The Canadian Neuromuscular Disease Registry 2010-2019: A Decade of Facilitating Clinical Research Througha Nationwide, Pan-NeuromuscularDisease Registry.

We report the recruitment activities and outcomes of a multi-disease neuromuscular patient registry in Canada. The Canadian Neuromuscular Disease Registry (CNDR) registers individuals across Canada with a confirmed diagnosis of a neuromuscular disease. Diagnosis and contact information are collected across all diseases and detailed prospective data is collected for 5 specific diseases: Amyotrophic Lateral Sclerosis (ALS), Duchenne Muscular Dystrophy (DMD), Myotonic Dystrophy (DM), Limb Girdle Muscular Dystrophy (LGMD), and Spinal Muscular Atrophy (SMA). Since 2010, the CNDR has registered 4306 patients (1154 pediatric and 3148 adult) with 91 different neuromuscular diagnoses and has facilitated 125 projects (73 academic, 3 not-for-profit, 3 government, and 46 commercial) using registry data. In conclusion, the CNDR is an effective and productive pan-neuromuscular registry that has successfully facilitated a substantial number of studies over the past 10 years.

Establishing a Canadian registry of patients with amyotrophic lateral sclerosis.

BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a devastating cause of progressive weakness, respiratory failure and death. To date there is no effective therapy to meaningfully extend survival but continuously emerging targets and putative treatments are studied in clinical trials. Canadian epidemiological data on ALS is scarce and the socioeconomic impact of ALS on Canadian society is unclear. The Canadian Neuromuscular Disease Registry (CNDR) is a national clinic-based registry of patients with neuromuscular diseases with the goal of facilitating the design and execution of clinical research. METHODS: We conducted a national stakeholder survey to assess interest for a Canadian ALS registry and an assessment of expected case ascertainment. A dataset derivation meeting was held to establish the registry medical dataset. RESULTS: We report the results of the national stakeholder survey, case ascertainment assessment, and the derived dataset that have resulted in the current implementation of a Canadian registry of patients with ALS. CONCLUSIONS: The development of this long sought-after resource is a significant step forward for the Canadian ALS patient and research communities that will result in more efficient clinical trial recruitment and advancements in our understanding of ALS in Canada.

Aldose reductase inhibitors for the treatment of diabetic polyneuropathy.

BACKGROUND: Polyneuropathy, a common complication of diabetes mellitus, causes pain and sensory and motor deficits in the limbs, and is also an important independent predictor of foot ulceration. Inhibiting the metabolism of glucose by the polyol pathway using aldose reductase inhibitors is a potential mechanism to slow or reverse the neuropathy's progression. OBJECTIVES: To assess the effects of aldose reductase inhibitors on the progression of symptoms, signs or functional disability in diabetic polyneuropathy. SEARCH STRATEGY: We searched the Cochrane Neuromuscular Disease Group Trials Register, MEDLINE (from January 1966 to May 2007), EMBASE (from January 1980 to May 2007) and LILACS (from 1982 to May 2007). We reviewed bibliographies of randomized trials identified, and contacted authors and experts in the field. SELECTION CRITERIA: We included randomized controlled trials comparing an aldose reductase inhibitor with control, and lasting at least six months. The primary outcome measure was change in neurological function, measured in various ways, including strength testing, sensory examination, and composite scores of neurological examination. Secondary outcome measures were nerve conduction studies, neuropathic symptoms, quality of life, occurrence of foot ulcers and adverse effects. DATA COLLECTION AND ANALYSIS: Trials included in the review were selected and assessed independently by at least two of us. Methodological criteria and study results were recorded on data extraction forms. MAIN RESULTS: Thirty-two randomized controlled trials meeting the inclusion criteria were identified. Many had significant methodological flaws. Change in neurological function, our primary outcome measure, was assessed in 29 trials, but sufficient data for meta-analysis were only available in 13 studies, involving 879 treated participants and 909 controls. There was no overall significant difference between the treated and control groups (SMD -0.25, 95% CI -0.56 to 0.05), although one subgroup analysis (four trials using tolrestat) favored treatment. A benefit for neuropathic symptoms was suggested by a group of trials using a dichotomized endpoint (improvement or not), but this was contradicted by another group of trials which measured symptoms on a continuous scale. There was no overall benefit on nerve conduction parameters (27 studies) or foot ulceration (one study). Quality of life was not assessed in any of the studies. While most adverse events were infrequent and minor, three compounds had dose limiting adverse events that lead to their withdrawal from human use: severe hypersensitivity reactions with sorbinil, elevation of creatinine with zenarestat, and alteration of liver function with tolrestat. AUTHORS' CONCLUSIONS: We found no statistically significant difference between aldose reductase inhibitors and placebo in the treatment of diabetic polyneuropathy. Any future clinical trials of aldose reductase inhibitors should be restricted to compounds proven to have substantial biological or preclinical advantages over previously tested agents.

