Office-based respiratory assessment in patients with generalized myasthenia gravis.

Patients with myasthenia gravis (MG) can present with respiratory dysfunction, ranging from exercise intolerance to overt respiratory failure, increased fatigue, or sleep-disordered breathing. To investigate the value of multiple respiratory tests in MG, we performed clinical and respiratory assessments in patients with mild to moderate generalized disease. One-hundred and thirty-six patients completed the myasthenia gravis quality-of-life score(MG-QOL-15), myasthenia gravis impairment index(MGII), Epworth sleepiness scale(ESS), University of California-San Diego Shortness of Breath Questionnaire(UCSD-SOB), Modified Medical Research Council Dyspnea Scales(MRC-DS), supine and upright forced vital capacity(FVC), maximal inspiratory pressures(MIPs) and sniff nasal inspiratory pressures(SNIP). Seventy-three (54 %) had respiratory and/or bulbar symptoms and 45 (33 %) had baseline abnormal FVC, with no significant postural changes (p = 0.89); 55 (40.4 %) had abnormal MIPs and 50 (37 %) had abnormal SNIPs. Overall, there were low scores on respiratory and disability scales. Females had increased odds of presenting with abnormal FVC (OR 2.89, p = 0.01) and MIPs (OR 2.48, p = 0.022). There were significant correlations between MIPs, FVC and SNIPs; between MGII/MG-QOL15 and UCSD-SOB/MRC-DS and between ESS and respiratory scales in the whole group. Our data suggests that office-based respiratory measurements are a useful screening method for stable MG patients, even when presenting with minimal respiratory symptoms and no significant disability.

Value of multi-modality small fiber assessments in a genotypically diverse cohort of transthyretin-related amyloidosis in the early stages of disease.

INTRODUCTION: Transthyretin-related amyloidosis (ATTRv) is a progressive multisystem disorder, predominantly involving the peripheral nerve system (PNS) and heart. Quantification of small fiber damage may help guide treatment decisions, as amyloid deposits frequently affect those fibers early in disease course. Corneal confocal microscopy (CCM) is a promising method to monitor patients with ATTRv, due to similarities between corneal nerves and PNS, as the cornea is innervated by Aδ and C fibers. METHODS: We compared CCM measures from ATTRv patients to a group of healthy individuals, matched by age and gender. We then investigated the correlations between small fiber tests (SFT): CCM, LDI-Flare and CDT, COMPASS-31 and disability scales (RODS and ONLS) in patients. RESULTS: Of 20 patients (6 with V30M), mean age 50.3±15.3Y, 7 female (35%), six (30%) had polyneuropathy and 10 (50%) carpal tunnel syndrome. CDT was abnormal in 9 and LDI-flare in 6 patients. CCM was abnormal in 19 tested patients and significantly reduced when compared to controls (CNFL: 6.31±0.31 vs. 15.21±1.02mm/mm2, p<0.001). Mean COMPASS-31-scores were 22.27±22.84; RODS and ONLS were 38.15±12.33 and 2.05±2.3, with no significant differences between sub-group scores. Disease duration was significantly correlated with ONLS (0.43, p=0.05) and RODS (0.46, p=0.03). There were no significant correlations between measures of disability and SFT. CONCLUSIONS: In a diverse cohort of ATTRv patients, CCM was the most frequent abnormal measurement. CCM can be a useful test to triage patients in the early disease stages and with few or equivocal symptoms.

Clinical characteristics and treatment outcomes in patients with double-seronegative myasthenia gravis.

