Chapter 36: Inflammatory Diseases of the Central Nervous System

IMMUNE-MEDIATED ENCEPHALOPATHIES

Autoimmune Encephalitis

Autoimmune encephalitis (AE) involves an abnormal immune response of the central nervous system (CNS) to autoantibodies binding to extracellular antigens such as neuronal cell surface proteins, synaptic receptors, and ion channels.¹ Symptoms in children are typically subacute in onset, may involve an infectious prodrome, and include altered level of consciousness, seizures, movement disorders, cognitive/speech decline, psychiatric symptoms, sleep disturbance, focal deficits, and/or autonomic disturbances. Established diagnostic criteria for pediatric AE (summarized below) exist to guide treatment decisions.²

Possible AE: Acute or subacute (<3 months) onset of at least 2 of the following clinical criteria and reasonable exclusion of other etiologies:

1. Altered mental status or electroencephalogram (EEG) abnormalities (epileptiform or slowing)

2. Focal neurologic deficits

3. Cognitive difficulties

4. Acute developmental regression

5. Movement disorder (excludes tics)

6. Psychiatric symptoms

7. Seizures not explained by previously diagnosed condition

Probable antibody-negative AE: Fulfills all clinical criteria and at least one of the following paraclinical criteria:

1. Cerebrospinal fluid (CSF) white blood cell count greater than 5 or positive oligoclonal bands

2. Abnormal magnetic resonance imaging (MRI) suggestive of encephalitis

3. Brain biopsy with inflammatory infiltrates consistent with AE

Definite AE: Fulfills clinical criteria and has presence of antibody associated with AE

The most common autoantibodies in children are myelin oligodendrocyte glycoprotein (MOG; discussed separately), anti-N-methyl-D-aspartate receptor (NMDAR), GAD65, GABA_A, and glycine receptor.^2,3 Serum laboratory evaluation generally includes inflammatory markers, infectious evaluation, rheumatologic autoantibodies, thyroid autoantibodies, and encephalopathy autoantibody panel. MRI of the brain with and without contrast should be performed, which may demonstrate focal areas of enhancement or T2/fluid-attenuated inversion recovery (FLAIR) hyperintensity. CSF evaluation is required for autoantibody and infectious disease testing. Most common CSF findings include pleocytosis, protein elevation, presence of oligoclonal bands, or elevated immunoglobulin (Ig) G index. Malignancy screening should be pursued, although malignancy is less common in pediatric patients.

After reasonable exclusion of alternative etiologies, particularly infectious encephalitis, first-line immunomodulatory treatment with intravenous (IV) steroids and/or IV immunoglobulin (IVIG) should be initiated while awaiting workup. Assuming a diagnosis of probable or definite AE is made, rituximab is an appropriate next-line therapy. For treatment-refractory cases, other options include cyclophosphamide, tocilizumab, and bortezomib.

NMDAR Encephalitis

NMDAR encephalitis typically presents with seizures, movement disorders, psychiatric symptoms, insomnia, reduced speech, cognitive decline, autonomic instability, and/or catatonia. The disease is more likely to present in children than adults with movement disorders (particularly orofacial dyskinesias and chorea) and seizures, with psychiatric symptoms often being less prominent at presentation.⁴ In younger children and toddlers, NMDAR encephalitis can present with early symptoms of developmental regression. In young woman, there may be an association with ovarian teratoma, but this is less commonly seen in pediatric NMDAR encephalitis.

First-line immunotherapy involves IV methylprednisolone, as well as IVIG and/or plasmapheresis. ...