ﺑﺎﺯﮔﺸﺖ ﺑﻪ ﺻﻔﺤﻪ ﻗﺒﻠﯽ
خرید پکیج
تعداد آیتم قابل مشاهده باقیمانده : 3 مورد
نسخه الکترونیک
medimedia.ir

Pathogenesis, clinical features, and diagnosis of pediatric multiple sclerosis

Pathogenesis, clinical features, and diagnosis of pediatric multiple sclerosis
Literature review current through: Jan 2024.
This topic last updated: Feb 22, 2022.

INTRODUCTION — Multiple sclerosis (MS) is typically considered a disease of young adults. However, pediatric MS, defined as onset of MS before the age of 18, is increasingly recognized. This disorder was previously known as early onset MS (EOMS) or juvenile MS.

The presentations, diagnostic evaluations, treatments, and prognosis for children with MS may differ from those of the more common adult form, yet they have been the subject of relatively few studies. Nevertheless, research in pediatric MS may provide clues into the underlying genetic substrate and environmental events that trigger this disease in both children and adults.

This topic will discuss the pathogenesis, clinical features, diagnosis, and differential diagnosis of pediatric MS. The treatment and prognosis of pediatric MS is discussed separately. (See "Treatment and prognosis of pediatric multiple sclerosis".)

EPIDEMIOLOGY — MS is a rare disease in the pediatric population. A systematic review covering the period from 1965 to 2018 identified 19 population-based studies of MS that included 1439 individuals ≤19 years of age with MS [1]. The overall incidence of pediatric-onset MS ranged from 0.05 to 2.85 per 100,000 children and adolescents, with most of the studies reporting incidence rates of <1 per 100,000; the overall prevalence ranged from 0.7 to 26.9 per 100,000. The wide range of incidence and prevalence rates may reflect differences in case ascertainment as well as ethnic and geographic variation.

Other studies suggest that MS presents before the age of 18 in approximately 5 percent of patients [2-4]. Less than 1 percent of patients have onset of MS before the age of 10 years [5]. Pediatric MS affects girls more than boys, with a female to male ratio of 2.8 in children ≥12 years of age [1].

PATHOGENESIS — MS is caused by dysregulation of the peripheral immune system, leading to injury in the central nervous system (CNS). Its pathogenesis requires the combination of a genetically susceptible individual and a particular environmental trigger.

Genetic susceptibility — Evidence supporting genetic susceptibility comes from risk projections for the development of MS in family members of affected patients [6]. In general, the lifetime risk of MS in first-degree relatives of MS patients is five percent. Studies of monozygotic twins have consistently demonstrated an even higher risk (ie, concordance) of 25 percent for the development of MS [7], whereas the risk for dizygotic twins is similar to that for first-degree relatives.

Twin studies have suggested a non-Mendelian inheritance pattern for MS that likely reflects complex interactions between a number of immunologic, neuroprotective, and myelin-related genes [8]. Certain immunologic human leukocyte antigen (HLA) genes are associated with an increased risk for the development of MS, including haplotypes HLA DRB1*1501, DQA1*0102, and DQB1*0602 [9]. The HLA-DR15 haplotype has been strongly associated with early disease onset in the MS population [8].

Environmental triggers — Possible but unproven environmental triggers for MS include exposure to infectious agents and low serum vitamin D levels.

Because the pathogenesis of MS is thought to involve the immune system, it has been hypothesized that vaccination may increase the risk of developing MS. However, substantial analysis has failed to identify an association between vaccines and MS in adults (see "Pathogenesis and epidemiology of multiple sclerosis", section on 'Vaccinations'). In addition, a well-performed large population-based case-control study in children found that vaccination against hepatitis B was not associated with an increased risk of childhood-onset MS [10].

There is limited evidence suggesting that childhood head trauma as a risk factor for MS [11].

Epstein-Barr virus — Environmental exposure to a specific infectious agent during a window of immunologic vulnerability in childhood may predispose some individuals to the development of MS [12]. Many viral and bacterial pathogens have been putatively linked to demyelination. Of these, the Epstein-Barr virus (EBV) has attracted much attention.

Exposure to EBV results in persistent B-cell infection, expansion of EBV-transformed B-cell clones, and the production of antibodies directed against specific EBV viral antigens as well as lifelong T-cell surveillance of infected B-cells [13]. EBV nuclear antigen (EBNA) has a similar structure to myelin basic protein, a major component of CNS myelin. T-cells directed against EBV antigens may be redirected to attack CNS myelin because of similarity between the antigens, a process termed molecular mimicry.

Adults with MS have near 100 percent seropositivity for EBV in comparison with 80 to 90 percent of healthy controls, a statistically significant difference. Nevertheless, given the high frequency of this infection in the general population, the pathobiologic significance remains uncertain.

Evidence of an etiologic role for EBV in MS may be stronger in the pediatric than the adult population. As examples, a multinational study found that serologic evidence for remote EBV infection was significantly higher in children with MS compared with age-matched controls (86 versus 64 percent) [14], and similar results were reported in case-control studies from Canada and Germany [15,16].

