Central Nervous System Inflammatory Demyelinating Disorders

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Introduction/Background

Pediatric Central Nervous System Inflammatory Demyelinating Disorders (CIDDs) are a heterogeneous group of diseases that include entities such as Clinically Isolated Syndrome (CIS), Acute Disseminated Encephalomyelitis (ADEM), Pediatric Multiple Sclerosis (MS), and Neuromyelitis Optica (NMO). Despite increasing awareness of their occurrence in pediatric populations, their prevalence remains underestimated (1).  Acute CIDDs, such as ADEM, are generally understood to occur more often in children than adults. Moreover, recent estimates project that as many as 10% of cases of MS begin in childhood (2). Lastly, NMO has also been reported to occur as early as infancy, and in as many as 8.5% of children with an inflammatory demyelinating disease.

 

The clinical presentation may vary between these disorders with some being monophasic (i.e., occurring as a single acute event) and monofocal (i.e., presenting with one neurological deficit), while others present as chronic disorders or with multifocal neurological deficits. However, it is important to recognize that substantial overlap between the different disorders exists.  For instance, ADEM was generally regarded to be a self-limited CIDD affecting the CNS in a monophasic and multifocal fashion, but relapses may occur and, in such instances, a diagnosis of MS may be more apt. In addition, CIS—a term used to describe a first-time inflammatory demyelinating episode, such as optic neuritis or transverse myelitis—may progress to relapsing NMO or MS, or remain a single acute event.

 

The precise epidemiology of each of these demyelinating disorders is difficult to determine given the lack of diagnostic biomarkers for all variants, the propensity for misdiagnosis, and the low incidence of CIDDs in pediatric patient populations.  Nevertheless, a precise diagnosis is essential, as therapies should be tailored to the etiology of the CIDD.

 

The most common presenting symptoms for children with CIDD vary by etiology, but in general are, in order of frequency: altered sensorium (~73%), seizures (~53%), ataxia (~27%), multiple cranial paralysis (20%), abnormal movements (20%), hemiparesis (13.3%), optic neuritis (13.3%), and quadriparesis (6.7%). ADEM and CIS are the two most commonly occurring forms of CIDD among children.

 

A thorough differential diagnosis would include, but not be limited to: CNS infection vs. Leukodystrophies vs. Collagen Vascular diseases (e.g., SLE, neurosarcoidosis, etc.) vs. Metabolic disease vs. Mitochondrial disease vs. Central Nervous System Angiitis.

 

Diagnosis

Acute Disseminating Encephalomyelitis (ADEM): Defined as a monophasic, multifocal CIDD oft preceded by conditions broadly defined as either: post-infectious, para-infectious, post exanthematous, or post vaccineal. It is generally considered to be an autoimmune process in which myelin auto antigens are produced due to shared antigenic determinants with infecting pathogens (i.e., type 3 hypersensitivity). May present as a mild, subclinical process, or as the more fulminant course, known as acute hemorrhagic leukoencephalitis. Patients often present with a fever and a stiff neck, as well as impaired consciousness, lethargy, or encephalopathy. Brain lesions are similarly aged, poorly defined, and numerous with a bilateral distribution; in addition, are commonly located in the thalamus and there is minimal injury to axons. Recurrent and multiphasic variants exist, but generally 3 or more ADEM demyelinating episodes suggest MS.

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Multiple Sclerosis (MS): In pediatric populations, relapse and remitting MS accounts for greater than 95% of cases. Childhood infections, remote EBV infection, vitamin D deficiency, and cigarette smoke are all risk factors. Children are more likely to present with isolated optic neuritis, isolated brainstem syndrome (e.g., encephalopathy, etc.), or encephalitis (e.g., vomiting, headaches, seizures, or altered mental status, etc.). MS brain lesions have well-defined margins, are often of different ages, may present as hypointense T1 lesions, and are typically located periventricularly. T-cell mediated (i.e., type 4 hypersensitivity) response to myelin oligodendrocyte glycoprotein and myelin basic protein has been shown to occur in pediatric MS, as it does in the adult version. Oligoclonal bands one confirmatory test.