Chapter 17. Multiple Sclerosis White Matter

Demyelination is a process that results in either partial or complete loss of the myelin sheath following a period of normal myelin development. Demyelinating diseases may affect the central nervous system (CNS), the peripheral nervous systems (PNS), or both. CNS demyelination may occur as a result of direct damage to the myelin sheath and/or the oligodendrocytes (primary demyelination), or is secondary to axonal damage with subsequent disruption of the axon-glia interaction essential to maintain normal myelination (secondary demyelination). Acquired CNS demyelinating diseases include self-limited monophasic disorders, such as acute disseminated encephalomyelitis (ADEM), as well as chronic, recurrent conditions such as multiple sclerosis (MS) and neuromyelitis optica (NMO). On the other hand, dysmyelination is a genetic or developmental abnormality of the myelin sheath seen in various leukodystrophies such as adrenal leukodystrophy and metachromatic leukodystrophy. A discussion of dysmyelinating diseases is beyond the scope of this chapter, which focuses on childhood demyelinating diseases of the CNS. In the last few years there has been increased interest in studying childhood-onset MS, and our understanding of acquired demyelinating disorders is increasing exponentially.

Multiple sclerosis (MS) is an acquired, immune-mediated, demyelinating disease affecting the brain and the spinal cord. Despite reports of childhood-onset MS1-3 soon after the initial descriptions of MS by Jean Marie Charcot,4 the diagnosis of MS in childhood was disputed for a long time. In addition, early on, the misdiagnosis of a number of diseases as MS, including leukodystrophies, metabolic disorders, and tumors, and the confusion surrounding the use of various terms to describe a single disorder, cast further doubt on the existence of childhood-onset MS.5 Although a few reports of childhood-onset MS6,7 were still published in the literature, on the whole, childhood-onset MS was largely ignored by both the researchers and the clinicians. In fact, one of the early diagnostic criteria8 proposed for the diagnosis of MS specifically restricted this diagnosis to patients between the ages of 10 and 50 years. The recognition of the fact that MS occurs as a distinct disease in children was brought forth by a series of articles published in the late 1950s and early 1960s.9-11 Later publications firmly established the occurrence of MS in children under the age of 18 years, even as early as infancy.12-15 Despite this renewed interest, the epidemiology, genetics, and natural history of pediatric-onset MS remain unclear at the present time.

Clinical Features

With an increasing number of reports being published, the clinical features of childhood-onset MS are beginning to be understood better. Despite limited natural history data, a clearer picture of this disease in children is emerging. The mean age of onset in most studies is reported to be between 8 and 14 years. Infants as young as 10 months have been reported to have findings suggestive of MS.15 In this case, which probably represents the earliest onset of MS in published literature, a girl developed five episodes of aseptic meningitis starting at age 10 months, followed by six additional episodes to relapsing neurological deficits with variable recovery. Following her death at the age of 6 years, her brain showed multiple white matter demyelinating lesions scattered throughout the brain and brainstem, with some larger lesions demonstrating a necrotic component. Similar to MS in adults, childhood-onset MS seems to have a female preponderance, with a male-female ratio ranging from 1:1.3 to 1:3.0.16

The initial clinical events noted in the various case series seem to vary depending on patient population, number of patients, and the reported details of the episode. Although sensory disturbances have been suggested as the most common initial symptom in a majority of the childhood-onset MS patients,12,17,18 other symptoms—such as motor weakness, cerebellar deficits, brainstem involvement, and optic neuritis—occur very frequently as well. In a review of the literature by Ness and associates, the reported frequency of various system involvement varied widely.16 In childhood-onset MS patients at initial presentation, optic nerve involvement was seen in 0% to 50%, sensory involvement in 13% to 69%, motor involvement in 6% to 90%, cerebellar involvement in 4% to 80%, brainstem involvement in 6% to 60%, and spine or bladder/bowel involvement in 1% to 31%.16 Polysymptomatic onset, which is the second most frequently encountered initial presentation in adults (after sensory complaints),19 was seen in 10% to 67% of the patients with childhood-onset MS. Altered mental status, which is a rare initial complaint in adult-onset MS, was seen in 5% to 39% of the children with MS; this raises the possibility that some of the patients reported in these case series may have had ADEM as their initial presentation.

Optic neuritis (ON) is a frequently encountered clinically isolated syndrome (CIS) in both adults and children who go on to develop MS. Although the risk of developing clinically definite MS in adults with unilateral ON is about 38%, this risk increases to 56% in patients who have optic neuritis and demyelinating lesions on cranial MRI.20 Long-term prospective data in children with ON is lacking. While some studies report a slightly lower risk of developing MS in children with ON,16,21 other studies report this risk to be similar to that seen in adults.22,23 Most studies, however, are limited because of relatively short-term follow-up while determining the subsequent risk of developing clinically definite MS. In a recent study, about one-third of the children with ON followed closely over a period of 2 years went on to develop MS.21 In this study, bilateral ON, abnormal findings on neurological examination, and asymptomatic lesions on MRI were associated with a significantly higher risk of developing MS. Bilateral simultaneous ON is generally considered to be less likely to progress to definite MS,24-26 but the studies by Wilejto, Lucchinetti, and their colleagues have reported a higher risk of developing MS following bilateral ON presentation.21,27 On the other hand, bilateral sequential ON or recurrent ON are reported to increase the risk of progressing to definite MS in children.27 The risk of developing MS may be lower if the child has a history of an infection within 2 weeks prior to the onset of visual symptoms.27