Vitamin D — There is a higher prevalence of MS at more northern latitudes, which has prompted other environmental considerations for the disease. Specific interest has arisen with vitamin D, which requires exposure of the skin to ultraviolet radiation for its normal biosynthesis. (See "Pathogenesis and epidemiology of multiple sclerosis", section on 'Geographic factors'.)

On a sunny day, up to 20,000 international units of vitamin D can be produced by cutaneous exposure to sunlight for 15 minutes.

Vitamin D is known to have immunoregulatory effects that include enhancing regulatory T-cell activity, upregulation of anti-inflammatory molecules, and downregulation of pro-inflammatory cytokines [17]. Benefit of treatment with 1,25 dihydroxy-vitamin D has been demonstrated in the experimental autoimmune encephalomyelitis animal model [17]. In addition, vitamin D may have important perinatal effects on normal immune system regulation that persist over a lifetime. One study demonstrated a greater risk of MS for patients born in the month of May in countries of more northern latitude but a lower risk if born in November, suggesting gestation during winter months with less sunlight might adversely affect normal vitamin D production in the fetus [18]. Other studies have found an inverse correlation between serum 25-hydroxyvitamin D levels and the risk for developing MS [19-21]. The greatest risk reduction was found for individuals with higher levels under the age of 21 years. A small study of pediatric MS found that there was a 34 percent decrease in attacks for every 10 ng/mL increase in the level of circulating 25-hydroxyvitamin D [22].

CLINICAL FEATURES AND DIAGNOSIS — MS is characterized by recurrent episodes of demyelination in the central nervous system (CNS) separated in space and time. Acute inflammation and demyelination in a critical area of the brain, optic nerves, or spinal cord will produce a corresponding clinical deficit. (See "Manifestations of multiple sclerosis in adults", section on 'Clinical symptoms and signs'.)

Presentation — Children with MS generally have a clinical presentation that is similar to adults, with one or more clinically distinct episodes of optic neuritis, diplopia, brainstem or cerebellar syndrome, or partial transverse myelitis, followed by at least partial resolution. (See "Clinical presentation, course, and prognosis of multiple sclerosis in adults".)

However, on a population basis, there are some differences between children and adults, and between older and younger children, as suggested by the following reports:

A European observational study of 394 children with pediatric-onset MS and 1775 patients with adult-onset MS found that children were more likely than adults to present with isolated optic neuritis, an isolated brainstem syndrome, or symptoms of encephalopathy (ie, headache, vomiting, seizure, or altered consciousness) [23].

A multinational observational study of 137 children with MS reported that the first MS attack resembled acute disseminated encephalomyelitis (ADEM), on the basis of multifocal symptoms with encephalopathy, in 16 percent of children [14]. The mean age of children with ADEM-like presentations (7.4 years) was significantly younger than children with multifocal (11.2 years) or monofocal (12.0 years) presentations. (See "Acute disseminated encephalomyelitis (ADEM) in children: Pathogenesis, clinical features, and diagnosis".)

In a prospective multicenter US observational study of 490 children and adolescents with MS, the age at the time of the first event was <12 years in 28 percent and ≥12 years in 72 percent [24]. Antecedent events, particularly infection, were significantly more common among subjects aged <12 years compared with those aged ≥12 years (47 versus 25 percent). Children <12 years of age were more likely to present with encephalopathy or coordination problems, while children ≥12 years of age were more likely to present with sensory symptoms. The racial composition of the cohort was diverse, including White (67 percent), Black/African American (21 percent), Asian (4 percent), American Indian/Alaskan Native (2 percent), and multiracial (7 percent) individuals.

Course — Approximately 85 to 90 percent of affected adults have relapsing-remitting multiple sclerosis (RRMS) with a clinical course characterized by intermittent attacks of increased disability followed by either partial or complete recovery to their baseline functioning. In children, RRMS is the initial form of MS in 97 to 99 percent [2,14,23,25,26].

Primary progressive multiple sclerosis (PPMS), a disease type characterized by continuous disability over time in the absence of specific attacks, is much less common than RRMS in children and adults. The rarity of PPMS in children should prompt the clinician to carefully exclude other possibilities that can be confused with it, including leukodystrophies, inborn errors of metabolism, mitochondrial disease, and neuromyelitis optica spectrum disorders (NMOSD). (See "Differential diagnosis of acute central nervous system demyelination in children", section on 'Neuromyelitis optica spectrum disorders' and "Neuromyelitis optica spectrum disorder (NMOSD): Clinical features and diagnosis".)

Fatigue and depression — Fatigue is one of the most common problems affecting children and adolescents with MS [27-32]. Fatigue may result simply from typical daily stressors encountered at school or home. It can also be related to deconditioning, becoming more pronounced in the setting of demyelinated nerve fibers.

The prevalence of depression in children with MS ranges from 20 to 50 percent [27,28,30,33-35]. Depression is often associated with fatigue in this patient population [29,32].

Cognitive impairment — Cognitive impairment is a common manifestation of MS in adults and is increasingly recognized in children with MS [36,37]. Cognitive deficits may include problems with general cognition, information processing, language, visuomotor integration, and verbal and visual memory. Although the degree of cognitive dysfunction may be related to the duration and severity of MS, cognitive problems can also occur in children with no physical disability.

