COLQ-Congenital myasthenic syndrome in an Iranian cohort: the clinical and genetics spectrum.

BACKGROUND: Congenital myasthenic syndrome (CMS) is a group of neuromuscular disorders caused by abnormal signal transmission at the motor endplate. Mutations in the collagen-like tail subunit gene (COLQ) of acetylcholinesterase are responsible for recessive forms of synaptic congenital myasthenic syndromes with end plate acetylcholinesterase deficiency. Clinical presentation includes ptosis, ophthalmoparesis, and progressive weakness with onset at birth or early infancy. METHODS: We followed 26 patients with COLQ-CMS over a mean period of 9 years (ranging from 3 to 213 months) and reported their clinical features, electrophysiologic findings, genetic characteristics, and therapeutic management. RESULTS: In our population, the onset of symptoms ranged from birth to 15 years. Delayed developmental motor milestones were detected in 13 patients (∼ 52%), and the most common presenting signs were ptosis, ophthalmoparesis, and limb weakness. Sluggish pupils were seen in 8 (∼ 30%) patients. All patients who underwent electrophysiologic study showed a significant decremental response (> 10%) following low-frequency repetitive nerve stimulation. Moreover, double compound muscle action potential was evident in 18 patients (∼ 75%). We detected 14 variants (eight novel variants), including six missense, three frameshift, three nonsense, one synonymous and one copy number variation (CNV), in the COLQ gene. There was no benefit from esterase inhibitor treatment, while treatment with ephedrine and salbutamol was objectively efficient in all cases. CONCLUSION: Despite the rarity of the disease, our findings provide valuable information for understanding the clinical and electrophysiological features as well as the genetic characterization and response to the treatment of COLQ-CMS.

Neutral lipid storage disease with myopathy: clinicopathological and genetic features of nine Iranian patients.

The rare disorder known as Neutral Lipid Storage Disease with Myopathy presents with a variety of clinical manifestations, including myopathy, cardiac dysfunction, and other organ complications. Early diagnosis is crucial due to the increased risk of cardiomyopathy. We describe the clinical, histopathological, muscle imaging, and genetic findings of nine neutral lipid storage myopathy patients. Proximal weakness and asymmetric involvement may suggest lipid storage myopathy. While skeletal muscle weakness was the main manifestation in our patients, one case presented only with hyperCKemia. Additionally, three patients had fertility issues, two suffered from diabetes mellitus, two had cardiomyopathy, and one had a history of hypothyroidism. Muscle histopathology revealed lipid depositions and rimmed vacuoles, prompting peripheral blood smears to detect Jordan Anomalies. All muscle biopsies and peripheral blood smear showed lipid droplets, rimmed vacuoles, and Jordan anomaly. Identifying PNPLA2 gene mutations is important for diagnosing neutral lipid storage myopathy; our cases showed some novel mutations. This study highlights the importance of early diagnosis and comprehensive evaluation in managing neutral lipid storage myopathy cases.

Iranian clinical practice guideline for amyotrophic lateral sclerosis.

Amyotrophic lateral sclerosis (ALS) is a rapidly progressive neurodegeneration involving motor neurons. The 3-5 years that patients have to live is marked by day-to-day loss of motor and sometimes cognitive abilities. Enormous amounts of healthcare services and resources are necessary to support patients and their caregivers during this relatively short but burdensome journey. Organization and management of these resources need to best meet patients' expectations and health system efficiency mandates. This can only occur in the setting of multidisciplinary ALS clinics which are known as the gold standard of ALS care worldwide. To introduce this standard to the care of Iranian ALS patients, which is an inevitable quality milestone, a national ALS clinical practice guideline is the necessary first step. The National ALS guideline will serve as the knowledge base for the development of local clinical pathways to guide patient journeys in multidisciplinary ALS clinics. To this end, we gathered a team of national neuromuscular experts as well as experts in related specialties necessary for delivering multidisciplinary care to ALS patients to develop the Iranian ALS clinical practice guideline. Clinical questions were prepared in the Patient, Intervention, Comparison, and Outcome (PICO) format to serve as a guide for the literature search. Considering the lack of adequate national/local studies at this time, a consensus-based approach was taken to evaluate the quality of the retrieved evidence and summarize recommendations.

