Clinical characterization of common pathogenic variants of SOD1-ALS in Germany.

Pathogenic variants in the Cu/Zn superoxide dismutase (SOD1) gene can be detected in approximately 2% of sporadic and 11% of familial amyotrophic lateral sclerosis (ALS) patients in Europe. We analyzed the clinical phenotypes of 83 SOD1-ALS patients focusing on patients carrying the most frequent (likely) pathogenic variants (R116G, D91A, L145F) in Germany. Moreover, we describe the effect of tofersen treatment on ten patients carrying these variants. R116G patients showed the most aggressive course of disease with a median survival of 22.0 months compared to 198.0 months in D91A and 87.0 months in L145F patients (HR 7.71, 95% CI 2.89-20.58 vs. D91A; p < 0.001 and HR 4.25, 95% CI 1.55-11.67 vs. L145F; p = 0.02). Moreover, R116G patients had the fastest median ALSFRS-R progression rate with 0.12 (IQR 0.07-0.20) points lost per month. Median diagnostic delay was 10.0 months (IQR 5.5-11.5) and therefore shorter compared to 57.5 months (IQR 14.0-83.0) in D91A (p < 0.001) and 21.5 months (IQR 5.8-38.8) in L145F (p = 0.21) carriers. As opposed to D91A carriers (50.0%), 96.2% of R116G (p < 0.001) and 100.0% of L145F (p = 0.04) patients reported a positive family history. During tofersen treatment, all patients showed a reduction of neurofilament light chain (NfL) serum levels, independent of the SOD1 variant. Patients with SOD1-ALS carrying R116G, D91A, or L145F variants show commonalities, but also differences in their clinical phenotype, including a faster progression rate with shorter survival in R116G, and a comparatively benign disease course in D91A carriers.

Different Patterns of Autoantibody Secretion by Peripheral Blood Mononuclear Cells in Autoimmune Nodopathies.

BACKGROUND AND OBJECTIVES: Autoimmune nodopathies with antibodies against the paranodal proteins show a distinct phenotype of a severe sensorimotor neuropathy. In some patients, complete remission can be achieved after treatment with rituximab whereas others show a chronic course. For optimal planning of treatment, predicting the course of disease and therapeutic response is crucial. METHODS: We stimulated peripheral blood mononuclear cells in vitro to find out whether secretion of specific autoantibodies may be a predictor of the course of disease and response to rituximab. RESULTS: Three patterns could be identified: In most patients with anti-Neurofascin-155-, anti-Contactin-1-, and anti-Caspr1-IgG4 autoantibodies, in vitro production of autoantibodies was detected, indicating autoantigen-specific memory B cells and short-lived plasma cells/plasmablasts as the major source of autoantibodies. These patients generally showed a good response to rituximab. In a subgroup of patients with anti-Neurofascin-155-IgG4 autoantibodies and insufficient response to rituximab, no in vitro autoantibody production was found despite high serum titers, indicating autoantibody secretion by long-lived plasma cells outside the peripheral blood. In the patients with anti-pan-Neurofascin autoantibodies-all with a monophasic course of disease-no in vitro autoantibody production could be measured, suggesting a lack of autoantigen-specific memory B cells. In some of them, autoantibody production by unstimulated cells was detectable, presumably corresponding to high amounts of autoantigen-specific plasmablasts-well in line with a severe but monophasic course of disease. DISCUSSION: Our data suggest that different B-cell responses may occur in autoimmune nodopathies and may serve as markers of courses of disease and response to rituximab.

Clinical and patient-reported outcomes and neurofilament response during tofersen treatment in SOD1-related ALS-A multicenter observational study over 18 months.

INTRODUCTION/AIMS: In amyotrophic lateral sclerosis (ALS) caused by SOD1 mutations (SOD1-ALS), tofersen received accelerated approval in the United States and is available via expanded access programs (EAP) outside the United States. This multicenter study investigates clinical and patient-reported outcomes (PRO) and serum neurofilament light chain (sNfL) during tofersen treatment in an EAP in Germany. METHODS: Sixteen SOD1-ALS patients receiving tofersen for at least 6 months were analyzed. The ALS progression rate (ALS-PR), as measured by the monthly change of the ALS functional rating scale-revised (ALSFRS-R), slow vital capacity (SVC), and sNfL were investigated. PRO included the Measure Yourself Medical Outcome Profile (MYMOP2), Treatment Satisfaction Questionnaire for Medication (TSQM-9), and Net Promoter Score (NPS). RESULTS: Mean tofersen treatment was 11 months (6-18 months). ALS-PR showed a mean change of -0.2 (range 0 to -1.1) and relative reduction by 25%. Seven patients demonstrated increased ALSFRS-R. SVC was stable (mean 88%, range -15% to +28%). sNfL decreased in all patients except one heterozygous D91A-SOD1 mutation carrier (mean change of sNfL -58%, range -91 to +27%, p < .01). MYMOP2 indicated improved symptom severity (n = 10) or yet perception of partial response (n = 6). TSQM-9 showed high global treatment satisfaction (mean 83, SD 16) although the convenience of drug administration was modest (mean 50, SD 27). NPS revealed a very high recommendation rate for tofersen (NPS +80). DISCUSSION: Data from this EAP supported the clinical and sNfL response to tofersen in SOD1-ALS. PRO suggested a favorable patient perception of tofersen treatment in clinical practice.

