Characteristics of Carpal Tunnel Syndrome in Wild-Type Transthyretin Amyloidosis.

BACKGROUND: Carpal tunnel syndrome (CTS) is one of the most common extra-cardiac manifestations of wild-type transthyretin amyloidosis (wtATTR); however, the characteristics of CTS in this population remain poorly understood. METHODS: This retrospective cohort study reports findings from a single-centre experience of comprehensive neurological screening at the time of wtATTR diagnosis by nerve conduction studies (NCS) and neurologist assessment. RESULTS: Seventy-nine patients underwent neurological screening, 73 (92%) males, mean age 79.2 ± 7.5 years. Seventy-four (94%) had electrodiagnostic findings of median neuropathy at the wrist (MNW), 37 (50%) of which had a prior diagnosis of CTS and 37 (50%) had a new diagnosis of MNW. Over half of wtATTR patients (42, 53%) had bilateral MNW on screening. Most with pre-existing CTS had bilateral disease (28, 76%) and underwent bilateral carpal tunnel release (CTR) (23, 62%) prior to screening. Twenty-one (19%) wrists had mild MNW, 43 (38%) moderate and 49 (43%) severe. Twenty-one (28%) wtATTR patients with MNW were asymptomatic, 10 of which (48%) had moderate disease. Nineteen (36%) wtATTR patients with symptomatic MNW had recurrent disease despite previous CTR. As a result of screening, 36 (68%) patients with symptomatic MNW were referred for CTR. CONCLUSIONS: MNW is exceptionally common at the time of wtATTR diagnosis, affecting 94% of our patients. Most had severe, bilateral MNW on NCS. Some were asymptomatic, despite having moderate disease. The rate of recurrence following CTR was observed to be higher in wtATTR patients than the general population.

Amyloidosis and Carpal Tunnel Syndrome: Surgical Technique for Extended Carpal Tunnel Release with Tenosynovium and Transverse Carpal Ligament Biopsies.

Carpal tunnel syndrome (CTS) is common in patients with transthyretin amyloidosis (ATTR), and many experience residual symptoms and/or develop recurrent disease following routine carpal tunnel release (CTR). An extended CTR with median nerve neurolysis is recommended for thorough nerve decompression. Tissue confirmation of amyloidosis can be performed at the time of CTR with biopsies of the transverse carpal ligament and/or tenosynovium. Methods: We describe a retrospective, single-center experience performing an extended CTR technique including unilateral and bilateral cases for 13 consecutive patients (18 wrists) with ATTR and symptomatic median neuropathy at the wrist. Results: The mean patient age was 83 (range 67-90) years and 11 (85%) were men. Notable intraoperative findings in all cases included thickened tenosynovium and median nerve epineurium, and adherence of the median nerve to the deep surface of transverse carpal ligament. Pathology findings were positive for amyloidosis from both the transverse carpal ligament and the tenosynovium biopsies in all patients. Conclusions: Extended CTR with simultaneous wrist tissue biopsy can be safely performed for ATTR patients with CTS. Characteristic intraoperative findings should increase clinical suspicion for undiagnosed ATTR and prompt performance of biopsy for diagnostic confirmation. Volar wrist tenosynovial biopsy is our preferred tissue for confirmation of ATTR, for patients with and without CTS, given its safety profile and 100% pathological yield in our series.

Gold Coast criteria expand clinical trial eligibility in amyotrophic lateral sclerosis.

INTRODUCTION/AIMS: Consensus criteria to formalize the diagnosis of amyotrophic lateral sclerosis (ALS) and refine clinical trial populations have evolved. The recently proposed Gold Coast consensus criteria are intended to simplify use and increase sensitivity. We aimed to evaluate the potential impact of these criteria on clinical trial eligibility. METHODS: We performed a single-center, retrospective study of people diagnosed with ALS between 2016 and 2021 to determine the numbers of those meeting Gold Coast, revised El Escorial (rEEC) criteria, and Awaji criteria. We identified the proportion of those who would have been eligible for participation in three major ALS clinical trials if Gold Coast were used in place of rEEC definite/probable criteria. (rEEC D/P). RESULTS: Two hundred six people with ALS were included in our study. 48.5% met Gold Coast criteria but not rEEC D/P. Using the Gold Coast criteria would result in higher rates of clinical trial eligibility after other inclusion criteria were met: 95.2% vs 42.5% (P < .001) in a phase III study of riluzole; 100% vs 31.0% (P = .002) in a phase III study of edaravone; and 95.6% vs 45.3% (P < .001) in an ongoing phase III study of sodium phenylbutyrate and taurursodiol. The sensitivity of the Gold Coast criteria (96.1%; 95% confidence interval [CI], 92.2%-98.2%) was significantly higher than that of rEEC D/P (47.6%; 95% CI, 40.6%-54.6%; for difference, χ2  = 117.6; P < .001). DISCUSSION: Until robust biomarkers are available to diagnose ALS, consensus diagnostic criteria remain necessary. Gold Coast criteria would expand research and clinical trial eligibility and improve external validity of clinical trial results.