BACKGROUND AND PURPOSE: Double-seronegative myasthenia gravis (dSNMG) is defined as myasthenia gravis (MG) without detectable or low affinity antibodies to acetylcholine receptor (AChR) and muscle-specific kinase (MuSK). There are limited data on detailed clinical features and outcomes after treatment in dSNMG patients. The aim was to describe the clinical characteristics and outcomes in dSNMG patients based on MG scales. METHODS: A retrospective study was performed of patients diagnosed with MG who had negative AChR or MuSK antibodies and they were compared with an AChR-positive MG cohort. Correlations were made with data from the first and last clinic visits, between demographics, clinical characteristics, treatment and disease severity, based on the Myasthenia Gravis Foundation of America category, Myasthenia Gravis Impairment Index (MGII), Patient Acceptable Symptom State and simple single question (SSQ). RESULTS: Eighty patients met the inclusion criteria for dSNMG. The baseline MGII and SSQ scores in the dSNMG cohort showed no significant differences from the AChR group (p = 0.94 and p = 0.46). The dSNMG cohort MGII and SSQ scores improved significantly at the last clinical evaluation (p = 0.001 and p = 0.047). The MGII improvement in the AChR cohort was significantly better (p = 0.003). CONCLUSIONS: The initial severity of dSNMG based on clinical scores is similar to antibody-positive MG patients. There is significant clinical improvement in dSNMG patients after therapy, measured in the last clinical evaluation. This supports an immune pathophysiology of many dSNMG patients.

Optimal cut-off value of the modified Toronto Clinical Neuropathy Score in the diagnosis of polyneuropathy.

BACKGROUND AND PURPOSE: The modified Toronto Clinical Neuropathy Score (mTCNS) is a valid and reliable scale for the diagnosis and staging of diabetic sensorimotor polyneuropathy (DSP). The aim of this study was to determine the optimal diagnostic cut-off value of the mTCNS in diverse polyneuropathies (PNPs). METHODS: Demographics and mTCNS values were retrospectively extracted from an electronic database of 190 patients with PNP and 20 normal controls. Sensitivity, specificity, and likelihood ratios and area under the receiver-operating characteristic (ROC) curve were determined for each diagnosis and different cut-off values of the mTCNS. Patients underwent clinical, electrophysiological and functional assessments of their PNP. RESULTS: Forty-three percent of PNP was related to diabetes or impaired glucose tolerance. mTCNS was significantly higher in patients with PNP than in those without (15.27 ± 8 vs. 0.79 ± 1.4; p = 0.001). The cut-off value for diagnosing PNP was ≥3 (sensitivity 98.4%, specificity 85.7%, positive likelihood ratio 6.88). The area under the ROC curve was 0.987. CONCLUSION: A value of 3 or more on the mTCNS is recommended for the diagnosis of PNP.

Outcomes of COVID-19 Infection and Vaccination Among Individuals With Myasthenia Gravis.

Importance: There are limited data regarding COVID-19 outcomes and vaccine uptake and safety among people with myasthenia gravis (MG). Objective: To investigate COVID-19-related outcomes and vaccine uptake among a population-based sample of adults with MG. Design, Setting, and Participants: This population-based, matched cohort study in Ontario, Canada, used administrative health data from January 15, 2020, and August 31, 2021. Adults with MG were identified using a validated algorithm. Each patient was matched by age, sex, and geographic area of residence to 5 controls from the general population and from a cohort of individuals with rheumatoid arthritis (RA). Exposure: Patients with MG and matched controls. Main Outcomes and Measures: Main outcomes were COVID-19 infection and related hospitalizations, intensive care unit admissions, and 30-day mortality among patients with MG vs controls. Secondary outcomes were uptake of COVID-19 vaccination among patients with MG vs controls. Results: Among 11 365 233 eligible Ontario residents, 4411 patients with MG (mean [SD] age, 67.7 [15.6] years; 2274 women [51.6%]) were matched to 22 055 general population controls (mean [SD] age, 67.7 [15.6] years; 11 370 women [51.6%]) and 22 055 controls with RA (mean [SD] age, 67.7 [15.6] years; 11 370 women [51.6%]). In the matched cohort, 38 861 of 44 110 individuals (88.1%) were urban residents; in the MG cohort, 3901 (88.4%) were urban residents. Between January 15, 2020, and May 17, 2021, 164 patients with MG (3.7%), 669 general population controls (3.0%), and 668 controls with RA (3.0%) contracted COVID-19. Compared with general population controls and controls with RA, patients with MG had higher rates of COVID-19-associated emergency department visits (36.6% [60 of 164] vs 24.4% [163 of 669] vs 29.9% [200 of 668]), hospital admissions (30.5% [50 of 164] vs 15.1% [101 of 669] vs 20.7% [138 of 668]), and 30-day mortality (14.6% [24 of 164] vs 8.5% [57 of 669] vs 9.9% [66 of 668]). By August 2021, 3540 patients with MG (80.3%) vs 17 913 general population controls (81.2%) had received 2 COVID-19 vaccine doses, and 137 (3.1%) vs 628 (2.8%), respectively had received 1 dose. Of 3461 first vaccine doses for patients with MG, fewer than 6 individuals were hospitalized for MG worsening within 30 days of vaccination. Vaccinated patients with MG had a lower risk than unvaccinated patients with MG of contracting COVID-19 (hazard ratio, 0.43; 95% CI, 0.30-0.60). Conclusions and Relevance: This study suggests that adults with MG who contracted COVID-19 had a higher risk of hospitalization and death compared with matched controls. Vaccine uptake was high, with negligible risk of severe MG exacerbations after vaccination, as well as evidence of effectiveness. The findings support public health policies prioritizing people with MG for vaccination and new COVID-19 therapeutics.

