Electro-clinical presentation of hereditary transthyretin related amyloidosis when presenting as a polyneuropathy of unknown origin in northern France.

INTRODUCTION: Hereditary transthyretin related amyloidosis (h-ATTR) classically presents as a small fiber neuropathy with positive family history, but can also be revealed by various other types of peripheral neuropathy. OBJECTIVE: To describe the initial electro-clinical presentation of patients from in a single region (northern France) of h-ATTR when it presents as a polyneuropathy of unknown origin. METHOD: We reviewed the records of patients referred to two neuromuscular centers from northern France with a peripheral neuropathy of unknown origin who were subsequently diagnosed with h-ATTR. RESULTS: Among 26 h-ATTR patients (10 Val30Met, 16 Ser77Tyr), only 14 patients had a suspicious family history (53.8%). The electro-clinical presentation was mostly a large-fiber sensory motor polyneuropathy (92.3%), which could be symmetric or not, length-dependent or not, or associated with nerve entrapment or not. Demyelinating signs were observed in 17 patients (70.8%), among whom nine fulfilled the criteria for a definite diagnosis of chronic inflammatory demyelinating polyradiculoneuropathy (37.5%). CONCLUSION: h-ATTR may have a wide spectrum of clinical profiles, and should be considered in the screening of polyneuropathies of unknown origin.

JCV serology in time: 3 years of follow-up.

OBJECTIVES: Although many neurologists are reluctant to use natalizumab in MS (multiple sclerosis) given the increased risk for PML (progressive multifocal leukoencephalopathy), trust was regained with the introduction of JCV antibody titres as a potent disease-modifying therapy. Literature shows that in patients with a negative JCV serology, the risk of PML is virtually non-existent. Unfortunately, seroconversion causes concern amongst many neurologists. Furthermore, when patients seroconvert, it is still unclear what the risk is of passing the important threshold of 1.5. MATERIALS & METHODS: JCV serology data of 161 patients were analysed, upon treatment with natalizumab at the University Hospital in Lille, France, between May 2012 and November 2014. RESULTS: Of the 81 patients who tested negative for JCV antibody at baseline, 23 (28.3%) seroconverted but only seven (8.6%) passed the threshold of 1.5. Of the 80 patients testing positive for JCV antibody at baseline, eight had an initial JCV antibody titre of 0.9 or lower of which only one of eight (12.5%) patients passed the threshold of 1.5 in the following 3 years. Eight of 15 (53.3%) patients passed this threshold if the initial serology was higher than 0.9. CONCLUSIONS: JCV-negative patients and JCV-positive patients with antibody levels below or equal to 0.9 both have a low risk of surpassing the 1.5 threshold.

Brain Magnetic Susceptibility Changes in Patients with Natalizumab-Associated Progressive Multifocal Leukoencephalopathy.

We investigated the brain magnetic susceptibility changes induced by natalizumab-associated progressive multifocal leukoencephalopathy. We retrospectively included 12 patients with natalizumab-progressive multifocal leukoencephalopathy, 5 with progressive multifocal leukoencephalopathy from other causes, and 55 patients with MS without progressive multifocal leukoencephalopathy for comparison. MR imaging examinations included T2* or SWI sequences in patients with progressive multifocal leukoencephalopathy (86 examinations) and SWI in all patients with MS without progressive multifocal leukoencephalopathy. Signal abnormalities on T2* and SWI were defined as low signal intensity within the cortex and/or U-fibers and the basal ganglia. We observed T2* or SWI signal abnormalities at the chronic stage in all patients with progressive multifocal leukoencephalopathy, whereas no area of low SWI signal intensity was detected in patients without progressive multifocal leukoencephalopathy. Among the 8 patients with asymptomatic natalizumab-progressive multifocal leukoencephalopathy, susceptibility changes were observed in 6 (75%). The basal ganglia adjacent to progressive multifocal leukoencephalopathy lesions systematically appeared hypointense by using T2* and/or SWI. Brain magnetic susceptibility changes may be explained by the increased iron deposition and constitute a useful tool for the diagnosis of progressive multifocal leukoencephalopathy.

