Time to Disability Milestones and Annualized Relapse Rates in NMOSD and MOGAD.

OBJECTIVE: To investigate accumulation of disability in neuromyelitis optica spectrum disorder (NMOSD) and myelin oligodendrocyte glycoprotein-antibody-associated disease (MOGAD) in a changing treatment landscape. We aimed to identify risk factors for the development of disability milestones in relation to disease duration, number of attacks, and age. METHODS: We analyzed data from individuals with NMOSD and MOGAD from the German Neuromyelitis Optica Study Group registry. Applying survival analyses, we estimated risk factors and computed time to disability milestones as defined by the Expanded Disability Status Score (EDSS). RESULTS: We included 483 patients: 298 AQP4-IgG+ NMOSD, 52 AQP4-IgG-/MOG-IgG- NMOSD patients, and 133 patients with MOGAD. Despite comparable annualized attack rates, disability milestones occurred earlier and after less attacks in NMOSD patients than MOGAD patients (median time to EDSS 3: AQP4-IgG+ NMOSD 7.7 (95% CI 6.6-9.6) years, AQP4-IgG-/MOG-IgG- NMOSD 8.7) years, MOGAD 14.1 (95% CI 10.4-27.6) years; EDSS 4: 11.9 (95% CI 9.7-14.7), 11.6 (95% lower CI 7.6) and 20.4 (95% lower CI 14.1) years; EDSS 6: 20.1 (95% CI 16.5-32.1), 20.7 (95% lower CI 11.6), and 37.3 (95% lower CI 29.4) years; and EDSS 7: 34.2 (95% lower CI 31.1) for AQP4-IgG+ NMOSD). Higher age at onset increased the risk for all disability milestones, while risk of disability decreased over time. INTERPRETATION: AQP4-IgG+ NMOSD, AQP4-IgG-/MOG-IgG- NMOSD, and MOGAD patients show distinctive relapse-associated disability progression, with MOGAD having a less severe disease course. Investigator-initiated research has led to increasing awareness and improved treatment strategies appearing to ameliorate disease outcomes for NMOSD and MOGAD. ANN NEUROL 2024;95:720-732.

Long-term Elevation of Complement Factors in Cerebrospinal Fluid of Patients With Borna Disease Virus 1 Encephalitis.

BACKGROUND: Borna disease virus 1 (BoDV-1) causes rare but severe zoonotic infections in humans, presenting as encephalitis. The case-fatality risk is very high and no effective countermeasures have been established so far. An immunopathology is presumed, while data on immune responses in humans are limited. Evidence of a role of the complement system in various neurological disorders and in viral infections of the central nervous system is increasing and specific inhibitors are available as therapeutic options. METHODS: In this study, we investigated factors of the complement system in the cerebrospinal fluid (CSF) of patients with BoDV-1 infections (n = 17) in comparison to noninflammatory control CSF samples (n = 11), using a bead-based multiplex assay. In addition, immunohistochemistry was performed using postmortem brain tissue samples. RESULTS: We found an intrathecal elevation of complement factors of all complement pathways and an active cascade during human BoDV-1 infections. The increase of certain complement factors such as C1q was persistent, and C3 complement deposits were detected in postmortem brain sections. Intrathecal complement levels were negatively correlated with survival. CONCLUSIONS: Further investigations are warranted to clarify whether targeting the complement cascade by specific inhibitors might be beneficial for patients suffering from severe BoDV-1 encephalitis.

Detection of virus-specific T cells via ELISpot corroborates early diagnosis in human Borna disease virus 1 (BoDV-1) encephalitis.