Comparison of Clinical, Ultrasound, and Electrophysiologic Changes in Chronic Inflammatory Demyelinating Polyneuropathy: A Prospective Study.

PURPOSE: The follow-up and monitoring of response to immunomodulatory therapy in patients with chronic inflammatory demyelinating polyneuropathy are still challenging. Various outcome measures have been proposed in recent years, and some are now frequently used in daily clinical practice; however, reliable biomarkers for the disease activity and treatment response are lacking. METHODS: Cross-sectional nerve area of the bilateral vagus, fifth and the sixth cervical spinal, median, ulnar, tibial, peroneal, and sural nerves were measured at 2 time points with an interval of 6 months using nerve ultrasound. The results were used to calculate the ultrasound pattern sumscore (UPSS). The correlation between UPSS change (ΔUPSS) and changes in functional and nerve conduction studies measures over the study period were assessed. RESULTS: Sixteen patients completed this prospective, observational study. General linear model showed that ΔUPSS is significantly associated with ΔMedical Research Council sumscore (ß = -0.72, P = 0.003), Δhandgrip strength (ß = -0.57, P = 0.014), ΔRasch-built overall disability scale (ß = -0.57, P = 0.010), and Δoverall neuropathy limitations scale (ß = 0.75, P < 0.001), after adjustment of confounding variables. Nevertheless, ΔUPSS was not correlated with other clinical measures, including Δpinch power, Δ9-hole peg test, Δ10-m walking test, and Δnerve conduction study sumscore ( P values > 0.05). CONCLUSIONS: Nerve ultrasound might be an efficient method for monitoring the functional status of patients with chronic inflammatory demyelinating polyneuropathy over time because the alterations in its scores could significantly reflect clinical changes.

Investigating the Association Between Muscular Ultrasonographic Alterations and Clinical Symptoms in Patients With Inflammatory Myopathy.

Introduction: Muscle biopsy is commonly used to diagnose inflammatory myopathies. We evaluated the ability of muscle ultrasound, a non-invasive and simple tool, to distinguish between healthy subjects and patients with inflammatory myopathy. Methods: This study was conducted on 17 patients recently diagnosed with biopsy inflammatory myopathies (12 dermatomyositis, 5 polymyositis) compared with 17 age- and gender-matched healthy control adults. All patients underwent clinical assessments, including manual muscle testing, hand-held dynamometry, and muscle ultrasound evaluations, including thickness and echo intensity in predefined muscle groups. Results: The disease duration was seven months (interquartile range: 3 to 11 months). Except for the biceps and gastrocnemius, patients' muscles had significantly higher echo intensity and lower thickness than the control group. The echo intensity sum-score manifested the highest area under the curve compared to the sum-scores of other variables (echo intensity vs manual muscle testing: Area under curves-difference=0.18, P<0.01; echo intensity vs dynamometry: Area under curves-difference=0.14, P=0.02; echo intensity vs thickness: Area under curves-differences-difference=0.25, P<0.01). Conclusion: The echo intensity of muscles differed significantly between healthy individuals and patients with inflammatory myopathies and may serve as a useful diagnostic biomarker.

Cerebrotendinous xanthomatosis and infertility: A case report.

Cerebrotendinous xanthomatosis (CTX) is a lipid storage disorder that causes neurological, ophthalmic, vascular, and musculoskeletal disorders due to the deposition of cholesterol in the tissues. Hence, we report clinical and imaging of a 31-year-old mentally retarded man with cerebellar ataxia, bilateral swelling of the posterior aspect of Achill, and infertility.

Clinical features and outcomes of patients with myasthenia gravis affected by COVID-19: A single-center study.