Bethlem myopathy: long-term follow-up identifies COL6 mutations predicting severe clinical evolution.

OBJECTIVE: Mutations in one of the 3 genes encoding collagen VI (COLVI) are responsible for a group of heterogeneous phenotypes of which Bethlem myopathy (BM) represents the milder end of the spectrum. Genotype-phenotype correlations and long-term follow-up description in BM remain scarce. METHODS: We retrospectively evaluated the long-term clinical evolution, and genotype-phenotype correlations in 35 genetically identified BM patients (23 index cases). RESULTS: Nineteen patients showed a typical clinical picture with contractures, proximal weakness and slow disease progression while 11 presented a more severe evolution. Five patients showed an atypical presentation, namely a limb girdle muscle weakness in 2 and a congenital myopathy pattern with either no contractures, or only limited to ankles, in 3 of them. Pathogenic COL6A1-3 mutations were mostly missense or in frame exon-skipping resulting in substitutions or deletions. Twenty one different mutations were identified including 12 novel ones. The mode of inheritance was, autosomal dominant in 83% of the index patients (including 17% (N=4) with a de novo mutation), recessive in 13%, and undetermined in one patient. Skipping of exon 14 of COL6A1 was found in 35% of index cases and was mostly associated with a severe clinical evolution. Missense mutations were detected in 39% of index cases and associated with milder forms of the disease. CONCLUSIONS: Long-term follow-up identified important phenotypic variability in this cohort of 35 BM patients. However, worsening of the functional disability appeared typically after the age of 40 in 47% of our patients, and was frequently associated with COL6A1 exon 14 skipping.

[Current issues in hereditary neuropathies]. / Actualités dans les neuropathies héréditaires.

This short review highlights five studies published in 2012 in the field of Charcot-Marie-Tooth disease (CMT) and transthyretin familial amyloid neuropathies (TTR-FAN). Regarding CMT, an Australian pediatric study shows the high prevalence of impaired speech perception and hearing disability in children with CMT1 or CMT2 with normal or near normal audiometry (Rance et al., 2012). In a second study, the clinical and electrophysiological characteristics of 14 patients with CMT4C due to mutations in SH3TC2 gene are described (Yger et al., 2012). The 3 clinical hallmarks of CMT4C patients in this French cohort are the high prevalence of scoliosis, the proximal motor weakness and the cranial nerves involvement. Concerning TTR-FAN, the first data from French and international registries are reported (Adams et al., 2012; Coelho et al., 2013) and a phase II trial describes the results of taurourodeoxycholic acid and doxycycline treatment (Obici et al., 2012).

The French Pompe registry. Baseline characteristics of a cohort of 126 patients with adult Pompe disease.

Pompe disease is a rare autosomal recessive muscle lysosomal glycogenosis, characterised by limb-girdle muscle weakness and frequent respiratory involvement. The French Pompe registry was created in 2004 with the initial aim of studying the natural history of French patients with adult Pompe disease. Since the marketing in 2006 of enzyme replacement therapy (alglucosidase alfa, Myozyme(®)), the French Pompe registry has also been used to prospectively gather the biological and clinical follow-up data of all adult patients currently treated in France. This report describes the main clinical and molecular features, at the time of inclusion in the French registry, of 126 patients followed up in 21 hospital-based neuromuscular or metabolic centres. Sixty-five men and 61 women have been included in the registry. Median age at inclusion was 49 years, and the median age at onset of progressive limb weakness was 35 years. Fifty-five percent of the patients were walking without assistance, 24% were using a stick or a walking frame, and 21% were using a wheelchair. Forty-six percent of the patients needed ventilatory assistance, which was non-invasive in 35% of the cases. When performed, muscle biopsies showed specific features of Pompe disease in less than two-thirds of the cases, confirming the importance of acid alpha-glucosidase enzymatic assessment to establish the diagnosis. Molecular analysis detected the common c.-32-13T>G mutation, in at least one allele, in 90% of patients. The French Pompe registry is so far the largest country-based prospective study of patients with Pompe disease, and further analysis will be performed to study the impact of enzyme replacement therapy on the progression of the disease.

