key: cord-0044999-mdzi04t9
authors: Nouri, Maryam Nabavi; Yeh, E. Ann
title: Neuroinflammatory and Demyelinating Disorders of Childhood
date: 2020-06-09
journal: Clinical Child Neurology
DOI: 10.1007/978-3-319-43153-6_20
sha: b59580e81d5b2023c469014b791de72713955ecd
doc_id: 44999
cord_uid: mdzi04t9

In this chapter, we will review monophasic and recurrent demyelinating disorders in children. We will first review consensus definitions and provide an approach to the evaluation of children with first episode of acquired demyelinating disorder. We will discuss typical clinical and radiological features of these syndromes. In the second section, we will review features of recurrent demyelinating syndromes in children, focusing on clinical presentation and treatment options.

In this chapter, we will review monophasic and recurrent demyelinating disorders in children. We will first review consensus definitions and provide an approach to the evaluation of children with first episode of acquired demyelinating disorder. We will discuss typical clinical and radiological features of these syndromes. In the second section, we will review features of recurrent demyelinating syndromes in children, focusing on clinical presentation and treatment options.

Acquired demyelinating syndromes (ADS) can be defined as syndromes resulting in single (monofocal) or multiple (polyfocal) lesions originating in the central nervous system (CNS) caused by inflammatory demyelination. Monophasic events may be classified as (1) clinically isolated syndrome (CIS), characterized by monofocal or polyfocal deficits without encephalopathy, or (2) acute disseminated encephalomyelitis (ADEM), characterized by polyfocal deficits and encephalopathy. Recurrent disorders include pediatric multiple sclerosis (MS), neuromyelitis optica spectrum disorders (NMOSD), and serum antibodies to myelin oligodendrocyte glycoprotein (MOG)-associated demyelination (see Table 20 .1) [1] .

Any patient with new, subacute focal neurologic deficits occurring after a known infection, and in the absence of trauma, metabolic derangements, or known underlying structural abnormalities, should be suspected of having acquired CNS demyelination. In addition to detailed history and physical examination, the suggested workup for these children includes cerebrospinal fluid (CSF) and serum analysis as well as neuroimaging ( Fig. 20.1 ). Laboratory features, suggestive of acquired demyelination, include mild to moderate CSF pleocytosis, elevated CSF protein, presence of oligoclonal bands (OCBs), and increased immunoglobulin G (IgG) index. Magnetic resonance imaging (MRI) features may include the presence of multifocal white and gray matter abnormalities, presence of spinal cord lesions, optic nerve thickening or hyperintensity on T2-weighted imaging, and the presence of enhancement of lesions after the administration of gadolinium. Specific features associated with each of the disorders will be discussed below.

Clinically isolated syndromes (CIS) include optic neuritis (ON), transverse myelitis (TM), and other isolated syndromes including those with isolated cerebellar and brainstem lesions. These disorders may be monophasic in many cases, but could also be the first presentation of a relapsing syndrome such as NMOSD or MS (see Clinical course and risk of recurrence after the first demyelinating episode). Below we review each entity separately. 

Optic neuritis (ON) is characterized by inflammation of the optic nerve. It may present as an isolated condition or can be associated with variety of other immunemediated CNS or systemic disorders [2] . Mean age of onset ranges from 9 to 12 years of age with an approximate 1.5:1 female-to-male ratio [3] . Its incidence is 1-5 per 100,000/year [3] . Between 13% and 36% of children with an initial episode of ON are eventually diagnosed with MS [4] .

