Publications by authors named "Christian Geis"

63 Publications

Super-resolving Microscopy in Neuroscience.

Chem Rev 2021 Mar 22. Epub 2021 Mar 22.

Section Translational Neuroimmunology, Department of Neurology, Jena University Hospital, Am Klinikum 1, 07747 Jena, Germany.

Fluorescence imaging techniques play a pivotal role in our understanding of the nervous system. The emergence of various super-resolution microscopy methods and specialized fluorescent probes enables direct insight into neuronal structure and protein arrangements in cellular subcompartments with so far unmatched resolution. Super-resolving visualization techniques in neurons unveil a novel understanding of cytoskeletal composition, distribution, motility, and signaling of membrane proteins, subsynaptic structure and function, and neuron-glia interaction. Well-defined molecular targets in autoimmune and neurodegenerative disease models provide excellent starting points for in-depth investigation of disease pathophysiology using novel and innovative imaging methodology. Application of super-resolution microscopy in human brain samples and for testing clinical biomarkers is still in its infancy but opens new opportunities for translational research in neurology and neuroscience. In this review, we describe how super-resolving microscopy has improved our understanding of neuronal and brain function and dysfunction in the last two decades.
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http://dx.doi.org/10.1021/acs.chemrev.0c01174DOI Listing
March 2021

Sepsis promotes gliogenesis and depletes the pool of radial glia like stem cells in the hippocampus.

Exp Neurol 2021 Apr 30;338:113591. Epub 2020 Dec 30.

Hans Berger Department of Neurology, Jena University Hospital, Am Klinkum 1, D-07747 Jena, Germany. Electronic address:

Sepsis associated encephalopathy (SAE) is a major complication of patients surviving sepsis with a prevalence up to 70%. Although the initial pathophysiological events of SAE are considered to arise during the acute phase of sepsis, there is increasing evidence that SAE leads to persistent brain dysfunction with severe cognitive decline in later life. Previous studies suggest that the hippocampal formation is particularly involved leading to atrophy in later stages. Thereby, the underlying cellular mechanisms are only poorly understood. Here, we hypothesized that endogenous neural stems cells and adult neurogenesis in the hippocampus are impaired following sepsis and that these changes may contribute to persistent cognitive dysfunction when the animals have physically fully recovered. We used the murine sepsis model of peritoneal contamination and infection (PCI) and combined different labeling methods of precursor cells with confocal microscopy studies to assess the neurogenic niche in the dentate gyrus at day 42 postsepsis. We found that following sepsis i) gliogenesis is increased, ii) the absolute number of radial glia-like cells (type 1 cells), which are considered the putative stem cells, is significantly reduced, iii) the generation of new neurons is not significantly altered, while iv) the synaptic spine maturation of new neurons is impaired with a shift to expression of more immature and less mature spines. In conclusion, sepsis mainly leads to depletion of the neural stem cell pool and enhanced gliogenesis in the dentate gyrus which points towards an accelerated aging of the hippocampus due to septic insult.
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http://dx.doi.org/10.1016/j.expneurol.2020.113591DOI Listing
April 2021

Autoimmune encephalitis: novel therapeutic targets at the preclinical level.

Expert Opin Ther Targets 2021 Jan 31;25(1):37-47. Epub 2020 Dec 31.

Section Translational Neuroimmunology, Department of Neurology, Jena University Hospital , Jena, Germany.

Introduction: Antibody-mediated encephalitides (AE) with pathogenic autoantibodies (aAB) against neuronal surface antigens are a growing group of diseases characterized by antineuronal autoimmunity in the brain. AE patients typically present with rapidly progressive encephalitis and characteristic disease symptoms dependent on the target antigen. Current treatment consists of an escalating immunotherapy strategy including plasma exchange, steroid application, and B cell depletion.

Areas Covered: For this review, we searched Medline database and google scholar with inclusive dates from 2000. We summarize current treatment strategies and present novel therapeutic approaches of target-specific interventions at the pre-clinical level as well as immunotherapy directed at antibody-induced pathology. Treatment options include modulation of target proteins, intervention with downstream pathways, antibody modification, and depletion of antibody-secreting cells.

Expert Opinion: Although current therapies in AE are effective in many patients, recovery is often prolonged and relapses as well as persistent deficits can occur. Specific immunotherapy together with supportive target-specific therapy may provide faster control of severe symptoms, shorten the disease course, and lead to long-lasting disease stability. Among the various novel therapeutic approaches, modulation of targeted receptors by small molecules crossing the blood-brain barrier as well as prevention of aAB binding is of particular interest.
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http://dx.doi.org/10.1080/14728222.2021.1856370DOI Listing
January 2021

Generate-Boost: study protocol for a prospective, multicenter, randomized controlled, double-blinded phase II trial to evaluate efficacy and safety of bortezomib in patients with severe autoimmune encephalitis.

Trials 2020 Jul 8;21(1):625. Epub 2020 Jul 8.

Section of Translational Neuroimmunology, Hans Berger Department of Neurology, Jena University Hospital, Am Klinikum 1, 07747, Jena, Germany.

Background: Autoimmune encephalitis is a new spectrum of autoimmune disorders of the central nervous system (CNS), which are characterized by pathogenic autoantibodies against neuronal surface antigens. Clinical presentations range from acute to subacute encephalopathy with neurological and psychiatric symptoms, and life-threatening autonomic dysfunction in severe cases. There exist no approved therapies nor is data available from controlled clinical trials. Patients are usually treated with diverse combinations of immunotherapy. However, effect of immunotherapy on antibody-producing cells and thus on levels of pathogenic autoantibodies is insufficient. Therefore, therapeutic response is sometimes prolonged with necessity of long-time intensive care treatment and also irreversible deficits occur in severe cases. This trial will investigate the efficacy and safety of bortezomib, a proteasome inhibitor known to selectively deplete plasma cells, in patients with severe autoimmune encephalitis who have been treated with rituximab with insufficient response.

Methods: Generate-Boost is an investigator-initiated, multicenter, double-blinded, randomized controlled phase II trial which will be conducted in specialized neurological hospitals within the GENERATE (GErman NEtwork for Research on AuToimmune Encephalitis) network in Germany. Adult patients with severe autoimmune encephalitis (modified Rankin scale, mRS ≥ 3), autoantibodies against neuronal surface antigens, and pretreatment with rituximab are eligible for study participation. Fifty patients will be randomized 1:1 and undergo up to 3 cycles (each 21 days with 4 s. c. applications) of bortezomib or placebo. All patients will receive concomitant medication with dexamethasone, acyclovir and co-trimoxazole. The primary efficacy endpoint is the mRS score 17 weeks after first treatment application. Secondary endpoints are neurocognitive function, antibody titers, markers of neuronal cell damage, length of ICU/hospital stay, and mRS and Glasgow coma scale scores throughout the trial up to week 17. General and bortezomib-specific adverse events are monitored continuously.

