Safety of COVID-19 vaccines in multiple sclerosis: A systematic review and meta-analysis.

BACKGROUND: Data are sparse regarding the safety of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccines in patients with multiple sclerosis (MS). OBJECTIVE: To estimate (1) the pooled proportion of MS patients experiencing relapse among vaccine recipients; (2) the rate of transient neurological worsening, adverse events, and serious adverse events; (3) the previous outcomes of interest for different SARS-CoV-2 vaccine types. METHODS: Systematic review and meta-analysis of pharmacovigilance registries and observational studies. RESULTS: Nineteen observational studies comprising 14,755 MS patients who received 23,088 doses of COVID-19 vaccines were included. Mean age was 43.3 years (95% confidence interval (CI): 40-46.6); relapsing-remitting, secondary-progressive, primary-progressive MS and clinically isolated syndrome were diagnosed in 82.6% (95% CI: 73.9-89.8), 12.6% (95% CI: 6.3-20.8), 6.7% (95% CI: 4.2-9.9), and 2.9% (95% CI: 1-5.9) of cases, respectively. The pooled proportion of MS patients experiencing relapse at a mean time interval of 20 days (95% CI: 12-28.2) from vaccination was 1.9% (95% CI: 1.3%-2.6%; I2 = 78%), with the relapse risk being independent of the type of administered SARS-CoV-2-vaccine (p for subgroup differences = 0.7 for messenger RNA (mRNA), inactivated virus, and adenovector-based vaccines). After vaccination, transient neurological worsening was observed in 4.8% (95% CI: 2.3%-8.1%) of patients. Adverse events and serious adverse events were reported in 52.8% (95% CI: 46.7%-58.8%) and 0.1% (95% CI: 0%-0.2%) of vaccinations, respectively. CONCLUSION: COVID-19 vaccination does not appear to increase the risk of relapse and serious adverse events in MS. Weighted against the risks of SARS-CoV-2-related complications and MS exacerbations, these safety data provide compelling pro-vaccination arguments for MS patients.

Neurometabolic Alterations in Motor Neuron Disease: Insights from Magnetic Resonance Spectroscopy.

Magnetic resonance spectroscopy (MRS) has contributed important academic insights in motor neuron diseases (MNDs), particularly in amyotrophic lateral sclerosis (ALS). Over the past three decades momentous methodological advances took place, including the emergence of high-field magnetic resonance imaging (MRI) platforms, multi-voxel techniques, whole-brain protocols, novel head-coil designs, and a multitude of open-source imaging suites. Technological advances in MRS are complemented by important conceptual developments in MND, such as the recognition of the importance of extra-motor brain regions, multi-timepoint longitudinal study designs, assessment of asymptomatic mutation carriers, description of genotype-associated signatures, and the gradual characterisation of non-ALS MND phenotypes. We have conducted a systematic review of published MRS studies in MND to identify important emerging research trends, key lessons from pioneering studies, and stereotyped shortcomings. We also sought to highlight notable gaps in the current literature so that research priorities for future studies can be outlined. While MRS remains relatively underutilised in MND compared to other structural, diffusivity and functional imaging modalities, our review suggests that MRS can not only advance our academic understanding of MND biology, but has a multitude of practical benefits for clinical and pharmaceutical trial applications.

Identifying jitter outliers in single fiber electromyography: Comparison of four methods.

BACKGROUND: Little is known about how different outlier estimation methods affect cutoff limits for outliers in single fiber electromyography. METHODS: We compared in a prospective fashion the established 18th jitter value (18thjv) method to three, whole-distribution based, outlier detection methods: the interquartile range (IQR), the log-normal, and the Z-score method. The reference limits were probed in a normal cohort and in myasthenia gravis (MG) patients. RESULTS: Differences in outlier cutoff values between the different methods were in the range of 2 µs. The number of abnormal muscles according to the computed criteria was similar for all four methods in the control group. Classification metrics (sensitivity, specificity, Youden's statistic, and predictive values) were also similar among the different methods. In the MG group, however, the Z-score method failed to identify the abnormal jitter values. Accordingly, Kappa agreement was substantial to perfect (0.658 to 1) between the three methods (18thjv, IQR, and log-normal), but was equivalent to chance between the three methods and the Z-score in the MG group. CONCLUSIONS: The established 18thjv method proved largely robust when compared to whole-distribution based methods, and its use in clinical practice is justified. Simple estimation of outlier limits by adding two SDs to the mean of the data, leads to unacceptable deviations from the true cutoff values. Moreover, in a clinical scenario in which the final electrodiagnosis depends only on the number of outliers, it is meaningful to accept a tolerance zone of about 2 µs, which is the approximate variation range among the different methods.

