INTRODUCTION — Differential diagnostic considerations for acute central nervous system demyelination in children include acute disseminated encephalomyelitis (ADEM), multiple sclerosis (MS), optic neuritis, transverse myelitis, neuromyelitis optica (Devic disease), and various infectious, metabolic, and rheumatologic conditions (table 1). Most of these conditions are thought to be caused by immune system dysregulation triggered by an infectious agent in a genetically susceptible host.

With the possible exception of the neuromyelitis optica immunoglobulin G (NMO-IgG) autoantibody found in neuromyelitis optica, there are no disease-specific biomarkers for these conditions, making it difficult to distinguish among them at the time of the initial presentation. However, certain clinical features, laboratory results, and imaging findings can usually lead to the correct diagnosis. Multiple sclerosis is to a large extent still a diagnosis of exclusion, and therefore requires intense investigation for other conditions that might present in a similar manner.

ACUTE DISSEMINATED ENCEPHALOMYELITIS — Acute disseminated encephalomyelitis (ADEM) is characterized by acute or subacute onset of multifocal neurologic deficits with encephalopathy, often following a viral illness. Additional typical signs associated with ADEM are headache, fever, or meningismus. Magnetic resonance imaging (MRI) demonstrates widespread asymmetric white and gray matter abnormalities (table 2). (See "Acute disseminated encephalomyelitis (ADEM) in children: Pathogenesis, clinical features, and diagnosis" and "Acute disseminated encephalomyelitis (ADEM) in children: Treatment and prognosis".)

In its classic form, ADEM is a monophasic disease, although the clinical features can fluctuate in severity and evolve in the first three months following disease onset [1]. However, relapsing ADEM (ie, multiphasic ADEM) has been reported in a minority. Multiphasic ADEM is defined as two episodes consistent with ADEM separated by three months, irrespective of glucocorticoid use, but not followed by any further events. The second ADEM event can involve either new or a re-emergence of prior neurologic symptoms, signs and MRI findings. Relapses beyond a second event are not consistent with ADEM according to current diagnostic criteria, but rather indicate a chronic disorder such as multiple sclerosis or neuromyelitis optica [1].

Acute hemorrhagic leukoencephalitis — Acute hemorrhagic leukoencephalitis is a rare entity that represents a more severe and fulminant form of ADEM and is associated with diffuse central nervous system hemorrhage. (See "Acute disseminated encephalomyelitis (ADEM) in children: Pathogenesis, clinical features, and diagnosis", section on 'Acute hemorrhagic leukoencephalitis'.)

MULTIPLE SCLEROSIS — Multiple sclerosis (MS) is a chronic disease characterized by recurrent episodes of demyelination in the central nervous system separated in space and time. Acute inflammation and demyelination in a critical area of the brain, optic nerves, or spinal cord will produce a corresponding clinical deficit.

Pediatric MS is briefly reviewed here, and discussed in detail separately. (See "Pathogenesis, clinical features, and diagnosis of pediatric multiple sclerosis" and "Treatment and prognosis of pediatric multiple sclerosis".)

Pediatric MS is defined as the onset of MS before the age of 18, which occurs in at least 5 percent of patients who have MS. Nevertheless, pediatric MS is a rare disease, with an estimated frequency of approximately 2.5 per 100,000 children.

Children with MS generally have a similar clinical presentation to adults, although some evidence suggests that children may be more likely than adults to present with isolated optic neuritis; an isolated brainstem syndrome; or encephalitic symptoms such as headache, vomiting, seizure, or altered consciousness.

More than 95 percent of children with MS initially have relapsing-remitting multiple sclerosis (RRMS), characterized by intermittent attacks of increased disability followed by either partial or complete recovery. Primary progressive multiple sclerosis (PPMS), characterized by continuous disability over time in the absence of specific attacks, is much less common than RRMS. Some patients with RRMS eventually convert to secondary progressive multiple sclerosis (SPMS), which is characterized by an initial RRMS disease course followed by progression with or without occasional relapses, minor remissions, and plateaus.