Discussion: The expected outcome of the study is to obtain first reliable data on a hypothesis-driven therapeutic option in severe and difficult-to-treat autoimmune encephalitis. If treatment with bortezomib is beneficial in these cases, this will be the basis for implementation in the current guidelines.

Trial Registration: Clinicaltrials.gov , NCT03993262 . Registered June 20, 2019; German Clinical Trials Register, DRKS00017497.
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http://dx.doi.org/10.1186/s13063-020-04516-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7346383PMC
July 2020

Anti-NMDA receptor encephalitis: epidemiological differences and common challenges.

Ann Transl Med 2020 Jun;8(11):716

Section Translational Neuroimmunology, Department of Neurology, Jena University Hospital, Jena, Germany.

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http://dx.doi.org/10.21037/atm.2020.02.34DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7327341PMC
June 2020

Glycine Receptor Autoantibodies Impair Receptor Function and Induce Motor Dysfunction.

Ann Neurol 2020 09 20;88(3):544-561. Epub 2020 Jul 20.

Institute for Clinical Neurobiology, University Hospital, Julius Maximilian University of Würzburg, Würzburg, Germany.

Objective: Impairment of glycinergic neurotransmission leads to complex movement and behavioral disorders. Patients harboring glycine receptor autoantibodies suffer from stiff-person syndrome or its severe variant progressive encephalomyelitis with rigidity and myoclonus. Enhanced receptor internalization was proposed as the common molecular mechanism upon autoantibody binding. Although functional impairment of glycine receptors following autoantibody binding has recently been investigated, it is still incompletely understood.

Methods: A cell-based assay was used for positive sample evaluation. Glycine receptor function was assessed by electrophysiological recordings and radioligand binding assays. The in vivo passive transfer of patient autoantibodies was done using the zebrafish animal model.

Results: Glycine receptor function as assessed by glycine dose-response curves showed significantly decreased glycine potency in the presence of patient sera. Upon binding of autoantibodies from 2 patients, a decreased fraction of desensitized receptors was observed, whereas closing of the ion channel remained fast. The glycine receptor N-terminal residues A to G were mapped as a common epitope of glycine receptor autoantibodies. An in vivo transfer into the zebrafish animal model generated a phenotype with disturbed escape behavior accompanied by a reduced number of glycine receptor clusters in the spinal cord of affected animals.

Interpretation: Autoantibodies against the extracellular domain mediate alterations of glycine receptor physiology. Moreover, our in vivo data demonstrate that the autoantibodies are a direct cause of the disease, because the transfer of human glycine receptor autoantibodies to zebrafish larvae generated impaired escape behavior in the animal model compatible with abnormal startle response in stiff-person syndrome or progressive encephalitis with rigidity and myoclonus patients. ANN NEUROL 2020;88:544-561.
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http://dx.doi.org/10.1002/ana.25832DOI Listing
September 2020

Sepsis-Associated Encephalopathy: From Delirium to Dementia?

J Clin Med 2020 Mar 5;9(3). Epub 2020 Mar 5.

Section Translational Neuroimmunology, Department of Neurology, Jena University Hospital, 07747 Jena, Germany.

Sepsis is a major cause of death in intensive care units worldwide. The acute phase of sepsis is often accompanied by sepsis-associated encephalopathy, which is highly associated with increased mortality. Moreover, in the chronic phase, more than 50% of surviving patients suffer from severe and long-term cognitive deficits compromising their daily quality of life and placing an immense burden on primary caregivers. Due to a growing number of sepsis survivors, these long-lasting deficits are increasingly relevant. Despite the high incidence and clinical relevance, the pathomechanisms of acute and chronic stages in sepsis-associated encephalopathy are only incompletely understood, and no specific therapeutic options are yet available. Here, we review the emergence of sepsis-associated encephalopathy from initial clinical presentation to long-term cognitive impairment in sepsis survivors and summarize pathomechanisms potentially contributing to the development of sepsis-associated encephalopathy.
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http://dx.doi.org/10.3390/jcm9030703DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7141293PMC
March 2020

Encephalitis with radial perivascular emphasis: Not necessarily associated with GFAP antibodies.

Neurol Neuroimmunol Neuroinflamm 2020 03 4;7(2). Epub 2020 Feb 4.

From the Hans Berger Department of Neurology (J.W., H.-Y.C., C.G., A.G.), Section of Translational Neuroimmunology, Jena University Hospital Germany; Department of Neuroradiology (K.K.), Jena University Hospital, Germany; Department of Neurology (D.B.), Sana Hospital Borna, Germany; Department of Neurology (S.M.), Heinrich-Braun Hospital, Zwickau; and Department of Neuropathology (P.K., W.C.M.), Leipzig University Hospital, Germany.

Objective: Autoimmune steroid-responsive meningoencephalomyelitis with linear perivascular gadolinium enhancement in brain MRI is regarded as glial fibrillary acidic protein (GFAP) astrocytopathy characterized by anti-GFAP antibodies (ABs). We questioned whether anti-GFAP ABs are necessarily associated with this syndrome.

Methods: Two patients with a strikingly similar disease course suggestive of autoimmune GFAP astrocytopathy are reported. Clinical examination, MRI, laboratory, and CSF analysis were performed. Neuropathologic examination of brain tissue was obtained from one patient. Serum and CSF were additionally tested using mouse brain slices, microglia-astrocyte cocultures, and a GFAP-specific cell-based assay.

Results: Both patients presented with subacute influenza-like symptoms and developed severe neurocognitive and neurologic deficits and impaired consciousness. MRIs of both patients revealed radial perivascular gadolinium enhancement extending from the lateral ventricles to the white matter suggestive of autoimmune GFAP astrocytopathy. Both patients responded well to high doses of methylprednisolone. Only one patient had anti-GFAP ABs with a typical staining pattern of astrocytes, whereas serum and CSF of the other patient were negative and showed neither reactivity to brain tissue nor to vital or permeabilized astrocytes. Neuropathologic examination of the anti-GFAP AB-negative patient revealed infiltration of macrophages and T cells around blood vessels and activation of microglia without obvious features of clasmatodendrosis.

Conclusions: The GFAP-AB negative patient had both a striking (para)clinical similarity and an immediate response to immunotherapy. This supports the hypothesis that the clinical spectrum of steroid-responsive meningoencephalomyelitis suggestive of autoimmune GFAP astrocytopathy may be broader and may comprise also seronegative cases.
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http://dx.doi.org/10.1212/NXI.0000000000000670DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7051210PMC
March 2020

Longitudinal optic neuritis-unrelated visual evoked potential changes in NMO spectrum disorders.

