Research

Case Report/Case Series

Episodic Bradycardia as Neurocardiac Prodrome to Voltage-Gated Potassium Channel Complex/Leucine-Rich, Glioma Inactivated 1 Antibody Encephalitis Georges Naasan, MD; Sarosh R. Irani, MRCP, DPhil; Brianne M. Bettcher, PhD; Michael D. Geschwind, MD, PhD; Jeffrey M. Gelfand, MD, MAS

IMPORTANCE Voltage-gated potassium channel complex antibody (VGKCc-Ab) encephalitis is

an immunotherapy-responsive syndrome usually associated with causative antibodies that target the leucine-rich, glioma inactivated 1 (LGI1) protein. Although it is expressed throughout the brain, LGI1 is not known to be expressed in cardiac tissue. We describe a novel neurocardiac prodrome of VGKCc-Ab/LGI1-encephalitis. OBSERVATIONS Among 14 patients with VGKCc/LGI1-Ab encephalitis evaluated in the University of California, San Francisco Autoimmune Encephalitis Clinic and Rapid Dementia Research Program, 3 patients (2 men and 1 woman; aged 53, 55, and 64 years) exhibited episodic bradycardia that preceded the onset of encephalopathy by approximately 2 months and was severe enough to lead to pacemaker implantation. Serum LGI1-Ab results were positive when tested at the time of the subsequent encephalopathy. All 3 patients developed hyponatremia; none had faciobrachial dystonic seizures or malignancy. Brain magnetic resonance imaging was abnormal in 2 cases. None of the patients experienced further symptomatic bradyarrythmias after 1.7 to 7 years of follow-up. CONCLUSIONS AND RELEVANCE Episodic bradycardia is a distinctive neurocardiac prodrome of VGKCc/LGI1-Ab encephalitis. The neuroanatomical localization most likely relates to insular and temporal lobe involvement, cortical regions that modulate cardiac autonomic function. Further study is needed to determine if recognition of this neurocardiac prodrome and earlier institution of immunosuppression can prevent the development of encephalopathy. JAMA Neurol. 2014;71(10):1300-1304. doi:10.1001/jamaneurol.2014.1234 Published online August 18, 2014.

V

oltage-gated potassium channel complex antibody (VGKCc-Ab) encephalitis is characterized by rapidonset dementia, seizures, and hyponatremia.1,2 The leucine-rich, glioma inactivated 1 (LGI1) protein, part of the VGKCcomplex, is the established antigenic target in most cases of this antibody-mediated limbic syndrome.3,4 We describe 3 patients with VGKCc/LGI1-Ab encephalitis who developed episodic bradycardia requiring pacemaker implantation prior to the onset of encephalopathy. As LGI1 is widely expressed throughout brain but not cardiac tissue4 and as cardiac conduction can be modulated by cortical autonomic centers,5 we propose that the antibody-associated encephalitis generates episodic bradycardia early within the disease process.

Methods We identified 14 patients with VGKCc-Ab encephalitis6,7 evaluated between January 1, 2006, and August 1, 2013, in the Uni1300

Author Affiliations: Memory and Aging Center, Department of Neurology, University of California, San Francisco (Naasan, Irani, Bettcher, Geschwind); Nuffield Department of Clinical Neurosciences, John Radcliffe Hospital, University of Oxford, Oxford, England (Irani); Comprehensive Center for Multiple Sclerosis and Neuroinflammation, Department of Neurology, University of California, San Francisco (Gelfand). Corresponding Author: Jeffrey M. Gelfand, MD, MAS, Comprehensive Center for Multiple Sclerosis and Neuroinflammation, Department of Neurology, University of California, San Francisco, 675 Nelson Rising Ln, Box 3206, San Francisco, CA 941433206 ([email protected]).

versity of California, San Francisco Rapid Dementia Research Program and Autoimmune Encephalitis Clinic. Testing for VGKCc-Abs and LGI1-Abs was performed in US clinical laboratories and/or the international research laboratories of Josep Dalmau, MD, PhD, University of Barcelona, University of Pennsylvania, and Angela Vincent, FRS, University of Oxford. All participants provided written informed consent. The University of California, San Francisco Committee on Human Research approved the study protocol.

Report of Cases Of these 14 patients with VGKCc-Ab encephalitis, 3 had prodromal bradycardia and pacemaker implantation (21%; 2 men and 1 woman; ages 53, 55, and 64 years). None of the patients had a prior cardiac history. All 3 cases had serum VGKCc-Abs and LGI1-Abs at the time of encephalitis, which was characterized by amnesia, seizures, and serum hyponatremia. None

JAMA Neurology October 2014 Volume 71, Number 10

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Episodic Bradycardia

Case Report/Case Series Research

Table. Demographic and Clinical Characteristics Case Characteristic

1

Age at onset, y

53

2

3

64

55

Sex

Male

Male

Female

Initial VGKCc-Ab titer

696 pmol/L (normal

leucine-rich, glioma inactivated 1 antibody encephalitis.

Voltage-gated potassium channel complex antibody (VGKCc-Ab) encephalitis is an immunotherapy-responsive syndrome usually associated with causative ant...
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