrins and their counter-receptors on endoneurial vascular endothelial cell walls (672,689). The role of integrins (a family of cell adhesion molecules) in the development of inflammation in experimental allergic neuritis and GBS and subsequent remyelination is critically reviewed by Archelos and colleagues (714).

The last step of the pathogenetic events occurs when activated T cells and autoantibody enter the endoneurium along with macrophages, where both antibody and T cell–targeting mechanisms identify autoantigens on axonal or Schwann cell constituents, resulting in tissue injury accompanied by active phagocytosis by cells of the monocyte/macrophage lineage (670,672,677,689,715). A series of serum antibodies have been extensively studied, both in the clinical and experimental settings; however, their role in the pathogenesis of GBS is unclear.

C. jejuni is the reported causal agent in one-third of patients with GBS, and molecular mimicry between the gangliosides and the lipopolysaccharide (LPS) of the bacterium is considered to contribute to the generation of antiganglioside antibodies (670,672,677,716,717,718). G_M1, G_M1b, G_D1a, G_Q1b, and GalNAc-G_D1a epitopes are expressed in the LPSs of C. jejuni isolated from patients with GBS, and a single strain of C. jejuni has several ganglioside-like LPSs (676,689,693,718,719,720). Antiganglioside antibodies are detected in high titers in serum samples of approximately 40% of patients with GBS, and they are of the three major subclasses, IgM, IgG, and IgA (721). These antibodies are believed to react with epitopes located mainly in the axoplasmic compartment of axons, but also, to a lesser degree, in the myelin sheaths. Immunization of mice with C. jejuni LPS generates a monoclonal antibody that reacts with G_M1 and binds to the peripheral nerves (720).

It has become increasingly apparent that the antigenic structure of the antecedent infectious agent determines the clinical manifestations of GBS. Patients whose sera have anti-G_M1 antibodies (IgG) tend to develop the acute motor axonal neuropathy form of GBS (718,721,722), whereas those who specifically develop antibodies to G_M1b (723) or to anti–GalNAc-G_D1a (724,725) tend to have a more rapidly progressive, more severe form of disease with predominantly distal weakness. C. jejuni also has been implicated in the demyelinating form of GBS (726). More than of 90% of patients with Miller Fisher syndrome have elevated serum antibodies against the G_Q1b ganglioside (677,693,721,727). However, different phenotypes of the anti G_Q1b IgG antibody syndrome can occur at different times in the same patient, showing that this syndrome may be a distinct entity with a wide clinical spectrum on a unique immunologic background. Patients with anti G_T1a IgG, which cross-reacts with G_Q1b in 75% of cases, often have cranial nerve palsy (728). CMV infection is related to ganglioside G_M2 (729), which is preferentially expressed in sensory nerves and causes a motor and sensory neuropathy (721); M. pneumoniae ganglioside GalC triggers antibodies that cause a poorly known neuropathy (721).

The pathogenicity of ganglioside-specific antibody (IgG) has been suggested lie in its capacity to reduce nerve conduction velocity (730) and activate phagocytes via IgG receptors (FcγR) (731). It has also been suggested that the participation of complement in the ganglioside-antibody reaction could lead to events that damage ion channels because there is experimental evidence that anti-G_M1 antibodies can cause ion channel dysfunction (670). Taguchi and collaborators (732) showed that GalNAc-G_D1a antibodies may block neuromuscular transmission by affecting the ion channels in the presynaptic motor axon. Similarly, in the study of Yuki and coworkers previously cited (720), the monoclonal antibody induced by C. jejuni LPS and anti-G_M1 IgG from patients with GBS does not induce paralysis, but blocks muscle action potentials in a muscle–spinal cord coculture (720).

Alternatively, other microbial structures rather than gangliosides per se may influence antigen presentation, thereby facilitating the proliferation of ganglioside-specific B- and T-cell clones. These are the so-called “superantigens,” which are molecules capable of activating lymphocytes, bypassing the classic interaction of T-cell receptors with MHC-antigen complexes and B-cell receptors with antigens (721,733).

Another postulated immunopathogenetic mechanism in GBS is the “heterotypic cross-linking of specific and innate leukocyte receptors” (721,733). Interaction of mucosal lymphocytes with GBS-associated pathogens may trigger an engagement of leukocyte pattern recognition receptors (PRR) in addition to ganglioside-specific B- and T-cell receptors. PRR are potent immune modulatory molecules recognizing prototypical bacterial or viral structures. Cross-linking of both PRR and B-cell receptors has been shown to induce B-cell activation (734).