Neurology 2020 01 3;94(4):e407-e418. Epub 2019 Dec 3.

From the Department of Neurology, Medical Faculty (M.R., J. Harmel, J.G., H.-P.H., O.A., P.A.), and Department of Neurology, Center for Neurology and Neuropsychiatry, LVR-Klinikum (M.R.), Heinrich Heine University Düsseldorf; NeuroCure Clinical Research Center and Experimental and Clinical Research Center (H.Z., A.U.B., F.P.), Charité Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, Berlin Institute of Health, and Max Delbrueck Center for Molecular Medicine, Germany; Department of Neurology (A.U.B.), University of California Irvine; Department of Neurology (A.H., M.B.), University of Würzburg; Department of Neurology (M.B.), Caritas Hospital, Bad Mergentheim; Clinical Neuroimmunology and Neurochemistry (M.W.H.), Department of Neurology (C.T.), Hannover Medical School; Department of Neurology (C.S., I.A., I.K., K.H.), St. Josef Hospital, Ruhr University Bochum, Germany; Department of Neurology (I.A.), Sechenov First Moscow State Medical University, Moscow, Russia; Marianne-Strauß-Klinik (I.K.), Behandlungszentrum Kempfenhausen für Multiple Sklerose Kranke, Berg; Institute of Clinical Neuroimmunology (J. Halva, T.K., H.P.), University Hospital, Ludwig-Maximilians University, Munich; Molecular Neuroimmunology Group, Department of Neurology (S.J., B.W.), University of Heidelberg, Germany; Department of Neurology (P.R.), Medical University of Vienna, Austria; Institute of Neuropathology (M.S.W.) and Department of Neurology (M.S.W., H.P., P.K.), University Medical Center Göttingen; Department of Neurology (L.R., C.G.), Jena University Hospital; Neuroimmunological Section, Department of Neurology (N.R., U.Z.), University of Rostock; Department of Neurology (M.D., L.K.), University of Münster; Department of Neurology and Institute of Neuroimmunology and MS (K.Y., J.-P.S.), University Medical Center Hamburg-Eppendorf; Department of Neurology (M.K., P.K.), Nordwest-Hospital Sanderbusch, Sande; Department of Neurology (W.M.), Helios Hanseklinikum Stralsund; Department of Neurology (F.L., H.T.), University of Ulm, Germany; and Faculty of Medicine and Health Sciences (A.K.), Macquarie University, Sydney, New South Wales, Australia.

Objective: To investigate if patients with neuromyelitis optica spectrum disorder (NMOSD) develop subclinical visual pathway impairment independent of acute attacks.

Methods: A total of 548 longitudinally assessed full-field visual evoked potentials (VEP) of 167 patients with NMOSD from 16 centers were retrospectively evaluated for changes of P100 latencies and P100-N140 amplitudes. Rates of change in latencies (RCL) and amplitudes (RCA) over time were analyzed for each individual eye using linear regression and compared using generalized estimating equation models.

Results: The rates of change in the absence of optic neuritis (ON) for minimal VEP intervals of ≥3 months between baseline and last follow-up were +1.951 ms/y (n = 101 eyes; SD = 6.274; = 0.012) for the P100 latencies and -2.149 µV/y (n = 64 eyes; SD = 5.013; = 0.005) for the P100-N140 amplitudes. For minimal VEP intervals of ≥12 months, the RCL was +1.768 ms/y (n = 59 eyes; SD = 4.558; = 0.024) and the RCA was -0.527 µV/y (n = 44 eyes; SD = 2.123; = 0.111). The history of a previous ON >6 months before baseline VEP had no influence on RCL and RCA. ONs during the observational period led to mean RCL and RCA of +11.689 ms/y (n = 16 eyes; SD = 17.593; = 0.003) and -1.238 µV/y (n = 11 eyes; SD = 3.708; = 0.308), respectively.

Conclusion: This first longitudinal VEP study of patients with NMOSD provides evidence of progressive VEP latency delay occurring independently of acute ON. Prospective longitudinal studies are needed to corroborate these findings and help to interpret the clinical relevance.
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http://dx.doi.org/10.1212/WNL.0000000000008684DOI Listing
January 2020

An update on anti-NMDA receptor encephalitis for neurologists and psychiatrists: mechanisms and models.

Lancet Neurol 2019 11 17;18(11):1045-1057. Epub 2019 Jul 17.

Neuroimmunology Programme, Institut d'Investigacions Biomèdiques August Pi i Sunyer Hospital Clínic, University of Barcelona, Barcelona, Spain.

The identification of anti-NMDA receptor (NMDAR) encephalitis about 12 years ago made it possible to recognise that some patients with rapidly progressive psychiatric symptoms or cognitive impairment, seizures, abnormal movements, or coma of unknown cause, had an autoimmune disease. In this disease, autoantibodies serve as a diagnostic marker and alter NMDAR-related synaptic transmission. At symptom onset, distinguishing the disease from a primary psychiatric disorder is challenging. The severity of symptoms often requires intensive care. Other than clinical assessment, no specific prognostic biomarkers exist. The disease is more prevalent in women (with a female to male ratio of around 8:2) and about 37% of patients are younger than 18 years at presentation of the disease. Tumours, usually ovarian teratoma, and herpes simplex encephalitis are known triggers of NMDAR autoimmunity. About 80% of patients improve with immunotherapy and, if needed, tumour removal, but the recovery is slow. Animal models have started to reveal the complexity of the underlying pathogenic mechanisms and will lead to novel treatments beyond immunotherapy. Future studies should aim at identifying prognostic biomarkers and treatments that accelerate recovery.
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http://dx.doi.org/10.1016/S1474-4422(19)30244-3DOI Listing
November 2019

Autoimmune encephalitis with anti-IgLON5 and anti-GABAB-receptor antibodies: A case report.

Medicine (Baltimore) 2019 May;98(20):e15706

Hans Berger Department of Neurology, Jena University Hospital, Jena, Germany.

Rationale: Anti-IgLON5 disease is a complex neurological illness which is characterized by progressive sleep and movement disorders and defined by specific autoantibodies to IgLON5. We here describe the first case of a patient with coexisting anti-IgLON5 as well as anti-γ-aminobutyric acid B (GABAB)-receptor antibodies and predominant clinical features of anti-IgLON5 disease.

Patient Concerns: The patient initially presented with subacute symptoms of severe sleep disorder, gait stability, dysarthria, cognitive impairment, depressive episode and hallucinations.

Diagnoses: The patient was diagnosed with autoimmune encephalitis, based on clinical features and positive anti-IgLON5 antibodies in serum as well as in cerebrospinal fluid and anti-GABAB-receptor antibodies in serum only.

