Pediatric Acquired Demyelinating Disorders

Abstract

PURPOSE OF REVIEW:

This article reviews the clinical presentation, diagnostic evaluation, treatment, and prognosis of the most common monophasic and relapsing acquired demyelinating disorders presenting in childhood.

RECENT FINDINGS:

Our understanding of neuroimmune disorders of the central nervous system is rapidly expanding. Several clinical and paraclinical factors help to inform the diagnosis and ultimately the suspicion for a monophasic versus relapsing course, including the age of the patient (prepubertal versus postpubertal), presence or absence of clinical encephalopathy, identification of serum autoantibodies (eg, myelin oligodendrocyte glycoprotein [MOG] and aquaporin-4), presence of intrathecally unique oligoclonal bands, and location/extent of radiologic abnormalities. Collaborative international research efforts have facilitated understanding of the safety and efficacy of currently available immunotherapies in children with acquired demyelinating disorders, particularly multiple sclerosis.

SUMMARY:

Although many of the demyelinating disorders presented in this article can affect children and adults across the age spectrum, the clinical and radiologic phenotypes, treatment considerations, and long-term prognoses are often distinct in children.

INTRODUCTION

Neuroimmune disorders of the central nervous system (CNS) encompass a wide spectrum of conditions that, collectively, are not uncommon in childhood. Many of these disorders result in acquired demyelination of the brain and/or spinal cord. Neuroimmune demyelinating disorders manifest across the age spectrum, but the clinical phenotypes, radiologic expression, treatment, and prognostic considerations are often distinct in children compared to adults. A significant subset of demyelinating disorders in children are monophasic and do not necessitate chronic immunotherapy. Accurately distinguishing monophasic disorders from those with a high propensity for a dynamic relapsing course requires close clinical and radiologic surveillance.

Our understanding of the pathobiology, classification and diagnosis, treatment, and long-term prognosis of acquired demyelinating disorders in children is rapidly growing. This growth is augmented by improved access to advanced neuroimaging, sensitive and specific autoantibody testing, consensus diagnostic criteria, international research collaborative efforts, and access to well-designed clinical drug trials. This article focuses on current knowledge and recent advances in the diagnosis and treatment of acquired demyelinating syndromes of childhood, including commonly monophasic demyelinating disorders (such as acute disseminated encephalomyelitis [ADEM], optic neuritis, and transverse myelitis) and relapsing demyelinating disorders (such as multiple sclerosis [MS], neuromyelitis optica spectrum disorder [NMOSD], and myelin oligodendrocyte glycoprotein [MOG]–associated disorders).

ACQUIRED DEMYELINATING SYNDROMES

Acquired demyelinating syndrome is an umbrella term that denotes a demyelinating event of a presumed inflammatory immune-mediated etiology that results in neurologic signs and symptoms related to the affected area(s) of the CNS. An acquired demyelinating syndrome may be classified based on the CNS location(s) and extent of involvement (eg, monofocal versus multifocal). The most common initial monofocal acquired demyelinating syndromes include optic neuritis and acute transverse myelitis; whereas, multifocal acquired demyelinating syndromes include ADEM.

The term acquired demyelinating syndrome does not denote a propensity for a monophasic course; in fact, for a subset of patients, an initial acquired demyelinating syndrome may represent the sentinel attack of a chronic demyelinating disorder such as MS. At the first presentation of an acquired demyelinating syndrome, it can be challenging to prognosticate the likelihood of a monophasic course. Several clinical, laboratory, and imaging factors can be used to predict the overall risk for relapsing disease. Still, in the majority of cases, clinician confidence regarding the course and prognosis of an acquired demyelinating syndrome necessitates close clinical and neuroimaging surveillance. This clinical vigilance is important to ensure that patients with a monophasic disorder are not inappropriately placed on chronic immunotherapy. Close monitoring also ensures that those who exhibit a propensity for ongoing CNS demyelination are classified accurately and treated early.

In general, the diagnostic evaluation for an initial acquired demyelinating syndrome includes a thorough history, physical and neurologic examination, blood/CSF testing, and high-quality neuroimaging. Although the purpose of this testing is to secure an accurate diagnosis, a thorough evaluation is equally essential for ruling out disease mimics, such as infectious, neoplastic, toxic/metabolic, or genetic etiologies. The patient history should focus on clarifying neurologic symptoms and the time course over which these symptoms evolved. Most acquired demyelinating syndromes result in continuous symptoms that exhibit a subacute course, with gradual onset and worsening over several days to weeks. A hyperacute presentation (reaching maximal severity within a few hours of onset) is less common and could be suggestive of a hemorrhagic/ischemic etiology. Further, neurologic symptoms that come and go (eg, symptoms lasting for seconds, minutes, or hours and then resolving), as opposed to those that are continuous, are more suggestive of paroxysmal disorders (eg, migraine, seizure). The history should also identify potential preceding factors, such as infection(s) or vaccine(s), travel outside of the country, insect/tick bites, rashes, or recent trauma/injury. In an initial acquired demyelinating syndrome, it is pertinent to pointedly review past neurologic symptoms with the child and their family. On deeper probing, it is not uncommon to identify previous neurologic signs and symptoms that could be attributed to a separate preceding event of inflammatory demyelination. In the author’s experience, these symptoms were either ignored by the patient as they were mild and gradually resolved or misclassified by a previous health care provider. This history is particularly important as it may provide valuable evidence of a relapsing disease course as opposed to a monophasic demyelinating syndrome.

Laboratory evaluation in a patient with an acquired demyelinating syndrome should include serum assessment for MOG and aquaporin-4 (AQP4) IgG antibodies. A rheumatologic evaluation (including antinuclear and extranuclear antibodies) is needed in patients with a history of sicca symptoms, photosensitivity, oral/nasal ulcers, arthritis, nephritis, or characteristic skin changes. An infectious evaluation may be needed based on seasonality and exposures. For example, Bartonella henselae may result in an optic neuropathy causing unilateral painless vision loss that can be mistaken for optic neuritis, and Lyme neuroborreliosis can manifest as polyradiculitis, meningitis, or encephalomyelitis. Less commonly, nutritional deficiencies may result in an acquired demyelinating syndrome–like phenotype (eg, copper deficiency myelopathy, vitamin B₁₂ deficiency optic neuropathy). CSF testing should be strongly considered in all children presenting with an initial acquired demyelinating syndrome. This evaluation should include cell counts, protein, glucose, IgG index, and oligoclonal bands (in serum and CSF). The presence of oligoclonal bands and the pattern of distribution (eg, unique to the intrathecal space versus a mirrored pattern with equivalent numbers in serum and CSF) can assist in diagnosis and prognosis for relapsing disease.

MRI of the CNS is critical in the accurate diagnosis and classification of an acquired demyelinating syndrome. MRI should be obtained with gadolinium contrast and should include the area of the CNS that is impacted (eg, MRI of the brain and orbits for an optic neuritis, MRI of the spinal cord for those with a myelitis presentation). Imaging outside the area affected can also yield important prognostic information. For example, in children presenting with acute transverse myelitis, lesions within the brain bode a significant future risk for relapse and ultimate MS diagnosis.¹

Depending on the presenting symptom, the treatment may only require reassurance and close observation. For example, in a child with an acquired demyelinating syndrome manifesting as right arm numbness without associated weakness, medical intervention may not be required, particularly if the child is already demonstrating a lack of symptom progression or evidence of recovery. For most children with an acquired demyelinating syndrome, IV methylprednisolone at a dose of 20 mg/kg/d to 30 mg/kg/d (maximum of 1 g/d) for 3 to 5 days is considered first-line treatment. An oral prednisone taper (starting at 1 mg/kg/d to 2 mg/kg/d) over 4 to 6 weeks may be considered, particularly for those with an incomplete recovery. When steroids are contraindicated or no response is seen to first-line treatment, IV immunoglobulin (IVIg) or plasma exchange may be considered. IVIg is given at a dose of 2 g/kg divided equally over 2 to 5 days. Plasma exchange involves performing 5 to 7 exchanges every other day.² No randomized trials have compared the efficacy of these two second-line options. Plasma exchange is a more invasive intervention and thus is often reserved for severe demyelination. However, it has a low risk of adverse events, and its potential benefits may not rely on time from demyelinating attack to exchange initiation. Plasma exchange is likely more effective in those with an antibody-mediated disorder (eg, AQP4, MOG).³

Optic Neuritis

Optic neuritis denotes inflammation along the course of the optic nerve and represents one of the most common acquired demyelinating syndrome subtypes, accounting for roughly one-fourth of all childhood acquired demyelinating syndrome cases.⁴ Clinically, optic neuritis manifests as reduced visual acuity, dyschromatopsia, eye pain that is worsened by eye movement, and visual field defects. The constellation of visual signs and symptoms typically evolves over several days and is persistent throughout this time. Neurologic examination may show evidence of reduced visual acuity, visual field loss, red color desaturation, an afferent pupillary defect, or optic disc edema in the acute/subacute setting.