Transverse myelitis in children usually presents with sensory disturbance in the extremities, which usually starts distally and then progresses, associated with weakness, gait difficulties, and bladder and bowel disturbances. A partial TM increases the risk of developing MS in adults and children alike.28,29 Other high-risk features in children with TM that predict future development of MS include asymmetric motor and sensory findings, asymptomatic lesions on brain MRI, presence of elevated IgG index or oligoclonal bands in CSF, and abnormal visual and brainstem auditory evoked potential studies.28

An isolated brainstem-cerebellar syndrome (BCS) may be seen in 6% to 60% of childhood MS patients. Diplopia is probably the most frequently encountered symptom in older children presenting with BCS as their initial event,30 while ataxia is more common in children under 10 years of age and in girls.14 Interestingly, males are reported to present with BCS as their initial symptoms more commonly (41.4% vs. 13.2%), and also tend to demonstrate more brainstem lesions on MRI (63% vs. 40.3%) during their disease course compared to females.31

In a large European study of 296 patients with onset of their initial demyelinating event before age 18 years, 57% of the children developed a second clinical episode (ie, definite MS) after a mean follow-up of 2.9 years.32 About 40% of the entire cohort presented with ADEM as their first clinical episode; and of this cohort, 29% experienced another event, thus declaring them as "definite MS." The risk of developing MS was higher in children who developed a CIS at age greater than 10 years, those who presented with ON (as opposed to TM or BCS), and those who had an initial brain MRI suggestive of demyelination. Although it is possible that some of the patients who presented with ADEM as their initial event may not meet the criteria proposed by the Internal Pediatric MS Study Group,33 this study does support the contention that a majority of patients presenting with a CIS develop MS over a relatively short follow-up period.

The natural history of childhood-onset MS is not entirely clear. Most studies are of relatively short duration, and trying to extrapolate these short-term results to the lifetime of a patient can be problematic. The clinical classification of childhood-onset MS is based on the adult classification,34 and at least 4 different clinical disease subtypes are identified.

• Relapsing remitting MS (RRMS) is characterized by clearly defined disease relapses with full recovery or with sequelae and residual deficit upon recovery; periods between disease relapses are stable, with a lack of disease progression.
• Secondary progressive MS (SPMS) is defined as disease that has an initial relapsing-remitting disease course followed by progression with or without occasional relapses, minor remissions, and plateaus.
• Primary progressive MS (PPMS) is defined as disease progression from the onset with occasional plateaus and temporary minor improvements.
• Progressive relapsing MS (PRMS) is defined as progressive disease from the onset, with clear acute relapses, with or without full recovery, and periods between relapses characterized by continuing progression.

As opposed to adults, the studies of childhood-onset MS reveal a higher incidence of RRMS and a relatively low risk of PPMS.18,35-37 More than 90% of childhood-onset MS patients present with RRMS and only 2% to 7% of young onset patients have PPMS. Generally, childhood-onset MS is believed to have a better prognosis, with relatively lower risk of progression and development of disability.14,18,36 MS patients are also believed to have a higher risk of second relapse in the first year, higher relapse rate, shorter interval between first and second relapses, and shorter duration of relapse with more complete recovery.16

Patients with childhood-onset MS are also noted to have a slower disease progression compared to adults. In some natural history studies, childhood-onset MS patients took almost twice as long to reach an expanded disability status scale (EDSS)38 of 3.0 or 4.0 as MS patients with adult onset do.18,36 The time to reach an EDSS of 6.0 (needing assistance to ambulate) was also longer for the childhood-onset MS cases compared to adult MS patients.36 The likelihood of changing to SPMS (14% vs. 24%), and time to conversion to SPMS (16 years vs. 7 years), also favor childhood-onset MS.36 However, the median age of childhood-onset SPMS patients was 30 years compared to 37 years for adult-onset MS patients. This is likely a result of developing MS at an earlier age, with childhood-onset MS patients being exposed to the effects of the disease for a much longer period of time. This highlights the facts that despite a slower rate of progression, childhood-onset MS is not benign. Also, once patients switch from the RRMS to SPMS stage, the subsequent rate of progression of disease does not appear to be different between childhood-onset and adult-onset MS patients.39 A shorter inter-relapse interval, poor recovery from the intial relapse, a greater number of relapses in the first 2 or first 5 years after disease onset, and an earlier SPMS disease course are all poor prognostic indicators.18,32,36 Age of onset, gender, type of initial event (polysymptomatic vs. monosymptomatic), and onset of MS pre- or postpuberty do not seem to have much of an impact on the disease progression.16

Paraclincial Studies

All children suspected of experiencing a demyelinating event should undergo a comprehensive history and examination followed by appropriate diagnostic studies. An array of diagnostic studies is available to determine the underlying etiology, including magnetic resonance imaging (MRI), cerebrospinal fluid (CSF) analysis, evoked potential (EP) studies, and laboratory tests.

