Compound Muscle Action Potential and Myosin-Loss Pathology in Patients With Critical Illness Myopathy: Correlation and Prognostication.

BACKGROUND AND OBJECTIVES: Prolonged compound muscle action potential (CMAP) duration and preferential loss of myosin are considered the diagnostic hallmarks of critical illness myopathy (CIM); however, their correlation and prognostic values have not been studied. We aimed to investigate the correlation between CMAP duration and myosin loss and their effect on mortality by comparing between patients with CIM with and without myosin loss. METHODS: We searched the Mayo Clinic Electromyography Laboratory databases (1986-2021) for patients diagnosed with CIM on the basis of prolonged distal CMAP durations (>15 msec in fibular motor nerve studies recording over the tibialis anterior or >8 msec in other motor nerves) and needle EMG findings compatible with myopathy. Electrodiagnostic studies were generally performed within 24 hours after weakness became noticeable. We included only patients who underwent muscle biopsy. Clinical, electrophysiologic, and myopathologic data were reviewed. We conducted myosin/actin ratio analysis when muscle tissue was available. We used the Fisher exact test for categorical data comparisons and the Mann-Whitney 2-tailed test for continuous data. We applied the Kaplan-Meier technique to analyze survival rates. RESULTS: Twenty patients (13 female patients) were identified [median age at diagnosis of 62.5 years (range: 19-80 years)]. The median onset of weakness was 24 days (range: 1-128) from the first day of intensive care unit admission. Muscle biopsy showed myosin loss in 14 patients, 9 of whom had >50% of myofibers affected (high grade). Type 2 fiber atrophy was observed in 19 patients, 13 of whom also had myosin loss. Patients with myosin loss had higher frequency of steroid exposure (14 vs 3; p = 0.004); higher median number of necrotic fibers per low-power field (2.5 vs 1, p = 0.04); and longer median CMAP duration (msec) of fibular (13.4 vs 8.75, p = 0.02), tibial (10 vs 7.8, p = 0.01), and ulnar (11.1 vs 7.95, p = 0.002) nerves compared with those without. Only patients with high-grade myosin loss had reduced myosin/actin ratios (<1.7). Ten patients died during median follow-up of 3 months. The mortality rate was similar between patients with and without myosin loss. Patients with high-grade myosin loss had a lower overall survival rate than those with low-grade or no myosin loss, but this was not statistically significant (p = 0.05). DISCUSSION: Myosin loss occurred in 70% of the patients with CIM with prolonged CMAP duration. Longer CMAP duration predicts myosin-loss pathology. The extent of myosin loss marginally correlates with the mortality rate. Our findings highlight the potential prognostic values of CMAP duration and myosin loss severity in predicting disease outcome.

Disease spectrum of myopathies with elevated aldolase and normal creatine kinase.

BACKGROUND AND PURPOSE: Elevation of serum creatine kinase (CK) or hyperCKemia is considered a biological marker of myopathies. However, selective elevation of serum aldolase with normal CK has been reported in a few myopathies, including dermatomyositis, immune-mediated myopathy with perimysial pathology and fasciitis with associated myopathy. The aim was to investigate the disease spectrum of myopathies with isolated aldolase elevation. METHODS: Medical records were reviewed to identify patients >18 years old seen between December 1994 and June 2020 who had pathologically proven myopathies with elevated aldolase and normal CK level. Patients with alternative causes of aldolase elevation were excluded. RESULTS: Thirty-four patients with various types of myopathies were identified. Myopathies were treatable in 27 patients. The three most common etiologies were dermatomyositis (n = 8), overlap myositis (n = 4) and nonspecific myopathy (n = 4). Perimysial pathology comprising inflammation, fragmentation, vasculitis, calcified perimysial vessels or extracellular amyloid deposition was found in 17/34 patients (50%). Eight dermatomyositis patients with selective elevated aldolase were compared to 24 sex- and age-matched patients with dermatomyositis and hyperCKemia. Dermatomyositis patients with normal CK significantly (p < 0.05) had less frequent cutaneous involvement (50.0% vs. 100.0%) and fibrillation potentials (50.0% vs. 90.5%) but higher median erythrocyte sedimentation rate (33.5 vs. 13.5 mm/h) and more common perifascicular mitochondrial pathology (37.5% vs. 4.2%). CONCLUSION: Isolated aldolase elevation can be found in a greater variety of myopathies than initially thought and most were treatable. Dermatomyositis is the most common myopathy with selective elevation of aldolase in our cohort, which features some unique characteristics compared to dermatomyositis with hyperCKemia.

Adolescent-onset multisystem proteinopathy due to a novel VCP variant.

