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Background and Objectives To evaluate costs and health-related quality of life (HRQoL) of neuromyelitis optica spectrum disorders (NMOSD) and myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD). Methods In this multicenter cross-sectional study, data on consumption of medical and nonmedical resources and work ability were assessed via patient questionnaires. Costs were analyzed in Euros for 2018 from the societal perspective. HRQoL was captured by the EuroQoL Group 5 Dimension 5 Level Scale (EQ-5D-5L) questionnaire. Clinical data were retrieved from the Neuromyelitis Optica Study Group (NEMOS) database. Results Two hundred twelve patients (80% women, median age 50 [19-83] years, median disease duration 7 [0-43] years, median Expanded Disability Status Scale [EDSS] score 3.5 [0-8.5], 66% aquaporin-4 immunoglobulin G [IgG] positive, 22% MOG IgG positive, 12% double seronegative) were analyzed. The mean total annual per capita cost of illness accounted for €59,574 (95% CI 51,225-68,293 or US dollars [USD] 70,297, 95% CI 60,445-80,586), and the mean index value of the EQ-5D-5L was 0.693 (95% CI 0.65-0.73). The most important cost drivers were informal care costs (28% of total costs), indirect costs (23%), and drugs (16%)

Additional file 1. Table S1. Patient and subgroup characteristics.

Supplemental material, sj-docx-1-tan-10.1177_17562864221141505 for Preserved T-cell response in anti-CD20-treated multiple sclerosis patients following SARS-CoV-2 vaccination by Simon Faissner, Neele Heitmann, Ricarda Rohling, Ulas Ceylan, Marielena Bongert, Carlos Plaza-Sirvent, Corinna Marheinecke, Xiomara Pedreiturria, Ilya Ayzenberg, Kerstin Hellwig, Ingo Schmitz, Stephanie Pfaender and Ralf Gold in Therapeutic Advances in Neurological Disorders

Additional file 1: Supplementary Figure 3: Flow chart of patients included in the study. During the study period 64 MOGAD patients were identified in participating centers. Five patients were excluded due to incomplete examination data (n=2) or an acute ON at the time of examination (n=3). Depending on the age of manifestation patients were divided into 2 groups: group (1) 20 MOG-IgG-positive patients with initial manifestation < 18 years (MOGADped) and group (2) 39 MOG-IgG-positive patients with initial manifestation ≥ 18 years (MOGADadult). Supplementary Figure 4: Beeswarm plots showing the distribution of pRNFL G thickness (A), GCIPL volume (B), HCVA (C) and 2,5% LCVA (D) in MOGADped-ON and MOGADadult-ON. Despite profound neuroaxonal retinal atrophy in both groups, MOGADadult-ON eyes showed significantly worse visual outcome (HCVA and 2,5% LCVA) in comparison to MOGADped-ON. Supplementary Figure 5: Scatterplots of VEP P100 latency (A) and number of previous ON (B) against visual outcome (HCVA and 2,5% LCVA). Neither the number of previous ON nor P100-latency correlated with HCVA (rho=0.030 CI95% -0.288 -0.152, p=0.840 [number of previous ON] and rho=-0.028 CI95% -0.354 -0.290, p=0.851 [VEP P100 latency]) or LCVA (rho=-0.237 CI95% -0.422 -0.106, p=0.104 [number of previous ON] and rho=-0.263 CI95% -0.503 -0.078, p=0.071 [VEP P100 latency]). Supplementary Table 3: Demographic and main clinical characteristics of pediatric and adult cohorts with ON history (MOGAD-ON). Abbreviations: MOGAD myelin oligodendrocyte glycoprotein-antibody-associated disease, ON optic neuritis, SD standard deviation. Supplementary Table 4. Comparison of all OCT and VEP measures as well as visual acuity between in ON- and non-ON-eyes in pediatric and adult MOGAD patients. Abbreviations: MOGAD-ON eyes with a history of ON, MOGAD-NON eyes without history of ON, pRNFL peripapillary retinal nerve fibre layer (G global, S superior, l inferior, T temporal, N nasal, PMB papillomacular bundle, N/T nasal/temporal ratio), TMV total macular volume, mRNFL macular RNFL, mGCIPL macular ganglion cell and inner plexiform layer, mINL macular inner nuclear layer, mOPONL macular outer plexiform and outer nuclear layer, HCVA high-contrast, LCVA low-contrast visusal acuity. pRNFL thickness in μm and macular volumes in mm3, VEP P100 latency in ms, VEP amplitude in uV, VA in number of correctly stated letters. GEE analysis: B regression coefficient, p-value: significant results p < 0.05 are indicated in bold letters.