MRI evidence of extraocular muscle atrophy and fatty replacement in myasthenia gravis.

PURPOSE: The aim of the study was to evaluate extraocular muscle (EOM) atrophy and fatty replacement in ocular myasthenia gravis (OMG) and generalized myasthenia gravis (GMG) patients with chronic and untreated ocular symptoms or with inadequate response to immunotherapy and unprovoked ocular exacerbations despite chronic immunotherapy. METHODS: Nineteen patients with either OMG or GMG and 19 healthy age-matched controls underwent an orbital MRI. Visually obvious muscle atrophy and muscle fatty replacement were evaluated by two raters independently. Maximum thickness of EOM was measured. Measurements of the muscles of each participant were added up, in order to calculate the total thickness. RESULTS: Eleven patients suffered from AChR-positive GMG, and 8 patients from OMG. All patients had chronic ocular symptoms or inadequate response to corticosteroids and unprovoked ocular exacerbations in spite of immunotherapy. Fatty replacement was reported in 6/19 (31.6%) patients and 0/19 (0%) controls (p = 0.02). Obvious atrophy in at least one muscle was reported in 8/19 (42.1%) patients and 1/19 (5.3%) controls (p = 0.019). Statistically significant differences between the two groups were also found in the mean total thickness, as well as in the thickness of superior recti, levator palpebrae, inferior recti, and superior oblique muscles. CONCLUSION: EOM atrophy and fatty replacement were seen frequently in our series of MG patients with treatment difficulties and frequent relapses of ocular involvement.

Cerebrospinal Fluid TAR DNA-Binding Protein 43 Combined with Tau Proteins as a Candidate Biomarker for Amyotrophic Lateral Sclerosis and Frontotemporal Dementia Spectrum Disorders.

BACKGROUND: Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are nowadays recognized as spectrum disorders with a molecular link, the TAR DNA-binding protein 43 (TDP-43), rendering it a surrogate biomarker for these disorders. METHODS: We measured cerebrospinal fluid (CSF) levels of TDP-43, beta-amyloid peptide with 42 amino acids (Aß42), total tau protein (τT), and tau protein phosphorylated at threonine 181 (τP-181) in 32 patients with ALS, 51 patients with FTD, and 17 healthy controls. Double-sandwich commercial enzyme-linked immunosorbent assays were used for measurements. RESULTS: Both ALS and FTD patients presented with higher TDP-43 and τT levels compared to the control group. The combination of biomarkers in the form of the TDP-43 × τT / τP-181 formula achieved the best discrimination between ALS or FTD and controls, with sensitivities and specificities >0.8. CONCLUSION: Combined analysis of TDP-43, τT, and τP-181 in CSF may be useful for the antemortem diagnosis of ALS and FTD.

Reversible cerebral vasoconstriction syndrome as a cause of thunderclap headache: a retrospective case series study.

Thunderclap headache is a common emergency department presentation. Although subarachnoid hemorrhage (SAH) should be the first diagnosis to exclude, reversible cerebral vasoconstriction syndrome (RCVS) is an important alternative cause, which may be commoner than appreciated. Reversible cerebral vasoconstriction syndrome is characterized by multifocal narrowing of cerebral arteries, typically manifested by acute, severe headache with or without neurologic deficits. To compare and discuss the clinical and radiologic characteristics of patients with RCVS. We report 4 cases of RCVS, presenting at a single unit in 1 year. All presented with thunderclap headache, whereas half of them had additional neurologic symptoms such as right homonymous hemianopia, right-sided weakness, and slurred speech. Brain computed tomography was normal in 2 of our patients, but subsequent cerebrospinal fluid analysis revealed xanthochromia consistent with SAH. The remaining 2 patients demonstrated intracerebral hemorrhage on computed tomography. All of our patients underwent digital subtraction angiography that showed segmental narrowing and dilatation of one or more cerebral arteries without any signs of aneurysm. Repeat digital subtraction angiography after 3 months was entirely normal prompting the diagnosis of RCVS. Thunderclap headache requires urgent workup to identify the underlying cause. Although SAH is the most important diagnosis to exclude in the first instance, emergency physicians should be aware of other causes and how they present, such as RCVS. Early recognition of this condition is important in order to remove precipitants, avoid unnecessary investigations, and inform patients about their prognosis.