BACKGROUND: Within endemic regions in southern and eastern Germany, Borna disease virus 1 (BoDV-1) causes rare zoonotic spill-over infections in humans, leading to encephalitis with a high case-fatality risk. So far, intra-vitam diagnosis has mainly been based on RT-qPCR from cerebrospinal fluid (CSF) and serology, both being associated with diagnostic challenges. Whilst low RNA copy numbers in CSF limit the sensitivity of RT-qPCR from this material, seroconversion often occurs late during the course of the disease. CASE PRESENTATION: Here, we report the new case of a 40 - 50 year-old patient in whom the detection of virus-specific T cells via ELISpot corroborated the diagnosis of BoDV-1 infection. The patient showed a typical course of the disease with prodromal symptoms like fever and headaches 2.5 weeks prior to hospital admission, required mechanical ventilation from day three after hospitalisation and remained in deep coma until death ten days after admission. RESULTS: Infection was first detected by positive RT-qPCR from a CSF sample drawn four days after admission (viral load 890 copies/mL). A positive ELISpot result was obtained from peripheral blood collected on day seven, when virus-specific IgG antibodies were not detectable in serum, possibly due to previous immune adsorption for suspected autoimmune-mediated encephalitis. CONCLUSION: This case demonstrates that BoDV-1 ELISpot serves as additional diagnostic tool even in the first week after hospitalisation of patients with BoDV-1 encephalitis.

Cerebrospinal fluid findings in COVID-19: a multicenter study of 150 lumbar punctures in 127 patients.

BACKGROUND: Comprehensive data on the cerebrospinal fluid (CSF) profile in patients with COVID-19 and neurological involvement from large-scale multicenter studies are missing so far. OBJECTIVE: To analyze systematically the CSF profile in COVID-19. METHODS: Retrospective analysis of 150 lumbar punctures in 127 patients with PCR-proven COVID-19 and neurological symptoms seen at 17 European university centers RESULTS: The most frequent pathological finding was blood-CSF barrier (BCB) dysfunction (median QAlb 11.4 [6.72-50.8]), which was present in 58/116 (50%) samples from patients without pre-/coexisting CNS diseases (group I). QAlb remained elevated > 14d (47.6%) and even > 30d (55.6%) after neurological onset. CSF total protein was elevated in 54/118 (45.8%) samples (median 65.35 mg/dl [45.3-240.4]) and strongly correlated with QAlb. The CSF white cell count (WCC) was increased in 14/128 (11%) samples (mostly lympho-monocytic; median 10 cells/µl, > 100 in only 4). An albuminocytological dissociation (ACD) was found in 43/115 (37.4%) samples. CSF L-lactate was increased in 26/109 (24%; median 3.04 mmol/l [2.2-4]). CSF-IgG was elevated in 50/100 (50%), but was of peripheral origin, since QIgG was normal in almost all cases, as were QIgA and QIgM. In 58/103 samples (56%) pattern 4 oligoclonal bands (OCB) compatible with systemic inflammation were present, while CSF-restricted OCB were found in only 2/103 (1.9%). SARS-CoV-2-CSF-PCR was negative in 76/76 samples. Routine CSF findings were normal in 35%. Cytokine levels were frequently elevated in the CSF (often associated with BCB dysfunction) and serum, partly remaining positive at high levels for weeks/months (939 tests). Of note, a positive SARS-CoV-2-IgG-antibody index (AI) was found in 2/19 (10.5%) patients which was associated with unusually high WCC in both of them and a strongly increased interleukin-6 (IL-6) index in one (not tested in the other). Anti-neuronal/anti-glial autoantibodies were mostly absent in the CSF and serum (1509 tests). In samples from patients with pre-/coexisting CNS disorders (group II [N = 19]; including multiple sclerosis, JC-virus-associated immune reconstitution inflammatory syndrome, HSV/VZV encephalitis/meningitis, CNS lymphoma, anti-Yo syndrome, subarachnoid hemorrhage), CSF findings were mostly representative of the respective disease. CONCLUSIONS: The CSF profile in COVID-19 with neurological symptoms is mainly characterized by BCB disruption in the absence of intrathecal inflammation, compatible with cerebrospinal endotheliopathy. Persistent BCB dysfunction and elevated cytokine levels may contribute to both acute symptoms and 'long COVID'. Direct infection of the CNS with SARS-CoV-2, if occurring at all, seems to be rare. Broad differential diagnostic considerations are recommended to avoid misinterpretation of treatable coexisting neurological disorders as complications of COVID-19.