INTRODUCTION: Myasthenia Gravis (MG) is an autoimmune disorder that can exacerbate for various reasons including infections. In this study, we describe clinical symptoms, outcomes, and management of MG patients affected by COVID-19 infection. METHODS: This observational retrospective study was performed on patients previously diagnosed as MG, presenting with COVID-19 in the clinic or emergency department between April 2020 and August 2021. The clinical data, outcome, and therapeutic interventions were assessed in 83 patients with MG and COVID-19 infection. RESULTS: Seventy-seven patients performed PCR testing for COVID-19, of which 73 (94.8 %) were positive. Seven patients had the positive serologic test for COVID-19 (IgG and IgM). Fifty-seven (68.7 %) patients had lung involvement. Thirty-five (42.1 %) of patients were admitted to the hospital. Twelve (14.5 %) patients needed hospitalization in an intensive care unit (ICU), with a mean stay of 7.36 ± 5.6 days (rang: 2-20 days). Four (4.8 %) patients were intubated and required mechanical ventilation. Sixteen (19.3 %) patients experienced an exacerbation of myasthenia gravis and were treated with PLEX (n = 2), IVIG (n = 7), and intravenous (IV) methylprednisolone (n = 7). The outcome was favorable in 79 patients and fatal in four patients, three of whom had other comorbidities. One patient died due to severe COVID-19 involvement. CONCLUSION: The findings from our study demonstrated that patients with previous MG concurrence with COVID-19 have favorable clinical outcomes. Most patients did not need to be hospitalized and more than 80 % of patients did not display MG exacerbation.

Iranian Consensus Recommendations for Treatment of Myasthenia Gravis.

Myasthenia gravis (MG) is an immune-mediated potentially treatable disease in which rapid diagnosis and proper treatment can control symptoms. Treatment should be individualized in each patient according to distribution (ocular or generalized) and severity of the weakness, antibody status, thymus pathology, patient comorbidities, and preferences. A group of Iranian neuromuscular specialists have written these recommendations to treat MG based on national conditions. Four of the authors performed an extensive literature review, including PubMed, EMBASE, and Google Scholar, from 1932 to 2020 before the central meeting to define headings and subheadings. The experts held a 2-day session where the primary drafts were discussed point by point. Primary algorithms for the management of MG patients were prepared in the panel discussion. After the panel, the discussions continued in virtual group discussions, and the prepared guideline was finalized after agreement and concordance between the panel members. Finally, a total of 71 expert recommendations were included. We attempted to develop a guideline based on Iran's local requirements. We hope that these guidelines help healthcare professionals in proper treatment and follow-up of patients with MG.

The value of MUNIX as an objective electrophysiological biomarker of disease progression in chronic inflammatory demyelinating polyneuropathy.

INTRODUCTION/AIMS: Objective outcome measures to monitor treatment response and guide treatment are lacking in chronic inflammatory demyelinating polyneuropathy (CIDP). In this study we aimed to evaluate the motor unit number index (MUNIX) as an outcome measurement in patients with CIDP and determine the correlation of MUNIX with functional and standard electrodiagnostic tests in a single follow-up study. METHODS: We evaluated MUNIX of the abductor pollicis brevis, abductor digiti minimi, and tibialis anterior (TA) muscles bilaterally. Muscle force was assessed by Medical Research Council Sum Score (MRCSS). Functional measures used were the Overall Neuropathy Limitation Score (ONLS) and the Rasch-built Overall Disability Scale (R-ODS) score at baseline and after 6 months of treatment. Standard electrophysiology was evaluated by the Nerve Conduction Study Score (NCSS). RESULTS: Twenty patients were included at baseline, and 16 completed the follow-up study. Significant correlations were found between the MUNIX sum score and both MRCSS and NCSS at baseline, between both the pinch strength and grip and upper limb MUNIX at baseline and follow-up, and between MUNIX of TA and both lower limb MRCSSs with lower limb ONLS at baseline and follow-up. Significant correlations also were found between MUNIX sum score change and MRCSS change, R-ODS change, and ONLS change. DISCUSSION: MUNIX changes correlated with strength and electrophysiological improvements in CIDP patients. This suggests that MUNIX may represent a useful objective biomarker for patient follow-up.

A retrospective study of the safety and efficacy of rituximab in Iranian patients with myasthenia gravis: A single-center experience.