Interventions: Initially, the patient was treated with high dosages of methylprednisolone and subsequently with plasmapheresis. Due to the lack of clinical improvement immunosuppressive treatment with intravenous cyclophosphamide was initiated.

Outcomes: Following the first year of cyclophosphamide treatment, neurological examination revealed an improvement in gait instability, visual and acoustic hallucinations and sleep disorder.

Lessons: The case report demonstrates that anti-IgLON5 and anti-GABAB-receptor antibodies can coexist in the same patient whereas clinical leading symptoms are determined by those antibodies that were tested positive in cerebrospinal fluid.
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http://dx.doi.org/10.1097/MD.0000000000015706DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6531245PMC
May 2019

N-methyl-D-aspartate receptor dysfunction by unmutated human antibodies against the NR1 subunit.

Ann Neurol 2019 05 2;85(5):771-776. Epub 2019 Apr 2.

German Center for Neurodegenerative Diseases (DZNE) Berlin, Germany.

Anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis is the most common autoimmune encephalitis related to autoantibody-mediated synaptic dysfunction. Cerebrospinal fluid-derived human monoclonal NR1 autoantibodies showed low numbers of somatic hypermutations or were unmutated. These unexpected germline-configured antibodies showed weaker binding to the NMDAR than matured antibodies from the same patient. In primary hippocampal neurons, germline NR1 autoantibodies strongly and specifically reduced total and synaptic NMDAR currents in a dose- and time-dependent manner. The findings suggest that functional NMDAR antibodies are part of the human naïve B cell repertoire. Given their effects on synaptic function, they might contribute to a broad spectrum of neuropsychiatric symptoms. Ann Neurol 2019;85:771-776.
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http://dx.doi.org/10.1002/ana.25460DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6593665PMC
May 2019

Autoimmune seizures and epilepsy.

J Clin Invest 2019 03 4;129(3):926-940. Epub 2019 Feb 4.

Institut D'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS) and.

The rapid expansion in the number of encephalitis disorders associated with autoantibodies against neuronal proteins has led to an incremental increase in use of the term "autoimmune epilepsy," yet has occurred with limited attention to the physiopathology of each disease and genuine propensity to develop epilepsy. Indeed, most autoimmune encephalitides present with seizures, but the probability of evolving to epilepsy is relatively small. The risk of epilepsy is higher for disorders in which the antigens are intracellular (often T cell-mediated) compared with disorders in which the antigens are on the cell surface (antibody-mediated). Most autoantibodies against neuronal surface antigens show robust effects on the target proteins, resulting in hyperexcitability and impairment of synaptic function and plasticity. Here, we trace the evolution of the concept of autoimmune epilepsy and examine common inflammatory pathways that might lead to epilepsy. Then, we focus on several antibody-mediated encephalitis disorders that associate with seizures and review the synaptic alterations caused by patients' antibodies, with emphasis on those that have been modeled in animals (e.g., antibodies against NMDA, AMPA receptors, LGI1 protein) or in cultured neurons (e.g., antibodies against the GABAb receptor).
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http://dx.doi.org/10.1172/JCI125178DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6391086PMC
March 2019

Stroke Accelerates and Uncouples Intrinsic and Synaptic Excitability Maturation of Mouse Hippocampal DCX Adult-Born Granule Cells.

J Neurosci 2019 02 7;39(9):1755-1766. Epub 2019 Jan 7.

Hans Berger Department of Neurology,

Stroke robustly stimulates adult neurogenesis in the hippocampal dentate gyrus. It is currently unknown whether this process induces beneficial or maladaptive effects, but morphological and behavioral studies have reported aberrant neurogenesis and impaired hippocampal-dependent memory following stroke. However, the intrinsic function and network incorporation of adult-born granule cells (ABGCs) after ischemia is unclear. Using patch-clamp electrophysiology, we evaluated doublecortin-positive (DCX) ABGCs as well as DCX dentate gyrus granule cells 2 weeks after a stroke or sham operation in DCXDsRed transgenic mice of either sex. The developmental status, intrinsic excitability, and synaptic excitability of ABGCs were accelerated following stroke, while dendritic morphology was not aberrant. Regression analysis revealed uncoupled development of intrinsic and network excitability, resulting in young, intrinsically hyperexcitable ABGCs receiving disproportionately large glutamatergic inputs. This aberrant functional maturation in the subgroup of ABGCs in the hippocampus may contribute to defective hippocampal function and increased seizure susceptibility following stroke. Stroke increases hippocampal neurogenesis but the functional consequences of the postlesional response is mostly unclear. Our findings provide novel evidence of aberrant functional maturation of newly generated neurons following stroke. We demonstrate that stroke not only causes an accelerated maturation of the intrinsic and synaptic parameters of doublecortin-positive, new granule cells in the hippocampus, but that this accelerated development does not follow physiological dynamics due to uncoupled intrinsic and synaptic maturation. Hyperexcitable immature neurons may contribute to disrupted network integration following stroke.
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http://dx.doi.org/10.1523/JNEUROSCI.3303-17.2018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6391573PMC
February 2019

Management and prognostic markers in patients with autoimmune encephalitis requiring ICU treatment.

Neurol Neuroimmunol Neuroinflamm 2019 01 30;6(1):e514. Epub 2018 Oct 30.

Hans-Berger-Department of Neurology (J.S., D.B., C.G., O.W.W., A.G.), Jena University Hospital; Department of Neurology (H.B.H., S.T.G.), University Hospital Erlangen; Department of Neurology and Neurophysiology (H.F), University Hospital Freiburg; Department of Neurology (N.M., A.D.), University Hospital Münster; Department of Neurology (H.P., L.-T.L), Charité University Medicine Berlin; Department of Neurology (K.F.), Bezirksklinikum Regensburg; Neuroimmunology Section (F.L., G.N.), Institute of Clinical Chemistry and Department of Neurology, University Hospital Schleswig-Holstein, Kiel; Department of Neurology (I.S.), University Hospital Giessen; Center for Neurology and Psychiatrics (C.D.), University Hospital Köln; Department of Neurology (J.B.), University Hospital Heidelberg; Department of Neurology (J.B.), Klinikum Kassel; Department of Neurology (J.L.), University Hospital Ulm; Institute of Clinical Neuroimmunology (F.T.), Ludwig-Maximillians-University München; Department of Neurology (A.K.), Martha Maria Hospital Halle; Department of Neurology (A.J.), Dortmund Hospital; Department of Neurology (M.R.), Medical Faculty, Heinrich Heine University Düsseldorf; Department of Neurology (K.-W.S.), University Hospital Hannover; Department of Neurology (C.U.), Hospital Ludwigshafen; Institute of Medical Statistics, Computer and Data Sciences (A.S), Jena University Hospital; and Center for Sepsis Control and Care (A.S., C.G.), Jena University Hospital, Germany.