Canadian Guidelines for Hereditary Transthyretin Amyloidosis Polyneuropathy Management.

Hereditary transthyretin-mediated (hATTR) amyloidosis is a progressive disease caused by mutations in the TTR gene leading to multisystem organ dysfunction. Pathogenic TTR aggregation, misfolding, and fibrillization lead to deposition of amyloid in multiple body organs and frequently involve the peripheral nerve system and the heart. Common neurologic manifestations include: sensorimotor polyneuropathy (PN), autonomic neuropathy, small-fiber PN, and carpal tunnel syndrome. Many patients have significant progression due to diagnostic delays as hATTR PN is not considered within the differential diagnosis. Recently, two effective novel disease-modifying therapies, inotersen and patisiran, were approved by Health Canada for the treatment of hATTR PN. Early diagnosis is crucial for the timely introduction of these disease-modifying treatments that reduce impairments, improve quality of life, and extend survival. In this guideline, we aim to improve awareness and outcomes of hATTR PN by making recommendations directed to the diagnosis, monitoring, and treatment in Canada.

Lignes directrices sur la prise en charge de l'amylose héréditaire à transthyrétine, accompagnée de polyneuropathie, au Canada.L'amylose héréditaire à transthyrétine (ATTRh) est une maladie évolutive, causée par des mutations du gène de la transthyrétine (TTR), qui entraînent un dysfonctionnement plurisystémique. L'agrégation, le mauvais repliement et la fibrillisation pathogènes de la TTR aboutissent au dépôt de protéines amyloïdes dans plusieurs organes, et affectent souvent le système nerveux périphérique et le cœur. Les troubles neurologiques fréquents comprennent une polyneuropathie sensorimotrice (PN), une neuropathie autonome, une polyneuropathie des petites fibres et le syndrome du canal carpien. Chez bon nombre de patients, la maladie a connu une évolution importante en raison de la pose tardive du diagnostic, la PN-ATTRh ne faisant pas l'objet d'un diagnostic différentiel. Santé Canada a approuvé, depuis peu, deux nouveaux médicaments modificateurs de la PN-ATTRh et efficaces contre l'affection, soit l'inotersen et le patisiran. La pose précoce du diagnostic revêt une importance cruciale dans l'instauration, en temps opportun, de ces tout nouveaux traitements qui atténuent les troubles, améliorent la qualité de vie et prolongent la survie. Les auteurs, par l'élaboration de la nouvelle ligne directrice, espèrent sensibiliser la communauté médicale à la PN-ATTRh, et améliorer les résultats cliniques qui y sont associés, en formulant des recommandations sur le diagnostic et le traitement de la maladie au Canada ainsi que sur la surveillance de son évolution.

Gender identity and sexual orientation affect health care satisfaction, but not utilization, in persons with Multiple Sclerosis.

