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Despite the development of new antiepileptic drugs, Dravet syndrome frequently remains therapy resistant and is a catastrophic epilepsy syndrome. Fenfluramine is an amphetamine-like drug that has been used in the past as a part of antiobesity treatments. Because of the possible cardiac adverse effects (valve thickening, pulmonary hypertension) associated with use of fenfluramine, it was withdrawn from the market in 2001. In Belgium, a Royal Decree permitted examination of the potential anticonvulsive effects of fenfluramine in a clinical trial consisting of a small group of patients diagnosed with Dravet syndrome.Herein, we report 12 patients, 7 female and 5 male, with a genetically proven (11 of 12) diagnosis of Dravet syndrome who received fenfluramine as add-on therapy.Their ages at their last evaluation ranged from 3-35 years. The mean dosage of fenfluramine was 0.34 (0.12-0.90) mg/kg/day. Exposure duration to fenfluramine ranged from 1-19 years. Seven of the patients who were still receiving the fenfluramine treatment at the time of the last visit had been seizure-free for at least 1 year. In total, patients had been seizure-free for a mean of 6 (1-19) years. In seven patients, the fenfluramine treatment was interrupted once during the follow-up; seizures reappeared in three of the seizure-free patients. Subsequent reintroduction of fenfluramine controlled the seizures in these three patients again. Only two patients exhibited a mild thickening of one or two cardiac valves without clinical significance.Compared with a recent long-term follow-up series in which a maximum of 16% of patients with Dravet syndrome were seizure-free, our result of 70% of patients with Dravet syndrome remaining seizure-free is noteworthy. Given the limitations of this observational study, a larger prospective study should be undertaken to confirm these promising results.

Background: Chronic inflammatory demyehnating polyneuroradiculopathy (CIDP) is an autoimmune disease of the peripheral nervous system, causing demyelination and even axonal degeneration. In children, abnormal gait as a first sign of muscle weakness is a frequent reason to seek medical attention. Diagnosis is made on the basis of clinical characteristics, electromyography and nerve conduction studies, and elevated protein in cerebrospinal fluid. Aims: We present three new cases of CIDP. The literature was reviewed in order to obtain more information on presentation, outcome and treatment strategies world-wide. Results: The course of disease can be relapsing-remitting or chronic-progressive. From case series it is known that first-line immunotherapy (intravenously administered immunoglobulin, corticosteroids or plasmapheresis) is initially of benefit in most children with CIDP. There is little evidence, however, on second-line therapies as azathioprine, cyclosporine A, mycophenolate mofetil, methothrexate, cyclophosphamide and IFN alpha. Although the outcome of children with CIDP is generally regarded to be good, disease related disability can be severe. Conclusion: Childhood CIDP is rare. In general and in comparison to adults, children tend to have a more acute progressive onset, with more severe symptoms. Showing a higher tendency towards a relapsing-remitting course, children often show a better and faster improvement after therapy, and a more favorable outcome. Swift recognition of CIDP and empiric start of treatment are considered important to avoid potentially irreversible axonal damage and associated disability. Response to first-line therapies is usually favorable, however recommendations regarding the choice of second-line therapy can only be made on the basis of current practice described in case reports. Safety and efficacy data are insufficient. The cases described show that trial and error are often involved in finding an optimal treatment strategy, especially in those patients refractory to first-line treatment or with a prolonged course. Clinical experience with immunomodulatory treatment is paramount when treating children with CIDP. (C) 2011 European Paediatric Neurology Society. Published by Elsevier Ltd. All rights reserved.

Contains fulltext : 110552.pdf (Publisher’s version ) (Closed access) In a male patient with West Syndrome we identified a perfectly balanced, de novo balanced translocation 46,XY,t(2;6)(p15;p22.3). No known protein coding genes were disrupted by the translocation and positional effects on nearby genes were excluded by expression studies. A putative long non-coding RNA, BX118339, spans the breakpoint on chromosome 6. It can be hypothesized that disruption of this non-coding transcript plays a role in the pathogenesis of the patient. 01 mei 2012