Objective: To assess intensive care unit (ICU) complications, their management, and prognostic factors associated with outcomes in a cohort of patients with autoimmune encephalitis (AE).

Methods: This study was an observational multicenter registry of consecutively included patients diagnosed with AE requiring Neuro-ICU treatment between 2004 and 2016 from 18 tertiary hospitals. Logistic regression models explored the influence of complications, their management, and diagnostic findings on the dichotomized (0-3 vs 4-6) modified Rankin Scale score at hospital discharge.

Results: Of 120 patients with AE (median age 43 years [interquartile range 24-62]; 70 females), 101 developed disorders of consciousness, 54 autonomic disturbances, 42 status epilepticus, and 39 severe sepsis. Sixty-eight patients were mechanically ventilated, 85 patients had detectable neuronal autoantibodies, and 35 patients were seronegative. Worse neurologic outcome at hospital discharge was associated with necessity of mechanical ventilation (sex- and age-adjusted OR 6.28; 95% CI, 2.71-15.61) tracheostomy (adjusted OR 6.26; 95% CI, 2.68-15.73), tumor (adjusted OR 3.73; 95% CI, 1.35-11.57), sepsis (adjusted OR 4.54; 95% CI, 1.99-10.43), or autonomic dysfunction (adjusted OR 2.91; 95% CI, 1.24-7.3). No significant association was observed with autoantibody type, inflammatory changes in CSF, or pathologic MRI.

Conclusion: In patients with AE, mechanical ventilation, sepsis, and autonomic dysregulation appear to indicate longer or incomplete convalescence. Classic ICU complications better serve as prognostic markers than the individual subtype of AE. Increased awareness and effective management of these AE-related complications are warranted, and further prospective studies are needed to confirm our findings and to develop specific strategies for outcome improvement.
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http://dx.doi.org/10.1212/NXI.0000000000000514DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6278855PMC
January 2019

Bioorthogonal Click Chemistry Enables Site-specific Fluorescence Labeling of Functional NMDA Receptors for Super-Resolution Imaging.

Angew Chem Int Ed Engl 2018 12 15;57(50):16364-16369. Epub 2018 Nov 15.

Department of Biotechnology and Biophysics, University of Würzburg, Biocenter, Am Hubland, 97074, Würzburg, Germany.

Super-resolution microscopy requires small fluorescent labels. We report the application of genetic code expansion in combination with bioorthogonal click chemistry to label the NR1 domain of the NMDA receptor. We generated NR1 mutants incorporating an unnatural amino acid at various positions in order to attach small organic fluorophores such as Cy5-tetrazine site-specifically to the extracellular domain of the receptor. Mutants were optimized with regard to protein expression, labeling efficiency and receptor functionality as tested by fluorescence microscopy and whole-cell patch clamp. The results show that bioorthogonal click chemistry in combination with small organic dyes is superior to available immunocytochemistry protocols for receptor labeling in live and fixed cells and enables single-molecule sensitive super-resolution microscopy experiments.
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http://dx.doi.org/10.1002/anie.201808951DOI Listing
December 2018

LGI1 antibodies alter Kv1.1 and AMPA receptors changing synaptic excitability, plasticity and memory.

Brain 2018 11;141(11):3144-3159

Hans-Berger Department of Neurology, Jena University Hospital, Jena, Germany.

Leucine-rich glioma-inactivated 1 (LGI1) is a secreted neuronal protein that forms a trans-synaptic complex that includes the presynaptic disintegrin and metalloproteinase domain-containing protein 23 (ADAM23), which interacts with voltage-gated potassium channels Kv1.1, and the postsynaptic ADAM22, which interacts with AMPA receptors. Human autoantibodies against LGI1 associate with a form of autoimmune limbic encephalitis characterized by severe but treatable memory impairment and frequent faciobrachial dystonic seizures. Although there is evidence that this disease is immune-mediated, the underlying LGI1 antibody-mediated mechanisms are unknown. Here, we used patient-derived immunoglobulin G (IgG) antibodies to determine the main epitope regions of LGI1 and whether the antibodies disrupt the interaction of LGI1 with ADAM23 and ADAM22. In addition, we assessed the effects of patient-derived antibodies on Kv1.1, AMPA receptors, and memory in a mouse model based on cerebroventricular transfer of patient-derived IgG. We found that IgG from all patients (n = 25), but not from healthy participants (n = 20), prevented the binding of LGI1 to ADAM23 and ADAM22. Using full-length LGI1, LGI3, and LGI1 constructs containing the LRR1 domain (EPTP1-deleted) or EPTP1 domain (LRR3-EPTP1), IgG from all patients reacted with epitope regions contained in the LRR1 and EPTP1 domains. Confocal analysis of hippocampal slices of mice infused with pooled IgG from eight patients, but not pooled IgG from controls, showed a decrease of total and synaptic levels of Kv1.1 and AMPA receptors. The effects on Kv1.1 preceded those involving the AMPA receptors. In acute slice preparations of hippocampus, patch-clamp analysis from dentate gyrus granule cells and CA1 pyramidal neurons showed neuronal hyperexcitability with increased glutamatergic transmission, higher presynaptic release probability, and reduced synaptic failure rate upon minimal stimulation, all likely caused by the decreased expression of Kv1.1. Analysis of synaptic plasticity by recording field potentials in the CA1 region of the hippocampus showed a severe impairment of long-term potentiation. This defect in synaptic plasticity was independent from Kv1 blockade and was possibly mediated by ineffective recruitment of postsynaptic AMPA receptors. In parallel with these findings, mice infused with patient-derived IgG showed severe memory deficits in the novel object recognition test that progressively improved after stopping the infusion of patient-derived IgG. Different from genetic models of LGI1 deficiency, we did not observe aberrant dendritic sprouting or defective synaptic pruning as potential cause of the symptoms. Overall, these findings demonstrate that patient-derived IgG disrupt presynaptic and postsynaptic LGI1 signalling, causing neuronal hyperexcitability, decreased plasticity, and reversible memory deficits.
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http://dx.doi.org/10.1093/brain/awy253DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6202570PMC
November 2018

Apheresis therapies for NMOSD attacks: A retrospective study of 207 therapeutic interventions.

Neurol Neuroimmunol Neuroinflamm 2018 Nov 26;5(6):e504. Epub 2018 Sep 26.

