Transthyretin amyloid polyneuropathy in France: A cross-sectional study with 413 patients and real-world tafamidis meglumine use (2009-2019).

OBJECTIVE: We aimed to describe characteristics of patients with ATTR variant polyneuropathy (ATTRv-PN) and ATTRv-mixed and assess the real-world use and safety profile of tafamidis meglumine 20mg. METHODS: Thirty-eight French hospitals were invited. Patient files were reviewed to identify clinical manifestations, diagnostic methods, and treatment compliance. RESULTS: Four hundred and thirteen patients (296 ATTRv-PN, 117 ATTRv-mixed) were analyzed. Patients were predominantly male (68.0%) with a mean age of 57.2±17.2 years. Interval between first symptom(s) and diagnosis was 3.4±4.3 years. First symptoms included sensory complaints (85.9%), dysautonomia (38.5%), motor deficits (26.4%), carpal tunnel syndrome (31.5%), shortness of breath (13.3%), and unexplained weight loss (16.0%). Mini-invasive accessory salivary gland or punch skin and nerve biopsies were most common, with a performance of 78.8-100%. TTR genetic sequencing, performed in all patients, revealed 31 TTR variants. Tafamidis meglumine was initiated in 156/214 (72.9%) ATTRv-PN patients at an early disease stage. Median treatment duration was 6.00 years in ATTRv-PN and 3.42 years in ATTRv-mixed patients. Tafamidis was well tolerated, with 20 adverse events likely related to study drug among the 336 patients. CONCLUSION: In France, ATTRv patients are usually identified early thanks to the national network and the help of diagnosis combining genetic testing and mini-invasive biopsies.

An amyotrophic lateral sclerosis hot spot in the French Alps associated with genotoxic fungi.

Between 1990 and 2018, 14 cases of amyotrophic lateral sclerosis (ALS) were diagnosed in residents of, and in visitors with second homes to, a mountainous hamlet in the French Alps. Systematic investigation revealed a socio-professional network that connected ALS cases. Genetic risk factors for ALS were excluded. Several known environmental factors were scrutinized and eliminated, notably lead and other chemical contaminants in soil, water or home-grown vegetation used for food, radon and electromagnetic fields. Some lifestyle-related behavioral risk factors were identified: Prior to clinical onset of motor neuron disease, some patients had a high degree of athleticism and smoked tobacco. Recent investigations on site, based on a new hypothesis, showed that all patients had ingested wild mushrooms, notably poisonous False Morels. Half of the ALS cohort reported acute illness following Gyromitra gigas mushroom consumption. This finding supports the hypothesis that genotoxins of fungal origin may induce motor neuron degeneration.

ALS and environment: Clues from spatial clustering?

A role for environmental factors in the etiology of amyotrophic lateral sclerocis (ALS) has been suspected for many years. A large body of work has implicated common exposures, conjugal cases, at-risk activities, heavy metals, organic solvents, and electric shocks, among others. One of the most demonstrative relationships between ALS and the environment is spatial clustering. We reviewed the most important and recent spatial clusters in a given area, whatever the geographical size, with either substantial epidemiological approaches or with highly significant associations, and with precise hypotheses. We present a broad, albeit incomplete overview of investigations in different areas, including examples of the difficulties and contradictions of some approaches. Most of the time, the implication of neurotoxins is suspected and, although not always strictly identified, some candidates are emerging: cycasin, MAM, L-BMAA, hydrazine, for example. One other important point is the possibility of interaction among risk/causal factors that increase the complexity of investigation. Additionally, with the exception of Western Pacific ALS, studies of spatial clustering are lacking a major methodological approach, namely a large cohort analysis extended over a long period of time, and probably for decades. Nevertheless, any spatial cluster needs to be identified, described and studied as deeply as possible to illuminate knowledge of the origin of this devastating disorder and to promote primary or secondary disease prevention.

[Neurologic disorders and Hepatitis E: Review of literature]. / Trouble neurologique et hépatite E : revue de la littérature.