MRI is the most sensitive diagnostic study, which not only helps with the diagnosis and in determining ongoing disease activity but also as an outcome measure to assess therapeutic efficacy in clinical trials. The typical appearance of childhood-onset MS on cranial MRI is similar to that seen in adults and consists of multiple T2 hyperintense white matter lesions present in periventricular, juxta-cortical, and infra-tentorial regions (see Figure 17-1). The likelihood of finding gadolinium-enhancing lesions on a brain MRI study appears to be lower in childhood-onset cases compared to adults (13-24% vs. >50%).40,41 Children with MS are also more likely to demonstrate tumefactive lesions that are large in size and associated with surrounding cerebral edema without much mass effect.42-44 Despite impressive and striking initial MRI images, these large lesions tend to resolve following treatment with glucocorticoids.45 In very young patients, the MS lesions may appear as bilateral, diffuse, white-matter lesions with poorly defined borders.40 Since MRI has become an important tool in establishing a diagnosis of MS and because the new adult diagnostic criteria46 rely heavily on MRI to prove dissemination in space and in time following a CIS, it is imperative to establish the utility of these adult MS MRI criteria in childhood patients. A few small studies seem to suggest that the sensitivity and specificity of the adult MS MRI criteria in childhood-onset MS are lower than seen in the adult population.40,42 A small study has also reported increased likelihood of cerebral atrophy over a 6- to 8-year time frame.43 Long-term studies to evaluate the predictive value of MRI in determining the disease course in childhood-onset MS are lacking.

CSF examination has been used to assist with the diagnosis of MS since the 1930s. The most specific abnormalities identified are qualitative and quantitative abnormalities of de novo immuno-globulin synthesis. An elevated IgG index and/or positive oligoclonal bands are seen in about 40% to 90% of childhood-onset MS patients.16 A study of MS patients presenting before the age of 16 years demonstrated presence of CSF abnormalities in about 92% of patients.42-44 The presence of IgG abnormalities alone in CSF is not sufficient to make a diagnosis of MS, as some MS patients have normal CSF; also, the CSF changes characteristic of MS are far from unique. Patients with other neurological disorders, such as ADEM, may also demonstrate oligoclonal bands and IgG synthesis abnormalities.48,49 Other CSF abnormalities—including total protein, cell count, and myelin basic protein measurements—are nonspecific and usually normal in MS patients.

Electrophysiologic studies are useful in MS because of their objectivity, sensitivity, reproducibility, quantifiability, and standardization and comparability.19 EP testing is used for detection of "clinically silent" lesions, thus providing objective evidence of dissemination in space. In general, EP studies of the visual system have the greatest yield and those of the brainstem auditory system the least. In one study, brainstem auditory evoked potential (BAEP) and somatosensory evoked potential (SEP) studies helped identify clinically asymptomatic lesions in only 12% of the childhood-onset MS patients.50 Visual evoked potential (VEP) studies were reported to be abnormal in 34% of the patients with no prior history of ON. Interestingly, 84% of these patients with abnormal VEP had normal visual acuity testing on standard measures.

These MRI, CSF, and EP studies are extremely helpful in increasing the confidence in a diagnosis of MS by demonstrating characteristic abnormalities and by ruling out other potential etiologies. An important consideration when interpreting the results of these studies is to remember that there is no confirmatory diagnostic test for MS and these results should only be considered clinically significant in the appropriate clinical context.

Diagnosis

The diagnosis of childhood-onset MS has been formalized by an International Pediatric MS Study Group. The hallmark of childhood-onset MS, as in adult-onset MS, is "dissemination of neurological symptoms, of the type seen in MS, both in space and in time."33,46 Thus, a definite diagnosis of childhood-onset MS requires one of the following46,51:

• Development of at least two clinical episodes of the type seen in MS separated by an arbitrarily determined interval of 30 days, if no other supportive evidence is present.
• At least 1 clinical episode (CIS) along with evidence of dissemination in space and time from MRI, CSF, and EP studies.
• As with adults, the requirement that a comprehensive evaluation of the patient has revealed "no better explanation" for the patient's symptoms.

The proposed criteria for diagnosis of dissemination in space and time established using MRI, CSF, and EP studies are outlined in Table 17-1. The major difference between the diagnosis of MS in adults and in childhood-onset MS is when the initial episode bringing the patient to medical attention is not a well-defined CIS such as optic neuritis (ON), transverse myelitis (TM), or brainstem-cerebellar syndrome (BCS) but rather ADEM. The consensus guidelines from the International Pediatric MS Study Group33 state that "in the special circumstance of a child whose initial clinical demyelinating event was diagnosed as ADEM, a second non-ADEM demyelinating event alone is not sufficient for a diagnosis of MS." In this instance, it is incumbent upon the neurologist to establish dissemination in space and in time by demonstrating either of the following:

• Two clinical events separated from the initial ADEM event by at least 3 months.
• At least one clinical event and development of new T2 lesions on MRI at least 3 months after the second non-ADEM event.