CLINICALLY ISOLATED SYNDROME — A clinically isolated syndrome (CIS) is a first acute episode of clinical symptoms referable to one or more central nervous system sites with a presumed inflammatory demyelinating etiology in a child with no previous history of a central demyelinating event [1]. Typical examples of a CIS include the following:

●Optic neuritis

●Transverse myelitis

●Neurologic symptoms and signs due to brainstem, cerebellar, or hemispheric dysfunction

The clinical event may be either monofocal or multifocal in terms of symptoms [1]. Unlike acute disseminated encephalomyelitis (ADEM), encephalopathy is not a typical feature, although it may occur in a CIS with brainstem involvement.

An episode of CIS can create a diagnostic and therapeutic dilemma. Most children will not have recurrence after a single demyelinating event of the central nervous system. However, the risk is high enough to be concerning, though not yet defined precisely. (See "Pathogenesis, clinical features, and diagnosis of pediatric multiple sclerosis", section on 'Clinically isolated syndromes'.)

DISTINGUISHING ADEM AND MULTIPLE SCLEROSIS — The most important alternative diagnosis to multiple sclerosis (MS) is acute disseminated encephalomyelitis (ADEM), a more common and a temporally limited disorder than pediatric MS.

At initial presentation, the two disorders cannot be distinguished with absolute certainty (algorithm 1). In children, subsequent attacks of MS may not occur for months or years. Furthermore, a small subset of children with ADEM may eventually develop MS, but it is difficult to accurately predict which patients will do so. Therefore, prolonged follow-up is required to establish a diagnosis.

Certain clinical features may be helpful in supporting the diagnosis of ADEM or MS [2-6]. However, there is substantial overlap.

●ADEM typically follows a prodromal viral illness, while MS does not

●ADEM patients often have fever and stiff neck, which is unusual in MS

●ADEM usually produces widespread central nervous system disturbance with impaired consciousness and/or encephalopathy, while MS typically is monosymptomatic (eg, optic neuritis or a subacute myelopathy) and has a relapsing-remitting course

●Ataxia is a common presenting feature of ADEM, but rare in MS

●Acute myelopathy is usually complete and accompanied by areflexia in ADEM, while myelopathy is typically partial in MS

Spinal cord symptoms secondary to an inflammatory myelopathy (or myelitis) can be described as "complete" or "partial" based upon clinical presentation and imaging findings. A complete myelopathy is characterized by bilateral flaccid muscle weakness, complete sensory loss, and bowel and bladder incontinence below the affected spinal cord level. A partial myelopathy is characterized by asymmetric and/or variable degrees of weakness, sensory loss, and bowel or bladder impairment below the affected spinal cord level. The imaging corollary of a complete myelopathy is often a longitudinally extensive lesion affecting the entire diameter of the cord, whereas a partial myelopathy is most often associated with a segmental lesion localized to the periphery of the spinal cord parenchyma.

In the acute setting of a complete myelopathy with a diffuse and longitudinal lesion of the spinal cord, areflexia may be found on examination. This is related to inflammation affecting the normal function of the anterior horn cells as well as the corticospinal tracts. With resolution of inflammation in the subacute to chronic phase of the disease, areflexia can be replaced by hyperreflexia, representing gliotic injury to the descending corticospinal tract.

Brain MRI features may also be helpful in distinguishing ADEM from MS, although complete differentiation is not possible on the basis of a single study [2,6,7].

●ADEM usually has more MRI lesions than MS, with larger bilateral but asymmetric white matter abnormalities

●Lesions tend to be poorly defined in ADEM and have better defined margins in MS

●The presence of brain lesions of about the same age on MRI is most consistent with ADEM, while the presence of brain lesions of different ages and/or the presence of black holes (hypointense T1 lesions) suggests MS

●Thalamic lesions are common in ADEM and rare in MS

●Periventricular lesions are less common in ADEM than MS

In a retrospective study that compared MRI scans obtained at first attack from 28 children later diagnosed with MS and 20 children with monophasic ADEM, any two of the following proposed criteria (Callen) were more suggestive of a first attack of MS rather than monophasic ADEM [8]:

●≥2 periventricular lesions

●Presence of black holes

●Absence of diffuse bilateral lesion distribution pattern

Prospective validation in larger cohorts is needed to confirm the clinical utility of the Callen criteria. In a retrospective study of 49 children with a first demyelinating event of central nervous system, the Callen criteria performed well for distinguishing MS from ADEM, with a sensitivity and specificity of 75 and 95 percent, respectively [9].