INTRODUCTION: Hepatitis E is an emerging, worldwide disease. It is often asymptomatic. Nevertheless, in few cases, clinical manifestation such as neurological disorder could be present. The aim of this article is to realize a literature review of the neurological symptoms associated with hepatitis E. METHODS: We searched the Pubmed database using the term "hepatitis E", "neurological disorder AND hepatitis E". RESULTS: One hundred and thirty cases have been described between 2000 and 2017. The majority of cases were associated with the genotype 3 and were reported in Europe or in Asia. It preferentially affected immunocompetent (93%) men with a median age of 52 years. The main neurologic disorders were Guillain-Barré syndrome (54 cases), Parsonage-Turner syndrome (35 cases), multiplex mononeuropathy (6 cases), meningitis and meningoencephalitis (9 cases). The diagnosis was done with HEV IgM serology in most cases (98%). Aminotranferases increase and cholestasis were found in 88% and 82% respectively. The outcome varied according to the neurological syndrome. Antiviral or immunomodulatory therapies did not seem to improve symptoms. CONCLUSION: Hepatitis E seems to be associated with acute, wide neurological disorders. These data should be confirmed with a long term prospective study.

[Limitations of active therapeutic and palliative care in chronic respiratory disease]. / Intensité des soins lors des exacerbations et des complications des pathologies respiratoires chroniques.

The issue of intensive and palliative care in patients with chronic disease frequently arises. This review aims to describe the prognostic factors of chronic respiratory diseases in stable and in acute situations in order to improve the management of these complex situations. The various laws on patients' rights provide a legal framework and define the concept of unreasonable obstinacy. For patients with chronic obstructive pulmonary disease, the most robust decision factors are good knowledge of the respiratory disease, the comorbidities, the history of previous exacerbations and patient preferences. In the case of idiopathic pulmonary fibrosis, it is necessary to know if there is a prospect of transplantation and to assess the reversibility of the respiratory distress. In the case of amyotrophic lateral sclerosis, treatment decisions depend on the presence of advance directives about the use of intubation and tracheostomy. For lung cancer patients, general condition, cancer history and the tumor treatment plan are important factors. A multidisciplinary discussion that takes into account the patient's medical history, wishes and the current state of knowledge permits the taking of a coherent decision.

Antibodies to clustered acetylcholine receptor: expanding the phenotype.

BACKGROUND AND PURPOSE: To provide a detailed phenotypical description of seronegative patients with generalized myasthenia gravis and antibodies to clustered acetylcholine receptors (AChRs) and to assess their frequency amongst a French seronegative generalized myasthenia gravis (SNMG) population. METHODS: A French SNMG database was created and the sera from the 37 patients included in it were analysed by immunofluorescence of cell-based assays using cotransfection of AChR subunit genes together with rapsyn to densely cluster the AChRs. RESULTS: Sixteen per cent (n = 6) of the SNMG patients were found to have antibodies to clustered AChR. They presented either with early onset MG and thymic hyperplasia, late onset MG and thymic involution, or thymoma associated MG. They responded well to cholinesterase inhibitors and immunosuppressants. CONCLUSIONS: Patients with antibodies to clustered AChR account for a significant proportion of SNMG patients and resemble patients with AChR antibodies detected by standard radio-immunoprecipitation.

Assessement of quadriceps strength, endurance and fatigue in FSHD and CMT: benefits and limits of femoral nerve magnetic stimulation.

OBJECTIVES: To (i) evaluate the feasibility and the reliability of a test assessing quadriceps strength, endurance and fatigue in patients with fascioscapulohumeral dystrophy (FSHD) and Charcot-Marie-Tooth disease (CMT), (ii) compare quadriceps function between patients and healthy controls. METHODS: Controls performed the test once and patients twice on two separate visits. It involved progressive sets of 10 isometric contractions each followed by neuromuscular assessments with FNMS. RESULTS: Volitional assessment of muscle strength, endurance and fatigue appeared to be reliable in FSHD and CMT patients. Supramaximal FNMS was achieved in ∼70% of FSHD patients and in no CMT patients. In FSHD patients, Femoral nerve magnetic stimulation (FNMS) provided reliable assessment of central (typical error as a coefficient of variation (CVTE)<8% for voluntary activation) and peripheral (CVTE<10% and intraclass coefficient correlation >0.85 for evoked responses) function. Patients and controls had similar reductions in evoked quadriceps responses, voluntary activation and similar endurance. CONCLUSIONS: This test provides reliable evaluation but FNMS exhibits limitations due to insufficient stimulation intensity particularly in neurogenic conditions. It showed similar central and peripheral quadriceps fatigability in patients and controls. SIGNIFICANCE: This test may be a valuable tool for patient follow-up although further development of magnetic stimulation devices is needed to extend its applicability.