Early Tracheostomy Is Associated With Shorter Ventilation Time and Duration of ICU Stay in Patients With Myasthenic Crisis-A Multicenter Analysis.

BACKGROUND: Myasthenic crisis (MC) requiring mechanical ventilation (MV) is a rare and serious complication of myasthenia gravis. Here we analyzed the frequency of performed tracheostomies, risk factors correlating with a tracheostomy, as well as the impact of an early tracheostomy on ventilation time and ICU length of stay (LOS) in MC. METHODS: Retrospective chart review on patients treated for MC in 12 German neurological departments between 2006 and 2015 to assess demographic/diagnostic data, rates and timing of tracheostomy and outcome. RESULTS: In 107 out of 215 MC (49.8%), a tracheostomy was performed. Patients without tracheostomy were more likely to have an early-onset myasthenia gravis (27 [25.2%] vs 12 [11.5%], p = 0.01). Patients receiving a tracheostomy, however, were more frequently suffering from multiple comorbidities (20 [18.7%] vs 9 [8.3%], p = 0.03) and also the ventilation time (34.4 days ± 27.7 versus 7.9 ± 7.8, p < 0.0001) and ICU-LOS (34.8 days ± 25.5 versus 12.1 ± 8.0, p < 0.0001) was significantly longer than in non-tracheostomized patients. Demographics and characteristics of the course of the disease up to the crisis were not significantly different between patients with an early (within 10 days) compared to a late tracheostomy. However, an early tracheostomy correlated with a shorter duration of MV at ICU (26.2 days ± 18.1 versus 42.0 ± 33.1, p = 0.006), and ICU-LOS (26.2 days ± 14.6 versus 42.3 ± 33.0, p = 0.003). CONCLUSION: Half of the ventilated patients with MC required a tracheostomy. Poorer health condition before the crisis and late-onset MG were associated with a tracheostomy. An early tracheostomy (≤ day 10), however, was associated with a shorter duration of MV and ICU-LOS by 2 weeks.

Active Case Finding of Current Bornavirus Infections in Human Encephalitis Cases of Unknown Etiology, Germany, 2018-2020.

Human bornavirus encephalitis is a severe and often fatal infection caused by variegated squirrel bornavirus 1 (VSBV-1) and Borna disease virus 1 (BoDV-1). We conducted a prospective study of bornavirus etiology of encephalitis cases in Germany during 2018-2020 by using a serologic testing scheme applied along proposed graded case definitions for VSBV-1, BoDV-1, and unspecified bornavirus encephalitis. Of 103 encephalitis cases of unknown etiology, 4 bornavirus infections were detected serologically. One chronic case was caused by VSBV-1 after occupational-related contact of a person with exotic squirrels, and 3 acute cases were caused by BoDV-1 in virus-endemic areas. All 4 case-patients died. Bornavirus etiology could be confirmed by molecular methods. Serologic testing for these cases was virus specific, discriminatory, and a practical diagnostic option for living patients if no brain tissue samples are available. This testing should be guided by clinical and epidemiologic suspicions, such as residence in virus-endemic areas and animal exposure.

Bornavirus Encephalitis Shows a Characteristic Magnetic Resonance Phenotype in Humans.