[Respiratory failure due to acid maltase deficiency]. / Déficit en maltase acide (glycogénose de type 2) de l'adulte. Une cause d'insuffisance respiratoire à ne pas méconnaître.

Acid maltase deficiency (AMD) is a metabolic myopathy which may be revealed at adulthood by respiratory muscle weakness, resulting in reduced vital capacity, alveolar hypoventilation and sleep apnoea. We observed two men, 39 and 42 years old respectively, suffering from asthenia and exertional dyspnoea for several months. After a stay in the intensive care unit, as a result of respiratory failure associated with pneumonia, these patients were referred to the respiratory medicine unit on account of persistent hypercapnia during the day and a fall in oxygen saturation at night. The investigations revealed proximal muscle weakness, a reduced vital capacity, alveolar hypoventilation (PaCO2: 67 and 49 mmHg), reduced maximum static inspiratory and expiratory pressures, carbon dioxide hyporesponsiveness and sleep apnoea on overnight polysomnography. Electromyography showed a myopathic pattern. Muscle biopsy confirmed the diagnosis of AMD. Non-invasive ventilation overnight partially corrected the clinical symptoms and the resting hypercapnia in both patients. The adulthood form of AMD is a rare disease that should be considered in a large number of clinical situations, particularly in unexplained respiratory failure. Our observations suggest that non invasive ventilation together with enzyme supplementation (Myozyme®) is effective in correcting alveolar hypoventilation.

Phenotype genotype analysis in 15 patients presenting a congenital myasthenic syndrome due to mutations in DOK7.

Congenital myasthenic syndromes (CMSs) are a heterogeneous group of diseases caused by genetic defects affecting neuromuscular transmission. Mutations of DOK7 have recently been described in recessive forms of CMS. Dok-7 is a cytoplasmic post-synaptic protein co-activator of the muscle-specific receptor-tyrosine kinase (MuSK) involved in neuromuscular synaptogenesis and maintenance. We report clinical, morphological and molecular data on 15 patients with mutations in DOK7. Eleven different mutations (5 novel) were identified and all patients but one were found to carry at least the common c.1124_1127dupTGCC mutation. Patients with DOK7 mutations have a particular limb-girdle pattern, without tubular aggregates but a frequent lipidosis on the muscle biopsy. Changes in pre- and post-synaptic compartments of the neuromuscular junction were also observed in muscle biopsies: terminal axons showed defective branching which resulted in a unique terminal axon contacting en passant postsynaptic cups. Clinical features, muscle biopsy findings or response to therapy were confusing in several patients. Characterization of this distinct phenotype is essential to provide clues for targeted genetic screening and to predict the therapeutic response to anticholinesterase treatments or ephedrine as has been suggested.

[Polymyositis revealing a Sjogren's syndrome]. / Polymyosite révélant un syndrome de Gougerot-Sjögren.

INTRODUCTION: Near 10 to 20% of patients with myositis have another systemic, sometimes inaugural, disease. CASE REPORT: A 48-year-old woman was admitted with progressive hypoesthesia in V2 and V3 areas on both sides, difficulties to chew and swallow and then, proximal and axial muscular deficiency, with weight loss. Brain MRI showed gadolinium-enhanced trigeminal nerves and biological tests revealed anti-SSA and anti-Pm/Scl antibodies and a grade IV in Chisholm scoring system on the labial salivary gland biopsy. Neurophysiological studies revealed a myogenic pattern on tibialis anterior muscles and a muscle biopsy confirmed the diagnosis of polymyositis. CONCLUSION: The diagnosis of primitive Sjogren's syndrome was suspected because of the association of bilateral trigeminal neuropathy and anti-SSA and anti-Pm/Scl antibodies.

Relapsing demyelinating disease affecting both the central and peripheral nervous systems.

