Voltage-gated potassium channel autoimmunity mimicking creutzfeldt-jakob disease

Abstract

Background: Rapidly progressive dementia has a variety of causes, including Creutzfeldt-Jakob disease (CJD) and neuronal voltage-gated potassium channel (VGKC) autoantibody-associated encephalopathy.

Objective: To describe patients thought initially to have CJD but found subsequently to have immunotherapy-responsive VGKC autoimmunity.

Design: Observational, prospective case series.

Setting: Department of Neurology, Mayo Clinic, and the Memory and Aging Center, University of California, San Francisco. Patients A clinical serologic cohort of 15 patients referred for paraneoplastic autoantibody evaluation. Seven patients were evaluated clinically by at least one of us. Clinical information for the remaining patients was obtained by physician interview or medical record review.

Main outcome measures: Clinical features, magnetic resonance imaging abnormalities, electroencephalographic patterns, cerebrospinal fluid analyses, and responses to immunomodulatory therapy.

Results: All the patients presented subacutely with neurologic manifestations, including rapidly progressive dementia, myoclonus, extrapyramidal dysfunction, visual hallucinations, psychiatric disturbance, and seizures; most (60%) satisfied World Health Organization diagnostic criteria for CJD. Magnetic resonance imaging abnormalities included cerebral cortical diffusion-weighted imaging hyperintensities. Electroencephalographic abnormalities included diffuse slowing, frontal intermittent rhythmic delta activity, and focal epileptogenic activity but not periodic sharp wave complexes. Cerebrospinal fluid 14-3-3 protein or neuron-specific enolase levels were elevated in 5 of 8 patients. Hyponatremia was common (60%). Neoplasia was confirmed histologically in 5 patients (33%) and was suspected in another 5. Most patients' conditions (92%) improved after immunomodulatory therapy.

Conclusions: Clinical, radiologic, electrophysiologic, and laboratory findings in VGKC autoantibody-associated encephalopathy may be confused with those of CJD. Serologic evaluation for markers of neurologic autoimmunity, including VGKC autoantibodies, may be warranted in suspected CJD cases.

Figure 1

Brain magnetic resonance images of a patient with immunotherapy-responsive voltage-gated potassium channel (VGKC) autoimmunity and renal oncocytoma illustrate increased signal in the left anterior cingulate gyrus and insular cortex on diffusion-weighted imaging (A, arrows) and fluid-attenuated inversion recovery sequences (B and C, arrows). Indirect immunofluorescence testing of the patient’s serum revealed IgG binding to VGKC-rich synapses in mouse cerebellar cortex (D). ML indicates molecular layer; GL, granular layer; and PC, Purkinje cells (unstained).

Figure 2

Diffusion-weighted magnetic resonance images in a patient with immunotherapy-responsive voltage-gated potassium channel autoimmunity illustrate increased signal in the left temporo-occipital cortex (A and C, arrows) and the bilateral mesial frontal cortex (B, arrows).