The rational for this is that the first demyelinating event following the initial ADEM may still be a continuation of the sentinel episode and may represent a monophasic illness rather than a chronic recurrent disease process. The Study Group did acknowledge that in rare cases ADEM may be recurrent (recurrent ADEM with similar clinical presentation) or multiphasic (recurrent ADEM with new clinical features), in which case a diagnosis of MS cannot be made with confidence (Figure 17-2).

Differential Diagnosis

One of the major caveats noted in establishing a diagnosis of MS since the initial Schumacher criteria and subsequently reaffirmed in all the proposed diagnostic criteria is the absence of any other potential neurological or systemic disease process that may potentially explain the patient's neurological symptoms.8,33,46,52 This, then, requires a low threshold for suspecting other causes, and a comprehensive clinical evaluation by the neurologist. This is especially important in the case of a young child, especially those 10 years of age or younger, because of the immense physical, psychological, and financial cost that a diagnosis of an incurable, chronic, and disabling disease like MS carries. The differential diagnosis of MS in children is more varied and involves conditions that are not of clinical significance in adults, raising special challenges. Also, the differential diagnosis varies depending on the age of the child. The broad categories of diseases that need consideration when evaluating a child with MS include ADEM, leukodystrophies, and metabolic, nutritional, endocrine, vascular, neoplastic, inflammatory, infectious, and genetic disorders. Therefore, any atypical clinical, MRI, or CSF features should lead to a detailed examination and diagnostic evaluation to confidently rule out other potential etiologies. Some of the differential diagnoses that need consideration at different ages during MS evaluation are listed in Table 17-2. Since the differential diagnosis is extensive and the potential for misdiagnosis significant, the specific evaluation required for an individual patient needs to be tailored based on clinical history and examination while maintaining a low threshold for more detailed testing in atypical cases.

Treatment

The organization of the delivery of care to adult MS patients can be categorized as

• Pharmacologic management
  • Treatment of acute demyelinating relapses
  • Treatment of the underlying disease
  • Treatment of symptoms
• Nonpharmacologic management
• Psychosocial management
• Patient and family education

The treatment of relapses with glucocorticoid therapy, ACTH, or oral prednisone was initially employed in the 1950s and formally tested in the late 1960s. In the first randomized trial of a treatment for an unpredictable disease it was shown that recovery from a relapse was accelerated, but the natural history of the disease was unaltered.53 The ability to alter the natural history of MS began in 1993, when interferon beta-1b (IFNβ-1b; Betaseron) was proven to reduce the relapse rate and accumulation of MRI lesions in RRMS. Since then other agents, intramuscular IFNβ-1a (Avonex), subcutaneous IFNβ-1a (Rebif), glatiramer acetate (GA; Copaxone), mitoxantrone (Novantrone), and natalizumab (Tysabri) have become available for use in MS patients. Symptom management was attempted by Charcot and others in the mid-19th century and continues to expand with the mostly unapproved new, or off-label use of medications. A number of clinical trials strongly suggest that early treatment for MS is extremely important in reducing further clinical and MRI disease activity and preventing neurological disability.54

Glucocorticoids have been the mainstay of therapy for an MS relapse since the late 1960s. Adrenocorticotropic hormone (ACTH) was the first agent to offer rapid recovery from relapses.53 Intravenous methylprednisolone (IVMP) has been shown to be effective in the treatment of MS relapses, with recovery being more rapid and consistent than that seen with ACTH.55-57 Oral prednisone is probably also effective and is substituted for IVMP by some clinicians primarily because of its easier route of administration. In general, glucocorticoid therapy is reserved for relapses that are severe enough to result in significant neurological impairment; while milder relapses can be managed expectantly. The most frequently used protocols consist of an initial steroid pulse with 3 to 5 days of IVMP with or without an oral prednisone taper. Despite a European study demonstrating efficacy over a 5-year period,58 most studies do not demonstrate effectiveness of chronic glucocorticoid therapy in preventing disease activity or accumulation of disability.59 The most common side effects of glucocorticoids are a metallic taste in mouth, insomnia, mood changes, increased appetite, weight gain, hypertension, and hyperglycemia. In pediatric populations, prolonged glucocorticoid use may also cause growth retardation and possibly osteopenia. Therapeutic plasma exchange (TPE) or plasmapharesis is a treatment modality that nonselectively removes plasma components that are potentially pathogenic in immune-mediated diseases. Several initial, small, uncontrolled clinical trials demonstrated results that were mixed and difficult to interpret. However, a double-blind, crossover study by Weinshenker and colleagues showed that TPE resulted in clinically significant improvement in about 40% of patients with severe acute steroid unresponsive inflammatory demyelinating episodes.60 In managing severe demyelinating relapses, TPE should be considered as a therapeutic option for patients who do not respond to high-dose glucocorticoids. Both these treatments are generally well tolerated in children, with the adverse effect profile similar to that seen in adults. The complications of TPE include those associated with insertion of a central venous catheter and those associated with the procedure itself. The most common complications of TPE include bleeding, infections, coagulopathy, hypotension, paresthesias, urticaria, and in rare instances, anaphylactic reactions. The vast majority of these complications are mild and easily tolerated by patients. Intravenous immunoglobulins (IVIg) is sometimes used as a treatment for glucocorticoid unresponsive relapses; however, its long-term use as a maintenance therapy has not been established.61

