Real-World experience with efgartigimod in patients with myasthenia gravis.

Recommendations for the treatment of myasthenia gravis (MG) have been difficult to develop because of limited evidence from large randomized controlled trials. New drugs and treatment approaches have recently been shown to be effective in phase 3 studies in seropositive generalized (g) MG. One such drug is efgartigimod, a human-Fc-fragment of IgG1, with a high affinity for the endosomal FcRn. We conducted a multicenter study to evaluate the real-world clinical and safety effects of efgartigimod in 22 gMG patients. We evaluated the strategies for the timing of re-treatment with it. The participants received a total of 59 efgartigimod -treatment cycles. The median number of cycles was 2 (range 1-6). Twenty patients (86.3%) improved by at least 2 MG-ADL points after the first treatment cycle. The median MG-ADL score at baseline was 6.5 (range: 3-17) and 2.5 (range: 0-9) post-treatment (p < 0.001). A consistent improvement of at least 2 points in the MG-ADL score after each cycle occurs in 18 patients. The effect duration of the treatment was usually between 4 and 12 weeks. Two major clinical patterns of treatment response were found. Treatment with efgartigimod was also associated with significant reductions of prednisone doses Overall, the treatment was safe and associated with only minor adverse events. The single fatality was apparently due tosevere respiratory failure. We found that efgartigimod is clinically effective, may be used as a steroid sparing agent and is generally safe for gMG patients. We recommend a personalized preventive treatment approach until clinical stabilization, followed by discontinuation and periodic evaluations.

Smartphone-based gait assessment for multiple sclerosis.

INTRODUCTION: Multiple Sclerosis causes gait alteration, even in the early stages of the disease. Traditional methods to quantify gait impairment, such as performance-based measures, lab-based motion analyses, and self-report, have limited ecological relevance. The Mon4t® app is a digital tool that uses sensors embedded in standard smartphones to measure various gait parameters. OBJECTIVES: To evaluate the use of Mon4t® technology in monitoring MS patients. METHODS: 100 MS patients and age-matched healthy controls were evaluated using both a human rater and the Mon4t Clinic™ app. Three motor tasks were performed: 3m Timed up and go test (TUG), 10m TUG, and tandem walk. The digital markers were used to compare MS vs. HC, MS with EDSS=0 vs. HC, and MS with EDSS=0 vs. MS with EDSS>0. Within the MS EDSS>0 group, correlations between digital gait markers and the EDSS score were calculated. RESULTS: Significant differences were found between MS patients and HC in multiple gait parameters. When comparing MS patients with minimal disability (EDSS=0) and HC: On the 3m TUG task, MS patients took longer to complete the task (mean difference 0.167seconds, p =0.034), took more steps (mean difference 1.32 steps, p =0.003), and had a weaker ML step-to-step correlation (mean difference 0.1, p = 0.001). The combination of features from the three motor tasks allowed distinguishing a nondisabled MS patient from a HC with high confidence (AUC of 85.65 on the ROC). When comparing MS patients with minimal disability (EDSS=0) to those with higher disability (EDSS>0): On the tandem walk task, patients with EDSS>0 took significantly longer to complete 10 steps than those with EDSS=0 (mean difference 4.63 seconds, p < 0.001), showed greater ML sway (mean difference 0.2, p < 0.001), and had larger angular velocity in the SI axis on average (mean difference 2.31 degrees/sec, p = 0.01). A classification model achieved 81.79 ROC AUC. In the subgroup of patients with EDSS>0, gait features significantly correlated with EDSS score in all three tasks. CONCLUSION: The findings demonstrate the potential of digital gait assessment to augment traditional disease monitoring and support clinical decision making. The Mon4t® app provides a convenient and ecologically relevant tool for monitoring MS patients and detecting early changes in gait impairment.

Olfactory function in Susac syndrome.

OBJECTIVES: Susac syndrome is a rare autoimmune endotheliopathy involving the brain, retina, and inner ear. Olfactory dysfunction is a common early manifestation of several central nervous system diseases, including neurodegenerative diseases and autoimmune-mediated diseases such as Multiple Sclerosis. While the literature is abundant about the Susac syndrome classic triad of encephalopathy, branch retinal artery occlusion, and low-frequency sensorineural hearing loss, little is known about the extent of olfactory sense involvement. METHODS: Using the Sniffin' Sticks test, this study evaluated olfactory function (identification and threshold) in ten recovering Susac syndrome patients under our clinic surveillance with a median of 3.1 (SD=1.53) years post-disease onset. RESULTS: olfactory assessment by threshold and odor identification were within the normal range. No differences between recovering Susac syndrome patients to standard norms of odor identification and threshold were found. CONCLUSIONS: Our findings do not support olfactory dysfunction in Susac syndrome and thereby, do not support olfactory assessment as a reliable biomarker for this condition.