Objective To report pregnancy outcomes and disease activity (DA) in women with MS, neuromyelitis optica spectrum disorders (NMOSDs), and other neuroimmunologic diseases (ONID) after treatment with rituximab (RTX)/ocrelizumab (OCR) 12 months before or during pregnancy. Methods Data were collected in the German MS and pregnancy registry and centers from the Neuromyelitis Optica Study Group. Sixty-eight known outcomes of 88 pregnancies from 81 women (64 MS, 10 NMOSD, and 7 ONID) were included and stratified in 3 exposure groups: >6M-group = RTX/OCR >6 but ≤12 months before the last menstrual period (LMP) (n = 8)

Additional file 7: Supplementary Figure 3. Regression analysis of QAlb and CSF total protein demonstrated a close relationship between the two parameters (r2=0.75, p

Additional file 1: Supplementary Table 1. CSF findings during acute attacks and during remission in the ‘acute MY subgroup’, the ‘acute ON subgroup’ and the ‘acute BRAIN subgroup’ (stratified results from Table 11).

Additional file 4: Supplementary Figure 4. Influence of age at LP on CSF parameters as detected by a pooled linear regression analysis of data from the pediatric and the adult cohort (r2=0.089 for CSF TP, p

Additional file 5: Supplementary Table 1. CSF findings during acute attacks and during remission in the ‘acute MY’ subgroup, the ‘acute ON’ subgroup and the ‘acute BRAIN’ subgroup (stratified results from Table 10).

Additional file 8: Supplementary Table 4. CSF findings in MOG-IgG-positive acute bilateral ON and in MOG-IgG-positive acute unilateral ON.

Additional file 6: Supplementary Figure 2. No statistically significant differences in serum IgG, IgM, IgA and albumin levels between the ‘acute MY’, the ‘acute ON’ and the ‘acute BRAIN’ (B) subgroup.

Additional file 4: Supplementary Table 4. CSF findings in MOG-IgG-positive acute bilateral ON and in MOG-IgG-positive acute unilateral ON.

Additional file 2: Supplementary Figure 2. No marked differences in serum IgG, IgM, IgA and albumin levels between the ‘acute MY’, the ‘acute ON’ and the ‘acute BRAIN’ (B) subgroup, except for slightly higher median IgM values in the ‘acute BRAIN’ subgroup as compared to the acute ‘ON’ subgroup.

Additional file 1: Supplementary Figure 1. CSF white cell counts in the ‘acute MY subgroup’, the ‘acute BRAIN subgroup' and the ‘acute ON subgroup’.

Additional file 3: Supplementary Table 3. CSF findings in MOG-IgG-positive acute longitudinally extensive transverse myelitis (LETM) and MOG-IgG-positive non-longitudinally extensive transverse myelitis (NETM).

Additional file 3: Supplementary Figure 3. Regression analysis of QAlb and CSF total protein, demonstrating a close relationship between the two parameters (r2=0.75, p

Additional file 5: Supplementary Figure 1. CSF white cell counts in the ‘acute MY subgroup’, the ‘acute BRAIN subgroup and the ‘acute ON subgroup’.

Additional file 7: Supplementary Table 3. CSF findings in MOG-IgG-positive acute longitudinally extensive transverse myelitis (LETM) and MOG-IgG-positive non-longitudinally extensive transverse myelitis (NETM).

\(\bf Background\) Hyperprolinemia type 2 (HPII) is a rare autosomal recessive disorder of the proline metabolism, that affects the ALDH4A1 gene. So far only four different pathogenic mutations are known. The manifestation is mostly in neonatal age, in early infancy or early childhood. \(\bf Case presentation\) The 64-years female patient had a long history of abdominal pain, and episode of an acute neuritis. Ten years later she was admitted into the neurological intensive-care-unit with acute abdominal pain, multiple generalized epileptic seizures, a vertical gaze palsy accompanied by extensive lactic acidosis in serum 26.0 mmol/l (reference: 0.55–2.2 mmol/l) and CSF 12.01 mmol/l (reference: 1.12–2.47 mmol/l). Due to repeated epileptic seizures and secondary complications a long-term sedation with a ventilation therapy over 20 days was administered. A diagnostic work-up revealed up to 400-times increased prolin-level in urine CSF and blood. Furthermore, a low vitamin-B\(_6\) serum value was found, consistent with a HPII causing secondary pyridoxine deficiency and seizures. The \(\it ALDH4A1\) gene sequencing confirmed two previously unknown compound heterozygous variants (\(\it ALDH4A1\) gene (NM_003748.3) Intron 1: c.62 + 1G > A - heterozygous and \(\it ALDH4A1\) gene (NM_003748.3) Exon 5 c.349G > C, p.(Asp117His) - heterozygous). Under high-dose vitamin-B\(_6\) therapy no further seizures occurred. \(\bf Conclusion\) We describe two novel \(\it ALDH4A1\)-variants in an adult patient with hyperprolinemia type II causing secondary pyridoxine deficiency and seizures. Severe and potentially life-threatening course of this treatable disease emphasizes the importance of diagnostic vigilance and thorough laboratory work-up including gene analysis even in cases with atypical late manifestation.