Pearls & Oy-sters: Thyroid-Associated Ophthalmopathy and Transient Neuromuscular Junction Disorder Due to Graves Disease.

The concomitant presentation of thyroid-associated ophthalmopathy (TAO) and ocular myasthenia gravis is well documented. In the course of Graves disease (GD), symptomatic transient neuromuscular junction disorder may occur due to the effect of thyroid hormones at the neuromuscular synapse. Diagnostic clues are the clinical and electrophysiologic remission synchronous with restoration of euthyroidism. Furthermore, the occurrence of thymic hyperplasia in GD poses further diagnostic and therapeutic considerations. These points are discussed in the case report of a 43-year-old male patient suffering from TAO and transient neuromuscular junction disorder due to GD.

A retrospective multicenter study on clinical and serological parameters in patients with MuSK myasthenia gravis with and without general immunosuppression.

Introduction: Muscle-specific kinase (MuSK)- myasthenia gravis (MG) is caused by pathogenic autoantibodies against MuSK that correlate with disease severity and are predominantly of the IgG4 subclass. The first-line treatment for MuSK-MG is general immunosuppression with corticosteroids, but the effect of treatment on IgG4 and MuSK IgG4 levels has not been studied. Methods: We analyzed the clinical data and sera from 52 MuSK-MG patients (45 female, 7 male, median age 49 (range 17-79) years) from Italy, the Netherlands, Greece and Belgium, and 43 AChR-MG patients (22 female, 21 male, median age 63 (range 2-82) years) from Italy, receiving different types of immunosuppression, and sera from 46 age- and sex-matched non-disease controls (with no diagnosed diseases, 38 female, 8 male, median age 51.5 (range 20-68) years) from the Netherlands. We analyzed the disease severity (assessed by MGFA or QMG score), and measured concentrations of MuSK IgG4, MuSK IgG, total IgG4 and total IgG in the sera by ELISA, RIA and nephelometry. Results: We observed that MuSK-MG patients showed a robust clinical improvement and reduction of MuSK IgG after therapy, and that MuSK IgG4 concentrations, but not total IgG4 concentrations, correlated with clinical severity. MuSK IgG and MuSK IgG4 concentrations were reduced after immunosuppression in 4/5 individuals with before-after data, but data from non-linked patient samples showed no difference. Total serum IgG4 levels were within the normal range, with IgG4 levels above threshold (1.35g/L) in 1/52 MuSK-MG, 2/43 AChR-MG patients and 1/45 non-disease controls. MuSK-MG patients improved within the first four years after disease onset, but no further clinical improvement or reduction of MuSK IgG4 were observed four years later, and only 14/52 (26.92%) patients in total, of which 13 (93.3%) received general immunosuppression, reached clinical remission. Discussion: We conclude that MuSK-MG patients improve clinically with general immunosuppression but may require further treatment to reach remission. Longitudinal testing of individual patients may be clinically more useful than single measurements of MuSK IgG4. No significant differences in the serum IgG4 concentrations and IgG4/IgG ratio between AChR- and MuSK-MG patients were found during follow-up. Further studies with larger patient and control cohorts are necessary to validate the findings.

Volume matters: the influence of different botulinum toxin-A dilutions for sialorrhea in amyotrophic lateral sclerosis.