Diagnostic criteria — The diagnosis of pediatric MS can be satisfied by fulfilling any one of the following diagnostic criteria [38,39]:

Two or more nonencephalopathic (ie, unlike acute disseminated encephalomyelitis or ADEM) clinical CNS events with presumed inflammatory cause, separated by more than 30 days and involving more than one area of the CNS

One nonencephalopathic episode typical of MS that is associated with magnetic resonance imaging (MRI) findings consistent with 2017 McDonald criteria (table 1) for dissemination in space (table 2) and in which a follow-up MRI shows at least one new enhancing or nonenhancing lesion consistent with criteria for dissemination in time

One ADEM attack followed by a nonencephalopathic clinical event, three or more months after symptom onset, that is associated with new MRI lesions that fulfill the 2017 McDonald dissemination in space criteria (table 2)

A first, single, acute event that does not meet ADEM criteria and for which MRI findings are consistent with the 2017 McDonald criteria for dissemination in space (table 2) and dissemination in time (table 3); this applies only to children ≥11 years of age

The McDonald diagnostic criteria for MS, first published in 2001 [40], were revised in 2005 [41], 2010 [42], and 2017 [39]. The 2010 McDonald criteria generally displayed a high sensitivity and specificity for the diagnosis of pediatric MS when applied to children ≥11 years of age without features suggestive of ADEM [43]. In comparison, the 2017 McDonald criteria were found to have an even higher accuracy (87.2 versus 66.7 percent) and sensitivity (84 versus 46.8 percent), but a slightly reduced specificity (91.9 versus 96.8 percent). The better performance of the 2017 McDonald criteria is likely related to the addition of cerebrospinal fluid (CSF) oligoclonal bands as a criterion fulfilling dissemination in time [44]. (See 'Unusual presentations' below.)

The core requirement of the diagnosis is the objective demonstration of dissemination of lesions in both space and time, based upon either clinical findings alone or a combination of clinical, CSF, and MRI findings.

Dissemination in space (table 2) is demonstrated on MRI by one or more T2 lesions in at least two of four MS-typical regions of the CNS (periventricular, cortical or juxtacortical, infratentorial, or spinal cord) or by the development of an additional clinical attack characteristic of MS, supported by objective clinical evidence, that implicates a different CNS site [39].

Dissemination in time (table 3) is demonstrated by the development of an additional clinical attack (supported by objective clinical evidence) that is characteristic of MS, or an MRI of the brain and/or spinal cord with the simultaneous presence of gadolinium-enhancing and nonenhancing lesions at any time, or by a new hyperintense T2 and/or gadolinium-enhancing lesion(s) on follow-up MRI, irrespective of its timing with reference to a baseline scan, or finding of CSF-specific oligoclonal bands (as a substitute for dissemination in time) [39]

The McDonald criteria can only be applied after careful clinical evaluation of the patient. The amount of additional data needed to confirm the diagnosis of MS depends upon the clinical presentation [42]:

For patients with two or more attacks who have objective clinical evidence of two or more lesions or objective clinical evidence of one lesion with reasonable historical evidence of a prior attack, no additional data are required. However, it is desirable to make the diagnosis of MS with access to imaging. If MRI and other tests (eg, CSF) are negative, alternative diagnoses must be considered. There must be no better explanation for the clinical presentation, and objective evidence must be present to support a diagnosis of MS.

For patients with two or more attacks who have objective clinical evidence of one lesion, the criteria require evidence of dissemination in space.

For patients with one attack who have objective clinical evidence of two or more lesions, the criteria require evidence of dissemination in time.

For patients with one attack who have objective clinical evidence of one lesion (ie, a clinically isolated syndrome), the criteria require evidence of dissemination in space and time.

The older Poser criteria for MS [45] are no longer in widespread use, having been superseded by the McDonald criteria.

Unusual presentations — The McDonald criteria should not be applied for children who present with encephalopathy and multifocal neurological deficits, and they should be applied only with caution for children who present with insidious neurological progression [42,43].

Approximately 15 to 20 percent of children diagnosed with MS initially present with encephalopathy and multifocal neurological deficits suggestive of ADEM; most such children are younger than 11 years of age [14,42,46]. Lesions associated with ADEM are typically bilateral but may be asymmetric and tend to be poorly marginated. Almost all patients have multiple lesions in the deep and subcortical white matter. In addition, children with early-onset MS (<11 years of age) tend to have larger and less well-defined brain lesions than the more typical MS lesions seen in teenagers [47].

Thus, in children <11 years of age with encephalopathy and multifocal neurologic deficits (ie, children with ADEM), application of the McDonald criteria for dissemination in space (table 2) and time (table 3) on initial MRI is considered inappropriate, and continued follow-up of clinical and MRI findings are needed to confirm a diagnosis of MS. The diagnosis of MS can be considered if one attack that fulfills ADEM criteria is followed, three or more months later, by a nonencephalopathic episode associated with new MRI lesions that fulfill the McDonald criteria for dissemination in space [38]. The initial ADEM event is considered the first MS attack in this regard. However, in such populations, alternative diagnoses should be excluded, including neuromyelitis optica spectrum disorders (NMOSD). (See "Acute disseminated encephalomyelitis (ADEM) in children: Pathogenesis, clinical features, and diagnosis", section on 'Evaluation and diagnosis' and "Acute disseminated encephalomyelitis (ADEM) in children: Pathogenesis, clinical features, and diagnosis", section on 'Neuroimaging'.)