Background: This retrospective cohort study was conducted to evaluate the efficacy and tolerance of rituximab (RTX) for the management of myasthenia gravis (MG). Methods: This retrospective cross-sectional study was conducted on 61 patients with refractory and non-refractory MG who received RTX. The Myasthenia Gravis Activities of Daily Living (MG-ADL) profile was used to assess MG symptoms and their effects on daily activities at the start of RTX and in the last follow-up. The Myasthenia Gravis Foundation of America Post-Intervention Status (MGFA-PIS) scale has been used as an outcome measure after treatment with RTX in the 12th month and the last follow-up. Results: The mean age of the patients was 40.31 ± 13.53 years (range: 15-78 years). Of 61 patients, eight (13.1%) were double seronegative, 29 (47.5%) had anti-acetylcholine receptor (AChR+) antibody, and 24 (39.3%) had anti-muscle-specific tyrosine kinase antibody (MuSK+). According to the mean rank table, the results of this study showed that the drug was more effective in improving the symptoms of MuSK+ patients compared to the other two groups (P = 0.006). The mean MG-ADL was 4.86 ± 1.83 before treatment and 1.51 ± 2.02 in the last follow-up visit. Paired t-test showed a significant association between MG-ADL before and after treatment in the last visit [t(55): 11.30, 95% confidence interval (CI): 2.79-3.99, P = 0.001)]. Conclusion: This retrospective study showed a considerable effect of RTX as induction therapy in patients with MG, especially those with MuSk+ MG.

Retrospective analysis of response to rituximab in chronic inflammatory demyelinating polyneuropathy refractory to first-line therapy.

Few case reports/series describe the efficacy of rituximab in refractory chronic inflammatory demyelinating polyradiculoneuropathy (CIDP), which is preferred in the presence of anti-nodal/paranodal antibodies. We aimed at evaluating the clinical response to rituximab in a subset of patients with refractory CIDP for whom the anti-nodal/paranodal antibodies status was unknown, as not available in Iran. We retrospectively analyzed the response to rituximab in 14 Iranian patients with refractory CIDP (3 children, 11 adults), in whom the anti-nodal/paranodal antibodies status was unknown. The subjects were evaluated with the Medical Research Council (MRC) sum score (MRCSS), Inflammatory Neuropathy Cause and Treatment (INCAT) disability scores, and electrophysiology, before and after treatment. Mean age was 34.4 ± 20.7 years, disease duration pre-rituximab treatment was 27.8 ± 18.8 (range: 6-60) months, and mean follow-up duration was 18.5 ± 11.0 (range: 4-36) months. Considering the INCAT sum score, one worsened during post-rituximab treatment, and three patients did not change. Considering MRCSS, notably, four patients achieved normalization of their MRCSS. Regarding the corticosteroid dose, two patients could discontinue prednisolone. As rated by a pre-defined scoring system, nerve conduction parameters improved significantly post-rituximab in the treated cohort (P = .006). All patients tolerated rituximab infusions without adverse effects. Rituximab may be effective in refractory CIDP, even though worsening may occur in some patients. Anti-nodal/paranodal antibodies assay, when available, and other criteria may help drive therapeutic decision-making on rituximab as second-line treatment.

Zytux in Refractory Myasthenia Gravis: A Multicenter, Open-Labeled, Clinical Trial Study of Effectiveness and Safety of a Rituximab Biosimilar.

Objectives: Myasthenia gravis (MG) is an immune-mediated neuromuscular disorder responsive to immunomodulatory treatments. 10-20% of MGs are not responsive to conventional first-line therapies. Here, we sought to investigate the efficacy and safety of rituximab therapy in the treatment of patients with refractory MG. Methods: In a 48-week, multicenter, open-labeled, prospective cohort setting, 34 participants with refractory MG were assigned to receive infusions of Zytux, which is a rituximab biosimilar, according to a validated protocol. Clinical, functional, and quality of life (QoL) measurements were recorded at baseline, and seven further visits using the Myasthenia Gravis Foundation of America (MGFA), Myasthenia Gravis Composite (MGC), Myasthenia Gravis Activities of Daily Living profile (MG-ADL), and Myasthenia Gravis Quality of Life (MGQoL-15) scales. Besides, the post-infusion side effects were systematically assessed throughout the study. Results: The correlation analysis performed by generalized estimating equations analysis represented a significant reduction of MGC, MG-ADL, and MGQoL-15 scores across the trial period. The subgroup analysis based on the patients' clinical status indicated a significant effect for the interaction between time and MGFA subtypes on MG-ADL score, MGC score, and pyridostigmine prednisolone dose, reflecting that the worse clinical condition was associated with a better response to rituximab. Finally, no serious adverse event was documented. Conclusions: Rituximab therapy could improve clinical, functional, and QoL in patients with refractory MG in a safe setting. Further investigations with larger sample size and a more extended follow-up period are warranted to confirm this finding. Clinical Trial Registration: The study was registered by the Iranian Registry of Clinical Trials (IRCT) (Code No: IRCT20150303021315N18).