ALS incidence in Nova Scotia over a 20-year-period: a prospective study.

OBJECTIVE: Previous studies have suggested that the incidence of amyotrophic lateral sclerosis (ALS) in Nova Scotia is relatively high and increasing over time. This study was performed to determine the current incidence of ALS in Nova Scotia and to compare this to data collected in 1984 and 1995. METHODS: All physiatrists and neurologists were surveyed on a monthly basis over one year to record all new cases of ALS diagnosed in Nova Scotia. Data was compared to that collected using similar methods in 1984 and 1995. To validate our methods, we also performed a retrospective study using a provincial health care database. RESULTS: There were 21 new ALS cases in Nova Scotia during the 2003 study period, yielding a crude incidence of 2.24/100,000. The age-adjusted incident rate for 2003 was 2.13 (95% CI = 0.11-4.15). The age-adjusted rate for 1995 was 2.3 (95% CI = 0.08-4.53) while the age-adjusted rate for 1984 was 2.22 (95% CI = 0.13-4.32). Analysis of provincial health records identified 24 cases of ALS and an age-adjusted incidence of 2.44/100,000. CONCLUSIONS: The age-adjusted incidence of ALS in Nova Scotia has remained stable over the period 1984-2003. The incidence is similar to that reported in several other parts of the world.

Progress in clinical neurosciences: Charcot-Marie-Tooth disease and related inherited peripheral neuropathies.

The classification of Charcot-Marie-Tooth disease and related hereditary motor and sensory neuropathies has evolved to incorporate clinical, electrophysiological and burgeoning molecular genetic information that characterize the many disorders. For several inherited neuropathies, the gene product abnormality is known and for others, candidate genes have been identified. Genetic testing can pinpoint a specific inherited neuropathy for many patients. However, clinical and electrophysiological assessments continue to be essential tools for diagnosis and management of this disease group. This article reviews clinical, electrophysiological, pathological and molecular aspects of hereditary motor and sensory neuropathies.

Minimum standards for electromyography in Canada: a statement of the Canadian Society of Clinical Neurophysiologists.

BACKGROUND: Electromyography (EMG) is a widely used diagnostic technique for disorders of the nervous system. The Canadian Society of Clinical Neurophysiologists (CSCN) promotes the education, evaluation and standards of EMG in Canada. A statement of practice standards was needed to clarify the position of the CSCN on several issues relevant to the practice of EMG. METHODS AND RESULTS: A subcommittee of the CSCN reviewed current patterns of practice and established guidelines for review by the CSCN. The guidelines developed by the subcommittee were reviewed by the CSCN and adopted as recommendations for EMG practice. The subcommittee was charged with formulation of a document for publication. CONCLUSIONS: This document deals with minimum standards for electromyographer education, laboratory operation, equipment and a variety of special circumstances relevant to the practice of EMG. The standards can be adopted by EMG laboratories to guide quality assurance.

Impact of plasma exchange on indices of demyelination in chronic inflammatory demyelinating polyradiculoneuropathy.

We studied the impact of plasma exchange (PE) on indices of primary demyelination in patients of the Canadian multicenter trial of PE in chronic inflammatory demyelinating polyneuropathy (CIDP). Individual motor nerves (median, ulnar, peroneal, tibial) were studied: distal motor latencies (DMLs), proximal and distal compound muscle action potential (M-wave) amplitudes, negative peak areas and durations, and motor conduction velocities (CVs). Proximal M-wave amplitudes in individual motor territories, particularly in the ulnar nerve (from below elbow, above elbow, and axillary stimulating sites) demonstrated significant improvement with PE, but not sham exchange. Proximal ulnar M-wave areas also had significant improvement with PE. Trends toward improvement of individual nerve motor CVs, M-wave durations, and DMLs did not achieve statistical significance. Proximal M-wave amplitudes, particularly in the ulnar motor territory, and proximal M-wave areas (providing a measure of conduction block) were the most sensitive indices of improvement conferred by PE in CIDP. In individual patients, these indices may help judge the efficacy of therapy.

