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  • 1
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    Online Resource
    A genome-wide association study in autoimmune neurological syndromes with anti-GAD65 autoantibodies
    Oxford University Press (OUP) ; 2023
    In:  Brain Vol. 146, No. 3 ( 2023-03-01), p. 977-990
    Details
    In: Brain, Oxford University Press (OUP), Vol. 146, No. 3 ( 2023-03-01), p. 977-990
    Abstract: Autoimmune neurological syndromes (AINS) with autoantibodies against the 65 kDa isoform of the glutamic acid decarboxylase (GAD65) present with limbic encephalitis, including temporal lobe seizures or epilepsy, cerebellitis with ataxia, and stiff-person-syndrome or overlap forms. Anti-GAD65 autoantibodies are also detected in autoimmune diabetes mellitus, which has a strong genetic susceptibility conferred by human leukocyte antigen (HLA) and non-HLA genomic regions. We investigated the genetic predisposition in patients with anti-GAD65 AINS. We performed a genome-wide association study (GWAS) and an association analysis of the HLA region in a large German cohort of 1214 individuals. These included 167 patients with anti-GAD65 AINS, recruited by the German Network for Research on Autoimmune Encephalitis (GENERATE), and 1047 individuals without neurological or endocrine disease as population-based controls. Predictions of protein expression changes based on GWAS findings were further explored and validated in the CSF proteome of a virtually independent cohort of 10 patients with GAD65-AINS and 10 controls. Our GWAS identified 16 genome-wide significant (P & lt; 5 × 10−8) loci for the susceptibility to anti-GAD65 AINS. The top variant, rs2535288 [P = 4.42 × 10−16, odds ratio (OR) = 0.26, 95% confidence interval (CI) = 0.187–0.358], localized to an intergenic segment in the middle of the HLA class I region. The great majority of variants in these loci ( & gt;90%) mapped to non-coding regions of the genome. Over 40% of the variants have known regulatory functions on the expression of 48 genes in disease relevant cells and tissues, mainly CD4+ T cells and the cerebral cortex. The annotation of epigenomic marks suggested specificity for neural and immune cells. A network analysis of the implicated protein-coding genes highlighted the role of protein kinase C beta (PRKCB) and identified an enrichment of numerous biological pathways participating in immunity and neural function. Analysis of the classical HLA alleles and haplotypes showed no genome-wide significant associations. The strongest associations were found for the DQA1*03:01-DQB1*03:02-DRB1*04:01HLA haplotype (P = 4.39 × 10−4, OR = 2.5, 95%CI = 1.499–4.157) and DRB1*04:01 allele (P = 8.3 × 10−5, OR = 2.4, 95%CI = 1.548–3.682) identified in our cohort. As predicted, the CSF proteome showed differential levels of five proteins (HLA-A/B, C4A, ATG4D and NEO1) of expression quantitative trait loci genes from our GWAS in the CSF proteome of anti-GAD65 AINS. These findings suggest a strong genetic predisposition with direct functional implications for immunity and neural function in anti-GAD65 AINS, mainly conferred by genomic regions outside the classical HLA alleles.
    Type of Medium: Online Resource
    ISSN: 0006-8950 , 1460-2156
    URL: Article
    DOI: 10.1093/brain/awac119
    RVK:
    XA 10000
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2023
    detail.hit.zdb_id: 1474117-9
    SSG: 12
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  • 2
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    Clinical, serological and genetic predictors of response to immunotherapy in anti-IgLON5 disease
    Oxford University Press (OUP) ; 2023
    In:  Brain Vol. 146, No. 2 ( 2023-02-13), p. 600-611
    Details
    In: Brain, Oxford University Press (OUP), Vol. 146, No. 2 ( 2023-02-13), p. 600-611
    Abstract: Anti-IgLON5 disease is a newly defined clinical entity characterized by a progressive course with high disability and mortality rate. While precise pathogenetic mechanisms remain unclear, features characteristic of both autoimmune and neurodegenerative diseases were reported. Data on immunotherapy are limited, and its efficacy remains controversial. In this study, we retrospectively investigated an anti-IgLON5 disease cohort with special focus on clinical, serological and genetic predictors of the immunotherapy response and long-term outcome. Patients were recruited from the GENERATE (German Network for Research on Autoimmune Encephalitis) registry. Along with clinical parameters, anti-IgLON5 immunoglobulin (Ig)G in serum and CSF, anti-IgLON5 IgG1-4, IgA and IgM in serum, neurofilament light chain and glial fibrillary acidic protein in serum as well as human leukocyte antigen-genotypes were determined. We