BACKGROUND: Clinical and electromyographic findings of chronic inflammatory demyelinating polyradiculopathy (CIDP) are occasionally observed in patients with multiple sclerosis (MS). OBJECTIVE: To define a new inflammatory demyelinating disease unlike MS or CIDP. RESULTS: This study reports on five patients with a demyelinating disease affecting the central nervous system (CNS) and peripheral nervous system (PNS). Each case presented a relapsing-remitting course in which CNS involvement preceded PNS involvement. All patients fulfilled Barkhof's criteria on MRI and the McDonald criteria for MS. Two patients had grey matter lesions with typical white matter changes. No systemic inflammatory disease and no metabolic or inflammatory factor for peripheral neuropathy were found. In all cases electromyography showed a demyelinating peripheral neuropathy without conduction block. Four patients fulfilled the European Federation of Neurological Societies/PNS guideline for CIDP and Nicolas et al's criteria for CIDP, one of whom also fulfilled the Ad Hoc Subcommittee criteria for CIDP. Nerve biopsy, performed in two patients, showed histological evidence of CIDP. An improvement in clinical status and neurophysiological parameters was observed in three patients after treatment with either intravenous immunoglobulin (n = 1) or cyclophosphamide (n = 2). CONCLUSION: The CNS and PNS demyelination, the absence of oligoclonal bands and the peripheral demyelination without conduction block indicate pathogenic mechanisms different from MS and CIDP. The chronology of events suggests an entity unlike that involved in acute demyelinating encephalomyelitis. Immunological reactivity against antigens common to peripheral and central myelin may explain why the demyelinating disease affected both the CNS and PNS.

Procalcitonin, IL-6, IL-8, IL-1 receptor antagonist and C-reactive protein as identificators of serious bacterial infections in children with fever without localising signs.

UNLABELLED: Fever without localising signs in very young children remains a diagnostic problem. Until present, a clinical scoring system combined with leucocyte count, urine analysis and determination of CRP are recognised as being helpful to identify patients at risk of serious bacterial illness. In this study we asked the question whether the determination of procalcitonin (PCT), interleukin (IL)-6, IL-8 and interleukin-1 receptor antagonist (IL- Ra) was superior to these commonly used markers for the prediction of a serious bacterial infection (SBI). Children, 7 days to 36 months of age, with a rectal temperature above 38 degrees C and without localising signs of infection were prospectively enrolled. For each infant, we performed a physical examination, a clinical score according to McCarthy, a complete white cell count, an urine analysis and a determination of CRP. We further determined PCT, IL-6, IL-8, and IL-1Ra concentrations and compared their predictive value with those of the usual management of fever without localising signs. Each infant at risk of SBI had blood culture, urine and cerebrospinal fluid cultures when indicated, and received antibiotics until culture results were available. A total of 124 children were included of whom 28 (23%) had SBI. Concentrations of PCT, CRP and IL-6 were significantly higher in the group of children with SBI but IL-8 and IL-1Ra were comparable between both groups. PCT showed a sensitivity of 93% and a specificity of 78% for detection of SBI and CRP had a sensitivity of 89% and a specificity of 75%. CONCLUSION: Compared to commonly used screening methods such as the McCarthy score, leucocyte count and other inflammatory markers such as interleukin-6, interleukin-8 and interleukin- receptor antagonist, procalcitonin and C-reactive protein offer a better sensitivity and specificity in predicting serious bacterial infection in children with fever without localising signs.

[Colonization by Ureaplasma urealyticum and chronic lung disease in premature newborn infants under 32 weeks of gestation]. / Colonisation par Ureaplasma urealyticum et maladie pulmonaire chronique chez les nouveau-nés prématurés de moins de 32 semaines de gestation.

