Neuroimmunology: Paraneoplastic and Other Autoimmune Syndromes—Central Nervous System

Limbic encephalitis is characterized by cognitive impairment, seizures, and behavioral abnormalities and may occur as a primary autoimmune or paraneoplastic condition. The most commonly associated neoplasm is small cell lung cancer (SCLC). Multiple autoantibody markers are associated with this syndrome; the specific serum autoantibody profile may predict a specific cancer risk. Other levels of the neuroaxis are frequently involved when associated with some paraneoplastic autoantibody markers, for instance, Ma2, antineuronal nuclear autoantibody type-1 (ANNA-1), antiglial neuronal nuclear antibody-1 (AGNA-1), whereas not so with others (voltage-gated potassium channels [VGKC], LGI1). Isolated paraneoplastic autoimmune cerebral cortex involvement is rare; current autoantibody markers are found infrequently. Instances of cortical encephalitis in association with neuronal acetylcholine receptor (AChR), and/or VGKC, collapsin response mediator protein-5 (CRMP-5), or glutamic acid decarboxylase (GAD-65) antibodies and thymoma are reported.

DIENCEPHALON

Hypothalamic dysfunction with excessive sleepiness and some features of cataplexy occur in patients with Ma2 autoantibody. Cerebrospinal fluid (CSF) hypocretin levels are low or undetectable. Features of diencephalic involvement are also quite prominent in NMDA encephalitis.

BASAL GANGLIA AND EXTRAPYRAMIDAL SYSTEM

Paraneoplastic chorea occurs most commonly with SCLC in association with an antibody to CRMP-5. Variable movement disorders occur with NMDA antibody. Orofacial dyskinesia may occur with lung cancer and ANNA-2. Myoclonus, including opsoclonus, is the most frequent of the rare paraneoplastic movement disorders. It occurs with a number of different neoplasms, particularly childhood neuroblastoma; it lacks specific syndromic serologic markers. Anatomic localization is difficult; this potentially arises from the brainstem or spinal cord, as with rigidity manifesting dystonia and “stiff-person” phenomena.

CEREBELLUM

Subacute cerebellar ataxia is the most common manifestation in patients seropositive for Purkinje cell cytoplasmic autoantibody-type-1 (PCA-1) or PCA-Tr. This may occur with other antibody markers, including P/Q-type voltage-gated calcium channel antibody and AGNA-1. With PCA-Tr, Hodgkin lymphoma diagnosis has often preceded the cerebellar syndrome. Otherwise, the antibody profile directs the cancer search. PCA-1 highly suggests gynecologic sources, especially occult ovarian cancer; AGNA-1 strongly predicts SCLC.

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