identified 53 patients (symptom onset 63.8 ± 10.3 years, female:male 1:1.5). The most frequent initial clinical presentations were bulbar syndrome, hyperkinetic syndrome or isolated sleep disorder [at least one symptom present in 38% (20/53)]. At the time of diagnosis, the majority of patients had a generalized multi-systemic phenotype; nevertheless, 21% (11/53) still had an isolated brainstem syndrome and/ or a characteristic sleep disorder only. About one third of patients [28% (15/53)] reported subacute disease onset and 51% (27/53) relapse-like exacerbations during the disease course. Inflammatory CSF changes were evident in 37% (19/51) and increased blood-CSF-barrier permeability in 46% (21/46). CSF cell count significantly decreased, while serum anti-IgLON5 IgG titre increased with disease duration. The presence of human leukocyte antigen-DRB1*10:01 [55% (24/44)] was associated with higher serum anti-IgLON5 IgG titres. Neurofilament light chain and glial fibrillary acidic protein in serum were substantially increased (71.1 ± 103.9 pg/ml and 126.7 ± 73.3 pg/ml, respectively). First-line immunotherapy of relapse-like acute-to-subacute exacerbation episodes resulted in improvement in 41% (11/27) of patients and early initiation within the first 6 weeks was a predictor for therapy response. Sixty-eight per cent (36/53) of patients were treated with long-term immunotherapy and 75% (27/36) of these experienced no further disease progression (observation period of 20.2 ± 15.4 months). Long-term immunotherapy initiation during the first year after onset and low pre-treatment neurofilament light chain were significant predictors for a better outcome. In conclusion, subacute disease onset and early inflammatory CSF changes support the primary role of autoimmune mechanisms at least at initial stages of anti-IgLON5 disease. Early immunotherapy, prior to advanced neurodegeneration, is associated with a better long-term clinical outcome. Low serum neurofilament light chain at treatment initiation may serve as a potential biomarker of the immunotherapy response.
    Type of Medium: Online Resource
    ISSN: 0006-8950 , 1460-2156
    URL: Article
    DOI: 10.1093/brain/awac090
    RVK:
    XA 10000
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2023
    detail.hit.zdb_id: 1474117-9
    SSG: 12
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  • 3
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    NMO-Spektrum-Erkrankungen
    Georg Thieme Verlag KG ; 2017
    In:  Aktuelle Neurologie Vol. 44, No. 03 ( 2017-5-3), p. 180-193
    Details
    In: Aktuelle Neurologie, Georg Thieme Verlag KG, Vol. 44, No. 03 ( 2017-5-3), p. 180-193
    Type of Medium: Online Resource
    ISSN: 0302-4350 , 1438-9428
    URL: Article
    DOI: 10.1055/s-0042-124178
    Language: German
    Publisher: Georg Thieme Verlag KG
    Publication Date: 2017
    detail.hit.zdb_id: 2056721-2
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  • 4
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    Amygdala enlargement and emotional responses in (autoimmune) temporal lobe epilepsy
    Springer Science and Business Media LLC ; 2018
    In:  Scientific Reports Vol. 8, No. 1 ( 2018-06-22)
    Details
    In: Scientific Reports, Springer Science and Business Media LLC, Vol. 8, No. 1 ( 2018-06-22)
    Abstract: Temporal lobe epilepsy with amygdala enlargement (TLE-AE) is increasingly recognized as a distinct adult electroclinical syndrome. However, functional consequences of morphological alterations of the amygdala in TLE-AE are poorly understood. Here, two emotional stimulation designs were employed to investigate subjective emotional rating and skin conductance responses in a sample of treatment-naïve patients with suspected or confirmed autoimmune TLE-AE ( n  = 12) in comparison to a healthy control group ( n  = 16). A subgroup of patients completed follow-up measurements after treatment. As compared to healthy controls, patients with suspected or confirmed autoimmune TLE-AE showed markedly attenuated skin conductance responses and arousal ratings, especially pronounced for anxiety-inducing stimuli. The degree of right amygdala enlargement was significantly correlated with the degree of autonomic arousal attenuation. Furthermore, a decline of amygdala enlargement following prompt aggressive immunotherapy in one patient suffering from severe confirmed autoimmune TLE-AE with a very recent clinical onset was accompanied by a significant improvement of autonomic responses. Findings suggest dual impairments of autonomic and cognitive discrimination of stimulus arousal as hallmarks of emotional processing in TLE-AE. Emotional responses might, at least partially, recover after successful treatment, as implied by first single case data.
