Gadoth, Avi

The clinical phenotype of leucine‐rich glioma‐inactivated protein 1 (LGI1) and contactin‐associated proteinlike 2 (CASPR2) autoimmunity is well defined in adults. Data for children are limited (<10 cases). Among 13,319 pediatric patients serologically tested for autoimmune neurological disorders (2010–2017), 264 were seropositive for voltage‐gated potassium channel‐complex–IgG (radioimmunoprecipitation). Only 13 (4.9%) were positive by transfected cell‐binding assay for LGI1‐IgG (n = 7), CASPR2‐IgG (n = 3), or both (n = 3). This is significantly less than in adults. Encephalopathy, seizures, and peripheral nerve hyperexcitability were common, as was coexisting autoimmunity. No faciobrachial dystonic seizures or cancers were identified. Functional neurologic disorders were frequently the initial diagnosis, and immunotherapy appeared beneficial. Ann Neurol 2018;84:473–480

SummaryObjectiveTo characterize seizure semiology and the utility of antiepileptic drug (AED) therapy in leucine‐rich glioma inactivated‐1 ( LGI1‐Ab) autoimmune epilepsy (AE).MethodsPatients with voltage‐gated potassium channel complex (VGKCc) titers higher than 0.02 nmol/L who were evaluated between May 2008 and June 2016 at the 3 Mayo Clinic sites (Arizona, Florida, or Minnesota) were identified. We then performed a retrospective review of those who were LGI1‐Ab positive and were treated for seizures.ResultsA total of 1,095 patients with VGKCc titers higher than 0.02 nmol/L were identified, in which 77 were LGI1 positive. Of these, 56 patients with seizures were included in the analysis. Mean age at symptom onset was 62.9 years; 66% (n = 37) were male. The most common seizure semiology was focal faciobrachial dystonic seizures with preserved awareness (FBDS) (n = 35, 63%), followed by focal with impaired awareness (FIA) (n = 29, 52%), generalized tonic–clonic (GTCs) (n = 28, 50%), and focal non‐motor seizures with preserved awareness (n = 28, 50%). The majority had more than one seizure type (n = 49, 88%; median = 2.5). Thirty‐eight patients (68%) became seizure free: 29 (76%) with immunotherapy, 3 (5%) with AEDs alone, 2 (3%) with AEDs before any immunotherapy, and 4 (7%) with AEDs after immunotherapy. Levetiracetam (n = 47, 84%) and valproic acid (n = 21, 38%) were the most commonly used AEDs, but neither were associated with seizure freedom. Sodium channel blocking (NCB) AEDs were associated with seizure freedom in 4 patients compared to none treated with non‐NCB AEDs. Regardless of class, AEDs prior to or apart from immunotherapy were associated with seizure freedom in only five patients (9%). In patients with FBDS, seizure freedom was more often associated with immunotherapy than AEDs (20/30 vs. 3/34, p = 0.001).SignificanceAlthough FBDS are the most characteristic seizure type seen in LGI1‐Ab AE, other seizure types including FIA and GTCs also occur. Immunotherapy was the treatment most frequently associated with seizure freedom in LGI1‐Ab AE. In general, AEDs seemed to confer a very low chance for seizure freedom, although AEDs with NCB‐blocking properties were associated with seizure freedom in a limited number. Levetiracetam in particular appears to be ineffective in this patient population.

AbstractTo determine whether CSF leucine‐rich glioma‐inactivated 1(LGI1)‐IgG titer, index or IgG subclass has prognostic significance, we tested serum and CSF specimens collected concomitantly from 39 seropositive patients. LGI1‐IgG index was elevated (>1) in 21 patients (54%), suggesting intrathecal synthesis. Patients with worse outcome at last follow‐up (modified Rankin Scale >2) had significantly higher index (median 6.57 vs. 0.5, P = 0.048) compared to those with better outcome. Higher CSF LGI1‐IgG4 subclass‐specific titer and index correlated with worse outcome (P < 0.005 for both). These data suggest that evidence of intrathecal LGI1‐IgG synthesis may correlate with neuronal injury and warrant consideration of aggressive immunotherapy.

