Risk of Seizure Recurrence Due to Autoimmune Encephalitis With NMDAR, LGI1, CASPR2, and GABABR Antibodies: Implications for Return to Driving.

BACKGROUND AND OBJECTIVES: Patients with ongoing seizures are usually not allowed to drive. The prognosis for seizure freedom is favorable in patients with autoimmune encephalitis (AIE) with antibodies against NMDA receptor (NMDAR), leucine-rich glioma-inactivated 1 (LGI1), contactin-associated protein-like 2 (CASPR2), and the gamma-aminobutyric-acid B receptor (GABABR). We hypothesized that after a seizure-free period of 3 months, patients with AIE have a seizure recurrence risk of <20% during the subsequent 12 months. This would render them eligible for noncommercial driving according to driving regulations in several countries. METHODS: This retrospective multicenter cohort study analyzed follow-up data from patients aged 15 years or older with seizures resulting from NMDAR-, LGI1-, CASPR2-, or GABABR-AIE, who had been seizure-free for ≥3 months. We used Kaplan-Meier (KM) estimates for the seizure recurrence risk at 12 months for each antibody group and tested for the effects of potential covariates with regression models. RESULTS: We included 383 patients with NMDAR-, 440 with LGI1-, 114 with CASPR2-, and 44 with GABABR-AIE from 14 international centers. After being seizure-free for 3 months after an initial seizure period, we calculated the probability of remaining seizure-free for another 12 months (KM estimate) as 0.89 (95% confidence interval [CI] 0.85-0.92) for NMDAR, 0.84 (CI 0.80-0.88) for LGI1, 0.82 (CI 0.75-0.90) for CASPR2, and 0.76 (CI 0.62-0.93) for GABABR. DISCUSSION: Taking a <20% recurrence risk within 12 months as sufficient, patients with NMDAR-AIE and LGI1-AIE could be considered eligible for noncommercial driving after having been seizure-free for 3 months.

Leucine-Rich Glioma-Inactivated 1 versus Contactin-Associated Protein-like 2 Antibody Neuropathic Pain: Clinical and Biological Comparisons.

Pain is a under-recognized association of leucine-rich glioma-inactivated 1 (LGI1) and contactin-associated protein-like 2 (CASPR2) antibodies. Of 147 patients with these autoantibodies, pain was experienced by 17 of 33 (52%) with CASPR2- versus 20 of 108 (19%) with LGI1 antibodies (p = 0.0005), and identified as neuropathic in 89% versus 58% of these, respectively. Typically, in both cohorts, normal nerve conduction studies and reduced intraepidermal nerve fiber densities were observed in the sampled patient subsets. In LGI1 antibody patients, pain responded to immunotherapy (p = 0.008), often rapidly, with greater residual patient-rated impairment observed in CASPR2 antibody patients (p = 0.019). Serum CASPR2 antibodies, but not LGI1 antibodies, bound in vitro to unmyelinated human sensory neurons and rodent dorsal root ganglia, suggesting pathophysiological differences that may underlie our clinical observations. ANN NEUROL 2021;90:683-690.

Autoimmune encephalitis: clinical spectrum and management.

Autoimmune encephalitis defines brain inflammation caused by a misdirected immune response against self-antigens expressed in the central nervous system. It comprises a heterogeneous group of disorders that are at least as common as infectious causes of encephalitis. The rapid and ongoing expansion of this field has been driven by the identification of several pathogenic autoantibodies that cause polysymptomatic neurological and neuropsychiatric diseases. These conditions often show highly distinctive cognitive, seizure and movement disorder phenotypes, making them clinically recognisable. Their early identification and treatment improve patient outcomes, and may aid rapid diagnosis of an underlying associated tumour. Here we summarise the well-known autoantibody-mediated encephalitis syndromes with neuronal cell-surface antigens. We focus on practical aspects of their diagnosis and treatment, offer our clinical experiences of managing such cases and highlight more basic neuroimmunological advances that will inform their future diagnosis and treatments.

Overexpression of PPARγ specifically in pancreatic ß-cells exacerbates obesity-induced glucose intolerance, reduces ß-cell mass, and alters islet lipid metabolism in male mice.

The contribution of peroxisomal proliferator-activated receptor (PPAR)-γ agonism in pancreatic ß-cells to the antidiabetic actions of thiazolidinediones has not been clearly elucidated. Genetic models of pancreatic ß-cell PPARγ ablation have revealed a potential role for PPARγ in ß-cell expansion in obesity but a limited role in normal ß-cell physiology. Here we overexpressed PPARγ1 or PPARγ2 specifically in pancreatic ß-cells of mice subjected to high-fat feeding using an associated adenovirus (ß-PPARγ1-HFD and ß-PPARγ2-HFD mice). We show ß-cell-specific PPARγ1 or PPARγ2 overexpression in diet-induced obese mice exacerbated obesity-induced glucose intolerance with decreased ß-cell mass, increased islet cell apoptosis, and decreased plasma insulin compared with obese control mice (ß-eGFP-HFD mice). Analysis of islet lipid composition in ß-PPARγ2-HFD mice revealed no significant changes in islet triglyceride content and an increase in only one of eight ceramide species measured. Interestingly ß-PPARγ2-HFD islets had significantly lower levels of lysophosphatidylcholines, lipid species shown to enhance insulin secretion in ß-cells. Gene expression profiling revealed increased expression of uncoupling protein 2 and genes involved in fatty acid transport and ß-oxidation. In summary, transgenic overexpression of PPARγ in ß-cells in diet-induced obesity negatively impacts whole-animal carbohydrate metabolism associated with altered islet lipid content, increased expression of ß-oxidative genes, and reduced ß-cell mass.

Overexpression of peroxisome proliferator-activated receptor α in pancreatic ß-cells improves glucose tolerance in diet-induced obese mice.

Lipotoxicity is implicated in pancreatic ß-cell dysfunction in obesity-induced type 2 diabetes. In vitro, activation of peroxisome proliferator-activated receptor α (PPARα) has been shown to protect pancreatic ß-cells from the lipotoxic effects of palmitate, thereby preserving insulin secretion. Utilizing an adeno-associated virus (dsAAV8), overexpression of PPARα was induced specifically in pancreatic ß-cells of adult, C57Bl/6 mice fed a high-fat diet for 20 weeks and carbohydrate metabolism and ß-cell mass assessed. We show that overexpression of PPARα in pancreatic ß-cells in vivo preserves ß-cell function in obesity, and this improves glucose tolerance by preserving insulin secretion in comparison to control mice with diet-induced obesity. No changes in ß-cell mass were observed in PPARα-overexpressing mice compared with diet-induced obese control animals. This model of ß-cell-specific PPARα overexpression provides a useful in vivo model for elucidating the mechanisms underlying ß-cell lipotoxicity in obesity-induced type 2 diabetes.