HLA dependency and possible clinical relevance of intrathecally synthesized anti-IgLON5 IgG4 in anti-IgLON5 disease.

Background: Anti-IgLON5 disease is a rare chronic autoimmune disorder characterized by IgLON5 autoantibodies predominantly of the IgG4 subclass. Distinct pathogenic effects were described for anti-IgLON5 IgG1 and IgG4, however, with uncertain clinical relevance. Methods: IgLON5-specific IgG1-4 levels were measured in 46 sera and 20 cerebrospinal fluid (CSF) samples from 13 HLA-subtyped anti-IgLON5 disease patients (six females, seven males) using flow cytometry. Intervals between two consecutive serum or CSF samplings (31 and 10 intervals, respectively) were categorized with regard to the immunomodulatory treatment active at the end of the interval, changes of anti-IgLON5 IgG1 and IgG4 levels, and disease severity. Intrathecal anti-IgLON5 IgG4 synthesis (IS) was assessed using a quantitative method. Results: The median age at onset was 66 years (range: 54-75), disease duration 10 years (range: 15-156 months), and follow-up 25 months (range: 0-83). IgLON5-specific IgG4 predominance was observed in 38 of 46 (83%) serum and 11 of 20 (55%) CSF samples. Anti-IgLON5 IgG4 levels prior clinical improvement in CSF but not serum were significantly lower than in those prior stable/progressive disease. Compared to IgLON5 IgG4 levels in serum, CSF levels in HLA-DRB1*10:01 carriers were significantly higher than in non-carriers. Indeed, IgLON5-specific IgG4 IS was demonstrated not only in four of five HLA-DRB1*10:01 carriers but also in one non-carrier. Immunotherapy was associated with decreased anti-IgGLON5 IgG serum levels. In CSF, lower anti-IgLON5 IgG was associated with immunosuppressive treatments used in combination, that is, corticosteroids and/or azathioprine plus intravenous immunoglobulins or rituximab. Conclusion: Our findings might indicate that CSF IgLON5-specific IgG4 is frequently produced intrathecally, especially in HLA-DRB1*10:01 carriers. Intrathecally produced IgG4 may be clinically relevant. While many immunotherapies reduce serum IgLON5 IgG levels, more intense immunotherapies induce clinical improvement and may be able to target intrathecally produced anti-IgLON5 IgG. Further studies need to confirm whether anti-IgLON5 IgG4 IS is a suitable prognostic and predictive biomarker in anti-IgLON5 disease.

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.

Whole-blood culture-derived cytokine combinations for the diagnosis of tuberculosis.

Introduction: The diagnosis of tuberculosis (TB) disease and TB infection (TBI) remains a challenge, and there is a need for non-invasive and blood-based methods to differentiate TB from conditions mimicking TB (CMTB), TBI, and healthy controls (HC). We aimed to determine whether combination of cytokines and established biomarkers could discriminate between 1) TB and CMTB 2) TB and TBI 3) TBI and HC. Methods: We used hemoglobin, total white blood cell count, neutrophils, monocytes, C-reactive protein, and ten Meso Scale Discovery analyzed cytokines (interleukin (IL)-1ß, IL-2, IL-4, IL-6, IL-8, IL-10, IL-12p70, IL-13, interferon (IFN)-É£, and tumor necrosis factor (TNF)-α) in TruCulture whole blood tubes stimulated by lipopolysaccharides (LPS), zymosan (ZYM), anti-CD3/28 (CD3), and unstimulated (Null) to develop three index tests able to differentiate TB from CMTB and TBI, and TBI from HC. Results: In 52 persons with CMTB (n=9), TB (n=23), TBI (n=10), and HC (n=10), a combination of cytokines (LPS-IFN-É£, ZYM-IFN-É£, ZYM-TNF-α, ZYM-IL-1ß, LPS-IL-4, and ZYM-IL-6) and neutrophil count could differentiate TB from CMTB with a sensitivity of 52.2% (95% CI: 30.9%-73.4%) and a specificity of 100 % (66.4%-100%). Null- IFN-É£, Null-IL-8, CD3-IL-6, CD3-IL-8, CD3-IL-13, and ZYM IL-1b discriminated TB from TBI with a sensitivity of 73.9% (56.5% - 91.3%) and a specificity of 100% (69.2-100). Cytokines and established biomarkers failed to differentiate TBI from HC with ≥ 98% specificity. Discussion: Selected cytokines may serve as blood-based add-on tests to detect TB in a low-endemic setting, although these results need to be validated.