Background and ObjectivesTo determine the real-world use of rituximab in autoimmune encephalitis (AE) and to correlate rituximab treatment with the long-term outcome.MethodsPatients with NMDA receptor (NMDAR)-AE, leucine-rich glioma-inactivated-1 (LGI1)- AE, contactin-associated protein-like-2 (CASPR2)-AE, or glutamic acid decarboxylase 65 (GAD65) disease from the GErman Network for Research on AuToimmune Encephalitis who had received at least 1 rituximab dose and a control cohort of non–rituximab-treated patients were analyzed retrospectively.ResultsOf the 358 patients, 163 (46%) received rituximab (NMDAR-AE: 57%, CASPR2-AE: 44%, LGI1-AE: 43%, and GAD65 disease: 37%). Rituximab treatment was initiated significantly earlier in NMDAR- and LGI1-AE (median: 54 and 155 days from disease onset) compared with CASPR2-AE or GAD65 disease (median: 632 and 1,209 days). Modified Rankin Scale (mRS) scores improved significantly in patients with NMDAR-AE, both with and without rituximab treatment. Although being more severely affected at baseline, rituximab-treated patients with NMDAR-AE more frequently reached independent living (mRS score ≤2) (94% vs 88%). In LGI1-AE, rituximab-treated and nontreated patients improved, whereas in CASPR2-AE, only rituximab-treated patients improved significantly. No improvement was observed in patients with GAD65 disease. A significant reduction of the relapse rate was observed in rituximab-treated patients (5% vs 13%). Detection of NMDAR antibodies was significantly associated with mRS score improvement. A favorable outcome was also observed with early treatment initiation.DiscussionWe provide real-world data on immunosuppressive treatments with a focus on rituximab treatment for patients with AE in Germany. We suggest that early and short-term rituximab therapy might be an effective and safe treatment option in most patients with NMDAR-, LGI1-, and CASPR2-AE.Class of EvidenceThis study provides Class IV evidence that rituximab is an effective treatment for some types of AE.

\(\textbf {Objective:}\) To report a rare case of brainstem encephalitis with low-titer acetylcholine receptor antibodies mimicking myasthenia gravis. \(\textbf {Methods:}\) The patient was investigated with repeated brain MRI, CSF examination, repetitive nerve stimulation, thoracic CT, and serologic screening. Our patient passed away and finally autopsy revealed a definitive diagnosis. Written informed consent was obtained from the relatives of the patient for access to clinical files for research purposes and publication. \(\textbf {Results:}\) We present a young woman with a subacute bulbar syndrome, who was initially diagnosed with myasthenia gravis based on clinical finding and elevated acetylcholine receptor antibodies. Episodes of numbness in the pharynx and tongue and moderate saccadic horizontal and vertical pursuits were atypical. Despite initial stabilization with intravenous immunoglobulins she developed acute asphyxia after regurgitation of food and had to be resuscitated with ultimately lethal outcome. Autopsy revealed an autoimmune T-cell mediated brainstem encephalitis. Serological screening revealed positive GAD and Ma2 autoantibodies, indicating its probable paraneoplastic nature. \(\textbf {Conclusions:}\) Brainstem encephalitis is an important differential diagnosis even in seropositive bulbar myasthenia gravis, as several autoimmune processes often co-occur. Sudden unexpected death must be taken into account in brainstem encephalitis, requiring prolonged monitoring of the patients.

