Seizures in autoimmune encephalitis-A systematic review and quantitative synthesis.

OBJECTIVE: This study aimed to evaluate the proportion of patients with seizures and electroencephalography (EEG) abnormalities in autoimmune encephalitis (AE) and its most common subtypes. METHODS: This systematic review followed Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) standards and was registered with the International Prospective Register of Systematic Reviews (PROSPERO). We searched Medline All, Embase, and PsychINFO in Ovid from inception to June 2019 for articles pertaining to AE and seizure. Included studies reported seizure and/or EEG data in cohorts of ≥10 AE patients. Patient demographics, antibody type, seizure incidence, and EEG findings were extracted. Review of studies and data extraction were performed in duplicate. In addition to descriptive analysis, quantitative synthesis stratified by autoantibody subtype was performed with logistic regression and chi-square analyses. RESULTS: Our search yielded 3856 abstracts: 1616 were selected for full-text review and 118 studies met eligibility criteria. Of 3722 antibody-positive AE patients, 2601 (69.9%) had clinical seizures during the course of their illness. Of the 2025 patients with antibody-positive AE and available EEG data, 1718 (84.8%) had some EEG abnormality (eg, epileptiform discharges, slowing, and so on). Anti- N-methyl-d-aspartate (NMDA) receptor encephalitis (anti-NMDARE) was the most commonly reported type of AE (1985/3722, 53.3%). Of the anti-NMDARE patients with available seizure or EEG data, 71.8% (n = 1425/1985) had clinical seizures during their illness, and 89.7% (n = 1172/1306) had EEG abnormalities. For all AE patients and in the anti-NMDARE subpopulation, seizures were more common in younger patients (p < .05). SIGNIFICANCE: This systematic review provides an estimate of the proportion of AE patients with seizures, confirming the magnitude of seizure burden in this population. Prospective studies are needed to understand population-based prevalence of seizures, identify factors associated with seizures, and evaluate particular EEG findings as biomarkers of seizures and outcomes in AE.

The long-term outcome of neuropsychological function is favorable in patients with non-malignancy related anti-GABABR encephalitis: a case series.

BACKGROUND: Anti-GABABR encephalitis is a rare type of autoimmune encephalitis, which often presents with memory impairments, behavioral changes and seizures. This case series describes the neuropsychological function recovery pattern in five adult patients with anti-GABABR encephalitis. CASE PRESENTATION: We recruited five patients with clinically confirmed anti-GABABR encephalitis without any accompanying malignancy. Comprehensive neuropsychological evaluation was conducted on each patient. All the five patients were evaluated in the chronic phase. Five age and gender matched healthy adults were recruited as control group. Our study demonstrated that the neuropsychological function of the patients with anti-GABABR encephalitis was no different with respect to the control group during the chronic phase (more than 6 months after onset). Moreover, one patients with neuropsychological evaluation at acute (within 2 months after onset of symptoms), post-acute (2 to 6 months after onset) and chronic phases respectively, presented neuropsychological function recovered as early as in the post-acute phase and only showed cognition impairment in the acute phase. CONCLUSIONS: The results of this retrospective study indicate a favorable long-term neuropsychological function outcome in adult patients with anti-GABABR encephalitis, despite severe memory deficits occurring during the acute phase. These findings improve our understanding related to the prognosis of neuropsychological function in anti-GABABR encephalitis.

A Rationale for Allopregnanolone Treatment of Alcohol Use Disorders: Basic and Clinical Studies.

For many years, research from around the world has suggested that the neuroactive steroid (3α,5α)-3-hydroxypregnan-20-one (allopregnanolone or 3α,5α-THP) may have therapeutic potential for treatment of various symptoms of alcohol use disorders (AUDs). In this critical review, we systematically address all the evidence that supports such a suggestion, delineate the etiologies of AUDs that are addressed by treatment with allopregnanolone or its precursor pregnenolone, and the rationale for treatment of various components of the disease based on basic science and clinical evidence. This review presents a theoretical framework for understanding how endogenous steroids that regulate the effects of stress, alcohol, and the innate immune system could play a key role in both the prevention and the treatment of AUDs. We further discuss cautions and limitations of allopregnanolone or pregnenolone therapy with suggestions regarding the management of risk and the potential for helping millions who suffer from AUDs.

