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Since the detection of autoantibodies against neuronal surface antigens, autoimmune encephalitis (AE) has been more frequently diagnosed, especially in patients with symptoms typical of limbic encephalitis, such as seizures, short-term memory deficits, or psychosis. However, the clinical spectrum of AE may be much wider, making correct clinical diagnosis difficult. We retrospectively analysed symptoms and admission diagnoses at first clinical presentation in 50 AE patients. We included patients with a clinical diagnosis of AE for whom a FDG-PET imaging was available. Final diagnoses were re-evaluated by a blinded investigator according to the most recent consensus suggestions published in 2016 for AE diagnostic criteria. We additionally describe two patients with Morvan syndrome who showed CASPR2 antibodies. In 40 patients (80.0%), the clinical presentation at first admission was typical for AE. Ten patients (20.0%) initially suffered from atypical symptoms; among these patients, isolated headache and cerebellar dysfunction were most frequent (three patients each). However, an initial diagnosis of suspected encephalitis was only reached in 16 patients (32.0%), nine (18.0) of which were suspected to have infectious encephalitis, and seven (14.0%) patients were suspected to have AE. In 34 patients (68.0%), a diagnosis other than encephalitis was considered, (e.g., epilepsy, psychiatric diseases, transient ischemic attack, dementia, meningitis, and cerebellitis). These data show the broad spectrum of initial symptoms of AE; the correct initial diagnosis of AE is often missed or delayed. Hence, clinicians in neurological and psychiatric hospitals should consider AE in the differential diagnosis of cases with atypical clinical presentations.

OBJECTIVE: Glucocorticoids seem to modify the release and effects of plasma arginine vasopressin (pAVP). However, underlying processes are not well understood. This study aimed to evaluate the mechanism of the modulating effects of glucocorticoids on pAVP and renal water reabsorption. DESIGN: Fluid deprivation tests were performed without (d0) and after one (d1) and five days (d5) of oral prednisolone (Pred) pretreatment in a dosage relevant to drug therapy (30 mg/day). PATIENTS: Twelve healthy male volunteers participated in this trial. MEASUREMENTS: Plasma and urinary osmolality, pAVP, renin, aldosterone, plasma atrial natriuretic peptide (ANP) as well as urinary secretion of aquaporin-2 (AQP2) and prostaglandin E(2) (PGE2) were analysed. RESULTS: An appropriate rise in pAVP was observable during thirsting (P < 0.001), which was absent after Pred pretreatment. However, the plasma and urinary osmolality after Pred treatment did not differ when compared with the basal thirsting test. Unchanged urinary AQP2 excretion suggests AVP-independent mechanisms of renal fluid reabsorption. Plasma renin concentration as well as ANP was substantially increased after Pred intake at d1 and d5 (both P < 0.05), which may mediate such AVP-independent mechanisms. Urinary PGE2 secretion was not influenced by Pred pretreatment, making a PGE2-mediated effect on renal AQP2 translocation and water permeability unlikely. Increased efficacy of exogenous desmopressin at d1 and d5 indicates also a relative increase in AVP sensitivity of the tubular cells after Pred intake. CONCLUSIONS: The here presented data are compatible with an increased AVP sensitivity and a partially AVP-independent regulation of AQP2 translocation and renal fluid reabsorption during glucocorticoid treatment.

History and initial findings | A patient with bilateral pain in his shoulders is presented at the emergency room. Investigations | There were strongly increased transaminases. Diagnosis | Serology and PCR led to the diagnosis of hepatitis E. Neurological examination revealed a neuralgic amyotrophy Treatment and course | The pain in the shoulders disappeared spontaneously after vanishing of HEV viremia. Conclusion | Patients with shoulder pain of unknown origin and elevated transaminases should be tested for hepatitis E.

Background: Balancing treatment benefits and risks is part of a shared decision-making process before initiating any treatment in multiple sclerosis (MS). Patients understand, appreciate and profit from evidence-based patient information (EBPI). While these processes are well known, long-term risk awareness and risk processing of patients has not been studied. Mitoxantrone treatment in MS is associated with long-term major potential harms – leukaemia (LK) and cardiotoxicity (CT). The risk knowledge and perception among patients currently or previously treated with mitoxantrone is unknown. Objectives: The objective of this article is to conduct a retrospective cohort study in greater Hamburg, Germany, to estimate risk awareness and perception in MS patients treated with mitoxantrone. Methods: MS patients with at least one dose of mitoxantrone between 1991 and 2010 from six major MS centres in greater Hamburg received a questionnaire assessing risk awareness and perception as well as a written EBPI about mitoxantrone-associated LK and CT. Results: Fifty-one per cent in the cohort of n = 575 patients returned the questionnaire. Forty per cent correctly estimated the risk of LK (CT 16%); 56% underestimated the risk (CT 82%). Reading the information increased the accuracy of LK risk estimation, and patients did not report an increase of worries. The EBPI was appreciated and recommended by 85%. Conclusion: Risk awareness of mitoxantrone-treated patients is insufficient, but can be increased by EBPI without increasing worries. Continued patient information during and after treatment should be implemented in management algorithms.