    Type of Medium: Online Resource
    ISSN: 2045-2322
    URL: Article
    DOI: 10.1038/s41598-018-27914-z
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2018
    detail.hit.zdb_id: 2615211-3
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  • 5
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    Translational imaging of TSPO reveals pronounced innate inflammation in human and murine CD8 T cell–mediated limbic encephalitis
    American Association for the Advancement of Science (AAAS) ; 2023
    In:  Science Advances Vol. 9, No. 23 ( 2023-06-09)
    Details
    In: Science Advances, American Association for the Advancement of Science (AAAS), Vol. 9, No. 23 ( 2023-06-09)
    Abstract: Imaging of the translocator protein detects innate inflammation in human and murine CD8 T cell-mediated limbic encephalitis.
    Type of Medium: Online Resource
    ISSN: 2375-2548
    URL: Article
    DOI: 10.1126/sciadv.abq7595
    Language: English
    Publisher: American Association for the Advancement of Science (AAAS)
    Publication Date: 2023
    detail.hit.zdb_id: 2810933-8
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  • 6
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    NMO Spectrum Disorders
    Georg Thieme Verlag KG ; 2017
    In:  Neurology International Open Vol. 01, No. 01 ( 2017-03), p. E36-E47
    Details
    In: Neurology International Open, Georg Thieme Verlag KG, Vol. 01, No. 01 ( 2017-03), p. E36-E47
    Abstract: Neuromyelitis optica spectrum disorders (NMOSD) represent a rare subset of chronic-inflammatory diseases of the central nervous system. Despite heterogeneities in disease activity, there is a higher degree of disability accumulation in NMOSD patients compared to MS patients. According to the revised diagnostic criteria, a recommendation was made to abandon the term NMO and to summarize these conditions as NMOSD. Clinical presentation of NMOSD patients in most cases is optic neuritis and transverse myelitis but nevertheless, NMOSD can affect most parts of the central nervous system (e. g. brainstem and hypothalamus). Originally characterized as AQP4-antibody-dependent disease, it has recently been discussed whether conditions with presence of antibodies against myelin oligodendrocyte glycoprotein (MOG) belong to the family of NMOSD. Due to the severity of the disease with often devastating relapses, systematic therapy is necessary. Usually, immunosuppressants or monoclonal antibodies with anti-inflammatory properties are used. Recently, four substances entered clinical testing for treatment of NMOSD.
    Type of Medium: Online Resource
    ISSN: 2511-1795
    URL: Article
    DOI: 10.1055/s-0043-102456
    Language: English
    Publisher: Georg Thieme Verlag KG
    Publication Date: 2017
    detail.hit.zdb_id: 2878288-4
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  • 7
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    Increased Intrathecal B and Plasma Cells in Patients With Anti-IgLON5 Disease : A Case Series
    Ovid Technologies (Wolters Kluwer Health) ; 2022
    In:  Neurology - Neuroimmunology Neuroinflammation Vol. 9, No. 2 ( 2022-03), p. 00-
    Details
    In: Neurology - Neuroimmunology Neuroinflammation, Ovid Technologies (Wolters Kluwer Health), Vol. 9, No. 2 ( 2022-03), p. 00-
    Abstract: Despite detection of autoantibodies, anti-IgLON5 disease was historically considered a tau-associated neurodegenerative disease, with limited treatment options and detrimental consequences for the patients. Observations in increasing case numbers hint toward underlying inflammatory mechanisms that, early detection provided, open a valuable window of opportunity for therapeutic intervention. We aimed to further substantiate this view by studying the CSF of patients with anti-IgLON5. Methods We identified 11 patients with anti-IgLON5 from our database and compared clinical, MRI, and CSF findings with a cohort of 20 patients with progressive supranuclear palsy (PSP) (as a noninflammatory tauopathy) and 22 patients with functional neurologic disorder. Results Patients with anti-IgLON5 show inflammatory changes in routine CSF analysis, an increase in B-lymphocyte frequency, and the presence of plasma cells in comparison to the PSP-control group and functional neurologic disease controls. Patients with intrathecal plasma cells showed a clinical response to rituximab. Discussion Our findings indicate the importance of inflammatory mechanisms, in particular in early and acute anti-IgLON5 cases, which may support the use of immune-suppressive treatments in these cases. The main limitation of the study is the small number of cases due to the rarity of the disease.