Clinical characteristics and prognostic analysis of anti-gamma-aminobutyric acid-B (GABA-B) receptor encephalitis in Northeast China.

OBJECTIVE: To investigate the clinical characteristics and prognosis of anti-gamma-aminobutyric acid-B (GABA-B) receptor encephalitis. METHODS: This retrospective study enrolled nineteen patients with anti-GABA-B receptor encephalitis. Clinical manifestations, radiological and electroencephalogram features, treatment and outcomes were collected and analyzed. The neurological function was evaluated according to the modified Rankin Scale (mRS). RESULTS: There were eleven patients in the favorable-prognosis group (mRS ≤ 2) and eight patients in the poor-prognosis group (mRS > 2). In the favorable-prognosis group, clinical symptoms included memory deterioration (n = 10; 90.9%), epileptic seizures (n = 9; 81.8%), psychiatric disorders (n = 9; 81.8%), and conscious disturbance (n = 5; 45.5%); magnetic resonance imaging (MRI) indicated an involvement of the limbic system in three (27.3%) cases in this group. Lung cancer was detected in one patient (9.1%). After an average follow-up period of 11.7 months, four (36.4%) patients were cured, and seven (63.6%) patients showed significant improvements. In the poor-prognosis group, all patients presented with memory deterioration, epileptic seizures, psychiatric disorders, and conscious disturbance; five (62.5%) patients had convulsive status epilepticus, and five (62.5%) patients developed respiratory failure; MRI indicated an involvement of the limbic system in seven (87.5%) cases. Malignant tumors were detected in five (62.5%) patients. After an average follow-up period of 14.8 months, seven (87.5%) patients died and one (12.5%) patient remained dependent in daily life. CONCLUSIONS: The clinical manifestations of anti-GABA-B receptor encephalitis include epileptic seizures, cognitive impairment and psychiatric disorders. Patients with convulsive status epilepticus or respiratory failure have poor outcomes. In anti-GABA-B receptor encephalitis, limbic system involvement is associated with a poor prognosis in and radiological examinations can reflect disease progression. Early diagnosis and appropriate treatment should be highlighted.

Clinical characteristics and long-term follow-up of seven cases of anti-GABABR encephalitis in patients of Han Chinese descent.

OBJECTIVE: To improve the diagnosis and treatment of anti-GABAB receptor (anti-GABABR) encephalitis and prevent misdiagnosis or non-diagnosis. METHODS: We retrospectively examined the chief clinical manifestations, auxiliary examination results, treatment strategies, treatment efficacy, and long-term follow-up results of seven consecutive patients with anti-GABABR encephalitis. RESULTS: Epileptic seizures were the first symptom in 100% of the patients; 85.7% had memory deficit in the hospital, 42.8% had residual symptoms of cognitive impairment at discharge, and 28.6% had cognitive impairment at the end of follow-up; 71.4% of the patients had psychosis in the hospital, 57.1% had residual symptoms of psychosis at discharge, and 14.3% still had psychosis at the end of follow-up. However, the clinical symptoms (psychiatric disorders, cognitive decline) and signs (consciousness disturbance) at onset and after follow-up were not significantly different (P > 0.05). In 71.4% of the patients, anti-GABABR antibody serum levels were higher than those in the cerebrospinal fluid (especially in patients with lung cancer). Magnetic resonance imaging in 71.4% of patients indicated that the marginal lobe demonstrated encephalitis lesions. The average modified Rankin Scale score (2.0 ± 2.31) at follow-up was significantly better than that (3.86 ± 0.90) at the time of admission (P < 0.05). CONCLUSION: The clinical characteristics of anti-GABABR encephalitis were refractory epilepsy, psychiatric disorders, and cognitive impairment. Multiple antiepileptic drugs are crucial for the treatment of intractable epilepsy. Clinicians should eliminate the possibility of small-cell lung cancer in patients with high anti-GABABR antibody levels. Early active immunotherapy is effective, and the long-term prognosis is good for patients without tumors.

GABABR-Mediated Paraneoplastic Limbic Encephalitis Due To Thymic Small Cell Carcinoma.

