Utility of the ALSFRS-R for predicting ALS and comorbid disease neuropathology: The Veterans Affairs Biorepository Brain Bank.

INTRODUCTION/AIMS: The amyotrophic lateral sclerosis (ALS) functional rating scale-revised (ALSFRS-R) is commonly used to track ALS disease progression; however, there are gaps in the literature regarding the extent to which the ALSFRS-R relates to underlying central nervous system (CNS) pathology. The current study explored the association between ALSFRS-R (total and subdomain) scores and postmortem neuropathology (both ALS-specific and comorbid disease). METHODS: Within our sample of 93 military veterans with autopsy-confirmed ALS, we utilized hierarchical cluster analysis (HCA) to identify discrete profiles of motor dysfunction based on ALSFRS-R subdomain scores. We examined whether emergent clusters were associated with neuropathology. Separate analyses of variance and covariance with post-hoc comparisons were performed to examine relevant cluster differences. RESULTS: Analyses revealed significant correlations between ALSFRS-R total and subdomain scores with some, but not all, neuropathological variables. The HCA illustrated three groups: Cluster 1-predominantly diffuse functional impairment; Cluster 2-spared respiratory/bulbar and impaired motor function; and Cluster 3-spared bulbar and impaired respiratory, and fine and gross motor function. Individuals in Cluster 1 (and to a lesser degree, Cluster 3) exhibited greater accumulation of ALS-specific neuropathology and less comorbid neuropathology than those in Cluster 2. DISCUSSION: These results suggest that discrete patterns of motor dysfunction based on ALSFRS-R subdomain scores are related to postmortem neuropathology. Findings support use of ALSFRS-R subdomain scores to capture the heterogeneity of clinical presentation and disease progression in ALS, and may assist researchers in identifying endophenotypes for separate assessment in clinical trials.

Epidemiological Study of Various HPV Strains in Cervical Fluid Samples in South-Eastern Iran, 2018-2020.

BACKGROUND: Uterine cervical malignancy is one of the commonly detected malignancies related to the human papillomavirus (HPV) and is increasing incidentally in developing countries. Therefore, the use of an efficient diagnostic method is required as an effectual step for cervical cancer prevention and treatment. The purpose of the study was to diagnose various types of HPV in the cervical cytology specimens in the South-East of Iran. METHODS: This cross-sectional study was performed on 1079 cervical fluid cytology specimens referred for two years, between 2018-2020. Polymerase chain reaction (PCR) and hybridization (INNO-LiPA HPV Genotyping EXTRA II assay) were used to determine HPV DNA and their genotypes, respectively. RESULTS: HPV was positive in 37.7% (407 of 1079) patients with a mean age of 34.62 ± 8.82. Among positive cases, 252 (62%) had only one HPV genotype and 155 (38.05%) had multiplex HPV genotypes, which included 94 (60.7%), 38 (24.6%), 18 (11.6%) and 5 (3.2%) cases with two, three, four and five or more genotypes, respectively. The samples with multiple strains revealed 31 HPV genotypes with the four most prevalent being HPV6 (14.7%), HPV16 (10.9%), HPV53 (9.6%) and HPV51 (5.9%). CONCLUSION: HPV infection is the main health challenge for women that requires improved health service programs and appropriate epidemic vaccination.

Median Nerve Ultrasonography Measurements Correlate With Electrodiagnostic Carpal Tunnel Syndrome Severity.

INTRODUCTION: The purpose of this study was to assess whether median nerve ultrasonography (US) measurements correlate with the severity scale of electrodiagnostic studies (EDS) of carpal tunnel syndrome (CTS). METHODS: A retrospective review was conducted of patients aged ≥18 years who underwent both median nerve US and EDS. US measurements of the median nerve cross-sectional area at the distal wrist crease and forearm were used to calculate the median nerve wrist-to-forearm ratio. EDS severity was classified according to guidelines from the American Association of Electrodiagnostic Medicine. RESULTS: A total of 112 wrists (n = 112) in 78 consecutive patients with a mean age of 59 (range, 26 to 88) years were included. Increased cross-sectional area at the distal wrist crease and wrist-to-forearm ratio were significantly correlated with increased EDS severity (P < 0.0001). DISCUSSION: Median nerve US measurements not only distinguished between normal and abnormal EDS but also correlated with the category of EDS severity. LEVEL OF EVIDENCE: Diagnostic III.

