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Objectives Rhombencephalosynapsis (RES) is a very rare cerebellar malformation. Neurodevelopmental outcome of apparently isolated RES remains poorly documented and standardized cognitive assessment, reported in only nine published cases so far, is lacking. Prenatal counselling is challenging considering the uncertain prognosis of isolated RES. The aim of this study was to focus on cognitive and motor outcome of isolated RES with a clinical description of six new cases and a detailed review of the literature. Methods A single-centre retrospective study of all RES patients over a 15-year period. Ataxia and fine motor skills were scored using a five-grade scale, according to the degree of disturbance of daily living. Intelligence Quotient (IQ) was established according to age-related Weschler Intelligence Scales. A systematic literature review included published cases with relevant outcome data. Results Six new cases of apparently isolated RES were reported, including three diagnosed in prenatal settings. The onset age for walking was delayed in four patients. Three patients had head shaking and three had a strabismus. One patient had a mild motor disability, one had subtle ataxia that did not impair daily life and four patients had a normal neurological examination at the last visit. Intellectual abilities were normal in all patients (full IQ score from 90 to 142), although three had ADHD. All received standard schooling. Based on these six new cases, as well as cases from 12 publications in the literature, a total of 28 patients with non-syndromic RES were analysed. Concerning motor outcome, 72% had no complaint or minimal impairment, 16% moderate and 12% severe impairment. Concerning cognitive outcome, 68% had normal cognitive skills, 18% borderline intellectual functioning and 14% moderate to severe disability.

Aromatic L-amino acid decarboxylase (AADC) deficiency is an autosomal recessive inborn error of metabolism, affecting catecholamines and serotonin biosynthesis. Cardinal signs consist in psychomotor delay, hypotonia, oculogyric crises, dystonia, and extraneurological symptoms.We present a retrospective descriptive multicentric study concerning ten French children with a biochemical and molecular confirmed diagnosis of AADC deficiency.Clinical presentation of most of our patients was consistent with the previous descriptions from the literature (hypotonia (nine children), autonomic signs (nine children), sleep disorders (eight children), oculogyric crises (eight children), motor disorders like hypertonia and involuntary movements (seven children)). We described however some phenotypic particularities. Two patients exhibited normal intellectual abilities (patients already described in the literature). We also underlined the importance of digestive symptoms like diarrhea, which occurred in five among the ten patients. We report in particular two children with chronic diarrhea, complicated by severe failure to thrive. Vanillactic acid (VLA) elevation in urines of one of these two patients led to suspect the diagnosis of AADC deficiency, as in two other patients from our population.Some symptoms like chronic diarrhea were atypical and have been poorly described in the literature up to now. Diagnosis of the AADC deficiency is sometimes difficult because of the phenotypic heterogeneity of the disease and VLA elevation in urines should suggest the diagnosis.

Wilson disease is an autosomal recessive disease that produces a copper accumulation in many organs, initially in the liver, progressing to liver cirrhosis, and in the brain, with different neurologic symptoms. Diagnosis is based on clinical, biochemical, and genetic tests. Different treatments based on chelating agents may help reduce the disease's spontaneous morbidity and mortality. We describe three patients who presented Wilson disease before 18 years of age, with initial neurologic symptoms between 1998 and 2010. After comparison with literature reports, their clinical symptoms, progression, and care allowed us to propose a treatment algorithm. Neurologic symptoms are present in 35% of the patients with Wilson disease such as dystonia, extrapyramidal syndrome, dysarthria, dysphagia, and psychiatric symptoms. The time to diagnosis remains too long and may account for the increased severity of the illness encountered and problems treating these patients. The first treatment choice must be triethylenetetramine, which causes fewer side effects of initial worsening of symptoms compared to D-penicillamine. Zinc therapy is the first treatment for asymptomatic patients or those on maintenance treatment. Finally, liver transplantation is a potential treatment even if the patient presents severe neurological disability because it may improve clinical symptoms. However, further research is warranted on this matter.