While there are no conclusive biomarkers for either ADEM or MS, serum antibodies directed against myelin oligodendrocyte glycoprotein (MOG) are nearly exclusively detected in patients with monophasic or relapsing events other than MS, including some patients with ADEM, multiphasic disseminated encephalomyelitis (MDEM), neuromyelitis optica spectrum disorders (NMOSD), and relapsing optic neuritis. (See 'MOG antibody-associated syndromes' below.)

OPTIC NEURITIS — Optic neuritis is inflammation of the optic nerve that can be caused by any inflammatory condition or may be idiopathic. It is believed that the demyelination in optic neuritis is immune-mediated, but the specific mechanism and target antigen(s) are unknown.

Optic neuritis is briefly reviewed here, and is discussed in detail separately. (See "Optic neuritis: Pathophysiology, clinical features, and diagnosis" and "Optic neuritis: Prognosis and treatment".)

Optic neuritis usually presents as an isolated symptom, and thus may occur as a clinically isolated syndrome (CIS) in a child with no previous history of a central demyelinating event. Optic neuritis can also occur as a feature that accompanies other demyelinating disorders, including acute disseminated encephalomyelitis (ADEM), multiple sclerosis, or neuromyelitis optica.

Optic neuritis is usually monocular in older children and adults but retrospective evidence suggests it is bilateral in approximately one-half of children younger than 12 to 15 years old. At the onset, the presentation can be asymmetrical. Patients may report headache or painful eye movements prior to the vision loss. Symptoms usually progress over several hours to a few days, with partial or complete vision loss, a relative afferent pupillary defect (Marcus Gunn pupil), and visual field defects. In addition to decreased visual acuity, an enlarged central scotoma may be detected by visual field testing.

The funduscopic examination is variable. The optic nerve appears swollen in 75 percent of children in the acute phase. However, optic disc swelling can be mild or absent, especially if the inflammation is retrobulbar.

MRI of the brain and orbits with gadolinium contrast provides confirmation of the diagnosis of acute demyelinating optic neuritis and important prognostic information regarding the risk of developing multiple sclerosis. Visual-evoked potentials are prolonged in affected patients. Prolongation may persist even years after the illness, despite a normal ophthalmologic examination and normal vision.

Patients typically have normal or near-normal recovery of vision. However, subtle color impairment and stereoscopic abnormalities may persist. When vision is more severely affected at onset, a good prognosis is less certain. In addition, optic neuritis is a risk factor for the subsequent development of multiple sclerosis. Lesions outside of the optic nerves on the baseline MRI correlate with a higher risk for developing multiple sclerosis.

TRANSVERSE MYELITIS — Transverse myelitis is defined as spinal cord dysfunction that develops over hours or days in patients in whom there is no evidence of a compressive lesion. Typically, it is due to an inflammatory lesion of the spinal cord. Transverse myelitis is reviewed briefly here, and discussed in greater detail separately. (See "Transverse myelitis".)

Most cases of transverse myelitis affecting children are idiopathic and presumably result from an autoimmune process [10], with up to one-half of 47 cases in one retrospective series preceded by a febrile illness, and approximately one-quarter by vaccination [11]. Transverse myelitis can present as a clinically isolated syndrome or may be a manifestation of an acquired demyelinating disease such as acute disseminated encephalomyelitis (ADEM), multiple sclerosis, or neuromyelitis optica (Devic disease) [12].

Symptoms are characterized by motor and sensory deficits attributable to involvement of one or both sides of the spinal cord. They include weakness, paresthesias, and sphincter dysfunction. These typically present over a few days, with paresthesias preceding the weakness and urinary retention. A hyperacute presentation sometimes occurs with rapid onset of paraplegia, sensory abnormalities, and urinary retention. This form is often associated with significant back pain. A discrete sensory level may or may not be detected with either presentation.