T cell–mediated pathways are clearly also involved in the pathogenesis of the autoimmune injury of peripheral nerves in GBS (672,677,689). This assertion is supported by several lines of evidence derived from immunopathologic findings in GBS patients: (a) Cellular infiltrates, mainly macrophages, but also CD4- and CD8+ T lymphocytes, are seen in nerve biopsies (735), (b) there is systemic T-cell activation: T cells reactive to nerve antigens are found in peripheral blood (736), (c) C. jejuni DNA has been detected in myelomonocytic cells, suggesting that neuritogenic antigens may be presented by MHC class II to T cells (737), (d) a T-cell subset that expresses Vγ8/δ1 T-cell receptor phenotype has recently been isolated from sural nerve, lending credence to the hypothesis that C. jejuni could stimulate such receptors in the gut, hence becoming neuritogenic (738), and (e) there is evidence of a T cell-dependent serum antibody response to gangliosides (739). This body of evidence points to selective recruitment of macrophages and T lymphocytes causing damage to the peripheral nervous system. To this end, cytokines and chemokines are active participants in this inflammatory process (677,689).

Cytokines regulate the amplitude and the duration of the immune-inflammatory responses (677,689). Once the immune cells are drawn into the peripheral nerves in GBS patients, cytokines are released by them and also by the Schwann cells. Recent studies have confirmed the immune capabilities of Schwann cells, which can initiate, regulate, and terminate the immune response. They are able to participate in the processes of antigen presentation and secretion of pro- and anti-inflammatory cytokines, chemokines, and neurotrophic factors. The discovery of the purinergic receptor P2X₇ in Schwann cells may help to explain how their secretion of cytokines is regulated (740). Some of the cytokines implicated in the pathogenesis of GBS include IL-18, IL-12, IL-10, leukemia inhibitory factor (LIF), and TNF-α (677,741,742). Cytokines induce the production of proinflammatory mediators such as granulocyte-macrophage colony-stimulating factor (GM-CSF), chemokines (MIP-1), prostaglandins, and nitric oxide (NO) (677,743). The importance of NO in the pathogenesis of axon damage in GBS has recently been emphasized (744). Cytokines also regulate the generation of effector T and B lymphocytes (677). The serum levels of some cytokines, for examples, TNF-α (745), correlate with neurophysiologic evidence of demyelination.

Chemokines are low-molecular-weight cytokines involved in chemotaxis and activation of phagocytes and lymphocytes (677). In GBS patients, high levels of chemokines have been demonstrated, like monocyte chemoattractant protein (MCP-1) in serum (746) and IFN-inducible protein (IP-10) in CSF (747). In addition, the expression of chemokines is increased in nerve biopsies of animals with EAN (748) and in GBS patients (747). Further evidence of the role of chemokines in GBS pathogenesis is provided by the work of Zou and coworkers (749), who demonstrated that the injection of anti–CCL-3 (MIP-1α) antibody ameliorates the clinical course of EAN induced in the Lewis rat.

Unlike autoimmune disorders where a genetic predisposition to develop the disease has been proved, the role of genetic factors in GBS is unclear. Disease heterogeneity and varying associations of preceding infections, antibody responses, and neurologic damage may be secondary to immunogenetic factors that direct the host immune response (689). Attempts to identify an immunogenetic susceptibility factor have largely focused on the HLA system. A study of HLA antigens in GBS by Adams and colleagues in 1977 (750) showed that the appearance of the disease is not influenced by genes associated with the
HLA-A or HLA-B locus. Other studies, however, reported an association between HLA-54, HLA-CW1, and HLA-DQB*3 antigens and GBS or Miller Fisher syndrome (751,752). In a British study, HLA-DQB1*03 was highly associated with a preceding infection with C. jejuni (751), whereas one Japanese study reported a high frequency of HLA-Bw54 in a clinically similar patient group (752). Recently, Magira and colleagues (753) demonstrated a positive association of AIDP with the DQB1*0401 allele with the unique DQβED^70-71 epitope and a negative association with the alleles AQB1*0503, DQB1*0601, DQB1*0602, and DQB1*0603, characterized by the epitope RDP^55-57. Moreover, the study revealed a differential distribution of HLA-DQB epitopes between AMAN and AIDP, providing immunogenetic evidence for differentiating these two GBS entities. Geleijns and coworkers (754) found that HLA-DRB1*01 is increased in patients who need mechanical ventilation. In this study, there was also a tendency toward an association between certain HLA alleles and several antiganglioside antibodies. Overall, these findings suggest that HLA class may be determinant in distinct groups of GBS, but that there is a need for further exploration in large-scale studies. In addition, information about the genetics of GBS has been provided by a recent study of GBS within 12 Dutch families, which concluded that GBS is a complex genetic disorder and its outcome is determined by both environmental and genetic factors. The genealogy and molecular genetics of a large number of families with GBS may give more insight into host factors determining an individual’s susceptibility to the condition (755).