Treatment of Guillain-Barré syndrome: a cost-effectiveness analysis.

Acute Guillain-Barré syndrome is the most common cause of neuromuscular paralysis. Plasma exchange and intravenous immune globulin (IV IgG) are both effective treatments for this condition and the purpose of this report was to compare the cost-effectiveness of these two modalities. A MEDLINE search was performed to identify randomized studies that compared the use of IV IgG and plasma exchange for treatment of acute Guillain-Barré syndrome to determine if one modality was more effective and/or safer for the management of this condition. A decision analysis was structured around the alternatives facing neurologists who must choose a treatment regimen for patients diagnosed with acute Guillain-Barré syndrome who require active therapy. Cost information was obtained directly from product manufacturers and hospital sources. Two head-to-head trials comparing the effectiveness of plasma exchange and IV IgG for treatment of acute Guillain-Barré syndrome determined that there was insufficient evidence to suggest one therapy was more effective than the other; therefore, a cost minimization analysis was performed. The costs per patient of plasma exchange and IV IgG for the treatment of acute Guillain-Barré syndrome were $6,204 and $10,165, respectively. A sensitivity analysis determined the model was sensitive to the cost of IV IgG. The cost savings per patient treatment for the use of plasma exchange varied from $304 to $6,625 depending on the IV IgG product selected. Plasma exchange and IV IgG are both effective treatments for Guillain-Barré syndrome. However, our analysis determined plasma exchange on average was almost $4,000 less costly per patient than IV IgG. Further research is required to determine the impact of patient and physician preferences on the treatment of this disorder.

EMG related anxiety and pain: a prospective study.

BACKGROUND: Electromyography (EMG) is a useful test, but unfortunately also painful. We frequently encounter patients who worry about its painful nature, but tolerate it very well. OBJECTIVES: We evaluated anxiety levels of patients referred for EMG to explore the possible correlating and contributing factors to high anxiety. METHODS: A structured questionnaire, including the State-Trait Anxiety Inventory was completed by patients immediately before EMG testing. Emergency, hospitalized, and seriously ill patients were excluded. RESULTS: Seventy-nine cases with ages ranging from 19-72 years (mean 43) were included. Thirty-five (44%) patients had a high pre-test anxiety level. The likelihood of high anxiety was increased if the patient was worried about the test (p < 0.001) or about other issues unrelated to the test or underlying diagnosis (p < 0.001), or was taking an anti-psychotic or anxiolytic drug (p = 0.008). The degree or source of knowledge regarding the test procedure, did not affect the pre-test anxiety level. CONCLUSIONS: The information about EMG testing received by patients in this group did not affect pre-test anxiety levels. The patient's expectations regarding the test did influence anxiety levels and this may reflect generalized anxiety regarding testing procedures or misinformation regarding the nature of the test, as patients in general reported a better than anticipated experience following the test.

Using problem-based learning in neurosciences education for medical students.

BACKGROUND: A Curriculum Task Force proposed problem-based learning as one important educational strategy and recommended changes to a traditional medical curriculum. METHODS: This paper describes how a problem-based learning course in neurosciences was developed and has evolved since its inception in the Dalhousie University Faculty of Medicine. The curriculum planning and design phases are outlined, followed by a description of how the course has been implemented and evaluated. RESULTS: Program evaluation results are presented, describing student performance on examinations and their feedback about the course. CONCLUSION: The authors summarize lessons learned and identify future issues to continue the ongoing development of the course.

Symptoms experienced by patients with carpal tunnel syndrome.

