Encephalitis with refractory seizures, status epilepticus, and antibodies to the GABAA receptor: a case series, characterisation of the antigen, and analysis of the effects of antibodies.
BACKGROUND
Increasing evidence suggests that seizures and status epilepticus can be immune-mediated. We aimed to describe the clinical features of a new epileptic disorder, and to establish the target antigen and the effects of patients' antibodies on neuronal cultures.


METHODS
In this observational study, we selected serum and CSF samples for antigen characterisation from 140 patients with encephalitis, seizures or status epilepticus, and antibodies to unknown neuropil antigens. The samples were obtained from worldwide referrals of patients with disorders suspected to be autoimmune between April 28, 2006, and April 25, 2013. We used samples from 75 healthy individuals and 416 patients with a range of neurological diseases as controls. We assessed the samples using immunoprecipitation, mass spectrometry, cell-based assay, and analysis of antibody effects in cultured rat hippocampal neurons with confocal microscopy.


RESULTS
Neuronal cell-membrane immunoprecipitation with serum of two index patients revealed GABAA receptor sequences. Cell-based assay with HEK293 expressing α1/β3 subunits of the GABAA receptor showed high titre serum antibodies (>1:160) and CSF antibodies in six patients. All six patients (age 3-63 years, median 22 years; five male patients) developed refractory status epilepticus or epilepsia partialis continua along with extensive cortical-subcortical MRI abnormalities; four patients needed pharmacologically induced coma. 12 of 416 control patients with other diseases, but none of the healthy controls, had low-titre GABAA receptor antibodies detectable in only serum samples, five of them also had GAD-65 antibodies. These 12 patients (age 2-74 years, median 26.5 years; seven male patients) developed a broader spectrum of symptoms probably indicative of coexisting autoimmune disorders: six had encephalitis with seizures (one with status epilepticus needing pharmacologically induced coma; one with epilepsia partialis continua), four had stiff-person syndrome (one with seizures and limbic involvement), and two had opsoclonus-myoclonus. Overall, 12 of 15 patients for whom treatment and outcome were assessable had full (three patients) or partial (nine patients) response to immunotherapy or symptomatic treatment, and three died. Patients' antibodies caused a selective reduction of GABAA receptor clusters at synapses, but not along dendrites, without altering NMDA receptors and gephyrin (a protein that anchors the GABAA receptor).


CONCLUSIONS
High titres of serum and CSF GABAA receptor antibodies are associated with a severe form of encephalitis with seizures, refractory status epilepticus, or both. The antibodies cause a selective reduction of synaptic GABAA receptors. The disorder often occurs with GABAergic and other coexisting autoimmune disorders and is potentially treatable.


BACKGROUND
The National Institutes of Health, the McKnight Neuroscience of Brain Disorders, the Fondo de Investigaciones Sanitarias, Fundació la Marató de TV3, the Netherlands Organisation for Scientific Research (Veni-incentive), the Dutch Epilepsy Foundation.
August Pi i Sunyer Biomedical Research Institute (IDIBAPS), Barcelona, Spain; Hospital Clinic, University of Barcelona, Barcelona, Spain.
Mar
M
Petit-Pedrol
August Pi i Sunyer Biomedical Research Institute (IDIBAPS), Barcelona, Spain; Department of Pediatric Neurology, Hospital Materno-Infantil Vall d'Hebron, Universitat Autònoma de Barcelona, Barcelona, Spain; Hospital Clinic, University of Barcelona, Barcelona, Spain.
Thaís
T
Armangue
Department of Neuroscience, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
Xiaoyu
X
Peng
Service of Neurology, University Hospital Politècnic La Fe, Valencia, Spain.
Luis
L
Bataller
Division of Rheumatology, Department of Pediatrics, McMaster University, Hamilton, Ontario, Canada.
Tania
T
Cellucci
Department of Neurology, University of Pennsylvania, Philadelphia, PA, USA.
Rebecca
R
Davis
Department of Neurology, University of Pennsylvania, Philadelphia, PA, USA.
Lindsey
L
McCracken
August Pi i Sunyer Biomedical Research Institute (IDIBAPS), Barcelona, Spain.
Eugenia
E
Martinez-Hernandez
Department of Medicine, Princess Margaret Cancer Center and University of Toronto, Toronto, Canada.
Warren P
WP
Mason
Sanford Children's Health Research Center, Sanford Children's Specialty Clinic, Sioux Falls, SD, USA.
Michael C
MC
Kruer
Division of Pediatric Neurology, Lurie Children's Hospital, Chicago, USA.
David G
DG
Ritacco
Service of Neurology, Ludwig Boltzmann Institute of Neurooncology, Vienna, Austria.
Wolfgang
W
Grisold
Division of Neurology, Department of Pediatrics, McMaster University, Hamilton, Ontario, Canada.
Brandon F
BF
Meaney
Service of Neurology, University Hospital Politècnic La Fe, Valencia, Spain.
Carmen
C
Alcalá
Department of Neurology, Erasmus Medical Center, Rotterdam, Netherlands.
Peter
P
Sillevis-Smitt
Department of Neurology, Erasmus Medical Center, Rotterdam, Netherlands.
Maarten J
MJ
Titulaer
Department of Neuroscience, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
Rita
R
Balice-Gordon
August Pi i Sunyer Biomedical Research Institute (IDIBAPS), Barcelona, Spain; Hospital Clinic, University of Barcelona, Barcelona, Spain.
Francesc
F
Graus
August Pi i Sunyer Biomedical Research Institute (IDIBAPS), Barcelona, Spain; Department of Neurology, University of Pennsylvania, Philadelphia, PA, USA; Hospital Clinic, University of Barcelona, Barcelona, Spain; Catalan Institution for Research and Advanced Studies (ICREA), Barcelona, Spain. Electronic address: jdalmau@clinic.ub.es.
Josep
J
Dalmau
D000293:Adolescent; D000328:Adult; D000368:Aged; D000818:Animals; D001323:Autoantibodies / Q000096:biosynthesis* / Q000502:physiology; D001324:Autoantigens / Q000737:chemistry / Q000276:immunology*; D015415:Biomarkers / Q000097:blood / Q000134:cerebrospinal fluid; D002648:Child; D002675:Child, Preschool; D004660:Encephalitis / Q000175:diagnosis / Q000276:immunology* / Q000378:metabolism; D005260:Female; D057809:HEK293 Cells; D006801:Humans; D008297:Male; D008875:Middle Aged; D019581:Neuropil / Q000737:chemistry / Q000276:immunology / Q000378:metabolism; D051381:Rats; D011963:Receptors, GABA-A / Q000276:immunology / Q000378:metabolism* / Q000502:physiology; D012640:Seizures / Q000175:diagnosis / Q000276:immunology* / Q000378:metabolism; D013226:Status Epilepticus / Q000175:diagnosis / Q000276:immunology* / Q000378:metabolism; D055815:Young Adult
D001323:Autoantibodies; D001324:Autoantigens; D015415:Biomarkers; D011963:Receptors, GABA-A