Objective: KCNQ2 and KCNQ3 mutations are known to be responsible for benign familial neonatal seizures (BFNS). A few reports on patients with a KCNQ2 mutation with a more severe outcome exist, but a definite relationship has not been established. In this study we investigated whether KCNQ2/3 mutations are a frequent cause of epileptic encephalopathies with an early onset and whether a recognizable phenotype exists. Methods: We analyzed 80 patients with unexplained neonatal or early-infantile seizures and associated psychomotor retardation for KCNQ2 and KCNQ3 mutations. Clinical and imaging data were reviewed in detail. Results: We found 7 different heterozygous KCNQ2 mutations in 8 patients (8/ 80; 10%); 6 mutations arose de novo. One parent with a milder phenotype was mosaic for the mutation. No KCNQ3 mutations were found. The 8 patients had onset of intractable seizures in the first week of life with a prominent tonic component. Seizures generally resolved by age 3 years but the children had profound, or less frequently severe, intellectual disability with motor impairment. Electroencephalography (EEG) at onset showed a burst-suppression pattern or multifocal epileptiform activity. Early magnetic resonance imaging (MRI) of the brain showed characteristic hyperintensities in the basal ganglia and thalamus that later resolved. Interpretation: KCNQ2 mutations are found in a substantial proportion of patients with a neonatal epileptic encephalopathy with a potentially recognizable electroclinical and radiological phenotype. This suggests that KCNQ2 screening should be included in the diagnostic workup of refractory neonatal seizures of unknown origin. ANN NEUROL 2012; 71: 15-25

Vagus nerve stimulation (VNS) is a therapeutic option for individuals with refractory epilepsy. Individuals with refractory epilepsy are prone to dysfunction of the autonomic nervous system. Reduced heart rate variability is a marker of dysfunction of the autonomic nervous system. Our goal was to study heart rate variability in children with refractory epilepsy and the influence of VNS on this parameter.In 17 children (13 male; four female; mean age 7 y 6 mo; age range 3-16 y) with refractory epilepsy, electroencephalographic and electrocardiographic data were obtained before and after implantation of VNS during stage 2 and slow-wave sleep. Time and frequency domain parameters were calculated and the results were compared with an age- and sex-matched group of individuals without refractory epilepsy.Our results show that autonomic cardiac control is affected in individuals with refractory epilepsy. There is a striking reduction in vagal tone during slow-wave sleep and modulation capacity is smaller than in individuals without refractory epilepsy. Implantation of VNS induces a shift in sympathovagal balance towards sympathetic predominance and an improvement in autonomic modulation.Heart rate variability is affected in children with refractory epilepsy, and changes after implantation of VNS. The observed changes could be of importance in the cardiac complications of individuals with epilepsy and should be explored in more detail.

Early onset hereditary motor and sensory neuropathies are rare disorders encompassing congenital hypomyelinating neuropathy with disease onset in the direct post-natal period and Dejerine-Sottas neuropathy starting in infancy. The clinical spectrum, however, reaches beyond the boundaries of these two historically defined disease entities. De novo dominant mutations in PMP22, MPZ and EGR2 are known to be a typical cause of very early onset hereditary neuropathies. In addition, mutations in several other dominant and recessive genes for Charcot-Marie-Tooth disease may lead to similar phenotypes. To estimate mutation frequencies and to gain detailed insights into the genetic and phenotypic heterogeneity of early onset hereditary neuropathies, we selected a heterogeneous cohort of 77 unrelated patients who presented with symptoms of peripheral neuropathy within the first year of life. The majority of these patients were isolated in their family. We performed systematic mutation screening by means of direct sequencing of the coding regions of 11 genes: MFN2, PMP22, MPZ, EGR2, GDAP1, NEFL, FGD4, MTMR2, PRX, SBF2 and SH3TC2. In addition, screening for the Charcot-Marie-Tooth type 1A duplication on chromosome 17p11.2-12 was performed. In 35 patients (45%), mutations were identified. Mutations in MPZ, PMP22 and EGR2 were found most frequently in patients presenting with early hypotonia and breathing difficulties. The recessive genes FGD4, PRX, MTMR2, SBF2, SH3TC2 and GDAP1 were mutated in patients presenting with early foot deformities and variable delay in motor milestones after an uneventful neonatal period. Several patients displaying congenital foot deformities but an otherwise normal early development carried the Charcot-Marie-Tooth type 1A duplication. This study clearly illustrates the genetic heterogeneity underlying hereditary neuropathies with infantile onset., Journal Article, Research Support, Non-U.S. Gov't, SCOPUS: ar.j, info:eu-repo/semantics/published

We screened a cohort of 5 male and 20 female patients with a Rett spectrum disorder for mutations in the coding region of FOXG1, previously shown to cause the congenital variant of Rett syndrome. Two de novo mutations were identified. The first was a novel missense mutation, p.Ala193Thr (c.577G>A), in a male patient with congenital Rett syndrome, and the second was the p.Glu154GlyfsX301 (c.460dupG) truncating mutation in a female with classical Rett syndrome, a mutation that was previously reported in an independent patient. The overall rate of FOXG1 mutations in our cohort is 8%. Our findings stress the importance of FOXG1 analysis in male patients with Rett syndrome and in female patients when mutations in the MECP2 and CDKL5 genes have been excluded.