OBJECTIVE: We aimed to determine the association between gender identity and sexual orientation on health care utilization in persons with multiple sclerosis (MS), as well as satisfaction with their doctor and comfort discussing sexual health with their doctor. METHODS: We surveyed participants from the North American Research Committee on Multiple Sclerosis (NARCOMS) Registry regarding their gender identity and sexual orientation in 2017. Participants also reported their sociodemographic characteristics, disability status, health behaviors and health care utilization, including whether any hospitalizations or emergency room (ER) visits occurred or any disease-modifying therapy (DMT) was used within the last six months. We compared the likelihood of hospitalizations, ER visits and DMT use between (i) cisgender and transgender participants; and (ii) heterosexual, homosexual, and "other sexual orientation" participants using multivariable logistic regression models adjusting for potential confounding factors. RESULTS: Of the 5,604 eligible responders, 1168 (20.8%) reported their sex at birth as male and 4436 reported their sex at birth as female (79.2%). Twenty-five (0.45%) participants identified as transgender and 260 (4.6%) as non-heterosexual individuals. As compared to participants who reported their sexual orientation as heterosexual, non-heterosexual participants were younger, with an earlier age at MS symptom onset, more likely to have a post-secondary education, and more likely to be single. The frequency of any ER visits, any hospital admissions, and DMT use did not differ according to gender identity did not differ according to gender identity or sexual orientation. As compared to cisgender participants, transgender participants reported less comfort (p < 0.042) discussing sexual health with their doctor; findings were similar for non-heterosexual participants as compared to heterosexual participants. Participants reporting other sexual orientation also reported lower satisfaction (p < 0.039) with their doctor than other participants. CONCLUSION: Gender identity and sexual orientation were not associated with differences in healthcare utilization in persons with MS. However, health care experiences and satisfaction with care may be altered by gender identity and sexual orientation.

Perturbations in reward-related decision-making induced by reduced prefrontal cortical GABA transmission: Relevance for psychiatric disorders.

The prefrontal cortex (PFC) is critical for higher-order cognitive functions, including decision-making. In psychiatric conditions such as schizophrenia, prefrontal dysfunction co-occurs with pronounced alterations in decision-making ability. These alterations include a diminished ability to utilize probabilistic reinforcement in guiding future choice, and a reduced willingness to expend effort to receive reward. Among the neurochemical abnormalities observed in the PFC of individuals with schizophrenia are alterations in the production and function of the inhibitory neurotransmitter gamma-aminobutyric acid (GABA). To probe how PFC GABA hypofunction may contribute to alterations in cost/benefit decision-making, we assessed the effects GABAA-receptor antagonist bicuculline (BIC; 50 ng in 0.5 µl saline/hemisphere) infusion in the medial PFC of rats during performance on a series of well-validated cost/benefit decision-making tasks. Intra-PFC BIC reduced risky choice and reward sensitivity during probabilistic discounting and decreased the preference for larger rewards associated with a greater effort cost, similar to the behavioral sequelae observed in schizophrenia. Additional experiments revealed that these treatments did not alter instrumental responding on a progressive ratio schedule, nor did they impair the ability to discriminate between reward and no reward. However, BIC induced a subtle but consistent impairment in preference for larger vs. smaller rewards of equal cost. BIC infusion also increased decision latencies and impaired the ability to "stay on task" as indexed by reduced rates of instrumental responding. Collectively, these results implicate prefrontal GABAergic dysfunction as a key contributing factor to abnormal decision-making observed in schizophrenia and other neuropsychiatric conditions with similar neurobiological and behavioral alterations.

Receptor-specific modulation of risk-based decision making by nucleus accumbens dopamine.

The nucleus accumbens (NAc) serves as an integral node within cortico-limbic circuitry that regulates various forms of cost-benefit decision making. The dopamine (DA) system has also been implicated in enabling organisms to overcome a variety of costs to obtain more valuable rewards. However, it remains unclear how DA activity within the NAc may regulate decision making involving reward uncertainty. This study investigated the contribution of different DA receptor subtypes in the NAc to risk-based decision making, assessed with a probabilistic discounting task. In well-trained rats, D1 receptor blockade with SCH 23,390 decreased preference for larger, uncertain rewards, which was associated with enhanced negative-feedback sensitivity (ie, an increased tendency to select a smaller/certain option after an unrewarded risky choice). Treatment with a D1 agonist (SKF 81,297) optimized decision making, increasing choice of the risky option when reward probability was high, and decreasing preference under low probability conditions. In stark contrast, neither blockade of NAc D2 receptors with eticlopride, nor stimulation of these receptors with quinpirole or bromocriptine influenced risky choice. In comparison, infusion of the D3-preferring agonist PD 128,907 decreased reward sensitivity and risky choice. Collectively, these results show that mesoaccumbens DA refines risk-reward decision biases via dissociable mechanisms recruiting D1 and D3, but not D2 receptors. D1 receptor activity mitigates the effect of reward omissions on subsequent choices to promote selection of reward options that may have greater long-term utility, whereas excessive D3 receptor activity blunts the impact that larger/uncertain rewards have in promoting riskier choices.