Compared to adult-onset optic neuritis, pediatric optic neuritis is more often bilateral, particularly in children younger than 10 years of age.⁵ Children also have greater rates of optic disc edema (up to 75%) and more severe vision loss, with more than 50% of children exhibiting a visual acuity of 20/200 or worse acutely.⁶ Despite this, long-term visual recovery is greater in children with optic neuritis than in adults.⁶

The differential diagnosis of a child presenting with acute or subacute vision loss is broad (TABLE 6-1). MOG antibodies are an important component of the laboratory evaluation, with approximately 30% of all cases of pediatric MOG-associated disorders manifesting as optic neuritis.⁷ Although bilateral optic neuritis is seen in AQP4-positive NMOSD, this disorder is quite rare in childhood; however, high-titer MOG antibodies are detected in nearly 70% of children with bilateral optic neuritis.⁸ In addition to serum and CSF testing, all children with suspected or definitive optic neuritis require dedicated brain and orbital MRI. Spinal MRI should be considered in any patient with a history of myelopathic symptoms or when a high index of suspicion for relapsing demyelinating disorders that commonly affect the spine (eg, MS, NMOSD) exists. Visual evoked potential testing can be a helpful ancillary test in pediatric optic neuritis, either in the acute setting or in patients with a remote history of optic neuritis, and will often demonstrate prolonged latencies.⁹ Optical coherence tomography (OCT) quantifies retinal structure. Within the first several weeks of the onset of optic neuritis, OCT testing typically shows swelling (ie, increased thickness) of the retinal nerve fiber layer of the affected eye(s); however, in the chronic setting, OCT demonstrates thinning of the retinal nerve fiber and ganglion cell/inner plexiform layers.¹⁰

TABLE 6-1.

Differential Considerations for Children Presenting With Acquired Demyelinating Syndromes

	Autoimmune/inflammatory	Infectious	Genetic
Optic neuritis	Granulomatous (eg, sarcoidosis), rheumatologic (eg, systemic lupus erythematosus [SLE], Sjögren syndrome), neuroinflammatory (multiple sclerosis [MS], neuromyelitis optica spectrum disorder [NMOSD], myelin oligodendrocyte glycoprotein [MOG]-associated disorders)	Lyme disease, syphilis, Bartonella, tuberculosis, viral infection (eg, human immunodeficiency virus [HIV], Epstein-Barr virus [EBV], cytomegalovirus)	Hereditary optic neuropathy (eg, Leber hereditary optic neuropathy)
Transverse myelitis	Granulomatous (eg, sarcoidosis), rheumatologic (eg, SLE, Sjögren syndrome), Behçet disease, neuroinflammatory (MS, NMOSD, MOG-associated disorders, Guillain-Barré syndrome)	Acute flaccid myelitis, viral (eg, EBV, varicella-zoster virus, enterovirus, human T-cell lymphotropic virus type 1 [HTLV-1], West Nile virus) Mycoplasma, Bartonella, Lyme disease	Mitochondrial disorders (eg, Leigh syndrome, LBSL)
Acute disseminated encephalomyelitis	Granulomatous (eg, sarcoidosis), rheumatologic (eg, SLE, Sjögren syndrome), neuroinflammatory (MS, NMOSD, MOG-associated disorders)	Viral encephalitis (eg, EBV, herpes simplex virus, HIV) Lyme disease, tuberculosis, Bartonella, Rickettsia	Mitochondrial disorders (eg, polymerase gamma [POLG]-related disorders, MELAS), leukodystrophies, inborn errors of metabolism

Toxic/metabolic	Vascular/traumatic	Neoplastic
Vitamin B12 deficiency, biotinidase deficiency	Vasculitis (polyarteritis nodosa, granulomatosis with polyangiitis), ischemic optic neuropathy, traumatic optic neuropathy	Optic nerve compression, optic glioma
Vitamin B12, folate, copper, vitamin E, or biotinidase deficiency; heroin myelopathy, radiation/chemotherapy-related myelopathy	Spinal cord infarction, fibrocartilaginous embolus, arteriovenous malformation, compressive myelopathy	Intramedullary tumor (eg, astrocytoma), extramedullary tumor causing cord compression (eg, meningioma)
Carbon monoxide poisoning, neuroleptic malignant syndrome	Central nervous system vasculitis, posterior reversible encephalopathy syndrome (PRES)	Hemophagocytic lymphohistiocytosis, gliomatosis cerebri, central nervous system lymphoma, infiltrative astrocytoma

LBSL = leukoencephalopathy with brainstem and spinal cord involvement and lactate elevation; MELAS = mitochondrial encephalopathy, lactic acidosis, and strokelike episodes.

Visual recovery following optic neuritis is quite good in children, with 72% to 84% of affected eyes achieving high-contrast visual acuity of 20/40 or better.^6,11,12 More sensitive acuity testing, such as low-contrast visual acuity, demonstrates persistent visual deficits in half of pediatric patients with optic neuritis.⁶ At presentation, distinguishing optic neuritis as a monophasic acquired demyelinating syndrome from the initial manifestation of a relapsing demyelinating disorder can be aided by several paraclinical findings. The presence of AQP4 or MOG antibodies has individual implications for the risk of relapse and long-term prognosis (refer to the sections on MOG-associated disorders and NMOSD), yet the presence of either of these antibodies suggests against a future diagnosis of pediatric MS. Secondly, the likelihood of MS following an isolated optic neuritis is increasingly higher if the patient is older (eg, peripubertal/postpubertal), has at least two oligoclonal bands unique to the intrathecal space, and has concurrent demyelinating lesions within the brain outside of the optic nerve/chiasm.^5,13

Acute Transverse Myelitis

Acute transverse myelitis denotes immune-mediated inflammation within the spinal cord and comprises one-fourth of cases of initial pediatric acquired demyelinating syndromes.⁴ In childhood, acute transverse myelitis exhibits a bimodal age of distribution, typically affecting the very young (eg, <5 years of age) and the peripubertal (eg, >10 to 12 years of age).¹⁴ Clinical manifestations include muscle weakness, numbness/paresthesia, bowel or bladder dysfunction, and autonomic impairment. Acute transverse myelitis may be idiopathic, which bodes a low risk of recurrence, or it may represent the initial attack of a relapsing neuroinflammatory disorder, such as MS, NMOSD, or MOG-associated disorders.

The differential diagnosis for an initial presentation of acute transverse myelitis is presented in TABLE 6-1.