Resume Le but de cette etude etait de decrire les resultats du depistage systematique du gliome des voies optiques (GVO) chez l’enfant atteint de neurofibromatose de type 1 (NF1). Patients et methodes Nous avons realise une etude retrospective sur la population d’enfants atteints de NF1 selon les criteres de Bethesda, suivis dans le service de neurologie pediatrique a Lyon depuis au moins un an, ayant eu un premier examen d’imagerie en resonance magnetique (IRM) cerebrale entre le 1 er mars 1998 et le 1 er juin 2007. L’IRM cerebrale a ete realisee a titre systematique chez les patients asymptomatiques âges de moins de 6 ans. Resultats Cent patients avec une duree mediane de suivi de 3,7 ans (1 a 8,6) ont ete inclus. L’IRM cerebrale a ete realisee chez 94 enfants. Cet examen a permis de mettre en evidence un GVO chez 16 enfants parmi lesquels 9 etaient symptomatiques. Six enfants presentaient des symptomes en lien direct avec le GVO. Les trois autres avaient des symptomes sans lien evident (cephalees, macrocephalie, troubles des apprentissages). Le GVO est reste stable chez 10 enfants sur 16 ; une seule enfant symptomatique a l’âge de 8 ans a ete traitee. Un cas de regression spontanee a ete observe dans notre serie. Conclusion Le resultat de l’IRM cerebrale realisee de facon systematique dans notre serie n’a pas modifie la prise en charge chez les patients asymptomatiques. La realisation systematique de l’IRM chez les patients porteurs de NF1 ne nous semble pas justifiee. Afin de confirmer ces donnees sur un plus grand nombre de patients, nous proposons de poursuivre l’etude en collaboration avec le reseau NF1-France.

Resume Nous rapportons le cas d’un garcon de 11 ans qui a presente 2 episodes d’hemiparesie droite en 1 mois revelant une maladie de Lyme. Depuis 1 an, il se plaignait d’asthenie et de cephalees. Le diagnostic de neuroborreliose a ete porte malgre l’absence d’antecedent de morsure de tique, sur la synthese intrathecale d’anticorps specifiques contre Borrelia burgdorferi. Les IRM realisees ont montre des signes d’inflammation et de vascularite partiellement resolutifs sous traitement. Par ailleurs, il a presente egalement une hypoglycorachie et une hyperlactatorachie ce qui pourrait etre un des marqueurs d’atteinte chronique. L’evolution a ete rapidement favorable sous ceftriaxone. Apres les causes vasculaires et inflammatoires, il faut evoquer le diagnostic de neuroborreliose devant tout symptome neurologique aigu, etant donne le bon pronostic sous antibiotherapie adaptee.

Resume Introduction. – Le regime cetogene a des proprietes anti-epileptiques connues depuis le debut du siecle. Il apporte une alimentation riche en lipides, pauvre en sucres, provoquant une cetonemie. Depuis quelques annees, le regime cetogene est reintroduit comme therapeutique anti-epileptique dans les epilepsies pharmaco-resistantes non chirurgicales. Population. – Nous rapportons notre experience a propos de 29 enfants ayant une epilepsie pharmaco-resistante, non chirurgicale. Les modalites d’applications sont precisees. Resultats. – Le regime cetogene a ete efficace dans 12 cas sur 29. Cette efficacite s’est averee remarquable au cours des etats de mal epileptiques ou au cours des crises subintrantes. L’epilepsie partielle migrante s’est averee toujours resistante au regime. Le regime etait moyennement accepte par l’enfant, sa tolerance etait bonne. Le regime peut etre maintenu plus d’un an en cas d’efficacite. Un seul cas d’effet secondaire serieux a ete observe en rapport avec une hypokaliemie. Conclusion. – Apres avoir discute les effets positifs et les effets indesirables du regime, le regime parait interessant dans l’arsenal therapeutique des epilepsies pharmaco-resistantes non chirurgicales.

Item does not contain fulltext BACKGROUND: Creatine transporter deficiency is a monogenic cause of X-linked intellectual disability. Since its first description in 2001 several case reports have been published but an overview of phenotype, genotype and phenotype-genotype correlation has been lacking. METHODS: We performed a retrospective study of clinical, biochemical and molecular genetic data of 101 males with X-linked creatine transporter deficiency from 85 families with a pathogenic mutation in the creatine transporter gene (SLC6A8). RESULTS AND CONCLUSIONS: Most patients developed moderate to severe intellectual disability; mild intellectual disability was rare in adult patients. Speech language development was especially delayed but almost a third of the patients were able to speak in sentences. Besides behavioural problems and seizures, mild to moderate motor dysfunction, including extrapyramidal movement abnormalities, and gastrointestinal problems were frequent clinical features. Urinary creatine to creatinine ratio proved to be a reliable screening method besides MR spectroscopy, molecular genetic testing and creatine uptake studies, allowing definition of diagnostic guidelines. A third of patients had a de novo mutation in the SLC6A8 gene. Mothers with an affected son with a de novo mutation should be counselled about a recurrence risk in further pregnancies due to the possibility of low level somatic or germline mosaicism. Missense mutations with residual activity might be associated with a milder phenotype and large deletions extending beyond the 3' end of the SLC6A8 gene with a more severe phenotype. Evaluation of the biochemical phenotype revealed unexpected high creatine levels in cerebrospinal fluid suggesting that the brain is able to synthesise creatine and that the cerebral creatine deficiency is caused by a defect in the reuptake of creatine within the neurones.