OBJECTIVE: The number of diagnosed fatal encephalitis cases in humans caused by the classical Borna disease virus (BoDV-1) has been increasing, ever since it was proved that BoDV-1 can cause human infections. However, awareness of this entity is low, and a specific imaging pattern has not yet been identified. We therefore provide the first comprehensive description of the morphology of human BoDV-1 encephalitis, with histopathological verification of imaging abnormalities. METHODS: In an institutional review board-approved multicenter study, we carried out a retrospective analysis of 55 magnetic resonance imaging (MRI) examinations of 19 patients with confirmed BoDV-1 encephalitis. Fifty brain regions were analyzed systematically (T1w, T2w, T2*w, T1w + Gd, and DWI), in order to discern a specific pattern of inflammation. Histopathological analysis of 25 locations in one patient served as correlation for MRI abnormalities. RESULTS: Baseline imaging, acquired at a mean of 11 ± 10 days after symptom onset, in addition to follow-up scans of 16 patients, revealed characteristic T2 hyperintensities with a predilection for the head of the caudate nucleus, insula, and cortical spread to the limbic system, whereas the occipital lobes and cerebellar hemispheres were unaffected. This gradient was confirmed by histology. Nine patients (47.4%) developed T1 hyperintensities of the basal ganglia, corresponding to accumulated lipid phagocytes on histology and typical for late-stage necrosis. INTERPRETATION: BoDV-1 encephalitis shows a distinct pattern of inflammation in both the early and late stages of the disease. Its appearance can mimic sporadic Creutzfeldt-Jakob disease on MRI and should be considered a differential diagnosis in the case of atypical clinical presentation. ANN NEUROL 2020;88:723-735.

Cyclophosphamide for salvage therapy of chronic graft-versus-host disease: a retrospective analysis.

We retrospectively analyzed the safety and efficacy of cyclophosphamide (cyclo) for salvage treatment of chronic graft-versus-host disease (cGvHD) and cGvHD-associated (glomerulo-)nephritis at our center between 01/2010 and 11/2019. We identified 13 patients (pts) receiving cyclo for treatment of moderate (3/13) and severe (6/13) steroid-refractory cGvHD, cGvHD-associated (glomerulo-)nephritis (3/13), or vasculitis-like CNS manifestation of cGvHD (1/13). Cyclo was started on median day 509 (range 42-8193) after cGvHD onset; the median duration of application was 153 days (range 14-486) with 2/13 currently continuing treatment. The National Institute of Health organ grading and the intensity of immunosuppression (IS) were assessed at cyclo start and repeated after 3, 6, and 12 months. Response assessment was stopped at the start of any additional new IS. The median time of follow up was 407 days (range 86-1534). Best response was 1/13 CR, 6/13 PR, 4/13 SD, 1/13 MR, and 1/13 PD (ORR 54%). Significant and durable response was observed especially in cGvHD-associated (glomerulo-)nephritis (3/3). Infectious complications > CTCAE grade III were observed in 3/12 pts. During cyclo therapy, none of the pts suffered from recurrence of underlying malignancy. Overall, cyclo was relatively well tolerated and showed responses in heavily pretreated patients but requires further evaluation within clinical trials.

The neuropathology of fatal encephalomyelitis in human Borna virus infection.

After many years of controversy, there is now recent and solid evidence that classical Borna disease virus 1 (BoDV-1) can infect humans. On the basis of six brain autopsies, we provide the first systematic overview on BoDV-1 tissue distribution and the lesion pattern in fatal BoDV-1-induced encephalitis. All brains revealed a non-purulent, lymphocytic sclerosing panencephalomyelitis with detection of BoDV-1-typical eosinophilic, spherical intranuclear Joest-Degen inclusion bodies. While the composition of histopathological changes was constant, the inflammatory distribution pattern varied interindividually, affecting predominantly the basal nuclei in two patients, hippocampus in one patient, whereas two patients showed a more diffuse distribution. By immunohistochemistry and RNA in situ hybridization, BoDV-1 was detected in all examined brain tissue samples. Furthermore, infection of the peripheral nervous system was observed. This study aims at raising awareness to human bornavirus encephalitis as differential diagnosis in lymphocytic sclerosing panencephalomyelitis. A higher attention to human BoDV-1 infection by health professionals may likely increase the detection of more cases and foster a clearer picture of the disease.