Common clinical features of ON include periorbital pain or headache made worse by eye movement, subacute decrease in visual acuity (VA), abnormal color vision, reduced low-contrast letter acuity, and visual field (VF) defects. Physical examination at the time of an acute event will reveal a relative afferent pupillary defect (RAPD) in unilateral cases. Initial visual acuity can range from 20/40 or better to no light perception. Close to 60% of children have a VA of 20/200 or worse [5] . Inflammation of the optic nerve head (papillitis) is reported in up to 64% of cases of ON in children [6] . Bilateral ON and papillitis at onset are seen in 72% of children younger than 10 years of age, in comparison to older children [5] . The absence of pain and presence of retinal exudates, retinal hemorrhages, severe disk swelling, and lack of response to treatment suggest alternative diagnosis (Table 20. 2). the chronic phase, reductions in the RNLFT will be seen, with an average reduction in RNFLT of around 25% after one episode [7] . In cases of bilateral optic neuritis or MRI features suggestive of NMOSD, aquaporin-4 (AQP4) antibody should be tested (see Sect. 20.7). A proposed relationship between serum anti-MOG antibodies and recurrent ON in children has also been reported [8] .

Patients who present with ON and no lesions on MRI typically have a monophasic course and a favorable prognosis. A retrospective multicenter cohort study of 357 

Twenty percent of children with a first episode of demyelination experience transverse myelitis. The mean age of presentation is 8 years, with a bimodal distribution (children under 5 and children 10-12 years) [10, 11] . Approximately 50% of patients report a preceding infection, typically a nonspecific upper respiratory tract infection in the previous month [12] . Close to 10% of patients with acute transverse myelitis (ATM) develop MS [13] .

Acute transverse myelitis (ATM) is characterized clinically by acute or subacute development of neurologic dysfunction in motor, sensory, and autonomic nerves and may be accompanied by bowel and bladder dysfunction. Children may present with complete or partial cord syndromes, manifesting as patchy motor or sensory deficits with occasional bladder involvement. One of the most common initial symptoms in children is pain, which is seen in up to 60% of children at presentation [14] . Sensory findings may include positive symptoms, such as burning, paresthesias, hyperesthesia, or negative symptoms, such as numbness. Importantly, a clearly 20 Neuroinflammatory and Demyelinating Disorders of Childhood defined sensory level may not be evident in up to 40% of children [15] . Sphincter involvement is reported in up to 72% of children with ATM [10] . Motor symptoms are predominantly in keeping with upper motor neuron (UMN) findings, such as weakness, increased tone, and hyperreflexia in the lower extremities. Signs of spinal shock, manifesting as flaccid paresis and absent reflexes, are reported in the initial phase and may last up to 12 weeks [14] . Acute and hyperacute deficits, suggestive of a spinal cord lesion, warrant urgent spinal imaging, as an earlier intervention for vascular disorders and spinal cord compression may improve the outcome. The presence of a sensory level, radicular pain, areflexia, and failure to respond to anti-inflammatory therapies raises concern for an alternative diagnosis ( 

In ATM, MRI lesions reveal T1-isointense and T2-hyperintense signals involving the gray matter and neighboring white matter (WM) and may enhance with gadolinium. Lesions may be contiguous or patchy. Longitudinally extensive TM (LETM), defined as expanding across greater than three vertebral segments, occurs in 66-85% of ATM in children. In some patients with suggestive clinical features, the initial spine MRI may be normal and should be repeated in 24-48 h after presentation [11] . While CSF pleocytosis (>5 WBC/mm 3 ) provides supporting evidence for ATM, normal CSF results have been reported in up to 50% of pediatric patients with ATM [12] . A complete recommended workup for ADS is reviewed in Table 20 .3. In patients with ATM, a higher risk of MS is seen in those with longitudinal lesions between 1 and 3 spinal segments. Similarly, the presence of CSF oligoclonal bands increases the risk for MS [17] . If none of the inflammatory criteria is met at symptom onset, repeat the MRI and lumbar puncture evaluation between 2 and 7 days following symptom onset to meet criteria

ADEM is monophasic in 70-90% of cases. Encephalopathy and multifocal brain lesions on MRI affecting the gray and white matter of the brain and spinal cord are characteristic of ADEM. Estimated incidence is 0.2/100,000 in Canada [18] . The mean age of onset of ADEM in the pediatric population is reported to be 7.4 ± 1.3 years of age [19] . A preceding triggering event is reported in the majority of children (69%) receiving a diagnosis of ADEM [19] . In addition, ADEM has been reported following vaccinations (postimmunization encephalomyelitis). Vaccination-associated ADEM has been observed after the measles/mumps/rubella vaccinations [20, 21] . Two prospective studies of children with ADEM showed that 5-18% had a second attack suggesting MS [22, 23] .

