title: Faciobrachial dystonic seizures: the influence of immunotherapy on seizure control and prevention of cognitive impairment in a broadening phenotype.
abstract: Voltage-gated potassium channel complex antibodies, particularly those directed against leucine-rich glioma inactivated 1, are associated with a common form of limbic encephalitis that presents with cognitive impairment and seizures. Faciobrachial dystonic seizures have recently been reported as immunotherapy-responsive, brief, frequent events that often predate the cognitive impairment associated with this limbic encephalitis. However, these observations were made from a retrospective study without serial cognitive assessments. Here, we undertook the first prospective study of faciobrachial dystonic seizures with serial assessments of seizure frequencies, cognition and antibodies in 10 cases identified over 20 months. We hypothesized that (i) faciobrachial dystonic seizures would show a differential response to anti-epileptic drugs and immunotherapy; and that (ii) effective treatment of faciobrachial dystonic seizures would accelerate recovery and prevent the development of cognitive impairment. The 10 cases expand both the known age at onset (28 to 92 years, median 68) and clinical features, with events of longer duration, simultaneously bilateral events, prominent automatisms, sensory aura, and post-ictal fear and speech arrest. Ictal epileptiform electroencephalographic changes were present in three cases. All 10 cases were positive for voltage-gated potassium channel-complex antibodies (346-4515 pM): nine showed specificity for leucine-rich glioma inactivated 1. Seven cases had normal clinical magnetic resonance imaging, and the cerebrospinal fluid examination was unremarkable in all seven tested. Faciobrachial dystonic seizures were controlled more effectively with immunotherapy than anti-epileptic drugs (P = 0.006). Strikingly, in the nine cases who remained anti-epileptic drug refractory for a median of 30 days (range 11-200), the addition of corticosteroids was associated with cessation of faciobrachial dystonic seizures within 1 week in three and within 2 months in six cases. Voltage-gated potassium channel-complex antibodies persisted in the four cases with relapses of faciobrachial dystonic seizures during corticosteroid withdrawal. Time to recovery of baseline function was positively correlated with time to immunotherapy (r = 0.74; P = 0.03) but not time to anti-epileptic drug administration (r = 0.55; P = 0.10). Of 10 cases, the eight cases who received anti-epileptic drugs (n = 3) or no treatment (n = 5) all developed cognitive impairment. By contrast, the two who did not develop cognitive impairment received immunotherapy to treat their faciobrachial dystonic seizures (P = 0.02). In eight cases without clinical magnetic resonance imaging evidence of hippocampal signal change, cross-sectional volumetric magnetic resonance imaging post-recovery, after accounting for age and head size, revealed cases (n = 8) had smaller brain volumes than healthy controls (n = 13) (P < 0.001). In conclusion, faciobrachial dystonic seizures can be prospectively identified as a form of epilepsy with an expanding phenotype. Immunotherapy is associated with excellent control of the frequently anti-epileptic drug refractory seizures, hastens time to recovery, and may prevent the subsequent development of cognitive impairment observed in this study.
authors.affiliation: 1 Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, UK.
authors.forename: Sarosh R
authors.initials: SR
authors.lastname: Irani
authors.forename: Charlotte J
authors.initials: CJ
authors.lastname: Stagg
authors.forename: Jonathan M
authors.initials: JM
authors.lastname: Schott
authors.forename: Clive R
authors.initials: CR
authors.lastname: Rosenthal
authors.forename: Susanne A
authors.initials: SA
authors.lastname: Schneider
authors.forename: Philippa
authors.initials: P
authors.lastname: Pettingill
authors.forename: Rosemary
authors.initials: R
authors.lastname: Pettingill
authors.forename: Patrick
authors.initials: P
authors.lastname: Waters
authors.forename: Adam
authors.initials: A
authors.lastname: Thomas
authors.forename: Natalie L
authors.initials: NL
authors.lastname: Voets
authors.forename: Manuel J
authors.initials: MJ
authors.lastname: Cardoso
authors.forename: David M
authors.initials: DM
authors.lastname: Cash
authors.forename: Emily N
authors.initials: EN
authors.lastname: Manning
authors.forename: Bethan
authors.initials: B
authors.lastname: Lang
authors.forename: Shelagh J M
authors.initials: SJ
authors.lastname: Smith
authors.forename: Angela
authors.initials: A
authors.lastname: Vincent
authors.forename: Michael R
authors.initials: MR
authors.lastname: Johnson
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000906:Antibodies / Q000627:therapeutic use*; D003072:Cognition Disorders / Q000517:prevention & control*; D004569:Electroencephalography / Q000379:methods; D005260:Female; D006801:Humans; D020363:Limbic Encephalitis / Q000188:drug therapy / Q000503:physiopathology; D008279:Magnetic Resonance Imaging / Q000379:methods; D008297:Male; D008875:Middle Aged; D010641:Phenotype; D011446:Prospective Studies; D012640:Seizures / Q000188:drug therapy* / Q000276:immunology / Q000503:physiopathology; D016896:Treatment Outcome
chemical_list: D000906:Antibodies
keywords: LGI1; autoimmune, epilepsy; faciobrachial dystonic seizures; limbic encephalitis