Genetic testing for amyotrophic lateral sclerosis in Canada - an assessment of current practices.

Objective: To understand current genetic testing practices at Canadian ALS clinics. Methods: An online survey and phone interviews, with clinicians practicing in 27 ALS clinics in Canada, were employed to collect data. Quantitative and qualitative analyses were conducted. Results: Ninety-three percent (25/27) of ALS clinics in Canada are routinely ordering genetic testing for familial ALS, while 33% (9/27) of clinics are routinely ordering genetic testing for sporadic ALS. Barriers to genetic testing include a perceived lack of an impact on treatment plan, difficulty in obtaining approvals, primarily from provincial Ministries of Health, and limited access to genetic counseling. Predictive testing practices were found to be the most variable across the country. The average wait time for a symptomatic patient living with ALS to see a genetic counselor in Canada is 10 months (range 0-36 months). Conclusions: Access to genetic testing, and testing practices, vary greatly across Canadian ALS clinics. There may be patients with a monogenetic etiology to their ALS who are not being identified given that genetic testing for patients diagnosed with ALS is not routinely performed at all clinics. This study highlights potential inequities for patients with ALS that can arise from variability in health care delivery across jurisdictions, in a federally-funded, but provincially-regulated, health care system. Clinical trials for both symptomatic ALS patients and pre-symptomatic ALS gene carriers are ongoing, and ALS clinicians in Canada are motivated to improve access to genetic testing for ALS.

Ultrasound examination predicts 6-month progression in carpal tunnel syndrome patients.

Carpal tunnel syndrome (CTS) is a peripheral neuropathy resulting from chronic median nerve compression. Chronic compression leads to neurological changes that are quantified through nerve conduction studies (NCS). Although NCS represents the gold standard in CTS assessment, they provide limited prognostic value. Several studies have identified ultrasound as a tool in diagnosing and potentially predicting the progression of CTS in patients. The purpose of this study was to evaluate the predictive value of ultrasound examination in CTS patients. Twenty patients recruited at their first visit with the neurologist completed two NCS and ultrasound examinations approximately 6 months apart. Ultrasound examination consisted of B-mode, pulse-wave Doppler and colour Doppler ultrasound videos and images to quantify median nerve cross-sectional area, intraneural blood flow velocity in three wrist postures (15° flexion, neutral, and 30° extension), and displacement of the flexor digitorum superficialis (FDS) tendon and the adjacent subsynovial connective tissue (SSCT) of the middle finger during repetitive finger flexion-extension cycles. A questionnaire was administered to assess the work-relatedness of CTS. Linear regression analyses revealed that intraneural blood flow velocity (R2 = 0.36, p = .03), assessed in wrist flexion, and relative FDS-SSCT displacement (R2 = 0.27, p = .04) and shear strain index (R2 = 0.28, p = .04) were significant predictors of nerve sensory and motor changes at 6 months. Results suggest the possibility of using a battery of ultrasound measures as viable markers to predict median nerve functional changes within 6 months.

Blood flow velocity but not tendon mechanics relates to nerve function in carpal tunnel syndrome patients.

Carpal tunnel syndrome (CTS) develops from chronic compression of the median nerve. Chronic compression results in a number of vascular, structural and functional changes to the carpal tunnel tissues which ultimately manifest in the characteristic symptoms of CTS. The purpose of this study was to investigate the interplay of median nerve function, median nerve hemodynamics, and finger flexor tendon and subsynovial connective tissue (SSCT) mechanics in CTS patients. Thirty-five patients were recruited following nerve conduction study for this double-blinded imaging study. Ultrasound B-mode, pulse-wave Doppler, and colour Doppler images and videos were collected at the proximal carpal tunnel to quantify: (1) median nerve cross-sectional area, (2) intraneural blood flow velocity in 3 wrist postures (neutral (0°), flexion (15°), extension (30°)), and (3) flexor digitorum superficialis and SSCT displacement. Results demonstrate that intraneural blood flow velocity is dependent on median nerve function and wrist posture such that patients with mild CTS are more susceptible to the effects of non-neutral wrist postures. Tendon-SSCT mechanics do not appear to differ based on severity. This study stresses the importance of limiting exposure to non-neutral wrist postures in patients with early signs of the condition.