Alcohol and drug consumption in pregnant women admitted to a hospital in the city of Buenos Aires, Argentina. Initial Impact Assessment on the Newborn / Consumo de alcohol y drogas en embarazadas internadas en un hospital de la ciudad de Buenos Aires, Argentina. Evaluación del impacto inicial en el recién nacido.

Introduction: The objective of our study was to estimate the prevalence of prenatal exposure to drugs and the neonatal impact. Material and methods: Prospective, observational, cross-sectional and analytical study of pregnant women and newborns admitted between March and September 2021. To estimate the prevalence of consumption, the survey and detection of drugs in maternal urine were used as a detection method. Results: Alcohol consumption had a prevalence of 46.32%, followed by tobacco with 12.12%, marijuana with 5.62% and cocaine with 4.76%. The weight of newborns with mothers with urine positive for some substance was significantly lower than the weight of newborns with mothers with negative urine (mean ± SE of 2800±184gr vs 3332±41gr and median ± MAD of 2950±380gr vs 3385± 335g p 0.002). Gestational age was also significantly lower in neonates with mothers with positive urine (38.00 vs 39.00 p 0.002). Although the prevalence of intrauterine growth retardation (IUGR), malformations, and prematurity was higher in those cases with positive urine, the difference did not become statistically significant. Conclusions: The prevalence of substance and alcohol use during pregnancy was high with a statistically significant impact on exposed newborns for both weight and gestational age.

Introducción: El objetivo de nuestro estudio fue estimar la prevalencia de exposición prenatal a drogas y el impacto neonatal. Materiales y métodos: Estudio prospectivo, observacional, transversal y analítico de embarazadas y recién nacidos ingresados entre marzo y septiembre del 2021. Para estimar la prevalencia de consumo se utilizaron como métodos de detección la encuesta y la detección de drogas en orina materna. Resultados: El consumo de alcohol tuvo una prevalencia del 46.32%, seguido por el tabaco con el 12.12%, la marihuana con el 5.62% y la cocaína con el 4.76%. El peso de los neonatos con madres con orina positiva para alguna sustancia fue significativamente menor que el peso de los neonatos con madres con orina negativa (media ± ES de 2800±184gr vs 3332±41gr y mediana ± DAM de 2950±380gr vs 3385±335gr p 0.002). La edad gestacional también fue significativamente menor en neonatos con madres con orina positiva (38.00 vs 39.00 p 0.002). Si bien la prevalencia de retardo en el crecimiento intrauterino (RCIU), de malformaciones y de prematurez fue superior en aquellos casos con orinas positivas, la diferencia no llegó a ser estadísticamente significativa. Conclusiones: La prevalencia de consumo de sustancias y alcohol durante el embarazo fue elevada con una repercusión estadísticamente significativa en los recién nacidos expuestos tanto para el peso como para la edad gestacional.

Temporal Dispersion and Duration of the Distal Compound Muscle Action Potential Do Not Distinguish Diabetic Sensorimotor Polyneuropathy From Chronic Inflammatory Demyelinating Polyneuropathy.