Children with ADEM present with encephalopathy in association with multifocal neurologic deficits, which reach a nadir 4-7 days after presentation. Encephalopathy may include irritability, confusion, lethargy, and coma [24] . Prodromal symptoms can include fever, malaise, headache, nausea, and vomiting. Neurologic signs and symptoms in ADEM include long-tract signs (60-95%), acute hemiparesis (76%), cerebellar ataxia (20-65%), visual loss due to optic neuritis (7-23%), cranial nerve involvement (22-45%), seizures (13-35%), spinal cord involvement (24%), and slurred speech (5-12%) [19, 22] . Viruses that have been described in single case reports in relation to ADEM include coronavirus, coxsackie, cytomegalovirus (CMV), Epstein-Barr (EBV), herpes simplex (HSV), hepatitis A, HIV, influenza, measles, rubella, varicella zoster (VZV), West Nile, and more recently Zika [25] [26] [27] [28] [29] .Typically, there is a latency period of 7-14 days between a febrile illness and the onset of neurologic symptoms. More aggressive variants of ADEM have been described in the literature, including acute hemorrhagic leukoencephalitis and acute necrotizing encephalopathy of childhood (ANEC).

Clinical features can often help differentiate between ADEM and MS [26] . ADEM usually follows a prodromal viral illness and can be associated with fever. ADEM usually produces widespread central nervous system disturbance with impaired consciousness and/or encephalopathy, while MS typically has a relapsing-remitting course. Disease activity more than 3 months after ADEM onset is suggestive of a more chronic disorder like MS. CSF oligoclonal bands are seen most consistently in patients with MS. ADEM has a monophasic course in a majority of patients; however, multiphasic cases have been reported. As such, the International Pediatric Multiple Sclerosis Study Group (IPMSSG) proposed a consensus definition for multiphasic ADEM (Table 20 .5). It is defined as two episodes consistent with ADEM separated by 3 months that can be associated with new or reemergence of prior clinical and MRI findings [22, [30] [31] [32] . Diagnosis of MS in children with prior diagnosis of ADEM requires a second non-ADEM attack together with either further MRI findings suggestive of new lesions or a third attack not meeting the criteria for ADEM.

Initial diagnostic workup includes MRI of the brain and spine, serologic and CSF testing for infections in suspicious cases (Table 20. 3). Lesions seen on MRI in ADEM include extensive, bilateral, asymmetric patchy areas of T2-weighted hyperintensity within the white matter, deep gray nuclei, and spinal cord. Lesions in the deep gray matter involve areas of the thalamus or the basal ganglia, which often occur bilaterally and are located at the gray-white junction [22] . Any two of the following MRI features such as (1) absence of diffuse bilateral lesion pattern, (2) presence of black holes, or (3) presence of two or more periventricular lesions can help distinguish ADEM from MS with a sensitivity of 81% and specificity of 95% [20] . CSF can be normal in up to 61% of patients with ADEM [19, 33] . The CSF examination is characterized by normal opening pressure, moderate lymphocytic pleocytosis (between 50 and 180 cells/mm 2 ) and may show elevated protein (40-100 mg/dL) [19, 27] . Oligoclonal bands are infrequently seen in the CSF (10%) [34] . Despite ADEM patients commonly reporting a recent infection before their neurologic presentation, testing for viral etiologies is rarely positive (17%) [19] . • Two or more CIS separated by more than 30 days involving more than one area of brain, optic nerves, or spinal cord • One CIS associated with MRI findings consistent with the 2010 McDonald MRI dissemination in space (DIS) (≥1 T2 lesion in two of the four following locations: periventricular, juxtacortical, infratentorial, or spinal cord) and in which a follow-up MRI shows at least one new lesion consistent with dissemination in time (DIT) (simultaneous presence of asymptomatic gadolinium-enhancing and nonenhancing lesions) criteria • One clinical event (CIS) whose MRI findings are consistent with criteria for DIS and DIT • One ADEM attack followed by one CIS 3 or more months after symptom onset that is associated with new MRI findings consistent with criteria for DIS Pediatric neuromyelitis optica (revised-see Sect. 20.7)

