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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.

Lynch syndrome is a hereditary predisposition to several cancers. The goals of our study were to know the different mutations in our Lynch population, to evaluate the prevalence of cancers in this population and to determine the mean age of onset of those cancers. This retrospective study includes proven carriers of a MMR mutation diagnosed either by the CHU of Liège or either by the CHC Saint-Joseph in Liège, Belgium. We noted a clear majority of MSH2 mutations (50 %) in the Lynch families recorded in Liège, which is different from the main literature. In our study population (106 subjects), 65 % of subjects were affected by at least one cancer. Prevalences for colorectal and endometrial cancers are, respectively, 50 % and 27.5 %. We found no difference in the mean age of onset of cancers compared to literature. We discuss the follow-up of Lynch patients and the interest of additional exams such as hysteroscopy and cystoscopy.Le syndrome de Lynch est un syndrome de prédisposition héréditaire à un certain nombre de cancers. Les objectifs de notre étude sont de connaître la répartition des différentes mutations dans la population Lynch prise en charge dans nos centres, d’évaluer la prévalence des cancers présentés par les patients Lynch de cette population et de déterminer l’âge moyen d’apparition de ces cancers. Cette étude rétrospective inclut les porteurs confirmés d’une mutation MMR ayant été diagnostiqués, soit par le CHU de Liège, soit par le CHC Saint-Joseph à Liège. Nous avons constaté une nette majorité de mutations MSH2 (50 %) parmi les familles Lynch répertoriées à Liège, ce qui est différent de ce qui est décrit dans la littérature. Dans notre population d’étude (106 sujets), 65 % des sujets ont présenté au moins un cancer. Les prévalences du cancer colorectal et de l’endomètre sont, respectivement, de 50 % et 27.5 %. Nous n’avons pas trouvé de différence dans les âges moyens de présentation des cancers par rapport à la littérature existante. Nous discutons du suivi des patients porteurs d’un syndrome de Lynch et de la place d’examens supplémentaires comme l’hystéroscopie et la cystoscopie.

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.

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.

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.

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.

The aim of this study was to evaluate the usefulness of systematic screening of asymptomatic neurofibromatosis type 1 (NF1) children with magnetic resonance imaging (MRI).We retrospectively reviewed the MRIs of children diagnosed with NF1 disease according to the National Institutes of Health criteria, who had been followed for at least 1 year by the department of pediatric neurology (Lyon, France). Brain MRI was systematically performed in asymptomatic patients under 6 years of age.One hundred patients with a median follow-up of 3.7 years (range, 1-8.6 years) were reviewed. Brain MRI was performed in a total of 94 children. Nine optic pathway gliomas were detected in symptomatic patients. Six children had symptoms caused by the tumor. Gliomas remained stable in 10 patients; 1 symptomatic glioma in an 8-year-old girl required treatment. Spontaneous regression was seen in 1 patient.Our results suggest that MRI screening of asymptomatic children to detect optic pathway gliomas does not improve the therapeutic decision and should not be performed systematically. We suggest further investigation in collaboration with the French NF Network.

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.

Cerebral creatine deficiency syndromes (CCDSs) are inborn errors of metabolism that include two autosomal recessive creatine biosynthesis defects (arginine–glycine amidinotransferase [AGAT; OMIM 602360] and guanidinoacetate methyl transferase [GAMT; OMIM 601240] deficiency) and an X-linked creatine transporter defect (OMIM 300036).1 The clinical phenotype is variable, associating nonspecific mental retardation, epilepsy, extrapyramidal movement disorders, and autistic behavior. The frequency of CCDS is unknown and probably underestimated. We report a high frequency of CCDS in mentally retarded children, mostly boys with an X-linked creatine transporter deficiency. Over a period of18 months, children referred to the Department of Pediatric Neurology with unexplained mild to severe mental retardation, normal karyotype, and absence of fragile X syndrome were prospectively screened for CCDS. Children were from diverse ethnic backgrounds. Children with polymalformative syndromes were excluded. Creatinine metabolism was evaluated using creatine/creatinine and guanidinoacetate (GAA)/creatinine ratios on a spot urine.2 Diagnosis was further confirmed using brain proton MR spectroscopy (H-MRS) and …

The association of inflammatory bowel disease and acute febrile neutrophilic dermatitis (Sweet's syndrome) has infrequently been reported in the literature. We describe the case of a 41-year-old Caucasian woman with ileo- anal Crohn's disease who presented simultaneously an erythema nodosum and a Sweet's syndrome. A dramatic regression of the cutaneous lesions was observed after infliximab treatment, indicating that this therapy might be useful for both Crohn's disease and Sweet's syndrome.