Valosin-containing protein (VCP) pathogenic variants are the most common cause of multisystem proteinopathy presenting with inclusion body myopathy, amyotrophic lateral sclerosis/frontotemporal dementia, and Paget disease of bone in isolation or in combination. We report a patient manifesting with adolescent-onset myopathy caused by a novel heterozygous VCP variant (c.467G > T, p.Gly156Val). The myopathy manifested asymmetrically in lower limbs and extended to proximal, axial, and upper limb muscles, with loss of ambulation at age 35. Creatine kinase value was normal. Alkaline phosphatase was elevated. Electromyography detected mixed low amplitude, short duration and high amplitude, long duration motor unit potentials. Muscle biopsy showed features of inclusion body myopathy, which in combination with newly diagnosed Paget disease of bone, supported the VCP variant pathogenicity. In conclusion, VCP-multisystem proteinopathy is not only a disease of adulthood but can have a pediatric onset and should be considered in differential diagnosis of neuromuscular weakness in the pediatric population.

Treatment-responsive glycogen storage myopathy in a patient with POEMS syndrome: A new monoclonal gammopathy-associated myopathy.

BACKGROUND: Myopathies associated with monoclonal gammopathy are relatively uncommon and underrecognized, treatable myopathies, and include sporadic late onset nemaline myopathy, light chain amyloid myopathy, and a recently described vacuolar myopathy with monoclonal gammopathy and stiffness (VAMGS). Herein, we report a new subtype of monoclonal gammopathy-associated myopathy (MGAM) in a polyneuropathy, organomegaly, endocrinopathy, M protein, and skin changes (POEMS) patient. METHOD: Case report. RESULTS: A 51-year-old woman presented with a 6-month history of progressive bilateral foot drop, lower limb edema, and a 15-lb weight loss. She denied muscle stiffness. Neurologic exam showed severe distal weakness, mild proximal weakness, and length-dependent sensory deficits. Laboratory studies revealed biclonal gammopathy (IgG kappa and IgA lambda), thrombocytosis, and elevated vascular endothelial growth factor. Creatine kinase was normal. Electrodiagnostic studies identified mixed demyelinating and axonal polyradiculoneuropathy and a superimposed proximal myopathy. Gluteus medius biopsy demonstrated scattered fibers with glycogen-filled vacuoles, similar to VAMGS, with additional rare myofibers containing polyglucosan bodies. She was diagnosed with POEMS syndrome and concomitant glycogen storage myopathy. Next-generation sequencing of glycogen storage and polyglucosan body myopathy-related genes was unrevealing. Proximal weakness resolved after autologous stem cell transplant. CONCLUSIONS: This patient expands a spectrum of MGAM. Recognition of this condition and other subtypes of MGAM is of utmost important because they are treatable.

Sural nerve biopsy utility by masked assessment of individual histologic preparations.

BACKGROUND AND AIMS: Comprehensive study of sural nerve biopsy utility based on individual histopathologic preparations is lacking. We aimed to quantify the value of different histologic preparations in diagnosis. METHODS: One hundred consecutive sural nerves were studied by standard histological preparations plus graded teased nerve fibers (GTNF), immunohistochemistry, and epoxy-semithin morphometry. Three examiners scored the individual preparations separately by a questionnaire of neuropathic and interstitial abnormalities, masked to the biopsy number, versus a gold-standard of all preparations. Multivariate modeling was utilized to determine best approach versus the gold-standard. RESULTS: Highest confidence (range 8-9 of 10) and inter-rater reliability (99%) for fiber abnormalities came from GTNF, and interstitial abnormalities from paraffin stains (range 7-8, 99%). Vasculitic neuropathy associated with GTNF axonal degeneration (moderate to severe 79%) with OR 3.8, 95% CI (1.001-14.7), p = .04, but not significantly with the other preparations. Clinicopathologic diagnoses associated with teased fiber abnormalities in chronic inflammatory demyelinating polyradiculoneuropathy, 80% (8/10); amyloidosis, 50% (1/2); adult-onset polyglucosan disease 100% (1/1). GTNF and paraffin stains significantly correlated with fiber density determined by morphometric analysis (GTNF: OR 9.9, p < .0001, paraffin: OR 3.8, p = .03). GTNF combined with paraffin sections had highest accuracy for clinicopathologic diagnoses and fiber density with 0.86 C-stat prediction versus morphometric analysis. Pathological results lead to initiation or changes of immunotherapy in 70% (35/50; initiation n = 22, reduction n = 9, escalation n = 4) with the remaining having alternative intervention or no change. INTERPRETATION: Nerve biopsy paraffin stains combined with GTNF have highest diagnostic utility, confidence, inter-rater reliability, improving accuracy for a pathologic diagnosis aiding treatment recommendations. Immunostains and epoxy preparations are also demonstrated useful supporting consensus guidelines. This study provides class II evidence for individual nerve preparation utility.