Validation of a risk score to differentiate autoimmune and viral encephalitis: a Nationwide Cohort Study in Denmark.

BACKGROUND: A score to differentiate autoimmune (AE) and viral encephalitis (VE) early upon admission has recently been developed but needed external validation. The objective of this study was to evaluate the performance of the score in a larger and more diagnostically diverse patient cohort. METHODS: We conducted a retrospective nationwide and population-based cohort study including all adults with encephalitis of definite viral (2015-2022) or autoimmune aetiology (2009-2022) in Denmark. Variables included in the score-model were extracted from patient records and individual risk scores were assessed. The performance of the score was assessed by receiver-operating characteristics (ROC) curve analyses and calculation of the area under the curve (AUC). RESULTS: A total of 496 patients with encephalitis [AE n = 90, VE n = 287 and presumed infectious encephalitis (PIE) n = 119] were included in the study. The score was highly accurate in predicting cases of AE reaching an AUC of 0.94 (95% CI 0.92-0.97). Having a score ≥ 3 predicted AE with a PPV of 87% and an NPV of 91%. The risk score was found to perform well across aetiological subgroups and applied to the PIE cohort resulted in an AUC of 0.88 (95% CI 0.84-0.93). CONCLUSION: The excellent performance of the score as reported in the development study was confirmed in this significantly larger and more diverse cohort of patients with encephalitis in Denmark. These results should prompt further prospective testing with wider inclusion criteria.

NORSE seasonality may vary geographically in adults.

The mechanisms causing new onset refractory status epilepticus (NORSE) are often unknown. Recently, a seasonal variation with NORSE peaking during the summer was described in a mixed cohort of adults and children why we here studied the seasonal variation in a Danish status epilepticus (SE) cohort. This retrospective cohort study comprised SE patients aged ≥18 diagnosed and treated 2008-2017 at the Odense University Hospital. Clinical characteristics and seasonality of patients fulfilling the diagnostic criteria for NORSE were compared with patients with refractory SE (RSE) due to other reasons and with the seasonal variation of autoantibodies associated with autoimmune encephalitis in the Danish autoimmune encephalitis register. In this cohort, 26 patients met NORSE criteria. As compared to RSE patients not fulfilling NORSE criteria (n = 152), NORSE patients were more likely to have symptoms of systemic inflammation (C-reactive protein concentrations ≥10 mg/L or fever ≥38°C) at admission; nine fulfilled the criteria for febrile infection related epilepsy syndrome (FIRES). In contrast to the even seasonal distribution of patients with RSE not fulfilling the NORSE criteria, admissions due to NORSE peaked during the winter (46.1%, p = 0.04 as compared to non-NORSE RSE); six out of nine FIRES episodes occurred in the winter season. The seasonal variation was not explained by a seasonal variation of the detection rates of autoantibodies associated with autoimmune encephalitis (incl. NMDAR, LGI1, CASPR2, GABAR, GFAP) in a Danish nationwide register (n = 259). In conclusion, we confirm the seasonality of NORSE in a Danish cohort, however, with a peak during winter suggesting a geographical variation not solely explained by autoimmune encephalitis associated with known autoantibodies. PLAIN LANGUAGE SUMMARY: The study investigated the seasonal patterns of new-onset refractory status epilepticus (NORSE), i.e. severe seizures that occur without an obvious cause and require very intensive treatment. In contrast to the previously observed peak frequency in summer, this Danish study found that NORSE cases peak in winter. Furthermore, the seasonal variation in NORSE cases was not found to be associated with autoimmune encephalitis caused by known autoantibodies. Together with the high rate of patients showing symptoms of systemic inflammation compared to other status epilepticus patients, the data suggest a link between misdirected immune system responses and NORSE. The study can therefore help in the further search for the currently unknown causes of NORSE.

Fatigue predicts quality of life after leucine-rich glioma-inactivated 1-antibody encephalitis.