MRI of the spine should be performed to rule out spinal cord compression, especially when presentation is rapidly progressive. The MRI typically shows gadolinium-enhancing signal abnormality, extending over one or more spinal cord segments. There is usually swelling of the affected segments, particularly on T2 sequences.

Most children with idiopathic transverse myelitis have at least a partial recovery, which usually begins within one to three months. Unfortunately, the prognosis for complete recovery is not as favorable as for ADEM or optic neuritis. Some degree of persistent disability is common, occurring in 40 percent or more [10].

NEUROMYELITIS OPTICA — Neuromyelitis optica (NMO, sometimes called Devic disease) is reviewed here briefly and discussed in detail elsewhere. (See "Neuromyelitis optica spectrum disorders (NMOSD): Clinical features and diagnosis".)

NMO and NMO spectrum disorders (NMOSD) are inflammatory disorders of the central nervous system characterized by severe, immune-mediated demyelination and axonal damage predominantly targeting the optic nerves and spinal cord. NMO and NMOSD are distinguished from multiple sclerosis and other central nervous system inflammatory disorders by the presence of the disease-specific anti-aquaporin-4 (AQP4) antibody, which plays a direct role in the pathogenesis of NMO. (See "Neuromyelitis optica spectrum disorders (NMOSD): Clinical features and diagnosis", section on 'History' and "Neuromyelitis optica spectrum disorders (NMOSD): Clinical features and diagnosis", section on 'Pathogenesis'.)

Hallmark features of NMO include acute attacks of bilateral or rapidly sequential optic neuritis (leading to visual loss) and transverse myelitis (often causing limb weakness and bladder dysfunction) with a typically relapsing course. Central nervous system involvement outside of the optic nerves and spinal cord is also recognized in NMO and NMO spectrum disorders. Other suggestive symptoms include episodes of intractable vomiting or hiccoughs, excessive daytime somnolence or narcolepsy, reversible posterior leukoencephalopathy syndrome, neuroendocrine disorders, and (in children) seizures. While no clinical features are disease-specific, some are highly characteristic. (See "Neuromyelitis optica spectrum disorders (NMOSD): Clinical features and diagnosis", section on 'Clinical features'.)

Although firm conclusions are limited by small numbers of patients, the available data suggest that a substantial minority of children with NMO have brain involvement at presentation associated with clinical features of encephalopathy, seizures, and/or lesions on brain MRI resembling those typically seen with multiple sclerosis or acute disseminated encephalomyelitis (see "Neuromyelitis optica spectrum disorders (NMOSD): Clinical features and diagnosis", section on 'Children'). In the author's clinical experience, patients with NMO have presented with hemispheric, brainstem, and diencephalon disease, and symptoms have included encephalopathy, ataxia, aphasia, endocrinopathies, headaches, and vomiting.

The clinical presentation of NMO can be primary progressive with fulminate disability at the time of presentation, though it usually follows a relapsing-remitting course. Thus, any child with a severe progressive disease course should be investigated for NMO. Severe attacks of myelitis or optic neuritis should raise suspicion for NMO.

In addition to a comprehensive history and examination, the evaluation of suspected NMOSD entails brain and spinal cord neuroimaging with MRI (table 3), determination of AQP4 antibody status, and often cerebrospinal fluid analysis. Patients who are seronegative for AQP4 antibodies should be tested for antibodies directed against myelin oligodendrocyte glycoprotein (MOG), as their presence suggests a more benign disease course. (See 'MOG antibody-associated syndromes' below.)

Diagnostic criteria for adults (table 4) are considered appropriate for pediatric patients, with the caveat that a longitudinally extensive spinal cord lesion on MRI associated with acute myelitis may be less specific for NMOSD in children compared with adults. These criteria require the presence of at least one core clinical characteristic (eg, optic neuritis, acute myelitis, area postrema syndrome), a positive test for AQP4-immunoglobulin G (IgG), and exclusion of alternative diagnoses. The diagnostic criteria are more exacting in the setting of negative or unknown AQP4-IgG antibody status. (See "Neuromyelitis optica spectrum disorders (NMOSD): Clinical features and diagnosis", section on 'Evaluation and diagnosis'.)