We report the case of a 55-year-old male who presented with several weeks of seizures, agitation, progressive confusion, and receptive aphasia. CSF showed a monocytic pleocytosis and tested positive for GABAB receptor autoantibodies. Pathological examination of an excisional mediastinal lymph node biopsy showed thymic small cell carcinoma, supporting a diagnosis of paraneoplastic limbic encephalitis (PLE). PLE is a subtype of limbic encephalitis and is associated with an array of autoantibodies. Neurologic symptoms related to PLE may precede the detection of the primary cancer. Recognition of the constellation of clinical features of limbic encephalitis should prompt initiation of diagnostic testing for this condition as well as evaluation for an underlying malignancy. A review of the literature reveals that this is the first case report of a patient with thymic small cell cancer presenting with PLE.

GABAB receptor encephalitis in a patient diagnosed with amyotrophic lateral sclerosis.

BACKGROUND: In 2010 the spectrum of known antigens in autoimmune encephalitis has been expanded by GABAB receptors. Until now over 80 patients with GABAB receptor encephalitis have been described. We report the occurrence of GABAB receptor antibodies in a patient with clinically diagnosed amyotrophic lateral sclerosis (ALS). GABAB receptor antibodies have not been described previously in an ALS patient. CASE PRESENTATION: A 75-year-old female patient presented with cerebellar ataxia, bulbar palsy and cognitive impairment. In the later course of disease signs for affection of the second motor neuron evolved and she was diagnosed with ALS. A post-mortem analysis of cerebrospinal fluid revealed high titers of GABAB receptor antibodies. CONCLUSIONS: This case provides an idea of the natural course of GABAB receptor encephalitis and demonstrates that antibody-mediated autoimmunity could be one of several pathways leading to the ALS phenotype. Furthermore this unique case stimulates the question whether neuronal antibodies might be more common in ALS than previously suspected.

Typical clinical and imaging manifestations of encephalitis with anti-γ-aminobutyric acid B receptor antibodies: clinical experience and a literature review.

OBJECTIVE: To explore the clinical, imaging, and electroencephalogram (EEG) findings, as well as the treatment and prognosis of five patients with anti-γ-aminobutyric acid B receptor (GABABR) encephalitis and review the current literature to gain a deeper understanding and improve the clinical diagnostic ability of the disease. METHODS: Clinical data such as blood examination, imaging, computed tomography (CT), EEG, and magnetic resonance imaging (MRI) findings from five patients with anti-GABABR encephalitis were retrospectively analyzed. RESULTS: Based on the imaging data, autoimmune encephalitis with anti-GABABR antibodies displayed subacute onset of episodic memory loss, seizures, and confusion, in addition to signal changes in the medial temporal lobe and/or hippocampus. Anti-GABABR antibodies were found in blood and cerebrospinal fluid (CSF) in all five patients, although the CSF leukocyte count and the levels of protein, sugar, and chloride showed no obvious abnormalities. On MRI, only two patients presented with abnormal signals in the medial temporal lobe and/or hippocampus. The EEG showed a slow wave rhythm in all five patients. After treatment with methylprednisolone pulse therapy combined with antiepileptic treatment, all five patients recovered well, without any complications. CONCLUSIONS: Autoimmune encephalitis with anti-GABABR antibodies may be a severe and refractory disease. Anti-GABABR antibodies tested in CSF and serum play a crucial role in the definitive diagnosis and treatment of autoimmune encephalitis. Early treatment is of vital importance to avoid serious complications and neurological sequelae.

Anti-GABAB receptor encephalitis in a patient with gastric adenocarcinoma.

Anti-γ-aminobutyric acid-B (GABAB) receptor encephalitis is an autoimmune encephalitis associated with antibodies against neuronal cell surface antigens, which are primarily observed with small-cell lung cancer, melanoma, and thymoma. Here, we first report a case on the association between a relatively frequent cancer, gastric adenocarcinoma (GAC), and a rare GABAB receptor antibody limbic encephalitis. The patient was treated with immunotherapy and combined-drug chemotherapy, which were partially effective in terms of stabilizing the tumor and relieving neurological symptoms. This report indicates that, when patients present with GABAB receptor antibody limbic encephalitis, regular and broad screening for tumors including gastric adenocarcinoma should also be considered.

