Summary 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 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). 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 Rese...

OBJECTIVE To determine whether early anatomical injury patterns in MRI correlate with the development of post-neonatal epilepsy in infants treated with selective head cooling for hypoxic ischemic encephalopathy. STUDY DESIGN A retrospective study of infants ≥35 weeks’ gestation born between 2008 and 2013 and followed for at least one year at Northwestern University. All had brain MRI at day 4–5 and EEGs during rewarming and at 3 to 6 months of age. RESULTS Outcome was favorable for our cohort of 73 with mean follow-up of 41 (± 7) months. The majority (66%) survived with no seizure recurrence, while 13 (18%) developed post neonatal epilepsy including 8, who had infantile spasms. Twelve infants (16%) died. The most common MRI pattern was diffuse brain injury involving both cortical and subcortical gray matter (26/73, 35%) followed by cortical and subcortical white matter injury (18/73, 25%), and normal MRI (16/73, 22%). In 13 infants (18%), the brainstem was involved in addition to cortical and subcortical gray matter; 9 died and all 4 surviving infants developed infantile spams. All 18 infants with cortical and subcortical white matter injury survived and none developed post neonatal epilepsy. Risk of post neonatal epilepsy was associated with injury involving subcortical regions (basal ganglia, thalamus ± brainstem) (12/39 vs 1/34, p<0.003). CONCLUSIONS Brainstem injury was highly predictive of infantile spams while cortical injury alone predicted low risk for short term post neonatal epilepsy. Location of anatomical injury on MRI can be an early predictive factor for development of infantile spams and inform prognostic decisions in newborns treated with selective head cooling for hypoxic ischemic encephalopathy.

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Although evidence supports the use of double-blind placebo medication trials to evaluate methylphenidate (MPH) effects on the core behavioral symptoms of attention-deficit/hyperactivity disorder (ADHD), few studies have demonstrated their utility in examining MPH effects on the cognitive deficits associated with ADHD. This article presents a technique for evaluating behavioral and cognitive dose-response relationships at the single-subject level of analysis. Case study results and multivariate analyses suggest that systematic evaluation of behavioral and cognitive MPH dose-response relationships could lead to more accurate MPH titration and greater long-term multimodal treatment efficacy.