Amyloid-like IgM deposition neuropathy with multiple mononeuropathies and generalized neuropathy.

Amyloid-like IgM deposition neuropathy is a distinct entity in the setting of IgM monoclonal gammopathy in which endoneurial perivascular entire IgM-particle accumulation leads to a painful sensory followed by motor peripheral neuropathy. We report a 77-year-old man presenting with progressive multiple mononeuropathies starting with painless right foot drop. Electrodiagnostic studies showed severe axonal sensory-motor neuropathy superimposed by multiple mononeuropathies. Laboratory investigations were remarkable for biclonal gammopathy of IgM kappa, IgA lambda and severe sudomotor and mild cardiovagal autonomic dysfunction. A right sural nerve biopsy showed multifocal axonal neuropathy, prominent microvasculitis, and prominent large endoneurial deposits of Congo-red negative amorphous material. Laser dissected mass spectrometry-based proteomics identified IgM kappa deposit without serum amyloid-P protein. This case has several distinctive features, including motor preceding sensory involvement, prominent IgM-kappa proteinaceous deposits replacing most of the endoneurium, a prominent inflammatory component, and improvement of motor strength after immunotherapy.

Corrigendum: The first molecular genotyping of Naegleria fowleri causing primary amebic meningoencephalitis in Thailand with epidemiology and clinical case reviews.

[This corrects the article DOI: 10.3389/fcimb.2022.931546.].

Anoctamin 5 (ANO5) Muscle Disorders: A Narrative Review.

Anoctaminopathy-5 refers to a group of hereditary skeletal muscle or bone disorders due to mutations in the anoctamin 5 (ANO5)-encoding gene, ANO5. ANO5 is a 913-amino acid protein of the anoctamin family that functions predominantly in phospholipid scrambling and plays a key role in the sarcolemmal repairing process. Monoallelic mutations in ANO5 give rise to an autosomal dominant skeletal dysplastic syndrome (gnathodiaphyseal dysplasia or GDD), while its biallelic mutations underlie a continuum of four autosomal recessive muscle phenotypes: (1). limb-girdle muscular dystrophy type R12 (LGMDR12); (2). Miyoshi distal myopathy type 3 (MMD3); (3). metabolic myopathy-like (pseudometabolic) phenotype; (4). asymptomatic hyperCKemia. ANO5 muscle disorders are rare, but their prevalence is relatively high in northern European populations because of the founder mutation c.191dupA. Weakness is generally asymmetric and begins in proximal muscles in LGMDR12 and in distal muscles in MMD3. Patients with the pseudometabolic or asymptomatic hyperCKemia phenotype have no weakness, but conversion to the LGMDR12 or MMD3 phenotype may occur as the disease progresses. There is no clear genotype-phenotype correlation. Muscle biopsy displays a broad spectrum of pathology, ranging from normal to severe dystrophic changes. Intramuscular interstitial amyloid deposits are observed in approximately half of the patients. Symptomatic and supportive strategies remain the mainstay of treatment. The recent development of animal models of ANO5 muscle diseases could help achieve a better understanding of their underlying pathomechanisms and provide an invaluable resource for therapeutic discovery.

The First Molecular Genotyping of Naegleria fowleri Causing Primary Amebic Meningoencephalitis in Thailand With Epidemiology and Clinical Case Reviews.

Primary amebic meningoencephalitis (PAM) is a rare and fatal central nervous system infection caused by Naegleria fowleri, a free-living amoeba found in the environment. To date, eight pathogenic N. fowleri genotypes have been reported worldwide. We aimed to explore the genotypes of N. fowleri that cause primary amebic meningoencephalitis in Thailand. In 2021, the 17th PAM case was reported, and a retrospective literature search of PAM cases in Thailand from 1982 through April 2021 was performed. Phylogenetic and genotyping analyses of the two mitochondrial (12S rRNA and 16S rRNA) and nuclear (ITS1 and 5.8s rRNA) genes of N. fowleri were performed on four available clinical isolates. Based on the mitochondrial and nuclear genes, N. fowleri genotype T3 was found to cause PAM in three out of four cases. However, disagreement between the genotype based on the mitochondrial and nuclear genes was found in one of the PAM cases, in which the 12S rRNA locus suggested the causative genotype as T1, while the ITS1 implied genotype T4. The discrepancy between the mitochondrial and nuclear genome was previously observed, which suggests the possible horizontal gene transfer among N. fowleri species. Based on the ITS1 gene, two N. fowleri genotypes, T3 and T4, were found to be the genotypes causing PAM in this study. In addition, N. fowleri genotype T2 was previously reported in a traveler who was infected in Thailand. Thus, at least three genotypes (T2, T3, and T4) of N. fowleri are found to be associated with PAM in Thailand.