Patient-reported quality-of-life (QoL) and carer impacts are not reported after leucine-rich glioma-inactivated 1-antibody encephalitis (LGI1-Ab-E). From 60 patients, 85% (51 out of 60) showed one abnormal score across QoL assessments and 11 multimodal validated questionnaires. Compared to the premorbid state, QoL significantly deteriorated (p < 0.001) and, at a median of 41 months, fatigue was its most important predictor (p = 0.025). In total, 51% (26 out of 51) of carers reported significant burden. An abbreviated five-item battery explained most variance in QoL. Wide-ranging impacts post-LGI1-Ab-E include decreased QoL and high caregiver strain. We identify a rapid method to capture QoL in routine clinic or clinical trial settings.

Differentiating anti-IgLON5 disease and Lewy body dementia: a systematic review.

BACKGROUND: Anti-IgLON5 disease is a rare but potentially reversible cause of cognitive impairment, sleep disturbances, dysautonomia, and movement disorders. It is an autoimmune encephalitis which, due to its insidious onset, could mimic neurodegenerative disorders, and multiple symptoms overlap with those seen in dementia with Lewy bodies (DLB). We hypothesized that the symptomatology and findings in patients with anti-IgLON5 disease overlapped with that of DLB. OBJECTIVES: To assess the commonality of features in anti-IgLON5 disease and DLB and identify potential red flags for anti-IgLON5 disease in patients undergoing diagnostic evaluation for DLB. METHODS: We searched in MEDLINE, Web of Science, and Embase from inception on December the 8th, 2022 with the search term "IgLON5". We performed a systematic review of case reports and case series of anti-IgLON5 disease, and two reviewers independently extracted data on symptoms and findings. Frequencies of symptoms were compared with consensus criteria for DLB. RESULTS: We included 57 studies with 127 individual case reports of anti-IgLON5 disease (mean age 63 years at diagnosis, median symptom duration 2 years). Cognitive dysfunction was reported in 45% of cases, REM-sleep behavioral disorder in 15%, and 14% had parkinsonism. Respiratory insufficiency was reported in 37%, and bulbar symptoms in 67%. CONCLUSIONS: We found a significant overlap between anti-IgLON5 disease and DLB. We propose that anti-IgLON5 disease should be considered in young patients with DLB with chorea, gaze palsy, early dysphagia, or prominent respiratory symptoms. Our study contributes to the emerging knowledge on symptoms and biomarkers in anti-IgLON5 disease.

Tick-borne encephalitis as a trigger for anti-N-Methyl-d-aspartate receptor encephalitis.

Tick Borne Encephalitis (TBE) is endemic to an increasing number of countries and is a common cause of meningoencephalitis in Europe and Asia making any potential complications of the disease increasingly relevant to clinicians. We present, what is to our knowledge, the second reported case of N-methyl-d-aspartate receptor (NMDAR) encephalitis following Tick Borne Encephalitis (TBE) in a 47-year-old Lithuanian man. The case provides further evidence of TBE being a possible trigger of NMDAR encephalitis and highlights the importance of being aware of symptoms of autoimmune encephalitis in patients with infectious encephalitis.

SARS-CoV-2 and autoantibodies in the cerebrospinal fluid of COVID-19 patients: prospective multicentre cohort study.