This is the traditionally recognized hallmark phenotype of GBS, and it is the most common clinical presentation among affected children in developed countries (670,672). Clinical symptoms result from disturbed saltatory conduction through myelinated axons (conduction block). GBS can occur at any time during childhood, but is most frequent between the ages of 4 and 9 years (756). A prodromal respiratory illness or gastroenteritis occurs in approximately two-thirds of the patients, approximately within 2 weeks before the onset of weakness (Table 8.9) (756,757).

Neurologic symptoms usually appear fairly suddenly (53). In a large proportion of cases, 89% of adult patients in the series of Moulin and colleagues (758), paralysis was accompanied by pain or paresthesias. In 47%, pain was severe and was described as a deep, aching pain in back and legs. Visceral pain was noted in 20%. In children, pain is also a prominent feature at presentation in 50% to 80% of cases and paresthesias in 18%(672).

The paralysis usually begins in the lower extremities, then ascends. Characteristically, it is symmetric, although minor differences between the sides are not rare. In approximately 50% of patients, the weakness is mostly distal, whereas in approximately 15%, the proximal musculature is more extensively involved (see Table 8.9). Ataxia is also common in children, and was present in 44% of patients in the series of Sladky (672). Cranial nerve palsies can appear at any time during the illness with variable frequency, from 15% to 43%. The facial nerve is most commonly affected; it was involved in more than one-half of patients in the series of Winer and colleagues (700). Papilledema is relatively rare. Although its appearance correlates well with increased intracranial pressure (759), papilledema is not always accompanied by elevation in CSF protein, and its pathogenesis is unexplained (760).

Paralysis of the respiratory muscles is a common complication in severely affected patients, but even in the absence of respiratory symptoms, vital capacity can be impaired with consequent carbon dioxide retention. Involvement of the sympathetic nervous system can produce a variety of dysautonomic abnormalities, including profuse sweating, hypertension, and postural hypotension, which often are predictors of a fatal cardiac arrhythmia (672,761). Sphincter disturbances are noted in up to one-third of patients (672,700).

Position sense is the sensory function most frequently impaired, followed by vibration, pain, and touch, in descending order of frequency. The deep tendon reflexes are generally absent, although increased reflexes and extensor plantar responses are occasionally recorded during the initial days of the illness (53). Recently, several adult patients with GBS exhibiting marked, persistent hyper-reflexia were reported (762,763).

An elevation in the CSF protein content is characteristic. This exceeds 45 mg/dL in 88% of affected children (see Table 8.9) and peaks by 4 to 5 weeks, thereafter gradually returning to normal. However, in the first 2 to 3 days the CSF protein level is not elevated in most cases, and the appearance of the electrodiagnostic features of demyelination–remyelination tend to lag behind clinical evolution (670). The CSF cell count is usually normal, although significant pleocytosis (100+ cells/mL) occurs in approximately 5% of patients (53).

Electromyography reveals a picture compatible with involvement of the lower motor neurons or peripheral nerves. Abnormalities in nerve conduction are the most specific electrophysiologic findings. The most characteristic is the presence of conduction block. These features include prolongation of distal latencies or F-wave latencies, conduction velocity greater than 5 m/sec among comparable nerve segments, and dispersion of proximally evoked compound motor action potentials (672).There is a reduction in amplitude of the muscle action potential after stimulation of the distal, as compared to proximal, portion of the nerve. Approximately 80% of patients have nerve conduction block or slowing at some time during the illness. Not infrequently, the conduction velocity does not become abnormal until several weeks into the illness (764,765). When axonal degeneration is the primary feature of GBS, the severity of axonal loss correlates well with the prognosis. Profound reduction in compound motor action potential amplitudes usually is associated with a prolonged, incomplete recovery (672).