Acute bilateral mydriasis associated with anti-GQ1b antibody.

Miller Fisher syndrome (MFS) is an autoimmune neuropathy characterized by external ophthalmoplegia, ataxia and areflexia. Mydriasis is present in 35% of typical MFS. We report five patients with acute bilateral mydriasis, either isolated or associated with external ophthalmoplegia for which the presumed diagnosis of "atypical MFS" was confirmed by the positivity of anti-GQ1b antibodies. Acute bilateral mydriasis raises important differential diagnoses in clinical practice. This report demonstrates that acute mydriasis can be autoimmune mediated and that anti-GQ1b antibodies are useful to confirm the diagnosis in unexplained cases.

[Validation of a French version of the short form of the Pelvic Organ Prolapse/Urinary Incontinence Sexual Questionnaire (PISQ-12)]. / Validation linguistique en français de la version courte du questionnaire sur la sexualité (PISQ-12) chez les patientes présentant un prolapsus génital et/ou une incontinence urinaire.

INTRODUCTION: The aim of this paper was to report a linguistically validated French version of the PISQ-12. PATIENTS AND METHODS: French validated version of the PISQ-12 was developed after two independent translations (English-French), one back-translation (French-English), a review by two French clinicians skilled in urogynecology and a testing on a sample of patients with pelvic floor disorders. This linguistic validation process was conducted by Mapi Research Institute in collaboration with the author of the original version, R. Rogers, and sponsored by Coloplast. RESULTS: PISQ-12 is the short form of a reliable specific condition, originally developed and psychometrically validated in English, and a self-administrated instrument to evaluate sexual function in women with pelvic organ prolapse and/or urinary incontinence. The questionnaire contains 12 items divided into three domains, labelled behavioral/emotive, physical and partner-related. French linguistic validation does not consist in literally translating the original questionnaire but rather in developing conceptually equivalent and an easily understood version by French women. CONCLUSION: This tool is essential to assess the sexual impact of pelvic floor disorders and to better understand the consequences of their treatments on sexuality.

[Sonography versus electrodiagnosis for the diagnosis of carpal tunnel syndrome in routine practice]. / Comparaison de l'échographie et de l'électroneurographie pour le diagnostic du syndrome du canal carpien en pratique courante.

INTRODUCTION: Many studies had been performed in the last years to prove the usefulness of ultrasonographic measurements of the median nerve in the diagnosis of carpal tunnel syndrome (CTS). We wanted to determine its reliability and to compare this technology with electromyography (EMG) in ordinary diagnostic conditions. METHODS: The study involved 90 wrists with suspected CTS, 35 controlateral wrists and 52 control wrists. The diagnosis of CTS was confirmed in 81 cases by the hand symptom diagram and the Tinnel and Phalen sign. The EMG examination evaluated medianulnar sensory latency difference to the ring finger and wrist-to-palm sensory conduction velocity. For the ultrasound diagnosis, the cross sectional area of the median nerve at the level of the pisiform bone, was considered. The sensitivity and specificity of the two techniques was calculated. RESULTS: Sensitive electroneurographic parameters showed a sensibility and specificity respectively of 79 and 80%. The cut-off point for ultrasound sensibility and specificity using ROC analysis was 11mm(2) for mean cross-sectional area. Sensitivity and specificity found in this way were 72% and 56%. Reliability was good with intra- and inter-reader intraclass correlation coefficients of 0.99, and interobserver coefficient of 0.88. Sonography found seven CTS among the 17 clinical CTS with normal electrophysiological findings. A statistically correlation was found between the cross-sectional section and the sensitive electrophysiologic parameters (r=0.43, p<0.001). CONCLUSIONS: In our study, ultrasonographic diagnostic value are not as good as electrophysiological value, like found in recent literature, probably because of the composition of our group of patients which is including many causes of acroparesthesias. This can mean that in clinical practice, sonography is a complementary tool instead, for example in cases of equivocal EMG.