Disease-modifying agents (DMA) that are currently available for use in adults with MS include IFNβ (subcutaneous IFNβ-1b, subcutaneous IFNβ-1a, and intra-muscular IFNβ-1a), a synthetic polypeptide (glatiramer acetate), a humanized monoclonal antibody (natalizumab), and an anthracenedione derivative (mitoxantrone). Interferon beta was the first agent to be evaluated for and proven to be effective in altering the natural history of MS. Although the exact mechanism underlying its therapeutic effectiveness in MS is not clear, it appears to work through matrix metalloproteinases (MMP), especially MMP-9, found in the endothelial lining of the blood–brain barrier. Subcutaneous IFNβ-1b (Betaseron) was the first drug to receive regulatory approval for use in the United States based on phase III study results that demonstrated reduction in clinical relapses and MRI disease activity.62,63 Subsequently, IFNβ-1b has been shown to be effective in CIS and in SPMS patients with ongoing relapses.64-67 Intramuscular IFNβ-1a (Avonex) has been shown to delay disability progression, relapse rate, MRI disease activity, cerebral atrophy, and conversion to definite MS from CIS.68-71 Subcutaneous IFNβ-1a (Rebif) reduces relapse rate, development of new and active MRI lesions, and disability progression in MS patients.72,73 Glatiramer acetate, a random polymer of four amino acids (l-glutamic acid, l-alanine, l-lysine, and l-tyrosine in fixed proportions of 1.9:6.0:4.7:1.0, respectively) has been proven to decrease annualized relapse rate and MRI disease activity in RRMS patients.74,75 Natalizumab, a humanized monoclonal antibody, decreases the frequency of relapses, progression of disability, and MRI activity both as monotherapy and in combination with intramuscular IFNβ-1a.76,77 Natalizumab is generally considered a second-line agent after patients have failed IFNβ or GA treatment because of the development of potentially serious adverse effects including progressive multifocal encephalopathy (PML) and melanoma.78,79 Mitoxantrone is a chemotherapeutic agent approved for patients with worsening RRMS, SPMS, and PRMS. It has been shown to reduce relapses, accumulation of disability, and MRI disease activity with a reasonable side effect profile. The side effect profile of mitoxantrone—including cardiotoxicity, acute myelocytic leukemia, and restrictive lifetime use (maximum lifetime dose is 140 mg/m2)— limits the use of this agent to a selected group of patients. Other agents used as treatments to favorably alter the course of MS include azathioprine, methotrexate, cyclophosphamide, rituximab, and alemtuzumab. The common indications, dosage, dosing regimen, adverse effects, and monitoring of these agents are outlined in Table 17-3.

The experience with these agents in childhood MS is very limited. There are no randomized controlled trials in childhood MS with any of the DMA approved for adults with MS. Single case reports and retrospective reviews of the safety and tolerability of IFNβ-1b in small numbers of children with MS have been reported. In summary, these reports demonstrate that these agents are safe, tolerated well, and cause relatively mild adverse effects.61 Small case series and a web-based survey of MS children suggest that GA is well tolerated and the side effects are relatively minor and similar to those seen in adults. Mitoxantrone has anecdotally been used in adolescents with worsening MS with acceptable safety and stabilization of disease.80 There are no data available regarding the use of natalizumab or other chemotherapeutic agents for the treatment of MS in children. Although most children treated with immunomodulatory agents seem to have the same adverse effects as adults, the long-term benefit of these drugs in childhood MS is not clear. The issues of appropriate dosage and dosing regimen; efficacy; effect(s) on growth and development, both physical and emotional; effect(s) on the immature central nervous system and immune system; and long-term safety; remain unresolved and need to be addressed.

MS causes a wide variety of symptoms in both adult and pediatric MS patients. These symptoms that either occur in the setting of an acute relapse or as chronic ongoing problems have a devastating effect on the quality of life of MS patients. Identifying and treating these symptoms constitutes a major part of the management of MS. The use of pharmacologic agents even in adult MS care is largely based on anecdotal reports or small case series. There are few, if any, controlled clinical trials of agents used in symptomatic management of MS. Thus, most agents prescribed for the management of MS-associated symptoms have not been approved by the FDA for this particular indication and thereby constitute "off-label use." Nonpharmacologic management strategies, including alternative and complimentary therapies, constitute a major component of symptomatic treatment of MS symptoms. Table 17-4 outlines some of the common MS symptoms and frequently used treatments for these symptoms.