Motor Neuron Disease: Pathophysiology, Diagnosis, and Management.

Patients with motor neuron diseases may present to primary care clinic or may be initially encountered in the inpatient setting. Timely diagnosis of these conditions is a key factor in early intervention and therapy, and accuracy of diagnosis is of extreme importance, in particular for amyotrophic lateral sclerosis with its poor prognosis. The aim of this review article is to provide a clinical and diagnostic framework for the diagnosis and evaluation of motor neuron disease for primary care physicians.

An Approach to Myopathy for the Primary Care Clinician.

Patients with muscle weakness are frequently encountered in the primary care clinic; however, the identification of an underlying disorder of muscle can pose a significant challenge. The aim of this review article is to provide a clinical and diagnostic framework to aid the primary care clinician in the detection and evaluation of suspected myopathies.

Myotonic disorders: A review article.

The myotonic disorders are a heterogeneous group of genetically determined diseases that are unified by the presence of myotonia, which is defined as failure of muscle relaxation after activation. The presentation of these disorders can range from asymptomatic electrical myotonia, as seen in some forms of myotonia congenita (MC), to severe disability with muscle weakness, cardiac conduction defects, and other systemic features as in myotonic dystrophy type I (DM1). In this review, we describe the clinical features and pathophysiology of the different myotonic disorders, their laboratory and electrophysiologic findings and briefly review the currently available treatments.

Myotonic Disorders and Channelopathies.

Myotonic dystrophies and channelopathies are rare but important causes of muscle diseases which may present with myotonia, episodic attacks of weakness, fixed muscle weakness, and atrophy or their combination. Here, the authors provide an overview of these disorders and describe their clinical and pathophysiological features, diagnostic methods, and management.

Postpartum spinal cord, root, plexus and peripheral nerve injuries involving the lower extremities: a practical approach.

Neurological complications after labor and delivery are most often caused by compressive trauma related to childbirth and rarely related to neuraxial anesthesia/analgesia. However, it is important for anesthesiologists to be able to recognize the common manifestations of these neuropathies in order to distinguish them from more ominous causes of neurologic disease. In this article, we review the anatomy and etiology of postpartum thoracolumbar spinal cord, lumbar nerve roots, plexus, and lower extremity peripheral nerve injuries. We will focus on a practical approach to their diagnosis, management, and treatment. Cases will be used to illustrate diagnosis and management.

Treatment of sporadic inclusion body myositis with bimagrumab.

OBJECTIVE: To study activin signaling and its blockade in sporadic inclusion body myositis (sIBM) through translational studies and a randomized controlled trial. METHODS: We measured transforming growth factor ß signaling by SMAD2/3 phosphorylation in muscle biopsies of 50 patients with neuromuscular disease (17 with sIBM). We tested inhibition of activin receptors IIA and IIB (ActRII) in 14 patients with sIBM using one dose of bimagrumab (n = 11) or placebo (n = 3). The primary outcome was the change in right thigh muscle volume by MRI at 8 weeks. Lean body mass, strength, and function were secondary outcomes. Twelve of the patients (10 bimagrumab, 2 placebo) participated in a subsequent 16-week observation phase. RESULTS: Muscle SMAD2/3 phosphorylation was higher in sIBM than in other muscle diseases studied (p = 0.003). Eight weeks after dosing, the bimagrumab-treated patients increased thigh muscle volume (right leg +6.5% compared with placebo, p = 0.024; left leg +7.6%, p = 0.009) and lean body mass (+5.7% compared with placebo, p = 0.014). Subsequently, bimagrumab-treated patients had improved 6-minute walking distance, which peaked at 16 weeks (+14.6%, p = 0.008) compared with placebo. There were no serious adverse events; the main adverse events with bimagrumab were mild acne and transient involuntary muscle contractions. CONCLUSIONS: Transforming growth factor ß superfamily signaling, at least through ActRII, is implicated in the pathophysiology of sIBM. Inhibition of ActRII increased muscle mass and function in this pilot trial, offering a potential novel treatment of sIBM. CLASSIFICATION OF EVIDENCE: This study provides Class I evidence that for patients with inclusion body myositis, bimagrumab increases thigh muscle volume at 8 weeks.