Characteristics and Outcomes of Patients with Invasive Pulmonary Aspergillosis and Respiratory Tract Aspergillus Colonization from a Tertiary University Hospital in Thailand.

Positive culture for Aspergillus spp. from respiratory specimens needs to be interpreted together with relevant clinical conditions/settings to differentiate invasive infection from colonization. In this study, we aimed to investigate the association between positive culture for Aspergillus spp. from respiratory specimens and the presence of invasive pulmonary aspergillosis. Hospitalized patients with positive culture for Aspergillus spp. from any respiratory sample were retrospectively recruited. Patients were classified into two groups: those with invasive pulmonary aspergillosis and those with non-invasive aspergillosis/colonization. Two hundred and forty-one patients (48.1% male; mean age: 59.8 ± 14.5 years) were included. The most common Aspergillus spp. was A. fumigatus (21.0%). The most common underlying condition was chronic lung disease (23.7%), followed by solid tumor (22.4%). Myeloproliferative disease (aOR: 69.2, 95% CI: 2.4-1991.9), neutropenia ≥ 10 days (aOR: 31.8; 95% CI: 1.10-920.53), and corticosteroid treatment (aOR: 42.8, 95% CI: 6.5-281.3) were independent predictors of the invasive form. Chronic lung disease was independently inversely related to invasive form (OR: 0.04; 95% CI: 0.003-0.49). Serum galactomannan was positive in 69.2% of patients with invasive aspergillosis (OR: 25.9, 95% CI: 5.2-127.8). All inappropriately treated patients with invasive form died. In conclusion, positive culture for Aspergillus spp. from respiratory specimens with coexisting myeloproliferative disease, neutropenia ≥ 10 days, corticosteroid treatment, or positive serum galactomannan is highly suggestive of invasive pulmonary aspergillosis.

Eosinophilic appendicitis caused by Schistosoma japonicum: a case report and review of the literature.

Parasitic appendicitis is uncommon. The authors reviewed the pathology of 4,130 appendices resected over the past 10 years (2000 to 2009). Only one case of eosinophilic appendicitis caused by Schistosoma japonicum was identified. The overall prevalence of schistosomal appendicitis was 0.024%. The case was a 61-year-old woman who presented with right lower quadrant abdominal pain. She had been a farmer in Chumphon and Surat Thani Provinces, which are endemic for schistosomiasis in Thailand. Physical, laboratory and ultrasound examinations were suggestive of acute appendicitis. She underwent emergency appendectomy. Intraoperative findings revealed a ruptured appendix with a fecalith in the appendiceal lumen. The histopathologic diagnosis was suppurative eosinophilic appendicitis with schistosomal ova in the mucosa, submucosa, muscular layer and vascular lumens, identified as S. japonicum eggs. The patient was treated for the parasite with praziquantal. We briefly review the clinicopathologic features and pathogenesis of schistosomal appendicitis.

Fungal rhinosinusitis: a retrospective analysis of clinicopathologic features and treatment outcomes at Ramathibodi Hospital.

The objective of this study was to determine the clinicopathologic findings of invasive and non-invasive fungal rhinosinusitis and to compare the features of the two diseases. The medical records of patients with invasive and noninvasive fungal rhinosinusitis at Ramathibodi Hospital between July 1999 and June 2009 were analyzed. The criterion for the diagnosis of fungal rhinosinusitis was the evidence of fungal elements from histopathologic section on sinonasal specimens. The age, gender, clinical manifestations, duration of symptoms, associated diseases, laboratory data, results of mycotic culture and treatment outcomes were analyzed. The relationship between fungal rhinosinusitis and patient characteristics as well as clinical presentations were assessed. The fungus-attributable mortality rate was determined. The study included 43 cases of invasive fungal rhinosinusitis and 68 cases of non-invasive fungal rhinosinusitis. There were 44 male, and 67 female patients. The mean age at diagnosis was 54.6 years (range: 5 to 86 years). A total of 70 (63.1%) were attributed to aspergillosis, 8 (7.2%) to candidiasis, 6 (5.4%) to zygomycosis, 4 (3.6%) to phaeohyphomycosis, 1 (0.9%) to pseudallescheriasis, 1 (0.9%) to entomophthoromycosis and 21 (18.9%) to nonspecific fungi. Cultures from sinonasal tissues were positive for fungus in 37 of 87 cases (42.5%). The clinical presentations of fungal rhinosinusitis included nasal stuffiness (27.9%), nasal discharge (27.9%), facial pain (27.9%), fever (24.3%) and headache (19.8%). One-fifth of cases had an underlying hematologic malignancy. Invasive fungal rhinosinusitis was significantly associated with hematologic malignancy and neutropenia. Fungus-attributable mortality rate was 44.2% in invasive fungal rhinosinusitis. Early antifungal therapy and surgical drainage were associated with a survival advantage.