Correction to: A review of electrophysiological studies of lower motor neuron involvement in amyotrophic lateral sclerosis.

The published version of this article unfortunately contained a mistake. The sequence of authorship and the corresponding author is incorrect. The correct sequence and corresponding author is presented here.

A review of electrophysiological studies of lower motor neuron involvement in amyotrophic lateral sclerosis.

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease involving both the upper and lower motor neuron diseases. In this review, we studied and compared different articles regarding the electrodiagnostic criteria for diagnosis of lower motor neuron pathology in ALS. We reviewed the most recent articles and metaanalysis regarding various lower motor neuron electrodiagnostic methods for ALS and their sensitivities. We concluded that Awaji Shima criteria is by far the most sensitive criteria for diagnosis of ALS.

Central Nervous System-Toxic Lidocaine Concentrations Unmask L-Type Ca²âº Current-Mediated Action Potentials in Rat Thalamocortical Neurons: An In Vitro Mechanism of Action Study.

BACKGROUND: High systemic lidocaine concentrations exert well-known toxic effects on the central nervous system (CNS), including seizures, coma, and death. The underlying mechanisms are still largely obscure, and the actions of lidocaine on supraspinal neurons have received comparatively little study. We recently found that lidocaine at clinically neurotoxic concentrations increases excitability mediated by Na-independent, high-threshold (HT) action potential spikes in rat thalamocortical neurons. Our goal in this study was to characterize these spikes and test the hypothesis that they are generated by HT Ca currents, previously implicated in neurotoxicity. We also sought to identify and isolate the specific underlying subtype of Ca current. METHODS: We investigated the actions of lidocaine in the CNS-toxic concentration range (100 µM-1 mM) on ventrobasal thalamocortical neurons in rat brain slices in vitro, using whole-cell patch-clamp recordings aided by differential interference contrast infrared videomicroscopy. Drugs were bath applied; action potentials were generated using current clamp protocols, and underlying currents were identified and isolated with ion channel blockers and electrolyte substitution. RESULTS: Lidocaine (100 µM-1 mM) abolished Na-dependent tonic firing in all neurons tested (n = 46). However, in 39 of 46 (85%) neurons, lidocaine unmasked evoked HT action potentials with lower amplitudes and rates of de-/repolarization compared with control. These HT action potentials remained during the application of tetrodotoxin (600 nM), were blocked by Cd (50 µM), and disappeared after superfusion with an extracellular solution deprived of Ca. These features implied that the unmasked potentials were generated by high-voltage-activated Ca channels and not by Na channels. Application of the L-type Ca channel blocker, nifedipine (5 µM), completely blocked the HT potentials, whereas the N-type Ca channel blocker, ω-conotoxin GVIA (1 µM), had little effect. CONCLUSIONS: At clinically CNS-toxic concentrations, lidocaine unmasked in thalamocortical neurons evoked HT action potentials mediated by the L-type Ca current while substantially suppressing Na-dependent excitability. On the basis of the known role of an increase in intracellular Ca in the pathogenesis of local anesthetic neurotoxicity, this novel action represents a plausible contributing candidate mechanism for lidocaine's CNS toxicity in vivo.

Truths and misinformation: a qualitative exploration of myotonic dystrophy.

BACKGROUND: Myotonic dystrophy (DM1) is an autosomal dominant, progressive, and multisystem condition that impacts affected individuals physically, socially, and emotionally. Understanding individuals' perceptions of their disease is critical to ensuring appropriate information, education, and counseling. METHODS: We conducted a content analysis of findings from a larger study that used a novel, qualitative research approach called photovoice to explore nine patients' experiences of living with DM1. Participants took pictures that illustrated barriers or facilitators to living with DM1; their photographs then formed the basis of semistructured interviews. Transcripts were analyzed and, among themes, we identified one titled "DM1 truths and misinformation" that described participants' disease knowledge. Analysis revealed four categories within this broader theme: "the physical and emotional cost of DM1," "managing my DM1," "genetics and me" and "patients as advocates and educators." RESULTS: Findings showed that DM1 participants had good core knowledge with respect to their disease and its implications. However, each participant held as fact fragments of misinformation that shaped decision-making and pointed to a clear need for strategies to mitigate variable interpretation of health information. CONCLUSIONS: We conclude that there is a need for increased education and awareness about symptoms, genetic information and treatment strategies for patients, their family members, and health care providers.