Objective: To investigate the contribution of duration and temporal dispersion (TD) of the distal compound muscle action potential (CMAP) in discriminating chronic inflammatory demyelinating polyneuropathy (CIDP) from diabetic sensorimotor polyneuropathy (DSP) and from CIDP+DSP. Methods: We performed a retrospective review of patients diagnosed with CIDP, DSP and CIDP+DSP (responsive to immunotherapy) and examined differences in CMAP duration and TD at baseline. Results: We included 59 subjects: 17 CIDP, 21 DSP and 21 CIDP+DSP. Of these, 16 (94.1%) CIDP, 18 (85.7%) CIDP+DSP and 1 (4.7%) DSP fulfilled the 2010 EFNS/PNS criteria for definite CIDP. There was no difference in CMAP duration or TD in all nerves (compound outcome) or in individual motor nerves. Patients with CIDP/CIDP+DSP had more conduction blocks, slower conduction velocities and more prolonged F wave latencies than those with DSP. Conclusion: Measures of CMAP duration and TD were not helpful in distinguishing CIDP, DSP or CIDP+DSP patients; however, parameters such as F-wave latencies, conduction blocks or the number of demyelinating parameters were useful in this separation. Significance: There are no definite nerve conduction criteria to distinguish patients with CIDP+DSP from DSP alone. Further studies focusing on measures of demyelination may provide stronger evidence to guide treatment decisions in CIDP + DSP patients.

An update on the use of immunoglobulins as treatment for myasthenia gravis.

INTRODUCTION: Myasthenia gravis (MG) is an antibody mediated disease where pathogenic antibodies interact with the acetylcholine receptor or other proteins at the post-synaptic neuromuscular junction. There is growing evidence that immunoglobulin infusions are beneficial for clinical exacerbations and chronic refractory disease and may be an option for patients unresponsive to conventional immunosuppressive therapies. AREAS COVERED: We performed an extensive literature review, looking for evidence on the use of immunoglobulins for the treatment of MG, by conducting a search in MEDLINE (1946 to present), EMBASE (1947 to present) and Clinicaltrials.gov. We have included studies on the use of intravenous immunoglobulins (IVIG) and subcutaneous immunoglobulins (SCIG) for acute deterioration and chronic disease. EXPERT OPINION: The use of IVIG in MG provides an option for rapid improvement in critical deterioration, being preferred over more invasive and less available therapies such as plasmapheresis. For refractory MG, the addition of IVIG can improve a patient's status and reduce the dosage of immunosuppressive medications. The alternative of SCIG is also effective and has advantages of infusion time flexibility, fewer side-effects, and patient independence. The safety and efficacy of both interventions, patient preferences and quality of life may direct therapeutic choices in the future.

Canadian Guidelines for Hereditary Transthyretin Amyloidosis Polyneuropathy Management.

Hereditary transthyretin-mediated (hATTR) amyloidosis is a progressive disease caused by mutations in the TTR gene leading to multisystem organ dysfunction. Pathogenic TTR aggregation, misfolding, and fibrillization lead to deposition of amyloid in multiple body organs and frequently involve the peripheral nerve system and the heart. Common neurologic manifestations include: sensorimotor polyneuropathy (PN), autonomic neuropathy, small-fiber PN, and carpal tunnel syndrome. Many patients have significant progression due to diagnostic delays as hATTR PN is not considered within the differential diagnosis. Recently, two effective novel disease-modifying therapies, inotersen and patisiran, were approved by Health Canada for the treatment of hATTR PN. Early diagnosis is crucial for the timely introduction of these disease-modifying treatments that reduce impairments, improve quality of life, and extend survival. In this guideline, we aim to improve awareness and outcomes of hATTR PN by making recommendations directed to the diagnosis, monitoring, and treatment in Canada.