The gamma-aminobutyric acid-B receptor (GABAB) encephalitis: clinical manifestations and response to immunotherapy.

PURPOSE: We report 11 patients diagnosed with GABAB receptor (GABABR) antibodies encephalitis in China and aim to analyze the clinical characteristics, laboratory and imaging findings, therapeutic modalities and outcomes. METHODS: Clinical data from patients diagnosed with anti-GABAB receptor encephalitis in the Second Affiliated Hospital of Hebei Medical University from February 2016 to October 2016 January were retrospectively collected and evaluated. RESULTS: Of the 11 patients, seven were males, and a mean age at presentation of 63 years (range: 47-79 years). The major clinical features include cognitive decline (9/11), epilepsy (10/11), mental and behavioral disorders (6/11), involuntary movement (4/11), sleep disorders (2/11), hearing loss (1/11), disturbance of consciousness (4/11) and fever (3/11). GABA-B receptor antibody was positive in serum and/or cerebrospinal fluid in 11 patients. Small-cell lung cancer was detected in five patients. Electroencephalogram monitoring demonstrated abnormal discharge in 10 cases. Epileptiform activities were found in five patients. Four patients showed abnormality in hippocampal region, parahippocampal gyrus, temporal and occipital lobe on magnetic resonance imaging. Ten patients accepted first-line immune therapy. Five patients with small-cell lung cancer received oncologic treatment. During a median follow-up of 11 months, eight patients showed a good outcome, two patients (cases 8 and 9) with tumors had a poor one and one patient (case 10) died of status epilepticus. CONCLUSION: Anti-GABAB receptor encephalitis is an uncommon autoimmune disease, which has been known to be often associated with cancer. Generally, patients associated with GABABR GABA-B receptor antibody encephalitis respond well to immunotherapy, especially if started early.

Neuronal central nervous system syndromes probably mediated by autoantibodies.

In the last few years, a rapidly growing number of autoantibodies targeting neuronal cell-surface antigens have been identified in patients presenting with neurological symptoms. Targeted antigens include ionotropic receptors such as N-methyl-d-aspartate receptor or the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor, metabotropic receptors such as mGluR1 and mGluR5, and other synaptic proteins, some of them belonging to the voltage-gated potassium channel complex. Importantly, the cell-surface location of these antigens makes them vulnerable to direct antibody-mediated modulation. Some of these autoantibodies, generally targeting ionotropic channels or their partner proteins, define clinical syndromes resembling models of pharmacological or genetic disruption of the corresponding antigen, suggesting a direct pathogenic role of the associated autoantibodies. Moreover, the associated neurological symptoms are usually immunotherapy-responsive, further arguing for a pathogenic effect of the antibodies. Some studies have shown that some patients' antibodies may have structural and functional in vitro effects on the targeted antigens. Definite proof of the pathogenicity of these autoantibodies has been obtained for just a few through passive transfer experiments in animal models. In this review we present existing and converging evidence suggesting a pathogenic role of some autoantibodies directed against neuronal cell-surface antigens observed in patients with central nervous system disorders. We describe the main clinical symptoms characterizing the patients and discuss conflicting arguments regarding the pathogenicity of these antibodies.

Prevalence of serum anti-neuronal autoantibodies in patients admitted to acute psychiatric care.

