Congenital Myasthenic Syndromes with COLQ mutations: Long term follow-up

Congenital myasthenic syndromes (CMS) are clinically and genetically heterogeneous inherited disorders characterized by impaired neuromuscular transmission. Mutations in the acetylcholinesterase (AChE) collagenlike tail subunit gene (ColQ) cause recessive forms of synaptic CMS with end plate AChE deficiency. We report the time course of clinical manifestations in 15 COLQ-mutated patients followed from 1987 to 2010. All patients suffered from a muscle weakness with onset at birth or in childhood. Ocular and bulbar signs were found in 60% of the patients and delayed pupillary light response in 20% of our patients. EMG study demonstrated a decrement on repetitive nerve stimulation and repetitive compound muscle action potential in all patients. Clinical symptoms strongly fluctuated daily, weekly, monthly or even yearly. Severe relapses were characterized by a general motor weakness associated with pain which resolved spontaneously after a few months whereas the relapses with these symptoms and bulbar signs could last up to several years. Genetic analyses identified 16 different mutations including 9 novel ones. There was no genotype-phenotype correlation. Our study confirms the predominance of oculobulbar signs and the frequency of respiratory distress in COLQrelated CMS. At the end of the follow up of 23 years, interesting findings were (i) the spontaneous reversibility of severe relapses, some of them lasting for up to 5 years (ii) the good prognosis of COLQ-related CMS, since at the end of the follow-up 80% of patients were ambulant and 87% of patients had no respiratory trouble (iii) the efficacy of Ephedrine and, to a lesser extend, of 3-4 DAP. The triggering factors of relapses were esterase inhibitors, effort, puberty, pregnancy and delivery highlighting the importance of hormonal factors in CMS. In conclusion, patients diagnosed with unknown congenital myopathy should undergo an electrophysiological study of neuromuscular junction to identify ColQ-related CMS.

Revue critique d'instruments pour evaluer la douleur chez les personnes cérébrolésées non communicantes aux soins intensifs [Critical review of instruments to assess pain in the non communicative brain injured persons in intensive care].

The purpose of this review is to critically appraise the pain assessment tools for non communicative persons in intensive care available in the literature and to determine their relevance for those with brain injury. Nursing and medical electronic databases were searched to identify pain tools, with a description of psychometric proprieties, in English and French. Seven of the ten tools were considered relevant and systematically evaluated according to the criteria and the indicators in the following five areas: conceptualisation, target population, feasibility and clinical utility, reliability and validity. Results indicate a number of well designed pain tools, but additional work is necessary to establish their accuracy and adequacy for the brain injured non communicative person in intensive care. Recommendations are made to choose the best tool for clinical practice and for research.

p.L1612P, a novel voltage-gated sodium channel Nav1.7 mutation inducing a cold sensitive paroxysmal extreme pain disorder.

BACKGROUND: Mutations in the SCN9A gene cause chronic pain and pain insensitivity syndromes. We aimed to study clinical, genetic, and electrophysiological features of paroxysmal extreme pain disorder (PEPD) caused by a novel SCN9A mutation. METHODS: Description of a 4-generation family suffering from PEPD with clinical, genetic and electrophysiological studies including patch clamp experiments assessing response to drug and temperature. RESULTS: The family was clinically comparable to those reported previously with the exception of a favorable effect of cold exposure and a lack of drug efficacy including with carbamazepine, a proposed treatment for PEPD. A novel p.L1612P mutation in the Nav1.7 voltage-gated sodium channel was found in the four affected family members tested. Electrophysiologically the mutation substantially depolarized the steady-state inactivation curve (V1/2 from -61.8 ± 4.5 mV to -30.9 ± 2.2 mV, n = 4 and 7, P < 0.001), significantly increased ramp current (from 1.8% to 3.4%, n = 10 and 12) and shortened recovery from inactivation (from 7.2 ± 5.6 ms to 2.2 ± 1.5 ms, n = 11 and 10). However, there was no persistent current. Cold exposure reduced peak current and prolonged recovery from inactivation in wild-type and mutated channels. Amitriptyline only slightly corrected the steady-state inactivation shift of the mutated channel, which is consistent with the lack of clinical benefit. CONCLUSIONS: The novel p.L1612P Nav1.7 mutation expands the PEPD spectrum with a unique combination of clinical symptoms and electrophysiological properties. Symptoms are partially responsive to temperature but not to drug therapy. In vitro trials of sodium channel blockers or temperature dependence might help predict treatment efficacy in PEPD.