INTRODUCTION: We aimed to determine the effect of different botulinum toxin-A (BTX-A) dilutions on the treatment efficacy and side effects for amyotrophic lateral sclerosis (ALS) related sialorrhea. METHODS: Ten patients were enrolled in the study. BTX-A dilution for Group A was 100 U in 1 ml of saline, whereas the dilution for Group B was 100 U in 2 ml of saline. Both groups received 20 U of BTX-A in each parotid gland, and assessments were made by means of the Drooling Impact Scale, items 1 and 3 of the ALS functional rating scale, and visual analog scales for drooling and swallowing function. RESULTS: Although both groups exhibited a similar improvement in drooling, Group B had a mild but significant deterioration in bulbar function that was not evident in Group A. CONCLUSIONS: These results suggest that BTX-A has a safer profile when reconstituted with 1 ml instead of 2 ml of saline.

Fabry Disease: Current and Novel Therapeutic Strategies. A Narrative Review.

BACKGROUND: Fabry disease (FD) is an inherited lysosomal storage disorder, leading to multisystemic manifestations and causing significant morbidity and mortality. OBJECTIVE: The aim of this narrative review is to present the current and novel therapeutic strategies in FD, including symptomatic and specific treatment options. METHODS: A systematic literature search was conducted to identify relevant studies, including completed and ongoing randomized-controlled clinical trials (RCTs), prospective or retrospective cohort studies, case series and case reports that provided clinical data regarding FD treatment. RESULTS: A multidisciplinary symptomatic treatment is recommended for FD patients, personalized according to disease manifestations and their severity. During the last two decades, FD-specific treatments, including two enzyme-replacement-therapies (agalsidase alfa and agalsidase beta) and chaperone treatment with migalastat have been approved for use and allowed for symptoms' stabilization or even disease burden reduction. More therapeutic agents are currently under investigation. Substrate reduction therapies, including lucerastat and venglustat, have shown promising results in RCTs and may be used either as monotherapy or as complementary therapy to established enzymereplacement- therapies. More stable enzyme-replacement-therapy molecules that are associated with less adverse events and lower likelihood of neutralizing antibodies formation have also been developed. Ex-vivo and in-vivo gene therapy is being tested in animal models and pilot human clinical trials, with preliminary results showing a favorable safety and efficacy profile. CONCLUSION: The therapeutic landscape in FD appears to be actively expanding with more treatment options expected to become available in the near future, allowing for a more personalized approach in FD patients.

Non-pharmacological Interventions on Pain and Quality of Life in Chemotherapy Induced Polyneuropathy: Systematic Review and Meta-Analysis.

BACKGROUND/AIM: Chemotherapy-induced peripheral neuropathy (CIPN) is a common side effect of cancer treatment, resulting in pain, numbness, instability, and thus affecting quality of life (QoL), occasionally leading to discontinuation of chemotherapy. Pharmacological treatments are not sufficient. Non-pharmacological interventions (NPIs) have also been tried. This study aimed to systematically review the efficacy of NPIs on pain and QoL in patients suffering from CIPN. MATERIALS AND METHODS: The databases searched were Pubmed, Cohrane, and Scopus for randomized controlled trials (RCTs) published in the last 5 years (2017-2022). Studies were considered eligible, if they assessed adult patients suffering from CIPN because of any chemotherapeutic drug for any type and any stage of cancer and if study protocols included non-pharmacological intervention with a structured protocol. RESULTS: A total of 1,496 records were identified. Finally, 10 RCTs including 495 patients (253 in the intervention group and 242 in the control group) were included for meta-analysis. Intervention protocols included acupuncture (n=6), exercise (n=3), and yoga (n=1). NPIs significantly reduced neuropathic pain. However, the effect on QoL was not significant. CONCLUSION: NPIs are beneficial in the treatment of pain in patients with CIPN but their impact on QoL is not statistically supported. Larger sample sizes, more homogenous in outcome measures and interventions are needed to further explore NPIs' efficacy on CIPN symptoms.

Immunological and Structural Characterization of Titin Main Immunogenic Region; I110 Domain Is the Target of Titin Antibodies in Myasthenia Gravis.

