Metabolic shift underlies recovery in reversible infantile respiratory chain deficiency.

Reversible infantile respiratory chain deficiency (RIRCD) is a rare mitochondrial myopathy leading to severe metabolic disturbances in infants, which recover spontaneously after 6-months of age. RIRCD is associated with the homoplasmic m.14674T>C mitochondrial DNA mutation; however, only ~ 1/100 carriers develop the disease. We studied 27 affected and 15 unaffected individuals from 19 families and found additional heterozygous mutations in nuclear genes interacting with mt-tRNAGlu including EARS2 and TRMU in the majority of affected individuals, but not in healthy carriers of m.14674T>C, supporting a digenic inheritance. Our transcriptomic and proteomic analysis of patient muscle suggests a stepwise mechanism where first, the integrated stress response associated with increased FGF21 and GDF15 expression enhances the metabolism modulated by serine biosynthesis, one carbon metabolism, TCA lipid oxidation and amino acid availability, while in the second step mTOR activation leads to increased mitochondrial biogenesis. Our data suggest that the spontaneous recovery in infants with digenic mutations may be modulated by the above described changes. Similar mechanisms may explain the variable penetrance and tissue specificity of other mtDNA mutations and highlight the potential role of amino acids in improving mitochondrial disease.

Local corticosteroid injection versus placebo for carpal tunnel syndrome.

BACKGROUND: Carpal tunnel syndrome (CTS) is a very common clinical syndrome manifested by signs and symptoms of irritation of the median nerve at the carpal tunnel in the wrist. Direct and indirect costs of CTS are substantial, with estimated costs of two billion US dollars for CTS surgery in the USA in 1995 alone. Local corticosteroid injection has been used as a non-surgical treatment for CTS many years, but its effectiveness is still debated. OBJECTIVES: To evaluate the benefits and harms of corticosteroids injected in or around the carpal tunnel for the treatment of carpal tunnel syndrome compared to no treatment or a placebo injection. SEARCH METHODS: We used standard, extensive Cochrane search Methods. The searches were 7 June 2020 and 26 May 2022. SELECTION CRITERIA: We included randomised controlled trials (RCTs) or quasi-randomised trials of adults with CTS that included at least one comparison group of local injection of corticosteroid (LCI) into the wrist and one group that received a placebo or no treatment. DATA COLLECTION AND ANALYSIS: We used standard Cochrane methods. Our primary outcome was 1. improvement in symptoms at up to three months of follow-up. Our secondary outcomes were 2. functional improvement, 3. improvement in symptoms at greater than three months of follow-up, 4. improvement in neurophysiological parameters, 5. improvement in imaging parameters, 6. requirement for carpal tunnel surgery, 7. improvement in quality of life and 8. ADVERSE EVENTS: We used GRADE to assess the certainty of evidence for each outcome. MAIN RESULTS: We included 14 trials with 994 participants/hands with CTS. Only nine studies (639 participants/hands) had useable data quantitatively and in general, these studies were at low risk of bias except for one quite high-risk study. The trials were conducted in hospital-based clinics across North America, Europe, Asia and the Middle East. All trials used participant-reported outcome measures for symptoms, function and quality of life. There is probably an improvement in symptoms measured at up to three months of follow-up favouring LCI (standardised mean difference (SMD) -0.77, 95% confidence interval (CI) -0.94 to -0.59; 8 RCTs, 579 participants; moderate-certainty evidence). Up to six months this was still evident favouring LCI (SMD -0.58, 95% CI -0.89 to -0.28; 4 RCTs, 234 participants/hands; moderate-certainty evidence). There is probably an improvement in function measured at up to three months favouring LCI (SMD -0.62, 95% CI -0.87 to -0.38; 7 RCTs, 499 participants; moderate-certainty evidence). We are uncertain if there is a difference in median nerve DML at up to three months of follow-up (mean difference (MD) -0.37 ms, 95% CI -0.75 to 0.02; 6 RCTs, 359 participants/hands; very low-certainty evidence). The requirement for surgery probably reduces slightly in the LCI group at one year (risk ratio 0.84, 95% CI 0.72 to 0.98; 1 RCT, 111 participants, moderate-certainty evidence). Quality of life, measured at up to three months of follow-up using the Short-Form 6 Dimensions questionnaire (scale from 0.29 to 1.0; higher is better) probably improved slightly in the LCI group (MD 0.07, 95% CI 0.02 to 0.12; 1 RCT, 111 participants; moderate-certainty evidence). Adverse events were uncommon (low-certainty evidence). One study reported 2/364 injections resulted in severe pain which resolved over "several weeks" and 1/364 injections caused a "sympathetic reaction" with a cool, pale hand that completely resolved in 20 minutes. One study (111 participants) reported no serious adverse events, but 65% of LCI-injected and 16% of the placebo-injected participants experienced mild-to-moderate pain lasting less than two weeks. About 9% of participants experienced localised swelling lasting less than two weeks. Four studies (229 participants) reported that they experienced no adverse events in their studies. Three studies (220 participants) did not specifically report adverse events. AUTHORS' CONCLUSIONS: Local corticosteroid injection is effective for the treatment of mild and moderate CTS with benefits lasting up to six months and a reduced need for surgery up to 12 months. Where serious adverse events were reported, they were rare.