Dehydroepiandrosterone for myotonic dystrophy type 1.

BACKGROUND: Myotonic dystrophy type 1 may be associated with low circulating dehydroepiandrosterone (DHEA) levels. This study was aimed at investigating the efficacy and safety of DHEA in myotonic dystrophy type 1 patients. METHODS: This was a prospective, multicenter, randomized, double-blind, placebo-controlled trial conducted from February 2005 to January 2006 at 10 university-affiliated neuromuscular disease centers in France. Seventy-five ambulatory adults with myotonic dystrophy type 1 received an oral replacement dose (100 mg/d) or a pharmacologic dose (400 mg/d) of DHEA, or placebo. The primary endpoint was the relative change in the manual muscle testing (MMT) score from baseline to week 12. Secondary outcome measures included changes from baseline to week 12 in quantitative muscle testing and timed functional testing, respiratory and cardiac function, and quality of life. This study was registered with ClinicalTrials.gov identifier NCT00167609. RESULTS: The median (1st, 3rd quartile) relative changes in MMT score from baseline to week 12 after randomization were 3.1 (-0.9, 6.7), 1.9 (-2.7, 3.5), and 2.2 (0, 7.9), in the DHEA 100 mg, DHEA 400 mg, and placebo groups, respectively. There were no differences between placebo and combined DHEA groups (p = 0.34), placebo and DHEA 100 mg (p = 0.86), or placebo and DHEA 400 mg (p = 0.15). There were also no evidence for a difference between groups for the changes from baseline to week 12 in any secondary outcome. CONCLUSIONS: There is no evidence that a 12-week treatment with replacement or pharmacologic doses of dehydroepiandrosterone improves muscle strength in ambulatory myotonic dystrophy type 1 patients.

[TVT Secur: more and more minimally invasive. Preliminary prospective study of 110 cases]. / TVT Secur: de plus en plus minimal invasif. Etude préliminaire prospective sur 110 cas.

OBJECTIVES: To present a new minimal invasive suburethral tape device derivative of the classic TVT, to describe the technique of laying, to evaluate complications and results to short term. MATERIALS AND METHODS: Prospective multicentric study of 110 patients presenting a stress urinary incontinence and benefiting from the laying of TVT Secur without associated operation. The tape is identical to that old-fashioned retropubic and obturator TVT, smaller, laying in "U" or in "hammock" without orifice of exit, to avoid complications due to crossed spaces of the other techniques. The device and the technique of laying are described by authors. The originality of the TVT Secur resides in the mechanism of insertion of the tape to a metallic divice. All patients have been controlled at two months and complications with notably pains (quotation VAS) as well as objective results have been reported. RESULTS: Pure and isolated stress urinary incontinence for 71 patients, mixed incontinence for 39 and sphincter deficient for 23. Preoperative urgency for 49 patients and dysuria for 10 of them. The method "hammock" has been used in 85.5% of cases. The type of anaesthesia has been pure local for 69.1% (0 to 98.8% for the different centers) with an average operative time of 8'30". Under local anaesthesia, the average per operative pain was quoted 2.8/10, and 0.7 at the end of intervention. Peroperative complications have revealed a wound of bladder, a vaginal wound and four bleeding of more than 100ml. In immediate continuations a total retention yielding to 24h and 13 postmicturition residual between 100 and 200ml have been mentioned. At two months, authors have observed the following: de novo urgency in 19.6%, de novo dysuria in 13.2%, one tape exposition, one granuloma, one urinary infection and seven perceptible lateral cords without pain. Thirteen patients have signalled to have had moderated pains on a duration of four to 30 days. Early objective results are globally 70.4% of dry patients (83% for pure isolated SUI, 72.2% for SUI with deficient sphincter, 50% for mixed incontinence). The pure local anaesthesia was recommended by 98% of patients. CONCLUSION: The diminution of complications ahead not to be made to the detriment of results, it is necessary to envisage multicentric studies with standardized modifications. The indications of this new device will have to be defined.

