Acute Disseminated Encephalomyelitis

Historically, ADEM was defined by the development of neurologic symptoms after a vaccination or a viral or bacterial infection. In 2007, an International Pediatric MS Study Group (IPMSSG) proposed working definitions for demyelinating disorders in children. ADEM is currently defined as a first demyelinating or inflammatory event in which the child is polysymptomatic and encephalopathic. Encephalopathy can be mild (e.g., confusion or irritability) but must be present to distinguish ADEM from a clinically isolated syndrome (described below). Although a preceding illness or infection is identifiable in approximately 75% of children (with an average latency between the febrile illness and neurologic symptoms of 7-14 days), such an event is not required for the diagnosis. Magnetic resonance imaging (MRI) of the brain typically reveals multiple large (>1-2 cm) asymmetric lesions affecting the supra- and infratentorial white matter that are easily visualized using T2-weighted and fluid-attenuated inversion recovery (FLAIR) sequences. Symmetric gray matter involvement of the thalami and basal ganglia and confluent spinal cord lesions have also been described in ADEM. CSF analysis may demonstrate an elevated white blood cell (WBC) count or protein or the presence of oligoclonal bands, although the latter is more frequent in MS. The presence of encephalopathy, a preceding illness or vaccination, large asymmetric white matter lesions on MRI, symmetric gray matter involvement, and CSF WBC greater than 50 cells/mm are highly suggestive of ADEM rather than a first attack of MS. The clinical and radiographic involvement may fluctuate for the first 3 months. Thereafter, relapses may occur in the same (recurrent ADEM) or a different (multiphasic) CNS site but must meet the diagnostic criteria for ADEM described above to differentiate these conditions from MS.

Clinically Isolated Syndrome

The IPMSSG defined a clinically isolated syndrome (CIS) as a first demyelinating event that may be monofocal or multifocal in the absence of encephalopathy (with the exception of a brainstem lesion, which may result in altered mental status, lethargy, or coma). Whereas the name suggests a single event, these disorders may represent the initial presentation of MS.

Optic Neuritis

Optic neuritis is characterized by acute or subacute visual loss, altered color vision, periorbital pain that is exacerbated by eye movements, and visual field defects. The neuro-ophthalmologic examination may reveal a relative afferent pupillary defect (in unilateral cases) or optic disc edema (Figure 78-1). MRI of the orbits often reveals T2/FLAIR abnormality in the optic nerve or chiasm with or without enhancement using gadolinium. Visual recovery from idiopathic optic neuritis is excellent for most children, especially in the absence of alternate diagnoses such as NMO.

Figure 78-1 Ocular manifestations of multiple sclerosis.

Multiple Sclerosis

MS is a chronic demyelinating inflammatory disorder characterized by the dissemination of neurologic signs and symptoms in time and space in both children and adults. The development of a neurologic symptom lasting more than 24 hours is referred to as an “attack” or “flare.” Children most often present with paresthesias or optic neuritis. Motor dysfunction, ataxia, cranial nerve palsies, vestibular symptoms, and other neurologic symptoms also occur. As described above, a first demyelinating event is called a CIS. The evolution of disease over time affecting multiple areas of the CNS distinguishes MS from a truly monophasic CIS. Using the 2005 Revisions to the McDonald Criteria established for adults, dissemination in time is defined clinically as the separation of symptom onset by 30 days or by the appearance of a new T2 or FLAIR lesion (compared with a reference scan) in the brain or spinal cord on MRI imaging performed at least 30 days after the onset of the initial attack (Figure 78-2). Alternatively, the detection of gadolinium enhancement on a repeat MRI scan performed at least 3 months after the onset of the initial clinical event at a different site (not corresponding to the initial clinical symptoms) also meets criteria for dissemination in time. The IPMSSG suggested that in children a time frame of 3 months be used for both the appearance of a new T2 or FLAIR lesion or gadolinium-enhancing lesion. Dissemination in space is defined by objective clinical evidence of two or more lesions (i.e., two or more abnormalities found on neurologic examination either transiently or permanently). MRI and lumbar puncture can also be performed to document dissemination in space. According to the McDonald criteria and IPMSSG, dissemination in space is fulfilled by three of the following four features: (1) at least one gadolinium-enhancing brain or spinal cord lesion or nine T2 hyperintense lesions in the brain or spinal cord in the absence of a gadolinium-enhancing lesion, (2) at least three periventricular lesions, (3) at least one juxtacortical lesion, or (4) at least one infratentorial or spinal cord lesion. Children are less likely than adults to fulfill these criteria. Therefore, dissemination in space can also be demonstrated in a patient with an MRI showing two or more lesions (one of which must be in the brain) consistent with MS and the presence of oligoclonal bands or an increased IgG index in the CSF. These criteria have not been validated in children but are supported by the IPMSSG and used in clinical practice. Most children have relapsing-remitting MS; primary progressive MS and progressive relapsing MS are rare. Although there are limited data, the natural history of pediatric MS suggests a slower progression of disease than in adults; however, children develop secondary progressive MS at younger ages than adults.

Figure 78-2 Imaging of multiple sclerosis.

Neuromyelitis Optica

NMO is a chronic, relapsing demyelinating disease of the CNS affecting the optic nerves and spinal cord either concurrently or sequentially (with attacks separated by months). The symptoms can be significant with complete vision loss and quadriplegia or paraplegia depending on the location and extent of spinal cord involvement. Clinical criteria for the diagnosis include the presence of optic neuritis and acute myelitis. In addition, children must have a longitudinally extensive lesion extending over three or more vertebral segments on spinal MRI or have a positive NMO-IgG antibody. This IgG autoantibody binds selectively to the aquaporin-4 water channel, a component of a protein complex found in the foot processes of astrocytes at the blood–brain barrier, causing complement activation and disrupting glutamate transport. The NMO–IgG antibody is also detected in other autoimmune diseases causing demyelination in the optic nerves, brain, and spinal cord, including Sjögren’s disease. Other autoimmune markers, such as antinuclear antibody, may also be elevated even in the absence of further evidence of another autoimmune process. Although the disease is defined by lesions elsewhere in the CNS, brain lesions in the hypothalamus, brainstem, or diffuse cerebral white matter have been described in children with typical features of NMO. CSF analysis, although not required for the diagnosis, may reveal a pleocytosis (≥50 WBC) or positive CSF NMO-IgG, although serum is preferred for the detection of the autoantibody.

Acute Therapy

Corticosteroids are used to decrease inflammation associated with demyelinating attacks. Intravenous (IV) methylprednisolone (15-30 mg/kg/d; maximum, 1 g) is given for 3 to 5 days followed by an oral corticosteroid taper (range, 2 weeks–3 months) depending on the clinical presentation and physician judgment. Relapses of all demyelinating disease may occur with corticosteroid tapers. In general, IV corticosteroids do not alter the long-term prognosis but may hasten recovery as demonstrated in the Optic Neuritis Treatment Trial (ONTT). The ONTT was a randomized clinical trial (RCT) performed in adults with acute optic neuritis. Some patients in the ONTT received oral corticosteroids without preceding IV corticosteroids. These patients had an increased recurrence rate; therefore, oral corticosteroids alone are not recommended in the management of acute optic neuritis. Second-line therapies include IV immunoglobulin (IVIG) and plasma exchange. There have been no clinical trials performed in children to evaluate the efficacy of corticosteroids, IVIG, plasma exchange, or any other therapy in acute demyelinating attacks.

Special Considerations