Neurological Syndromes Associated with Anti-GAD Antibodies.

Glutamic acid decarboxylase (GAD) is an intracellular enzyme whose physiologic function is the decarboxylation of glutamate to gamma-aminobutyric acid (GABA), the main inhibitory neurotransmitter within the central nervous system. GAD antibodies (Ab) have been associated with multiple neurological syndromes, including stiff-person syndrome, cerebellar ataxia, and limbic encephalitis, which are all considered to result from reduced GABAergic transmission. The pathogenic role of GAD Ab is still debated, and some evidence suggests that GAD autoimmunity might primarily be cell-mediated. Diagnosis relies on the detection of high titers of GAD Ab in serum and/or in the detection of GAD Ab in the cerebrospinal fluid. Due to the relative rarity of these syndromes, treatment schemes and predictors of response are poorly defined, highlighting the unmet need for multicentric prospective trials in this population. Here, we reviewed the main clinical characteristics of neurological syndromes associated with GAD Ab, focusing on pathophysiologic mechanisms.

Spatial and Ecological Factors Modulate the Incidence of Anti-NMDAR Encephalitis-A Systematic Review.

Anti-NMDAR encephalitis has been associated with multiple antigenic triggers (i.e., ovarian teratomas, prodromal viral infections) but whether geographic, climatic, and environmental factors might influence disease risk has not been explored yet. We performed a systematic review and a meta-analysis of all published papers reporting the incidence of anti-NMDAR encephalitis in a definite country or region. We performed several multivariate spatial autocorrelation analyses to analyze the spatial variations in the incidence of anti-NMDA encephalitis depending on its geographical localization and temperature. Finally, we performed seasonal analyses in two original datasets from France and Greece and assessed the impact of temperature using an exposure-lag-response model in the French dataset. The reported incidence of anti-NMDAR encephalitis varied considerably among studies and countries, being higher in Oceania and South America (0.2 and 0.16 per 100,000 persons-year, respectively) compared to Europe and North America (0.06 per 100,000 persons-year) (p < 0.01). Different regression models confirmed a strong negative correlation with latitude (Pearson's R = -0.88, p < 0.00001), with higher incidence in southern hemisphere countries far from the equator. Seasonal analyses showed a peak of cases during warm months. Exposure-lag-response models confirmed a positive correlation between extreme hot temperatures and the incidence of anti-NMDAR encephalitis in France (p = 0.03). Temperature analyses showed a significant association with higher mean temperatures and positive correlation with higher ultraviolet exposure worldwide. This study provides the first evidence that geographic and climatic factors including latitude, mean annual temperature, and ultraviolet exposure, might modify disease risk.

Quantitative brain imaging analysis of neurological syndromes associated with anti-GAD antibodies.

Neurological disorders associated with anti-glutamic acid decarboxylase (GAD) autoimmunity are rare and include a variety of neurological syndromes: stiff-person syndrome, cerebellar ataxia or limbic encephalitis. The diagnosis remains challenging due to the variety of symptoms and normal brain imaging. The morphological MRI of 26 patients (T1-weighted and Fluid-attenuated inversion recovery (FLAIR)-weighted images) was analyzed at the initial stage of diagnosis, matched by age and sex to 26 healthy subjects. We performed a vertex-wise analysis using a generalized linear model, adjusting by age, to compare the brain cortical thickness of both populations. In addition, we used a voxel-based morphometry of cerebellum thickness obtained by CEREbellum Segmentation (CERES), as well as the hippocampus volumetry comparison using HIPpocampus subfield Segmentation (HIPS). Finally, we extracted 62 radiomics features using LifeX to assess the classification performance using a random forest model to identify an anti-GAD related MRI. The results suggest a peculiar profile of atrophy in patients with anti-GAD, with a significant atrophy in the temporal and frontal lobes (adjusted p-value < 0.05), and a focal cerebellar atrophy of the V-lobule, independently of the anti-GAD phenotype. Finally, the MRIs from anti-GAD patients were correctly classified when compared to the control group, with an area under the curve (AUC) of 0.98. This study suggests a particular pattern of cortical atrophy throughout all anti-GAD phenotypes. These results reinforce the notion that the different neurological anti-GAD phenotypes should be considered as a continuum due to their similar cortical thickness profiles.