New Insights on DR and DQ Human Leukocyte Antigens in Anti-LGI1 Encephalitis.

BACKGROUND AND OBJECTIVES: To explore the clinical characteristics and HLA associations of patients with anti-leucine-rich glioma-inactivated 1 encephalitis (LGI1E) from a large single center in Israel. Anti-LGI1E is the most commonly diagnosed antibody-associated encephalitic syndrome in adults. Recent studies of various populations reveal significant associations with specific HLA genes. We examined the clinical characteristics and HLA associations of a cohort of Israeli patients. METHODS: Seventeen consecutive patients with anti-LGI1E diagnosed at Tel Aviv Medical Center between the years 2011 and 2018 were included. HLA typing was performed using next-generation sequencing at the tissue typing laboratory of Sheba Medical Center and compared with data from the Ezer Mizion Bone Marrow Donor Registry, containing over 1,000,000 samples. RESULTS: Our cohort displayed a male predominance and median age at onset in the 7th decade, as previously reported. The most common presenting symptom was seizures. Notably, paroxysmal dizziness spells were significantly more common than previously reported (35%), whereas faciobrachial dystonic seizures were found only in 23%. HLA analysis revealed overrepresentation of DRB1*07:01 (OR: 3.18, CI: 20.9 p < 1.e-5) and DRB1*04:02 (OR: 3.8, CI: 20.1 p < 1.e-5), as well as of the DQ allele DQB1*02:02 (OR: 2.8, CI: 14.2 p < 0.0001) as previously reported. A novel overrepresentation observed among our patients was of the DQB1*03:02 allele (OR: 2.3, CI: 6.9 p < 0.008). In addition, we found DR-DQ associations, among patients with anti-LGI1E, that showed complete or near-complete linkage disequilibrium (LD). By applying LD analysis to an unprecedentedly large control cohort, we were able to show that although in the general population, DQB*03:02 is not fully associated with DRB1*04:02, in the patient population, both alleles are always coupled, suggesting the DRB1*04:02 association to be primary to disease predisposition. In silico predictions performed for the overrepresented DQ alleles reveal them to be strong binders of LGI1-derived peptides, similarly to overrepresented DR alleles. These predictions suggest a possible correlation between peptide binding sites of paired DR-DQ alleles. DISCUSSION: Our cohort presents distinct immune characteristics with substantially higher overrepresentation of DRB1*04:02 and slightly lower overrepresentation of DQB1*07:01 compared with previous reports implying differences between different populations. DQ-DR interactions found in our cohort may shed additional light on the complex role of immunogenetics in the pathogenesis of anti-LGI1E, implying a possible relevance of certain DQ alleles and DR-DQ interactions.

From pathology to MRI and back: Clinically relevant biomarkers of multiple sclerosis lesions.

Focal lesions in both white and gray matter are characteristic of multiple sclerosis (MS). Histopathological studies have helped define the main underlying pathological processes involved in lesion formation and evolution, serving as a gold standard for many years. However, histopathology suffers from an intrinsic bias resulting from over-reliance on tissue samples from late stages of the disease or atypical cases and is inadequate for routine patient assessment. Pathological-radiological correlative studies have established advanced MRI's sensitivity to several relevant MS-pathological substrates and its practicality for assessing dynamic changes and following lesions over time. This review focuses on novel imaging techniques that serve as biomarkers of critical pathological substrates of MS lesions: the central vein, chronic inflammation, remyelination and repair, and cortical lesions. For each pathological process, we address the correlative value of MRI to MS pathology, its contribution in elucidating MS pathology in vivo, and the clinical utility of the imaging biomarker.

CTGF/CCN2 has a possible detrimental role in the inflammation and the remyelination failure in the early stages of multiple sclerosis.