High serum titers of anti-myelin-oligodendrocyte glycoprotein (MOG) immunoglobulin G (IgG) antibodies can occur in patients with NMOSD, ADEM followed by recurrent optic neuritis, and in chronic relapsing optic neuritis. Seropositivity for anti-MOG-IgG is rarely encountered in MS and, when present, typically has a very low titer level. As such, testing for this antibody in atypical presentations can be help to distinguish MS from other etiologies [48]. (See "Myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD): Clinical features and diagnosis".)

As noted earlier, 97 to 99 percent children with MS present with a relapsing-remitting course (see 'Clinical features and diagnosis' above). Primary progressive MS (PPMS) is extraordinarily rare in children, and children who present with insidious neurological progression suggestive of PPMS should be carefully evaluated for alternative diagnoses [42,49-52]. For a diagnosis of PPMS, the McDonald criteria require evidence of one year of disease progression, independent of clinical relapse, plus two of the three following criteria [39]:

One or more hyperintense T2 lesions characteristic of MS in one or more of the periventricular, cortical or juxtacortical, or infratentorial areas

Two or more hyperintense T2 lesions in the spinal cord

Presence of CSF-specific oligoclonal bands

Clinically isolated syndromes — A clinically isolated syndrome (CIS) is a single attack compatible with MS, such as optic neuritis, transverse myelitis, a brain stem syndrome, or symptoms related to supratentorial lesions. Approximately 80 percent of pediatric-onset MS cases and nearly all adolescent-onset MS cases present with attacks similar to those seen in adult CIS [53-55].

Diagnostic criteria for pediatric CIS require all of the following [38]:

A monofocal or polyfocal clinical CNS event with presumed inflammatory demyelinating cause

Absence of a prior clinical history of CNS demyelinating disease (eg, absence of past optic neuritis, transverse myelitis, or hemispheric or brain-stem related syndromes)

No encephalopathy (ie, no alteration in consciousness or behavior), with the exception of encephalopathy due to fever

The diagnosis of MS based on baseline MRI is not fulfilled

An episode of CIS can create diagnostic and therapeutic dilemmas (algorithm 1).

The majority of children will not have recurrence after a single demyelinating event of the CNS. Clinical investigations, including brain MRI, CSF analysis, and other laboratory studies, can provide useful information regarding which children are at higher risk for developing MS from among those who have a CIS, but even with these studies, the ability to identify those at high risk for recurrence is inexact.

In a cohort study from France that followed 296 children for an average of 2.9 years after a single acute CNS demyelinating event, the diagnosis of MS was confirmed in 57 percent of the children by the end of the study [56]. Factors present at the time of the initial attack that were associated with an increased risk of a second demyelinating event included:

Age 10 years or older (hazard ratio [HR] 1.67, 95% CI 1.04-2.67)

Optic nerve lesions (HR 2.59, 95% CI 1.27-5.29)

An MRI pattern typical for MS (ie, multiple well-limited periventricular or subcortical lesions) (HR 1.54, 95% CI 1.02-2.33)

Factors present at the time of initial attack that were associated with a decreased risk of a second attack included [56]:

Spinal cord lesions (HR 0.23, 95% CI 0.10-0.56)

Acute mental status changes (HR 0.59, 95% CI 0.33-1.07)

As noted earlier, the McDonald criteria require evidence of dissemination in space (table 2) and time (table 3) for patients with a CIS to make a diagnosis of MS (see 'Diagnostic criteria' above). The 2017 McDonald criteria allow dissemination in time to be met on a single MRI demonstrating the presence of both gadolinium-enhancing and nonenhancing lesions [39]. This can include the baseline MRI taken at the time of the patient’s initial presentation. In the absence of meeting such criteria at initial presentation, careful monitoring with detailed neurologic examination, psychometric testing, and imaging studies should be employed. A repeat MRI performed at any time after the initial study (most likely about one to two months later) that shows a single new T2 and/or gadolinium-enhancing lesion will also fulfill the dissemination in time criteria. Such close surveillance allows for early diagnosis and initiation of immunomodulatory therapies that may prevent greater disability over time. Alternatively, dissemination in time can be met in the absence of MRI criteria by the presence of CSF-specific oligoclonal bands. (See "Treatment and prognosis of pediatric multiple sclerosis", section on 'Interferon beta drugs'.)

MRI — Children being evaluated for the diagnosis of MS should have MRI of the brain without and with gadolinium contrast [57]. Full spinal cord MRI should be performed if there are spinal cord signs or symptoms or if brain MRI findings are inconclusive. Dedicated optic nerve MRI is not routinely recommended but can be useful for excluding alternative diagnoses such as neuromyelitis optica spectrum disorders (NMOSD) or myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) [57]. (See "Neuromyelitis optica spectrum disorder (NMOSD): Clinical features and diagnosis" and "Myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD): Clinical features and diagnosis".)