NMO syndromes must be distinguished from multiple sclerosis, which is the most common disorder likely to cause central nervous system demyelination. Other conditions that should be considered in the differential diagnosis include systemic lupus erythematosus, Sjögren syndrome, neuro-Behçet disease, acute disseminated encephalomyelitis, and intrathecal spinal cord tumors. (See "Neuromyelitis optica spectrum disorders (NMOSD): Clinical features and diagnosis", section on 'Differential diagnosis'.)

MOG ANTIBODY-ASSOCIATED SYNDROMES — Myelin oligodendrocyte glycoprotein (MOG) is a myelin protein expressed on the outer surface of oligodendrocytes and the outermost myelin sheath. The presence of anti-MOG antibodies may represent a unique antibody-mediated group of demyelinating conditions distinct from multiple sclerosis. Anti-MOG antibodies are nearly exclusively detected in patients with monophasic or relapsing events other than multiple sclerosis (MS), including some patients with acute disseminated encephalomyelitis (ADEM), multiphasic disseminated encephalomyelitis (MDEM), encephalitis other than ADEM, neuromyelitis optica spectrum disorders (NMOSD), transverse myelitis, and relapsing optic neuritis [13]. The detection of such antibodies in ADEM or optic neuritis suggests an increased risk of relapse and the need for close monitoring. However, the outcome for patients who are seropositive for MOG antibodies is generally thought to be favorable and the course temporally limited rather than chronic.

The wide spectrum of MOG antibody-associated syndromes is illustrated by a prospective cohort study that enrolled children with demyelinating syndromes (n = 239) or encephalitis other than ADEM (n = 296) [13]. MOG antibodies were detected in 116 children; these children presented with ADEM (68 percent), encephalitis other than ADEM (19 percent), optic neuritis (17 percent), myelitis (11 percent), NMOSD (5 percent), and other disorders (8 percent). Among all patients with autoimmune encephalitis (n = 64), positivity for MOG antibody was similar to that of all neuronal antibodies combined (34 percent vs 33 percent). In follow-up (median 42 months) of 100 patients with MOG antibody positivity who were diagnosed with a first attack, relapses occurred in 17 percent. Notably, MOG antibodies were not detected in any patient with non-inflammatory neurologic disease; their detection in patients with non-ADEM encephalitis allowed for the diagnosis of an autoimmune etiology, which might otherwise have been missed.

In a prospective study that followed 210 children presenting with their first demyelinating event, serum anti-MOG antibodies were detected in 31 percent at onset [14]. After 24 months, the following observations were noted:

●A monophasic disease course was still present in 96 patients, of whom anti-MOG antibodies at disease onset were found in 42 percent.

●MS was the diagnosis for 79 patients, with anti-MOG antibodies at disease onset detected in only 4 percent

●Further demyelinating episodes other than MS occurred in 35 patients, with anti-MOG antibodies in 63 percent and AQP4 antibodies in 17 percent at disease onset. No patients had antibodies to both antigens. A recurrent non-MS course was predicted by higher titers of anti-MOG antibodies (>1:1,280), older age (>10 years) at onset, female sex, and MRI lesions atypical for MS. The presence of anti-MOG antibodies was also associated with the occurrence of optic neuritis at some point during the disease course for patients with recurrence. For most patients with anti-MOG antibodies and a recurrent disease course, the first recurrence was within the first year, with a mean of 2.2 relapses in the first two years [14].

●Patients seronegative for anti-MOG antibodies did not seroconvert to detectable antibody levels for the 24 months of follow-up. Anti-MOG antibody titers declined over 24 months in both the monophasic and recurrent disease groups, but the greatest declines occurred in the monophasic group, with many having undetectable levels, suggesting an increased relapse risk in those with persistent high titers. A monophasic course was more often encountered in males, younger children, and in those without optic neuritis.