The differential diagnosis for children with suspected first-time demyelination is broad (Table 20. 2). The workup includes neuroimaging, CSF studies, laboratory testing, and special tests (Table 20. 3).

In the absence of evidence-based data for the pediatric population with demyelinating disorders, most treatment recommendations are extrapolated from adult studies, case reports, case series, and retrospective analyses. There are no studies to date comparing the efficacy of the different immunomodulatory therapies in children with ADS. Acute management of patients with ADS is reviewed here.

Corticosteroids are the mainstay of treatment in demyelinating conditions, particularly in an acute relapse. High-dose corticosteroids suppress the immunologic activation associated with ADS and MS relapses via several mechanisms such as hindering the cytokine cascade, inhibiting the activation of T cells, facilitating the apoptosis of activated immune cells, among others [35] . The standard empiric therapy for ADS consists of high-dose corticosteroids, with 30 mg/kg/dose (maximum 1000 mg) of methylprednisolone intravenously (IV MP) once a day for 3-5 days. In adults with optic neuritis, the optic neuritis treatment trial (ONTT) showed that IV MP hastened the recovery of vision when administered in a timely manner, and decrease in recurrence rate in the first 2 years [36] . A multicenter open-label study of 12 children and 17 historical controls with severe ATM treated with IV MP showed a significant difference in the proportion of patients treated with steroids walking independently within 1 month and achieving full recovery at 1 year compared to historical controls, with no difference in the frequency of complications between the treatment group and historical controls [37] .

IVIg has an impact on inflammation by decreasing levels of cytokines, binding to antibodies against myelin, and blocking fragment crystallizable (Fc) receptors. Additionally, it may promote remyelination. IVIg use has been reported to be of benefit in small case series in steroid-refractory acute ON and ATM cases [19] . A total of 2 g/kg is administered, divided in one to five equal consecutive daily doses. Advantages include ease of administration, safety profile, and high tolerability [38] . Frequently reported side effects include headache and allergic reaction. Risk of thrombosis is increased with IVIg and should be considered and watched for.

Benefits of plasma exchange occur through the elimination of pathogenic inflammatory mediators, including autoantibodies, complement components, and cytokines [39] . Case series suggest that plasmapheresis is safe in pediatric demyelinating disorders. Furthermore, in a double-blinded randomized-controlled trial of PLEX in CNS demyelinating disease where 22 patients refractory to steroids were randomized to PLEX or sham therapy, PLEX was found to have statistically significant benefits [40] . As per the American Academy of Neurology (AAN) updated guidelines, plasmapheresis may be considered in the treatment of fulminant CNS demyelinating diseases (NMODS included) that fail to respond to high-dose corticosteroid treatment (Level C) [41] .

ATM in the context of rheumatological conditions such as systemic lupus erythematosus (SLE) has been treated with cyclophosphamide [42] .

Risk of recurrence after a single demyelinating event in youth can be stratified according to the age of presentation, CSF composition, presence of antibodies such as astrocytic water channel aquaporin-4 (AQP4) antibodies, and MRI manifestations. Children under the age of 12 presenting with an ADEM phenotype and those with CIS and no brain lesions have a low risk of developing MS (1.9-3.3%). On the other hand, children over the age of 12 presenting with multifocal lesions on brain MRI are at high risk of an eventual diagnosis of MS (60.6%) [43] . Below, we outline clinical features of the two most recognized recurrent demyelinating syndromes.

