Nonparaneoplastic Anti-GAD Limbic Encephalitis: Seizure Outcome and Long-term Neuropsychological Follow-up After Immunotherapy.

Antibodies against glutamate decarboxylase (GAD-Abs), especially GAD65 antibodies, are associated with limbic encephalitis (LE) manifested by temporal lobe epilepsy and neuropsychological deficits. We present the case of a 42-year-old Greek woman with nonparaneoplastic anti-GAD LE, discussing the therapeutic management and highlighting the role of neuropsychological assessment. The patient underwent functional and structural brain studies and was investigated longitudinally over a 6-year period with a battery of neuropsychological tests that were designed to document her intellectual function and verbal and visual memory. The patient suffered from refractory temporal-impaired awareness seizures and memory impairment that was mediated by autoimmune nonparaneoplastic LE and comorbid autoimmune disorders (ie, Hashimoto thyroiditis and vitiligo). Neuroimaging studies demonstrated hyperintensities in the medial temporal lobes bilaterally on T2WI MRI sequences. Serial EEGs showed bitemporal intermittent delta activity as well as epileptiform discharges. Tumor blood markers and onconeural antibodies were negative. Immunological screening revealed extremely high GAD-Abs titers in both serum and CSF, as well as the presence of CSF oligoclonal bands. Neuropsychological testing revealed anterograde amnesia with relative preservation of more remote, premorbid memories. The patient underwent first-line immunotherapy followed by immunosuppressive maintenance treatment that led to a reduction of seizures, EEG improvement, and a significant decline in GAD-Abs titers. Neuropsychological evaluations at 5 months, 1 year, and 6 years posttreatment demonstrated improvement, particularly in recent memory and everyday functionality. In this case of anti-GAD LE, the long-term seizure reduction and the improvement of neuropsychological deficits were most likely related to the immunotherapy.

Anti-Neuronal Antibodies Within the IVIg Preparations: Importance in Clinical Practice.

Our study objective was testing for anti-neuronal autoantibodies within commercially available intravenous immunoglobulin (IVIg) preparations. Sixteen samples from 5 different commercially available IVIg preparations were tested with cell-based assays (CBA) and enzyme-linked immunosorbent assay (ELISA) to detect and characterize common neuronal autoantibodies, and with immunohistochemistry on teased fibers from mouse sciatic nerve and on mouse brain sections to screen for nodal and not yet identified neuronal antigens. In 15/16 IVIg preparations, anti-GAD antibodies were detected in titers ranging from 40 to 1507 IU/mL, as typically seen in type 1 diabetes, but not in the range (> 2000 IU/mL) seen in GAD-positive neurological patients. None of the preparations was however positive with anti-GAD CBA. Antibodies to AQP4 were also detected by ELISA in 15/16 IVIg preparations with titers comparable to those seen in AQP4-seropositive NMO patients; with CBA, however, all IVIg samples were AQP4-negative. IVIg preparations contained IgG-anti-MAG antibodies by ELISA at statistically significant higher titers compared to controls. Two of the 16 IVIg samples were positive for human 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR) antibodies. All IVIg preparations were negative for antibodies to MOG, NMDAR, anti-nodal, and other neuronal-specific proteins. IVIg preparations contain antibodies against GAD and AQP4 in titers comparable to those seen in autoimmune patients when tested by ELISA, but not by CBA or tissue immunohistochemistry, suggesting that the autoantibodies within the IVIg are against linear rather than structural epitopes, as part of the natural antibody immune repertoire. The information is clinically important for diagnosis when testing patients' sera after they have received therapy with IVIg to avoid false interpretation.

Parkinsonism in autoimmune diseases.