International audience; Creatine and guanidinoacetate are biomarkers of creatine metabolism. Their assays in body fluids may be used for detecting patients with primary creatine deficiency disorders (PCDD), a class of inherited diseases. Their laboratory values in blood and urine may vary with age, requiring that reference normal values are given within the age range. Despite the long known role of creatine for muscle physiology, muscle signs are not necessarily the major complaint expressed by PCDD patients. These disorders drastically affect brain function inducing, in patients, intellectual disability, autistic behavior and other neurological signs (delays in speech and language, epilepsy, ataxia, dystonia and choreoathetosis), being a common feature the drop in brain creatine content. For this reason, screening of PCDD patients has been repeatedly carried out in populations with neurological signs. This report is aimed at providing reference laboratory values and related age ranges found for a large scale population of patients with neurological signs (more than 6 thousand patients) previously serving as a background population for screening French patients with PCDD. These reference laboratory values and age ranges compare rather favorably with literature values for healthy populations. Some differences are also observed, and female participants are discriminated from male participants as regards to urine but not blood values including creatine on creatinine ratio and guanidinoacetate on creatinine ratio values. Such gender differences were previously observed in healthy populations; they might be explained by literature differential effects of testosterone and estrogen in adolescents and adults, and by estrogen effects in prepubertal age on SLC6A8 function. Finally, though they were acquired on a population with neurological signs, the present data might reasonably serve as reference laboratory values in any future medical study exploring abnormalities of creatine metabolism and transport.

Reperfusion-induced ventricular fibrillation has been dem onstrated in animal models of myocardial ischaemia, but no evidence exists for this in humans. The European Myocar dial Infarction Project compared the efficacy and safety of pre-hospital thrombolytic therapy with that of hospital therapy. The objective of this study was to investigate the occurrence of reperfusion-induced ventricular fibrilla tion in acute myocardial infarction patients following thrombolytic therapy. In a double-blind multicentre trial, eligible patients were randomized to receive anistreplase at home followed by placebo in the hospital (A/P group), or placebo followed by anistreplase (P/A group). The occurrence of ventricular fibrillation, and other adverse events were recorded on specific study forms and could be attributed to defined time intervals. The incidence of ventricular fibrillation in the A/P group was significantly higher following the pre-hospital injection than in the P/A group (2.5% vs 1.6%; P =0.021); the situation was reversed following the hospital injection (3.6% vs 5.3%; P =0.002). No relationship was found be tween this excess of ventricular fibrillation and the patients condition, with the exception of the site of the infarct. These results suggest the existence of reperfusion-induced ventricular fibrillation in patients developing myocardial infarction who receive thrombolytic treatment.

A population of patients with unexplained neurological symptoms from six major French university hospitals was screened over a 28-month period for primary creatine disorder (PCD). Urine guanidinoacetate (GAA) and creatine:creatinine ratios were measured in a cohort of 6,353 subjects to identify PCD patients and compile their clinical, 1H-MRS, biochemical and molecular data. Six GAMT [N-guanidinoacetatemethyltransferase (EC 2.1.1.2)] and 10 X-linked creatine transporter (SLC6A8) but no AGAT (GATM) [L-arginine/glycine amidinotransferase (EC 2.1.4.1)] deficient patients were identified in this manner. Three additional affected sibs were further identified after familial inquiry (1 brother with GAMT deficiency and 2 brothers with SLC6A8 deficiency in two different families). The prevalence of PCD in this population was 0.25% (0.09% and 0.16% for GAMT and SLC6A8 deficiencies, respectively). Seven new PCD-causing mutations were discovered (2 nonsense [c.577C > T and c.289C > T] and 1 splicing [c.391 + 15G > T] mutations for the GAMT gene and, 2 missense [c.1208C > A and c.926C > A], 1 frameshift [c.930delG] and 1 splicing [c.1393-1G > A] mutations for the SLC6A8 gene). No hot spot mutations were observed in these genes, as all the mutations were distributed throughout the entire gene sequences and were essentially patient/family specific. Approximately one fifth of the mutations of SLC6A8, but not GAMT, were attributed to neo-mutation, germinal or somatic mosaicism events. The only SLC6A8-deficient female patient in our series presented with the severe phenotype usually characterizing affected male patients, an observation in agreement with recent evidence that is in support of the fact that this X-linked disorder might be more frequent than expected in the female population with intellectual disability.