Type 1 interferons inhibit myotube formation independently of upregulation of interferon-stimulated gene 15.

INTRODUCTION: Type 1 interferon (IFN)-inducible genes and their inducible products are upregulated in dermatomyositis muscle. Of these, IFN-stimulated gene 15 (ISG15) is one of the most upregulated, suggesting its possible involvement in the pathogenesis of this disease. To test this postulate, we developed a model of type 1 IFN mediated myotube toxicity and assessed whether or not downregulation of ISG15 expression prevents this toxicity. METHODS: Mouse myoblasts (C2C12 cell line) were cultured in the presence of type 1 or type 2 IFNs and ISG15 expression assessed by microarray analysis. The morphology of newly formed myotubes was assessed by measuring their length, diameter, and area on micrographs using imaging software. ISG15 expression was silenced through transfection with small interference RNA. RESULTS: Type 1 IFNs, especially IFN-beta, increased ISG15 expression in C2C12 cells and impaired myotube formation. Silencing of ISG15 resulted in knockdown of ISG15 protein, but without phenotypic rescue of myotube formation. DISCUSSION: IFN-beta affects myoblast differentiation ability and myotube morphology in vitro.These studies provide evidence that ISG15, which is highly upregulated in dermatomyositis muscle, does not appear to play a key role in IFN-beta-mediated C2C12 myoblast cell fusion.

Non-dystrophic myotonia: prospective study of objective and patient reported outcomes.

Non-dystrophic myotonias are rare diseases caused by mutations in skeletal muscle chloride and sodium ion channels with considerable phenotypic overlap between diseases. Few prospective studies have evaluated the sensitivity of symptoms and signs of myotonia in a large cohort of patients. We performed a prospective observational study of 95 participants with definite or clinically suspected non-dystrophic myotonia recruited from six sites in the USA, UK and Canada between March 2006 and March 2009. We used the common infrastructure and data elements provided by the NIH-funded Rare Disease Clinical Research Network. Outcomes included a standardized symptom interview and physical exam; the Short Form-36 and the Individualized Neuromuscular Quality of Life instruments; electrophysiological short and prolonged exercise tests; manual muscle testing; and a modified get-up-and-go test. Thirty-two participants had chloride channel mutations, 34 had sodium channel mutations, nine had myotonic dystrophy type 2, one had myotonic dystrophy type 1, and 17 had no identified mutation. Phenotype comparisons were restricted to those with sodium channel mutations, chloride channel mutations, and myotonic dystrophy type 2. Muscle stiffness was the most prominent symptom overall, seen in 66.7% to 100% of participants. In comparison with chloride channel mutations, participants with sodium mutations had an earlier age of onset of stiffness (5 years versus 10 years), frequent eye closure myotonia (73.5% versus 25%), more impairment on the Individualized Neuromuscular Quality of Life summary score (20.0 versus 9.44), and paradoxical eye closure myotonia (50% versus 0%). Handgrip myotonia was seen in three-quarters of participants, with warm up of myotonia in 75% chloride channel mutations, but also 35.3% of sodium channel mutations. The short exercise test showed ≥10% decrement in the compound muscle action potential amplitude in 59.3% of chloride channel participants compared with 27.6% of sodium channel participants, which increased post-cooling to 57.6% in sodium channel mutations. In evaluation of patients with clinical and electrical myotonia, despite considerable phenotypic overlap, the presence of eye closure myotonia, paradoxical myotonia, and an increase in short exercise test sensitivity post-cooling suggest sodium channel mutations. Outcomes designed to measure stiffness or the electrophysiological correlates of stiffness may prove useful for future clinical trials, regardless of underlying mutation, and include patient-reported stiffness, bedside manoeuvres to evaluate myotonia, muscle specific quality of life instruments and short exercise testing.