Myasthenia gravis (MG) is an autoimmune disease caused by antibodies targeting the neuromuscular junction (NJ) of skeletal muscles. The major MG autoantigen is nicotinic acetylcholine receptor. Other autoantigens at the NJ include MuSK, LRP4 and agrin. Autoantibodies to the intra-sarcomeric striated muscle-specific gigantic protein titin, although not directed to the NJ, are invaluable biomarkers for thymoma and MG disease severity. Thymus and thymoma are critical in MG mechanisms and management. Titin autoantibodies bind to a 30 KDa titin segment, the main immunogenic region (MIR), consisting of an Ig-FnIII-FnIII 3-domain tandem, termed I109-I111. In this work, we further resolved the localization of titin epitope(s) to facilitate the development of more specific anti-titin diagnostics. For this, we expressed protein samples corresponding to 8 MIR and non-MIR titin fragments and tested 77 anti-titin sera for antibody binding using ELISA, competition experiments and Western blots. All anti-MIR antibodies were bound exclusively to the central MIR domain, I110, and to its containing titin segments. Most antibodies were bound also to SDS-denatured I110 on Western blots, suggesting that their epitope(s) are non-conformational. No significant difference was observed between thymoma and non-thymoma patients or between early- and late-onset MG. In addition, atomic 3D-structures of the MIR and its subcomponents were elucidated using X-ray crystallography. These immunological and structural data will allow further studies into the atomic determinants underlying titin-based autoimmunity, improved diagnostics and how to eventually treat titin autoimmunity associated co-morbidities.

Hippocampal Metabolic Alterations in Amyotrophic Lateral Sclerosis: A Magnetic Resonance Spectroscopy Study.

BACKGROUND: Magnetic resonance spectroscopy (MRS) in amyotrophic lateral sclerosis (ALS) has been overwhelmingly applied to motor regions to date and our understanding of frontotemporal metabolic signatures is relatively limited. The association between metabolic alterations and cognitive performance in also poorly characterised. MATERIAL AND METHODS: In a multimodal, prospective pilot study, the structural, metabolic, and diffusivity profile of the hippocampus was systematically evaluated in patients with ALS. Patients underwent careful clinical and neurocognitive assessments. All patients were non-demented and exhibited normal memory performance. 1H-MRS spectra of the right and left hippocampi were acquired at 3.0T to determine the concentration of a panel of metabolites. The imaging protocol also included high-resolution T1-weighted structural imaging for subsequent hippocampal grey matter (GM) analyses and diffusion tensor imaging (DTI) for the tractographic evaluation of the integrity of the hippocampal perforant pathway zone (PPZ). RESULTS: ALS patients exhibited higher hippocampal tNAA, tNAA/tCr and tCho bilaterally, despite the absence of volumetric and PPZ diffusivity differences between the two groups. Furthermore, superior memory performance was associated with higher hippocampal tNAA/tCr bilaterally. Both longer symptom duration and greater functional disability correlated with higher tCho levels. CONCLUSION: Hippocampal 1H-MRS may not only contribute to a better academic understanding of extra-motor disease burden in ALS, but given its sensitive correlations with validated clinical metrics, it may serve as practical biomarker for future clinical and clinical trial applications. Neuroimaging protocols in ALS should incorporate MRS in addition to standard structural, functional, and diffusion sequences.

Delayed Leucoencephalopathy as a Complication after Endovascular Therapy of Intracranial Aneurysms-A Case Series.

We describe the clinical presentation, radiological findings, treatment and outcomes of three patients with delayed leukoencephalopathy occurring after endovascular treatment (EVT) for cerebral aneurysms-a rare, albeit recurring, complication. The symptoms occurred 6 to 12 months following the EVT of the cerebral aneurysm. Characteristic imaging findings included high-signal changes on T2 images in the white matter without diffusion restriction predominantly at the distribution of the vascular territory of the catheterized arteries, coupled with patchy gadolinium enhancement or low susceptibility weighted imaging (SWI) signals within the white-matter lesions. Steroid pulse therapy is the treatment of choice and promptly improves clinical and imaging findings. Tapering or cessation of steroids may result in clinical and imaging relapses; close- and long-term follow-up for patients presenting this complication is warranted.

Immunotherapies in MuSK-positive Myasthenia Gravis; an IgG4 antibody-mediated disease.