Acute disseminated encephalomyelitis (ADEM) is an acute immune-mediated inflammatory episode involving the central nervous system. ADEM usually occurs following an infection or vaccination. Although at times the terms "postinfectious encephalomyelitis" or "postvaccinal encephalomyelitis" are used to describe these clinical entities, these encephalomyelites and idiopathic ADEM have the same expected course and neuropathologic changes. Acute hemorrhagic leukoencephalitis and acute necrotizing hemorrhagic leukoencephalitis probably represent the most severe forms of ADEM.

Acute disseminated encephalomyelitis is a rare disorder that usually has a monophasic presentation and clinical course. ADEM has been reported to occur at all ages, but appears to be more common in the pediatric age group, with 5- to 8-year-old children developing it most frequently.81 It has been described in all racial and ethnic groups and in both genders.81 Some case series suggest a higher male-to-female ratio among pediatric patients.82,83 Its frequency following certain infections and immunizations has been reported as 1 case in several hundreds to thousands of exposures. Some studies suggest a seasonal increase in the incidence of ADEM in spring and winter months. ADEM is very frequently (50-100% of the time) preceded by symptoms and signs of infection, usually a nonspecific upper respiratory tract infections.81 Other infections linked to subsequent development of ADEM include varicella, mumps, rubella, enterovirus, Epstein-Barr virus, human herpes virus-6, human lymphotrophic virus type-I, adenovirus, influenza A and B, herpes simplex, Listeria, Mycoplasma pneumoniae, leptospirosis, and Rocky Mountain spotted fever.19

An increased risk of ADEM has also been reported to occur within 4 weeks of a vaccination84 with immunization for rabies, measles, pertussis, rubella, Japanese B encephalitis, influenza, typhoid, and hepatitis B, and with tetanus antitoxin, among others.19 The etiology of ADEM is not known, but it probably is due to the activation of immune cells directed against myelin antigen(s), due to direct damage to oligodendrocytes, or as a result of a nonspecific immune system activation. The target of this immune attack is most likely a myelin protein such as myelin basic protein (MBP), proteolipid protein (PLP), or myelin oligodendrocyte glycoprotein (MOG). ADEM is pathologically very similar to experimental allergic encephalomyelitis (EAE). Neuropathologic examination shows a severely edematous brain with prominent vasculature in the white matter and perivenular region. Acute lesions appear to be of similar age, predominantly involve the white matter, are well-demarcated, surround small- and medium-size veins, and microscopically contain perivascular mononuclear cells, reactive microglia, lipid-laden macrophages, variable myelin damage, and relatively preserved axons. Older lesions have a more marked astrocytic gliosis and myelin loss. In more severe cases, acute lesions contain a significant hemorrhagic component, warranting the terms "acute hemorrhagic leukoencephalitis" or "necrotizing leukoencephalitis"; this is associated with fibrinoid vascular necrosis, exudation of blood components including fibrin into perivascular regions, tissue necrosis, a polymorphonuclear lymphocytic infiltration, and myelin loss with some axonal loss.

Clinically, ADEM presents with acute onset of fever, malaise, headache, nausea and/or vomiting, neck stiffness, seizures, somnolence, and behavioral changes frequently leading to encephalopathy, stupor, and coma. These symptoms are commonly associated with focal neurological deficits that include visual loss, weakness, ataxia, sensory disturbances, cranial nerve palsies, dysarthria, aphasia, extrapyramidal movement disorders, and bowel/bladder dysfunction. The typical clinical course is one of acute presentation and rapid progression with development of maximum deficits in less than a week.83 Although these clinical features may be seen in both pediatric-onset and adult-onset cases, prolonged fever, headaches, seizures, and even status epilepticus occur more frequently in the children.81 Paresthesias and acute polyradiculoneuropathy tend to be rare in children and common in adult-onset ADEM. ADEM is typically a monophasic illness that gradually improves over days to weeks to sometimes months, but may leave permanent, mild to moderate, residual neurological deficits. Occasionally ADEM symptoms may recur within 3 months following glucocorticoid treatment and recovery; this is usually termed "recurrent ADEM." In 5% to 20% of cases, the patients develop "multiphasic ADEM," where clinical symptoms and MRI abnormalities reoccur following an initial episode that had resolved completely on follow-up clinical and MRI examinations. Some of these patients with multiphasic ADEM may progress to RRMS while others do not.81 In the more aggressive cases, increased intracranial pressure with resultant herniation, and/or respiratory failure from brainstem involvement, may result in death.