A typical pattern consistent with MS on brain MRI is that of multiple well-demarcated lesions in the periventricular, cortical or juxtacortical, infratentorial, and spinal cord white matter. These areas of demyelination are best recognized on T2-weighted sequences. T2 fluid-attenuated inversion recovery (FLAIR) image sequences are the most sensitive in this evaluation, especially for periventricular lesions (image 1). T1-weighted sequences may demonstrate "black holes" or T1 hypointense lesions that represent complete tissue loss resulting from a previous inflammatory event (image 1). Enhancement of active areas of inflammation and blood-brain barrier compromise can be seen with T1 gadolinium contrast sequences.

In patients with an acquired demyelinating syndrome, brain MRI can be helpful for assessing risk of developing MS. In a prospective population-based cohort study of 302 children from Canada presenting with an acquired demyelinating syndrome who were followed for a median time of three years, the diagnosis of MS was made in 63 (21 percent) [58]. The factors most strongly associated with the risk of MS were the presence of one or more T2 lesions on initial brain MRI (HR 37.9, 95% CI 5.3-273.9) and the presence of oligoclonal bands in the CSF (HR 6.33, 95% CI 3.4-12). A subsequent report analyzed 284 children from the same cohort using a multivariate model of MRI parameters of MS and found the likelihood of MS was predicted by the presence on baseline brain MRI of either one or more hypointense T1 lesions (HR 20.6, 95% CI 5.5-78.0) or one or more periventricular lesions (HR 3.3, 95% CI 1.3-8.8) [59]. The risk of MS was highest when both findings were noted (HR 34.3, 95% CI 16.7-70.4).

Retrospective data suggest that at the onset of MS, children have more T2 bright lesions in the posterior fossa and more gadolinium enhancing lesions than adults at the same point in their history [53]. In addition, the lesions in children were more likely to reverse on follow-up imaging than lesions in adults, suggesting better recovery of demyelination in children.

While rare, some children are found to have large, tumor-like demyelinating lesions (image 2) [60]. Some of these patients may have only modest neurologic deficits despite the remarkable size of these lesions. It is important to consider tumefactive demyelination in this setting to avoid unnecessary brain biopsy. Distinguishing characteristics might include the presence of "black holes" and MRI of the spine showing areas of demyelination.

Cerebrospinal fluid analysis — Detection of increased discrete immunoglobulin production solely within the CSF is useful for satisfying the criteria for dissemination in time criteria for the diagnosis of MS (table 3). A positive CSF result is based upon the finding of oligoclonal IgG bands (OCBs) different from any such bands in serum.

Children with MS may have a CSF profile that differs from the typical profile in adults [61]. However, data are limited to mainly small retrospective studies, and these have yielded inconsistent results, with positive OCBs reported in 8 to 92 percent, elevated IgG index in 64 to 75 percent, and pleocytosis in 33 to 73 percent of children with MS [62-67]. The wide disparities between these studies may be related to differences in patient age, timing of lumbar puncture, laboratory methods used to analyze CSF, or to chance.

Evoked potentials — Visual evoked potentials and somatosensory evoked potentials are electrophysiologic tests that provide information on the integrity of axons and their surrounding myelin. In adults, these studies provide supportive evidence for demyelination in the optic nerve, brainstem, or spinal cord [68]. While abnormal findings supportive of demyelination have been described in pediatric series, their direct utility in confirming a diagnosis of MS is not yet defined [69].

DIFFERENTIAL DIAGNOSIS — Given the availability of disease-modifying therapies for MS and the impact on future prognosis, it is important to consider the possibility of pediatric MS in all children with white matter disease.

MS is still largely a diagnosis of exclusion and therefore requires intense investigation for other conditions that might present in a similar manner (table 4). The figure provides a diagnostic algorithm for various demyelinating diseases of childhood (algorithm 1). (See "Differential diagnosis of acute central nervous system demyelination in children".)

In the setting of nonspecific cerebrospinal fluid abnormalities and MRI evidence of white matter lesions, various inflammatory, demyelinating, infectious, metabolic, and rheumatologic conditions should be considered, including the following:

Acute disseminated encephalomyelitis (ADEM) (see "Acute disseminated encephalomyelitis (ADEM) in children: Pathogenesis, clinical features, and diagnosis")

Optic neuritis (see "Optic neuritis: Pathophysiology, clinical features, and diagnosis")

Transverse myelitis (see "Transverse myelitis: Etiology, clinical features, and diagnosis")

Neuromyelitis optica spectrum disorders (NMOSD) (See "Neuromyelitis optica spectrum disorder (NMOSD): Clinical features and diagnosis".)

Myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) (see "Myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD): Clinical features and diagnosis")

Central nervous system malignancies

Leukodystrophies

Mitochondrial disease

The most important alternative diagnosis to MS is ADEM, a more common and a temporally limited disorder than pediatric MS. At initial presentation, the two disorders cannot be distinguished with absolute certainty (algorithm 1). In children, subsequent attacks of MS may not occur for months or years. Furthermore, a small subset of children with ADEM may eventually develop MS, but it is difficult to accurately predict which patients will do so. Therefore, prolonged follow-up is required to establish a diagnosis. (See "Differential diagnosis of acute central nervous system demyelination in children", section on 'Distinguishing ADEM and multiple sclerosis'.)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Multiple sclerosis and related disorders".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

Basics topics (see "Patient education: Multiple sclerosis in adults (The Basics)" and "Patient education: Multiple sclerosis in children (The Basics)")

SUMMARY AND RECOMMENDATIONS

Pediatric multiple sclerosis (MS), defined as onset of MS before the age of 18, is increasingly recognized. MS begins before the age of 18 in at least 5 percent of patients who have MS, while onset before age 10 occurs in less than 1 percent. Nevertheless, pediatric MS is a rare disease. (See 'Epidemiology' above.)

MS is caused by dysregulation of the peripheral immune system leading to injury in the central nervous system (CNS). Its pathogenesis requires the combination of a genetically susceptible individual and a particular environmental trigger. (See 'Pathogenesis' above.)

MS is characterized by recurrent episodes of demyelination in the CNS separated in space and time. Children with MS typically present with a clinically isolated syndrome such as optic neuritis, transverse myelitis, or a brainstem syndrome. A minority of children present with symptoms of encephalopathy (ie, headache, vomiting, seizure, or altered consciousness). In addition, the first attack of MS can resemble acute disseminated encephalomyelitis (ADEM) on the basis of multifocal symptoms with encephalopathy in approximately 16 to 20 percent of children, most of whom are ≤11 years of age. (See 'Clinical features and diagnosis' above and 'Clinically isolated syndromes' above.)

The McDonald diagnostic criteria for MS require objective evidence of dissemination of demyelinating CNS lesions in both space (table 2) and time (table 3), based upon either clinical findings alone or a combination of clinical and MRI findings. In a number of patients, the diagnosis of MS can be made with these criteria even in the absence of new clinical findings, and, for some patients, at the time of the initial attack. (See 'Diagnostic criteria' above.)

A clinically isolated syndrome (CIS) is a single attack compatible with MS, such as optic neuritis. An episode of CIS can create a diagnostic and therapeutic dilemma. Most children will not have recurrence after a single demyelinating event of the CNS. However, the risk is probably high enough to be concerning, though as yet not defined precisely. (See 'Clinically isolated syndromes' above.)

The most important alternative diagnosis to MS is ADEM (table 4). At the initial presentation, the two disorders cannot be distinguished with absolute certainty (algorithm 1). While certain clinical features may be helpful in supporting the diagnosis of ADEM or MS, there is substantial overlap. (See 'Differential diagnosis' above.)

The treatment and prognosis of pediatric MS is reviewed separately. (See "Treatment and prognosis of pediatric multiple sclerosis".)