Connective tissue growth factor (CTGF/CCN2) is a proinflammatory and an oligodendrocyte-differentiating blocking agent. It is found in MS lesions, which raises the possibility of involvement in MS pathogenesis. We found that its CSF and serum levels were higher in RR-MS patients than in controls and for serum compared to PP and SP-MS. Immune cells of both RR-MS and controls secreted CTGF/CCN2, which was enhanced by CD3/CD28 stimulation or by LPS. Anti-CTGF treatment of mice with experimental autoimmune encephalitis ameliorated its clinical severity. CTGF/CCN2 may play a role in the immune pathogenesis of MS and in remyelination failure in early stages of MS.

BNT162b2 mRNA COVID-19 vaccine three-dose safety and risk of COVID-19 in patients with myasthenia gravis during the alpha, delta, and omicron waves.

COVID-19 affects the respiratory parenchyma and may potentially contribute to the tendency of myasthenia gravis (MG) patients to develop respiratory failure. It is, therefore, important to study the safety of vaccines against SARS-CoV-2 and to assess the risk of COVID-19 in MG patients. The safety of the three-dose BNT162b2 mRNA vaccine and outcomes of COVID-19 during the alpha, delta, and omicron waves were studied in MG patients as well as the rate of exacerbations and safety for a period of up to 6 weeks from each vaccine dose and patient morbidity and mortality during COVID-19 compared to the general population. 430 vaccine doses were administered across 150 patients. Thirteen patients (8.7%) complained of exacerbation within 6 weeks of each vaccine dose. Both MG onset rate and exacerbation rate were similar to previous years. MG exacerbation rate among fifteen patients who had COVID-19 was significantly higher (40%) compared to the rate following vaccination. During the alpha and delta waves, COVID-19 mortality and severe disease were significantly higher (26.7%) compared to the general population (0.96%). All of them were unvaccinated and had generalized MG. During the omicron wave, all the MG patients who contracted COVID-19 were vaccinated and had mild disease. We concluded that COVID-19 is hazardous for generalized MG patients, while the vaccination did not raise the risk for either exacerbation or new onset of MG and was associated with a reduced risk for severe COVID-19. Hence, it is recommended for generalized MG patients to get vaccinated.

Differences in MS clinical and epidemiological characteristics between Ashkenazi and non-Ashkenazi Jewish patients in Israel: a retrospective single center study.

The prevalence and severity of Multiple Sclerosis (MS) varies across different ethnicities, with a tendency to a more severe phenotype in non-Caucasian populations.  Our objective was to evaluate the differences in disease phenotype between Ashkenazi Jewish and Non-Ashkenazi Jewish patients in Israel. We conducted a single center retrospective cohort study in which subjects were assigned to Ashkenazi or Non-Ashkenazi groups according to self-reported ancestry and disease severity was assessed using the expanded disability status (EDSS), MS severity score (MSSS), progression index (PI) and MRI metrics. 330 Ashkenazi Jewish (AJ) and 207 Non-Ashkenazi Jewish patients (Non-AJ) were included. Non-AJ had a younger age of disease onset (32.7 years vs. 35.7 years, p = 0.05), with a lower proportion of females (62.3% vs. 73.3%, p = 0.01). These differences were maintained within the subgroup of Israeli native patients. Ethnicity was a significant predictor of MSSS (ß = 0.601, p = 0.003), with a higher estimate than that of other epidemiological factors. To conclude, Non-AJ patients had an earlier age of onset and a more disabling disease as well as having a more balanced female to male ratio compared to AJ patients. These findings demonstrate variability of disease phenotype within Caucasian patient's dependent on their ethnicity despite equivalent access to healthcare services.

7T MRI Differentiates Remyelinated from Demyelinated Multiple Sclerosis Lesions.