Acute flaccid myelitis is an important differential consideration in this group as its manifestations are similar to and overlap with those seen in acute transverse myelitis. Acute flaccid myelitis is characterized by injury to the anterior horn cells of the spinal cord, often resulting in monolimb flaccid weakness. Acute flaccid myelitis, unlike acute transverse myelitis, is likely secondary to direct viral infection of motor neurons (similar to that observed in poliomyelitis) and has been linked to enteroviruses.¹⁵ Acute treatments used in acquired demyelinating syndromes, such as corticosteroids, IVIg, and plasma exchange, have not demonstrated any evidence of direct benefit in acute flaccid myelitis.¹⁵ It is important to test for MOG and AQP4 antibodies as isolated acute transverse myelitis (particularly if longitudinally extensive) may be the initial manifestation of either entity. CSF testing is important to rule out alternative (eg, infectious or neoplastic) etiologies.

IV methylprednisolone is the first-line treatment for acute transverse myelitis and likely improves the chances of walking independently in addition to the chances of full neurologic recovery.¹⁶ For acute transverse myelitis in children that proves refractory to corticosteroids, plasma exchange may lead to additional functional improvement.³ Although the majority of pediatric patients with acute transverse myelitis exhibit good recovery, approximately 18% to 30% of patients will exhibit a poor outcome (ie, Expanded Disability Status Scale [EDSS] score of ≥4 or American Spinal Injury Association [ASIA] Impairment Scale grade A to C) at last follow-up.^1,17 Potential factors (at onset) that denote a higher risk of poor outcome include female sex, ASIA scale A to C at presentation, gadolinium enhancement on MRI, absence of CSF pleocytosis, and absence of cervical inflammatory lesions.¹

Approximately 17% to 29% of patients with acute transverse myelitis will relapse in the long term. The risk for a future diagnosis of MS following acute transverse myelitis is approximately 14% to 22% and is highest in those of female sex with concurrent demyelinating lesions in the brain and the presence of CSF oligoclonal bands.^1,17 Compared to adult cohorts, the presence of MOG or AQP4 antibodies is less common in pediatric acute transverse myelitis. MOG antibodies are detected in 14% (with a small minority exhibiting relapsing disease),¹⁷ and AQP4 antibodies are found in 3% (with the majority exhibiting relapsing disease) of pediatric acute transverse myelitis cohorts.^1,18

Acute Disseminated Encephalomyelitis

The clinical hallmark of ADEM is encephalopathy with multifocal neurologic signs and symptoms. ADEM predominantly affects younger prepubescent children and is typically monophasic, with a median age of onset from 5 to 8 years of age.² More than half retrospectively report a preceding infection 1 to 3 weeks before clinical onset, typically in the form of a nonspecific upper respiratory infection or gastrointestinal illness. ADEM following vaccination is rare, with less than 5% of reported cases showing a temporal association.^19–22 Prodromal symptoms of ADEM may include fever, fatigue, malaise, headache, and gastrointestinal symptoms.

The clinical manifestations of ADEM include subacute onset of encephalopathy unexplained by fever/illness or postictal symptoms in addition to multifocal neurologic abnormalities that vary based on the CNS area(s) impacted (eg, paresis with motor tract involvement, truncal or limb ataxia with cerebellar involvement). Cranial neuropathies, including the optic nerve, can be seen, and gray matter involvement is not uncommon.²³ Seizures are noted in more than one-third of pediatric patients with ADEM.²⁴

The differential diagnosis for a child with suspected ADEM is broad but can be significantly narrowed with a good history, neurologic examination, laboratory testing, and imaging (TABLE 6-1). For typical ADEM, the CSF will show evidence of a mild to moderate lymphocytic and/or monocytic pleocytosis. Intrathecal oligoclonal bands are rare but, when present, exhibit a mirrored pattern with the serum (eg, three bands in the serum and three bands in the CSF), indicating a lack of intrathecally unique bands.^20,24 MOG antibodies are detected in more than half of all pediatric patients with ADEM⁷ and should be tested for in any child presenting with an ADEM phenotype. Rarely, AQP4-positive NMOSD can present with tumefactive demyelination that mimics ADEM in children.²⁵

In addition to the clinical signs/symptoms discussed above, children with ADEM also exhibit bilateral large (>1 cm to 2 cm) T2/fluid-attenuated inversion recovery (FLAIR) hyperintense lesions that are poorly demarcated (smudgededge appearance) and predominantly involve the cerebral white matter. Gray matter involvement is not infrequent, but T1-hypointense lesions should be absent.²⁶ Gadolinium enhancement is variable, reported in one-third of cases.²⁴ Neuroimaging can be normal early in the course of ADEM; therefore, if clinical suspicion remains high, repeat imaging should be obtained.²⁷ Following treatment and clinical recovery, the majority of children exhibit complete or partial resolution of previously noted MRI abnormalities.²⁸

Treatment approaches for ADEM often include high-dose IV steroids followed by an oral prednisone taper over 4 to 6 weeks. IVIg may also be tried, either concurrent with or following corticosteroid treatment. Plasma exchange is used for fulminant ADEM or cases that prove refractory to steroids and/or IVIg (eg, lack of any clinical improvement within 2 to 3 days or lack of marked improvement within 1 to 2 weeks from treatment).

The majority of pediatric patients with ADEM experience a monophasic course with good neurologic outcomes. Repeat imaging at least 3 to 6 months following the initial attack is useful to provide a new imaging baseline for the patient and should demonstrate improvement of prior MRI abnormalities. Less than 10% of children with ADEM will experience a second demyelinating attack more than 3 months after the sentinel attack,²⁴ and the majority of these patients who relapse exhibit evidence of MOG antibodies.²⁹ When a relapse occurs, this may be a second ADEM event (multiphasic ADEM) or isolated optic neuritis (termed ADEM-ON). CASE 6-1 is an example of MOG antibody–associated ADEM-ON. Rarely, children with ADEM could go on to receive a diagnosis of MS, which requires at least one non-ADEM attack (>3 months from the initial ADEM attack) and meeting 2017 McDonald criteria for dissemination in time and space.³⁰ In these rare situations, MOG and AQP4 antibodies should be confirmed as negative before attributing a diagnosis to MS.

CASE 6–1

An 8-year-old boy presented to the hospital with increasing lethargy, gait instability, and urinary retention. The child was afebrile at presentation but had experienced a mild respiratory infection 2 weeks earlier, from which he had fully recovered.

Neurologic examination demonstrated excessive somnolence, diffuse hyperreflexia, and refusal to walk. MRI of his brain demonstrated multiple patchy asymmetric cerebral lesions within the white matter, some of which demonstrated patchy enhancement (FIGURE 6-1). MRI of his cervical spine showed a longitudinally extensive, ill-defined T2 hyperintensity from C2 to C7. CSF was significant for a white blood cell count of 100 cells/mm³ (monocytic and lymphocytic predominance) with elevated protein (68 mg/dL). Oligoclonal bands were negative. He was treated with high-dose IV methylprednisolone and exhibited a full neurologic recovery. Myelin oligodendrocyte glycoprotein (MOG) antibodies returned positive following discharge.

Twelve months later, he returned with subacute vision loss in his right eye. Neurologic examination and imaging findings were consistent with a right optic neuritis. He was treated with high-dose IV methylprednisolone with good visual recovery and was placed on chronic immunotherapy with rituximab for 2 years, after which time rituximab was discontinued. He remained neurologically stable without evidence of further relapse after treatment and is now 3 years post-rituximab discontinuation.

COMMENT

The patient in this case had relapsing MOG-associated demyelination, manifesting first as acute disseminated encephalomyelitis (ADEM) followed by a separate attack of optic neuritis 1 year later. Although the majority of pediatric patients with MOG-associated demyelination exhibit a monophasic course, relapsing disease should prompt consideration of maintenance steroid-sparing immunotherapy for at least 1 to 2 years.

Maximal recovery may take months to achieve, and previous ADEM-related neurologic symptoms may mildly reappear or become more apparent when the child experiences an illness or sleep deprivation (pseudorelapse). Problems with attention, executive function, visuomotor integration, and behavior may be noted on formalized testing in long-term follow-up.³¹ As such, detailed neuropsychological testing following ADEM is recommended and educational support (eg, an individualized education plan) is paramount for children with post-ADEM cognitive or behavioral impairments.