Revisiting the evidence for neuropathy caused by pyridoxine deficiency and excess.

Pyridoxine deficiency and excess have been implicated as a cause for peripheral neuropathy. As a result, unrelated neuropathies are often treated with pyridoxine based on questionable evidence. However, neurological practitioners frequently discourage patients from taking pyridoxine in excess of 50 mg/d given concerns around the development of a toxic sensory neuronopathy. There is no systematic review to support either of the 2 practices. To address this gap in knowledge, we reviewed the available literature on neuropathy attributed to pyridoxine deficiency and excess. Based on the current limited data, it can be concluded that very low doses of daily pyridoxine are required to prevent peripheral neuropathy. There is inadequate evidence to support routine pyridoxine supplementation in patients with disorders of peripheral nervous system. Supplementation with pyridoxine at doses greater than 50 mg/d for extended duration may be harmful and should be discouraged.

Management of patients with spontaneous intracranial hypotension causing altered level of consciousness: report of two cases and review of literature.

BACKGROUND: Decreased level of consciousness is a rare neurological manifestation of spontaneous intracranial hypotension (SIH), which typically presents with orthostatic headache. The optimal management of this uncommon presentation remains uncertain. METHODS: We analyzed the presentation, management and outcome of two patients in our institution and reviewed 22 patients reported in the literature with SIH and decreased level of consciousness, defined as any decrease in the patient's Glasgow Coma Scale score. RESULTS: There were 20 male and four female patients (M:F ratio of 5:1) with an average age of 52 years (range 37 to 68 years). There was a variable time interval of up to many months between the initial presentation of SIH and changes in the level of consciousness. An epidural autologous blood patch was eventually successful in 79% of the patients, although up to three trials were necessary in seven of these patients. Intrathecal saline infusion used as a temporizing measure resulted in excellent response within hours in five out of six patients who received this treatment. Drainage of the subdural collection either did not result in any sustained improvement or resulted in clinical deterioration in 12 out of 12 patients who received this treatment. CONCLUSIONS: In the absence of a clinical trial because of the rarity of this entity, the treatment of SIH complicated by decreased level of consciousness remained controversial in the past. However, current collective experience supports early treatment of patients with SIH and decreased level of consciousness with one or more epidural blood patches. Fibrin glue and surgical duroplasty are the next steps in the management of patients in whom epidural blood patches fail. Drainage of the subdural collections may be detrimental.

Comparison of infectious and noninfectious intracranial caseating granulomas.

Although caseating granulomas are classically associated with infectious processes, a subgroup of intracranial caseating granulomas without identifiable infectious pathology (ICGN) is described. We aimed to identify clinical, laboratory, radiological and histological markers with potential to distinguish patients with ICGN from those with intracranial caseating granulomas with infectious etiology (ICGI) on tissue microbiological examinations. In a referral hospital setting, we identified 11 patients with ICGNs and 6 patients with ICGI over an 11-year period. The two groups had similar demographics (other than higher infection risk factors in ICGIs), clinical presentation, serology, location of lesions and cellular composition of the inflammatory infiltrate. Significant differences were the homogenous vs. ring pattern of enhancement on neuroimaging and small (<1 mm) vs. large (>1 mm) area of necrosis on histological examination, in ICGNs and ICGIs, respectively. The dichotomy was best reflected in the response of ICGNs to immunomodulatory and not antimicrobial treatment and the reverse pattern in ICGIs. Based on these findings, we suggest a scheme for the diagnosis of ICGN: (i) caseating granulomas with areas of necrosis predominantly <1 mm in diameter; (ii) absence of an identifiable infectious agent in extensive tissue examinations; and (iii) no clinical and radiological response within 2 months of appropriate antimicrobial treatment.

Intracranial caseating granulomas with no infectious organism detected.