BACKGROUND: Autoimmune encephalitis associated with anti-neuronal antibodies may be challenging to distinguish from primary psychiatric disorders. The significance of anti-neuronal antibodies in psychiatric patients without clear evidence of autoimmune encephalitis is unknown. We investigated the serum prevalence of six anti-neuronal autoantibodies in a cohort of unselected patients admitted to acute psychiatric care. METHOD: Serum was drawn from 925 patients admitted to acute psychiatric in-patient care. Psychiatric diagnoses were set according to International Classification of Diseases (ICD)-10 criteria. Antibody analysis was performed with an indirect immunofluorescence test for N-methyl d-aspartate receptor (NMDAR) antibodies and five other anti-neuronal autoantibodies of the immunoglobulin (Ig) classes IgA, IgG and IgM isotype. RESULTS: Anti-neuronal autoantibodies were found in 11.6% of patients: NMDAR antibodies in 7.6%, contactin-associated protein-like 2 (CASPR2) antibodies in 2.5%, glutamic acid decarboxylase-65 (GAD65) antibodies in 1.9%, and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor antibodies in 0.1%. Leucine-rich glioma-inactivated protein-1 (LGI1) and γ-aminobutyric acid B (GABAB) receptor antibodies were not detected. NMDAR antibodies of class IgG were present in five patients only (0.5%). NMDAR antibodies of all Ig classes were equally prevalent in patients with and without psychosis. There were no significant differences in antibody prevalence in the different diagnostic categories, except for a higher odds ratio of being NMDAR antibody positive for patients without a specific psychiatric diagnosis. CONCLUSIONS: NMDAR IgG autoantibodies, which are known to be strongly associated with anti-NMDAR encephalitis, were rarely found. CASPR2 and GAD65 antibodies were more frequently encountered in the present study than previously reported. Further research on the clinical significance of anti-neuronal autoantibodies in patients with acute psychiatric symptoms is needed.

Four cases of GABAB receptor encephalitis.

GABAB receptor (gamma-aminobutyric acid type B receptors - GABABR) encephalitis is a rare manifestation of autoimmune encephalitides. We report four cases - including the first two Hungarian patients - with some peculiar features. One patient developed subacute disorientation and almost complete loss of short-term memory, but no epilepsy. Without immunotherapy, his memory spontaneously improved up to mild cognitive impairment in six weeks. GABABR antibodies persisted in his serum, and 18 months later, FDG-PET detected abnormal mediastinal lymph nodes and small cell lung cancer (SCLC). Another patient had persistently decreased sodium content in the peripheral blood. In those three patients who died, CSF was abnormal, but CSF was not pathological in the patient, who spontaneously improved. Brain MRI indicated signal intensity changes in the medial temporal areas in three cases. SCLC was found in three patients. Only the patient, who spontaneously improved, survived for more than 24 months. In summary, our cases show that (i) GABABR encephalitis may develop without epilepsy; (ii) the severe short-term memory loss can spontaneously improve; (iii) persistent hyponatremia can be present in the blood; (iv) the patient with benign course without epilepsy and CSF abnormality survived; (v) spontaneously remitting encephalitis can precede SCLC by 1.5 year, which emphasizes that repeated search for cancer is of paramount importance even in cases with spontaneous improvement.

Limbic encephalitis due to GABAB and AMPA receptor antibodies: a case series.

BACKGROUND: Two novel antibodies (abs) directed to γ-aminobutyric acid B receptor (GABA(B)R) and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) in patients with limbic encephalitis (LE) were first described by the Philadelphia/Barcelona groups and confirmed by the Mayo group. We present a novel series for further clinical and paraclinical refinement. METHODS: Serum and cerebrospinal fluid samples from a diagnostic laboratory were selected if found to be positive for GABA(B)R or AMPAR abs within a broad antineuronal ab panel. Data were retrospectively compiled. RESULTS: In 10 patients, we detected abs to GABA(B)R. Median age was 70 years. Five of them were diagnosed with small cell lung cancer (SCLC). Intrathecal GABA(B)R ab synthesis was found in all six patients with sufficient data available (median ab-index: 76.8). On MRI, we found bilateral mediotemporal and in two cases cortical abnormalities. EEG revealed encephalopathy, partly with epileptiform discharges. Five patients received immunotherapy, two patients tumour treatment and three both therapies. Three patients died, in five patients cognitive functions declined, one patient improved slightly and one patient fully recovered. AMPAR abs were detected in three patients with mnestic disturbances. Median age was 60.7 years. The only female patient was diagnosed with ovarian cancer. None of the patients had intrathecal ab synthesis. MRI findings showed bilateral mediotemporal abnormalities. EEG was normal in all patients. Two of the three immunologically treated patients improved, one patient stabilised on a low level. DISCUSSION: GABA(B)R and AMPAR abs are well associated with LE. GABA(B)R abs lead to severe clinical, neuroradiological and EEG abnormalities with poorer outcome.

Identification of novel autoantibodies to GABA(B) receptors in patients with neuropsychiatric systemic lupus erythematosus.