Cytosolic 5'-nucleotidase 1A autoimmunity in sporadic inclusion body myositis.

OBJECTIVE: We previously identified a circulating autoantibody against a 43 kDa muscle autoantigen in sporadic inclusion body myositis (IBM) and demonstrated the feasibility of an IBM diagnostic blood test. Here, we sought to identify the molecular target of this IBM autoantibody, understand the relationship between IBM autoimmunity and muscle degeneration, and develop an IBM blood test with high diagnostic accuracy. METHODS: IBM blood samples were screened using mass spectrometry and a synthetic human peptidome. Plasma and serum samples (N=200 patients) underwent immunoblotting assays, and results were correlated to clinical features. Muscle biopsy samples (n=30) were examined by immunohistochemistry and immunoblotting. Exome or whole genome sequencing was performed on DNA from 19 patients. RESULTS: Both mass spectrometry and screening of a 413,611 human peptide library spanning the entire human proteome identified cytosolic 5'-nucleotidase 1A (cN1A; NT5C1A) as the likely 43 kDa IBM autoantigen, which was then confirmed in dot blot and Western blot assays using recombinant cN1A protein. Moderate reactivity of anti-cN1A autoantibodies was 70% sensitive and 92% specific, and high reactivity was 34% sensitive and 98% specific for the diagnosis of IBM. One to 3 major cN1A immunodominant epitopes were identified. cN1A reactivity by immunohistochemistry accumulated in perinuclear regions and rimmed vacuoles in IBM muscle, localizing to areas of myonuclear degeneration. INTERPRETATION: Autoantibodies against cN1A are common in and highly specific to IBM among muscle diseases, and may provide a link between IBM's dual processes of autoimmunity and myodegeneration. Blood diagnostic testing is feasible and should improve early and reliable diagnosis of IBM.

Mexiletine for symptoms and signs of myotonia in nondystrophic myotonia: a randomized controlled trial.

CONTEXT: Nondystrophic myotonias (NDMs) are rare diseases caused by mutations in skeletal muscle ion channels. Patients experience delayed muscle relaxation causing functionally limiting stiffness and pain. Mexiletine-induced sodium channel blockade reduced myotonia in small studies; however, as is common in rare diseases, larger studies of safety and efficacy have not previously been considered feasible. OBJECTIVE: To determine the effects of mexiletine for symptoms and signs of myotonia in patients with NDMs. DESIGN, SETTING, AND PARTICIPANTS: A randomized, double-blind, placebo-controlled 2-period crossover study at 7 neuromuscular referral centers in 4 countries of 59 patients with NDMs conducted between December 23, 2008, and March 30, 2011, as part of the National Institutes of Health-funded Rare Disease Clinical Research Network. INTERVENTION: Oral 200-mg mexiletine or placebo capsules 3 times daily for 4 weeks, followed by the opposite intervention for 4 weeks, with 1-week washout in between. MAIN OUTCOME MEASURES: Patient-reported severity score of stiffness recorded on an interactive voice response (IVR) diary (scale of 1 = minimal to 9 = worst ever experienced). Secondary end points included IVR-reported changes in pain, weakness, and tiredness; clinical myotonia assessment; quantitative measure of handgrip myotonia; and Individualized Neuromuscular Quality of Life summary quality of life score (INQOL-QOL, percentage of maximal detrimental impact). RESULTS: Mexiletine significantly improved patient-reported severity score stiffness on the IVR diary. Because of a statistically significant interaction between treatment and period for this outcome, primary end point is presented by period (period 1 means were 2.53 for mexiletine and 4.21 for placebo; difference, -1.68; 95% CI, -2.66 to -0.706; P < .001; period 2 means were 1.60 for mexiletine and 5.27 for placebo; difference, -3.68; 95% CI, -3.85 to -0.139; P = .04). Mexiletine improved the INQOL-QOL score (mexiletine, 14.0 vs placebo, 16.7; difference, -2.69; 95% CI, -4.07 to -1.30; P < .001) and decreased handgrip myotonia on clinical examination (mexiletine, 0.164 seconds vs placebo, 0.494 seconds; difference, -0.330; 95% CI, -0.633 to -0.142; P < .001). The most common adverse effect was gastrointestinal (9 mexiletine and 1 placebo). Two participants experienced transient cardiac effects that did not require stopping the study (1 in each group). One serious adverse event was determined to be not study related. CONCLUSION: In this preliminary study of patients with NDMs, the use of mexiletine compared with placebo resulted in improved patient-reported stiffness over 4 weeks of treatment, despite some concern about the maintenance of blinding. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00832000.