Congenital heart defects in Europe: prevalence and perinatal mortality, 2000 to 2005.

BACKGROUND: This study determines the prevalence of Congenital Heart Defects (CHD), diagnosed prenatally or in infancy, and fetal and perinatal mortality associated with CHD in Europe. METHODS AND RESULTS: Data were extracted from the European Surveillance of Congenital Anomalies central database for 29 population-based congenital anomaly registries in 16 European countries covering 3.3 million births during the period 2000 to 2005. CHD cases (n=26 598) comprised live births, fetal deaths from 20 weeks gestation, and terminations of pregnancy for fetal anomaly (TOPFA). The average total prevalence of CHD was 8.0 per 1000 births, and live birth prevalence was 7.2 per 1000 births, varying between countries. The total prevalence of nonchromosomal CHD was 7.0 per 1000 births, of which 3.6% were perinatal deaths, 20% prenatally diagnosed, and 5.6% TOPFA. Severe nonchromosomal CHD (ie, excluding ventricular septal defects, atrial septal defects, and pulmonary valve stenosis) occurred in 2.0 per 1000 births, of which 8.1% were perinatal deaths, 40% were prenatally diagnosed, and 14% were TOPFA (TOPFA range between countries 0% to 32%). Live-born CHD associated with Down syndrome occurred in 0.5 per 1000 births, with > 4-fold variation between countries. CONCLUSION: Annually in the European Union, we estimate 36 000 children are live born with CHD and 3000 who are diagnosed with CHD die as a TOFPA, late fetal death, or early neonatal death. Investing in primary prevention and pathogenetic research is essential to reduce this burden, as well as continuing to improve cardiac services from in utero to adulthood.

Intrauterine exposure to carbamazepine and specific congenital malformations: systematic review and case-control study.

OBJECTIVE: To identify specific major congenital malformations associated with use of carbamazepine in the first trimester of pregnancy. DESIGN: A review of all published cohort studies to identify key indications and a population based case-control study to test these indications. SETTING: Review of PubMed, Web of Science, and Embase for papers about carbamazepine exposure in the first trimester of pregnancy and specific malformations, and the EUROCAT Antiepileptic Study Database, including data from 19 European population based congenital anomaly registries, 1995-2005. PARTICIPANTS: The literature review covered eight cohort studies of 2680 pregnancies with carbamazepine monotherapy exposure, and the EUROCAT dataset included 98 075 registrations of malformations covering over 3.8 million births. MAIN OUTCOME MEASURES: Overall prevalence for a major congenital malformation after exposure to carbamazepine monotherapy in the first trimester. Odds ratios for malformations with exposure to carbamazepine among cases (five types of malformation identified in the literature review) compared with two groups of controls: other non-chromosomal registrations of malformations and chromosomal syndromes. RESULTS: The literature review yielded an overall prevalence for a major congenital malformation of 3.3% (95% confidence interval 2.7 to 4.2) after exposure to carbamazepine monotherapy in the first trimester. In 131 registrations of malformations, the fetus had been exposed to carbamazepine monotherapy. Spina bifida was the only specific major congenital malformation significantly associated with exposure to carbamazepine monotherapy (odds ratio 2.6 (95% confidence interval 1.2 to 5.3) compared with no antiepileptic drug), but the risk was smaller for carbamazepine than for valproic acid (0.2, 0.1 to 0.6). There was no evidence for an association with total anomalous pulmonary venous return (no cases with carbamazepine exposure), cleft lip (with or without palate) (0.2, 0.0 to 1.3), diaphragmatic hernia (0.9, 0.1 to 6.6), or hypospadias (0.7, 0.3 to 1.6) compared with no exposure to antiepileptic drugs. Further exploratory analysis suggested a higher risk of single ventricle and atrioventricular septal defect. CONCLUSION: Carbamazepine teratogenicity is relatively specific to spina bifida, though the risk is less than with valproic acid. Despite the large dataset, there was not enough power to detect moderate risks for some rare major congenital malformations.

De l'invalide à l'adunatos: réflexions sur l'invalidité et le trouble somatoforme douloureux [From disability to the adunatos: some thoughts on disability and somatoform pain disorder].

Disability, especially if related to a psychiatric disorder, such as somatoform pain disorder, is characterized by medical, psychological, relational, social and societal, as well as financial and political aspects. This manuscript, part of a PhD thesis which reflects on a possible dialogue between an ancient text and the modern conceptualization of disability, tries to address the phenomenological, historical and political dimensions of disability.