Proposed diagnostic criteria for MOG antibody-associated disorders, based upon data from a series of 51 patients, require serum positivity for MOG-immunoglobulin G (IgG) by cell-based assay, a clinical presentation consistent with central nervous system demyelination (ie, ADEM, optic neuritis, transverse myelitis, a brain or brainstem demyelinating syndrome, or any combination of these), and exclusion of an alternative diagnosis [15]. In the absence of serum, positivity for MOG-IgG in the cerebrospinal fluid allowed fulfillment of the criteria; a transient seropositivity favored a lower risk of relapse.

In general, most patients with detectable anti-MOG antibodies respond quickly to glucocorticoid treatment and have good long-term outcomes with little to no disability, although patients with transverse myelitis may have more severe residual deficits [16]. Among children who have relapsing MOG antibody-associated disease, retrospective data suggest that select immunotherapies including intravenous immune globulin, azathioprine, mycophenolate mofetil, and rituximab are associated with a reduced relapse frequency, whereas disease-modifying therapies used for multiple sclerosis are ineffective [17].

COLLAGEN VASCULAR DISEASE — Collagen vascular disease, including systemic lupus erythematosus and neurosarcoidosis, can present at a young age with principal central nervous system involvement. Other markers of systemic inflammation, such as abnormal antinuclear antibody profile, positive double-stranded DNA antibodies, elevated angiotensin converting enzyme, and positive antiphospholipid antibodies, help to distinguish these entities. (See "Childhood-onset systemic lupus erythematosus (SLE): Clinical manifestations and diagnosis".)

PRIMARY ANGIITIS OF THE CENTRAL NERVOUS SYSTEM — Primary angiitis of the central nervous system, also known as central nervous system angiitis, is a rare disorder in children that can have a similar presentation to demyelinating disease [18], including multifocal T2-hyperintensities on the MRI. Diffusion weighted MRI sequences may demonstrate restricted diffusion in areas of acute ischemic injury.

Patients may present with clinical features similar to acute disseminated encephalomyelitis (ADEM), such as multifocal neurologic impairments, headaches, focal seizures, and behavior changes. Cerebral angiography may demonstrate vascular beading and intraluminal narrowing. Meningeal biopsy is sometimes required to confirm the diagnosis. (See "Vasculitis in children: Incidence and classification", section on 'Primary angiitis of the central nervous system'.)

OTHER DISORDERS — A number of noninflammatory disorders can affect the white matter and mimic acute inflammatory demyelination on imaging studies. These include malignancies, mitochondrial disease, and certain leukodystrophies [19].

Malignancy — Large areas of tumefactive demyelination can give rise to concern for possible central nervous system lymphoma or high-grade glioma [20-22]. In the absence of other imaging suggestive of demyelination, further investigation with cerebrospinal fluid cytology may demonstrate atypical cells. Brain biopsy may be needed in such circumstances to clarify the diagnosis.

Mitochondrial disease — Mitochondrial disease may present acutely in the setting of intercurrent infection. Typical features on brain MRI include increased (bright) T2 signal in the basal ganglia or predominate, symmetric involvement of the parieto-occipital region. Other features of mitochondrial disorders include elevation of serum and cerebrospinal fluid lactate levels. Symmetry of imaging abnormalities should prompt strong consideration for an underlying metabolic disease. (See "Mitochondrial myopathies: Clinical features and diagnosis", section on 'Predominantly multisystem disease with myopathy'.)

Leukodystrophies — The leukodystrophies are rare disorders that may occasionally be confused with multiple sclerosis or acute disseminated encephalomyelitis. White matter disease, typically symmetric, is the hallmark of these conditions (algorithm 2), which include the following:

●Metachromatic leukodystrophy (see "Metachromatic leukodystrophy")

●X-linked adrenoleukodystrophy (see "X-linked adrenoleukodystrophy and adrenomyeloneuropathy").

●Alexander disease (see "Alexander disease")

●Krabbe disease (see "Krabbe disease")

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

SUMMARY

●Differential diagnostic considerations for acute central nervous system demyelination in children include acute disseminated encephalomyelitis (ADEM), multiple sclerosis, optic neuritis, transverse myelitis, neuromyelitis optica, and various infectious, metabolic, and rheumatologic conditions (table 1).