UNLABELLED: Colonization of the respiratory tract of premature newborn infants by genital mycoplasma is suspected to be associated with chronic lung disease. METHODS AND PATIENTS: We prospectively determined the prevalence of genital mycoplasma colonization with nasopharyngeal or endotracheal culture in preterm neonates younger than 32 weeks gestation and its possible association with the development of chronic lung disease in a prospective study. RESULTS: Fifty-nine infants were enrolled and 11 (19%) were colonized with Ureaplasma urealyticum. In the subgroup of 45 ventilated infants, seven of seven U. urealyticum-positive infants developed chronic pulmonary disease versus ten of 38 (26%) of U. urealyticum-negative infants (relative risk [RR] = 3.8; 95% confidence interval [CI] 2.2 to 6.5, P < 0.001). U. urealyticum-colonized infants had a lower median birth weight (760 vs 1,083 g, P = 0.04), a lower gestational age (26 vs 28 weeks, P = 0.03), and a higher incidence of symptomatic patent ductus arteriosus (P = 0.03). These potential confounding factors may partially explain the association between U. urealyticum and chronic pulmonary disease. However, this association remained statistically significant when the analysis was restricted to infants with birth weight of 1,000 g or less (RR = 2.3; 95% CI 1.3 to 4, P = 0.02) or to infants with a patent ductus arteriosus (RR = 2; 95% CI 1.3 to 3.1, P = 0.02). CONCLUSION: Colonization with U. urealyticum in ventilated preterm neonates younger than 32 weeks gestation is a significant risk factor of developing chronic pulmonary disease.

[Pseudotumor forms of demyelinating diseases. Report of three cases and review of the literature]. / Formas pseudotumorales de enfermedad desmielinizante. Presentación de tres casos y revisión de la literatura.

INTRODUCTION AND CLINICAL CASES: We present three patients with unusual clinical findings studied in our hospital, after a period of follow-up of at least two years from the time of diagnosis of their demyelinating condition. We discuss the clinical onset, CT and magnetic resonance findings, neuropathological studies and posterior clinical course. Anatomopathological studies were done in two of the cases, since the diagnoses were not clear and the other paraclinical investigations did not clarify things. DISCUSSION: The presence of large space-occupying lesions or ring-like outlines in myelinating disorders may make it difficult to make a differential diagnosis from other conditions such as neoplasias and abscesses. This may lead to an erroneous initial diagnosis and even to the use of unsuitable, aggressive treatments. CONCLUSIONS: In young patients in whom radiological imaging suggests space-occupying lesions (single or multiple) one should consider the possibility of a primary demyelinating disease of the central nervous system with the appearance of a pseudo-tumour. In certain cases, stereotaxic biopsy should be considered if the diagnosis remains in doubt, rather than begin unsuitable treatment. The fundamental reason for the presentation of our cases is to emphasize that these pseudo-tumoral forms of demyelinating diseases should be considered in diagnosis.

[Mass screening programs for breast cancer in France. Comparative evaluation]. / Les programmes de dépistage de masse du cancer du sein en France. Evaluation comparative.

OBJECTIVE: The purpose of this work was to comparatively assess the results of mass screening programs for breast cancer implemented in six French departments in 1986, within the scope of the National Fund for Health Prevention, Education and Information of the National Health Insurance Office of Salaried Workers. MATERIAL AND METHODS: The data collected by the screening centres were analyzed by ten assessment teams that were independent from the program promotion staff, all using the same evaluation form. A complementary population study performed in eight French districts then, allowed assessing the frequency of self-referred screening (mammography performed out of program). RESULTS: The rate of participation in screening programs, in relation to the invited population, ranged from 21 to 48%, according to the district (36% in average). This low participation was probably related to the extent of self-referred screening. In fact, 19 to 40% of women, according to the district, had previously had a screening mammographic coverage: rate was around 68% in women aged 50 to 69 years. Positive findings with mammography ranged from 4.5 to 15.8% (10.1% in average), while intervention rates ranged from 0.7 to 1.6% and detection rates from 3.8 to 6.2%. The ratio between benign tumors and cancers ranged from 0.7 to 2.1 according to the district. In order to enlighten the judgement on French results, we propose a comparison with the international standards in force. CONCLUSION: The various experiences with breast cancer screening in France show that this screening is technically feasible on the basis of existing medical structures. However, some criteria are still below the expected values, especially if compared with international standards. This result is probably accounted for by the high rate self-referred screening before age 40 in France. In these conditions, the question is whether extending breast cancer screening programs in France is an appropriate course of action.