This neurologic picture evolves rapidly, and paralysis can be maximal within a few hours of the initial symptoms. More commonly, however, the paralysis becomes more extensive over 1 to 2 weeks, often, as in the classic Landry type of paralysis, progressively affecting the trunk, upper extremities, and cranial nerves. After the paralysis reaches a plateau, clinical improvement is usually first noted by the second to fourth weeks of the illness, and the majority of children experience complete recovery. Recovery is usually achieved within 2 months, although it can take as long as 18 months (53).

Some patients, approximately 10% of the Dublin series of Briscoe and coworkers (766) and 5% in the series of Das and collaborators (767), experience one or more relapses over the subsequent 2 months to several years. Such patients are considered to have CIDP. This condition is covered in a subsequent section.

Feasby and coworkers (768,769) first described a subgroup of patients who developed a fulminant, extensive, and severe weakness with delayed and incomplete recovery. Electrophysiologic studies in these patients suggested a primary axonal degeneration, which was confirmed by nerve biopsy performed on patients who died shortly after the onset of their illness. This demonstrated severe axonal degeneration with little demyelination and scanty lymphocytic infiltration, an indication that in this condition the primary insult is to motor and sensory nerve axons (683). In these patients the earliest identifiable changes are in the nodes of Ranvier of motor fibers (770). Patients with this form of neuropathy are much more likely to have experienced an antecedent C. jejuni infection than control populations and are more likely to have high titers of serum anti-G_Dla antibodies (722,771). This subtype is thought to be a more severe and widespread (both sensory and motor) version of acute motor-axonal neuropathy (670). The clinical presentation is indistinguishable from that of AIDP, but the prognosis is worse; therefore, elucidation of this diagnosis is clinically important (672). Electrophysiologic testing will confirm the presence of markedly decreased compound motor action potential and sensory-evoked potential amplitude and widespread denervation on EMG (672).

A pure motor axonal neuropathy has been reported from Mexico, China, and India, and is increasingly recognized in the Western world. In the Chinese cases, the disease appeared in annual summer epidemics and manifested as a severe motor neuropathy, with involvement of the proximal portion of the motor neurons or cell bodies and good recovery. Electrophysiologic studies show decreased motor action potential amplitude, preservation of motor nerve conduction velocities, denervation on EMG, and normal sensory nerve conduction velocities (672,772,773). In the Indian paralytic disease, fever and hemorrhagic conjunctivitis occur at the onset of the illness, the weakness is asymmetric, and the CSF demonstrates a pleocytosis. This form of neuropathy also is closely associated with C. jejuni infection (698,721).

Another variant of GBS, MFS, was first described by Fisher in 1956 (774). It is characterized by the evolution, within approximately 1 week, of external ophthalmoplegia, ataxia, and areflexia (670,672). The first symptom is usually diplopia, with bilateral facial paresis being present in approximately one-half of the affected children (775). Internal ophthalmoplegia is present in approximately two-thirds.

The CSF shows a mild elevation in protein content and, occasionally, pleocytosis, but typical albumino-cytologic dissociation, as seen in AIDP, can be present (672). Electrophysiologic testing shows abnormalites confined to sensory axonal populations. Some patients may exhibit slowing of motor and sensory nerve conduction (672). In a recent study of 6 patients with MFS, 5 had electrophysiologic evidence of an axonal, predominantly sensory
polyneuropathy characterized by reduced amplitude or absent sensory responses, accentuated in their arms, and mild F-wave abnormalities. However, 3 patients had the patterns of low median, normal sural responses, raising the possibility of demyelinating neuropathy. Needle EMG found patchy fibrillation in 2 patients (776). The EEG can show excessive slow-wave activity or can be normal (777). Neuroimaging studies exclude a mass lesion (778,779).

Symptoms remain severe for 1 to 2 weeks before recovery commences. Recovery proceeds at a variable rate, but generally is complete.

The Miller Fisher syndrome is associated with strains of C. jejuni that have the ability to induce antibodies against ganglioside G_Q1b (677,693,721,780,781). Such antibodies can be demonstrated in 95% of patients with MFS, and their titers parallel the course of the disease. These antibodies have the ability to block the release of acetylcholine from motor nerve terminals, with oculomotor fibers having the highest concentration of G_Q1b-reactive antigens (693,773,782,783). The effect resembles that induced by α-latrotoxin (784) (see Table 10.6).