Nonspecific X-linked mental retardation (MRX) includes several distinct entities with mental retardation but without additional distinguishing features. The MRX family reported here has been classified previously as MRX9. In this study, we performed linkage analysis of MRX9 with a panel of 43 polymorphic DNA markers dispersed over chromosome X. Two-point linkage analysis revealed lod scores of 3.52 and 3.82 at 0% recombination for OATL1 and MAOA, both located in Xp11.2-p11.4. Lod scores for linkage with PGK1P1, DXS106, and DXS132, all located in Xq11-q13, were 3.83, 3.82, and 3.52, respectively, all at 0% recombination. Multipoint linkage analysis showed two peaks with MAOA and DXS132/DXS106, respectively. Analysis of recombinational events indicated a position of the MRX9 gene between DXS164 and DXS453. These findings are compatible with a location of the MRX9 gene in the pericentromeric region of the X chromosome at Xp21-q13.

Mutations in CDKL5, which encodes cyclin dependent kinase-like 5, cause a form of severe infantile epileptic encephalopathy (EIEE2, OMIM 300672) predominantly in girls [1–3]. The clinical consequences of CDKL5 mutations characteristically comprise infantile spasms, early-onset seizures, and severe mental retardation. Clinically, there is some overlap with Rett syndrome (RTT, OMIM 312750), and female patients with CDKL5 mutations are often considered as suffering from atypical RTT or the Hanefeld variant of RTT. Other genes associated with atypical RTT are FOXG1, MEF2C, and NTNG1 [4]. To date, about 80 patients have been reported with CDKL5 mutations. The distribution of mutations over most of the presently known coding exons indicates that there are no mutational hotspots. The function of CDKL5/Cdkl5 is largely unexplored. Its gene product interacts with MeCP2, which is mutated in over 90% of patients with classic RTT. More recent studies have shown that CDKL5 controls the morphology of nuclear speckles [5] and that Cdkl5 is required for neuronal morphogenesis. By performing RT-PCR experiments on mouse total brain RNA with different primer pairs, we obtained products of the expected size, but also an additional larger product in each reaction (data not shown). Sequencing of the larger products revealed an insertion of 123 bp between exons 16 and 17. We have termed this insert “exon 16a.” This exon is predicted to code for an in-frame addition of 41 amino acids into the presently known Cdkl5 gene variants (Fig. 1). In the meantime, Fichou et al. reported that in the mouse, Cdkl5 transcripts containing this exon are expressed in all brain regions tested [6]. RT-PCR analysis using RNA from different Electronic supplementary material The online version of this article (doi:10.1007/s10048-011-0277-6) contains supplementary material, which is available to authorized users. N. Rademacher :M. Hambrock :U. Fischer : B. Moser : A. Tzschach :V. M. Kalscheuer (*) Max Planck Institute for Molecular Genetics, Department of Human Molecular Genetics, Ihnestr. 73, D-14195 Berlin, Germany e-mail: kalscheu@molgen.mpg.de

Monitoring of epileptic patients is usually done by video/EEG-monitoring which is considered as the golden standard. Due to some disadvantages of this method, this method is not feasible to use in long term home monitoring. Video monitoring provides a solution to this problem as it can monitor the patient in a non-contacting way. An algorithm is developed to detect movement epochs in nocturnal datasets for pediatric epileptic patients. The performance was measured using a threefold crossvaildation, which resulted in a sensitivity of 1 and a positive predictive value above 0.85.

The monitoring of epileptic seizures is mainly done by means of video/EEG-monitoring. Although this method is considered as the golden standard, it is not comfortable for the patient as the EEG-electrodes have to be attached to the scalp which hampers the patient’s movement. This makes long term home monitoring not feasible. A detection system with accelerometers attached to the wrists and ankles can solve this problem. Nocturnal frontal lobe seizures often include bicycle pedaling movements or uncontrolled movements with the arms which are clearly visible in the accelerometer signals. Data from three patients suffering from nocturnal frontal lobe seizures is used in this paper for the development of an automatic detection algorithm for this type of seizure. First movement epochs are detected as a preprocessing step by calculating the standard deviation of a sliding window. Afterwards a moving average filter is applied to the data and thresholds are set to the signals of the arms and legs to detect the seizures. This resulted in an algorithm with a sensitivity of 91.67% and a specificity of 83.92%.