●ADEM is characterized by acute or subacute onset of multifocal neurologic deficits with encephalopathy, often following a viral illness or vaccination. Additional typical signs associated with ADEM are headache, fever, or meningismus. Brain MRI demonstrates widespread asymmetric white and gray matter abnormalities (table 2). (See 'Acute disseminated encephalomyelitis' above.)

●Multiple sclerosis is a chronic disease characterized by recurrent episodes of demyelination in the central nervous system separated in space and time. Acute inflammation and demyelination in a critical area of the brain, optic nerves, or spinal cord will produce a corresponding clinical deficit. The most important alternative diagnosis to multiple sclerosis is acute disseminated encephalomyelitis, which is a more common and a temporally limited disorder than pediatric multiple sclerosis. At initial presentation, it can be difficult to distinguish the two disorders with absolute certainty. (See 'Multiple sclerosis' above and 'Distinguishing ADEM and multiple sclerosis' above.)

●A clinically isolated syndrome is a first acute episode of clinical symptoms referable to one or more central nervous system sites with a presumed inflammatory demyelinating etiology in a child with no previous history of a central demyelinating event. Typical examples of a clinically isolated syndrome include optic neuritis, transverse myelitis, and neurologic symptoms and signs due to brainstem, cerebellar, or hemispheric dysfunction. (See 'Clinically isolated syndrome' above.)

●Optic neuritis is inflammation of the optic nerve that can be caused by any inflammatory condition or may be idiopathic. Optic neuritis is usually monocular in older children and adults but is bilateral in a significant percentage of children younger than 12 to 15 years old. (See 'Optic neuritis' above.)

●Transverse myelitis is defined as spinal cord dysfunction that develops over hours or days in the absence of a compressive spinal cord lesion. Typically, it is due to an inflammatory lesion of the spinal cord. (See 'Transverse myelitis' above.)

●Neuromyelitis optica (NMO) and NMO spectrum disorders (NMOSD) are inflammatory disorders characterized by severe, immune-mediated demyelination and axonal damage predominantly targeting the optic nerves and spinal cord. NMO and NMOSD are distinguished from multiple sclerosis and other central nervous system inflammatory disorders by the presence of the disease-specific anti-aquaporin-4 (AQP4) antibody. Hallmark features include acute attacks of bilateral or rapidly sequential optic neuritis (leading to visual loss) and transverse myelitis (often causing limb weakness and bladder dysfunction) with a typically relapsing course. Central nervous system involvement outside of the optic nerves and spinal cord is also recognized in NMO and NMOSD. Other suggestive symptoms include episodes of intractable vomiting or hiccoughs, excessive daytime somnolence or narcolepsy, reversible posterior leukoencephalopathy syndrome, neuroendocrine disorders, and seizures. (See 'Neuromyelitis optica' above.)

●Myelin oligodendrocyte glycoprotein (MOG) is a myelin protein expressed on the outer surface of oligodendrocytes and the outermost myelin sheath. MOG antibody-associated syndromes encompass a wide spectrum of disorders and may present as acute disseminated encephalomyelitis (ADEM), multiphasic disseminated encephalomyelitis (MDEM), encephalitis other than ADEM, neuromyelitis optica spectrum disorders (NMOSD), transverse myelitis, and relapsing optic neuritis. (See 'MOG antibody-associated syndromes' above.)

●Collagen vascular disease, including systemic lupus erythematosus and neurosarcoidosis, can present at a young age with principal central nervous system involvement. (See 'Collagen vascular disease' above.)

●Central nervous system angiitis, also known as primary angiitis of the central nervous system, is a rare disorder in children that can have a similar presentation to demyelinating disease. (See 'Primary angiitis of the central nervous system' above.)

●A number of noninflammatory disorders can affect the white matter and mimic acute inflammatory demyelination on imaging studies. These include malignancies, mitochondrial disease, and certain leukodystrophies (algorithm 2). (See 'Malignancy' above and 'Mitochondrial disease' above and 'Leukodystrophies' above.)