Use of mammography as a breast cancer screening tool in six districts in France.

Mass screening programs to detect breast cancer are currently under way in many countries. In France, several districts have been running mammographic screening programs since 1989. A survey was conducted in five of these districts and in a sixth district where no screening program was implemented. Using a self-addressed questionnaire mailed to a sample of 1500 women aged over 20 years, the survey was aimed at assessing women's use of mammography as well as their knowledge and perception of mammographic breast cancer screening. According to district, the compliance of the women replying to the questionnaire ranged from 72 to 82%. The proportion of women who had at least one mammography during their life ranged from 41 to 54%, according to district. The percentage of women aged 50 to 69 who had one mammography within 3 years before the survey ranged from 57 to 78% in the experimental districts and was only 48% in the control district. In all districts, women did not know exactly at what age it is recommended to start screening and with what periodicity, but, when invited to do so, they were satisfied with the program and intended to participate again.

Mass screening programs for breast cancer in France--average values of assessment criteria.

Breast cancer is the most common cancer in women worldwide. Many studies have been performed worldwide to assess the effectiveness of screening in terms of reduced mortality due to breast cancer. Since the end of 1989, 10 breast cancer mass screening programs using mammography have been carried out in France under the sponsorship of the National Fund for Health Prevention, Education, and Information (FNPEIS) from the National Health Insurance of Salaried Workers (CNAMTS). These 10 campaigns, which are on a district scale, are organized according to variable methods and are assessed using a common procedure. Four groups of criteria are measured in this procedure, which investigates the impact, quality, effectiveness, and costs of screening programs. The average and extreme values of each criterion as calculated from the campaigns are presented in this paper. In order to enlighten the judgment on the French results, a comparison with the international standards in force and with the results of foreign screening programs is proposed.

Prognostic value of viremia in patients with long-standing human immunodeficiency virus infection. Swiss HIV Cohort Study Group.

Human immunodeficiency virus (HIV) viremia was evaluated in 73 patients with long-standing infection to investigate its relationship with clinical or biologic parameters and to assess its use as a predictor of clinical progression and death. After adjustment for other parameters, baseline HIV RNA level was significantly associated with baseline clinical stage and CD4 cell count. During follow-up (mean, 14.6 months), 16 patients died; 34 others had clinical progression of disease. In multivariate analysis, mortality was better predicted by baseline CD4 cell count (relative hazard [RH] for 100-cell decrease, 3.5; 95% confidence interval [CI], 1.5-8.2; P = .003) than by HIV RNA (P = .28) or clinical stage. HIV RNA level was the best predictor of clinical progression (RH for 1 log increase, 2.8; 95% CI, 1.6-4.9; P < .001). Monitoring of HIV RNA level may help to identify patients who might benefit from antiretroviral or prophylactic therapy.

[Economic evaluation of screening for neuroblastoma]. / Evaluation économique du dépistage du neuroblastome.

Though neuroblastoma, a cancer occurring in children, is infrequent, several countries run screening programs to detect it early since advanced stages show high mortality rates. The aim of this study is to propose a non empirical medico-economic evaluation model for the screening program for neuroblastoma, adaptable to various contexts. A marginal cost-effectiveness analysis was performed. The effectiveness and cost criteria were respectively the number of children who do not die from neuroblastoma and the cost of the screening programs, together with the cost of the treatments. The major parameters of the model were: size of target population, incidence, over-incidence rate, compliance rate, test sensitivity, distribution of cases and mortality rates according to the stage of the disease. The aim of the model was to determine, within a specific context (fixed parameters), the cost of an additional life saved, or less pragmatically to calculate the threshold values for the parameters for which the screening program for neuroblastoma is worthwhile (ie marginal cost equal to zero). We illustrate this model presentation with simulations elaborated from the neuroblastoma screening program performed in the Rhône area, France.