Disease mechanisms underlying neurological and neuropsychiatric symptoms after coronavirus disease 2019 (COVID-19), termed neuro-COVID, are poorly understood. Investigations of the cerebrospinal fluid (CSF) for the presence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) RNA and antibodies, as well as autoantibodies against neuronal surface antigens, could improve our understanding in that regard. We prospectively collected CSF and blood from patients investigated by lumbar puncture for neurological or neuropsychiatric symptoms during or after COVID-19. Primary outcomes were the presence of (i) SARS-CoV-2 RNA in CSF via polymerase chain reaction (PCR), (ii) SARS-CoV-2 immunoglobulin G (IgG) anti-S receptor-binding-domain antibodies via the Euroimmun and Wantai assays and (iii) IgG autoantibodies against neuronal surface antigens using commercial cell- and tissue-based assays (Euroimmun). Secondary outcomes were (i) routine CSF investigations and (ii) correlation between SARS-CoV-2 antibody levels in CSF with serum levels, blood-brain barrier permeability and peripheral inflammation. We obtained CSF from 38 COVID-19 patients (mean age 56.5 ± 19.2 years, 53% women) who developed neurological and neuropsychiatric symptoms. CSF pleocytosis (>5 cells) was observed in 9/38 patients (23.7%), elevated CSF protein (>0.50 g/L) in 13/38 (34.2%) and elevated CSF/serum albumin ratio in 12/35 (34.3%). PCR for SARS-CoV-2 RNA in CSF was negative in all. SARS-CoV-2 CSF antibodies were detected in 15/34 (44.1%; Euroimmun assay) and 7/31 (22.6%; Wantai assay) individuals, but there were no signs of intrathecal SARS-CoV-2 IgG production. SARS-CoV-2 CSF antibodies were positively correlated with serum levels (R = 0.93, P < 0.001), blood-brain barrier permeability (R = 0.47, P = 0.006), peripheral inflammation (R = 0.51, P = 0.002) and admission to the intensive care unit [odds ratio (OR) 17.65; 95% confidence interval (CI) 1.18-264.96; P = 0.04; n = 15]. Cell-based assays detected weakly positive NMDAR, LGI1 and CASPR2 antibodies in serum of 4/34 (11.8%) patients but not in CSF. The tissue-based assay showed anti-neuronal fluorescence in CSF from one individual, staining for Purkinje cells. In summary, whereas we did not detect active SARS-CoV-2 infection in the CSF, SARS-CoV-2 antibodies were prevalent. The absence of intrathecal antibody production points towards blood-brain barrier impairment as the origin of CSF SARS-CoV-2 antibodies. In contrast, CSF autoantibodies against neuronal surface antigens were rare. There was no evidence for a clinical correlate of these antibodies. We conclude that, rather than specific autoimmune neuronal injury, non-specific effects of critical illness including an impaired blood-brain barrier are more likely to contribute to neuro-COVID.

Retinal vein occlusion as an age-dependent marker of incident dementia in a long-term Danish national cohort.

PURPOSE: The aim of this study was to investigate retinal vein occlusion (RVO) as an independent marker of incident dementia. METHODS: In a prospective nationwide cohort study, we identified 2 225 568 individuals through the Danish national health registers. Individuals older than 65 years, without unspecified retinal vascular occlusion or dementia were included from 1998 to 2020 and followed until 2022. We calculated the incidence rate (IR) and performed a Cox regression analysis with a hazard ratio (HR) and 95% confidence interval (CI) for RVO (exposure) as a marker of all-cause dementia adjusted for systemic comorbidity. RESULTS: We identified 19 669 individuals with RVO who had a higher prevalence of systemic comorbidity at inclusion compared to those without RVO (n = 2 185 483). We performed a Cox regression analysis for age-dependent exposure due to non-proportional hazards in the pre-planned analysis. Exposed individuals younger than 75 years had an increased risk of all-cause dementia (adjusted HR 1.09, 95% CI 1.01-1.18), whereas individuals older than 75 years had a decreased risk of all-cause dementia (adjusted HR 0.92, 95% CI 0.86-0.98). CONCLUSION: Individuals with RVO had an age-dependent risk of dementia, with a 9% increased risk in individuals with RVO younger than 75 years and an 8% decreased risk in individuals older than 75 years at the time of exposure.

Retinal artery occlusion does not act as an independent marker of upcoming dementia: results from a Danish 20-year cohort study.

PURPOSE: Retinal artery occlusion (RAO) is a vision threatening disease associated with cerebral vascular dysfunction, which may reflect initial signs of cerebral pathology. Early detection of patients in risk of dementia could allow for preventative treatment. Hence, this study aimed to investigate RAO as an independent biomarker of incident dementia. METHODS: This study was a nationwide, 20-year longitudinal cohort study in Denmark with inclusion from 1998 to 2020 and follow up until the end of 2022. We identified 2 205 159 individuals aged 65 or older through the Danish national health registers and monitored RAO (exposure) and dementia (outcome) status. We calculated incidence rate and performed a Cox regression analysis with hazard ratio (HR) and 95% confidence interval (CI) for RAO as a marker of dementia in a crude, a semi-adjusted (age and sex), and a fully adjusted model (furthermore adjusted for marital status and systemic comorbidity.) RESULTS: We identified 8 863 individuals with RAO. Incidence rates were higher among exposed compared to unexposed individuals (12.28 and 8.18 per 1000 person-years at risk, respectively). Individuals with RAO were more likely to be male and older at inclusion, to have hypertension, dyslipidaemia, cardiovascular disease, chronic kidney disease, and diabetes (p < 0.001). RAO was not associated with all-cause dementia in the crude analysis (HR 1.07 CI [1.00-1.17]) or in the fully adjusted analysis (HR 0.98 CI [0.91-1.06]. CONCLUSION: Although individuals with RAO had a higher incidence of dementia compared to unexposed individuals, these associations were lost when confounders were taken into account.