FIGURE 6-1.

Imaging of the patient in CASE 6-1. A, Axial fluid-attenuated inversion recovery (FLAIR) image shows patchy asymmetric cerebral white matter lesions with involvement that spans the body and splenium of the corpus callosum. B, Axial postcontrast T1-weighted image shows patchy gadolinium enhancement of many of the aforementioned lesions.

RELAPSING DEMYELINATING SYNDROMES

Relapsing demyelinating syndromes require evidence of ongoing, dynamic disease. At the initial presentation of an acquired demyelinating syndrome, this may not be readily apparent; however, evolving diagnostic criteria for these relapsing demyelinating syndromes enable a provider to make earlier (and accurate) diagnoses as opposed to waiting for a definitive second clinical event.

Multiple Sclerosis

MS is a relapsing neuroinflammatory demyelinating disease that is considered to be of autoimmune etiology. MS has peak incidence in young adults aged 20 to 30 years; however, onset of MS before the age of 18 occurs in up to 10% of cases,³² termed pediatric MS. The incidence of pediatric MS appears to vary based on geography; however, the pooled global incidence of pediatric MS is 0.87 per 100,000 individuals per year.³³

MS is a disorder of both environment and genetic/epigenetic factors.³⁴ Environmental risk factors include vitamin D deficiency,^35,36 seropositivity for remote Epstein-Barr virus infection,^36–38 smoking (passive or active),³⁹ and obesity.^40,41 Although numerous single-nucleotide polymorphisms are hypothesized to contribute to overall genetic risk, the greatest genetic contributor in children is the HLA-DRB1*1501 haplotype.⁴²

MS in childhood is almost exclusively a relapsing-remitting phenotype that is characterized by relapses (eg, period of acute/subacute neurologic dysfunction) interspersed by periods of remission (eg, neurologic recovery followed by periods of clinical stability). The progressive MS phenotype in childhood is very rare and perhaps less common than pediatric neurogenetic disorders that cause progressive neurologic decline (eg, inherited leukodystrophies, metabolic or mitochondrial disorders). Clinically, pediatric patients with MS may present with a variety of neurologic attacks followed by relapses, including optic neuritis, transverse myelitis, and brainstem/cerebellar syndromes. Compared to their adult-onset counterparts, pediatric patients with MS exhibit a more inflammatory disease course, with a clinical relapse rate that is 2 to 3 times greater⁴³ and significantly higher inflammatory lesion volumes on brain neuroimaging.⁴⁴

When a diagnosis of pediatric MS is considered, a thorough evaluation should include both CSF testing and neuroimaging of the brain and spine. A diagnosis of MS can be made clinically in a child who has two separate clinical attacks that localize to at least two of four critical CNS areas (eg, cerebellum and spinal cord). Alternatively, a child may meet the criteria for MS after a single attack if imaging provides evidence of both enhancing and nonenhancing typical demyelinating lesions in at least two of four CNS areas (eg, cortical or juxtacortical, periventricular, infratentorial brain regions, and spinal cord). For the child who meets dissemination in space criteria but does not yet meet dissemination in time criteria using clinical or radiologic end points, the presence of oligoclonal bands unique to the intrathecal space can be used to fulfill dissemination in time criteria.³⁰ An MS clinical attack (defined as an acute/subacute demyelinating event resulting in focal/multifocal neurologic dysfunction that lasts for at least 24 hours in the absence of fever/infection) is required for a diagnosis of MS. Rarely, a child may be found to have MRI findings strongly suggestive of MS without definite clinical manifestations. These imaging abnormalities may be incidentally found in children who undergo MRI for alternative reasons (eg, concussion, headache), and this clinical scenario is termed radiologically isolated syndrome. In these cases, the presence of at least two intrathecally unique oligoclonal bands in addition to demyelinating lesions within the spinal cord is associated with an increased risk of a first clinical event.⁴⁵

The 2017 McDonald criteria for MS have 71% sensitivity and 95% specificity when applied to the pediatric population, but caution should be used in children younger than 11 years of age.³⁰ In the rare circumstance in which a child with a previous history of ADEM is considered to now have possible MS, the initial ADEM attack cannot be used to achieve the required McDonald criteria. It is recommended that all children with a demyelinating syndrome undergo testing for MOG antibodies (the presence of which would argue against a diagnosis of MS); however, MOG testing does not appear to greatly improve the specificity or sensitivity of the 2017 McDonald criteria for pediatric MS.⁴⁶ Rarely, low-titer and transient MOG antibodies may be detected in typical MS and thus should not exclude a diagnosis of MS, particularly if the clinical history, neuroimaging, and CSF testing are most supportive of an MS diagnosis. CASE 6-2 is a typical example of a pediatric patient with a relapsing-remitting MS diagnosis determined at the time of the first clinical attack.

CASE 6–2

A 14-year-old previously healthy boy presented to his primary care physician with the subacute onset of left arm numbness that was followed 2 days later with left-hand weakness, such that he was no longer able to play his guitar.

Neurologic examination demonstrated left intrinsic hand weakness and sensory changes within the left arm as described above. Reflexes were 3+ in the left arm and 2+ elsewhere. Neuroimaging demonstrated multiple juxtacortical and periventricular T2-hyperintense lesions within his brain and several discrete spinal cord lesions. A single lesion within the cervical spine demonstrated associated gadolinium enhancement (FIGURE 6-2). CSF testing showed a mild lymphocytic pleocytosis (white blood cell count of 24 cells/mm³) and intrathecally unique oligoclonal bands. Once the remaining serologic and CSF evaluation returned and mimics were ruled out, he was diagnosed with relapsing-remitting multiple sclerosis (MS) and started on an appropriate disease-modifying therapy with close clinical and radiologic surveillance.

FIGURE 6-2.

Imaging of the patient in CASE 6-2. A, Axial fluid-attenuated inversion recovery (FLAIR) image shows well-circumscribed lesions in a periventricular and juxtacortical distribution. B, Sagittal T2-weighted image of the cervical spine shows several hyperintense well-circumscribed partial cord lesions.

COMMENT

This case of pediatric relapsing-remitting MS met full 2017 McDonald criteria at the time of the first clinical attack. Children with MS have a more inflammatory course, with higher relapse rates and greater brain lesion volumes. Treatment should be commenced once other diagnoses are ruled out and once the patient meets full criteria for relapsing-remitting MS.

Treatment of an MS relapse is similar to the treatment of other acquired demyelinating syndromes. Once a child has been definitively diagnosed with MS and alternative etiologies have been effectively ruled out, an appropriate disease-modifying therapy (DMT) should be initiated as early as possible. The major goals for treatment of children with MS include eliminating clinical relapses and the accrual of new lesions on MRI and halting the progression of neurologic disability.

Although several DMTs have received approval for use in adults with MS, the number of randomized controlled clinical trials assessing the safety and efficacy of these medications in children with MS is limited (TABLE 6-2). The landmark PARADIGMS (Safety and Efficacy of Fingolimod in Pediatric Patients With Multiple Sclerosis) study was a phase 3 randomized, double-blind, active-controlled, parallel-group clinical trial that compared fingolimod (n = 107) to IM interferon beta-1a (n = 108) for up to 24 months.⁴⁷ Fingolimod significantly reduced the annualized relapse rate (adjusted annualized relapse rate 0.12 versus 0.67; P<.001) and the annual rate of new/newly enlarged T2-hyperintense lesions on MRI (4.39 versus 9.27; P<.001) compared to interferon. Fingolimod also significantly reduced the number of gadolinium-enhancing lesions per scan and the annual rate of new T1-hypointense lesions compared to interferon.⁴⁸ In post hoc analyses, fingolimod significantly reduced the risk of confirmed disability progression (as measured by the EDSS) compared to interferon.⁴⁹ Although the safety profile of fingolimod in pediatric patients was relatively similar to that in adult patients, six pediatric patients (5.6%) receiving fingolimod experienced convulsions, which appears unique to the pediatric population.⁴⁷ In 2018, fingolimod was granted US Food and Drug Administration (FDA) and European Commission approval for the treatment of MS in children aged 10 years and older. At the time of this writing, it remains the only FDA-approved medication for children with MS.