Implementation study of a clinical prediction score to rule out cardiogenic chest pain in community: Cluster randomized trial

1.1 Fundamentals Chest pain is a common complaint in primary care patients (1 to 3% of all consultations) (1) and its aetiology can be miscellaneous, from harmless to potentially life threatening conditions. In primary care practice, the most prevalent aetiologies are: chest wall syndrome (43%), coronary heart disease (12%) and anxiety (7%) (2). In up to 20% of cases, potentially serious conditions as cardiac, respiratory or neoplasic diseases underlie chest pain. In this context, a large number of laboratory tests are run (42%) and over 16% of patients are referred to a specialist or hospitalized (2).¦A cardiovascular origin to chest pain can threaten patient's life and investigations run to exclude a serious condition can be expensive and involve a large number of exams or referral to specialist -­‐ often without real clinical need. In emergency settings, up to 80% of chest pains in patients are due to cardiovascular events (3) and scoring methods have been developed to identify conditions such as coronary heart disease (HD) quickly and efficiently (4-­‐6). In primary care, a cardiovascular origin is present in only about 12% of patients with chest pain (2) and general practitioners (GPs) need to exclude as safely as possible a potential serious condition underlying chest pain. A simple clinical prediction rule (CPR) like those available in emergency settings may therefore help GPs and spare time and extra investigations in ruling out CHD in primary care patients. Such a tool may also help GPs reassure patients with more common origin to chest pain.

Trunk neuromuscular responses to a single whole-body vibration session in patients with chronic low back pain: a cross-sectional study.

OBJECTIVE: Whole-body vibration (WBV) exercise is progressively adopted as an alternative therapeutic modality for enhancing muscle force and muscle activity via neurogenic potentiation. So far, possible changes in the recruitment patterns of the trunk musculature after WBV remain undetermined. The main objective of this study was to evaluate the short-term effects of a single WBV session on trunk neuromuscular responses in patients with chronic low back pain (cLBP) and healthy participants. METHODS: Twenty patients with cLBP and 21 healthy participants performed 10 trunk flexion-extensions before and after a single WBV session consisting of five 1-minute vibration sets. Surface electromyography (EMG) of erector spinae at L2-L3 and L4-L5 and lumbopelvic kinematic variables were collected during the trials. Data were analyzed using 2-way mixed analysis of variance models. RESULTS: The WBV session led to increased lumbar EMG activity during the flexion and extension phases but yielded no change in the quiet standing and fully flexed phases. Kinematic data showed a decreased contribution to the movement of the lumbar region in the second extension quartile. These effects were not different between patients with cLBP and healthy participants. CONCLUSIONS: Increased lumbar EMG activity after a single WBV session most probably results from potentiation effects of WBV on lumbar muscles reflex responses. Decreased EMG activity in full trunk flexion, usually observed in healthy individuals, was still present after WBV, suggesting that the ability of the spine stabilizing mechanisms to transfer the extension torque from muscles to passive structures was not affected.

Indicators used by clinicians to assess pain in the brain injured

INTRODUCTION. The assessment of pain in critically ill brain-injured patients is challenging for health professionals. In addition to be unable to self-report, the confused and stereotyped behaviors of these patients are likely to alter their ''normal'' pain responses. Therefore, the pain indicators observed in the general critically ill population may not be appropriate. OBJECTIVES. To identify behavioral and physiological indicators used by clinicians to assess pain in critically ill brain-injured patients who are unable to self-report. METHODS.Amixed-method design was used with the first step being the combination of the results of an integrative literature review with the results of nominal groups of 12 nurses and four physicians. The second step involved a web-based survey to establish content validity. Fourteen experts (clinicians and academics) from three French speaking European countries rated the relevance of each indicator. A content validity index (CVI) was computed for each indicator (I-CVI) and for each category (S-CVI). RESULTS. The first step generated 52 indicators. These indicators were classified into six categories: facial expressions, position/movement, muscle tension, vocalization, compliance with ventilator, and physiological indicators. In the second step, the agreement between raters was high with an Intraclass Correlation Coefficient of 0.88 (95% CI 0.83-0.92). The I-CVIs ranged from 0.07 to 1. Indicators with an I-CVI below 0.5 (n = 12) were not retained, resulting in a final list of 30 indicators. The CVI for this final list was 0.75 with categories ranging from 0.67 (compliance with ventilation) to 0.87 (vocalization). CONCLUSIONS. This process identified specific pain indicators for critically ill braininjured patients. Further evaluation is in progress to test the validity and relevance of these indicators in the clinical setting.