Practice Guidelines for Canadian Neurophysiology Laboratories During the COVID-19 Pandemic.

The COVID-19 pandemic has had a major impact on clinical practice. Safe standards of practice are essential to protect health care workers while still allowing them to provide good care. The Canadian Society of Clinical Neurophysiologists, the Canadian Association of Electroneurophysiology Technologists, the Association of Electromyography Technologists of Canada, the Board of Registration of Electromyography Technologists of Canada, and the Canadian Board of Registration of Electroencephalograph Technologists have combined to review current published literature about safe practices for neurophysiology laboratories. Herein, we present the results of our review and provide our expert opinion regarding the safe practice of neurophysiology during the COVID-19 pandemic in Canada.

Access to Allied Health Care Services in Canadian Interdisciplinary Complex Nerve Injury Programs.

Nerve transfer surgery for patients with nerve and spinal cord injuries can result in dramatic functional improvements. As a result, interdisciplinary complex nerve injury programs (CNIPs) have been established in many Canadian centers, providing electrodiagnostic and surgical consultations in a single encounter. We sought to determine which allied health care services are included in Canadian CNIPs, at the 3rd Annual Canadian Peripheral Nerve Symposium. Twenty CNIPs responded to a brief survey and reported access as follows: occupational therapy = 60%, physiotherapy = 40%, social work = 20%, and mental health = 10%. Access to allied health services is variable in CNIPs across Canada, possibly resulting in heterogeneity in patient care.

A National Spinal Muscular Atrophy Registry for Real-World Evidence.

BACKGROUND: Spinal muscular atrophy (SMA) is a devastating rare disease that affects individuals regardless of ethnicity, gender, and age. The first-approved disease-modifying therapy for SMA, nusinursen, was approved by Health Canada, as well as by American and European regulatory agencies following positive clinical trial outcomes. The trials were conducted in a narrow pediatric population defined by age, severity, and genotype. Broad approval of therapy necessitates close follow-up of potential rare adverse events and effectiveness in the larger real-world population. METHODS: The Canadian Neuromuscular Disease Registry (CNDR) undertook an iterative multi-stakeholder process to expand the existing SMA dataset to capture items relevant to patient outcomes in a post-marketing environment. The CNDR SMA expanded registry is a longitudinal, prospective, observational study of patients with SMA in Canada designed to evaluate the safety and effectiveness of novel therapies and provide practical information unattainable in trials. RESULTS: The consensus expanded dataset includes items that address therapy effectiveness and safety and is collected in a multicenter, prospective, observational study, including SMA patients regardless of therapeutic status. The expanded dataset is aligned with global datasets to facilitate collaboration. Additionally, consensus dataset development aimed to standardize appropriate outcome measures across the network and broader Canadian community. Prospective outcome studies, data use, and analyses are independent of the funding partner. CONCLUSION: Prospective outcome data collected will provide results on safety and effectiveness in a post-therapy approval era. These data are essential to inform improvements in care and access to therapy for all SMA patients.