It is a matter of dispute whether Miller Fisher syndrome should be distinguished from brainstem encephalitis, as delineated by Bickerstaff and others (785,786). According to some, ataxia in Miller Fisher syndrome is caused entirely by peripheral nerve involvement, and pathologic changes are restricted to the peripheral nervous system (787). Others believe that the CNS also is involved and that in some cases a combined central and peripheral demyelination exists. MRI studies do not appear to help in the differential diagnosis. Whereas the MRI is normal in some cases of MFS, in others T2-weighted images demonstrate areas of increased signal in the brainstem. Conversely, there are several instances of clinically diagnosed brainstem encephalitis in which electrophysiologic evidence exists for involvement of the peripheral nerves (788). MFS also must be distinguished from posterior fossa tumors. Before neuroimaging studies this differentiation was difficult. However, the constellation of a severe and sometimes complete external ophthalmoplegia, ataxia, and loss of deep tendon reflexes in a fairly alert child is unique (53).

CIDP has a childhood incidence of 0.5 in 100,000 per year. It can occur as early as in infancy, frequently with motor delay. Usually children present with a subacute onset of symmetric proximal weakness that progresses over at least 2 months (789). CIDP has some of the clinical features of GBS, but the evolution of the neurologic symptoms is slower, a matter of weeks or months rather than days. The motor component of the picture is usually predominant (716,790), and weakness is greatest in the distal muscles. Fatigue and sensory symptoms, including dysesthesias and sensory loss, are common (789). Some children progress to maximal weakness over the course of 3 months or less and tend to have a monophasic course. Recovery with long-term remission is common in this group. Some other children have a chronic fluctuating course without complete recovery between exacerbations (789,791,792). The initiating factor responsible for CIDP is unknown in most children, although evidence suggests an immune-mediated mechanism. There is presence of T cells, predominantly CD8+, in the endoneurium, which correlates with the activity of demyelination, suggesting that a T cell-mediated process is of pathogenetic significance in CIDP (689,793). Antibodies directed at G_M1, G_D1b, and asialo-G_M1 glycolipids have been identified in some cases, suggesting that the galactosyl (α1-3) N-acetogalactosaminyl moiety of myelin may be an important target antigen in some cases (794). Connolly and Pestronk (795) reported selective polyclonal β-tubulin (epitope 301–314) autoantibodies in about one-half of patients with CIDP; the pathogenic significance of these antibodies is unclear. The 301-314 tubulin epitope has sequence homology to several human viruses, including herpes simplex and CMV, but no homologies to sequences have been indentified in any myelin surface component. Unlike GBS, in which no association with histocompatibility antigens has been established, CIDP has been shown to be associated with haplotypes B8, Cw7, DR3, and Dw3 (796,797).

The diagnostic clinical research criteria include (a) progressive or relapsing motor and sensory dysfunction of more than one limb and (b) hyporeflexia or areflexia, which usually involves all four limbs (798) The CSF shows albumino-cytologic dissociation, and in some cases oligoclonal bands and IgG synthesis may be identified (789,799). Electrophysiologic studies must fulfill three of the following four criteria for research diagnosis (798): (a) a slowing of motor conduction velocity, (b) partial conduction block, abnormal temporal dispersion in one or two motor nerves, (c) prolonged distal latencies in two or more nerves, and (d) absent or prolonged minimal F-wave latencies. In a series of 18 patients from Brazil, electrophysiologic studies revealed demyelination in all of them and axonal damage in 94% (800). On biopsy, the peripheral nerves show mononuclear infiltrates, a segmental demyelination, and increased numbers of Schwann cells, with subsequent remyelination of various proportions. Their processes are arranged in whorls around the demyelinated axons. Termed onion bulbs, they are characteristic of not only the hereditary peripheral neuropathies (see Chapter 3), but also of most chronic recurrent neuropathies, and their presence correlates with the duration of symptoms (801). Table 8.10 shows the differential diagnosis of CIDP of childhood, together with some salient diagnostic features of each of the major entities.