Parkinsonism can be manifested and complicate either systemic or organ-specific autoimmune diseases. Even though it is a rare co-morbidity, it merits attention from clinicians as it affects the quality of life of patients. In systemic autoimmune diseases such as systemic lupus erythematosus, antiphospholipid syndrome and Sjogren's syndrome reported cases of parkinsonism are attributed to the underlying disease and its mechanisms, whether this is brain vasculitis or immune complexes. Regarding antibody-mediated autoimmune neurological disorders, parkinsonism is, in most cases, a manifestation within the spectrum of each disorder and is attributed to the action of humoral and cellular immunity in brain regions such as the basal ganglia. Depending on the pathophysiology, immunotherapy can be effective, while Parkinson's specific therapies are usually less effective.

New-Onset Refractory Status Epilepticus with Claustrum Damage: Definition of the Clinical and Neuroimaging Features.

New-onset refractory status epilepticus (NORSE) is a rare but challenging condition occurring in a previously healthy patient, often with no identifiable cause. We describe the electro-clinical features and outcomes in a group of patients with NORSE who all demonstrated a typical magnetic resonance imaging (MRI) sign characterized by bilateral lesions of the claustrum. The group includes 31 patients (12 personal and 19 previously published cases; 17 females; mean age of 25 years). Fever preceded status epilepticus (SE) in 28 patients, by a mean of 6 days. SE was refractory/super-refractory in 74% of the patients, requiring third-line agents and a median of 15 days staying in an intensive care unit. Focal motor and tonic-clonic seizures were observed in 90%, complex partial seizures in 14%, and myoclonic seizures in 14% of the cases. All patients showed T2/FLAIR hyperintense foci in bilateral claustrum, appearing on average 10 days after SE onset. Other limbic (hippocampus, insular) alterations were present in 53% of patients. Within the personal cases, extensive search for known autoantibodies was inconclusive, though 7 of 11 patients had cerebrospinal fluid lymphocytic pleocytosis and 3 cases had oligoclonal bands. Two subjects died during the acute phase, one in the chronic phase (probable sudden unexplained death in epilepsy), and one developed a persistent vegetative state. Among survivors, 80% developed drug-resistant epilepsy. Febrile illness-related SE associated with bilateral claustrum hyperintensity on MRI represents a condition with defined clinical features and a presumed but unidentified autoimmune etiology. A better characterization of de novo SE is mandatory for the search of specific etiologies.

Neuronal surface and glutamic acid decarboxylase autoantibodies in Nonparaneoplastic stiff person syndrome.

IMPORTANCE: High titers of autoantibodies to glutamic acid decarboxylase (GAD) are well documented in association with stiff person syndrome (SPS). Glutamic acid decarboxylase is the rate-limiting enzyme in the synthesis of γ-aminobutyric acid (GABA), and impaired function of GABAergic neurons has been implicated in the pathogenesis of SPS. Autoantibodies to GAD might be the causative agent or a disease marker. OBJECTIVE: To investigate the characteristics and potential pathogenicity of GAD autoantibodies in patients with SPS and related disorders. DESIGN: Retrospective cohort study and laboratory investigation. SETTING: Weatherall Institute of Molecular Medicine, University of Oxford. PARTICIPANTS: Twenty-five patients with SPS and related conditions identified from the Neuroimmunology Service. EXPOSURES: Neurological examination, serological characterization and experimental studies. MAIN OUTCOMES AND MEASURES: Characterization of serum GAD antibodies from patients with SPS and evidence for potential pathogenicity. RESULTS: We detected GAD autoantibodies at a very high titer (median, 7500 U/mL) in 19 patients (76%), including all 12 patients with classic SPS. The GAD autoantibodies were high affinity (antibody dissociation constant, 0.06-0.78 nmol) and predominantly IgG1 subclass. The patients' autoantibodies co-localized with GAD on immunohistochemistry and in permeabilized cultured cerebellar GABAergic neurons, as expected, but they also bound to the cell surface of unpermeabilized GABAergic neurons. Adsorption of the highest titer (700 000 U/mL) serum with recombinant GAD indicated that these neuronal surface antibodies were not directed against GAD itself. Although intraperitoneal injection of IgG purified from the 2 available GAD autoantibody­ositive purified IgG preparations did not produce clinical or pathological evidence of disease, SPS and control IgG were detected in specific regions of the mouse central nervous system, particularly around the lateral and fourth ventricles. CONCLUSIONS AND RELEVANCE: Autoantibodies to GAD are associated with antibodies that bind to the surface of GABAergic neurons and that could be pathogenic. Moreover, in mice, human IgG from the periphery gained access to relevant areas in the hippocampus and brainstem. Identification of the target of the non-GAD antibodies and peripheral and intrathecal transfer protocols, combined with adsorption studies, should be used to demonstrate the role of the non-GAD IgG in SPS.