International audience; BACKGROUND: Myotonia is unusual in infants, and not well-known. METHODS: We describe neonatal life-threatening features of myotonia caused by de novo mutations in the muscle sodium channel gene SCN4A. RESULTS: Three male neonates initially displayed episodic laryngospasms, with face and limb myotonia appearing later. We found SCN4A de novo mutations in these neonates: p.Gly1306Glu in 2 unrelated cases and a novel mutation p.Ala799Ser in the third. Two patients survived their respiratory attacks and were efficiently treated by sodium channel blockers (mexiletine, carbamazepine) following diagnosis of myotonia. CONCLUSION: Severe neonatal episodic laryngospasm is a new phenotype caused by a sodium channelopathy, which can be alleviated by channel blockers.

Background and Purpose— We hypothesized that direct cervical investigation with Power M-Mode Doppler (PMD) combined with single-gate Doppler spectral analysis (SGDSA) using a 2-MHz pulsed-wave Doppler transducer would show reasonable accuracy parameters when compared with standard color-coded carotid duplex ultrasound (CDU). Methods— We prospectively screened for cervical internal carotid artery (ICA) stenosis by direct observation using a 2 MHz PMD/SGDSA device. PMD identified the artery (location, depth, flow direction) and SGDSA assessed waveform; peak systolic, end diastolic, and mean flow velocities (MFV) of the common carotid artery; cervical ICA proximally and distally; and external carotid artery. Diagnostic accuracy was compared with concurrent carotid duplex ultrasound. The continuity principle was applied using the proximal/distal cervical ICA MFV ratio. Results— We examined 456 vessels (228 patients). Using ICA proximally/ICA distally MFV ratio of 1.5 or greater or absence of ICA signature, for 40% to 59% or greater stenosis (including occlusions), sensitivity was 75.4%, specificity 99.8%, positive predictive value 97.7%, negative predictive value 96.6%, and accuracy 96.7%. For MFV ratio 1.6 or greater or absence of ICA signature and 60% to 79% or greater stenosis (including occlusions), sensitivity was 92.3%, specificity 98.1%, positive predictive value 81.8%, negative predictive value 99.3%, and accuracy 97.6%. Conclusions— Use of combined PMD and SGDSA to directly observe the extracranial ICA is reasonably accurate compared with carotid duplex ultrasound. Using the MFV ratio of proximal/distal extracranial ICA improves accuracy parameters and provides a quick and effective bedside screen for ICA stenosis. This novel technique should be considered part of the standard PMD/transcranial Doppler examination.

The effect of an initial single-blind placebo period in a phase I clinical trial was assessed in 12 volunteers who underwent five weekly treatment periods, consisting of treatment on the first day and a six-day wash-out period. An initial single-blind placebo period was followed by three different single doses of a platelet-aggregation factor inhibitor and another placebo period, under a double-blind Latin square design. Reports of abnormal symptoms were collected using a questionnaire designed by our group. A total of 13 abnormal symptoms were reported during the first period and only nine for the following four periods, indicating a clear placebo period effect. These preliminary results suggest that an initial single-blind period may be usefully included in phase I clinical trials.

OBJECTIVE 131I therapy may be beneficial for patients with advanced differentiated thyroid cancer (DTC) but there have been relatively few studies of the prognostic factors which influence the outcome. We have evaluated differences in outcome in relation to histology, localization of tumour, differentiation grade, age and sex after 131I as the only secondary treatment for advanced stages of DTC. DESIGN Retrospective study of a selected patient group treated according to a fixed protocol. PATIENTS We studied the outcome in 86 patients with stage pN3, pT4 or pM1 out of total of 432 patients treated for DTC from 1970 until 1991. RESULTS The overall cure rate of 131I therapy after a mean follow-up of 12.1 years was 50% (papillary 65% vs follicular 23%). The overall 5-year progression free survival (PFSR) was 66%. Three out of 11 patients with bone metastases from follicular cancer were cured after a mean dose of 13.2 GBq, significantly less than the average dose of 28.4 GBq given to all patients with bone metastases. In the univariate analysis of 5-year PFSR histology (papillary 79% vs follicular 43%), differentiation grade (well differentiated 81% and moderately differentiated 31%), tumour stage (pN3100%, pT4 77% and M1 48%), and age (≤ 60 years 85% vs > 60 years 46%) were significant prognostic factors. A multivariate analysis showed differentiation grade, histology and age to be significant prognostic variables for outcome (moderately vs well differentiated: RR = 3.16, follicular vs.papillary: RR = 2.56 and age > 60 vs age ≤ 60: RR = 2.43). CONCLUSIONS 131I can be an effective treatment in patients with advanced differentiated thyroid cancer at all sites and can cure, on average, 50% of all patients with advanced differentiated thyroid cancer.