Neuromyelitis optica: Evaluation of 871 attacks and 1,153 treatment courses.

OBJECTIVE: Neuromyelitis optica (NMO) attacks often are severe, are difficult to treat, and leave residual deficits. Here, we analyzed the frequency, sequence, and efficacy of therapies used for NMO attacks. METHODS: A retrospective review was made of patient records to assess demographic/diagnostic data, attack characteristics, therapies, and the short-term remission status (complete remission [CR], partial remission [PR], no remission [NR]). Inclusion criteria were NMO according to Wingerchuk's 2006 criteria or aquaporin-4 antibody-positive NMO spectrum disorder (NMOSD). Remission status was analyzed with generalized estimating equations (GEEs), a patient-based statistical approach. RESULTS: A total of 871 attacks in 185 patients (142 NMO/43 NMOSD, 82% female) were analyzed. The 1,153 treatment courses comprised high-dose intravenous steroids (HD-S; n = 810), plasma exchange (PE; n = 192), immunoadsorption (IA; n = 38), other (n = 80), and unknown (n = 33) therapies. The first treatment course led to CR in 19.1%, PR in 64.5%, and NR in 16.4% of attacks. Second, third, fourth, and fifth treatment courses were given in 28.2%, 7.1%, 1.4%, and 0.5% of attacks, respectively. This escalation of attack therapy significantly improved outcome (p < 0.001, Bowker test). Remission rates were higher for isolated optic neuritis versus isolated myelitis (p < 0.001), and for unilateral versus bilateral optic neuritis (p = 0.020). Isolated myelitis responded better to PE/IA than to HD-S as first treatment course (p = 0.037). Predictors of CR in multivariate GEE analysis were age (odds ratio [OR] = 0.97, p = 0.011), presence of myelitis (OR = 0.38, p = 0.002), CR from previous attack (OR = 6.85, p < 0.001), and first-line PE/IA versus HD-S (OR = 4.38, p = 0.006). INTERPRETATION: Particularly myelitis and bilateral optic neuritis have poor remission rates. Escalation of attack therapy improves outcome. PE/IA may increase recovery in isolated myelitis.

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

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-ß (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-ß, 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-ß.

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

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.

Activation of TGF-ß-induced non-Smad signaling pathways during Th17 differentiation.

Although transforming growth factor-ß (TGF-ß) has been shown to positively regulate the development of murine T helper type 17 (Th17) cells, which of the intracellular signaling pathways are involved is controversial. We examined Smad-dependent and -independent signaling molecules downstream of the TGF-ß receptor (TGFßR) involved in Th17 differentiation of naive murine CD4(+)CD62L(+) T cells. During Th17 differentiation of wild-type T cells, Smad2/3 was phosphorylated, indicating activation of the canonical Smad pathway. T cells lacking TGFßRII did not differentiate into Th17, whereas T cells treated with a TGFßRI kinase inhibitor (SB-431542) or overexpression of inhibitory Smad7 retained a low amount of Th17 polarization despite absent Smad2/3 phosphorylation. Using protein antibody arrays we found an increase of expression and phosphorylation of the following Smad-independent signaling molecules in Th17-polarized wild-type T cells: AKT1(Tyr474), AKT2 (Ser474), ERK1-p44/42 MAPK(Tyr204), mTOR(Thr2446), p38 MAPK(Thr180), Rac1/cdc42(Ser71), SAPK/JNK(Tyr185) and SP1(Thr739). Pharmacological inhibition of AKT/mammalian target of rapamycin (mTOR) signaling with rapamycin or LY294002 decreased Th17 differentiation of wild-type T cells, and completely abolished interleukin-17 production in T cells with overexpression of Smad7. Rapamycin and LY294002 also decreased induced regulatory T cell differentiation, but only had minor additive effects to Smad7 overexpression. Finally, inhibitors of mitogen-activated protein kinase (MAPK) blocked in vitro polarization of Th17 cells. Our data show that Smad-dependent and -independent intracellular pathways contribute to murine Th17 differentiation.