Ropper in 1986 (802) and 1994 (803) described a series of patients who did not strictly fulfill the diagnostic criteria of GBS but had clinical and neurophysiologic characteristics compatible with GBS. The latter included acute monophasic polyneuropathy followed by improvement or remission, CSF with albumino-cytologic dissociation, and electrophysiologic findings of demyelinating or axonal pattern of nerve damage. The diagnoses established by Ropper included: (a) pharyngeal-cervical-brachial weakness (PCBW), (b) paraparesis, (c) severe ptosis without ophthalmoplegia, (d) facial diplegia and paresthesias, and (e) combination of MFS and PCBW. Recently, the pediatric neurology group from the Garrahan Hospital in Buenos Aires, Argentina, described (804), for the first time in children, a series of patients with similar diagnoses to the ones described by Ropper (802,803). In addition, the authors described a new variant, the so-called “saltatoria” (“jumping”) form, in a patient who presented as a classic AIDP but progressed to lower cranial nerve paresis without compromising the upper limbs. Recently, MacLeann and colleagues described one case of PCBW variant in a 12-year-old, emphasizing that this diagnosis should be considered in a child presenting with bulbar palsy and/or respiratory failure (805). Whether the concept of variant polyneuritis can be extended to explain pure multiple cranial nerve palsies as an “oligosymptomatic” form of GBS or these should be classified separately is unclear (803). Osaki and coworkers (806) reported a case of asymmetric PCBW with anti-G_T1a IgG antibody. Further studies with antiganglioside antibodies should help to better define these unusual GBS variants and clarify their pathogenesis (804).

Steroids have been shown to be not beneficial in the treatment of GBS and possibly are contraindicated (772,813,814,816). A Cochrane systematic review published in 1999 and including all trials in which any form of corticosteroid or ACTH treatment was used for the management of patients with GBS evaluated the results of six randomized studies. The authors concluded that there was no difference in the Improvement in Disability Scale, which was the primary outcome. There was also no significant difference between the groups for secondary outcome measures of recovery, time to recovery of unaided walking, time to discontinue ventilation in the subgroup who needed it, mortality, and combined mortality and disability after 1 year.

A comparison of a series of corticosteroid-treated patients with historical controls pointed to a beneficial effect from corticosteroids when given in combination with IVIG (817). However, a double-blind, placebo-controlled, multicenter, randomized study of 233 GBS patients showed no significant difference in disability score between patients treated with IVIG alone and those treated with combination of IVIG and methylprednisolone (818). In conclusion, corticosteroids are not recommended for the treatment of patients with GBS (816).

In contrast, many patients who experience CIDP show a clear-cut response to corticosteroids (772,814,819). Thus, Dyck and colleagues (820) reported that prednisone treatment beginning at a daily dose of 120 mg and slowly tapered over 13 weeks led to a small but statistically significant improvement in adult patients compared to those receiving no drug treatment. Patients began to improve after 2 weeks and had a maximum response after 6 months.

Treatment with IVIG has shown in case reports, case series, and retrospective reviews to accelerate recovery from GBS. Although no placebo-controlled trials have been performed, IVIG has been compared with plasmapheresis or plasma exchange (PE) in controlled clinical trials. The predominant mechanisms by which IVIG therapy exerts its action appears to be a combined effect of complement inactivation, neutralization of idiotypic antibodies, cytokine inhibition, and saturation of Fc receptors on macrophages (676). The most likely mechanism is that it modulates the immune response in GBS by selective suppression of the proinflammatory cytokines (821).

The results of the first large, randomized trial comparing IVIG and PE in treating GBS in adults were published in 1992 (822). In this Dutch study, 150 GBS patients who were unable to walk independently were randomized to treatment with IVIG, 0.4 mg/kg per day for 5 days, or PE, 200 to 250 mL/kg, within 2 weeks of symptom onset. Patients treated with IVIG showed a greater and faster improvement than those subjected to PE. Moreover, there was significantly less need for assisted ventilation and fewer complications in the IVIG group. A recent Cochrane Database System Review by Hughes and collaborators (823) evaluated through a meta-analysis 536 GBS patients, mostly adults, from six randomized trials comparing IVIG and PE. Patients were unable to walk unaided and had been ill for less than 2 weeks. The authors concluded that IVIG hastens recovery from GBS as much as PE. Giving IVIG after PE is not significantly better than PE alone. However, in the study of Hadden and coworkers (696) in adult GBS patients, those with pure motor GBS had a better outcome if treated with both IVIG and PE compared with PE alone. Other reports have suggested that IVIG is superior to PE in GBS patients with a preceding C. jejuni infection and a predominantly motor syndrome and G_M1 and G_M1b antibodies. However, none of these correlations is absolute, and testing for ganglioside antibodies and preceding infections is not warranted for guiding therapeutic decisions (689).

Because of inconsistencies in reporting, it is not clear whether adverse events are more common with IVIG or PE (816). The possible side effects of IVIG include fever, myalgia, headache, hypotension, meningismus, urticaria, eczema, and, rarely, renal tubular necrosis, thromboembolic events, pancytopenia, alopecia, and anaphylaxis. IVIG probably has a higher risk of infection transmission than PE (824). There have been reports of patients whose symptoms may worsen during and after the infusion or who may suffer relapses (825,826).