TABLE 6-2.

Disease-modifying Therapies for Pediatric Multiple Sclerosis

Disease-modifying therapy	Dosing	Side effects in children	Monitoring considerations in children	Highest level of evidence for children
Injectable therapies
Interferon beta-1a and -1b	IM or subcutaneous injection provided as frequently as every other day to as infrequently as once every 2 weeks	Flulike symptoms, injection site reactions, depression, leukopenia, elevated transaminases	Monitoring: blood counts and hepatic function testing every 6 months and thyroid function annually	Retrospective, observational,97–103 and prospective database104
Glatiramer acetate	Subcutaneous injection provided daily or 3 times a week	Injection site reactions, lipoatrophy, postinjection systemic reaction	Monitoring: no laboratory monitoring required	Retrospective, observational,103,105 and prospective database104
Oral therapies
Fingolimoda	If child is <10 years of age and weighs ≤40 kg, dosage is 0.25 mg/d orally; if child is ≥10 years of age and weighs >40 kg, dosage is 0.5 mg/d orally	Headache, lymphopenia, seizures,b first-dose bradycardia, transaminase elevation, infection, skin cancer, macular edema	Pretreatment: ophthalmologic examination, blood counts, hepatic function, 12-lead ECG, varicella-zoster virus IgG Day of treatment start: first-dose 6-hour observation with blood pressure checks and ECG On-treatment monitoring: blood counts and hepatic function every 3–6 months; ophthalmologic examination at 4 months; annual dermatology screen	Phase 3 randomized controlled trial in children aged 10 to 17 years,47 with primary end point annualized relapse rate (0.12 with fingolimod versus 0.67 with interferon beta-1a; absolute difference 0.55 relapses; 95% confidence interval, 0.36–0.74; P < 0.001)
Teriflunomide	7 mg/d orally for 8 weeks followed by 14 mg/d orally	Headache, elevated transaminases, hair thinning, gastrointestinal intolerance, peripheral neuropathy, pancreatitis,b increased risk of infection, embryofetal toxicity	Pretreatment: blood counts, hepatic function, tuberculosis screening, blood pressure check, pregnancy test On-treatment monitoring: hepatic function monthly for first 6 months, blood counts every 6 months, intermittent blood pressure checks	Phase 3 randomized placebo-controlled trial in children aged 10 to 17 years, with primary end point time to first relapse (teriflunomide at 75.3 weeks versus placebo at 39.1 weeks; hazard ratio, 0.66; 95% confidence interval, 0.39–1.1; P = 0.29)
Dimethyl fumarate	240 mg orally 2 times a day	Gastrointestinal intolerance, flushing, lymphopenia, transaminase elevation	Pretreatment: blood counts and hepatic function On-treatment monitoring: blood counts and hepatic function every 3–6 months	Phase 2 open-label study in children aged 10–17 years (n = 22); safety profile consistent with adult trials106,107; phase 3 randomized controlled trial of dimethyl fumarate versus interferon beta-1a is ongoing, with primary end point proportion of participants free of new/newly enlarging T2 brain lesions
Infusion therapies
Natalizumab	6 mg/kg dose (up to 300 mg) IV every 4 weeks	Headache, hypersensitivity reaction, transaminase elevation, progressive multifocal leukoencephalopathy	Monitoring: JC virus antibodies every 3–6 months in addition to periodic blood counts and hepatic function testing	Retrospective cohort108–110 and prospective database111
Rituximab	750 mg/m2/dose (up to 1 g) IV every 2 weeks for 2 doses followed by 750 mg/m2/dose (up to 1 g) IV once every 6 monthsc	Rash, hypotension, lymphopenia, nausea/vomiting, hypogammaglobulinemia, infusion reaction/anaphylaxis, increased risk of infection, hepatitis B reactivation	Pretreatment: blood counts, hepatic function, hepatitis B profile, IgG level On-treatment monitoring: CD19 counts monthly starting 3 months after infusion, hepatic function and blood counts every 6 months, and IgG level yearly	Retrospective cohort112,113
Cyclophosphamide	Monthly IV dosing titrated per individual patient absolute lymphocyte counts	Gastrointestinal intolerance, cytopenias, increased risk of infection, amenorrhea, alopecia, hemorrhagic cystitis, infertility, secondary malignancies	Pretreatment: blood counts and urinalysis On-treatment monitoring: blood counts at 1, 2, and 4 weeks postinfusion; urinalysis at each infusion	Retrospective cohort114

ECG = electrocardiogram; IgG = immunoglobulin G; IM = intramuscular; IV = intravenous.

^aUS Food and Drug Administration (FDA)–approved for the treatment of pediatric patients with multiple sclerosis.

^bAdverse effects that were unique to the pediatric clinical trials.

^cEarlier dosing of anti-CD20 therapy may be employed based on when the CD19 count shows evidence of repopulation.

TERIKIDS (Efficacy, Safety and Pharmacokinetics of Teriflunomide in Pediatric Patients With Relapsing Forms of Multiple Sclerosis) was a phase 3 randomized double-blind clinical trial that assessed the safety and efficacy of teriflunomide (n = 109) compared to placebo (n = 57) in children aged 10 to 17 years for up to 24 months. Teriflunomide prolonged the median time to first clinical relapse; however, the difference was not significant (75.3 weeks versus 39.1 weeks; hazard ratio, 0.66; 95% confidence interval, 0.39 to 1.1; P=.29) and thus, TERIKIDS did not meet its primary end point. Teriflunomide did significantly reduce the number of new/enlarging T2-hyperintense lesions (−55%, P=.0006) and gadolinium-enhancing lesions (−75%, P<.0001) relative to placebo. The safety profile was generally consistent with adult data; eight patients discontinued treatment with teriflunomide in the open-label portion of the study because of elevated transaminases, pancreatitis, and peripheral neuropathy.⁵⁰ The FDA rejected approval of teriflunomide for the treatment of pediatric MS; however, the European Commission approved teriflunomide for the treatment of pediatric patients aged 10 to 17 years.

Other clinical trials studying the safety and efficacy of DMTs in children with MS are under way, including clinical trials for dimethyl fumarate (CONNECT [Phase 3 Efficacy and Safety Study of BG00012 in Pediatric Subjects With Relapsing-remitting Multiple Sclerosis]), peginterferon beta-1a (A Study to Evaluate the Safety, Tolerability, and Efficacy of BIIB017 [Peginterferon Beta-1a] in Pediatric Participants for the Treatment of Relapsing-Remitting Multiple Sclerosis), alemtuzumab (LemKids [A Study to Evaluate Efficacy, Safety, and Tolerability of Alemtuzumab in Pediatric Patients With RRMS With Disease Activity on Prior DMT]), ocrelizumab (Operetta 2 [A Study to Evaluate Safety and Efficacy of Ocrelizumab in Comparison With Fingolimod in Children and Adolescents With Relapsing-Remitting Multiple Sclerosis]), and ofatumumab and siponimod (NEOS [Efficacy and Safety of Ofatumumab and Siponimod Compared to Fingolimod in Pediatric Patients With Multiple Sclerosis]).^51–55

The majority of children/teenagers can provide valuable insight into their ability and willingness to adhere to a given DMT based on its form of administration, frequency of dosing, and side effect profile. Adherence rates for DMTs in youth with MS may be similar to those in the adult MS population, and parental involvement appears to associate with greater adherence.⁵⁶ The potential risk of side effects must be fully discussed with each child and family unit. Pretreatment laboratory evaluation may play a large role in these discussions; for example, a child who is strongly positive for the JC virus may consider treatment with natalizumab too high of a risk. Likewise, treatment with anti-CD20 monoclonal antibody therapies may be less than ideal for an adolescent with remote infection with hepatitis B.