Real-world analysis of brain atrophy in multiple sclerosis patients with an artificial intelligence based software tool.

BACKGROUND: Atrophy of white and grey matter volumes occurs early in the brains of people with multiple sclerosis (pwMS) and has great clinical relevance. In clinical trials, brain atrophy can be quantified by magnetic resonance imaging (MRI) with automated software tools. METHODS: In this study, we analyze volumes of various brain regions with the software "md brain" based on routine MRI scans of 53 pwMS in a real-world setting. We compare brain volumes of pwMS with an EDSS ≥ 3.5 and a disease duration ≥ 10 years to the brain volumes of pwMS with an EDSS < 3.5 and a disease duration < 10 years as well as with or without immunotherapy. RESULTS: pwMS with an EDSS ≥ 3.5 and a disease duration ≥ 10 years had significantly lower volumes of the total brain, the grey matter and of the frontal, temporal, parietal and occipital lobe regions as compared to pwMS with an EDSS < 3.5 and a disease duration < 10 years. Regional brain volumes were significantly lower in pwMS without immunotherapy. CONCLUSIONS: The study showed that higher EDSS, longer disease duration and absence of immunotherapy was associated with lower volumes in a number of brain regions. Further real-world studies may include larger patient cohorts in longitudinal analyses.

Weaning and extubation failure in myasthenic crisis: a multicenter analysis.

Myasthenic crisis (MC) requiring mechanical ventilation is a serious complication of myasthenia gravis (MG). Here we analyze the frequency and risk factors of weaning- and extubation failure as well as its impact on the clinical course in a large cohort. We performed a retrospective chart review on patients treated for MC in 12 German neurological departments between 2006 and 2015. Weaning failure (WF) was defined as negative spontaneous breathing trial, primary tracheostomy, or extubation failure (EF) (reintubation or death). WF occurred in 138 episodes (64.2%). Older Age (p = 0.039), multiple comorbidities (≥ 3) (p = 0.007, OR = 4.04), late-onset MG (p = 0.004, OR = 2.84), complications like atelectasis (p = 0.008, OR = 3.40), pneumonia (p < 0.0001, OR = 3.45), cardio-pulmonary resuscitation (p = 0.005, OR = 5.00) and sepsis (p = 0.02, OR = 2.57) were associated with WF. WF occurred often in patients treated with intravenous immungloblins (IVIG) (p = 0.002, OR = 2.53), whereas WF was less often under first-line therapy with plasma exchange or immunoadsorption (p = 0.07, OR = 0.57). EF was observed in 58 of 135 episodes (43.0%) after first extubation attempt and was related with prolonged mechanical ventilation, intensive care unit stay and hospital stay (p ≤ 0.0001 for all). Extubation success was most likely in a time window for extubation between day 7 and 12 after intubation (p = 0.06, OR = 2.12). We conclude that WF and EF occur very often in MC and are associated with poor outcome. Older age, multiple comorbidities and development of cardiac and pulmonary complications are associated with a higher risk of WF and EF. Our data suggest that WF occurs less frequently under first-line plasma exchange/immunoadsorption compared with first-line use of IVIG.

Eculizumab Use in Neuromyelitis Optica Spectrum Disorders: Routine Clinical Care Data From a European Cohort.