OBJECTIVE: To noninvasively assess myelin status in chronic white matter lesions of multiple sclerosis (MS), we developed and evaluated a simple classification scheme based on T1 relaxation time maps derived from 7-tesla postmortem and in vivo MRI. METHODS: Using the MP2RAGE MRI sequence, we classified 36 lesions from 4 postmortem MS brains as "long-T1," "short-T1," and "mixed-T1" by visual comparison to neocortex. Within these groups, we compared T1 times to histologically derived measures of myelin and axons. We performed similar analysis of 235 chronic lesions with known date of onset in 25 MS cases in vivo and in a validation cohort of 222 lesions from 66 MS cases, investigating associations with clinical and radiological outcomes. RESULTS: Postmortem, lesions classified qualitatively as long-T1, short-T1, and mixed-T1 corresponded to fully demyelinated, fully remyelinated, and mixed demyelinated/remyelinated lesions, respectively (p ≤ 0.001). Demyelination (rather than axon loss) dominantly contributed to initial T1 prolongation. We observed lesions with similar characteristics in vivo, allowing manual classification with substantial interrater and excellent intrarater reliability. Short-T1 lesions were most common in the deep white matter, whereas long-T1 and mixed-T1 lesions were prevalent in the juxtacortical and periventricular white matter (p = 0.02) and were much more likely to have paramagnetic rims suggesting chronic inflammation (p < 0.001). Older age at the time of lesion formation portended less remyelination (p = 0.007). INTERPRETATION: 7-tesla T1 mapping with MP2RAGE, a clinically available MRI method, allows qualitative and quantitative classification of chronic MS lesions according to myelin content, rendering straightforward the tracking of lesional myelination changes over time. ANN NEUROL 2021;90:612-626.

Navigator-Guided Motion and B0 Correction of T2*-Weighted Magnetic Resonance Imaging Improves Multiple Sclerosis Cortical Lesion Detection.

BACKGROUND: Cortical lesions are common in multiple sclerosis (MS). T2*-weighted (T2*w) imaging at 7 T is relatively sensitive for cortical lesions, but quality is often compromised by motion and main magnetic field (B0) fluctuations. PURPOSE: The aim of this study was to determine whether motion and B0 correction with a navigator-guided gradient-recalled echo sequence can improve cortical lesion detection in T2*w magnetic resonance imaging. MATERIALS AND METHODS: In this prospective study, a gradient-recalled echo sequence incorporating a navigator allowing for motion and B0 field correction was applied to collect T2*w images at 7 T from adults with MS between August 2019 and March 2020. T2*-weighted images were acquired in 1 to 3 partially overlapping scans per individual and were reconstructed using global average B0 correction ("uncorrected") or motion correction and spatially linear B0 correction ("corrected"). Image quality rating and manual segmentation of cortical lesions were performed on uncorrected and corrected images. Lesions seen on a single scan were retrospectively evaluated on the complementary scan. The association of cortical lesions with clinical disability was assessed. Mixed models were used to determine the effect of correction on lesion detection as well as on the relationship between disability and lesion count. RESULTS: A total of 22 T2*w scans were performed on 11 adults with MS (mean [SD] age, 49 [11] years; 8 women). Quality improved for 20 of 22 scans (91%) after correction. A total of 69 cortical lesions were identified on uncorrected images (median per scan, 2; range, 0-11) versus 148 on corrected images (median per scan, 4.5; range, 0-25; rate ratio [RR], 2.1; P < 0.0001). For low-quality uncorrected scans with moderate to severe motion artifact (18/22, 82%), there was an improvement in cortical lesion detection with correction (RR, 2.5; P < 0.0001), whereas there was no significant change in cortical lesion detection for high-quality scans (RR, 1.3; P = 0.43). CONCLUSIONS: Navigator-guided motion and B0 correction substantially improves the overall image quality of T2*w magnetic resonance imaging at 7 T and increases its sensitivity for cortical lesions.

Increased Expression of Ephrins on Immune Cells of Patients with Relapsing Remitting Multiple Sclerosis Affects Oligodendrocyte Differentiation.

The effect of the inflammatory response on regenerative processes in the brain is complex. This complexity is even greater when the cause of the tissue damage is an autoimmune response. Multiple sclerosis (MS) is an immune-mediated disease in which demyelination foci are formed in the central nervous system. The degree of repair through oligodendrocyte regeneration and remyelination is insufficient. Ephrins are membrane-bound ligands activating tyrosine kinase signaling proteins that are known to have an inhibitory effect on oligodendrocyte regeneration. In this study, we examined the expression of ephrins on immune cells of 43 patients with relapsing-remitting (RR) MS compared to 27 matched healthy controls (HC). We found an increased expression of ephrin-A2, -A3 and -B3, especially on T cell subpopulations. We also showed overexpression of ephrins on immune cells of patients with RR-MS that increases the forward signaling pathway and that expression of ephrins on immune cells has an inhibitory effect on the differentiation of oligodendrocyte precursor cells (OPCs) in vitro. Our study findings support the concept that the immune activity of T cells in patients with RR-MS has an inhibitory effect on the differentiation capacity of OPCs through the expression and forward signaling of ephrins.