Developing International Classification of Disease code definitions for the study of enteric infection sequelae in Canada.

Background: Enteric infections and their chronic sequelae are a major cause of disability and death. Despite the increasing use of administrative health data in measuring the burden of chronic diseases in the population, there is a lack of validated International Classification of Disease (ICD) code-based case definitions, particularly in the Canadian context. Our objective was to validate ICD code definitions for sequelae of enteric infections in Canada: acute kidney injury (AKI); hemolytic uremic syndrome (HUS); thrombotic thrombocytopenic purpura (TTP); Guillain-Barré syndrome/Miller-Fisher syndrome (GBS/MFS); chronic inflammatory demyelinating polyneuropathy (CIDP); ankylosing spondylitis (AS); reactive arthritis; anterior uveitis; Crohn's disease, ulcerative colitis, celiac disease, erythema nodosum (EN); neonatal listeriosis (NL); and Graves' disease (GD). Methods: We used a multi-step approach by conducting a literature review to identify existing validated definitions, a clinician assessment of the validated definitions, a chart review to verify proposed definitions and a final clinician review. We measured the sensitivity and positive predictive value (PPV) of proposed definitions. Results: Forty studies met inclusion criteria. We identified validated definitions for 12 sequelae; clinicians developed three (EN, NL, GD). We reviewed 181 charts for 6 sequelae (AKI, HUS, TTP, GBS/MFS, CIDP, AS). Sensitivity (42.8%-100%) and PPV (63.6%-100%) of ICD code definitions varied. Six definitions were modified by clinicians following the chart review (AKI, TTP, GBS/MFS, CIDP, AS, reactive arthritis) to reflect coding practices, increase specificity or sensitivity, and address logistical constraints. Conclusion: The multi-step design to derive ICD code definitions provided flexibility to identify existing definitions, to improve their sensitivity and PPV and adapt them to the Canadian context.

A Canadian Adult Spinal Muscular Atrophy Outcome Measures Toolkit: Results of a National Consensus using a Modified Delphi Method.

BACKGROUND: Spinal Muscular Atrophy (SMA) is a rare disease that affects 1 in 11 000 live births. Recent developments in SMA treatments have included new disease-modifying therapies that require high quality data to inform decisions around initiation and continuation of therapy. In Canada, there are no nationally agreed upon outcome measures (OM) used in adult SMA. Standardization of OM is essential to obtain high quality data that is comparable among neuromuscular clinics. OBJECTIVE: To develop a recommended toolkit and timing of OM for assessment of adults with SMA. METHODS: A modified delphi method consisting of 2 virtual voting rounds followed by a virtual conference was utilized with a panel of expert clinicians treating adult SMA across Canada. RESULTS: A consensus-derived toolkit of 8 OM was developed across three domains of function, with an additional 3 optional measures. Optimal assessment frequency is 12 months for most patients regardless of therapeutic access, while patients in their first year of receiving disease-modifying therapy should be assessed more frequently. CONCLUSIONS: The implementation of the consensus-derived OM toolkit will improve monitoring and assessment of adult SMA patients, and enrich the quality of real-world evidence. Regular updates to the toolkit must be considered as new evidence becomes available.

Dexamethasone in Cryptococcus gattii central nervous system infection.

Clinical outcomes were reviewed for 4 patients with Cryptococcus gattii central nervous system infection who received dexamethasone for the treatment of persisting mental status abnormalities and focal lesions on brain scan despite culture-negative cerebrospinal fluid and the management of intracranial pressure. Favorable clinical responses were observed in 3 patients. Although corticosteroids are not recommended for the treatment of cryptococcal meningitis, these observations suggest that dexamethasone should be further evaluated in this subset of patients.

A novel KCNA1 mutation associated with global delay and persistent cerebellar dysfunction.