Absence epilepsies of childhood are heterogeneous with most cases following complex inheritance. Those cases with onset before 4 years of age represent a poorly studied subset. We screened 34 patients with early-onset absence epilepsy for mutations in SLC2A1, the gene encoding the GLUT1 glucose transporter. Mutations leading to reduced protein function were found in 12% (4/34) of patients. Two mutations arose de novo, and two were familial. These findings suggest GLUT1 deficiency underlies a significant proportion of early-onset absence epilepsy, which has both genetic counseling and treatment implications because the ketogenic diet is effective in GLUT1 deficiency.

In epileptic patients fractures are six times more frequent than in the general population. Known predisposing factors are anticonvulsant drugs, malnutrition, lack of physical activity and sunlight exposure.In this study we describe two patients, one with a bilateral supracondylar fracture and one with a unilateral supracondylar fracture after an epileptic seizure. The literature concerning femur fracture following an epileptic insult is reviewed.A review of the literature revealed several cases of femur fractures associated with epilepsy, however no cases were found involving a supracondylar femur.Our hypothesis is that a tonic seizure with simultaneous contraction of both agonists and antagonists can cause this type of fracture in predisposing patients.

Contains fulltext : 71291.pdf (Publisher’s version ) (Closed access) Mutations in the receptor expression enhancing protein 1 (REEP1) have recently been reported to cause autosomal dominant hereditary spastic paraplegia (HSP) type SPG31. In a large collaborative effort, we screened a sample of 535 unrelated HSP patients for REEP1 mutations and copy number variations. We identified 13 novel and 2 known REEP1 mutations in 16 familial and sporadic patients by direct sequencing analysis. Twelve out of 16 mutations were small insertions, deletions or splice site mutations. These changes would result in shifts of the open-reading-frame followed by premature termination of translation and haploinsufficiency. Interestingly, we identified two disease associated variations in the 3'-UTR of REEP1 that fell into highly conserved micro RNA binding sites. Copy number variation analysis in a subset of 133 HSP index patients revealed a large duplication of REEP1 that involved exons 2-7 in an Irish family. Clinically most SPG31 patients present with a pure spastic paraplegia; rare complicating features were restricted to symptoms or signs of peripheral nerve involvement. Interestingly, the distribution of age at onset suggested a bimodal pattern with the appearance of initial symptoms of disease either before the age of 20 years or after the age of 30 years. The overall mutation rate in our clinically heterogeneous sample was 3.0%; however, in the sub-sample of pure HSP REEP1 mutations accounted for 8.2% of all patients. These results firmly establish REEP1 as a relatively frequent autosomal dominant HSP gene for which genetic testing is warranted. We also establish haploinsufficiency as the main molecular genetic mechanism in SPG31, which should initiate and guide functional studies on REEP1 with a focus on loss-of-function mechanisms. Our results should be valid as a reference for mutation frequency, spectrum of REEP1 mutations, and clinical phenotypes associated with SPG31.

OBJECTIVE: Dominant mutations in the three collagen VI genes cause Bethlem myopathy, a disorder characterized by proximal muscle weakness and commonly contractures of the fingers, wrists, and ankles. Although more than 20 different dominant mutations have been identified in Bethlem myopathy patients, the biosynthetic consequences of only a subset of these have been studied, and in many cases, the pathogenic mechanisms remain unknown. METHODS: We have screened fourteen Bethlem myopathy patients for collagen VI mutations and performed detailed analyses of collagen VI biosynthesis and intracellular and extracellular assembly. RESULTS: Collagen VI abnormalities were identified in eight patients. One patient produced around half the normal amount of alpha1(VI) messenger RNA and reduced amounts of collagen VI protein. Two patients had a previously reported mutation causing skipping of COL6A1 exon 14, and three patients had novel mutations leading to in-frame deletions toward the N-terminal end of the triple-helical domain. These mutations have different and complex effects on collagen VI intracellular and extracellular assembly. Two patients had single amino acid substitutions in the A-domains of COL6A2 and COL6A3. Collagen VI intracellular and extracellular assembly was normal in one of these patients. INTERPRETATION: The key to dissecting the pathogenic mechanisms of collagen VI mutations lies in detailed analysis of collagen VI biosynthesis and assembly. The majority of mutations result in secretion and deposition of structurally abnormal collagen VI. However, one A-domain mutation had no detectable effect on assembly, suggesting that it acts by compromising collagen VI interactions in the extracellular matrix of muscle.