BACKGROUND: Patients with carpal tunnel syndrome (CTS) sometimes report sensory symptoms outside the median nerve distribution. This study was designed to provide a more detailed assessment of these symptoms. METHODS: Patients with clinical suspicion of upper limb neuromuscular lesions were divided into those with electrodiagnostic (EDX) evidence of CTS, and those without. CTS patients with superimposed nerve abnormalities were excluded. Motor and sensory symptoms were assessed in the exclusive CTS patients. RESULTS: Over 50% of patients with exclusive CTS reported tingling or numbness over the whole hand, ulnar or radial nerve distributions. Some patients reported symptoms proximal to the wrist. Sensory signs did not extend beyond the median nerve distribution. Numbness and nocturnal pain were predictive of positive EDX evidence of CTS. CONCLUSIONS: Sensory symptoms outside the distribution of the median nerve are common in CTS. For enhanced sensitivity in diagnosis it is useful to be aware of these "atypical" symptoms. Reports of numbness and nocturnal pain are strong indicators of CTS.

A case of Isaacs' syndrome with associated central nervous system findings.

We report a 44-year-old female with Isaacs' syndrome, peripheral motor neuropathy, and features of central pontine myelinolysis (CPM). The patient presented with stiffness and muscle spasms accompanied by profound sweating. She also had bilateral Babinski signs. Electrodiagnostic abnormalities were characteristic of Isaacs' syndrome. Magnetic resonance imaging demonstrated features of CPM. She gained modest relief from baclofen, valproate, and diazepam. She improved dramatically following plasmapheresis and continued to recover on prednisone. She was weaned from steroids without relapse.

Correlation of the pilo-pupil ratio average, a new test for autonomic denervation, to the severity of diabetic retinopathy.

OBJECTIVE: To evaluate the association between the degree of diabetic retinopathy and autonomic neuropathy, and to test whether ocular parasympathetic denervation is correlated to the degree of diabetic retinopathy. DESIGN: Cross-sectional pilot study. SETTING: The tertiary ophthalmic centre for the Atlantic provinces in Halifax. PATIENTS: Twelve randomly selected patients (six women and six men with a mean age of 36.6 years) with insulin-dependent diabetes mellitus who had diabetic retinopathy. OUTCOME MEASURES: Degree of diabetic retinopathy, hemoglobin Alc level, orthostatic change in systolic and diastolic blood pressure and in serum catecholamine levels, degree of pupillary supersensitivity to 0.125% pilocarpine (pilo-pupil ratio average [PPRA]). RESULTS: The degree of diabetic retinopathy was significantly correlated with the duration of diabetes (p = 0.035), the hemoglobin Alc level (p = 0.004), the orthostatic change in diastolic blood pressure (p = 0.022) and the PPRA (p = 0.0007). CONCLUSIONS: The degree of diabetic retinopathy was significantly correlated with autonomic neuropathy and with the PPRA. Given these results, further study is indicated to determine whether autonomic neuropathy is a predictor of the severity of diabetic retinopathy.

Plasma-exchange therapy in chronic inflammatory demyelinating polyneuropathy. A double-blind, sham-controlled, cross-over study.

Eighteen patients with definite, untreated chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) of chronic progressive (nine patients) or relapsing course (nine patients) were randomized prospectively to receive 10 plasma-exchange (PE) or sham plasma-exchange (SPE) treatments over 4 weeks in a double-blind trial. After a wash-out period of 5 weeks or when they returned to baseline scores, patients were crossed over to the alternate treatments. Neurological function was assessed serially using a quantitative neurological disability score (NDS), a functional clinical grade (CG) and grip strength (GS) measurements. Electrophysiological studies were done at the beginning and end of each treatment. A primary 'intention to treat' analysis showed significant improvement with PE in all clinical outcome measures: NDS by 38 points, P < 0.001; CG by 1.6 points, P < 0.001; GS by +13 kg, P < 0.003 and in selected electrophysiological measurements, sigma proximal CMAP, P < 0.01; sigma motor conduction velocities, P < 0.006; sigma distal motor latencies, P < 0.01. Fifteen patients completed the trial and of those, 12 patients (80%) improved substantially with PE; i.e. five out of seven patients with chronic progressive course and seven out of eight patients with relapsing CIDP improved. There were three drop-outs; one patient lost venous access; one patient suffered a stroke and one patient left the trial to receive open treatment elsewhere. The improvement in motor functions correlated with the electrophysiological data, i.e. with improved motor conduction velocities and reversal of conduction block. Eight of 12 PE responders (66%) relapsed within 7-14 days after stopping PE. All improved with subsequent open label PE; all but two patients required long-term immunosuppressive drug therapy for stabilization. The PE non-responders improved with prednisone. We conclude that PE is a very effective adjuvant therapy for CIDP of both chronic progressive and relapsing course; concurrent immunosuppressive drug treatment is required. Exchange treatments should be given two to three times per week until improvement is established; the treatment frequency should then be tapered over several months.