Paraneoplastic neurologic syndromes.

Diagnosis of paraneoplastic neurologic syndromes (PNS) requires an understanding of the clinical, immunologic and oncologic heterogeneity. The 2004 PNS criteria were partially outdated due to advances in the field, and updated consensus criteria for PNS have been proposed in 2021, including the PNS-Care score for assessment of PNS probability. Furthermore, knowledge on the limitations of autoantibody testing is crucial to ensure accurate interpretation. This review presents the updated diagnostic criteria for PNS, in a Danish context.

Pathophysiological Effects of Autoantibodies in Autoimmune Encephalitides.

The heterogeneity of autoantibody targets in autoimmune encephalitides presents a challenge for understanding cellular and humoral pathophysiology, and the development of new treatment strategies. Thus, current treatment aims at autoantibody removal and immunosuppression, and is primarily based on data generated from other autoimmune neurological diseases and expert consensus. There are many subtypes of autoimmune encephalitides, which now entails both diseases with autoantibodies targeting extracellular antigens and classical paraneoplastic syndromes with autoantibodies targeting intracellular antigens. Here, we review the current knowledge of molecular and cellular effects of autoantibodies associated with autoimmune encephalitis, and evaluate the evidence behind the proposed pathophysiological mechanisms of autoantibodies in autoimmune encephalitis.

Brain proteome profiling implicates the complement and coagulation cascade in multiple system atrophy brain pathology.

BACKGROUND: Multiple system atrophy (MSA) is a rare, progressive, neurodegenerative disorder presenting glia pathology. Still, disease etiology and pathophysiology are unknown, but neuro-inflammation and vascular disruption may be contributing factors to the disease progression. Here, we performed an ex vivo deep proteome profiling of the prefrontal cortex of MSA patients to reveal disease-relevant molecular neuropathological processes. Observations were validated in plasma and cerebrospinal fluid (CSF) of novel cross-sectional patient cohorts. METHODS: Brains from 45 MSA patients and 30 normal controls (CTRLs) were included. Brain samples were homogenized and trypsinized for peptide formation and analyzed by high-performance liquid chromatography tandem mass spectrometry (LC-MS/MS). Results were supplemented by western blotting, immuno-capture, tissue clearing and 3D imaging, immunohistochemistry and immunofluorescence. Subsequent measurements of glial fibrillary acid protein (GFAP) and neuro-filament light chain (NFL) levels were performed by immunoblotting in plasma of 20 MSA patients and 20 CTRLs. Finally, we performed a proteome profiling of 144 CSF samples from MSA and CTRLs, as well as other parkinsonian disorders. Data were analyzed using relevant parametric and non-parametric two-sample tests or linear regression tests followed by post hoc tests corrected for multiple testing. Additionally, high-throughput bioinformatic analyses were applied. RESULTS: We quantified more than 4,000 proteins across samples and identified 49 differentially expressed proteins with significantly different abundances in MSA patients compared with CTRLs. Pathway analyses showed enrichment of processes related to fibrinolysis and complement cascade activation. Increased fibrinogen subunit ß (FGB) protein levels were further verified, and we identified an enriched recognition of FGB by IgGs as well as intra-parenchymal accumulation around blood vessels. We corroborated blood-brain barrier leakage by a significant increase in GFAP and NFL plasma levels in MSA patients that correlated to disease severity and/or duration. Proteome profiling of CSF samples acquired during the disease course, confirmed increased total fibrinogen levels and immune-related components in the soluble fraction of MSA patients. This was also true for the other atypical parkinsonian disorders, dementia with Lewy bodies and progressive supra-nuclear palsy, but not for Parkinson's disease patients. CONCLUSION: Our results implicate activation of the fibrinolytic cascade and immune system in the brain as contributing factors in MSA associated with a more severe disease course.