Neuromyelitis optica spectrum disorders (NMOSD) are an increasingly recognized group of disorders characterized by the presence of AQP4 antibodies [44] . The mean age at presentation ranges from 32 to 45 years in most case series [45] . Pediatric onset of the disease is relatively rare and accounts for 3-5% of all NMOSD cases. The frequency of AQP4 in children with inflammatory disorders of the CNS is 78% for relapsing neuromyelitis optica (NMO) and 20% for partial forms of NMO [46] .

While AQP4 antibodies are seen in two-thirds of pediatric patients with clinical manifestations satisfying diagnostic criteria for NMOSD [44] , more recently, antibodies to myelin oligodendrocyte glycoprotein (MOG) have been implicated as potentially pathological in individuals with clinical syndromes suggestive of NMOSD. Anti-MOG antibodies have been found to be present in children with recurrent disease who are AQP4 negative with a clinical phenotype, which includes optic neuritis, longitudinally extensive transverse myelitis, and multifocal brain lesions [47, 48] . The relevance of these antibodies for clinical practice is currently under investigation.

In 2015, the International Panel for NMOSD Diagnosis (IPND) proposed revised criteria (Table 20 .6), which addressed distinctive features of pediatric NMOSD [44] . The current diagnostic criteria divide NMOSD into two major subtypes based on the serum AQP4-IgG status. The IPND recommended the current criteria also be applied to the pediatric population, but with some minor modifications. This includes less specificity of LETM, as this can also be observed in pediatric patients with MS and ADEM, also acknowledging that AQP4-IgG is rarely positive in monophasic LETM in children. The new criteria aim to facilitate earlier and more accurate diagnosis of patients with NMOSD. This is especially important for AQP4-IgG-seronegative cases where detailed clinical, neuroimaging, and laboratory descriptions of patients will be necessary to better characterize this heterogeneous population.

Clinical features at onset include ON (most often bilateral), LETM, area postrema syndrome (intractable hiccups, nausea/vomiting), brainstem and diencephalic syndromes such as narcolepsy/hypersomnolence (Table 20 .6). In a study from the Mayo Clinic with 48 children with AQP4-IgG-positive NMOSD, at least one episode of ON or transverse myelitis was seen in 83% and 78% of children, respectively. Additionally, 45% of the cohort had other symptoms such as encephalopathy, seizures, ophthalmoparesis, ataxia, or area postrema syndrome [49] . This study also reported coexisting autoimmune disorders in 42% of their pediatric cohort (SLE, Sjögren syndrome, juvenile rheumatoid arthritis, Graves' disease). A recent prospective multicenter study compared the clinical features of pediatric NMOSD to other pediatric demyelinating diseases and validated the new 2015 IPND diagnostic criteria in children [50] . Of 38 pediatric NMO cases, 97% met the revised 2015 IPND diagnostic criteria. The mean age at onset was 10.2 ± 4.7 years. Serum or CSF NMO IgG was positive in 65% of NMO cases on initial presentation; however, a few cases became seropositive within 3 years of disease onset, supporting the notion that repeat testing up to 3-4 years should be considered in patients with a high likelihood of NMOSD. Moreover, there were no distinctive clinical features that set apart seropositive versus seronegative NMOSD patients besides a predominance of seropositivity in African-Americans compared to Caucasians.

The course of NMO is characterized by a high relapse rate with accumulation of neurologic disability [46] . One study comparing 12 individuals with pediatriconset NMOSD to those with adult onset NMOSD demonstrated a longer time to irreversible disability in those with pediatric onset disease but greater levels of visual impairment [51] .

Acute treatment follows the same algorithm discussed in Sect. 20.6. Additionally, information on three agents has been published in relation to pediatric-onset NMOSD.