Imaging studies using MRI usually demonstrate multiple lesions of T2-weighted hyperintensity in the white matter of the cerebrum, cerebellum, brainstem, and spinal cord. As opposed to MS, ADEM lesions are large, patchy, poorly circumscribed areas, with gadolinium-enhancement noted in 30% to 100% of the patients (Figure 17-3).81 These lesions tend to occur in the periventrcular and subcortical white matter, brainstem, cortical and subcortical gray matter, and extensive regions of the spinal cord. Some large lesions may show evidence of hemorrhage, which usually denotes a more aggressive course and is sometimes termed acute hemorrhagic encephalomyelitis. Various patterns of T2-weighted and gadolinium-enhancing lesions have been reported but none seem to correlate with the clinical prognosis.81 Spinal cord MRI abnormalities are seen in 11% to 28% of the pediatric ADEM patients; these generally occur in the thoracic region, and as opposed to MS, demonstrate longitudinally extensive, gadolinium-enhancing lesions associated with cord edema.81 Cranial MRI abnormalities tend to completely resolve on follow-up imaging studies in 50% to 75% of the affected individuals within 6 months.85 In addition to conventional MRI studies, newer MRI techniques such as MR spectroscopy (reduced N-acetyl aspartate and elevated lactate levels), perfusion-weighted MRI (reduced or normal perfusion pattern), PET scanning (diffusely decreased cerebral metabolism), and SPECT scanning using 99m Tc-HMPAO or acetazolamide (focal areas of hypoperfusion) may be helpful in differentiating ADEM lesions from infectious, neoplastic, or vascular processes.81 CSF may be normal but usually shows an elevated opening pressure, lymphocytic pleocytosis, normal glucose, and an increased protein and MBP. IgG index is rarely abnormal, and OCB, if present, is usually transient. CSF cultures and serologic testing are typically negative but PCR technology may assist in identifying the inciting agent. EP studies have a limited role in the evaluation of ADEM. An electroencephalogram (EEG) usually reveals nonspecific diffuse slowing. Additional laboratory investigations should include CSF cultures and acute and convalescent titers for infectious agents, serology for connective tissue diseases, and other appropriate studies to identify the inciting etiology.

ADEM shares clinical and MRI features with a number of infectious, inflammatory, demyelinating, and other disorders; the following diseases should be considered in the differential diagnosis of ADEM:

• Infectious disorders such as acute viral encephalitis; bacterial, Lyme, syphilitic, tuberculous, or cryptococcal meningitis; cysticercosis; coccidiomycosis; toxoplasmosis; intracranial parenchymal or epidural abscesses; and multiple septic emboli from subacute bacterial endocarditis.
• Demyelinating disorders such as leukodystrophies, MS, Marburg variant of MS, Balo concentric sclerosis, Schilder disseminated sclerosis, and Devic neuromyelitis optica.
• Inflammatory disorders such as vasculitis, polyarteritis nodosa, Churg-Strauss disease, Wegener granulomatousis, neuro-Beçhet syndrome, Sjögren syndrome, and systemic lupus erythematosis.
• Neoplastic disorders such as primary CNS neoplasms including gliomas, and brain metastases.
• Other disorders such as cerebral venous thrombosis, acute necrotizing encephalopathy, extra-pontine myelinolysis, and metabolic disorders.

These disorders need to be considered and ruled out when evaluating a patient for ADEM.

There is no standard or widely accepted, proven treatment for ADEM. The management consists of supportive care, reduction of increased intracranial pressure if present, treatment of infection if clinically suspected at presentation, and, once infection is excluded, high-dose glucocorticoid therapy. For patients who do not respond to glucocorticoid agents, courses of therapeutic plasma exchange (TPE) or intravenous immunoglobulin (IVIg) may be tried. Immunization against a triggering virus, when available, should be done as the risk of ADEM following immunization is usually markedly lower compared to that after primary infection with the same virus. With or without treatment, between half and three-quarters of pediatric ADEM patients recover completely or almost completely.81 The most common long-term residual complications of ADEM include focal weakness, ataxia, visual loss, behavioral and cognitive problems, and seizures.

Neuromyelitis optica (NMO), or Devic disease, is an idiopathic, inflammatory, necrotizing demyelination of the CNS, clinically characterized by simultaneous or successive involvement of optic nerves and spinal cord. Eugène Devic, in 1884, presented a case of "myélite subaiguë compliquée de névrite optique" that summarized the cardinal neurpathologic features and coined the term "neuroptico-myélite."86,87 Other terms used to describe this condition in the literature include neuro-myélite, neuromyélite optic aiguë, acute optic neuromyelitis, neuromyelitis optica of Devic-Gault, Devic disease, ophthalmo-neuromyelitis, optic encephalomyelitis, ophthalmoencephalomyelopathy, and disseminated myelitis with optic neuritis. The debate over NMO as a variant of MS versus a separate disease entity started soon after the original descriptions and continues to date; however, most experts now believe it to be a distinct clinicopathologic entity.

NMO is a relatively rare disease, with its incidence and prevalence currently not known. It is probably under-diagnosed because of the confusion regarding its association with MS. The geographic and socioeconomic distribution of NMO is quite different from that of MS, with NMO being more prevalent in the tropics, among those in the lower socioeconomic strata, and in the Asian and African populations. The gender ratio among the reported cases seems to suggest a slightly higher incidence among females (female-male ratio = >1.4:1). Most cases are sporadic and may present at any age including the pediatric age group. An underlying hereditary component in the pathogenesis of NMO is also suggested by cases of the disease in siblings and monozygote twins. The etiology and pathogenesis of NMO is poorly understood. The temporal association with preceding viral infections in some cases and the isolation of human herpesvirus species from the neural tissue of NMO patients suggests either an infectious or infection-induced immune-mediated etiology for NMO. Frequent association with a variety of immune-mediated connective tissue disorders and frequent presence of autoantibodies (anti-cardiolipin, anti-thyroglobulin, anti-microsomal, anti-parietal cell, antinuclear, and anti-smooth muscle antibodies) in NMO patients imply an underlying immunopathogenic mechanism. Antibodies to astrocytic glial fibrillary acidic protein (GFAP), and T-cell lines sensitive to glial S100 beta protein, have also been isolated from patients with NMO. Based on these observations, NMO is possibly the phenotypic clinical expression of a systemic immune-mediated process involving the CNS. The optic nerve and spinal cord presumably contain antigens that are targets for this neuroimmunologic process.