RhoA Signaling in Neurodegenerative Diseases.

Ras homolog gene family member A (RhoA) is a small GTPase of the Rho family involved in regulating multiple signal transduction pathways that influence a diverse range of cellular functions. RhoA and many of its downstream effector proteins are highly expressed in the nervous system, implying an important role for RhoA signaling in neurons and glial cells. Indeed, emerging evidence points toward a role of aberrant RhoA signaling in neurodegenerative diseases such as Parkinson's disease, Alzheimer's disease, Huntington's disease, and amyotrophic lateral sclerosis. In this review, we summarize the current knowledge of RhoA regulation and downstream cellular functions with an emphasis on the role of RhoA signaling in neurodegenerative diseases and the therapeutic potential of RhoA inhibition in neurodegeneration.

Impact of MRI on decision-making in ICU patients with disorders of consciousness.

BACKGROUND: Recovery of consciousness is the most important survival factor in patients with acute brain injury and disorders of consciousness (DoC). Since most deaths in the intensive care unit (ICU) occur after withdrawal of life-support, medical decision-making is crucial for acute DoC patients. Neuroimaging informs decision-making, yet the precise effects of MRI on decision-making in the ICU are poorly understood. We investigated the impact of brain MRI on prognostication, therapeutic decisions and physician confidence in ICU patients with DoC. METHODS: In this simulated decision-making study utilizing a prospective ICU cohort, a panel of neurocritical experts first reviewed clinical information (without MRI) from 75 acute DoC patients and made decisions about diagnosis, prognosis and treatment. Following review of the MRI, the panel then decided if the initial decisions needed revision. In parallel, a blinded neuroradiologist reassessed all neuroimaging. RESULTS: MRI led to changes in clinical management of 57 (76%) of patients (Number-Needed-to-Test for any change: 1.32), including revised diagnoses (20%), levels of care (21%), diagnostic confidence (43%) and prognostications (33%). Decisions were revised more often with stroke than with other brain injuries (p = 0.02). However, although MRI revealed additional pathology in 81%, this did not predict revised clinical decision-making (p-values ≥0.08). CONCLUSION: MRI results changed decision-making in 3 of 4 ICU patients, but radiological findings were not predictive of clinical decision-making. This highlights the need to better understand the effects of neuroimaging on management decisions. How MRI influences decision-making in the ICU is an important avenue for research to improve acute DoC management.

NMDA-receptor encephalitis in Denmark from 2009 to 2019: a national cohort study.

BACKGROUND: To describe the national Danish N-methyl-D-aspartate receptor encephalitis (NMDARE) cohort. METHODS: All NMDAR immunoglobulin G (IgG) positive cases in Denmark from 2009 to 2019 were included. Medical information was assessed retrospectively for clinical phenotype, workup, treatment and outcome. RESULTS: Seventy-seven patients were NMDAR IgG positive in serum/CSF. Fifty-five fulfilled the criteria of NMDARE, 18 did not and 4 had missing data. Incidence was 0.17/100,000 persons per year in 2018, and incidence rates increased since 2009. Of the 55 NMDARE patients (median age 27; 60% female), 9 had post-herpes simplex (HSE) NMDARE and 7 had a tumor (four teratomas). MRI was normal in 51% of patients. Brain FDG PET was performed in 17 patients, and was abnormal in 47% of patients with a normal MRI. First-line therapy was administered to 91%, and 24% required second-line therapy. Maintenance therapy during recovery was given 84% of patients, with no effect on relapse-risk. ICU admission occurred in 29%. Poor outcome (mRS > 2) was reported in 27% and dependent on age and etiology. Patients > 45 years had a poorer outcome (71% vs 8%, p < 0.0001), more frequently post-HSE NMDARE (47% vs 3%, p < 0.0001) and underlying malignancies (18% vs 0%). CONCLUSION: The incidence of NMDARE in Denmark is currently 0.17/100,000 persons per year, and has increased since 2009. NMDARE patients in Denmark display a higher median age, lower female:male ratio, a less frequent tumor association and need for ICU admission. Maintenance therapy did not reduce relapse rate. Poor outcome was seen with higher age, likely related to underlying etiology.

Diabetic retinopathy as a potential marker of Parkinson's disease: a register-based cohort study.

