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.

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.

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.

Prediction of Cognitive Status and 5-Year Survival Rate for Elderly with Cardiovascular Diseases: A Canadian Study of Health and Aging Secondary Data Analysis.

BACKGROUND: Given the important association between cardiovascular disease and cognitive decline, and their significant implications on frailty status, the contribution of neurocognitive frailty measure helping with the assessment of patient outcomes is dearly needed. OBJECTIVES: The present study examines the prognostic value of the Neurocognitive Frailty Index (NFI) in the elderly with cardiovascular disease. DESIGN: Secondary analysis of the Canadian Study of Health and Aging (CSHA) dataset was used for prediction of 5-year cognitive changes. SETTING: Community and institutional sample. PARTICIPANTS: Canadians aged 65 and over [Mean age: 80.4 years (SD=6.9; Range of 66-100)]. MEASUREMENT: Neurocognitive Frailty Index (NFI) and Modified Mini-Mental State (3MS) scores for cognitive functioning of all subjects at follow-up and mortality rate were measured. RESULTS: The NFI mean score was 9.63 (SD = 6.04) and ranged from 0 to 33. This study demonstrated that the NFI was significantly associated with cognitive changes for subjects with heart disease and this correlation was a stronger predictor than age. CONCLUSION: The clinical relevance of this study is that our result supports the prognostic utility of the NFI tool in treatment planning for those with modifiable cardiovascular disease risk factors in the development of dementia.

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.

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.

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.

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.

Microvessel basement membrane reduplication is not associated with repeated nerve fiber degeneration and regeneration.

To determine whether repeated nerve fiber degeneration and regeneration can induce reduplication of endoneurial microvessel basement membranes (BMs), typical of such conditions as diabetic polyneuropathy, electronmicrographs of endoneurial microvessels of rat peroneal and tibial nerves were studied in repeatedly crushed (10 x) sciatic nerves and compared to microvessels of sham-operated uncrushed nerves. On average, crushed nerves had 2.6, SE +/- 0.1 BMs, whereas control nerves had 2.7, SE +/- 0.1 (P > 0.05). Microvessel cellular components were significantly increased in both number and size in the crushed nerves. These nerves also demonstrated a trend to increased vessel numbers and density. These results are not in keeping with the hypothesis that BM reduplication of endoneurial microvessels is simply due to repeated fiber degeneration and regeneration.

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.

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.

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.

A motivational model of leisure participation in the elderly.

We developed a motivational model of leisure participation to examine the factors that may encourage involvement by the elderly in leisure activities. This model posits that opportunities and constraints determine motivation to participate, which in turn predicts satisfaction. Satisfaction is expected to lead to participation. In a study testing the proposed model, 102 elderly Canadians answered a questionnaire assessing the variables in the model. As predicted, results of a path analysis supported the proposed motivational model and accounted for 32% of the variance in the elderly's leisure participation. These results are discussed in the light of self-determination theory (Deci & Ryan, 1985).

{The perception of mental health professionals of barriers to the delivery of mental health services for the aged in New Brunswick}. / La perception des professionnels de la santé mentale quant à la prestation aux personnes âgées du Nouveau-Brunswick des services de consultation en santé mentale.

The present survey examines the barriers associated with the delivery of mental health services to the elderly as perceived by mental health professionals. The sample consisted of 139 professionals of the New Brunswick Mental Health Commission. The results reveal that the mean percentage of elderly clients in the practice of mental health professionals is low. The percentage of elderly clients in the practice of mental health professionals was positively correlated with training in gerontology. The attitudes of the respondents toward the elderly were either positive or neutral rather than negative. In addition, the results show that the barriers perceived by the professionals to explain the low utilization rates differ in order of importance from those acknowledged by the elderly. The lack of human resources was identified as the major barrier to the development of specific consultation services to the elderly. Finally, the implications of these results for the development of mental health consultation services for the elderly are examined.

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.

Time estimation and concurrent nontemporal processing: specific interference from short-term-memory demands.

Previous studies have shown that the effect of concurrent nontemporal processing on time estimation may vary depending on the level of difficulty of the nontemporal task. This is commonly interpreted within the context of so-called distraction/interruption models of temporal processing, which propose that as concurrent task difficulty or complexity is increased, temporal processing receives less attention. We hypothesize that the effect of nontemporal processing does not depend on the level of difficulty as such, but rather on the extent to which the concurrent nontemporal task specifically involves processing in short-term memory. Four experiments were run in which the short-term memory requirements of concurrent tasks were systematically varied, although all of the tasks were of comparable levels of difficulty. In the first experiment, the effect of memory search on simultaneous temporal productions was proportional to the number of items to search. As with reaction time, produced intervals were shown to increase linearly with the number of items in the memorized set. In Experiment 2, a visual search involving some load on short-term memory interfered in the same way with time production, although to a lesser extent. The last two experiments showed that performing attention-demanding visual search tasks that did not involve short-term memory did not lengthen simultaneously produced time intervals. This suggests that interference of nontemporal processing on time processing may not be a matter of nonspecific general purpose attentional resources, but rather of concurrent short-term-memory processing demands.

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.

Effect of functional appliances on jaw muscle activity.

The electromyographic (EMG) activity of masticatory muscles was monitored longitudinally with chronically implanted EMG electrodes to determine whether functional appliances produce a change in postural EMG activity of the muscles. Preappliance and postappliance EMG levels in four experimentals that had been fitted with functional appliances were compared against the background of EMG levels in controls without appliances. The insertion of two types of functional appliance to induce mandibular protrusion was associated with a decrease in postural EMG activity of the superior and inferior heads of the lateral pterygoid, superficial masseter, and anterior digastric muscles; the decrease in the first three muscles was statistically significant. This decreased postural EMG activity persisted for approximately 6 weeks, with a gradual return toward preappliance levels during a subsequent 6-week period of observation. Progressive mandibular advancement of 1.5 to 2 mm every 10 to 15 days did not prevent the decrease in postural EMG activity.