The clinical impact and efficacy of MS DMTs appear to be highly associated with age, with youth with MS deriving the greatest benefits. The efficacy of these treatments on MS disability declines with advancing age,⁵⁷ arguing in favor of treating children with MS early with DMTs that effectively eliminate clinical and radiologic progression while maintaining or enhancing overall quality of life. Further, pediatric patients with MS treated with newer higher-efficacy DMTs (eg, fingolimod, dimethyl fumarate, teriflunomide, natalizumab, ocrelizumab, rituximab) exhibit lower rates of clinical relapses, new/enlarging T2-hyperintense lesions, and gadolinium-enhancing lesions.⁵⁸ Because of this, lower-efficacy medications (eg, injectable interferons and glatiramer acetate) are now less utilized in pediatric MS,⁵⁹ in part because of their modest reduction in disease activity and less than desirable route/frequency of administration.

Six months after starting a patient on a DMT, the author performs an MRI with contrast to establish a new baseline for the patient. Evidence of multiple gadolinium-enhancing lesions on this scan may prompt consideration of switching versus maintaining the current DMT along with earlier neuroimaging follow-up (eg, 3 to 6 months), as most DMTs reach full efficacy within the first 4 to 6 months of initiation. Following the new baseline imaging, surveillance noncontrast MRIs every 6 to 12 months are recommended if no concern exists for relapse or clinical instability. If concern for relapse is present, gadolinium contrast is used. If a patient admits to poor adherence or intolerable side effects, a change in DMT should be strongly considered. “Treatment failure” is defined differently by each treating neurologist (and family unit); however, in general, treatment failure should be declared with any confirmed clinical relapse or new T2-hyperintense lesions in the setting of good adherence.

Because the majority of pediatric patients with MS are of reproductive age, the importance of contraception must be discussed at (or before) DMT initiation and regularly thereafter. According to the pre-2015 letter category ratings, all DMTs are considered pregnancy Category C or higher (with the exception of glatiramer acetate). Teriflunomide is pregnancy Category X because of its high risk of teratogenicity.

In conjunction with DMT initiation, children with MS and their families should be counseled on modifiable risk factors that may impact their MS, including smoking (passive or active),⁶⁰ vitamin D deficiency,⁶¹ diet quality,⁶² obesity⁶³ or sedentary lifestyle.⁶⁴ Cognitive impairment in children with MS affects up to one-third of patients⁶⁵ and is more common than in those with adult-onset disease, independent of disease duration.⁶⁶ For this reason, it is recommended to obtain a full neuropsychologic evaluation on all pediatric patients with MS within the first year of diagnosis. Findings from this testing can be used by the school to implement an individualized education plan to help overcome MS-related cognitive obstacles.

Natural history studies show that patients who have onset of MS before the age of 18 years (pediatric onset) take longer to reach sustained neurologic disability milestones compared to those with adult-onset disease; however, patients with pediatric onset ultimately reach these milestones at a younger age overall.^67,68 Compared to a matched non-MS reference population, patients with pediatric-onset MS are less likely to attend college, earn lower yearly incomes, and have a higher rate of use of disability benefits as working adults.⁶⁹ Currently, long-term natural history data are unavailable to provide insight into the impact of the current treatment approach on long-term outcomes in patients with pediatric-onset MS. Earlier diagnosis, more timely DMT initiation, and more stringent criteria for treatment failure are individual factors that likely impact the long-term outcomes of children with MS, although the degree of this impact is currently unknown.

Neuromyelitis Optica Spectrum Disorders

Distinct from MS, NMOSD is a CNS inflammatory disorder that preferentially affects the optic nerves and spinal cord but can also involve the area postrema, hypothalamus, and periaqueductal gray. NMOSD is much less common in children, with pediatric NMOSD accounting for 2% to 5% of all NMOSD cases.^18,70 Although AQP4 antibodies are found in approximately one-half to two-thirds of children with NMOSD,¹⁸ MOG antibodies have been detected in cases of AQP4-negative NMOSD. In fact, one study found that in 33 pediatric patients with NMOSD, 42% had AQP4 antibodies, 40% had MOG antibodies, and the remaining 18% were seronegative for both AQP4 and MOG.⁷¹ The median age of onset in pediatric NMOSD ranges from 10 to 14, and a female predominance is seen, particularly when onset occurs in the teenage years.^18,72,73 Pediatric NMOSD prevalence is higher in people of color.¹⁸

The first clinical manifestations of pediatric NMOSD often include unilateral or bilateral optic neuritis, transverse myelitis, and brainstem/cerebellar syndromes. Simultaneous optic neuritis and transverse myelitis are seen in a minority of pediatric patients at the initial attack. When the area postrema is involved, hiccups and/or intractable vomiting may be part of the initial manifestations.¹⁸ Given that the diencephalon can be affected, more than half of all children with NMOSD may exhibit evidence of endocrinopathies, including hyponatremia, morbid obesity, amenorrhea, and hyperinsulinism.⁷⁴ Pediatric NMOSD can coexist with systemic autoimmune disorders, such as systemic lupus erythematosus, Sjögren syndrome, and Graves disease.

In any child presenting with suspected NMOSD, serum MOG and AQP4 antibodies should be checked. The majority of children with AQP4-positive NMOSD will have detectable antibodies at presentation. However, a subgroup of children may not exhibit evidence of AQP4 IgG until later in the disease course, and thus AQP4 antibodies should be rechecked periodically when a high index of suspicion exists. CSF often shows evidence of a lymphocytic or neutrophilic leukocytosis, and protein and IgG index may also be elevated. Intrathecally unique oligoclonal bands are seen in less than one-third of pediatric patients.^18,75

Neuroimaging in pediatric NMOSD may mimic other pediatric acquired demyelinating syndromes but has some distinctive attributes. Optic neuritis in the setting of NMOSD often exhibits longitudinally extensive T2/FLAIR hyperintensities extending posteriorly along the optic tract and into the chiasm. Longitudinally extensive transverse myelitis often involves the central cord and extends for at least three spinal cord segments. Additionally, T2-hyperintense lesions may be noted within the diencephalon and brainstem, particularly in areas juxtapositioned to the ventricles as these areas have high AQP4 expression. T1-hypointense lesions or gadolinium enhancement, or both, can be noted in a subset of children.⁷⁶ Large tumefactive lesions within the cerebral hemispheres may be observed in a small subset of children with AQP4-positive NMOSD.⁷²

The diagnostic criteria for NMOSD in pediatric patients are the same criteria used for adult patients with NMOSD⁷⁷ but with some important considerations. Firstly, longitudinally extensive transverse myelitis is not specific to pediatric NMOSD and can be seen in the setting of ADEM, MOG-associated disorders, and MS. In addition, the clinical and radiologic presentation of NMOSD may have features that mimic ADEM, such as the presence of encephalopathy and multifocal demyelination. It is important to note that children with ADEM should not have AQP4 IgG. Further, the presence of MOG antibodies (and absence of AQP4 antibodies) may assist in correctly categorizing and prognosticating the risk of recurrence for this subgroup of children.