An ongoing problem: Rhesus hemolytic disease of the newborn - A decade of experience in a single centre.

BACKGROUND: The objectives were to evaluate the descriptive features of newborns with a diagnosis of Rhesus (Rh) hemolytic disease, to determine the morbidity and mortality rates, to evaluate the treatment methods and the factors affecting treatment requirements and clinical outcomes during a ten-year period at a tertiary center. METHODS: Newborn infants who had a positive direct Coombs test and/or had a history of intrauterine transfusion (IUT) due to Rh hemolytic disease were included. The data regarding the prenatal, natal and postnatal periods were collected from hospital records. RESULTS: A total of 260 neonates were included of which 51.2% were female. The mean ± standard deviation gestational age was 36.9 ± 2.7 weeks. The rate of preterm birth was 41.2%. Of 257 mothers whose obstetric medical history could be accessed, 87.2% were multigravida, whereas 76.3% were multiparous. Among mothers who had a reliable history of anti-D immunoglobulin prophylaxis (n=191), 51.3% had not received anti-D immunoglobulin prophylaxis in their previous pregnancies. The antenatal transfusion rate was 31.7% and the frequency of hydrops fetalis was 8.8%. While combined exchange transfusion (ET) and phototherapy (PT) was performed in 15.4% of the babies, the majority either needed phototherapy only (51.1%) or no treatment (33.5%). The mortality rate was 3.8 % (n = 10), and nine babies out of these 10 were those with severe hydrops fetalis. CONCLUSION: This study showed that Rh hemolytic disease is still a major problem in developing countries. Multiple comorbidities may occur in addition to life threatening complications, including hydrops fetalis, anemia and severe hyperbilirubinemia. High rates of multiparity and low rates of anti-D immunoglobulin prophylaxis are potential barriers for the eradication of the disease. It should be remembered that Rh hemolytic disease is a preventable disease in the presence of appropriate antenatal follow-up and care facilities.

Effects of tofersen treatment in patients with SOD1-ALS in a "real-world" setting - a 12-month multicenter cohort study from the German early access program.

Background: In April 2023, the antisense oligonucleotide tofersen was approved by the U.S. Food and Drug Administration (FDA) for treatment of SOD1-amyotrophic lateral sclerosis (ALS), after a decrease of neurofilament light chain (NfL) levels had been demonstrated. Methods: Between 03/2022 and 04/2023, 24 patients with SOD1-ALS from ten German ALS reference centers were followed-up until the cut-off date for ALS functional rating scale revised (ALSFRS-R), progression rate (loss of ALSFRS-R/month), NfL, phosphorylated neurofilament heavy chain (pNfH) in cerebrospinal fluid (CSF), and adverse events. Findings: During the observation period, median ALSFRS-R decreased from 38.0 (IQR 32.0-42.0) to 35.0 (IQR 29.0-42.0), corresponding to a median progression rate of 0.11 (IQR -0.09 to 0.32) points of ALSFRS-R lost per month. Median serum NfL declined from 78.0 pg/ml (IQR 37.0-147.0 pg/ml; n = 23) to 36.0 pg/ml (IQR 22.0-65.0 pg/ml; n = 23; p = 0.02), median pNfH in CSF from 2226 pg/ml (IQR 1061-6138 pg/ml; n = 18) to 1151 pg/ml (IQR 521-2360 pg/ml; n = 18; p = 0.02). In the CSF, we detected a pleocytosis in 73% of patients (11 of 15) and an intrathecal immunoglobulin synthesis (IgG, IgM, or IgA) in 9 out of 10 patients. Two drug-related serious adverse events were reported. Interpretation: Consistent with the VALOR study and its Open Label Extension (OLE), our results confirm a reduction of NfL serum levels, and moreover show a reduction of pNfH in CSF. The therapy was safe, as no persistent symptoms were observed. Pleocytosis and Ig synthesis in CSF with clinical symptoms related to myeloradiculitis in two patients, indicate the potential of an autoimmune reaction. Funding: No funding was received towards this study.

Clinical-epidemiological and radiological characteristics of stroke patients: A multicentre study.

