Provincial Differences in the Diagnosis and Care of Amyotrophic Lateral Sclerosis.

BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a progressive motor neuron disease resulting in muscle weakness, dysarthria and dysphagia, and ultimately respiratory failure leading to death. Half of the ALS patients survive less than 3 years, and 80% of the patients survive less than 5 years. Riluzole is the only approved medication in Canada with randomized controlled clinical trial evidence to slow the progression of ALS, albeit only to a modest degree. The Canadian Neuromuscular Disease Registry (CNDR) collects data on over 140 different neuromuscular diseases including ALS across ten academic institutions and 28 clinics including ten multidisciplinary ALS clinics. METHODS: In this study, CNDR registry data were analyzed to examine potential differences in ALS care among provinces in time to diagnosis, riluzole and feeding tube use. RESULTS: Significant differences were found among provinces, in time to diagnosis from symptom onset, in the use of riluzole and in feeding tube use. CONCLUSIONS: Future investigations should be undertaken to identify factors contributing to such differences, and to propose potential interventions to address the provincial differences reported.

Nutrition with Gastrostomy Feeding Tubes for Amyotrophic Lateral Sclerosis in Canada.

BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a rapidly progressing degenerative motor neuron disease that results in significant muscle weakness. Defects in energy metabolism and difficulties in swallowing eventually lead to a reduction in body mass. Weight loss exacerbates symptoms and serves as an independent negative prognostic factor. Percutaneous endoscopic gastrostomy (PEG) is often inserted in patients with ALS to either supplement or replace oral feeding. However, the criteria for PEG placement and timing of insertion are important clinical decisions that have not been fully studied. Given the absence of guiding evidence, the aim of this project was to better understand how Canadian ALS clinics make decisions regarding gastrostomy feeding. METHODS: ALS clinical directors across Canada were asked if they had written guidelines for timing of PEG insertion and if not, what criteria they use to make this decision. Responses from 10 of 17 centres contacted were received. RESULTS: The approach to supplemental nutrition management in Canadian clinics varies in the absence of formal guidelines. Only one centre has a written set of centre-specific protocols in place. Most clinics considered some combination of respiratory decline, weight loss, dysphagia and/or patient readiness when reaching a decision. However, the absolute threshold and mechanism of measuring the individual criteria differed between clinics. CONCLUSIONS: Practices generally reflect international published recommendations but vary on the emphasis of specific criteria. Further research is required to determine the optimal timing and criteria to place gastrostomy feeding tubes in the ALS population.

Fibular (peroneal) neuropathy.

Fibular neuropathy has variable presenting features depending on the site of the lesion. Anatomical features make it susceptible to injury from extrinsic factors, particularly the superficial location of the nerve at the head of the fibula. There are many mechanisms of compression or other traumatic injury of the fibular nerve, as well as entrapment and intrinsic nerve lesions. Intraneural ganglion cysts are increasingly recognized when the mechanism of neuropathy is not clear from the medical history. Electrodiagnostic testing can contribute to the localization as well as the characterization of the pathologic process affecting the nerve. When the mechanism of injury is unclear from the analysis of the presentation, imaging with MRI and ultrasound may identify nerve lesions that warrant surgical intervention. The differential diagnosis of foot drop includes fibular neuropathy and other neurologic conditions, which can be distinguished through clinical and electrodiagnostic assessment. Rehabilitation measures, including ankle splinting, are important to improve function and safety when foot drop is present. Fibular neuropathy is less frequently painful than many other nerve lesions, but when it is painful, neuropathic medication may be required. Failure to spontaneously recover or the detection of a mass lesion may require surgical management.

The CNDR: collaborating to translate new therapies for Canadians.

BACKGROUND: Patient registries represent an important method of organizing "real world" patient information for clinical and research purposes. Registries can facilitate clinical trial planning and recruitment and are particularly useful in this regard for uncommon and rare diseases. Neuromuscular diseases (NMDs) are individually rare but in aggregate have a significant prevalence. In Canada, information on NMDs is lacking. Barriers to performing Canadian multicentre NMD research exist which can be overcome by a comprehensive and collaborative NMD registry. METHODS: We describe the objectives, design, feasibility and initial recruitment results for the Canadian Neuromuscular Disease Registry (CNDR). RESULTS: The CNDR is a clinic-based registry which launched nationally in June 2011, incorporates paediatric and adult neuromuscular clinics in British Columbia, Alberta, Ontario, Quebec, New Brunswick and Nova Scotia and, as of December 2012, has recruited 1161 patients from 12 provinces and territories. Complete medical datasets have been captured on 460 "index disease" patients. Another 618 "non-index" patients have been recruited with capture of physician-confirmed diagnosis and contact information. We have demonstrated the feasibility of blended clinic and central office-based recruitment. "Index disease" patients recruited at the time of writing include 253 with Duchenne and Becker muscular dystrophy, 161 with myotonic dystrophy, and 71 with ALS. CONCLUSIONS: The CNDR is a new nationwide registry of patients with NMDs that represents an important advance in Canadian neuromuscular disease research capacity. It provides an innovative platform for organizing patient information to facilitate clinical research and to expedite translation of recent laboratory findings into human studies.

Mutation in the gene encoding ubiquitin ligase LRSAM1 in patients with Charcot-Marie-Tooth disease.