Limbic encephalitis (LE) associated with voltage-gated potassium channel-complex antibodies (VGKC-LE) is frequently non-paraneoplastic and associated with marked improvement following corticosteroid therapy. Mesial temporal lobe abnormalities are present in around 80 % of patients. If associated or preceded by faciobrachial dystonic seizures, basal ganglia signal changes may occur. In some patients, blurring of the supratentorial white matter on T2-weighted images (SWMB) may be seen. The purpose of this study was to evaluate the incidence of SWMB and whether it is specific for VGKC-LE. Two experienced neuroradiologists independently evaluated signal abnormalities on FLAIR MRI in 79 patients with LE while unaware on the antibody type. SWMB was independently assessed as present in 10 of 36 (28 %) compared to 2 (5 %) of 43 non-VGKC patients (p = 0.009). It was not related to the presence of LGI1 or CASPR2 proteins of VGKC antibodies. MRI showed increased temporomesial FLAIR signal in 22 (61 %) VGKC compared to 14 (33 %) non-VGKC patients (p = 0.013), and extratemporomesial structures were affected in one VGKC (3 %) compared to 11 (26 %) non-VGKC patients (p = 0.005). SWMB is a newly described MRI sign rather specific for VGKC-LE.

Recent association studies have linked numerous genetic variants with an increased risk for multiple sclerosis, although their functional relevance remains largely unknown. Here we investigated phenotypical and functional consequences of a genetic variant in the CD226 gene that, among other autoimmune diseases, predisposes to multiple sclerosis. Phenotypically, effector and regulatory CD4(+) memory T cells of healthy individuals carrying the predisposing CD226 genetic variant showed, in comparison to carriers of the protective variant, reduced surface expression of CD226 and an impaired induction of CD226 after stimulation. This haplotype-dependent reduction in CD226 expression on memory T cells was abrogated in patients with multiple sclerosis, as CD226 expression was comparable to healthy risk haplotype carriers irrespective of genetic variant. Functionally, FOXP3-positive regulatory T cells from healthy carriers of the genetic protective variant showed superior suppressive capacity, which was again abrogated in multiple sclerosis patients. Mimicking the phenotype of human CD226 genetic risk variant carriers, regulatory T cells derived from Cd226-deficient mice showed similarly reduced inhibitory activity, eventually resulting in an exacerbated disease course of experimental autoimmune encephalomyelitis, the animal model of multiple sclerosis. Therefore, by combining human and mouse analyses we show that CD226 exhibits an important role in the activation of regulatory T cells, with its genetically imposed dysregulation impairing regulatory T cell function.

Recent findings indicate a pathogenic involvement of IL-17-producing CD8(+) T cells in multiple sclerosis (MS). IL-17 production has been attributed to a subset of CD8(+) T cells that belong to the mucosal-associated invariant T (MAIT) cell population. Here, we report a reduction of CD8(+) MAIT cells in the blood of MS patients compared with healthy individuals, which significantly correlated with IL-18 serum levels in MS patients. In vitro stimulation of peripheral blood mononuclear cells from healthy individuals and MS patients with IL-18 specifically activated CD8(+) MAIT cells. Moreover, IL-18 together with T-cell receptor stimulation induced, specifically on CD8(+) MAIT cells, an upregulation of the integrin very late antigen-4 that is essential for the infiltration of CD8(+) T cells into the CNS. Notably, we were able to identify CD8(+) MAIT cells in MS brain lesions by immunohistochemistry while they were almost absent in the cerebrospinal fluid (CSF). In summary, our findings indicate that an IL-18-driven activation of CD8(+) MAIT cells contributes to their CNS infiltration in MS, in turn leading to reduced CD8(+) MAIT-cell frequencies in the blood. Therefore, CD8(+) MAIT cells seem to play a role in the innate arm of immunopathology in MS.

In multiple sclerosis, an inflammatory disease of the central nervous system (CNS), axonal and neuronal loss are major causes for irreversible neurological disability. However, which molecules contribute to axonal and neuronal injury under inflammatory conditions remains largely unknown. Here we show that the transient receptor potential melastatin 4 (TRPM4) cation channel is crucial in this process. TRPM4 is expressed in mouse and human neuronal somata, but it is also expressed in axons in inflammatory CNS lesions in experimental autoimmune encephalomyelitis (EAE) in mice and in human multiple sclerosis tissue. Deficiency or pharmacological inhibition of TRPM4 using the antidiabetic drug glibenclamide resulted in reduced axonal and neuronal degeneration and attenuated clinical disease scores in EAE, but this occurred without altering EAE-relevant immune function. Furthermore, Trpm4(-/-) mouse neurons were protected against inflammatory effector mechanisms such as excitotoxic stress and energy deficiency in vitro. Electrophysiological recordings revealed TRPM4-dependent neuronal ion influx and oncotic cell swelling upon excitotoxic stimulation. Therefore, interference with TRPM4 could translate into a new neuroprotective treatment strategy.

Systematic analysis of the neuronal receptor interactome in multiple sclerosis brains reveals the metabotropic glutamate receptor 8 as a disbalanced hub. Its activation constitutes a novel treatment strategy to enhance neuronal resilience by inhibiting pathological calcium overload in inflammation-induced neurodegeneration., Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system with continuous neuronal loss. Treatment of clinical progression remains challenging due to lack of insights into inflammation-induced neurodegenerative pathways. Here, we show that an imbalance in the neuronal receptor interactome is driving glutamate excitotoxicity in neurons of MS patients and identify the MS risk–associated metabotropic glutamate receptor 8 (GRM8) as a decisive modulator. Mechanistically, GRM8 activation counteracted neuronal cAMP accumulation, thereby directly desensitizing the inositol 1,4,5-trisphosphate receptor (IP3R). This profoundly limited glutamate-induced calcium release from the endoplasmic reticulum and subsequent cell death. Notably, we found Grm8-deficient neurons to be more prone to glutamate excitotoxicity, whereas pharmacological activation of GRM8 augmented neuroprotection in mouse and human neurons as well as in a preclinical mouse model of MS. Thus, we demonstrate that GRM8 conveys neuronal resilience to CNS inflammation and is a promising neuroprotective target with broad therapeutic implications., Graphical Abstract