We present the case report of a 13-month-old Caucasian toddler with symptoms of loss of consciousness, central cyanosis and uncontrolled movements of the upper limbs while taking a warm bath. The diagnosis of hot water epilepsy was supported by an ictal EEG. Hot water epilepsy, also known as bathing epilepsy or water-immersion epilepsy is, in the Caucasian population, a rare form of benign epilepsy, where seizures are provoked by immersion in a hot or even just a warm bath. This is the first comprehensive video publication of a seizure provoked by water-immersion in a Caucasian child. [Published with video sequences].

We present a family with dystrophinopathy in whom the proband is a female aged 4.5 years, who presented with exertional muscle pain without weakness. Familial analysis identified a maternal nephew of the proband who demonstrated a similar clinical picture, with asymptomatic cardiomyopathy. A DNA analysis revealed an in-frame deletion in the proximal part of domain II of the dystrophin gene. Extensive familial analysis indicated that the asymptomatic maternal grandfather transmitted the deletion. This is the first report of a young female patient with exertional muscle pain as the only early presenting symptom of dystrophinopathy.

Several studies have reported favorable effects of intravenous immunoglobulins (IVIG) in refractory epilepsy. Evidence substantiating an immunomodulatory action is scarce. In an open-label study, we prospectively investigated the effect of IVIG on clinical, EEG and serum/CSF immunological parameters in patients with refractory childhood-onset epilepsy.Thirteen patients (median age 6.9 years; range 1.6-25.8) with refractory seizures despite 3-4 antiepileptic drug regimens were given IVIG (Sandoglobulin, ZLB-Behring, add-on, 4 x 400 mg/kg/3 weeks). Seizure frequency, 24-h video-EEG, and CSF/serum immunological parameters and cytokine profiles (IL-6/IL-8/IL-12/IL-10) were documented before and after completion of the course.Seizure frequency was reduced byor = 50% in four, and by 25%-50% in three patients. In contrast, variation in automatically recorded spike counts (1-h-wake and -sleep) did not correlate with clinical improvement. Serum immunological parameters showed variable deviations in eight patients (e.g., IgG(2) deficiency) and CSF immunoblotting showed oligoclonal bands in two patients. Blood-brain barrier permeability was normal in 12 patients. IL-6 and IL-8 were clearly detectable in CSF of all patients; the levels were significantly higher than those in plasma but remained unaffected by IVIG treatment.Despite unchanged EEG spike counts, substantial reductions in seizure frequency occurred in 7 of 13 patients, suggesting that IVIG hinder progression of central epileptic activity into clinical seizures. Intrathecal presence of IL-8 and IL-6 was documented in all patients, but was unaffected by IVIG, suggesting that their production is directly related to electrical seizure activity and that IVIG may act through interference with immune pathways downstream to IL-6 and IL-8.

Objective To study the frequency and distribution of mutations in SPG3A in a large cohort of patients with hereditary spastic paraplegia. Design We screened a large cohort of 182 families and isolated cases with pure or complex hereditary spastic paraplegia phenotypes, which were negative for mutations in SPG4 . Results In 12 probands (6.6%), we identified 12 different SPG3A mutations (11 missense and 1 insertion/frameshift) of which 7 were novel and 3 were de novo. We found incomplete penetrance in 1 family (G482V). In most cases, SPG3A mutations were associated with an early age at onset (mean, 3 y); however, in 1 family (R495W mutation), symptoms started later (mean, 14 y) with clear intrafamilial variability (8-28 y). Six patients with an SPG3A mutation (F151S, Q191R, M408T, G469A, R495W) originating from 5 unrelated families presented with a complex form of hereditary spastic paraplegia associated with a neuropathy (17%). Our electrophysiological and pathological findings confirmed an axonal sensory-motor neuropathy. There was no correlation between the genotype and the presence of a neuropathy. Conclusions We conclude that mutations in SPG3A represent an important cause of patients in the overall hereditary spastic paraplegia population. SPG3A is more often associated with a neuropathy than previously assumed. Therefore, patients with a bipyramidal syndrome and a neuropathy should be screened for mutations in SPG3A .