Thigh and Leg Muscle MRI Findings in GNE Myopathy.

BACKGROUND: Muscle MRI protocols have been developed to assess muscle involvement in a wide variety of muscular dystrophies. Different muscular dystrophies can involve muscle groups in characteristic patterns. These patterns can be identified in muscle MRI in the form of fatty infiltration. OBJECTIVE: This study was conducted to add the existing knowledge of muscle MRI in GNE myopathy and evaluate the correlation of muscular involvement with different gene mutations. METHODS: The MRI scans of the 18 GNE patients were analyzed retrospectively. Cluster analysis was done for grouping the muscles and patients. RESULTS: The four muscles with the highest fat infiltration were adductor magnus, tibialis anterior, semitendinosus, and semimembranosus. Furthermore, three clusters of muscle involvement were found, including cluster 1, typical muscle involvement indicating muscles with the highest infiltration: extensor digitorum longus, gracilis, biceps femoris, soleus, gastrocnemius medial, adductor longus, tibialis anterior, adductor magnus, semimembranosus, semitendinosus; cluster 2, less typical muscle involvement indicating muscles with intermediate fat infiltration, peroneus longus, gastrocnemius lateral, and minimal fat infiltration in most of the patients, i.e., tibialis posterior; and cluster 3, atypical muscle involvement with low-fat infiltration: rectus femoris, sartorius, vastus intermedius, vastus medialis, and vastus lateralis. CONCLUSIONS: This study found three clusters of muscle involvement and three groups of patients among GNE patients. Hamstring muscles and the anterior compartment of the lower leg were the muscles with the highest fat infiltration. Moreover, a weak genotype-muscle MRI association was found in which tibialis posterior was more involved in patients with the most frequent mutation, i.e., C.2228T > C (p.M743T) mutation; however, this finding may be related to longer disease duration.

Myasthenia gravis associated with novel coronavirus 2019 infection: A report of three cases.

Several neurological presentations have been reported following coronavirus 2019 (COVID-19) infection. This case report describes three myasthenia gravis (MG) patients presented following COVID-19 infection. We report three adult patients with myasthenic Gravis and COVID-19 infection. The patients are between 38 and 61 years old. Case 1 is a 61-year-old woman with progressive dysphagia, nasal speech, ocular ptosis, diplopia, and proximal muscle weakness for 10 days. She had a COVID-19 infection 6 weeks ago. Case 2 is a 57-year-old man with clinical symptoms of muscular fatigability, diplopia, ptosis, and dysphagia for a week and a positive COVID-19 infection 10 days ago. Case 3 is a 38-year-old woman with fatigability, ptosis, dysphagia, and a diagnosis of COVID-19 infection 4 weeks ago. All patients had a positive RT-PCR for COVID-19 infection by nasopharyngeal swab test and a high-level acetylcholine receptor antibody in the serum. All patients were treated with pyridostigmine and prednisolone with a favorable outcome. MG may appear following COVID-19 infection, and the role of molecular mimicry and latent MG activation should be considered the cause of the disease onset.

Application of CMAP scan for the evaluation of patients with chronic inflammatory demyelinating polyneuropathy: a prospective study.

AIMS: We aimed to assess the compound muscle action potential (CMAP) scan in the follow-up of chronic inflammatory demyelinating polyneuropathy (CIDP) patients and investigate the correlation of CMAP scan parameters with functional and standard electrodiagnostic tests. METHODS: We evaluated four parameters of abductor pollicis brevis (APB) CMAP scan (i.e., step numbers, step percentage, S10, S90), functional measures (e.g., Medical Research Council Sum Scores), and electrodiagnostic tests, including nerve conduction study (NCS) and motor NCS of the median nerve in the baseline and after six months of treatment. RESULTS: Twenty patients completed baseline clinical and electrodiagnostic studies. However, sixteen patients completed the follow-up study. The median of step numbers at baseline was 3.5 (2-4.2), which decreased to 2.5 (0-3) (p = 0.005). After the treatment, step percentage reduced from 28.6 (23.9-38.7) to 13.4 (0-23.6) (p = 0.001). The scores obtained from the clinical scales showed significant recovery of most of the functions, while the alterations of NCSS and NCS of the median nerve were not significant. CONCLUSIONS: We found a significant reduction in step number and step percentage after follow-up. This alteration was not reflected in standard electrodiagnostic values. The improvement of functional scales alongside the CMAP scan parameters suggests that the CMAP scan could be considered an appropriate outcome measurement in research and clinical fields.