Objective To evaluate the incidence and prevalence of autoimmune encephalitis and compare it to that of infectious encephalitis. Methods We performed a population‐based comparative study of the incidence and prevalence of autoimmune and infectious encephalitis in Olmsted County, Minnesota. Autoimmune encephalitis diagnosis and subgroups were defined by 2016 diagnostic criteria, and infectious encephalitis diagnosis required a confirmed infectious pathogen. Age‐ and sex‐adjusted prevalence and incidence rates were calculated. Patients with encephalitis of uncertain etiology were excluded. Results The prevalence of autoimmune encephalitis on January 1, 2014 of 13.7/100,000 was not significantly different from that of all infectious encephalitides (11.6/100,000; p = 0.63) or the viral subcategory (8.3/100,000; p = 0.17). The incidence rates (1995–2015) of autoimmune and infectious encephalitis were 0.8/100,000 and 1.0/100,000 person‐years, respectively ( p = 0.58). The number of relapses or recurrent hospitalizations was higher for autoimmune than infectious encephalitis ( p = 0.03). The incidence of autoimmune encephalitis increased over time from 0.4/100,000 person‐years (1995–2005) to 1.2/100,000 person‐years (2006–2015; p = 0.02), attributable to increased detection of autoantibody‐positive cases. The incidence (2.8 vs 0.7/100,000 person‐years, p = 0.01) and prevalence (38.3 vs 13.7/100,000, p = 0.04) of autoimmune encephalitis was higher among African Americans than Caucasians. The prevalence of specific neural autoantibodies was as follows: myelin oligodendrocyte glycoprotein, 1.9/100,000; glutamic acid decarboxylase 65, 1.9/100,000; unclassified neural autoantibody, 1.4/100,000; leucine‐rich glioma‐inactivated protein 1, 0.7/100,000; collapsin response‐mediator protein 5, 0.7/100,000; N‐methyl‐D‐aspartate receptor, 0.6/100,000; antineuronal nuclear antibody type 2, 0.6/100,000; and glial fibrillary acidic protein α, 0.6/100,000. Interpretation This study shows that the prevalence and incidence of autoimmune encephalitis are comparable to infectious encephalitis, and its detection is increasing over time. Ann Neurol 2018;83:166–177

Objective To describe an expanded phenotypic spectrum and longitudinal outcome in 256 LGI1‐IgG–seropositive and/or CASPR2‐IgG–seropositive patients. Methods Patients were identified through service neural autoantibody evaluation. Ninety‐five had longitudinal follow‐up (7–456 months; median = 35). Results Among 3,910 patients tested, 196 were LGI1‐IgG positive, 51 were CASPR2‐IgG positive, and 9 were dual positive. Cerebrospinal fluid testing was less sensitive than serum testing, detecting only 24 of 38 (63%) LGI1‐IgG–positive and 5 of 6 (83%) CASPR2‐IgG–positive patients. LGI1‐IgG–positive specimens had higher voltage‐gated potassium channel–IgG immunoprecipitation values (0.33nmol/l, range = 0.02–5.14) than CASPR2‐IgG–positive specimens (0.10nmol/l, range = 0.00–0.45, p < 0.001). Of patients presenting with pain or peripheral nervous system (PNS) manifestations, 39% were LGI1‐IgG seropositive (7% had solely neuropathy or pain). Multivariate analysis identified age as the only significant predictor of central nervous system (CNS) versus PNS involvement (>50 years; odds ratio = 15, p < 0.001). Paroxysmal dizziness spells (PDS), a unique LGI1‐IgG accompaniment (14% of patients), frequently delayed the diagnosis. T2‐mesiotemporal hyperintensity was more common in LGI1‐IgG–positive (41%) than in CASPR2‐IgG–positive patients ( p = 0.033). T1‐bright basal ganglia were confined to LGI1‐IgG–positive patients with faciobrachial–dystonic seizures (9 of 39, 31%). Cancer was found in 44% of LGI1‐IgG/CASPR2‐IgG dual seropositive patients (one‐third thymoma). Response to initial immunotherapy was favorable in 97%; mean modified Rankin score was 3 (range = 1–5) at onset and 1.74 (range = 0–6) at last follow‐up, with 9% having severe refractory disability, 20% being asymptomatic, 28% receiving immunotherapy, and 58% receiving antiepileptic medication. Interpretation Older age is a strong predictor of CNS involvement in patients seropositive for CASPR2‐IgG or LGI1‐IgG. Pain, peripheral manifestations, and stereotypic paroxysmal dizziness spells are common with LGI1‐IgG. Response to initial immunotherapy is often favorable, but some patients remain severely disabled, requiring long‐term immunotherapy and/or antiepileptic medications. Ann Neurol 2017;82:79–92