Ultrahigh-resolution MRI Reveals Extensive Cortical Demyelination in a Nonhuman Primate Model of Multiple Sclerosis.

Cortical lesions are a primary driver of disability in multiple sclerosis (MS). However, noninvasive detection of cortical lesions with in vivo magnetic resonance imaging (MRI) remains challenging. Experimental autoimmune encephalomyelitis (EAE) in the common marmoset is a relevant animal model of MS for investigating the pathophysiological mechanisms leading to brain damage. This study aimed to characterize cortical lesions in marmosets with EAE using ultrahigh-field (7 T) MRI and histological analysis. Tissue preparation was optimized to enable the acquisition of high-spatial resolution (50-µm isotropic) T2*-weighted images. A total of 14 animals were scanned in this study, and 70% of the diseased animals presented at least one cortical lesion on postmortem imaging. Cortical lesions identified on MRI were verified with myelin proteolipid protein immunostaining. An optimized T2*-weighted sequence was developed for in vivo imaging and shown to capture 65% of cortical lesions detected postmortem. Immunostaining confirmed extensive demyelination with preserved neuronal somata in several cortical areas of EAE animals. Overall, this study demonstrates the relevance and feasibility of the marmoset EAE model to study cortical lesions, among the most important yet least understood features of MS.

The Role of Molecular Imaging as a Marker of Remyelination and Repair in Multiple Sclerosis.

The appearance of new disease-modifying therapies in multiple sclerosis (MS) has revolutionized our ability to fight inflammatory relapses and has immensely improved patients' quality of life. Although remarkable, this achievement has not carried over into reducing long-term disability. In MS, clinical disability progression can continue relentlessly irrespective of acute inflammation. This "silent" disease progression is the main contributor to long-term clinical disability in MS and results from chronic inflammation, neurodegeneration, and repair failure. Investigating silent disease progression and its underlying mechanisms is a challenge. Standard MRI excels in depicting acute inflammation but lacks the pathophysiological lens required for a more targeted exploration of molecular-based processes. Novel modalities that utilize nuclear magnetic resonance's ability to display in vivo information on imaging look to bridge this gap. Displaying the CNS through a molecular prism is becoming an undeniable reality. This review will focus on "molecular imaging biomarkers" of disease progression, modalities that can harmoniously depict anatomy and pathophysiology, making them attractive candidates to become the first valid biomarkers of neuroprotection and remyelination.

Fingolimod Increases Brain-Derived Neurotrophic Factor Level Secretion from Circulating T Cells of Patients with Multiple Sclerosis.

BACKGROUND: The pathophysiology of multiple sclerosis involves an autoimmune and a neurodegenerative mechanism. Central nervous system-infiltrating immune cells in multiple sclerosis also possess a neuroprotective activity through secretion of neurotrophins, such as brain-derived neurotrophic factor. Fingolimod was shown to slow the progression of disability and loss of brain volume. OBJECTIVE: The objective of this study was to explore whether fingolimod induces secretion of neurotrophins by immune cells. METHODS: Blood was drawn from 21 patients before the initiation of treatment with fingolimod and at 6 and 12 months of follow-up. The levels of the neurotrophic factors brain-derived neurotrophic factor, glial cell-derived neurotrophic factor, ß-nerve growth factor, neurotrophin-3, neurotrophin-4, basic fibroblast growth factor, epidermal growth factor, and vascular endothelial growth factor were screened in the supernatants of separated T cells and monocyte cultures using a customized, multiplex enzyme-linked immunosorbent assay. Brain-derived neurotrophic factor levels were further validated by a specific enzyme-linked immunosorbent assay. RESULTS: Treatment with fingolimod significantly increased brain-derived neurotrophic factor secretion from T cells. A specific enzyme-linked immunosorbent assay confirmed these results in the supernatant of T cells after 6 and 12 months of therapy. CONCLUSIONS: T cells that reach the bloodstream of fingolimod-treated patients with multiple sclerosis may contribute to the neuroprotective effect of this therapy by increased secretion of brain-derived neurotrophic factor. This mechanism of action of fingolimod in patients with multiple sclerosis has not been previously reported.

Association of Chronic Active Multiple Sclerosis Lesions With Disability In Vivo.