NMO patients may present with unilateral (40-45%) or simultaneous bilateral (25-30%) optic neuritis (ON), transverse myelitis (TM) (10-15%), or simultaneous ON and TM (10-15%). The interval between relapses is generally less than 3 months. The deficits noted in ON and TM associated with NMO tend to be severe and recovery is usually incomplete with permanent neurological deficits persisting in most patients. Death usually results from respiratory paralysis or the complications of severe neurological disability and bed-bound status. According to one retrospective study, NMO may present as a rapidly progressive disease invariably resulting in severe disability and death, as a relapsing disease with attacks of ON and TM occurring at unpredictable intervals with varying degrees of recovery, or as a monophasic illness followed by variable, usually poor, recovery.88 In this series, patients with relapsing disease were generally females, were older at the time of first symptoms, had a longer inter-attack interval (>3 months), had an associated systemic immune-mediated disorder, and generally had a better prognosis. A more benign form of NMO with near complete or total recovery and no relapses or long-term sequelae has been reported in the pediatric population.89 In a recent series of 58 patients with NMO spectrum disorders, median age was reported to be 12 years.90 There were more African-American patients than Caucasians, Hispanics, or Native Americans, and 88% were females. About 16% of the patients demonstrated brain abnormalities at the time of their initial presentation. The clinical course was relapsing in 93% and monophasic in the rest over a fairly short, 1-year follow-up period. About 40% of the patients had associated antoantibodies to other systemic autoimmune disorders. After a median follow-up of 12 months, only 6% had normal neurological examination and about half of the patients had significant neurological disability.

NMO is a clinical diagnosis supported by imaging and paraclinical studies. A number of diagnostic criteria based on characteristic clinical, laboratory, imaging, and pathologic features have been suggested to distinguish "pure" NMO from MS.91-94 A more recent set of criteria have been proposed not only to assist with the diagnosis of NMO but also to identify clinical presentations at high risk of developing into NMO.88 These criteria are detailed in Table 17-5.95 It is, however, important to realize the limitations of these criteria, as they are derived from a retrospective data set from a tertiary referral clinic. Spinal cord MRI in NMO patients typically demonstrates hyperintense signal on T2-weighted images and swelling and cavitation on T1-weighted images extending 3 or more spinal segments in length (Figure 17-4B). Cranial MRI is usually normal or may demonstrate nonspecific white matter abnormalities; thalamic and brainstem lesions have been reported in some patients (Figure 17-4A).88 MRI of the orbits may reveal optic nerves with abnormal T2W signal and gadolinium enhancement. CSF studies may be normal or may show mildly elevated protein and pleocytosis (cell count >50 WBC/mm3 or >5 neutrophils/ mm3), with a predominance of lymphocytes in the acute phase; IgG synthesis is normal and oligoclonal bands are absent in most cases. Visual and somatosensory EPs are expected to be abnormal, reflecting lesions of the optic nerves and spinal cord, respectively. Pathologic studies demonstrate demyelination, perivascular and parenchymal infiltration of inflammatory cells, edema, tissue necrosis and cavitation, arterial hyalinization, and astrogliosis limited to the optic nerves and the spinal cord. Recently a serologic marker, the so-called "NMO IgG antibody," has been described in more than half of patients with clinical diagnosis of NMO.96 This autoantibody binds to an astrocytic water channel aquaporin-4 in the CNS. This antibody has also been shown to predict relapses in patients who present with initial episodes of severe optic neuritis or longitudinally extensive myelitis.97,98 The frequency of NMO IgG in pediatric CNS inflammatory demyelinating disorders appears to be about 78% for definite NMO and 20% for recurrent optic neuritis or myelitis.99

The prognosis for neurological recovery and long-term survival in NMO is poor but has improved some in the recent years because of the recent advancements in technology and supportive care. The acute episodes are usually treated with high-dose glucocorticoid therapy with variable benefit and with some patients exhibiting glucocorticoid dependency. Other therapeutic approaches, such as immunosuppressants, IVIg, TPE, and lymphocytopharesis, have been used over the years with little success. Combined therapy with oral prednisone and azathioprine may be of some benefit in preventing long-term disability and recurrences. Recently, an anti-CD20 monoclonal antibody, rituximab, has been reported in small series of NMO patients to be an effective therapy in preventing more exacerbations and increasing disability.100,101