BACKGROUND AND OBJECTIVES: Attack prevention is crucial in managing neuromyelitis optica spectrum disorders (NMOSDs). Eculizumab (ECU), an inhibitor of the terminal complement cascade, was highly effective in preventing attacks in a phase III trial of aquaporin-4 (AQP4)-IgG seropositive(+) NMOSDs. In this article, we evaluated effectiveness and safety of ECU in routine clinical care. METHODS: We retrospectively evaluated patients with AQP4-IgG+ NMOSD treated with ECU between December 2014 and April 2022 at 20 German and 1 Austrian university center(s) of the Neuromyelitis Optica Study Group (NEMOS) by chart review. Primary outcomes were effectiveness (assessed using annualized attack rate [AAR], MRI activity, and disability changes [Expanded Disability Status Scale {EDSS}]) and safety (including adverse events, mortality, and attacks after meningococcal vaccinations), analyzed by descriptive statistics. RESULTS: Fifty-two patients (87% female, age 55.0 ± 16.3 years) received ECU for 16.2 (interquartile range [IQR] 9.6 - 21.7) months. Forty-five patients (87%) received meningococcal vaccination before starting ECU, 9 with concomitant oral prednisone and 36 without. Seven of the latter (19%) experienced attacks shortly after vaccination (median: 9 days, IQR 6-10 days). No postvaccinal attack occurred in the 9 patients vaccinated while on oral prednisone before starting ECU and in 25 (re-)vaccinated while on ECU. During ECU therapy, 88% of patients were attack-free. The median AAR decreased from 1.0 (range 0-4) in the 2 years preceding ECU to 0 (range 0-0.8; p < 0.001). The EDSS score from start to the last follow-up was stable (median 6.0), and the proportion of patients with new T2-enhancing or gadolinium-enhancing MRI lesions in the brain and spinal cord decreased. Seven patients (13%) experienced serious infections. Five patients (10%; median age 53.7 years) died on ECU treatment (1 from myocardial infarction, 1 from ileus with secondary sepsis, and 3 from systemic infection, including 1 meningococcal sepsis), 4 were older than 60 years and severely disabled at ECU treatment start (EDSS score ≥ 7). The overall discontinuation rate was 19%. DISCUSSION: Eculizumab proved to be effective in preventing NMOSD attacks. An increased risk of attacks after meningococcal vaccination before ECU start and potentially fatal systemic infections during ECU-particularly in patients with comorbidities-must be considered. Further research is necessary to explore optimal timing for meningococcal vaccinations. CLASSIFICATION OF EVIDENCE: This study provides Class IV evidence that eculizumab reduces annualized attack rates and new MRI lesions in AQP4-IgG+ patients with NMOSD.

Incidence and Outcome of Atypical Manifestations of Chronic Graft-versus-Host Disease: Results From a Retrospective Single-Center Analysis.

Chronic graft-versus-host disease (cGVHD) is the leading cause of late nonrelapse mortality (NRM) after allogeneic hematopoietic stem cell transplantation (alloHSCT) and defined by 8 diagnostic target organs. Recently, provisional criteria for atypical manifestations of cGVHD that include manifestations in nonclassic organs as well as atypical manifestations in National Institutes of Health (NIH)-defined organs, were proposed by a NIH task force. Little is known about the incidence, risk factors, and impact on survival of atypical cGVHD, however. The aim of the present study was to analyze these parameters in a sequential patient population. We retrospectively screened 623 patients who underwent alloHSCT at the University Medical Center Regensburg between January 2008 and December 2020 for atypical cGVHD manifestations, applying the provisional NIH taskforce criteria. A total of 102 patients (16.4%) met the criteria, representing 25% of all cGVHD cases, and 14 patients (2.2%) had only atypical cGVHD. The most frequent manifestations were immune-mediated cytopenias (24.5%), renal cGVHD (13.7%) and (poly)serositis (13.7%). Multivariate analysis identified prior acute GVHD (odds ratio [OR], 2.28 and 2.93) and infusion of donor lymphocytes (OR, 1.77 for both) as risk factors for classic cGVHD and atypical cGVHD, whereas total body irradiation was an independent risk factor for atypical cGVHD manifestations only (OR, 1.76). Compared to patients without cGVHD, those with atypical and NIH-defined cGVHD showed similarly better overall survival (P = .034 and < .001) and low relapse-related mortality (P < .001 for both). NRM was significantly increased by atypical GVHD, but not by NIH-defined cGVHD (P = .019 and .10), which was driven only by a few atypical organ manifestations (eg, renal, restrictive lung disease, peripheral neuropathy), whereas others did not contribute to NRM (eg, thyroid gland, musculoskeletal, pancreas). In summary, atypical cGVHD is more common than previously estimated and has both similarities with and differences from NIH-defined cGVHD. In particular, the increased NRM and a subset of patients with only atypical cGVHD point to the urgent need to capture these manifestations in cGVHD cohorts, including analysis of treatment outcomes.