Lignes directrices sur la prise en charge de l'amylose héréditaire à transthyrétine, accompagnée de polyneuropathie, au Canada.L'amylose héréditaire à transthyrétine (ATTRh) est une maladie évolutive, causée par des mutations du gène de la transthyrétine (TTR), qui entraînent un dysfonctionnement plurisystémique. L'agrégation, le mauvais repliement et la fibrillisation pathogènes de la TTR aboutissent au dépôt de protéines amyloïdes dans plusieurs organes, et affectent souvent le système nerveux périphérique et le cœur. Les troubles neurologiques fréquents comprennent une polyneuropathie sensorimotrice (PN), une neuropathie autonome, une polyneuropathie des petites fibres et le syndrome du canal carpien. Chez bon nombre de patients, la maladie a connu une évolution importante en raison de la pose tardive du diagnostic, la PN-ATTRh ne faisant pas l'objet d'un diagnostic différentiel. Santé Canada a approuvé, depuis peu, deux nouveaux médicaments modificateurs de la PN-ATTRh et efficaces contre l'affection, soit l'inotersen et le patisiran. La pose précoce du diagnostic revêt une importance cruciale dans l'instauration, en temps opportun, de ces tout nouveaux traitements qui atténuent les troubles, améliorent la qualité de vie et prolongent la survie. Les auteurs, par l'élaboration de la nouvelle ligne directrice, espèrent sensibiliser la communauté médicale à la PN-ATTRh, et améliorer les résultats cliniques qui y sont associés, en formulant des recommandations sur le diagnostic et le traitement de la maladie au Canada ainsi que sur la surveillance de son évolution.

Metacyclogenesis defects and gene expression hallmarks of histone deacetylase 4-deficient Trypanosoma cruzi cells.

Trypanosoma cruzi-the causative agent of Chagas disease-like other kinetoplastids, relies mostly on post-transcriptional mechanisms for regulation of gene expression. However, trypanosomatids undergo drastic changes in nuclear architecture and chromatin structure along their complex life cycle which, combined with a remarkable set of reversible histone post-translational modifications, indicate that chromatin is also a target for control of gene expression and differentiation signals in these organisms. Chromatin-modifying enzymes have a direct impact on gene expression programs and DNA metabolism. In this work, we have investigated the function of T. cruzi histone deacetylase 4 (TcHDAC4). We show that, although TcHDAC4 is not essential for viability, metacyclic trypomastigote TcHDAC4 null mutants show a thin cell body and a round and less condensed nucleus located very close to the kinetoplast. Sixty-four acetylation sites were quantitatively evaluated, which revealed H2AT85ac, H4K10ac and H4K78ac as potential target sites of TcHDAC4. Gene expression analyses identified three chromosomes with overrepresented regions of differentially expressed genes in the TcHDAC4 knockout mutant compared with the wild type, showing clusters of either up or downregulated genes. The adjacent chromosomal location of some of these genes indicates that TcHDAC4 participates in gene expression regulation during T. cruzi differentiation.

Electrophysiological predictors of response to subcutaneous immunoglobulin therapy in chronic inflammatory demyelinating polyneuropathy.

OBJECTIVE: To assess axonal function prior to subcutaneous immunoglobulin (SCIG) therapy or placebo in relation to relapse in chronic inflammatory demyelinating polyneuropathy (CIDP) to determine whether axonal damage can predict therapy response. METHODS: Relapse rates in patients from the Polyneuropathy and Treatment with Hizentra (PATH) study, where patients were treated with placebo or SCIG (IgPro20), were analyzed by baseline (post-intravenous immunoglobulin stabilization) axonal damage (≤1 mV peroneal compound muscle action potential) status. RESULTS: In patients with non-axonal damage, relapses were significantly higher with placebo (73.0%) than IgPro20 (0.2 g/kg: 39.1%, 0.4 g/kg: 19.2%). In patients with axonal damage, IgPro20 had no effect on relapse (placebo: 25.0%, IgPro20: 0.2 g/kg: 30.0%, 0.4 g/kg: 19.4%). Patients with axonal damage relapsed significantly less on placebo versus non-axonal damage, but they also demonstrated higher baseline disability. CONCLUSION: Axonal damage may correspond to relapse upon treatment withdrawal; patients with axonal damage relapse less, possibly reflecting poor response to immunoglobulin therapy, while non-axonal damage patients may experience more relapse, perhaps indicating better treatment response. SIGNIFICANCE: In CIDP patients with axonal loss, immunoglobulin therapy may not be as effective. Assessing axonal damage could help guide therapy, with immunoglobulins ideally used before substantial axonal damage arises.