Episodic Ataxia Type 1 is an autosomal dominant disorder characterized by episodes of ataxia and myokymia. It is associated with mutations in the KCNA1 voltage-gated potassium channel gene. In the present study, we describe a family with novel clinical features including persistent cerebellar dysfunction, cerebellar atrophy, and cognitive delay. All affected family members have myokymia and epilepsy, but only one individual has episodes of vertigo. Additional features include postural abnormalities, episodic stiffness and weakness. A novel KCNA1 mutation (c.1222G>T) which replaces a highly conserved valine with leucine at position 408 (p.Val408Leu) was identified in affected family members, and was found to augment the ability of the channel to inactivate. Together, our data suggests that KCNA1 mutations are associated with a broader clinical phenotype, which may include persistent cerebellar dysfunction and cognitive delay.

Concurrent inflammatory myopathy and myasthenia gravis with or without thymic pathology: A case series and literature review.

OBJECTIVES: The association of myasthenia gravis (MG) and inflammatory myositis (IM) is rare and typically only one of the diseases is present. The management of the 2 diseases differs, therefore it is important to recognize the concomitant presentation. Here, we report a case series of 7 patients with co-existing MG and IM with review of the literature. METHOD: We identified 7 patients with concurrent MG and IM who were followed at the Neuromuscular Disease Program at a tertiary referral center in Vancouver, British Columbia from 2004 to 2017. RESULT: All 7 patients had ocular or bulbar involvement as manifestation of MG. Three patients had simultaneous onset of MG and IM, 2 of whom presented with myasthenia crisis and fulminant myositis. In the other 4 patients, MG was the initial presentation and IM occurred 3-11 years after MG. Among these 7 patients, 4 had underlying thymic pathology, including 2 with benign thymoma and 2 with stage IV thymoma; all 4 patients had antibodies to acetylcholine receptor (AChR). Of the 3 patients with no thymic pathology by imaging or histology, 2 had positive AChR antibody titer. For treatment, the thymoma was resected and chemotherapy was administered if appropriate. Additional immunosuppressive therapies including high-dose glucocorticoid, intravenous immunoglobulin (IVIG), methotrexate, mycophenolate, or cyclosporine were necessary to achieve remission. Two patients with no thymoma had refractory MG and IM, and both responded to rituximab. We also conducted a literature review on the clinical characteristics and management of this condition, and compared the previously reported cases to the patients in our series. CONCLUSION: This is one of the largest case series of MG-IM overlap with or without thymic pathology. In this cohort, the 2 disease entities can occur simultaneously, or one presents before the other. Most of the patients responded well to steroid, acetylcholinesterase inhibitor, and immunosuppressive agents. In very refractory cases, rituximab appeared to be effective, which has not been reported for the treatment of this condition before.

Prevalence of ulnar neuropathy in patients receiving hemodialysis.

BACKGROUND: Ulnar neuropathy can cause pain, weakness, and sensory changes in the hand and can result in functional impairment. Patients with end-stage renal disease receiving hemodialysis may be predisposed to ulnar neuropathy by factors such as arm positioning during hemodialysis, underlying polyneuropathy, and upper extremity vascular access. OBJECTIVE: To determine the prevalence of clinically evident ulnar neuropathy in a cohort of 102 patients with end-stage renal disease receiving hemodialysis. DESIGN: All eligible patients in a single dialysis unit were screened for symptoms and signs of ulnar neuropathy. Those with at least 1 symptom or sign underwent nerve conduction studies to confirm the presence of ulnar neuropathy. RESULTS: Clinically evident, electrophysiologically confirmed ulnar neuropathy was present in 37 (51%) of the 73 subjects with both screening and nerve conduction study data available. The true prevalence of ulnar neuropathy in this cohort was estimated between 41% and 60%. CONCLUSIONS: There is a high prevalence of ulnar neuropathy in patients with end-stage renal disease receiving hemodialysis, which has not been previously recognized. The high prevalence of ulnar neuropathy in this population suggests that preventative efforts are indicated to prevent this functionally limiting complication.

Amyotrophic lateral sclerosis presentation of a human T-lymphotropic virus type-1 myelopathy--insight into pathogenesis.