Importance: In multiple sclerosis (MS), chronic active lesions, which previously could only be detected at autopsy, can now be identified on susceptibility-based magnetic resonance imaging (MRI) in vivo as non-gadolinium-enhancing lesions with paramagnetic rims. Pathologically, they feature smoldering inflammatory demyelination at the edge, remyelination failure, and axonal degeneration. To our knowledge, the prospect of long-term in vivo monitoring makes it possible for the first time to determine their contribution to disability and value as a treatment target. Objective: To assess whether rim lesions are associated with patient disability and long-term lesion outcomes. Design, Setting, Participants: We performed 3 studies at the National Institutes of Health Clinical Center: (1) a prospective clinical/radiological cohort of 209 patients with MS (diagnosis according to the 2010 McDonald revised MS criteria, age ≥18 years, with 7-T or 3-T susceptibility-based brain MRI results) who were enrolled from January 2012 to March 2018 (of 209, 17 patients [8%] were excluded because of uninterpretable MRI scans); (2) a radiological/pathological analysis of expanding lesions featuring rims; and (3) a retrospective longitudinal radiological study assessing long-term lesion evolution in 23 patients with MS with yearly MRI scans for 10 years or more (earliest scan, 1992). Main Outcomes and Measures: (1) Identification of chronic rim lesions on 7-T or 3-T susceptibility-based brain MRI in 192 patients with MS and the association of rim counts with clinical disability (primary analysis) and brain volume changes (exploratory analysis). (2) Pathological characterization of 10 expanding lesions from an adult with progressive MS who came to autopsy after 7 years of receiving serial in vivo MRI scans. (3) Evaluation of annual lesion volume change (primary analysis) and T1 times (exploratory analysis) in 27 rim lesions vs 27 rimless lesions. Results: Of 209 participants, 104 (50%) were women and 32 (15%) were African American. One hundred seventeen patients (56%) had at least 1 rim lesion regardless of prior or ongoing treatment. Further, 84 patients (40%) had no rims (mean [SD] age, 47 [14] years), 66 (32%) had 1 to 3 rims (mean [SD] age, 47 [11] years), and 42 (20%) had 4 rims or more (mean [SD] age, 44 [11] years). Individuals with 4 rim lesions or more reached motor and cognitive disability at an earlier age. Normalized volumes of brain, white matter, and basal ganglia were lower in those with rim lesions. Whereas rimless lesions shrank over time (-3.6%/year), rim lesions were stable in size or expanded (2.2%/year; P < .001). Rim lesions had longer T1 times, suggesting more tissue destruction, than rimless lesions. On histopathological analysis, all 10 rim lesions that expanded in vivo had chronic active inflammation. Conclusions and Relevance: Chronic active lesions are common, are associated with more aggressive disease, exert ongoing tissue damage, and occur even in individuals treated with effective disease-modifying therapies. These results prompt the planning of MRI-based clinical trials aimed at treating perilesional chronic inflammation in MS.

A tri-modal distribution of age-of-onset in female patients with myasthenia gravis is associated with the gender-related clinical differences.

BACKGROUND: A tri-modal distribution of age-at-onset emerged among females patients with myasthenia gravis (MG) in our database. This finding may be indicative of different gender-based disease mechanisms. METHODS: We retrospectively reviewed the files of 127 MG patients for the clinical, serology and thymus pathology according to their age at disease onset: ≤40 years (early-onset, EOMG), 40-70 years (intermediate-onset, IOMG) and >70 years (late-onset, LOMG). RESULTS: EOMG was more common among females, and IOMG was more common among males. Ocular MG was more common among the male MG patients with an IOMG. Patients with EOMG had lower rates of positive anti-acetylcholine receptor (anti-AChR). IOMG females, but not IOMG males, had lower rates of positive anti-AChR. IOMG and EOMG females had high rates of thymic hyperplasia, while EOMG males had high rates of thymoma. Comorbidity with autoimmune diseases was common among females with IOMG and LOMG. CONCLUSIONS: The prevalence of IOMG was the reason for the trend reversal of MG prevalence between genders. The clinical features of patients with IOMG differed between genders in the rates of positive anti-AChR, follicular hyperplasia of the thymus and comorbidity with autoimmune diseases. This may suggest a different gender-based mechanism of immune intolerance towards AChR and other antigens.