OBJECTIVE: The gamma-aminobutyric acid type B receptors (GABAR(B)) are G-protein coupled receptors for GABA, the main inhibitory neurotransmitter in the brain. We identified GABAR(B) subunits as candidate antigens in patients with SLE using a random peptide display library. The aim of this study was to investigate the possible link between anti-GABAR(B) antibodies and disease activity and NPSLE. METHODS: ELISA was performed with recombinant proteins of GABAR(B1b) and GABAR(B2) on serum samples from patients with SLE (n = 88), scleroderma (n = 20), myositis (n = 20) or vasculitis (n = 20) as well as healthy subjects (n = 20). Cerebrospinal fluid (CSF) from 23 patients with SLE was also examined. RESULTS: Autoantibodies to GABAR(Bs) were exclusive to patients with SLE (P < 0.001) and positively associated with SLEDAI (anti-GABAR(B1b), P = 0.001; anti-GABAR(B2), P < 0.001). Of note, autoantibodies were positively linked with NPSLE (anti-GABAR(B1b), P = 0.02; anti-GABAR(B2), P = 0.03). Moreover, anti-GABAR(Bs) was detected in 61.5% of CSF samples from patients with active NPSLE, a frequency that was significantly higher than that for patients with non-SLE syndromes. CONCLUSION: Anti-GABAR(B) antibodies could represent novel candidate markers for disease activity and NPSLE.

Treatment responsive GABA(B)-receptor limbic encephalitis presenting as new-onset super-refractory status epilepticus (NORSE) in a deployed U.S. soldier.

A 23-year-old, previously healthy, deployed U.S. soldier presented with bilateral temporal lobe seizures recalcitrant to multiple antiepileptic drugs and anti-seizure anaesthetic agents. He received methylprednisolone, intravenous immunoglobulins, plasma exchange, and rituximab for presumed autoimmune encephalitis before achieving seizure freedom. Six weeks after presentation, the aetiology of his refractory seizures was found to be due to autoantibodies targeting the anti-GABA(B)-receptor. This case is noteworthy for being the first reported case of anti-GABA(B)-receptor limbic encephalitis presenting with new-onset refractory status epilepticus (NORSE), a clinical syndrome that often carries a grave prognosis and in which a treatable aetiology is often never discovered. Our case also supports testing for GABA-receptor autoantibodies and the upfront use of multi-modal immunotherapy in patients presenting with limbic encephalitis and new refractory seizures.

Comparative Study of Paraneoplastic and Nonparaneoplastic Autoimmune Encephalitis With GABABR Antibodies.

BACKGROUND AND OBJECTIVES: While patients with paraneoplastic autoimmune encephalitis (AE) with gamma-aminobutyric-acid B receptor antibodies (GABABR-AE) have poor functional outcomes and high mortality, the prognosis of nonparaneoplastic cases has not been well studied. METHODS: Patients with GABABR-AE from the French and the Dutch Paraneoplastic Neurologic Syndromes Reference Centers databases were retrospectively included and their data collected; the neurologic outcomes of paraneoplastic and nonparaneoplastic cases were compared. Immunoglobulin G (IgG) isotyping and human leukocyte antigen (HLA) genotyping were performed in patients with available samples. RESULTS: A total of 111 patients (44/111 [40%] women) were enrolled, including 84 of 111 (76%) paraneoplastic and 18 of 111 (16%) nonparaneoplastic cases (cancer status was undetermined for 9 patients). Patients presented with seizures (88/111 [79%]), cognitive impairment (54/111 [49%]), and/or behavioral disorders (34/111 [31%]), and 54 of 111 (50%) were admitted in intensive care unit (ICU). Nonparaneoplastic patients were significantly younger (median age 54 years [range 19-88] vs 67 years [range 50-85] for paraneoplastic cases, p < 0.001) and showed a different demographic distribution. Nonparaneoplastic patients more often had CSF pleocytosis (17/17 [100%] vs 58/78 [74%], p = 0.02), were almost never associated with KTCD16-abs (1/16 [6%] vs 61/70 [87%], p < 0.001), and were more frequently treated with second-line immunotherapy (11/18 [61%] vs 18/82 [22%], p = 0.003). However, no difference of IgG subclass or HLA association was observed, although sample size was small (10 and 26 patients, respectively). After treatment, neurologic outcome was favorable (mRS ≤2) for 13 of 16 (81%) nonparaneoplastic and 37 of 84 (48%) paraneoplastic cases (p = 0.03), while 3 of 18 (17%) and 42 of 83 (51%) patients had died at last follow-up (p = 0.008), respectively. Neurologic outcome no longer differed after adjustment for confounding factors but seemed to be negatively associated with increased age and ICU admission. A better survival was associated with nonparaneoplastic cases, a younger age, and the use of immunosuppressive drugs. DISCUSSION: Nonparaneoplastic GABABR-AE involved younger patients without associated KCTD16-abs and carried better neurologic and vital prognoses than paraneoplastic GABABR-AE, which might be due to a more intensive treatment strategy. A better understanding of immunologic mechanisms underlying both forms is needed.