Muscle-specific kinase (MuSK) Myasthenia Gravis (MG) represents a prototypical antibody-mediated disease characterized by predominantly focal muscle weakness (neck, facial, and bulbar muscles) and fatigability. The pathogenic antibodies mostly belong to the immunoglobulin subclass (Ig)G4, a feature which attributes them their specific properties and pathogenic profile. On the other hand, acetylcholine receptor (AChR) MG, the most prevalent form of MG, is characterized by immunoglobulin (Ig)G1 and IgG3 antibodies to the AChR. IgG4 class autoantibodies are impotent to fix complement and only weakly bind Fc-receptors expressed on immune cells and exert their pathogenicity via interfering with the interaction between their targets and binding partners (e.g. between MuSK and LRP4). Cardinal differences between AChR and MuSK-MG are the thymus involvement (not prominent in MuSK-MG), the distinct HLA alleles, and core immunopathological patterns of pathology in neuromuscular junction, structure, and function. In MuSK-MG, classical treatment options are usually less effective (e.g. IVIG) with the need for prolonged and high doses of steroids difficult to be tapered to control symptoms. Exceptional clinical response to plasmapheresis and rituximab has been particularly observed in these patients. Reduction of antibody titers follows the clinical efficacy of anti-CD20 therapies, a feature implying the role of short-lived plasma cells (SLPB) in autoantibody production. Novel therapeutic monoclonal against B cells at different stages of their maturation (like plasmablasts), or against molecules involved in B cell activation, represent promising therapeutic targets. A revolution in autoantibody-mediated diseases is pharmacological interference with the neonatal Fc receptor, leading to a rapid reduction of circulating IgGs (including autoantibodies), an approach already suitable for AChR-MG and promising for MuSK-MG. New precision medicine approaches involve Chimeric autoantibody receptor T (CAAR-T) cells that are engineered to target antigen-specific B cells in MuSK-MG and represent a milestone in the development of targeted immunotherapies. This review aims to provide a detailed update on the pathomechanisms involved in MuSK-MG (cellular and humoral aberrations), fostering the understanding of the latest indications regarding the efficacy of different treatment strategies.

Image analysis can reliably quantify median nerve echogenicity and texture changes in patients with carpal tunnel syndrome.

OBJECTIVE: To study the ability of image analysis measures to quantify echotexture changes of median nerve in order to provide a complementary diagnostic tool in CTS. METHODS: Image analysis measures (gray level co-occurrence matrix (GLCM), brightness, hypoechoic area percentage using max entropy and mean threshold) were calculated in normalized images of 39 (19 younger and 20 older than 65y) healthy controls and 95 CTS patients (37 younger and 58 older than 65y). RESULTS: Image analysis measures were equivalent or superior (older patients) to subjective visual analysis. In younger patients, GLCM measures showed equivalent diagnostic accuracy with cross sectional area (CSA) (Area Under Curve (AUC for inverse different moment = 0.97). In older patients all image analysis measures showed similar diagnostic accuracy to CSA (AUC for brightness = 0.88). Moreover, they had abnormal values in many older patients with normal CSA values. CONCLUSIONS: Image analysis reliably quantifies median nerve echotexture alterations in CTS and offers similar diagnostic accuracy to CSA measurement. SIGNIFICANCE: Image analysis may offer added value to existing measures in the evaluation of CTS, especially in older patients. Its clinical implementation would require incorporation of mathematically simple software code for online nerve image analysis in ultrasound machines.

Characterization of the nicotinic acetylcholine receptor antibodies after an unexpected increase of antibody titer in thymoma associated myasthenia gravis patients.

Two thymoma-associated myasthenia gravis patients with chronic well-controlled disease but an unexpected increase in anti-nAChR autoantibodies titer are reported. The specificity of anti-nAChR autoantibodies directed against extracellular parts of the receptor was studied in order to investigate the discrepancy between clinical and immunological status. Analysis of the anti-nAChR autoantibodies recognizing the extracellular parts of the nAChR revealed that when the concentration of anti-nAChR autoantibodies titer increased both patients had non-anti-α1 autoantibodies. Since the clinical profile of both patients remained unchanged, the increase of non-anti-α1 autoantibodies did not affect the 2 patients' disease progression. Thus, immunotherapy modification due to an increase of anti-nAChR autoantibodies titer could be erroneous and potentially harmful.