Department of Neurology (I.K., A.G., K.H.), St. Josef Hospital, Ruhr University Bochum; Marianne-Strauß-Klinik (I.K.), Behandlungszentrum Kempfenhausen für Multiple Sklerose Kranke, Berg; NeuroCure Clinical Research Center and Experimental and Clinical Research Center (N.B., F. Pache), Charité Universitätsmedizin Berlin, and Max Delbrueck Center for Molecular Medicine, Berlin; Department of Neurology (K.F., J.F.), Asklepios Fachklinikum Teupitz; CRO Sostana GmbH and Charité Universitätsmedizin Berlin (K.-D.W.); Department of Neurology and Clinical and Experimental Multiple Sclerosis Research Center (F.Pache, K.R.), Charité Universitätsmedizin Berlin; Institute of Clinical Neuroimmunology (J.H., T.K.), Ludwig Maximilians University, Munich; Department of Neurology (O.A., H.-P.H., M.R.), Medical Faculty, Heinrich Heine University Düsseldorf; Department of Neurology (C.G., M. Schwab), Jena University Hospital; Department of Neurology (C.K.), University Hospital Essen; Department of Neurology (A.B.), Klinikum rechts der Isar, Technische Universität München, Munich; Department of Neurology (B.H.), Klinikum rechts der Isar, Technische Universität München and Munich Cluster for Systems Neurology (SyNergy); Department of Neurology (K.A.), University Hospital Regensburg; Institute of Neuroimmunology and MS (INIMS) and Department of Neurology (J.-P.S.), University Medical Centre Hamburg-Eppendorf, HamburgKlinik und Poliklinik für Neurologie (S.S.), Universitätsklinikum Hamburg-Eppendorf; Clinical Neuroimmunology and Neurochemistry (M. Stangel), Department of Neurology, Hannover Medical School; Department of Neurology (F.L., H.T.), University of Ulm; Fachklinik für Neurologie Dietenbronn (H.T.), Akademisches Krankenhaus der Universität Ulm, Schwendi; Department of Neurology (C.M.), Goethe University Frankfurt; Department of Neurology & Stroke (M.K., L.Z., U. Ziemann), and Hertie-Institute for Clinical Brain Research, University of Tübingen; Department of Neurology (R.L.), Friedrich-Alexander University Erlangen-Nuremberg; Department of Neurology and Neurological Intensive Care (M.M.), Isar-Amper-Clinic, Munich-East, Haar; Department of Neurology (F.T.B.), University of Leipzig; Department of Neurology (U. Hofstadt-van Oy), Klinikum Westfalen, Dortmund; Department of Neurology (O.N.), SRH Krankenhaus Sigmaringen; Neuroimmunological Section (U. Zettl), Department of Neurology, University of Rostock; Molecular Neuroimmunology Group (B.W., S.J.), Department of Neurology, University of Heidelberg; NeuroCure Clinical Research Center (F. Paul), Charité Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, and Experimental and Clinical Research Center, Max Delbrück Center for Molecular Medicine and Charité-Universitätsmedizin Berlin; and Department of Neurology (C.T.), Hannover Medical School, Germany.

Objective: To analyze whether 1 of the 2 apheresis techniques, therapeutic plasma exchange (PE) or immunoadsorption (IA), is superior in treating neuromyelitis optica spectrum disorder (NMOSD) attacks and to identify predictive factors for complete remission (CR).

Methods: This retrospective cohort study was based on the registry of the German Neuromyelitis Optica Study Group, a nationwide network established in 2008. It recruited patients with neuromyelitis optica diagnosed according to the 2006 Wingerchuk criteria or with aquaporin-4 (AQP4-ab)-antibody-seropositive NMOSD treated at 6 regional hospitals and 16 tertiary referral centers until March 2013. Besides descriptive data analysis of patient and attack characteristics, generalized estimation equation (GEE) analyses were applied to compare the effectiveness of the 2 apheresis techniques. A GEE model was generated to assess predictors of outcome.

Results: Two hundred and seven attacks in 105 patients (87% AQP4-ab-antibody seropositive) were treated with at least 1 apheresis therapy. Neither PE nor IA was proven superior in the therapy of NMOSD attacks. CR was only achieved with early apheresis therapy. Strong predictors for CR were the use of apheresis therapy as first-line therapy (OR 12.27, 95% CI: 1.04-144.91, = 0.047), time from onset of attack to start of therapy in days (OR 0.94, 95% CI: 0.89-0.99, = 0.014), the presence of AQP4-ab-antibodies (OR 33.34, 95% CI: 1.76-631.17, = 0.019), and monofocal attack manifestation (OR 4.71, 95% CI: 1.03-21.62, = 0.046).

Conclusions: Our findings suggest early use of an apheresis therapy in NMOSD attacks, particularly in AQP4-ab-seropositive patients. No superiority was shown for one of the 2 apheresis techniques.

Classification Of Evidence: This study provides Class IV evidence that for patients with NMOSD, neither PE nor IA is superior in the treatment of attacks.
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http://dx.doi.org/10.1212/NXI.0000000000000504DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6192689PMC
November 2018

B-cell depletion is ineffective in a patient with granulomatous optic neuropathy.

Neurol Neuroimmunol Neuroinflamm 2018 Sep 10;5(5):e493. Epub 2018 Aug 10.

Hans Berger Department of Neurology (F.W., O.W.W., C.G.), Jena University Hospital, Jena; and Department of Neuropathology (H.R.), Charité Universitätsmedizin Berlin, Germany.

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http://dx.doi.org/10.1212/NXI.0000000000000493DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6117191PMC
September 2018

Human Autoantibodies against the AMPA Receptor Subunit GluA2 Induce Receptor Reorganization and Memory Dysfunction.

Neuron 2018 10 23;100(1):91-105.e9. Epub 2018 Aug 23.

Hans-Berger Department of Neurology, Jena University Hospital, Am Klinikum 1, 07747 Jena, Germany; Center for Sepsis Control and Care (CSCC), Jena University Hospital, Am Klinikum 1, 07747 Jena, Germany. Electronic address:

AMPA receptors are essential for fast excitatory transmission in the CNS. Autoantibodies to AMPA receptors have been identified in humans with autoimmune encephalitis and severe defects of hippocampal function. Here, combining electrophysiology and high-resolution imaging with neuronal culture preparations and passive-transfer models in wild-type and GluA1-knockout mice, we analyze how specific human autoantibodies against the AMPA receptor subunit GluA2 affect receptor function and composition, synaptic transmission, and plasticity. Anti-GluA2 antibodies induce receptor internalization and a reduction of synaptic GluA2-containing AMPARs followed by compensatory ryanodine receptor-dependent incorporation of synaptic non-GluA2 AMPARs. Furthermore, application of human pathogenic anti-GluA2 antibodies to mice impairs long-term synaptic plasticity in vitro and affects learning and memory in vivo. Our results identify a specific immune-neuronal rearrangement of AMPA receptor subunits, providing a framework to explain disease symptoms.
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http://dx.doi.org/10.1016/j.neuron.2018.07.048DOI Listing
October 2018

Defective synaptic transmission causes disease signs in a mouse model of juvenile neuronal ceroid lipofuscinosis.