BACKGROUND: Caseating granuloma is a classic histopathological feature of mycobacterial infections. Occasionally, no infectious organism is demonstrated despite extensive examination of intracranial caseating granulomas. The pathogenesis and optimal management strategy for patients with such intracranial caseating granulomas with no detectable infectious organism (ICGNs) remain unclear. METHODS: The study was a retrospective case-series design in a referral hospital setting. Patients with intracranial caseating granulomas in whom no infectious etiology was identified after appropriate investigations were reviewed. RESULTS: Eight patients with ICGN (four females and four males) were identified in an eight-year-period. Average age on presentation was 46 years (range 21-69 years). Cerebrospinal fluid showed lymphocytic pleocytosis, elevated protein and decreased glucose. Neuroimaging showed multiple or single intraparenchymal and meningeal enhancements. Intracranial ICGN were demonstrated on biopsy. Immunomodulation was tried and resulted in improvement in five out of eight patients. In four patients, anti-mycobacterial treatment resulted in no improvement or worsening of clinical or radiological features. CONCLUSIONS: The response to therapy of intracranial caseating granulomas where no organism is identified after thorough investigations hints to non-infectious causes, and suggests current dogma regarding the significance of necrosis in granulomatous diseases should be re-evaluated. Our retrospective series suggests that patients may benefit from an early trial of immunomodulation therapy, a hypothesis to be tested in a randomized trial.

Optimizing fluctuation analysis of GABAAergic IPSCs for accurate unitary currents.

Nonstationary fluctuation analysis of synaptic currents requires division of currents into bins of time, with little agreement on how to select an optimal bin width. We used simulated inhibitory postsynaptic currents (simIPSCs) in an empirical approach to establish the optimal bin width needed for estimation of the unitary current, ie. We found acceptable accuracy (< or = 5%) at bin widths shorter than the length of the stationary segment of simIPSCs that persisted when Gaussian noise was added to the simulated currents. We also studied evoked and spontaneous IPSCs mediated by receptors for gamma-aminobutyrate (GABA) in thalamic neurons. Similar to simIPSCs, analysis of the IPSCs yielded saturating relationships between bin width and accuracy of unitary current estimate. Whereas standard error decreased, the accuracy of ie estimates increased with decreasing bin width, forming a plateau at bins below 2-3 ms in duration. Using this approach, one can reliably determine the optimal bin width for nonstationary noise analysis.

Distinctive glycinergic currents with fast and slow kinetics in thalamus.

We examined functional properties of inhibitory postsynaptic currents (IPSCs) evoked by medial lemniscal stimulation, spontaneous IPSCs (sIPSCs), and single-channel, extrasynaptic currents evoked by glycine receptor agonists or gamma-aminobutyric acid (GABA) in rat ventrobasal thalamus. We identified synaptic currents by reversal at E(Cl) and sensitivity to elimination by strychnine, GABA(A) antagonists, or combined application. Glycinergic IPSCs featured short (about 12 ms) and long (about 80 ms) decay time constants. These fast and slow IPSCs occurred separately with monoexponential decays, or together with biexponential decay kinetics. Glycinergic sIPSCs decayed monoexponentially with time constants, matching fast and slow IPSCs. These findings were consistent with synaptic responses generated by two populations of glycine receptors, localized under different nerve terminals. Glycine, taurine, or beta-alanine applied to excised membrane patches evoked short- and long-duration current bursts. Extrasynaptic burst durations resembled fast and slow IPSC time constants. The single, intermediate time constant (about 22 ms) of GABA(A)ergic IPSCs cotransmitted with glycinergic IPSCs approximated the burst duration of extrasynaptic GABA(A) channels. We noted differences between synaptic and extrasynaptic receptors. Endogenously activated glycine and GABA(A) receptor channels had higher Cl- permeability than that of their extrasynaptic counterparts. The beta-amino acids activated long-duration bursts at extrasynaptic glycine receptors, consistent with a role in detection of ambient taurine or beta-alanine. Heterogeneous kinetics and permeabilities implicate molecular and functional diversity in thalamic glycine receptors. Fast, intermediate, and slow inhibitory postsynaptic potential decays, mostly attributed to cotransmission by glycinergic and GABAergic pathways, allow for discriminative modulation and integration with voltage-dependent currents in ventrobasal neurons.