• Azathioprine (AZA): Recommended dose: 2-3 mg/kg/day. AZA is a prodrug form of 6-mercaptopurine (6-MP), which works as a purine antagonist that gives negative feedback on purine metabolism and inhibits DNA and RNA synthesis. Its use is associated with relapse rate reduction in children, with 60% remaining relapse-free for 18 months [52] .

• Rituximab (RTX): Recommended dose: 375 mg/m 2 once weekly for 4 weeks or 500 mg/m 2 once, then 2 weeks later. RTX is a monoclonal antibody directed against the CD20 antigen. Use in the pediatric population is well described. A multicenter retrospective study of 16 children with NMOSD receiving more than two rituximab courses and followed for 6 years showed significant reduction of annualized relapse rate pre-and post-rituximab (p = 0.003). A close monitoring of CD19 (+) B cells is suggested, as B cell repopulation creates a risk of relapse [53] . A case series of youth with NMOSD receiving rituximab as a first-line therapy experienced complete cessation of disease activity and stabilization of neurologic disability [54] . Mycophenolate Mofetil (MMF): Recommended dose: 2000 mg/day. MMF is a prodrug that inhibits the proliferation of B and T lymphocytes. Retrospective studies including children have shown that MMF is effective in reducing relapse frequency and improving disability [55] .

Pediatric MS, defined as the onset of MS before the age of 18, is seen in 5% of MS patients, with almost three-quarters (72%) experiencing their first symptoms after the age of 12 [56] [57] [58] . The prevalence of pediatric MS is 1.35-2.5 per 100,000 children [57] and the female-to-male ratio is 2.8:1.

Diagnostic criteria for pediatric MS, based on clinical and MRI features, which support the presence of dissemination of MS events in time and space, are outlined below [32] :

• Two or more nonencephalopathic (i.e., unlike acute disseminated encephalomyelitis or ADEM), clinical central nervous system (CNS) events with presumed inflammatory cause, separated by more than 30 days and involving more than one area of the CNS. MRI is an important tool in the diagnosis of demyelinating syndromes [59] (Table 20 .5). The criterion of dissemination in space (DIS) in both pediatric and adult patients with MS can be met by the presence of at least one lesion in at least two of four typical white matter locations, including juxtacortical, periventricular, infratentorial, and spinal cord. In patients presenting with a spinal cord or brainstem syndrome, these symptomatic lesions do not count toward the MRI lesions. Dissemination in time (DIT) in older patients (older than 12 years of age) can be met at the time of a baseline scan, provided that there is evidence of both a gadoliniumenhancing and nonenhancing clinically silent lesion. Radiologically isolated syndrome (RIS) symptoms in which MRI features consistent with MS are present in the absence of clinical symptoms do not satisfy the diagnostic criteria for MS.

Clinical features of MS include visual loss, ataxia, diplopia, long-tract signs (paresthesias, weakness), urinary symptoms, and cranial nerve palsies. Older children mostly present with monofocal symptoms, whereas in younger children demyelinating events are mostly polyfocal and can be associated with encephalopathy, as described earlier in Sect. 20.7. A European observational study of 394 children with pediatric-onset MS found that children were more likely than adults to present with isolated optic neuritis, an isolated brainstem syndrome, or symptoms of encephalopathy (i.e., headache, vomiting, seizure, or altered consciousness) [60] .

A relapsing course is seen in 98% of pediatric MS cases. As in the adult population, individuals with pediatric-onset MS with a relapsing course eventually reach a stage of irreversible disability. The median time from diagnosis to this (EDSS = 4) is 20 years or at 34 years of age [61] . Children who demonstrate progressive disease at onset should be investigated for alternative diagnoses (Table 20. 2). Relapse rates are significantly higher in pediatric-onset MS than adult onset disease (0.8 in pediatriconset MS vs. 0.3 in adult onset MS, p < 0.001) [62] . A short interval between the first two demyelinating episodes and incomplete recovery after the first attack have been associated with increased risk of further attacks and/or reaching a higher disability score [63, 64] . Disease severity is currently measured by the Expanded Disability Status Scale (EDSS) that scores the disability based on the functional system scores [65] . Up to 35% of pediatric MS patients have some identifiable cognitive dysfunction at the time of diagnosis. Younger age at onset, higher EDSS score, and number of relapses together with low scores on measures of intellectual function predict greater impairment across cognitive domains [66] .