Elife 2017 11 14;6. Epub 2017 Nov 14.

Hans-Berger Department of Neurology, Jena University Hospital, Jena, Germany.

Juvenile neuronal ceroid lipofuscinosis (JNCL or Batten disease) caused by mutations in the gene is the most prevalent inherited neurodegenerative disease in childhood resulting in widespread central nervous system dysfunction and premature death. The consequences of mutation on the progression of the disease, on neuronal transmission, and on central nervous network dysfunction are poorly understood. We used knockout ( mice and found increased anxiety-related behavior and impaired aversive learning as well as markedly affected motor function including disordered coordination. Patch-clamp and loose-patch recordings revealed severely affected inhibitory and excitatory synaptic transmission in the amygdala, hippocampus, and cerebellar networks. Changes in presynaptic release properties may result from dysfunction of CLN3 protein. Furthermore, loss of calbindin, neuropeptide Y, parvalbumin, and GAD65-positive interneurons in central networks collectively support the hypothesis that degeneration of GABAergic interneurons may be the cause of supraspinal GABAergic disinhibition.
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http://dx.doi.org/10.7554/eLife.28685DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5724993PMC
November 2017

Immunotherapies in neuromyelitis optica spectrum disorder: efficacy and predictors of response.

J Neurol Neurosurg Psychiatry 2017 08 1;88(8):639-647. Epub 2017 Jun 1.

Department of Neurology, St. Josef Hospital, Ruhr University Bochum, Bochum, Germany.

Objective: To analyse predictors for relapses and number of attacks under different immunotherapies in patients with neuromyelitis optica spectrum disorder (NMOSD).

Design: This is a retrospective cohort study conducted in neurology departments at 21 regional and university hospitals in Germany. Eligible participants were patients with aquaporin-4-antibody-positive or aquaporin-4-antibody-negative NMOSD. Main outcome measures were HRs from Cox proportional hazard regression models adjusted for centre effects, important prognostic factors and repeated treatment episodes.

Results: 265 treatment episodes with a mean duration of 442 days (total of 321 treatment years) in 144 patients (mean age at first attack: 40.9 years, 82.6% female, 86.1% aquaporin-4-antibody-positive) were analysed. 191 attacks occurred during any of the treatments (annual relapse rate=0.60). The most common treatments were rituximab (n=77, 111 patient-years), azathioprine (n=52, 68 patient-years), interferon-β (n=32, 61 patient-years), mitoxantrone (n=34, 32.1 patient-years) and glatiramer acetate (n=17, 10 patient-years). Azathioprine (HR=0.4, 95% CI 0.3 to 0.7, p=0.001) and rituximab (HR=0.6, 95% CI 0.4 to 1.0, p=0.034) reduced the attack risk compared with interferon-β, whereas mitoxantrone and glatiramer acetate did not. Patients who were aquaporin-4-antibody-positive had a higher risk of attacks (HR=2.5, 95% CI 1.3 to 5.1, p=0.009). Every decade of age was associated with a lower risk for attacks (HR=0.8, 95% CI 0.7 to 1.0, p=0.039). A previous attack under the same treatment tended to be predictive for further attacks (HR=1.5, 95% CI 1.0 to 2.4, p=0.065).

Conclusions: Age, antibody status and possibly previous attacks predict further attacks in patients treated for NMOSD. Azathioprine and rituximab are superior to interferon-β.
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http://dx.doi.org/10.1136/jnnp-2017-315603DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5537514PMC
August 2017

Autoantibodies to Synaptic Receptors and Neuronal Cell Surface Proteins in Autoimmune Diseases of the Central Nervous System.

Physiol Rev 2017 04;97(2):839-887

Institut d'Investigacions Biomèdiques August Pi i Sunyer, Hospital Clínic, Universitat de Barcelona, Barcelona, Spain; Department of Neurology, University of Pennsylvania, Philadelphia, Pennsylvania; Institució Catalana de Recerca i Estudis Avançats, Barcelona, Spain; Hans-Berger Department of Neurology, Jena University Hospital, Jena, Germany; Servei de Neurologia, Hospital Clínic, Universitat de Barcelona, Barcelona, Spain.

Investigations in the last 10 years have revealed a new category of neurological diseases mediated by antibodies against cell surface and synaptic proteins. There are currently 16 such diseases all characterized by autoantibodies against neuronal proteins involved in synaptic signaling and plasticity. In clinical practice these findings have changed the diagnostic and treatment approach to potentially lethal, but now treatable, neurological and psychiatric syndromes previously considered idiopathic or not even suspected to be immune-mediated. Studies show that patients' antibodies can impair the surface dynamics of the target receptors eliminating them from synapses (e.g., NMDA receptor), block the function of the antigens without changing their synaptic density (e.g., GABAb receptor), interfere with synaptic protein-protein interactions (LGI1, Caspr2), alter synapse formation (e.g., neurexin-3α), or by unclear mechanisms associate to a new form of tauopathy (IgLON5). Here we first trace the process of discovery of these diseases, describing the triggers and symptoms related to each autoantigen, and then review in detail the structural and functional alterations caused by the autoantibodies with special emphasis in those (NMDA receptor, amphiphysin) that have been modeled in animals.
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http://dx.doi.org/10.1152/physrev.00010.2016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5539405PMC
April 2017

NOX4 is an early initiator of neuropathic pain.

Exp Neurol 2017 Feb 14;288:94-103. Epub 2016 Nov 14.

Department of Neurology, University Hospital Würzburg, Josef-Schneider Straße 11, 97080 Würzburg, Germany; Department of Neurology, University Hospital Essen, Hufelandstraße 55, 45147 Essen, Germany.

