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.