Specific CSF findings are not required for MS diagnosis. CSF pleocytosis (lymphocytic) has been described in 52-66% of pediatric MS patients, with a white blood cell (WBC) count of <60 cells/mL. Oligoclonal bands and elevated IgG index may be seen in approximately two-thirds (63% and 68%, respectively) of children older than 11 with MS, and fewer younger children (43% and 35%) [67] . Notably, however, OCBs are nonspecific markers and may be detected in 8-15% of children with monophasic demyelinating syndromes [65] .

Low vitamin D has been associated with increased risk of MS and an increased relapse rate [23, 68] . Patients usually require 800-3000 IU oral vitamin D per day to achieve normal serum levels. In children, second hand smoke has been associated with an increased risk for MS [69] .

The United States Food and Drug Administration (FDA) has not approved any of the disease-modifying therapies approved for use in adult MS and for use in pediatric MS. However, a number of treatments are currently being used off-label in these children. We have provided details regarding these therapies below.

Glatiramer acetate (GA) and interferon beta (IFN-b) have been routinely used in adults with MS for the past 15-20 years. These treatments are associated with a decrease in relapse rate of 30% [70] . There have been no randomized trials in children; however, two position papers have reported on expert consensus on the use of IFN-b and GA in pediatric patients [71, 72] . The International Pediatric Multiple Sclerosis Study Group (IPMSSG) recommends that all pediatric patients with MS should be considered for treatment with either an IFN-b or GA as first-line therapy.

In the presence of inadequate treatment response or persistent side effects, transition to a different first-line therapy or escalation to a second-line therapy should be considered.

Following the IPMSSG consensus criteria, inadequate treatment response in pediatric MS is defined as [71] :

(a) Minimum time on full-dose therapy 6 months (b) Fully compliant on treatment (c) At least one of the following:

• Increase or no reduction in relapse rate, or new T2 or contrast-enhancing lesions on MRI from pretreatment period • ≥Two confirmed relapses (clinical or MRI relapses) within a 12-month period or less 

Knowledge about pediatric demyelinating disorders has grown significantly in recent years. Above, we have provided a summary of clinical features, investigations, and both acute and prophylactic therapies in these conditions. Future multiinstitutional, international collaborative studies are needed to advance knowledge regarding therapies and outcomes of these disorders.

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Natalizumab in the pediatric MS population: results of the Italian registry

Natalizumab therapy for highly active pediatric multiple sclerosis

A placebocontrolled trial of oral fingolimod in relapsing multiple sclerosis

Relapse and disability outcomes in patients with multiple sclerosis treated with fingolimod: subgroup analyses of the double-blind, randomised, placebo-controlled FREEDOMS study

Fingolimod prescribed for the treatment of multiple sclerosis in patients younger than age 18 years

evidence report: the efficacy and safety of mitoxantrone (Novantrone) in the treatment of multiple sclerosis: report of the therapeutics and technology assessment subcommittee of the American Academy of Neurology

Mitoxantrone in progressive multiple sclerosis: a placebo-controlled, double-blind, randomised, multicentre trial

Long-term followup of pediatric patients treated with mitoxantrone for multiple sclerosis

Utility and safety of rituximab in pediatric autoimmune and inflammatory CNS disease

Rituximab use in pediatric central demyelinating disease

Intermittent cyclophosphamide pulse therapy in progressive multiple sclerosis: final report of the Northeast Cooperative Multiple Sclerosis Treatment Group

Cyclophosphamide therapy in pediatric multiple sclerosis

Daclizumab use in patients with pediatric multiple sclerosis