Objective Dravet syndrome is a severe epileptic encephalopathy beginning in infancy. The characteristic electroclinical picture is well known. With the discovery of SCN1A, molecular confirmation is possible in 75% of the patients. In approximately 70% a mutation is found and in 3–5% a copy number variant (CNV). CNVs frequently involve deletions, which not only contain SCN1A but the whole SCN gene cluster. This cluster contains five sodium channel genes (SCN3A, SCN2A, SCN1A, SCNC9A and SCN7A) along with GRB14 and GALNT3. The aim of this study was to determine whether patients with a SCN cluster deletion show a more severe form of the Dravet syndrome or have a specific continuous gene deletion syndrome. Methods We retrospectively reviewed the files of children with a deletion of the SCN gene cluster. Results We report six patients with a SCN cluster deletion (5 confirmed by aCGH, one with MLPA). All patients have a large de novo deletion (mean 5.6 Mb, SD 2.5). The mean age of presentation was 14.8 w (SD 7.3 w). Four infants presented with myoclonus, one with a febrile status epilepticus and one with an afebrile focal seizure with secondary generalization. Three had dysmorphic features and an abnormal development prior to the onset of convulsions. All patients showed a disastrous course with a severe mental retardation, hypotonia, failure to thrive and therapy resistant epilepsy in infancy. Two patients died around the age of one year, one at the age of 15 years. Three patients (8m, 20m and 4y of age) are still in follow-up. Conclusion Patients with a SCN cluster deletion frequently show a more severe form than the classic Dravet syndrome phenotype. The slightly earlier presentations with myoclonic seizures, abnormal development prior to the onset of convulsions, severe developmental delay or dead in infancy are suggestive for the SCN cluster deletion syndrome.

Objective Further evaluation of efficacy of fenfluramine in Dravet syndrome. Methods Dravet syndrome remains, notwithstanding the introduction of newer anti-epileptic drugs, a therapy resistant epilepsy syndrome. Fenfluramine is an amphetamine-like drug used in the past as part of anti-obesity treatment. Because of possible cardiac side effects (valve thickening, pulmonary hypertension), it has been withdrawn from the market in the US and Europe. In Belgium, it was allowed to study its potential anti-convulsive effect and possible side effects in a small group of well-defined patients with Dravet syndrome. Results Twelve patients, seven girls and five boys, with a genetically proven (11/12) diagnosis of Dravet syndrome received add-on therapy with fenfluramine. The retrospective data were published in 2012 (Ceulemans et al, Epilepsia 2012). We present here the results of 5 years (10 patients) and 4 years (2 patients) prospective follow-up. Overall, looking at the prospective period only, 50% (29/58) of the patient-years were seizure free years, and in 21% (12/58) were only rare seizures ( Conclusion These five-year prospective follow-up data confirms the promising results of fenfluramine as add on in Dravet syndrome. Patients were seizure free or only had rare seizures for at least one year in 71%. Valve thickening never seems a progressive problem and is never clinically significant.

Opisthotonus is a relatively rare, but challenging neurological symptom of spasticity or dystonia that most often results from a dramatic event such as near-drowning. The classic treatment option for opisthotonus is the oral administration of medication such as benzodiazepines and baclofen. However, results with these medications are usually not very beneficial. Numerous studies however have shown that intrathecal treatment with baclofen (ITB) is an efficient and safe treatment for generalized therapy-resistant spasticity, even in children. In this retrospective study, we describe 11 children (mean age 9 years) with pronounced opisthotonus and quadriplegia caused by different types of acquired lesions who were treated with intrathecal baclofen. Results show that in addition to an expected decrease in muscle tonus, there was also a clear improvement in patient comfort and nursing. A remarkable weight gain was observed in most patients, even when calorie intake did not change. This increase in weight might be due to a reduction in energy expenditure as a result of the decrease in spasticity. Intrathecal treatment with baclofen should be considered in every child with opisthotonus.

Introduction: Vagus nerve stimulation (VNS) is a symptomatic add-on treatment for patients with medically refractory epilepsy. It consists of continuous electrical stimulation of the left vagus nerve by means of a helical electrode and an implantable, programmable pulse generator. Currently, over 50,000 patients are treated with VNS worldwide. Aim: This uncontrolled, open-label retrospective study evaluates long-term outcome in patients treated with VNS for refractory epilepsy in seven different epilepsy centres in Belgium. Methods: For the purpose of this study, a minimum of essential inclusion criteria were defined to collect relevant data. This limited the results to basic findings with regards to efficacy on the long term. Inclusion criteria were a follow-up of at least 12 months and a documented seizure diary before implantation and at maximum follow-up. Primary outcome measures were the reduction in mean monthly seizure frequency and the percentage of patients with a seizure reduction of at least 50% (responder rate). Results: About 138 patients (67M/71F) had a mean age of 30 years (range 4-59) at time of implantation and a mean post-implantation follow-up of 44 months (range 12-120). The mean number of AEDs before implantation was 3 (range 1-5). About 117/138 patients had focal epilepsy, 21 patients had symptomatic generalised epilepsy. About 117/138 patients were older than 16 years, 21 patients were 16 or younger. At maximum follow-up, mean stimulation output current was 1.84 mA (range 0-3.25). Mean number of AEDs at maximum follow-up remained unchanged. The overall reduction in mean monthly seizure frequency was 51%. Mean seizure frequency before implantation was 41 seizures/month (SD = 61; range 1-300), mean seizure frequency after implantation at maximum follow-up was 7 seizures/month (SD = 25; range 0-120). Responder rate was 59%. 13% of patients had a seizure frequency decrease between 30% and 50%. About 28% had a seizure frequency decrease of