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.

Comparison of the clinical syndromes of anti-GABAa versus anti-GABAb associated autoimmune encephalitis: A systematic review.

The main objective of this article is to improve our understanding of the differences and similarities of these two anti-gamma-aminobutyric acid receptor encephalitis, anti-GABAaR and anti-GABAbR. The data were systematically collected and we found 26 studies: seven studies and 37 patients corresponded to anti-GABAaR encephalitis, and 21 manuscripts and 116 patients were diagnosed with anti-GABAbR encephalitis. Both anti-GABAR encephalitis were marked by prominent seizures. Anti-GABAaR patients were younger and showed multifocal encephalitis. On the other hand, anti-GABAbR patients were older and showed temporal limbic encephalitis. Tumor occurred in a fifth of anti-GABAaR encephalitis and in half of anti-GABAbR encephalitis. The main tumor associated with anti-GABAbR encephalitis is SCLC, whereas the most common tumor associated with anti-GABAaR encephalitis was thymoma. Our data confirms the differences in clinical features between both encephalitis.

Phosphonate-Modified Cellulose Nanocrystals Potentiate the Th1 Polarising Capacity of Monocyte-Derived Dendritic Cells via GABA-B Receptor.

Purpose: Phosphonates, like 3-AminoPropylphosphonic Acid (ApA), possess a great potential for the therapy of bone tumours, and their delivery via cellulose nanocrystals (CNCs) seems a promising approach for their increased efficacy in target tissues. However, the immunological effects of CNC-phosphonates have not been investigated thoroughly. The main aim was to examine how the modification of CNCs with phosphonate affects their immunomodulatory properties in human cells. Methods: Wood-based native (n) CNCs were modified via oxidation (ox-CNCs) and subsequent conjugation with ApA (ApA-CNCs). CNCs were characterised by atomic force microscopy (AFM) and nanoindentation. Cytotoxicity and immunomodulatory potential of CNCs were investigated in cultures of human peripheral blood mononuclear cells (PBMCs) and monocyte-derived dendritic cells (MoDCs)/T cells co-cultures by monitoring phenotype, cytokines production, allostimulatory and Th/Treg polarisation capacity. Results: AFM showed an increase in CNCs' thickens, elasticity modulus and hardness during the modification with ApA. When applied at non-toxic doses, nCNCs showed a tolerogenic potential upon internalisation by MoDCs, as judged by their increased capacity to up-regulate tolerogenic markers and induce regulatory T cells (Treg), especially when present during the differentiation of MoDCs. In contrast, ox- and ApA-CNCs induced oxidative stress and autophagy in MoDCs, which correlated with their stimulatory effect on the maturation of MoDCs, but also inhibition of MoDCs differentiation. ApA-CNC-treated MoDCs displayed the highest allostimulatory and Th1/CTL polarising activity in co-cultures with T cells. These effects of ApA-CNCs were mediated via GABA-B receptor-induced lowering of cAMP levels in MoDCs, and they could be blocked by GABA-B receptor inhibitor. Moreover, the Th1 polarising and allostimulatory capacity of MoDCs differentiated with ApA-CNC were largely preserved upon the maturation of MoDCs, whereas nCNC- and ox-CNC-differentiated MoDCs displayed an increased tolerogenic potential. Conclusion: The delivery of ApA via CNCs induces potent DC-mediated Th1 polarisation, which could be beneficial in their potential application in tumour therapy.