Treatment of neuropathic pain remains challenging as the etiology is heterogeneous and pathomechanisms are incompletely understood. One possible mechanism is oxidative stress due to unphysiological reactive oxygen species (ROS) formation. The only know dedicated enzymatic source of ROS are NADPH oxidases of which the type 4 isoform (NOX4) has been suggested to be involved in the subacute and chronic phase of neuropathic pain. Here, we aim to translate this finding into a treatment strategy by examining the efficacy of the NOX1/4-specific inhibitor GKT136901 using the chronic constriction injury (CCI) mouse model of neuropathic pain. Unexpectedly, post-nerve lesion treatment using GKT136901 was ineffective to reduce pain-related behavior after CCI. We therefore re-investigated the role of NOX4 using an independent KO mouse model. Early after CCI we found an increase in pro-inflammatory cytokines, ROS formation and the oxidative stress marker nitrotyrosine in the lesioned nerve together with an upregulated Nox4 gene expression. In NOX4 KO mice, mechanical allodynia was markedly reduced from day 4 after nerve injury as were all ROS related and acute biomarkers. In addition, we observed a reduction in the CCI-induced upregulation of pro-inflammatory cytokines in the sciatic nerve and dorsal root ganglia along with NOX4-deficiency. Thus, we conclude that NOX4 is involved in the development of neuropathic pain states by producing oxidative stress and subsequent cytokine dysregulation at the lesion site. This appears at very early stages immediately after nerve injury explaining ineffectiveness of post-acute pharmacological NOX inhibition. We suggest that future target validation of NOX4 should now focus on defining the possible therapeutic window in human neuropathic pain.
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http://dx.doi.org/10.1016/j.expneurol.2016.11.008DOI Listing
February 2017

Influence of female sex and fertile age on neuromyelitis optica spectrum disorders.

Mult Scler 2017 Jul 6;23(8):1092-1103. Epub 2016 Oct 6.

Department of Neurology, St. Josef Hospital, Ruhr University Bochum, Bochum, Germany.

Background: Gender and age at onset are important epidemiological factors influencing prevalence, clinical presentation, and treatment response in autoimmune diseases.

Objective: To evaluate the impact of female sex and fertile age on aquaporin-4-antibody (AQP4-ab) status, attack localization, and response to attack treatment in patients with neuromyelitis optica (NMO) and its spectrum disorders (neuromyelitis optica spectrum disorder (NMOSD)).

Methods: Female-to-male ratios, diagnosis at last visit (NMO vs NMOSD), attack localization, attack treatment, and outcome were compared according to sex and age at disease or attack onset.

Results: A total of 186 NMO/SD patients (82% female) were included. In AQP4-ab-positive patients, female predominance was most pronounced during fertile age (female-to-male ratio 23:1). Female patients were more likely to be positive for AQP4-abs (92% vs 55%; p < 0.001). Interval between onset and diagnosis of NMO/SD was longer in women than in men (mean 54 vs 27 months; p = 0.023). In women, attacks occurring ⩽40 years of age were more likely to show complete remission ( p = 0.003) and better response to high-dose intravenous steroids ( p = 0.005) compared to woman at >40 years.

Conclusion: Our data suggest an influence of sex and age on susceptibility to AQP4-ab-positive NMO/SD. Genetic and hormonal factors might contribute to pathophysiology of NMO/SD.
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http://dx.doi.org/10.1177/1352458516671203DOI Listing
July 2017

Efficacy of Polyvalent Human Immunoglobulins in an Animal Model of Neuromyelitis Optica Evoked by Intrathecal Anti-Aquaporin 4 Antibodies.

Int J Mol Sci 2016 Aug 26;17(9). Epub 2016 Aug 26.

Hans-Berger Department of Neurology, Jena University Hospital, Am Klinikum 1, 07747 Jena, Germany.

Neuromyelitis Optica Spectrum Disorders (NMOSD) are associated with autoantibodies (ABs) targeting the astrocytic aquaporin-4 water channels (AQP4-ABs). These ABs have a direct pathogenic role by initiating a variety of immunological and inflammatory processes in the course of disease. In a recently-established animal model, chronic intrathecal passive-transfer of immunoglobulin G from NMOSD patients (NMO-IgG), or of recombinant human AQP4-ABs (rAB-AQP4), provided evidence for complementary and immune-cell independent effects of AQP4-ABs. Utilizing this animal model, we here tested the effects of systemically and intrathecally applied pooled human immunoglobulins (IVIg) using a preventive and a therapeutic paradigm. In NMO-IgG animals, prophylactic application of systemic IVIg led to a reduced median disease score of 2.4 on a 0-10 scale, in comparison to 4.1 with sham treatment. Therapeutic IVIg, applied systemically after the 10th intrathecal NMO-IgG injection, significantly reduced the disease score by 0.8. Intrathecal IVIg application induced a beneficial effect in animals with NMO-IgG (median score IVIg 1.6 vs. sham 3.7) or with rAB-AQP4 (median score IVIg 2.0 vs. sham 3.7). We here provide evidence that treatment with IVIg ameliorates disease symptoms in this passive-transfer model, in analogy to former studies investigating passive-transfer animal models of other antibody-mediated disorders.
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http://dx.doi.org/10.3390/ijms17091407DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5037687PMC
August 2016

Ephrin-B2 prevents N-methyl-D-aspartate receptor antibody effects on memory and neuroplasticity.

Ann Neurol 2016 09 2;80(3):388-400. Epub 2016 Aug 2.

Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Hospital Clínic, Universitat de Barcelona, Barcelona, Spain.

Objective: To demonstrate that ephrin-B2 (the ligand of EphB2 receptor) antagonizes the pathogenic effects of patients' N-methyl-D-aspartate receptor (NMDAR) antibodies on memory and synaptic plasticity.

Methods: One hundred twenty-two C57BL/6J mice infused with cerebrospinal fluid (CSF) from patients with anti-NMDAR encephalitis or controls, with or without ephrin-B2, were investigated. CSF was infused through ventricular catheters connected to subcutaneous osmotic pumps over 14 days. Memory, behavioral tasks, locomotor activity, presence of human antibodies specifically bound to hippocampal NMDAR, and antibody effects on the density of cell-surface and synaptic NMDAR and EphB2 were examined at different time points using reported techniques. Short- and long-term synaptic plasticity were determined in acute brain sections; the Schaffer collateral pathway was stimulated and the field excitatory postsynaptic potentials were recorded in the CA1 region of the hippocampus.

Results: Mice infused with patients' CSF, but not control CSF, developed progressive memory deficit and depressive-like behavior along with deposits of NMDAR antibodies in the hippocampus. These findings were associated with a decrease of the density of cell-surface and synaptic NMDAR and EphB2, and marked impairment of long-term synaptic plasticity without altering short-term plasticity. Administration of ephrin-B2 prevented the pathogenic effects of the antibodies in all the investigated paradigms assessing memory, depressive-like behavior, density of cell-surface and synaptic NMDAR and EphB2, and long-term synaptic plasticity.

Interpretation: Administration of ephrin-B2 prevents the pathogenic effects of anti-NMDAR encephalitis antibodies on memory and behavior, levels of cell-surface NMDAR, and synaptic plasticity. These findings reveal a strategy beyond immunotherapy to antagonize patients' antibody effects. Ann Neurol 2016;80:388-400.
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http://dx.doi.org/10.1002/ana.24721DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5832041PMC
September 2016