BVVL/ FL: features caused by SLC52A3 mutations; WDFY4 and TNFSF13B may be novel causative genes.

Brown-Vialetto-Van Laere (BVVL) and Fazio-Londe are disorders with amyotrophic lateral sclerosis-like features, usually with recessive inheritance. We aimed to identify causative mutations in 10 probands. Neurological examinations, genetic analysis, audiometry, magnetic resonance imaging, biochemical and immunological testings, and/or muscle histopathology were performed. Mutations in known causative gene SLC52A3 were found in 7 probands. More importantly, only 1 mutated allele was observed in several patients, and variable expressivity and incomplete penetrance were clearly noted. Environmental insults may contribute to variable presentations. Putative causative mutations in other genes were identified in 3 probands. Two of the genes, WDFY4 and TNFSF13B, have immune-related functions. Inflammatory responses were implicated in the patient with the WDFY4 mutation. Malfunction of the immune system and mitochondrial anomalies were shown in the patient with the TNFSF13B mutation. Prevalence of heterozygous SLC52A3 BVVL causative mutations and notable variability in expressivity of homozygous and heterozygous genotypes are being reported for the first time. Identification of WDFY4 and TNFSF13B as candidate causative genes supports conjectures on involvement of the immune system in BVVL and amyotrophic lateral sclerosis.

Sporadic late-onset nemaline myopathy with monoclonal gammopathy of undetermined significance: Report of four patients.

Sporadic late-onset nemaline myopathy (SLONM) is a rare, acquired muscle disease presenting with subacute progression in adulthood. It can be accompanied by a monoclonal gammopathy of undetermined significance (MGUS). We describe clinical and histopathological findings of four SLONM patients with MGUS. In all patients, nemaline rod, inter-myofibrillary network disruption, atrophic changes, peripheral basophilic discoloration, vacuole without rim, and cytoplasmic body without inflammation were seen. Three out of four patients were treated with prednisolone in combination with IVIG monthly and had an appropriate response to the treatment. The optimal first-line treatment remains unclear in SLONM-MGUS, although corticosteroids plus IVIg is associated with favorable clinical response. These treatment modalities might be used as an optional treatment before autologous stem cell transplantation; however, further studies with a higher number of patients are required.

Associations between adherence to dietary approaches to stop hypertension (DASH) diet and migraine headache severity and duration among women.

Purpose/introduction: Migraine is a common disorder, with attacks causing neurological dysfunction and pain. Many foods are involved in reducing the severity of migraine attacks. This study aimed to assess the effects that adhering to the Dietary approaches to stop hypertension (DASH) diet had on headache severity and duration among women suffering from migraine.Methods and materials: Two hundred and sixty-six women (18-45 years) were enrolled after being referred to a headache clinic for the first time. Dietary intake was assessed daily using a Food Frequency Questionnaire. Anthropometric measurements were assessed for all cases, as well as headache duration of each attack; Visual Analog Scale and Migraine Disability Assessment questionnaires were evaluated by a neurologist.Results: The mean age, weight, and height of the study participants were 34.32 (SD 7.86) years, 69.41 (13.02) kg, and 161 (0.05) cm, respectively. The results of analysis in the crude model showed that individuals with the greatest adherence to the DASH diet displayed a 30% lower prevalence in severe headaches, compared to those with the lowest adherence (OR=0.70, 95%CI=0.49-0.99, P<0.05). Also, after controlling for potential confounders, subjects in the highest quartile of DASH diet adherence were 46% less likely to have severe headaches, and also saw a 36% lower occurrence of moderate headaches, compared to those in the bottom quartile (OR=0.54, 95%CI=0.35-0.83, P<0.005 and OR=0.64, 95%CI=0.44-0.95, P<0.005, respectively). These results showed a significant positive correlation between adherence to DASH diets and lower rates of mean headache duration for each attack in the last month (ß=-1.49, CI=0.21-2.7, P=0.02).Conclusion: This study showed that the DASH diet is associated with lower headache severity and duration in migraine patients.