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.

Whole-exome sequencing is a valuable diagnostic tool for inherited peripheral neuropathies: Outcomes from a cohort of 50 families.

The inherited peripheral neuropathies (IPNs) are characterized by marked clinical and genetic heterogeneity and include relatively frequent presentations such as Charcot-Marie-Tooth disease and hereditary motor neuropathy, as well as more rare conditions where peripheral neuropathy is associated with additional features. There are over 250 genes known to cause IPN-related disorders but it is estimated that in approximately 50% of affected individuals a molecular diagnosis is not achieved. In this study, we examine the diagnostic utility of whole-exome sequencing (WES) in a cohort of 50 families with 1 or more affected individuals with a molecularly undiagnosed IPN with or without additional features. Pathogenic or likely pathogenic variants in genes known to cause IPN were identified in 24% (12/50) of the families. A further 22% (11/50) of families carried sequence variants in IPN genes in which the significance remains unclear. An additional 12% (6/50) of families had variants in novel IPN candidate genes, 3 of which have been published thus far as novel discoveries (KIF1A, TBCK, and MCM3AP). This study highlights the use of WES in the molecular diagnostic approach of highly heterogeneous disorders, such as IPNs, places it in context of other published neuropathy cohorts, while further highlighting associated benefits for discovery.

Subcutaneous Immunoglobulin Therapy in the Chronic Management of Myasthenia Gravis: A Retrospective Cohort Study.

BACKGROUND: Immunoglobulin therapy has become a major treatment option in several autoimmune neuromuscular disorders. For patients with Myasthenia Gravis (MG), intravenous immunoglobulin (IVIg) has been used for both crisis and chronic management. Subcutaneous Immunoglobulins (SCIg), which offer the advantage of home administration, may be a practical and effective option in chronic management of MG. We analyzed clinical outcomes and patient satisfaction in nine cases of chronic disabling MG who were either transitioned to, or started de novo on SCIg. METHODS AND FINDINGS: This was a retrospective cohort study for the period of 2015-2016, with a mean follow-up period of 6.8 months after initiation of SCIg. All patients with MG treated with SCIg at the Ottawa Hospital, a large Canadian tertiary hospital with subspecialty expertise in neuromuscular disorders were included, regardless of MG severity, clinical subtype and antibody status. The primary outcome was MG disease activity after SCIg initiation. This outcome was measured by 1) the Myasthenia Gravis Foundation of America (MGFA) clinical classification, and 2) subjective scales of disease activity including the Myasthenia Gravis activities of daily living profile (MG-ADL), Myasthenia Gravis Quality-of-life (MG-QOL 15), Visual Analog (VA) satisfaction scale. We also assessed any requirement for emergency department visits or hospitalizations. Safety outcomes included any SCIg related complication. All patients were stable or improved for MGFA class after SCIg initiation. Statistically significant improvements were documented in the MG-ADL, MG-QOL and VAS scales. There were no exacerbations after switching therapy and no severe SCIg related complications. CONCLUSIONS: SCIg may be a beneficial therapy in the chronic management of MG, with favorable clinical outcome and patient satisfaction results.

Diagnosis and outcome of childhood perineurioma.

INTRODUCTION: Intraneural perineurioma is a rare peripheral nerve tumor of childhood and early adulthood. Patients demonstrate progressive muscle weakness and atrophy largely without sensory complaints. CASE: We report two children with perineurioma affecting the radial and femoral nerves. Electromyography (EMG), ultrasound, and 3-T MR imaging were important tools for localizing perineurioma and permitting its differentiation from other nerve lesions. The first patient underwent surgical excision of the perineurioma and a traditional nerve graft. At 10 months post-operative follow-up, she demonstrated no meaningful recovery of muscle strength compared to her pre-operative assessment. EMG did confirm axonal continuity indicating that reinnervation had occurred via the nerve graft. The second patient underwent a two-staged surgical procedure that included an end-to-side nerve transfer. At 18 months post-operative follow-up, she demonstrated mild improvement in muscle strength and EMG evidence of ongoing reinnervation. CONCLUSION: The surgical management of perineurioma remains controversial, and reports of clinical recovery after nerve grafts and nerve transfers vary. Nerve transfers have been reported to provide superior results to traditional nerve grafting in adults with post-traumatic plexus injuries. The modest gain in strength of our patient who underwent a nerve transfer raises the question if this may also apply to patients with perineurioma. Additional studies will be required, which must also take into consideration that features of long-standing neuropathy (i.e., limb length discrepancy) have the potential to reduce the likelihood of reinnervation and clinical recovery.

Diabetic Cranio-Cervico-Radiculoplexus Neuropathy.