Effect of ethnic origin and gender on the clinical manifestations of myasthenia gravis among the Jewish population in Israel.

Reports on patients with myasthenia gravis (MG) of different ethnic origins demonstrated differences in weakness distribution and serological results. We studied MG characteristics in a cohort of Ashkenazi (ASH) and non-Ashkenazi (NASH) Jewish origin according to their ethnic origins and gender. The frequency of age of MG onset was distributed in a bi-modal fashion in the female patients and increased gradually over time, with a peak around 70years of age in the male patients. Ocular MG was more frequent in males and ASH patients. Unlike previous reports, our male patients had a higher proportion of positive serum anti-acetyl choline receptor (AChR) than female patients, with no ethnic-based differences in the rates of anti-AChR or anti-muscle specific kinase. Comorbidity with another autoimmune disease was more frequent among female patients with late-onset MG and NASH patients (mainly Israel-born). Male MG patients tended to have more malignant comorbidities than female MG patients. These results demonstrate the effect of ethnicity on clinical aspects of MG within the Jewish population in Israel, and reveal novel effects of gender-associated comorbidities in patients with MG.

Thymus involvement in myasthenia gravis: Epidemiological and clinical impacts of different self-tolerance breakdown mechanisms.

The reasons for the abrogation of self-immunological tolerance in patients with myasthenia gravis (MG) may be different between those with concomitant thymic hyperplasia or thymoma, and those with no evidence of thymic involvement. We conducted a retrospective observational case series study to investigate the epidemiology as well as the clinical, serologic, and electromyographic (EMG) characteristics of individuals diagnosed as having MG. We found that the average age at MG onset of patients with either thymic hyperplasia or thymoma was much younger (by ~20years) than that of MG patients without thymic involvement. Thymic hyperplasia was more common in females than males. There were no differences in the rates of ocular MG vs. generalized MG among those three study groups. There were also no group differences in the rates of neuromuscular junction disfunction, as observed on EMG or by the results of serology tests for acetyl choline receptor antibody. Interestingly, only patients without thymic involvement had other autoimmune diseases, and most of them were females. The patients with other coexisting autoimmune disease had a similar age at MG onset as the other patients with no thymic involvement. These results shed light on the impact of epidemiological and clinical factors that result from different mechanisms of self-immunological tolerance breakdown that occurs in MG.

Differential screening-selected gene aberrative in neuroblastoma (DAN) is increased in the CSF of patients with MS and may be induced by therapy with interferon-ß.

Bone morphogenic proteins (BMPs) signaling blockade induce neurogenesis and oligodendrogenesis. Differential screening-selected gene aberrative in neuroblastoma (DAN) is a glycoprotein that antagonizes BMPs. We found that DAN levels were higher in CSF compared to serum in all participants. CSF-DAN levels were elevated in RR-and progresssive MS patients compared to controls. Moreover, serum-DAN levels were reduced in those patients, but elevated in IFN-ß1a treated patients. The main source of DAN is apparently CNS- resident cells. The enhanced levels of CSF-DAN in MS patients suggest a tendency to induce neurogenesis/oligodendrogenesis in the patients CNS. Our results suggest an unreported mode of action of IFN-ß1a.

Characterization of patients with ocular myasthenia gravis - A case series.

Ocular myasthenia gravis (OMG) is sometimes difficult to diagnose and is probably both under-diagnosed and misdiagnosed. We studied the epidemiological parameters, relevant serology, electromyographic (EMG) findings, and the relationship between OMG and thymoma, thymus hyperplasia and other autoimmune disorders compared to generalized MG (GMG) in a case control study of 133 patients with MG (32 patients with OMG and 101 patients with GMG). The proportion of OMG among all MG patients was relatively high (24.1%). It affected more males than females and its onset was at an older age. Although anti-AChR Ab was detected in fewer OMG patients compared to GMG patients, the rate of positive serology in OMG patients was higher than previously reported. Male OMG patients had a higher positive serology rate than female OMG patients. OMG patients tended to have less supportive EMG evidence of neuromuscular disorder. Female OMG patients had higher rates of thymus hyperplasia and higher rates of other autoimmune disorders than males. Diagnosing MG in patients with solitary ocular manifestation may be difficult due to lower rates of paraclinic supportive tests. Awareness of the characteristics of OMG is important in order to avoid delayed or misdiagnosis of MG and to prevent avoidable iatrogenic complications.