  1. Jeong A, Oleske DM, Holman J. Epidemiology of Pediatric-Onset Multiple Sclerosis: A Systematic Review of the Literature. J Child Neurol 2019; 34:705.
  2. Boiko A, Vorobeychik G, Paty D, et al. Early onset multiple sclerosis: a longitudinal study. Neurology 2002; 59:1006.
  3. Duquette P, Murray TJ, Pleines J, et al. Multiple sclerosis in childhood: clinical profile in 125 patients. J Pediatr 1987; 111:359.
  4. Bigi S, Banwell B. Pediatric multiple sclerosis. J Child Neurol 2012; 27:1378.
  5. Gadoth N. Multiple sclerosis in children. Brain Dev 2003; 25:229.
  6. Oksenberg JR, Hauser SL. Genetics of multiple sclerosis. Neurol Clin 2005; 23:61.
  7. Willer CJ, Dyment DA, Risch NJ, et al. Twin concordance and sibling recurrence rates in multiple sclerosis. Proc Natl Acad Sci U S A 2003; 100:12877.
  8. Banwell BL. Pediatric multiple sclerosis. Curr Neurol Neurosci Rep 2004; 4:245.
  9. Ramagopalan SV, Knight JC, Ebers GC. Multiple sclerosis and the major histocompatibility complex. Curr Opin Neurol 2009; 22:219.
  10. Mikaeloff Y, Caridade G, Rossier M, et al. Hepatitis B vaccination and the risk of childhood-onset multiple sclerosis. Arch Pediatr Adolesc Med 2007; 161:1176.
  11. Montgomery S, Hiyoshi A, Burkill S, et al. Concussion in adolescence and risk of multiple sclerosis. Ann Neurol 2017; 82:554.
  12. Ascherio A, Munch M. Epstein-Barr virus and multiple sclerosis. Epidemiology 2000; 11:220.
  13. Bray PF, Luka J, Bray PF, et al. Antibodies against Epstein-Barr nuclear antigen (EBNA) in multiple sclerosis CSF, and two pentapeptide sequence identities between EBNA and myelin basic protein. Neurology 1992; 42:1798.
  14. Banwell B, Krupp L, Kennedy J, et al. Clinical features and viral serologies in children with multiple sclerosis: a multinational observational study. Lancet Neurol 2007; 6:773.
  15. Alotaibi S, Kennedy J, Tellier R, et al. Epstein-Barr virus in pediatric multiple sclerosis. JAMA 2004; 291:1875.
  16. Pohl D, Krone B, Rostasy K, et al. High seroprevalence of Epstein-Barr virus in children with multiple sclerosis. Neurology 2006; 67:2063.
  17. VanAmerongen BM, Dijkstra CD, Lips P, Polman CH. Multiple sclerosis and vitamin D: an update. Eur J Clin Nutr 2004; 58:1095.
  18. Willer CJ, Dyment DA, Sadovnick AD, et al. Timing of birth and risk of multiple sclerosis: population based study. BMJ 2005; 330:120.
  19. Ascherio A, Munger KL. Environmental risk factors for multiple sclerosis. Part II: Noninfectious factors. Ann Neurol 2007; 61:504.
  20. Munger KL, Levin LI, Hollis BW, et al. Serum 25-hydroxyvitamin D levels and risk of multiple sclerosis. JAMA 2006; 296:2832.
  21. Nielsen NM, Munger KL, Koch-Henriksen N, et al. Neonatal vitamin D status and risk of multiple sclerosis: A population-based case-control study. Neurology 2017; 88:44.
  22. Mowry EM, Krupp LB, Milazzo M, et al. Vitamin D status is associated with relapse rate in pediatric-onset multiple sclerosis. Ann Neurol 2010; 67:618.
  23. Renoux C, Vukusic S, Mikaeloff Y, et al. Natural history of multiple sclerosis with childhood onset. N Engl J Med 2007; 356:2603.
  24. Belman AL, Krupp LB, Olsen CS, et al. Characteristics of Children and Adolescents With Multiple Sclerosis. Pediatrics 2016; 138.
  25. Gusev E, Boiko A, Bikova O, et al. The natural history of early onset multiple sclerosis: comparison of data from Moscow and Vancouver. Clin Neurol Neurosurg 2002; 104:203.
  26. Simone IL, Carrara D, Tortorella C, et al. Course and prognosis in early-onset MS: comparison with adult-onset forms. Neurology 2002; 59:1922.
  27. Amato MP, Goretti B, Ghezzi A, et al. Cognitive and psychosocial features of childhood and juvenile MS. Neurology 2008; 70:1891.
  28. Amato MP, Goretti B, Ghezzi A, et al. Cognitive and psychosocial features in childhood and juvenile MS: two-year follow-up. Neurology 2010; 75:1134.
  29. Goretti B, Portaccio E, Ghezzi A, et al. Fatigue and its relationships with cognitive functioning and depression in paediatric multiple sclerosis. Mult Scler 2012; 18:329.
  30. Ketelslegers IA, Catsman-Berrevoets CE, Boon M, et al. Fatigue and depression in children with multiple sclerosis and monophasic variants. Eur J Paediatr Neurol 2010; 14:320.
  31. MacAllister WS, Christodoulou C, Troxell R, et al. Fatigue and quality of life in pediatric multiple sclerosis. Mult Scler 2009; 15:1502.
  32. Carroll S, Chalder T, Hemingway C, et al. Understanding fatigue in paediatric multiple sclerosis: a systematic review of clinical and psychosocial factors. Dev Med Child Neurol 2016; 58:229.
  33. MacAllister WS, Belman AL, Milazzo M, et al. Cognitive functioning in children and adolescents with multiple sclerosis. Neurology 2005; 64:1422.
  34. Banwell BL, Anderson PE. The cognitive burden of multiple sclerosis in children. Neurology 2005; 64:891.
  35. MacAllister WS, Boyd JR, Holland NJ, et al. The psychosocial consequences of pediatric multiple sclerosis. Neurology 2007; 68:S66.
  36. Amato MP, Goretti B, Ghezzi A, et al. Neuropsychological features in childhood and juvenile multiple sclerosis: five-year follow-up. Neurology 2014; 83:1432.
  37. Cardoso M, Olmo NR, Fragoso YD. Systematic Review of Cognitive Dysfunction in Pediatric and Juvenile Multiple Sclerosis. Pediatr Neurol 2015; 53:287.