Treatment of acute attacks includes high-dose IV methylprednisolone for 3 to 5 days, although plasma exchange should be employed early if little to no neurologic recovery is seen, given the propensity for disability accumulation in NMOSD. The majority of pediatric NMOSD cases (>90%) exhibit a relapsing course,⁷² and thus chronic preventive immunotherapy is often required to reduce the risk of future relapses and accumulating neurologic disability. No therapies are currently FDA approved for use in children with NMOSD. Retrospective studies have shown benefit with mycophenolate mofetil (titrated over 3 to 4 weeks to goal dosing of 600 mg/m² 2 times a day, maximum of 1 g 2 times a day),⁷³ azathioprine (2 mg/kg/d to 3 mg/kg/d),⁷⁸ and rituximab (dosed as noted in TABLE 6-2),^74,75 and a small case series supports the use of tocilizumab (8 mg/kg every 4 weeks, maximum of 800 mg per dose).⁷⁹ The author typically avoids azathioprine in children given its higher risk of intolerable side effects. Currently, a small (N = 15 subjects) open-label single-arm trial is seeking to evaluate the safety and efficacy of eculizumab in pediatric NMOSD.⁸⁰

AQP4-positive NMOSD is a highly relapsing disorder that can lead to significant permanent neurologic disability at an early age. The median time to a second attack is 4 to 8 months, and a more aggressive disease course (including a shorter time to second attack) is observed in patients of color.^72,75 When followed for up to 4 years, moderate neurologic disability (ie, EDSS score ≥3) is noted in nearly half of pediatric patients with AQP4-positive NMOSD. One-third of patients exhibit visual acuity of 20/200 or less, and persistent motor deficits are seen in approximately 20% of patients. Predictors of poorer neurologic outcomes include younger age at onset, those with optic neuritis as a first attack, and higher EDSS scores at the clinical nadir. Cognitive deficits are noted in one-fourth of patients. Patients who have a younger age at onset and those with brainstem/cerebral attacks are at highest risk for cognitive impairments.⁷⁵

Compared to AQP4-positive NMOSD, the current literature suggests that children with MOG-positive NMOSD have a lower propensity for relapse and better visual/motor outcomes (refer to the section on MOG-associated demyelination).⁸¹ Although the treatment and long-term outcomes of children with MOG-positive NMOSD need further exploration, the available research supports treating these patients similar to children with other MOG antibody–associated disorders as opposed to children with AQP4-positive NMOSD.

Myelin Oligodendrocyte Glycoprotein–associated Demyelination

MOG is a protein expressed exclusively in the CNS on the surface of myelin. Anti-MOG antibodies are detected in one-third of all children at the time of initial onset of acquired demyelinating syndrome.⁸² The incidence of MOG-associated demyelination is higher in children (0.31 per 100,000) than in adults (0.13 per 100,000) and occurs with a relatively equal sex ratio, particularly in younger children.⁸³

The clinical presentation of children with MOG-associated demyelination most commonly includes ADEM and optic neuritis; less common are acute transverse myelitis, AQP4-negative NMOSD, non-ADEM encephalitis, and brainstem syndromes.⁷ The phenotype of MOG-associated demyelination is somewhat age dependent, with younger children presenting with ADEM spectrum disorders, whereas older children (>11 years of age) tend to manifest with optic neuritis.⁸² CASE 6-3 is an example of pediatric optic neuritis associated with MOG antibodies.

CASE 6–3

A 6-year-old girl presented to the emergency department after several days of headaches, pain with eye movements, bumping into things at home, and difficulty seeing pictures on her dad’s smartphone. In the previous 2 weeks, she had experienced recurrent fevers in association with abdominal pain that had been labeled as nonspecific viral gastroenteritis.

Neurologic examination was significant for bilateral dyschromatopsia, optic disc edema, and reduced visual acuity of 20/200 in the right eye and 20/400 in the left eye. MRI of her brain and orbits demonstrated increased T2 signal and gadolinium enhancement of both optic nerves (left more than right). In addition, several callosal and deep white matter T2 hyperintensities were seen in both cerebral hemispheres without associated enhancement, with the largest measuring 1 cm in greatest diameter (FIGURE 6-3). CSF analysis demonstrated a lymphocytic pleocytosis, with 27 cells/mm³, protein of 28 mg/dL, and glucose of 51 mg/dL. Oligoclonal bands were negative, and IgG index was within normal limits.

She was treated with high-dose IV steroids and experienced good visual recovery. One week after discharge, serum myelin oligodendrocyte glycoprotein (MOG) testing returned positive.

COMMENT

MOG antibodies are detected in approximately one-third of pediatric patients with optic neuritis.⁷ The detection of these antibodies is important for prognostication discussions with families. The majority of pediatric patients with MOG-associated disorders experience good recovery and exhibit a monophasic course. The presence of MOG antibodies (particularly those with high titers) suggests against a future diagnosis of multiple sclerosis.⁸⁴ Children with MOG-positive optic neuritis can exhibit T2/fluid-attenuated inversion recovery (FLAIR)–hyperintense lesions outside of the optic nerve; however, these tend to be small and nonspecific.⁸⁵

FIGURE 6-3.

Imaging of the patient in CASE 6-3. A, Axial postcontrast T1-weighted MRI shows anterior segment longitudinal enhancement of the bilateral optic nerves (left greater than right). B, Sagittal fluid-attenuated inversion recovery (FLAIR) image of the brain shows a hyperintense lesion (arrow) in the callosal white matter not involving the callosal septal interface.

No clinical or radiologic features of MOG-positive ADEM reliably differentiate it from seronegative ADEM; however, patients who are MOG positive are more likely to have spinal cord involvement and complete radiologic resolution in long-term follow-up.²⁹ A higher risk of post-ADEM seizures exists in patients with MOG antibodies.⁸⁶ A leukodystrophylike pattern has been described in pediatric patients with MOG antibodies and is often noted in those with younger age.⁸⁷ In patients with MOG-positive optic neuritis, optic nerve involvement is more likely to be bilateral and longitudinal and preferentially involves the anterior optic pathway as compared to seronegative optic neuritis.⁷

Relapsing MOG-associated disorders can occur in a subset of pediatric patients (less than 50%) and most commonly is restricted to the optic nerve or spinal cord. Children exhibit a lower risk of relapse than adult patients.⁸⁸ Clinical relapse may occur in one-fourth of children presenting with MOG-positive optic neuritis. A relapsing course occurs in less than 10% of patients with MOG-positive ADEM. Children who remain seropositive for MOG antibodies are at higher risk for relapse compared to those who convert to seronegative (38% versus 13%); however, patients who are seronegative for MOG antibodies and patients with a fluctuating serostatus can also experience relapsing disease.⁸²

Serum MOG testing should be considered in any child presenting with an acquired demyelinating syndrome, myelitis (including acute flaccid myelitis), or encephalitis. CSF rarely (approximately 10% of cases) shows evidence of intrathecally unique oligoclonal bands. A CSF lymphocytic or monocytic pleocytosis can be seen in more than half of children.⁸⁹ MOG antibody testing is typically completed in the blood, although recent evidence suggests that a subset of patients may exhibit evidence of MOG antibodies unique to the intrathecal space.⁹⁰ The value of long-term monitoring of MOG IgG serostatus remains unclear. Although persistence of MOG antibodies may be associated with a higher risk of relapse,⁹¹ patients who become seronegative can seroconvert back to positive. Further, the majority of children (72%) with persistent MOG positivity (followed for a median of 4 years) do not experience a second attack.⁸² Thus, the utility of long-term MOG antibody titer surveillance requires further research, and decisions on implementation of chronic immunotherapy in children should not be based solely on persistent MOG IgG positivity.

The first-line treatment of an acute attack is similar to that noted above for individual acquired demyelinating syndromes. A subset of patients who are MOG seropositive may exhibit worsening or rebounding symptoms as corticosteroids are weaned and thus may require a slower taper over time. In most situations, chronic immunotherapy is not used after the first demyelinating attack, given that the majority of pediatric patients with MOG exhibit a monophasic course. The author considers use of chronic immunotherapy after a first attack when the patient exhibits marked residual neurologic impairments following adequate acute treatment and time for recovery. For example, the author may be more likely to initiate chronic immunotherapy in a child who experiences MOG-associated unilateral optic neuritis with subsequent poor visual recovery given the future risk of significant impairment should a second event of optic neuritis affect the other eye.