To the Editor: Neurologic complications of schistosomiasis may occur early as well as late in the course of infection; they result when a pair of worms becomes lodged in the vasculature, and their eggs become trapped in the microcirculation of the brain or spinal cord. There, they elicit a strong inflammatory response, which causes the clinical manifestations (1–3). Magnetic resonance and computed tomographic images of the brain show nonspecific, contrast-enhancing infiltrates, which suggests brain tumors (4). Definitive diagnosis requires finding Schistosoma eggs in feces, urine, rectal biopsy specimen, or biopsy specimen of central nervous system lesions (5), while a positive antibody test result provides a probable diagnosis only. To prevent irreversible damage, early treatment with corticosteroids is essential, after which the adult worms can be eliminated with praziquantel (3,4). A high degree of suspicion is therefore needed to avoid treatment delay. Neuroschistosomiasis has been reported in persons living near Lake Malawi, in Malawi (6). Four members of a Belgian expatriate family (both parents and 2 children, a 12-year-old boy and a 7-year-old girl) went swimming in Lake Malawi in September 1998. On the advice of a physician, they took praziquantel 2 weeks afterward as postexposure prophylaxis. Nevertheless, fever, hypereosinophilia, cough, and abdominal discomfort developed in the mother and both children 6–8 weeks after they had been swimming; these symptoms were indicative of Katayama syndrome. The father remained asymptomatic but had a moderately raised eosinophil count (760 cells/mm3) and tested positive for Schistosoma antibodies. Schistosoma hematobium eggs were found in feces and urine of the mother and girl. All family members tested negative for schistosomiasis on a screening visit the previous year. The boy was admitted to a Zambian hospital because of high fever, cough, and a pulmonary infiltrate. He did not improve on antimicrobial drugs given for suspected pneumonia, and a gradually worsening neurologic syndrome developed, with left-sided hemiparesis, slurred speech, and slow movements. The boy's condition prompted repatriation ≈10 weeks after the exposure. On admission at the University Hospital of Antwerp, his symptoms included fever, left-sided paresis with left-sided Babinski sign, and high eosinophil count (3,080 cells/mm3). An ELISA for Schistosoma antibodies was weakly positive. Examination of spinal fluid showed normal cell and protein content and a slightly lowered glycorrachia. A nuclear magnetic resonance (NMR) image of the brain showed multiple, small, contrast-enhanced white matter lesions around the semiovale center (cranially from the lateral ventricles) bilaterally and in the right parietal cortex. A tentative diagnosis of acute neuroschistosomiasis was made, and the patient was given corticosteroids with praziquantel, 750 mg twice a day for 14 days. At the end of this treatment, his condition had markedly improved; discrete hemiparesis was the only residual symptom. One month later, the patient had returned to normal, apart from left leg hyperreflexia. An NMR of the brain still showed residual lesions around the semiovale centers. Ten months later, results of clinical and neurologic examinations were normal, but NMR of the brain still showed minor residual lesions around the semiovale center on the right side. During follow-up, a serologic shift (indirect hemagglutination schistosomal antibody test) was seen, and eosinophil count decreased gradually to normal (Table). Although the boy never excreted eggs, S. hematobium infection was presumptively diagnosed on the basis of active infection in his relatives and the response to treatment. Table Evolution of acute neuroschistosomiasis in 12-year-old boy after treatment When neurologic symptoms appear soon after primary infection with Schistosoma flukes, confirming the diagnosis may prove difficult, and schistosomiasis should be suspected when the patient has bathed in potentially infected water. Furthermore, hypereosinophilia is an early warning sign, as seroconversion and egg excretion may be slower to evolve. Both elements provide sufficient circumstantial evidence to strongly suspect the diagnosis (2). In this case, the full-blown Katayama syndrome contributed to the evidence. Praziquantel only kills adult worms and does not inactivate schistosomules, nor the miracidium inside the eggs, which will continue to elicit a damaging immunologic response for some time. Early antischistosomal treatment might, in fact, worsen symptoms (7). Because schistosomules may require up to 8 weeks to mature, early postexposure treatment with praziquantel cannot be used to forestall disease after primary infection. Furthermore, Katayama syndrome may occur as early as 3 weeks after exposure. On the other hand, withholding praziquantel until larvae have matured (8 weeks after exposure) would not prevent Katayama syndrome in many cases (7). Acute symptoms, including early neuroschistosomiasis, may therefore still develop during this 5-week window after exposure, despite early praziquantel administration. Artemether has shown promising activity against schistosomules (8). Repeated administration throughout the transmission season has prevented Katayama syndrome in S. japonicum infection (9). Its use, singly or in combination with praziquantel, should be investigated as true postexposure prophylaxis for primary schistosomal infection in nonimmune travelers (10).