Etiology of limb girdle muscular dystrophy 1D/1E determined by laser capture microdissection proteomics.

Limb girdle muscular dystrophy 1D/1E (OMIM nomenclature LGMD1D, Human Gene Nomenclature Committee LGMD1E), a skeletal and cardiac myopathy, has previously been linked to chromosome 6q23. We used laser capture microdissection to isolate cytoplasmic inclusions from skeletal muscle from a patient with LGMD1D/1E, performed mass spectrometry-based proteomics on these minute inclusions, and identified through bioinformatics desmin as their major constituent. Sequencing in this patient and family members identified the genetic basis of the previously reported 6q23 linked LGMD1D/1E to be due to an intron splice donor site mutation (IVS3+3A>G) of the desmin gene located on chromosome 2q35.

Escherichia coli O157:H7/NM prevalence in raw beef, camel, sheep, goat, and water buffalo meat in Fars and Khuzestan provinces, Iran.

Enterohemorrhagic Escherichia coli (EHEC) of the O157:H7 serotype is a worldwide zoonotic pathogen responsible for the majority of severe cases of human EHEC disease. The aim of the present study was to investigate the prevalence of E. coli O157: H7/NM in raw meat samples from two provinces of Iran. During a period from March 2010 to March 2011. Two hundred and ninety five raw meat samples were collected from beef (n= 85), camel, (n= 50), sheep (n= 62), goat (n= 60), and water buffalo (n=38). Fourteen (4.7%) of the 295 samples were positive for E. coli O157. The highest prevalence of E. coli O157 was found in beef samples (8.2%), followed by water buffalo (5.3%), sheep (4.8%), camel (2.0%), and goat (1.7%). Of fourteen E. coli O157 isolates, only one was determined to be serotype O157: H7 while 13 were determined as serotype O157: NM. Of the 14 E. coli O157:H7/NM isolates, one, four, two, and one strains were positive for stx1, stx2, eaeA and ehlyA genes, respectively. The prevalence of this organism varied between seasons with the highest prevalence of E. coli O157 occurring in summer (9.3%). The results of this study showed that beef and water buffalo meat are a significant source for human EHEC E. coli O157:H7/NM infection in Iran. The data reported in this study provides some useful baseline in formation for future research such as molecular or epidemiologic works.

Autoantibodies against a 43 KDa muscle protein in inclusion body myositis.

BACKGROUND: Inclusion body myositis (IBM) is a poorly understood and refractory autoimmune muscle disease. Though widely believed to have no significant humoral autoimmunity, we sought to identify novel autoantibodies with high specificity for this disease. METHODOLOGY/PRINCIPAL FINDINGS: Plasma autoantibodies from 65 people, including 25 with IBM, were analyzed by immunoblots against normal human muscle. Thirteen of 25 (52%) IBM patient samples recognized an approximately 43 kDa muscle protein. No other disease (N = 25) or healthy volunteer (N = 15) samples recognized this protein. CONCLUSIONS: Circulating antibodies against a 43-kDa muscle autoantigen may lead to the discovery of a novel biomarker for IBM. Its high specificity for IBM among patients with autoimmune myopathies furthermore suggests a relationship to disease pathogenesis.