Charcot-Marie-Tooth disease (CMT) represents a family of related sensorimotor neuropathies. We studied a large family from a rural eastern Canadian community, with multiple individuals suffering from a condition clinically most similar to autosomal recessive axonal CMT, or AR-CMT2. Homozygosity mapping with high-density SNP genotyping of six affected individuals from the family excluded 23 known genes for various subtypes of CMT and instead identified a single homozygous region on chromosome 9, at 122,423,730-129,841,977 Mbp, shared identical by state in all six affected individuals. A homozygous pathogenic variant was identified in the gene encoding leucine rich repeat and sterile alpha motif 1 (LRSAM1) by direct DNA sequencing of genes within the region in affected DNA samples. The single nucleotide change mutates an intronic consensus acceptor splicing site from AG to AA. Direct analysis of RNA from patient blood demonstrated aberrant splicing of the affected exon, causing an obligatory frameshift and premature truncation of the protein. Western blotting of immortalized cells from a homozygous patient showed complete absence of detectable protein, consistent with the splice site defect. LRSAM1 plays a role in membrane vesicle fusion during viral maturation and for proper adhesion of neuronal cells in culture. Other ubiquitin ligases play documented roles in neurodegenerative diseases. LRSAM1 is a strong candidate for the causal gene for the genetic disorder in our kindred.

Guidelines on the use of intravenous immune globulin for neurologic conditions.

Canada's per capita use of intravenous immune globulin (IVIG) grew by approximately 115% between 1998 and 2006, making Canada one of the world's highest per capita users of IVIG. It is believed that most of this growth is attributable to off-label usage. To help ensure IVIG use is in keeping with an evidence-based approach to the practice of medicine, the National Advisory Committee on Blood and Blood Products (NAC) and Canadian Blood Services convened a panel of national experts to develop an evidence-based practice guideline on the use of IVIG for neurologic conditions. The mandate of the expert panel was to review evidence regarding use of IVIG for 22 neurologic conditions and formulate recommendations on IVIG use for each. A panel of 6 clinical experts, one expert in practice guideline development and 4 representatives from the NAC met to review the evidence and reach consensus on the recommendations for the use of IVIG. The primary sources used by the panel were 2 recent evidence-based reviews. Recommendations were based on interpretation of the available evidence and, where evidence was lacking, consensus of expert clinical opinion. A draft of the practice guideline was circulated to neurologists in Canada for feedback. The results of this process were reviewed by the expert panel, and modifications to the draft guideline were made where appropriate. This practice guideline will provide the NAC with a basis for making recommendations to provincial and territorial health ministries regarding IVIG use management. Recommendations for use of IVIG were made for 14 conditions, including acute disseminated encephalomyelitis, chronic inflammatory demyelinating polyneuropathy, dermatomyositis, diabetic neuropathy, Guillain-Barré syndrome, Lambert-Eaton myasthenic syndrome, multifocal motor neuropathy, multiple sclerosis, myasthenia gravis, opsoclonus-myoclonus, pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections, polymyositis, Rasmussen's encephalitis, and stiff person syndrome; IVIG was not recommended for 8 conditions including adrenoleukodystrophy, amyotropic lateral sclerosis, autism, critical illness polyneuropathy, inclusion body, myositis, intractable childhood epilepsy, paraproteinemic neuropathy (IgM variant), and POEMS syndrome. Development and dissemination of evidence-based clinical practice guidelines may help to facilitate appropriate use of IVIG.

Correlating factors in the recommendation of feeding tubes in the nutritional management of amyotrophic lateral sclerosis.

Amyotrophic lateral sclerosis (ALS) is associated with nutritional deficits. Gastrostomy tubes are often inserted in patients with ALS to supplement or replace oral intake. The aim of this study was to better understand the practices of gastrostomy tube insertion in patients with ALS. Pre-collected de-identified data were obtained from the Canadian Neuromuscular Disease Registry (CNDR). Feeding tube status was compared with markers of dysphagia, respiratory compromise, and weight status in both univariate and multivariate analysis by employing odds ratios. Results showed that abnormal ALSFRS-R dysphagia scores were associated with higher rates of feeding tube referrals. The use of non-invasive ventilation also increased the likelihood that a tube was recommended. A higher FVC was found to decrease the likelihood of recommendation. BMI and ALSFRS-R dyspnoea scores were not found to be independently associated. In conclusion, our findings demonstrate that symptoms of dysphagia and respiratory status are associated with higher rates of recommendation for feeding tubes. While not independently significant, individuals with a lower BMI had more feeding tube referrals compared to individuals with a normal or elevated BMI. A similar trend was noted for ALSFRS-R dyspnoea scores. Further research is required to determine if these represent optimal criteria for placement.

Critical illness myopathy in a cervical spine-injured patient.

Neuromuscular weakness acquired in the intensive care unit (ICU) causes significant impairment in critically ill patients. The spectrum of critical illness neuromuscular disease includes critical illness myopathy, critical illness polyneuropathy or both, and occurs in approximately one-third of patients admitted to the ICU and those who are ventilated for at least 7 days. Recognized risk factors include sepsis, systemic inflammatory response syndrome, multi-organ failure, neuromuscular blocking agents and corticosteroids, however the absence of predisposing factors should not preclude critical illness neuromuscular disease. A 23-year-old male suffered a cervical spine injury and was admitted to the ICU. Two weeks post admission, he lost all power in his upper limbs, neck and face. Nerve conduction studies and needle electromyography were performed 4 weeks and 3 months after the injury, suggesting that myopathy was the likely cause of weakness. The definitive diagnosis of critical illness myopathy was based on muscle biopsy demonstrating myosin filament loss. Evaluation of new-onset weakness in ICU patients is essential to distinguish neurological causes from complications of critical illness. Signs and symptoms of critical illness neuromuscular disease must be identified early to encourage recovery, promote rehabilitation, and reduce morbidity and mortality.