The ketogenic diet is a treatment option for patient with intractable or refractory epilepsy. It is a high-fat, low protein, low carbohydrate diet developed in 1920s. Recent research publications and media interest have renewed debate on the merits of ketogenic diet.We report our experience with 29 children suffering from refractory epilepsy, treated with the ketogenic diet. No surgical option was available. Modalities are explained.The ketogenic diet improved seizure control in 12/29 cases. It appeared effective in infants with infantile spasms. Refractory-status epilepticus responded to the ketogenic diet (3/6 cases). Migrating partial seizures in infancy were always refractory to the diet. Compliance with the diet was good. Adverse effects must be compared with the toxicity of antiepileptic drugs. One child had hypokaliemia with cardiac complication.The ketogenic diet should be continued during one or 2 years when it is effective. It should be considered as an alternative therapy for children with refractory epilepsy.

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.

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.

This study compares the loop diuretic piretanide 6 mg in a slow-release formulation (PIR) with hydrochlorothiazide 25 mg (HCT) and the fixed combination altizide 15 mg-spironolactone 25 mg (ALT-SP) in hypertension. 1105 mild to moderate hypertensive patients entered a three-week placebo wash-out period; 899 were randomized in a 6-month, double-blind, parallel group treatment phase; 800 completed the study. Primary end-points; serum potassium concentration and quality of life at one month; secondary end-points: ionic, renal and metabolic variables; blood pressure (BP) measurements. HCT and ALT-SP were compared only to PIR using Dunnett's or chi 2 tests.No difference was found for the overall quality of life. No change of serum potassium concentration at one month was found in PIR while small decreases were detected with ALT-SP (-0.1 mM) and HCT (-0.26 mM). Serum creatinine concentration increased significantly in ALT-SP when compared to PIR. All the drugs were effective in reducing BP: HCT had a higher rate of responders than PIR with similar mean BP falls and ALT-SP induced greater falls in blood pressure.PIR proves to be a potent antihypertensive drug without significant effect on serum electrolytes, plasma glucose and lipids. HCT was slightly more potent but induced a fall in serum potassium concentration with a significant risk of hypokalaemia. The addition of SP to ALT led to a more potent diuretic with a higher level of serum potassium and plasma creatinine disturbances.

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.

To assess the equivalence of four antihypertensive treatments in patients with mild-to- moderate hypertension, and to compare the effects of those drugs on the subjective quality of life and clinical safety.653 patients agedor = 18 years with untreated hypertension were randomly allocated to receive a combination of two diuretics (altizide and spironolactone), a beta-blocker (bisoprolol), a calcium antagonist (verapamil), or an angiotensin converting enzyme (ACE) inhibitor (enalapril). Follow-up lasted for 1 year.A composite outcome of the following measures was used to define success: attendance at the 12-month visit; at least nine supine DBP measurements during the study; and median supine DBP90 mmHg and a reduction of at least 10 mmHg compared with the baseline value. Failure was defined as one or more of those criteria not being fulfilled. Equivalence was concluded if the 95% confidence interval for the success rates differed between two groups by less than +/- 10%. Clinical safety and subjective quality of life were also assessed.No statistically significant differences in the change in DBP or systolic blood pressure were observed between the groups. The success rates were 43.9, 42.0, 32.5 and 43.9% in diuretic, beta-blocker, calcium antagonist and ACE inhibitor groups, respectively. Equivalence between the treatments could not be concluded, although analysis with a larger equivalence interval showed that some comparisons indicated equivalence. Significant improvement in satisfaction was observed for certain items for subjective quality of life at 1 month in the calcium antagonist treatment group, and significant differences in the responses to the clinical safety questionnaire were observed after 1-month follow-up in calcium antagonist and beta-blocker groups. Differences were no longer significant after 9 months.These results do not provide evidence on the basis of efficacy of blood pressure lowering or ability to increase short-term (1-year) safety and quality of life favouring any particular treatment among the studied drugs for newly diagnosed patients with mild-to-moderate hypertension.