Neurodegeneration is an early event in the pathogenesis of diabetic retinopathy, and an association between diabetic retinopathy and Parkinson's disease has been proposed. In this nationwide register-based cohort study, we investigated the prevalence and incidence of Parkinson's disease among patients screened for diabetic retinopathy in a Danish population-based cohort. Cases (n = 173 568) above 50 years of age with diabetes included in the Danish Registry of Diabetic Retinopathy between 2013 and 2018 were matched 1:5 by gender and birth year with a control population without diabetes (n = 843 781). At index date, the prevalence of Parkinson's disease was compared between cases and controls. To assess the longitudinal relationship between diabetic retinopathy and Parkinson's disease, a multivariable Cox proportional hazard model was estimated. The prevalence of Parkinson's disease was 0.28% and 0.44% among cases and controls, respectively. While diabetic retinopathy was not associated with present (adjusted odds ratio 0.93, 95% confidence interval 0.72-1.21) or incident Parkinson's disease (adjusted hazard ratio 0.77, 95% confidence interval 0.56-1.05), cases with diabetes were in general less likely to have or to develop Parkinson's disease compared to controls without diabetes (adjusted odds ratio 0.79, 95% confidence interval 0.71-0.87 and adjusted hazard ratio 0.88, 95% confidence interval 0.78-1.00). In a national cohort of more than 1 million persons, patients with diabetes were 21% and 12% were less likely to have prevalent and develop incident Parkinson's disease, respectively, compared to an age- and gender-matched control population without diabetes. We found no indication for diabetic retinopathy as an independent risk factor for incident Parkinson's disease.

Frequency and Characterization of Movement Disorders in Anti-IgLON5 Disease.

OBJECTIVE: Anti-IgLON5 disease is a recently described neurological disease that shares features of autoimmunity and neurodegeneration. Abnormal movements appear to be frequent and important but have not been characterized and are under-reported. Here we describe the frequency and types of movement disorders in a series of consecutive patients with this disease. METHODS: In this retrospective, observational study, the presence and phenomenology of movement disorders were assessed with a standardized clinical questionnaire. Available videos were centrally reviewed by three experts in movement disorders. RESULTS: Seventy two patients were included. In 41 (57%) the main reason for initial consultation was difficulty walking along with one or several concurrent movement disorders. At the time of anti-IgLON5 diagnosis, 63 (87%) patients had at least one movement disorder with a median of three per patient. The most frequent abnormal movements were gait and balance disturbances (52 patients, 72%), chorea (24, 33%), bradykinesia (20, 28%), dystonia (19, 26%), abnormal body postures or rigidity (18, 25%), and tremor (15, 21%). Other hyperkinetic movements (myoclonus, akathisia, myorhythmia, myokymia, or abdominal dyskinesias) occurred in 26 (36%) patients. The craniofacial region was one of the most frequently affected by multiple concurrent movement disorders (23 patients, 32%) including dystonia (13), myorhythmia (6), chorea (4) or myokymia (4). Considering any body region, the most frequent combination of multiple movement disorders consisted of gait instability or ataxia associated with craniofacial dyskinesias or generalized chorea observed in 31(43%) of patients. In addition to abnormal movements, 87% of patients had sleep alterations, 74% bulbar dysfunction, and 53% cognitive impairment. Fifty-five (76%) patients were treated with immunotherapy, resulting in important and sustained improvement of the movement disorders in only seven (13%) cases. CONCLUSIONS: Movement disorders are a frequent and leading cause of initial neurological consultation in patients with anti-IgLON5 disease. Although multiple types of abnormal movements can occur, the most prevalent are disorders of gait, generalized chorea, and dystonia and other dyskinesias that frequently affect craniofacial muscles. Overall, anti-IgLON5 disease should be considered in patients with multiple movement disorders, particularly if they occur in association with sleep alterations, bulbar dysfunction, or cognitive impairment.

[Autoimmune encephalitis].

Autoimmune encephalitis is an important, treatable subtype of acute encephalitis where autoantibodies target intra- or extracellular neural antigens. Despite research advances, diagnosis is often delayed or incorrect, which affects outcome negatively. We summarise clinical features of the most common autoantibody-mediated autoimmune encephalitis subtypes and focus on classification, current diagnostic challenges using commercially available diagnostic assays, in an attempt to increase awareness.