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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
#MMPMID24462240
Petit-Pedrol M
; Armangue T
; Peng X
; Bataller L
; Cellucci T
; Davis R
; McCracken L
; Martinez-Hernandez E
; Mason WP
; Kruer MC
; Ritacco DG
; Grisold W
; Meaney BF
; Alcalá C
; Sillevis-Smitt P
; Titulaer MJ
; Balice-Gordon R
; Graus F
; Dalmau J
Lancet Neurol
2014[Mar]; 13
(3
): 276-86
PMID24462240
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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.
FINDINGS: Neuronal cell-membrane immunoprecipitation with serum of two index
patients revealed GABAA receptor sequences. Cell-based assay with HEK293
expressing ?1/?3 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). INTERPRETATION: 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.
FUNDING: 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.
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