A 41-year-old human T-lymphotropic virus type 1-positive woman developed a syndrome with upper and lower motor neuron signs sometime after bilateral vertebral artery dissections. Over 2 years, she developed a progressive myelopathy affecting predominantly the motor system. She had the picture of a 'person in a barrel' and died from complications. At autopsy, spinal cord revealed inflammatory infiltrates and extensive gliosis involving mainly the anterior horns. The vertebral arterial dissections may have permitted the entry of infected lymphocytes and macrophages, secreting cytokines and metalloproteinases, into the medulla progressing to the spinal cord. Few cases with pathological correlation have been reported.

Repetitive nerve stimulation for the evaluation of peripheral nerve hyperexcitability.

OBJECTIVE: To examine the utility of repetitive nerve stimulation (RNS) in the evaluation of peripheral nerve hyperexcitability (PNH). BACKGROUND: PNH describes a group of disorders characterized by muscle cramps, twitching and stiffness. When severe, PNH may be characterized by the presence of continuous muscle fiber activity on routine needle electromyography (EMG). In milder forms of the disease, nerve hyperexcitability may be evidenced by the presence of after-discharges or cramp potentials following RNS. METHODS: Fifty-four patients were prospectively recruited and classified into one of three groups-PNH, other neuromuscular disease and controls. We recorded and quantified the after-discharges and cramp potentials following RNS at 1, 5, 10 and 30 Hz. RESULTS: The proportion of nerves with after-discharges and/or cramp potentials was significantly greater in the PNH group than the control group at both 5 Hz (p=0.03) and 10 Hz (p=0.01), as well as in the neuromuscular disease group compared to controls at 5 Hz (p=0.02). There was also a significant concordance between complaints of muscle cramps and fasciculations and the finding of after-discharges and/or cramp potentials at both 5 Hz (p=0.005) and 10 Hz (p=0.004). At a stimulation frequency of 10 Hz, the sensitivity of RNS for the diagnosis of PNH (primary or secondary) was 79% and the specificity was 88%. CONCLUSION: Our findings suggest that RNS at or below a stimulation frequency of 10 Hz (when positive) is a useful test for the diagnosis of PNH, whether it is primary or secondary.

Antiglycine receptor antibody and encephalomyelitis with rigidity and myoclonus (PERM) related to small cell lung cancer.

A 39-year-old man (a lifetime non-smoker) presented with a locked left jaw and leg myoclonus. Clinical and electromyographic findings were in keeping with progressive encephalomyelitis with rigidity and myoclonus (PERM) syndrome. A thoracic CT scan demonstrated a 19 mm right hilar nodule, which was proven to be small cell lung cancer on bronchoscopic biopsy. Serological evaluation of the patient's plasma revealed antibodies against glycine receptors (serology negative for anti-GAD, anti-Yo, anti-Hu, anti-Ri, antiamphiphysin, anti-Ma2/Ta, anti-CRMP5 and anti-NMDA receptor). After his cancer was treated with chemotherapy and intravenous immunoglobulins (IVIg), neurological symptoms resolved but returned several months later without any evidence of cancer recurrence. Symptoms were refractory to corticosteroids and IVIg therapy. Rituximab was then initiated, which led to a dramatic and sustained resolution of symptoms. To our knowledge, this is the first case of PERM related to antiglycine receptor antibodies from paraneoplastic syndrome, which resolved with rituximab.

Postvaccination Miller Fisher syndrome.

BACKGROUND: Although postvaccination Guillain-Barré syndrome is commonly reported, there have only been 2 previously reported cases of postvaccination Miller Fisher syndrome, and none in association with the novel influenza A(H1N1) vaccine. OBJECTIVE: To describe a case of Miller Fisher syndrome following receipt of the seasonal influenza and novel influenza A(H1N1) vaccine. DESIGN: Case report and literature review. SETTING: Vancouver General Hospital. PATIENT: A 77-year-old Chinese woman. RESULTS: The patient presented with ophthalmoplegia, ataxia, areflexia, and a sensory neuropathy within 2 weeks of immunization. Findings of parainfectious evaluation were unremarkable. Treatment with 2 courses of intravenous immunoglobulin led to clinical improvement. Her presentation and natural history of disease were similar to the 2 previously published cases. CONCLUSIONS: We present the third case of postvaccination Miller Fisher syndrome in the literature and the first associated with the novel influenza A(H1N1) vaccine.