Randomized trials are needed to decide the effect of IVIG in children, in adults with mild disease, and in adults who start treatment after more than 2 weeks (827).

High-dose IVIG has also been effective in the treatment of CIDP (689,772,789,791,813,814).

PE has been extensively used in the treatment of GBS; however, since the introduction of IVIG to treat this condition, the indication for PE has decreased (828). Controlled studies have confirmed that in pediatric patients PE shortens the interval to independent ambulation (829) and the duration of mechanical ventilation (830). One study, involving patients older than 16 years, indicated that for mild cases of GBS two exchanges are better than none. For moderate or severe cases, four exchanges, conducted in the course of 1 week, are better than two. The use of more than four exchanges does not confer additional benefits (831).

PE is also useful in the treatment of CIDP (689,772,789,791,813,814). A recent Cochrane Database Systematic Review by Mehndiratta and colleagues (832) concluded that evidence from two small trials show significant short-term benefit of PE in about two-thirds of patients with CIDP, but rapid deterioration may occur afterward. More research is needed to identify agents that may prolong the beneficial effect of PE.

The report on immunotherapy for GBS of the Quality Standards Subcommittee of the American Academy of Neurology concluded the following (816):

Filtration of CSF has been investigated in a small prospective study of 37 GBS patients (491). The repeated removal of small volumes of CSF through a lumbar catheter followed by filtration through a Millipore filter and reinfusion through the same catheter is well tolerated and equally effective to conventional PE. The rationale for this therapeutic approach rests on the notion that the nerve roots are prominently affected in GBS cases and, therefore, filtration of CSF rather than whole PE might be more efficient (689).

Immunosuppressive drugs have been used successfully in the treatment of CIDP, including azathioprine, cyclophosphamide, and cyclosporine. Other immunomodulatory therapies that may be useful in CIDP are mycophenolate and interferon-β (772,789,813,814). In refractory patients, Rosenberg and colleagues (833) reported good response in 3 of 4 patients subjected to total lymphoid irradiation (200 rads). Vermeulen and Van Oers (834) described the remarkable improvement of a patient with CIDP after undergoing autologous stem-cell transplantation.

In the future, a better understanding of the immunopathogenesis of GBS and its clinical variants will improve our therapeutic intervention (672). Possible strategies may include using monoclonal antibodies against B cells, modifying agents of the macrophage Fcγ.

The clinical presentation of CNS vasculitis is heterogeneous and may be in the form of a diffuse encephalopathy with headache, stroke, and/or seizures. The clinical presentation of childhood PACNS is highly variable and often nonspecific, some children presenting with a rapidly progressive neurologic deficit and others exhibiting slowly evolving diffuse or focal lesions (893). It is believed that the type of neurologic manifestation may correlate with the size of blood vessel involvement as well as with the distribution and degree of luminal compromise of the affected vessels. Two groups of patients are identified on clinicopathologic grounds: those with predominant involvement of small vessels and those with predominant involvement of large to medium-sized arteries (897,898).

As a rule, in PACNS affecting the small vessels, the clinical picture is more “encephalopathic,” and the disease course tends to be variable but on the whole less fulminant. Such patients typically present with headaches, behavioral changes, multifocal neurologic deficits, and/or seizures. Occasionally, multifocal infarcts and “tumor-like” lesions may be detected on MRI (898). In contrast, in PACNS affecting large and/or medium-sized arteries, children present with either transient ischemic attacks or strokes (predominantly of an ischemic and to a lesser extent hemorrhagic nature) (898).

The most common presentations, in descending order of frequency, are acute severe headache (80% of cases), focal neurologic deficit (78%), gross motor deficit or hemiparesis (62%), cranial nerve involvement (59%), and cognitive dysfunction, including mood and behavioral changes (54%). Conversely, new onset of seizures (18%), movement abnormalities, and constitutional symptoms such as fever, fatigue, and weight loss (18%) are less common in children than adults (893,899). Mental status may range from normal with irritability to various degrees of confusion and obtundation. In some cases ischemic strokes, single or multiple cranial nerve palsies, or spinal cord syndromes are either the preponderant or the sole manifestations of PACNS (900). In other instances, children with PACNS can present with acute loss of consciousness or with symptoms and signs of increased intracranial pressure owing to edema or spontaneous parenchymal and/or subarachnoid hemorrhage (893,901). The latter are similar to those described in adult patients with PACNS (902,903).