[Breech presentation and vaginal delivery: evolution of acceptability by obstetricians and patients]. / Accouchement du siège par voie vaginale: évolution de l'acceptabilité par les obstétriciens et les patientes.

OBJECTIVE: To investigate the influence of obstetrician and patient respectively on mode of delivery in case of breech presentation at term. PATIENTS AND METHODS: This retrospective study included all women with a singleton pregnancy in a breech presentation delivered at term in a tertiary care maternity unit from January 1998 to December 2004. Mode of delivery was suggested by a score based on maternal age, parity, obstetrical past history, radiopelvimetry and cephalopelvic confrontation. The obstetrician was free to follow or not the score indication and patient's informed consent was required concerning the mode of delivery. Our main outcome measurements were mode of delivery and neonatal parameters. RESULTS: Two hundred cases were identified. Elective cesarean section increased progressively (from 52% in 1998 to 80% in 2004 [P=0,002]). Neonatal status and proportion of score in favour of vaginal birth remained stable during the study period. The rise in cesarean section rate was mainly due to patient's request (P=0,001) whereas the trend of obstetrician in favour of cesarean did not reach significance (P=0,3). DISCUSSION AND CONCLUSION: The rise of elective cesarean section for term breech delivery in a maternity unit using a predefinite score is mainly induced by patient's request. This evolution has no effect on neonatal status.

Bilateral subthalamic nucleus stimulation improves health-related quality of life in PD.

In order to assess the impact of bilateral subthalamic nucleus (STN) stimulation in PD on quality of life, the PD Quality of Life questionnaire was assessed in 60 consecutive patients with PD before surgery and 12 months after surgery. All aspects of quality of life, including motor (+48%), systemic (+34%), emotional (+29%), and social (+63%) dimensions, significantly improved with long-term STN stimulation.

Demyelinating X-linked Charcot-Marie-Tooth disease: unusual electrophysiological findings.

X-linked Charcot-Marie-Tooth disease (CMT-X) is caused by mutations of connexin-32 (Cx-32), which encodes a gap-junction protein. Whether the neuropathy is primarily demyelinative or axonal remains to be established. We report findings of prominent demyelination in a 71-year-old woman with late-onset disease. Electrophysiological studies revealed a nonuniform slowing of motor conduction velocities and dispersion of compound action potentials indicative of a demyelinating process which was confirmed by nerve biopsy. Such electrophysiological features are unusual in hereditary neuropathies and are more commonly found with acquired chronic demyelinating neuropathies. A systematic search confirmed the molecular genomic diagnosis of CMT-X, illustrating the value of such tests in sporadic cases. Severity of clinical symptoms and signs may vary with age and sex of the patient. The pathology of CMT-X in other reported cases has been variably interpreted as axonal, demyelinating, or showing both features. Our observations emphasize the demyelinative nature.

[The involvement of myelin proteins in hereditary neuropathies]. / Implications des protéines myéliniques dans les neuropathies héréditaires.

Hereditary sensoro-motor neuropathies such as Charcot-Marie-Tooth disease (CMT) form a heterogeneous group including some genetic conditions whose clinical manifestations differ in severity within a group or even within a sub-group. Diagnosis is based on the clinical, electrophysiological and pathological findings along with a genetic analysis. The current classification of CMT encompasses the clinical signs, mode of transmission, genomic localization and identification of the proteins actually involved. Several authors have identified the mutations on genes coding for proteins of peripheral myelin in CMT patients. Recent advances in molecular genetics have thrown more light on the differences between phenotypes within a sub-group, and have established genotype-phenotype relationships. It has been shown recently that the severity of the clinical signs depends on the nature and site of various mutations affecting the genes coding for certain myelin proteins. These mutations give rise to "dominant negative effects" or "mutations with loss of function of the allele". These observations may be extended to other proteins as many of them belong to the super family of immunoglobulins and have similar structures. In this study, we present a review of the literature focussing on the principal myelin proteins and the genomic modifications observed in patients with CMT.