  38. Krupp LB, Tardieu M, Amato MP, et al. International Pediatric Multiple Sclerosis Study Group criteria for pediatric multiple sclerosis and immune-mediated central nervous system demyelinating disorders: revisions to the 2007 definitions. Mult Scler 2013; 19:1261.
  39. Thompson AJ, Banwell BL, Barkhof F, et al. Diagnosis of multiple sclerosis: 2017 revisions of the McDonald criteria. Lancet Neurol 2018; 17:162.
  40. McDonald WI, Compston A, Edan G, et al. Recommended diagnostic criteria for multiple sclerosis: guidelines from the International Panel on the diagnosis of multiple sclerosis. Ann Neurol 2001; 50:121.
  41. Polman CH, Reingold SC, Edan G, et al. Diagnostic criteria for multiple sclerosis: 2005 revisions to the "McDonald Criteria". Ann Neurol 2005; 58:840.
  42. Polman CH, Reingold SC, Banwell B, et al. Diagnostic criteria for multiple sclerosis: 2010 revisions to the McDonald criteria. Ann Neurol 2011; 69:292.
  43. Sadaka Y, Verhey LH, Shroff MM, et al. 2010 McDonald criteria for diagnosing pediatric multiple sclerosis. Ann Neurol 2012; 72:211.
  44. Hacohen Y, Brownlee W, Mankad K, et al. Improved performance of the 2017 McDonald criteria for diagnosis of multiple sclerosis in children in a real-life cohort. Mult Scler 2020; 26:1372.
  45. Poser CM, Paty DW, Scheinberg L, et al. New diagnostic criteria for multiple sclerosis: guidelines for research protocols. Ann Neurol 1983; 13:227.
  46. Mikaeloff Y, Adamsbaum C, Husson B, et al. MRI prognostic factors for relapse after acute CNS inflammatory demyelination in childhood. Brain 2004; 127:1942.
  47. Chabas D, Castillo-Trivino T, Mowry EM, et al. Vanishing MS T2-bright lesions before puberty: a distinct MRI phenotype? Neurology 2008; 71:1090.
  48. Hennes EM, Baumann M, Schanda K, et al. Prognostic relevance of MOG antibodies in children with an acquired demyelinating syndrome. Neurology 2017; 89:900.
  49. Yeh EA, Chitnis T, Krupp L, et al. Pediatric multiple sclerosis. Nat Rev Neurol 2009; 5:621.
  50. Banwell B, Ghezzi A, Bar-Or A, et al. Multiple sclerosis in children: clinical diagnosis, therapeutic strategies, and future directions. Lancet Neurol 2007; 6:887.
  51. Venkateswaran S, Banwell B. Pediatric multiple sclerosis. Neurologist 2010; 16:92.
  52. Hahn JS, Pohl D, Rensel M, et al. Differential diagnosis and evaluation in pediatric multiple sclerosis. Neurology 2007; 68:S13.
  53. Waubant E, Chabas D, Okuda DT, et al. Difference in disease burden and activity in pediatric patients on brain magnetic resonance imaging at time of multiple sclerosis onset vs adults. Arch Neurol 2009; 66:967.
  54. Ghassemi R, Antel SB, Narayanan S, et al. Lesion distribution in children with clinically isolated syndromes. Ann Neurol 2008; 63:401.
  55. Yeh EA, Weinstock-Guttman B, Ramanathan M, et al. Magnetic resonance imaging characteristics of children and adults with paediatric-onset multiple sclerosis. Brain 2009; 132:3392.
  56. Mikaeloff Y, Suissa S, Vallée L, et al. First episode of acute CNS inflammatory demyelination in childhood: prognostic factors for multiple sclerosis and disability. J Pediatr 2004; 144:246.
  57. Wattjes MP, Ciccarelli O, Reich DS, et al. 2021 MAGNIMS-CMSC-NAIMS consensus recommendations on the use of MRI in patients with multiple sclerosis. Lancet Neurol 2021; 20:653.
  58. Banwell B, Bar-Or A, Arnold DL, et al. Clinical, environmental, and genetic determinants of multiple sclerosis in children with acute demyelination: a prospective national cohort study. Lancet Neurol 2011; 10:436.
  59. Verhey LH, Branson HM, Shroff MM, et al. MRI parameters for prediction of multiple sclerosis diagnosis in children with acute CNS demyelination: a prospective national cohort study. Lancet Neurol 2011; 10:1065.
  60. McAdam LC, Blaser SI, Banwell BL. Pediatric tumefactive demyelination: case series and review of the literature. Pediatr Neurol 2002; 26:18.
  61. Chabas D, Ness J, Belman A, et al. Younger children with MS have a distinct CSF inflammatory profile at disease onset. Neurology 2010; 74:399.
  62. Riikonen R. The role of infection and vaccination in the genesis of optic neuritis and multiple sclerosis in children. Acta Neurol Scand 1989; 80:425.
  63. Hanefeld F, Bauer HJ, Christen HJ, et al. Multiple sclerosis in childhood: report of 15 cases. Brain Dev 1991; 13:410.
  64. Ruggieri M, Polizzi A, Pavone L, Grimaldi LM. Multiple sclerosis in children under 6 years of age. Neurology 1999; 53:478.
  65. Ghezzi A, Pozzilli C, Liguori M, et al. Prospective study of multiple sclerosis with early onset. Mult Scler 2002; 8:115.
  66. Pohl D, Rostasy K, Reiber H, Hanefeld F. CSF characteristics in early-onset multiple sclerosis. Neurology 2004; 63:1966.
  67. Atzori M, Battistella PA, Perini P, et al. Clinical and diagnostic aspects of multiple sclerosis and acute monophasic encephalomyelitis in pediatric patients: a single centre prospective study. Mult Scler 2009; 15:363.
  68. Gronseth GS, Ashman EJ. Practice parameter: the usefulness of evoked potentials in identifying clinically silent lesions in patients with suspected multiple sclerosis (an evidence-based review): Report of the Quality Standards Subcommittee of the American Academy of Neurology. Neurology 2000; 54:1720.
  69. Boutin B, Esquivel E, Mayer M, et al. Multiple sclerosis in children: report of clinical and paraclinical features of 19 cases. Neuropediatrics 1988; 19:118.
Topic 6229 Version 29.0

References

آیا می خواهید مدیلیب را به صفحه اصلی خود اضافه کنید؟