Nerve microvessel changes in diabetes are prevented by aldose reductase inhibition.

BACKGROUND: Despite the potential importance of endoneurial microvessel abnormalities in diabetic neuropathy, the pathogenesis of these abnormalities is incompletely understood. We wished to evaluate the effect of experimental diabetes on endoneurial microvessels and determine if an aldose reductase inhibitor alters any of the changes induced by diabetes. METHODS: We compared streptozocin diabetic rats with and without aldose reductase inhibitor treatment to non-diabetic rats after 10 months of diabetes. Transverse microvessels from the mid-sciatic level were studied by electron microscopic morphometric evaluation. RESULTS: Microvessel endothelial, pericyte, basement membrane and total mural area were greater in untreated diabetic animals than non-diabetic animals. Aldose reductase inhibitor treated diabetic animals had greater endothelial area and possibly pericyte area but not basement membrane or total mural area. CONCLUSIONS: This study demonstrates that endoneurial microvessel abnormalities can be detected in experimental diabetic neuropathy. Microvessel basement membrane thickening will be prevented by an aldose reductase inhibitor. One mechanism by which abnormal polyol pathway activity may contribute to diabetic neuropathy could be through damage to microvessels.

Encephalomyeloradiculopathy of infectious or parainfectious etiology--a new entity?

Between 19 March 1990 and 24 December 1992, six persons in Nova Scotia presented with a unique neurological illness. A prodrome of fever and headache was followed by neurogenic bladder, transverse myelitis, and encephalopathy in association with mononuclear pleocytosis of the CSF and nerve-conduction study findings consistent with polyradiculopathy. The spinal cords of three of the patients appeared abnormal on myelograms or magnetic resonance imaging studies. No microbial agent was isolated or demonstrated serologically. All of the patients were treated with antimicrobial agents and corticosteroids. Three recovered completely, but neurogenic bladder persisted in the remaining three. We suggest that this group of patients manifested an encephalomyeloradiculopathy that is likely a new clinical entity of infectious or parainfectious etiology.

Acute endothelial swelling is induced in endoneurial microvessels by ischemia.

Structural alterations of endoneurial microvessels occur in diabetic neuropathy and are statistically associated with severity of nerve fiber loss and teased fiber abnormality. It is therefore hypothesized that the microvessel alterations may cause or contribute to pathologic alterations of nerve fibers in diabetic neuropathy, possibly through hypoxic injury. The mechanism of the microvessel change in diabetic neuropathy is unknown. The role of microvessels and details of microvessel structure in other possible ischemic neuropathies has not been studied completely. Already there is evidence that hypoxia induces endothelial swelling but this has not been characterized or quantitated in nerve. To determine the acute morphologic effect of ischemia on ultrastructural features of transverse profiles of endoneurial microvessels major pelvic arteries were ligated in rats. At 36 h mean lumen and mural areas were greater in ischemic than in control nerves. All components (endothelium, pericytes and basement membrane) were on average greater in ischemic than controls. The greatest increase was in endothelial cells. In these cells swollen mitochondria were abundant. This study demonstrates that acute ischemia induces swelling of the cells and organelles of endoneurial microvessels.

The electrophysiologic profile of Dejerine-Sottas disease (HMSN III).

Electrophysiologic studies in 11 patients with Dejerine-Sottas disease (hereditary motor and sensory neuropathy type III, HMSN III) showed median and ulnar motor nerve conduction velocities less than 6 m/sec in all but 1 patient. Marked temporal dispersion without conduction block was present in all patients. Uniform slowing in adjacent motor nerves was consistent with other studies of inherited neuropathies, although marked temporal dispersion may make HMSN III more difficult to distinguish from acquired neuropathies than other hereditary conditions. The electrophysiologic features of HMSN III patients were significantly different from a series of patients with other hereditary neuropathies chosen because of very slow nerve conduction velocity.