We describe a case of a 53-year-old man with type 2 diabetes mellitus in whom cervical-radiculoplexus neuropathy developed, with concomitant cranial and phrenic nerve involvement, occurring as a stepwise, monophasic course. The patient had a presumed remote history of idiopathic cervical-radiculoplexus neuropathy.

Myopathy with hexagonally cross-linked tubular arrays: a new autosomal dominant or sporadic congenital myopathy.

We describe a slowly progressive myopathy with unique crystalloid inclusions in type 2 muscle fibers in a father and his son, as well as one more unrelated individual. The inclusions were strongly eosinophilic and purple by the Gomori method. They were composed of vesicular profiles, approximately 20 nm in cross-diameter, connected by radially arranged double spokes arising at 60 degrees angles. The inclusions were not related to any normal cellular organelle. Extensive immunohistochemical studies failed to reveal their chemical nature. It is suggested that this is a new congenital myopathy with characteristic intracytoplasmic inclusions, occurring sporadically or with an autosomal dominant pattern of inheritance.

The abductor pollicis brevis R1 response: normative data and physiological behavior.

BACKGROUND: Although H reflexes cannot be reliably recorded from resting human hand intrinsic muscles, a short latency R1 response, thought to be similar to the H reflex, is readily obtained from upper extremity muscles during voluntary contraction. METHODS: The right and left median nerves of 20 normal subjects were repetitively stimulated at 3 Hz at stimulus intensities corresponding to threshold and 20%, 40% and 60% of maximal M response, recording from the abductor pollicis brevis muscle. Studies were done during both minimal and moderate voluntary contraction. RESULTS: The R1 response was present in all subjects at the 40% stimulation intensity level during moderate contraction. The mean latency was 27 ms (SD 1.77 ms) with a good correlation to arm length. The mean amplitude was 1.17 mV (SD 0.79 mV). CONCLUSIONS: Abductor pollicis muscle R1 response can be reliably measured, although latency showed much less intersubject and side to side variability than amplitude. This technique may be useful for the assessment of demyelinative lesions of the inferior segments of the brachial plexus and C8-T1 roots.

Vasculitic basilar artery thrombosis in chronic Candida albicans meningitis.

BACKGROUND: Cerebrovascular complications of meningitis have been most extensively documented in the setting of acute bacterial or chronic tuberculous meningitis. Involvement of major cerebral vessels is rare and basilar artery thrombosis has not been reported in fungal meningitis secondary to candida infection. METHODS: We describe the clinical course and neuropathological findings in a woman with chronic meningitis due to Candida albicans. RESULTS: The diagnosis remained elusive antemortem despite analysis of 7 large volume CSF samples and examination of a meningeal and cortical biopsy. Death followed extensive brainstem and temporo-occipital infarction secondary to basilar artery thrombosis. The basilar artery occlusion was secondary to an intense, granulomatous and necrotizing basal meningitis focally extending to the media and intima. CONCLUSIONS: This paroxysmal and devastating complication of untreated chronic candida meningitis reinforces that a trial of empirical therapy with both antituberculous and antifungal agents should be considered in most cases of chronic culture-negative lymphocytic meningitis.

Musical auditory hallucinosis from Listeria rhombencephalitis.

BACKGROUND: Complex auditory hallucinations have rarely been reported in cases of brainstem stroke or tumor. METHOD: Case study. RESULTS: A patient with acute Listeria rhombencephalitis complained of formed musical auditory hallucinations on the side of recent sensorineural deafness. MRI revealed an abscess in the middle cerebellar peduncule with extensive surrounding edema. CONCLUSIONS: Disruption of brainstem auditory pathways may cause complex auditory hallucinations. Potential pathogenetic mechanisms are discussed and a diagnostic approach is proposed.

Selective calf weakness suggests intraspinal pathology, not peripheral neuropathy.

Four patients, referred as having peripheral neuropathy, were noted to be able to walk on their heels but not on their toes. In each, intraspinal disease was found: ependymoma of the filum terminale, spinal muscular atrophy, spinal stenosis, and meningeal carcinomatosis. By comparison, in 86 cases of hereditary motor and sensory neuropathy type 1, ankle plantar flexors were never weaker than ankle dorsiflexors. Patients with greater weakness in plantar flexors than in dorsiflexors should be suspected of having intraspinal disease rather than peripheral neuropathy. Physiologic and biomechanical factors may explain why muscles innervated by the peroneal nerve are weaker, or graded weaker, in peripheral neuropathy.

Chest-tube thoracostomy causing Horner's syndrome.

Horner's syndrome developing early after lung biopsy is reported in a 42-year-old woman. At the end of the procedure a thoracostomy tube was inserted with its tip at the T1-2 posterior intercostal space. The authors conclude that direct injury to the second order preganglionic neuron in the vicinity of the stellate ganglion caused the Horner's syndrome. They recommend placing the tip of the thoracostomy tube below the level of the second rib posteriorly to prevent this complication.