Adaptive sugar sensors in hypothalamic feeding circuits.

Brain glucose sensing is critical for healthy energy balance, but how appropriate neurocircuits encode both small changes and large background values of glucose levels is unknown. Here, we report several features of hypothalamic orexin neurons, cells essential for normal wakefulness and feeding: (i) A distinct group of orexin neurons exhibits only transient inhibitory responses to sustained rises in sugar levels; (ii) this sensing strategy involves time-dependent recovery from inhibition via adaptive closure of leak-like K(+) channels; (iii) combining transient and sustained glucosensing allows orexin cell firing to maintain sensitivity to small fluctuations in glucose levels while simultaneously encoding a large range of baseline glucose concentrations. These data provide insights into how vital behavioral orchestrators sense key features of the internal environment while sustaining a basic activity tone required for the stability of consciousness.

Tandem-pore K+ channels mediate inhibition of orexin neurons by glucose.

Glucose-inhibited neurons orchestrate behavior and metabolism according to body energy levels, but how glucose inhibits these cells is unknown. We studied glucose inhibition of orexin/hypocretin neurons, which promote wakefulness (their loss causes narcolepsy) and also regulate metabolism and reward. Here we demonstrate that their inhibition by glucose is mediated by ion channels not previously implicated in central or peripheral glucose sensing: tandem-pore K(+) (K(2P)) channels. Importantly, we show that this electrical mechanism is sufficiently sensitive to encode variations in glucose levels reflecting those occurring physiologically between normal meals. Moreover, we provide evidence that glucose acts at an extracellular site on orexin neurons, and this information is transmitted to the channels by an intracellular intermediary that is not ATP, Ca(2+), or glucose itself. These results reveal an unexpected energy-sensing pathway in neurons that regulate states of consciousness and energy balance.

Metabolic state signalling through central hypocretin/orexin neurons.

Hypothalamic neurons that produce the peptide transmitters hypocretins/orexins have attracted much recent attention. They provide direct and predominantly excitatory inputs to all major brain areas except the cerebellum, with the net effect of stimulating wakefulness and arousal. These inputs are essential for generating sustained wakefulness in mammals, and defects in hypocretin signalling result in narcolepsy. In addition, new roles for hypocretins/orexins are emerging in reward-seeking, learning, and memory. Recent studies also indicate that hypocretin/orexin neurons can alter their intrinsic electrical activity according to ambient fluctuations in the levels of nutrients and appetite-regulating hormones. These intriguing electrical responses are perhaps the strongest candidates to date for the elusive neural correlates of after-meal sleepiness and hunger-induced wakefulness. Hypocretin/orexin neurons may thus directly translate rises and falls in body energy levels into different states of consciousness.

Low-voltage-activated A-current controls the firing dynamics of mouse hypothalamic orexin neurons.

The activity of hypothalamic neurons that release the neuropeptides orexin-A and orexin-B is essential for normal wakefulness. Orexin neurons fire spontaneously and are hyperpolarized and inhibited by physiological neuromodulators, but the intrinsic determinants of their electrical activity are poorly understood. We show that mouse orexin neurons coexpress orexin-A and orexin-B, and possess a low-voltage-activated A-type K(+) current (A-current) likely to be composed of Kv4.3 subunits. The A-current enhances the inhibitory influence of hyperpolarizing currents via two mechanisms: by delaying the resumption of spiking after hyperpolarization and by increasing the slope of the relation between the firing frequency and injected current. These results identify an important determinant of the firing dynamics of orexin neurons, and support the idea that the A-current can control neuronal gain.