    Type of Medium: Online Resource
    ISSN: 2332-7812
    URL: Article
    DOI: 10.1212/NXI.0000000000001137
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2022
    detail.hit.zdb_id: 2767740-0
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  • 8
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    Neuropsychological Performance in Autoimmune Limbic Encephalitis: Evidence from an Immunotherapy-Naïve Cohort
    Oxford University Press (OUP) ; 2022
    In:  Archives of Clinical Neuropsychology Vol. 37, No. 4 ( 2022-05-16), p. 738-752
    Details
    In: Archives of Clinical Neuropsychology, Oxford University Press (OUP), Vol. 37, No. 4 ( 2022-05-16), p. 738-752
    Abstract: Autoimmune limbic encephalitis (ALE) is characterized by memory impairment, psychiatric symptoms, and epileptic seizures. Though, the neuropsychological profile of ALE is not yet well defined. However, there is some evidence that neuropsychological impairments might exceed those related to the limbic system and that different autoantibodies (AABs) are associated with distinguishable pattern of neuropsychological impairments. We provide a comprehensive presentation of neuropsychological performance of ALE in an immune therapy-naïve sample. Methods We retrospectively analyzed 69 immunotherapy-naïve ALE-patients (26 seropositive—[8 LGI1-, 4 CASPR2-, 2 GABAB-R-, 3 Hu-, 4 GAD65-, 2 Ma2-, 2 unknown antigen, and 1 Yo-AABs] and 43 seronegative patients, mean age 56.0 years [21.9–78.2] , mean disease duration 88 weeks [0–572]). Neuropsychological evaluations comprised of the domains memory, attention, praxis, executive functions, language, social cognition, and psychological symptoms. We compared these functions between seronegative −, seropositive patients with AABs against intracellular neural antigens and seropositive patients with AABs against surface membrane neural antigens. Results No effect of AAB group on neuropsychological performance could be detected. Overall, ALE predominantly presents with deficits in long-term memory and memory recognition, autobiographical-episodic memory loss, impairment of emotion recognition, and depressed mood. Furthermore, deficits in praxis of pantomimes and imitations, visuo-construction, and flexibility may occur. Conclusion ALE shows a wide spectrum of neuropsychological impairments, which might exceed the limbic system, with no evidence of differences between AAB groups. Neuropsychological assessment for diagnosing ALE should include long-term memory, memory recognition, autobiographical-episodic memory, emotion recognition, and a detailed investigation of depression.
    Type of Medium: Online Resource
    ISSN: 1873-5843
    URL: Article
    DOI: 10.1093/arclin/acac001
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2022
    detail.hit.zdb_id: 2003528-7
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  • 9
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    Complement activation contributes to GAD antibody-associated encephalitis
    Springer Science and Business Media LLC ; 2022
    In:  Acta Neuropathologica Vol. 144, No. 2 ( 2022-08), p. 381-383
    Details
    In: Acta Neuropathologica, Springer Science and Business Media LLC, Vol. 144, No. 2 ( 2022-08), p. 381-383
    Type of Medium: Online Resource
    ISSN: 0001-6322 , 1432-0533
    URL: Article
    DOI: 10.1007/s00401-022-02448-x
    RVK:
    XA 10000
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2022
    detail.hit.zdb_id: 1458410-4
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  • 10
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    Occurrence of status epilepticus in persons with epilepsy is determined by sex, epilepsy classification, and etiology: a single center cohort study
    Springer Science and Business Media LLC ; 2021
    In:  Journal of Neurology Vol. 268, No. 12 ( 2021-12), p. 4816-4823
    Details
    In: Journal of Neurology, Springer Science and Business Media LLC, Vol. 268, No. 12 ( 2021-12), p. 4816-4823
    Abstract: Status epilepticus (SE) can occur in persons with or without epilepsy and is associated with high morbidity and mortality. Methods This survey aimed to record self-reported frequency of SE in persons with epilepsy, its association with clinical characteristics and patient level of information on SE and rescue medication. 251 persons with epilepsy at a tertiary epilepsy center were included in the study. Results 87 (35%) had a history of SE defined as seizure duration of more than 5 min. These patients were less likely to be seizure-free, and had a higher number of present and past anti-seizure medication. Female sex, cognitive disability, younger age at epilepsy onset, defined epilepsy etiology, and focal epilepsy were associated with a history of SE. On Cox regression analysis, female sex, defined etiology and focal classification remained significant. 67% stated that they had information about prolonged seizures, and 75% knew about rescue medication. 85% found it desirable to receive information about SE at the time of initial diagnosis of epilepsy, but only 16% had been offered such information at the time. Conclusion SE is frequent among persons with epilepsy and there remain unmet needs regarding patient education.
    Type of Medium: Online Resource
    ISSN: 0340-5354 , 1432-1459
    URL: Article
    DOI: 10.1007/s00415-021-10600-y
    RVK:
    XA 10000
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2021
    detail.hit.zdb_id: 1421299-7
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