INTRODUCTION AND AIM: Stroke is the leading cause of disability in adults and the second most common cause of death, at a rate of 11.8% worldwide. The purpose of this study was to examine the aetiological, demographic, and clinical characteristics of patients admitted to hospital because of acute strokes. MATERIALS AND METHODS: This multicentre study retrieved information for all patients admitted to hospital because of an acute cerebrovascular event over a six-month period, and sociodemographic, aetiological, and clinical characteristics were recorded. RESULTS: A total of 1136 patients, 520 of whom were women (45.7%), with a mean age of 70.3 ± 12.8 years, were included in the study. Of these, 967 were diagnosed with ischaemic stroke (IS) (85.1%), 99 with haemorrhagic stroke (HS) (8.7%), and 70 with transient ischaemic attack (6.1%). The most common risk factor for stroke was hypertension (73%). Carotid disease and hyperlipidaemia rates were higher in patients with HS. Numbers of functionally dependent patients with severe neurological status according to the National Institutes of Health Stroke Scale and modified Rankin scale were significantly higher in the HS group (P < .001). When IS was classified according to the Trial of Org 10172 in Acute Stroke Treatment, small vessel disease emerged as the most common cause (41%). The most common lesion localisations were the parietal lobe (23%) in the IS group and the thalamus (35.3%) in the HS group. Eighty-eight patients (7.7%), 62 (6.4%) in the ischaemic subgroup, and 26 (26.3%) in the haemorrhagic subgroup, died within the first month. CONCLUSION: Current and accurate evaluations of stroke aetiology are essential for stroke prevention and treatment planning. This study, shows that no change occurred in the aetiology of stroke and epidemiological characteristics and that accurate identification of modifiable stroke risk factors is still a major goal.

Assessment of the relation between the neutrophil to lymphocyte ratio and severity of ischemic stroke in a large cohort.

AIM OF STUDY: The NLR is a simple and inexpensive parameter that is useful as a marker of subclinical inflammation. The purpose of this study was to investigate the clinical characteristics of patients diagnosed with acute cerebral ischemia at the time of initial evaluation in the emergency department. PATIENTS AND METHODS: The study was designed as a multicentre cross-sectional study of acute ischemic stroke patients. Neurological evaluations were assessed using the NIHSS and mRS. Evaluations included the results of patients' laboratory tests performed at the time of presentation to the emergency department. RESULTS: Seven hundred and thirty-five ischemic stroke patients were included in the study. Stroke cases assessed by the mRS as mild or severe showed significant differences with respect to age, leukocyte counts, neutrophil counts, NLR, LDL cholesterol values, and serum glucose values (P = .001). When analysed using NIHSS, lymphocyte levels were significantly higher in very severe stroke cases compared with mild, moderate, and severe cases. NLR was also significantly higher in very severe stroke cases and severe stroke cases as compared with the mild and moderate stroke groups. Neurological evaluations assessed using the mRS showed a mild positive correlation with neutrophil and leukocyte count and a weak correlation with the NLR. CONCLUSION: The NLR exhibited a significant correlation with the results of the mRS and NIHSS. The NLR measured in the very early period was also significantly associated with clinical condition. These results suggest that high NLR values may be a marker of stroke' severity.What's known Stroke is an important disease that has a significant impact on mortality and morbidity and is closely related to the aging world population. In recent years, highly innovative approaches have been developed in the treatment of stroke. Although a long distance has been covered in the early diagnosis of stroke, the ability to predict the severity of the disease with many parameters is still up to date. What's new At the time of admission, in the absence of infection, parameters such as leukocytelymphocyte count and NLR may be telling about stroke severity. Demonstrating the utility of these simple, practical, inexpensive and naninvasive parameters to predict stroke severity can contribute to the scoring to be established at the time of initial diagnosis.

Choroidal thickness changes in patients with migraine.

This observational study evaluated choroidal thickness using spectral domain optical coherence tomography (SD-OCT) in patients with migraine and compared the results with healthy controls. The study population consisted of 42 migraine patients (36 females and 6 males) who were referred from neurology clinics and 42 controls (36 female and 6 male) with no systemic or ocular disease and no headache of any type. All 84 patients underwent complete ophthalmic examination as well as determination of choroidal thickness using a high-speed, high-resolution SD-OCT device (λ = 840 nm, 27.000 A-scans/s, 5-µm axial resolution). The migraine patients were classified into the migraine with aura group or the migraine without aura group, and a pain score from 1 to 10 was determined for each patient based on the Visual Analogue Scale (VAS). The mean choroidal thicknesses were 276.81 ± 37.76 µm in the migraine group and 300.44 ± 24.93 µm in controls. The difference in choroidal thickness between the migraine patients and the controls was significant (P = 0.001). Choroidal thickness measurements of five patients during an attack showed an acute decrease (mean 45.50 µm) in choroidal thickness from the values in the same patients during the attack-free period. There was no correlation between VAS score and the type of migraine with choroidal thickness (P > 0.05). The decrease in mean choroidal thickness in patients with migraine compared to controls may be related to the vascular pathology of the migraine. The acute decrease in choroidal thickness during an attack also lends support to this hypothesis of reduced ocular blood flow in these patients.