Cerebrospinal fluid in Borna disease virus 1 (BoDV-1) encephalitis.

Borna disease virus 1 (BoDV-1) has been recognized as a rare cause of very severe encephalitis with rapid onset in central Europe. Data on cerebrospinal fluid (CSF) analysis have not yet been analyzed in detail. Here, we present the first study on CSF changes in BoDV-1 encephalitis. We retrospectively analyzed CSFs from 18 BoDV-1 encephalitis cases from Bavaria, Germany, an endemic region, from 1996 to 2021. Data were obtained through review of medical records and institutional databases. We found that white blood cell count (WBC) in CSF is elevated in 13 of our 18 patients at first examination (average 83.2 ± 142.3 leukocytes/µl) and cytology showed predominance of lymphocytes. Patients with typical symptoms of meningoencephalitis had higher WBC in first CSF analyzation (133.5 ± 163.1 vs 4.0 ± 3.2/µl; p = 0.065). BoDV-1 PCR of CSF is not always positive when tested (7 of 9 cases). Four of five patients tested showed a polyvalent reaction against multiple viruses in the CSF suggesting that BoDV-1 may trigger autoimmune mechanisms. CSF changes in BoDV-1 encephalitis seem similar to those of other viral encephalitis and at the beginning WBC can be normal in up to 28%, making the diagnosis even more challenging. All in all, BoDV-1 should be included in the diagnostic workup of patients with rapidly evolving and/or severe encephalitis and patients with severe neuropathy and secondary encephalopathy with and without CSF changes. Repeated CSF examinations as well as BoDV-1 serology and CSF PCR have to be considered in endemic areas.

IFN-γ-Based ELISpot as a New Tool to Detect Human Infections with Borna Disease Virus 1 (BoDV-1): A Pilot Study.

More than 40 human infections with the zoonotic Borna disease virus 1 (BoDV-1) have been reported to German health authorities from endemic regions in southern and eastern Germany. Diagnosis of a confirmed case is based on the detection of BoDV-1 RNA or BoDV-1 antigen. In parallel, serological assays such as ELISA, immunoblots, and indirect immunofluorescence are in use to detect the seroconversion of Borna virus-reactive IgG in serum or cerebrospinal fluid (CSF). As immunopathogenesis in BoDV-1 encephalitis appears to be driven by T cells, we addressed the question of whether an IFN-γ-based ELISpot may further corroborate the diagnosis. For three of seven BoDV-1-infected patients, peripheral blood mononuclear cells (PBMC) with sufficient quantity and viability were retrieved. For all three patients, counts in the range from 12 to 20 spot forming units (SFU) per 250,000 cells were detected upon the stimulation of PBMC with a peptide pool covering the nucleocapsid protein of BoDV-1. Additionally, individual patients had elevated SFU upon stimulation with a peptide pool covering X or phosphoprotein. Healthy blood donors (n = 30) and transplant recipients (n = 27) were used as a control and validation cohort, respectively. In this pilot study, the BoDV-1 ELISpot detected cellular immune responses in human patients with BoDV-1 infection. Its role as a helpful diagnostic tool needs further investigation in patients with BoDV-1 encephalitis.