PACNS is a diagnosis of exclusion, and a thorough search of a host of mimicking conditions, especially infections, is mandatory in every case in which suspicion for CNS vasculitis exists on clinical and/or angiographic grounds (896). Some cases may present with what is described as “vanishing” saccular- or mycotic-like aneurysms (904,905). Despite certain apparent similarities, pediatric cases frequently have different or atypical clinical, anatomic, and angiographic features than those in adults. To this end, PACNS in children may exhibit a proclivity for large-vessel involvement and unilateral disease based on angiography (897). Mention should be made of a number of diseases that can mimic childhood PACNS (893). These include secondary vasculitides involving the CNS (see later discussion), cases of migraine or vasospasm, hemoglobinopathies (sickle cell anemia and thalassemia), thromboembolism (906), antiphospholipid antibody syndrome (907), metabolic diseases (908), moyamoya disease (909), and fibromuscular dysplasia (910). In cases with seizures, PACNS may also be mimicked by Rasmussen encephalitis (911).

Untreated PACNS is a potentially fulminant disease that can be fatal. Currently, therapeutic recommendations for childhood PACNS are made from earlier experience in adults (935), and on the basis of case reports or small series of pediatric cases (893,936). In view of the rarity of the disease and because of inherent difficulties and pitfalls in diagnosis, no controlled clinical trials have been conducted (893,896). In a small series of 5 pediatric patients with PACNS affecting large and medium-sized arteries and in which none of the children received immunosuppressive treatment, 4 patients succumbed within 10 days from the onset of neurologic manifestations, whereas 1 child died 7 years after initial presentation (898). Notwithstanding the likelihood of biologic heterogeneity within the spectrum of pediatric PACNS, patients treated with corticosteroids and cyclophosphamide exhibited improvement both with respect to clinical outcome and resolution of neuroimaging findings (897). Taken collectively, these observations speak in favor of use of immunosuppressive therapy.

Therapy is twofold and is aimed at suppressing or abrogating immune-mediated inflammation of brain blood vessels and preventing thrombotic phenomena. Therapeutic recommendations are as follows.

A thorough follow-up is mandatory particularly during the first year and should include determination of biomarkers of inflammation (especially if these were elevated from the outset) and sequential neuroimaging. In addition, CSF examination should be repeated, especially if abnormalities were detected in the initial analysis, because they may be serve as indices of relapse (893).

The prognosis of children with CNS vasculitis is unknown and largely unpredictable. Early reports in the literature pointed to an overall poor prognosis in both adults and children (901,904,905,913,934,938). Predictably, large ischemic strokes result in variably severe and permanent neurologic deficits; however, it should be noted that a number of patients also have made remarkable recoveries (893).

The long-term cognitive or behavioral outcomes are unknown, and no longitudinal studies have been conducted in pediatric populations (893). In a relatively large cohort of 41 adult PACNS patients with a mean follow-up of 4 years, the rate of relapse was 29%, whereas 80% of patients had an overall favorable outcome; the mortality rate was 10% (939).

The clinical, microbiologic, and pathologic aspects of varicella and HZV infection of the nervous system were reviewed extensively by Kleinschmidt-DeMasters and Gilden (962). HZV infection can give rise to a wide range of neurologic manifestations and complications. The latter include aseptic meningitis/meningoencephalitis (including cerebellitis), ventriculitis, multifocal leukoencephalopathy, transverse myelitis, postherpetic neuralgia, neuritis/peripheral neuropathy, and, rarely, Reye encephalopathy (943,962).

The neurologic features of HZV CNS vasculopathy are protean, and the onset of neurologic manifestations often occurs months after clinically apparent disease and in fact occasionally without any history of cutaneous rash (963). In immunocompromised patients, reactivation of HZV from dorsal ganglia roots can lead to serious neurologic complications including disseminated leukoencephalopathy and ventriculitis (964). CNS vasculitis can be the result of primary varicella infection and/or HZV reactivation either spontaneously or in the setting of immunocompromise.

Varicella (chickenpox) has been implicated in the pathogenesis of ischemic stroke in children and is regarded as a major risk factor for cerebral infarction in the pediatric population (949,965). The absolute risk of HZV-associated stroke in children is 1 in 15,000 (949). As varicella is becoming increasingly recognized as a significant cause of stroke