\(\bf Background:\) Cranial irradiation is a common therapy for the treatment of brain tumors, but unfortunately patients suffer from side effects, particularly cognitive impairment, caused by neurodegenerative and neuroinflammatory mechanisms. Finding a therapeutic agent protecting hippocampal neurons would be beneficial. Fingolimod (FTY720), a sphingosine-1-phosphate receptor modulator approved for multiple sclerosis, is an immunosuppressant and known to enhance proliferation and differentiation of neuronal precursor cells (NPCs). \(\bf Objectives:\) To investigate whether pre-treatment with FTY720 protects NPCs \(\textit {in vitro}\) and \(\textit {in vivo}\) from irradiation-induced damage. \(\bf Methods:\) Neuronal precursor cells were isolated from E13 C57BL/6 wildtype mice, treated at day 0 of differentiation with FTY720 and irradiated on day 6 with 1 Gy. NPCs were analyzed for markers of cell death (PI, caspase-3), proliferation (Ki67), and differentiation (DCX, \(\beta\)III-tubulin). Adult C57BL/6 wildtype mice were treated with FTY720 (1 mg/kg) and received a single dose of 6 Gy cranial irradiation at day 7. Using immunohistochemistry, we analyzed DCX and BrdU as markers of neurogenesis and Iba1, GFAP, and CD3 to visualize inflammation in the dentate gyrus (DG) and the subventricular zone (SVZ). B6(Cg)-Tyrc-2J/J DCX-luc reporter mice were used for bioluminescence imaging to evaluate the effect of FTY720 on neurogenesis in the DG and the spinal cord of naïve mice. \(\bf Results:\) FTY720 protected NPCs against irradiation induced cell death \(\textit {in vitro}\). Treatment with FTY720 dose-dependently reduced the number of PI\(^{+}\) cells 24 and 96 h after irradiation without effecting proliferation or neuronal differentiation. \(\textit {In vivo}\) treatment resulted in a significant survival of DCX\(^{+}\) neurons in the DG and the SVZ 4 weeks after irradiation as well as a slight increase of proliferating cells. FTY720 inhibited microglia activation 24 h after X-ray exposure in the DG, while astrocyte activation was unaffected and no lymphocyte infiltrations were found. In naïve mice, FTY720 treatment for 4 weeks had no effect on neurogenesis. \(\bf Conclusion:\) FTY720 treatment of NPCs prior to X-ray exposure and of mice prior to cranial irradiation is neuroprotective. No effects on neurogenesis were found.

\(\bf Background:\) The oral immunomodulatory agent laquinimod is currently evaluated for multiple sclerosis (MS) treatment. Phase II and III studies demonstrated a reduction of degenerative processes. In addition to anti-inflammatory effects, laquinimod might have neuroprotective properties, but its impact on the visual system, which is often affected by MS, is unknown. The aim of our study was to investigate potential protective effects of laquinimod on the optic nerve and retina in an experimental autoimmune encephalomyelitis (EAE) model. \(\bf Methods:\) We induced EAE in C57/BL6 mice via MOG\(_{35–55}\) immunization. Animals were divided into an untreated EAE group, three EAE groups receiving laquinimod (1, 5, or 25 mg/kg daily), starting the day post-immunization, and a nonimmunized control group. Thirty days post-immunization, scotopic electroretinograms were carried out, and mice were sacrificed for histopathology (HE, LFB), immunohistochemistry (MBP, Iba1, Tmem119, F4/80, GFAP, vimentin, Brn-3a, cleaved caspase 3) of the optic nerve and retina, and retinal qRT-PCR analyses (\(\textit {Brn-3a, Iba1, Tmem119, AMWAP, CD68, GFAP}\)). To evaluate the effect of a therapeutic approach, EAE animals were treated with 25 mg/kg aquinimod from day 16 when 60% of the animals had developed clinical signs of EAE. \(\bf Results:\) Laquinimod reduced neurological EAE symptoms and improved the neuronal electrical output of the inner nuclear layer compared to untreated EAE mice. Furthermore, cellular infiltration, especially recruited phagocytes, and demyelination in the optic nerve were reduced. Microglia were diminished in optic nerve and retina. Retinal macroglial signal was reduced under treatment, whereas in the optic nerve macroglia were not affected. Additionally, laquinimod preserved retinal ganglion cells and reduced apoptosis. A later treatment with laquinimod in a therapeutic approach led to a reduction of clinical signs and to an improved b-wave amplitude. However, no changes in cellular infiltration and demyelination of the optic nerves were observed. Also, the number of retinal ganglion cells remained unaltered. \(\bf Conclusion:\) Fromour study, we deduce neuroprotective and anti-inflammatory effects of laquinimod on the optic nerve and retina in EAE mice, when animals were treated before any clinical signs were noted. Given the fact that the visual system is frequently affected by MS, the agent might be an interesting subject of further neuro-ophthalmic investigations.

Analyses of different mRNAs via qRT-PCR. Values are median and interquartile range. Significant differences are marked in bold. (DOCX 16.4 kb)