We compared the efficacy and safety of three doses of beraprost sodium, an epoprostenol analogue, with placebo in the treatment of intermittent claudication (Fontaine's stage II). One hundred sixty-four patients were randomized to receive either placebo, 20 micrograms beraprost sodium (BPS60 group), 40 micrograms beraprost sodium (BPS120 group), or 60 micrograms beraprost sodium (BPS180 group) three times daily administered orally in a double-blind manner for 12 weeks. Treadmill exercise tests were performed twice during an initial selection phase (D-28 and D0) at week 10 (at trough beraprost concentration) and week 12 (at peak beraprost concentration) of the treatment phase. At week 10, all groups showed an increase in pain-free walking distance, and this distance was greatest in the BPS60 and BPS120 groups (p = 0.055). At week 12, a similar pattern was observed, and the difference was significant between the groups (p = 0.023). The most frequent adverse events reported were gastrointestinal disorders, headaches, skin disorders, and flushes. Patients who received either 60 or 120 micrograms of beraprost sodium daily had an increased pain-free walking distance. Further studies are required to investigate why the highest dose used (180 micrograms daily) showed lower efficacy. Having both vasodilating and antiplatelet properties and being able to increase pain-free walking distance in the short term, beraprost sodium is a promising drug for the treatment of intermittent claudication.

We report the case of splenic subcapsular haematoma, that happens to a woman after three months. Breaking and fistulation of the splenic haematoma into the gastric cavity and its subsequent evacuation made it first identify as digestive haemorrhage.

14016 Background: Definitive chemoradiation therapy is the standard of care for squamous or cloacogenic cell ACC. The chemotherapy regimen comprising 5-FU and MMC is the most commonly used among patients with ACC, nearly 70% of patients can get complete response (CR), with the benefit of sphincter preservation, but patients with a large tumors (T3/T4) or nodal metastases have a response of 50%. Methods: To improve outcome, we conducted a phase II, study of 5-FU and CDDP followed by combined XRT plus 5-FU and MMC. Eligibility included patients withT3/T4 ACC with limited locoregional nodal involvement (N0/N1). Treatment: 5-FU 1000 mg/m2/days 1 to 5 in continuous i.v. infusion plus CDDP 100 mg/m2 i.v. day 1 q21d was administered for 2 cycles (weeks 1 and 4) followed by XRT (4.5 Gy) during 6 weeks (weeks 7 to12) with concurrent 5-FU 1000 mg/m2/days 1 to 4 in continuous i.v. infusion plus MMC 10 mg/m2 i.v. day 1 (weeks 9 and 17). RECIST criteria were used to assess tumor response Results: 59 patients were entered on this study from 8/2000 to 2/2005. Median age: 57 yrs (37–83), 49 F/10 M, median ECOG PS 0 (0–1), T3/T4 44/15, N0/N1 20/39. 54 patients were evaluable for clinical response: Induction chemotherapy led to 13 (24%) CR, 38 (70%) partial responses (PR) and 2 (6%) stable disease. After combined modality treatment, there were a total of 36 (67%) CR, 13 (24%) PR, 5 (9%) SD. Median follow up was 21.6 months (5–52).The median time to progression is 20.5 months (3–52). Toxicity grade 3/4: Neutropenia 20% (10/54), thrombocytopenia 13% (7/54), radiodermatitis 13% (7/54), nausea/vomiting 7% (4/54). Our previous experience with concurrent treatment without induction (n=27) resulted in a CR 59%, PR 37%, and 4% progressive disease Conclusions: We concluded that induction chemotherapy followed by combined XRT and chemotherapy could be an option in treatment of locally advanced ACC. No significant financial relationships to disclose.