For patients who experience a clinical relapse, maintenance immunotherapy is strongly recommended. Although MS DMTs are not effective for relapsing MOG-associated demyelination, monthly IVIg, anti-CD20 therapies (rituximab), mycophenolate mofetil, and azathioprine have demonstrated benefits.^91,92 The duration of maintenance immunotherapy remains unclear; however, the author considers using chronic immunotherapy for at least 1 to 3 years following the last relapse. Before discontinuation of treatment, the provider, patient, and their family should have a detailed discussion of relapse risk versus the associated risks of a given long-term immunotherapy.

Many children with MOG-associated disorders experience a monophasic course (particularly if the presenting phenotype is ADEM) and good functional outcomes. Compared to adults, children exhibit better neurologic recovery, with complete recovery occurring in 75% to 96% of all children.⁸⁸ Cognitive concerns are more prominently noted in children who are younger (ie, younger than 10 years of age) with intracranial demyelination (eg, ADEM).⁹³ Silent brain lesions develop in the minority (14%) of children with MOG-associated demyelination and typically occur within the first few months after the onset of the clinical event. The formation of new clinically silent lesions has a low positive predictive value for relapsing disease and thus, in isolation, should not prompt initiation of chronic immunotherapy.⁹⁴

TRANSITION OF CARE

In adolescents with a chronic neuroinflammatory disease, the transition of care from a pediatric neurologist to adult-based care is most often a time of apprehension. In particular, patients with higher neurologic disability and/or cognitive impairments may find themselves less ready for the transition.⁹⁵

When transitioning youth, the author will often “sandwich” pediatric neurology visits with the initial adult provider visit. This provides the pediatric neurologist with the chance to reassess the patients’ acceptance, willingness, and preparedness to engage and establish treatment with the selected adult-based provider. Additional troubleshooting for successful transition can be done at this visit based on any concerns raised. Other ways to ease the transition include joint appointments with the pediatric and adult MS neurologists or having the pediatric provider see the transitioning patient in the adult MS clinic for one or two visits before handing off care.

CONCLUSION

Acquired inflammatory demyelination is not uncommon in children. Accurately distinguishing monophasic from relapsing disease is of paramount importance given the obvious implications of diagnosing a child with a chronic neuroinflammatory disease. To this end, close longitudinal clinical and radiologic surveillance is needed. Further, autoantibody testing has helped to define and categorize specific subtypes of demyelinating disorders of childhood.

Although rigorous clinical trials have yet to be conducted in rare pediatric demyelinating disease subtypes (eg, NMOSD), at least one MS DMT is now FDA and European Commission approved for the treatment of pediatric MS and several other therapies are under active study. The progress toward clinical trials in children with MS is highly promising; however, unique obstacles must be considered as new trials are developed, including the relative rarity of pediatric MS, ethical considerations around the study of children with a highly inflammatory disease, and thoughtful selection of meaningful feasible study end points. The International Pediatric Multiple Sclerosis Study Group has put forth recommendations for future development of clinical trials in children with MS.⁹⁶

The importance of assessing long-term safety and disease stability/progression in children with MS using highly effective DMTs cannot be overstated. The therapeutic decisions made early in the course of an MS diagnosis likely have long-term implications for the future well-being and functioning of patients. Although high-efficacy DMTs appear effective in children, the long-term safety and impact on future neurologic function and cognitive disability requires further study.

KEY POINTS.

• Neuroimmune demyelinating disorders manifest across the age spectrum, but the clinical phenotypes, radiologic expression, treatment, and prognostic considerations are often distinct in children compared to adults.

• Clinical vigilance is important to ensure that patients with a monophasic disorder are not inappropriately placed on chronic immunotherapy. Close monitoring also ensures that those who exhibit a propensity for ongoing central nervous system demyelination are classified accurately and treated early.

• CSF testing should be strongly considered in all children presenting with an initial acquired demyelinating syndrome. This evaluation should include cell counts, protein, glucose, IgG index, and oligoclonal bands (in serum and CSF).

• Compared to adult-onset optic neuritis, pediatric optic neuritis is more often bilateral, particularly in children younger than 10 years of age. Children also have greater rates of optic disc edema (up to 75%) and more severe vision loss, with more than 50% of children exhibiting a visual acuity of 20/200 or worse acutely.

• Myelin oligodendrocyte glycoprotein (MOG) antibodies are an important component of the laboratory evaluation of a child presenting with acute or subacute vision loss, with approximately 30% of all pediatric MOG-associated disorder cases manifesting as optic neuritis.

• The likelihood of multiple sclerosis (MS) following an isolated optic neuritis is increasingly higher if the patient is older (eg, peripubertal/postpubertal), has at least two oligoclonal bands unique to the intrathecal space, and has concurrent demyelinating lesions within the brain outside of the optic nerve/chiasm.

• The risk for a future diagnosis of MS following acute transverse myelitis is approximately 14% to 22% and is highest in those of female sex with concurrent demyelinating lesions in the brain and the presence of CSF oligoclonal bands.

• The clinical manifestations of acute disseminated encephalomyelitis (ADEM) include subacute onset of encephalopathy unexplained by fever/illness or postictal symptoms in addition to multifocal neurologic abnormalities that vary based on the central nervous system area(s) impacted.

• MOG antibodies are detected in more than half of all pediatric patients with ADEM and should be tested for in any child presenting with an ADEM phenotype.

• Less than 10% of children with ADEM will experience a second demyelinating attack more than 3 months after the sentinel attack, and the majority of these patients who relapse exhibit evidence of MOG antibodies.

• The progressive MS phenotype in childhood is very rare and perhaps less common than pediatric neurogenetic disorders that cause progressive neurologic decline (eg, inherited leukodystrophies, metabolic or mitochondrial disorders).

• Compared to their adult-onset counterparts, pediatric patients with MS exhibit a more inflammatory disease course, with a clinical relapse rate that is 2 to 3 times greater and significantly higher inflammatory lesion volumes on brain neuroimaging.

• The 2017 McDonald criteria for MS have 71% sensitivity and 95% specificity when applied to the pediatric population, but caution should be used in children younger than 11 years of age.

• In 2018, fingolimod was granted US Food and Drug Administration and European Commission approval for the treatment of MS in children aged 10 years and older.

• The clinical impact and efficacy of MS disease-modifying therapies appear to be highly associated with age, with youth with MS deriving the greatest benefits. The efficacy of these treatments on MS disability declines with advancing age, arguing in favor of treating children with MS early with disease-modifying therapies that effectively eliminate clinical and radiologic progression while maintaining or enhancing overall quality of life.

• Cognitive impairment affects up to one-third of children with MS and is more common than in those with adult-onset MS, independent of disease duration.

• Longitudinally extensive transverse myelitis is not specific to pediatric neuromyelitis optica spectrum disorder (NMOSD) and can be seen in the setting of ADEM, MOG-associated disorders, and MS. In addition, the clinical and radiologic presentation of NMOSD may have features that mimic ADEM, such as the presence of encephalopathy and multifocal demyelination.

• Aquaporin-4–positive NMOSD is a highly relapsing disorder that can lead to significant permanent neurologic disability at an early age.

• Anti-MOG antibodies are detected in one-third of all children at the time of initial onset of an acquired demyelinating syndrome.

• The phenotype of MOG-associated demyelination is somewhat age dependent, with younger children more likely to present with an ADEM phenotype and older children (>11 years of age) more likely to present with optic neuritis.

• Children who remain seropositive for MOG antibodies are at higher risk for relapse compared to those who convert to seronegative (38% versus 13%); however, patients who are seronegative for MOG antibodies and patients with a fluctuating serostatus can also experience relapsing disease.

• Many children with MOG-associated demyelination experience a monophasic course (particularly if the presenting phenotype is ADEM) and good functional outcomes. Compared with adults, children exhibit better neurologic recovery, with complete recovery occurring in 75% to 96% of all children.