Severe myoclonic epilepsy of infancy (SMEI) or Dravet syndrome is a rare epilepsy syndrome. In 30 to 70% of SMEI patients, truncating and missense mutations in the neuronal voltage-gated sodium-channel α-subunit gene (SCN1A) have been identified. The majority of patients have truncating mutations that are predicted to be loss-of-function alleles. Because mutation detection studies use PCR-based sequencing or conformation sensitive gel electrophoresis (CSGE), microdeletions, which are also predicted to be loss-of-function alleles, can easily escape detection. We selected 11 SMEI patients with or without additional features who had no SCN1A mutation detectable with sequencing analysis. In addition, none of the patients was heterozygous for any of the SNPs in SCN1A, indicating that they were either homozygous for all SNPs or hemizygous due to a microdeletion of the gene. We subsequently analyzed these patients for the presence of microdeletions in SCN1A using a quantitative PCR method named multiplex amplicon quantification (MAQ), and observed three patients missing one copy of the SCN1A gene. All three microdeletions were confirmed by fluorescence in situ hybridization (FISH). These findings demonstrate that a substantial percentage of SCN1A-mutation-negative SMEI patients with or without additional features carry a chromosomal microdeletion comprising the SCN1A gene and that haploinsufficiency of the SCN1A gene is a cause of SMEI. Hum Mutat 27(9), 914–920, 2006. © 2006 Wiley-Liss, Inc.

We report on a 3-year-old girl with psychomotor retardation, cardiopathy, strabismus, umbilical hernia, and facial dysmorphism in whom a de novo unbalanced submicroscopic translocation (10p;18q) was found by MLPA (Multiplex Ligation dependent Probe Amplification) and FISH analyses. Additional FISH studies with locus specific RP11 BAC probes and analyses with microsatellites revealed that the translocation resulted in a deletion estimated between 6 and 9 Mb on the maternal chromosome 18 and a subtelomeric 10p duplication of approximately 6.9 Mb. The proband's karyotype is 46,XX.ish der(18) t(10;18)(18pter--18q23:10p15 --10pter). A subterminal duplication of 10p, as well as a subterminal deletion of 18q have been rarely reported so far. The clinical phenotype of this patient is reviewed and discussed.

Although previous studies of Gillespie syndrome have systematically reported a generalized delay of cognitive development (mental retardation or oligophrenia), psychometric data to substantiate this view are strikingly absent. In the present study two first degree relatives (mother and daughter) with Gillespie syndrome were neuropsychologically investigated. Aside from a marked asymmetry in the Wechsler-IQ profile, consisting of significantly better results on the verbal [Verbal IQ (VIQ)] than on the nonverbal part [Performance IQ (PIQ)] of the test, cognitive and behavioral assessments revealed a pattern of abnormalities that closely resembles the ''cerebellar cognitive and affective syndrome'' (CeCAS) (Schmahmann and Sherman, 1998). Aside from prefrontal dysexecutive dysfunctions such as disturbed cognitive planning and set-shifting, parietal lobe involvement was reflected by impaired visuo-spatial memory and visuo-spatial disorganization in constructional tasks. Within the linguistic domain involvement of the prefrontal and temporal language regions was indicated by impaired letter fluency, incidences of agrammatism, apraxia of speech and disrupted language dynamics. With regard to mood and behavior, a number of personality and affective characteristics were found that are typically associated with prefrontal lobe damage and dysfunction of limbic related regions in the cingulate and parahippocampal gyri. Disinhibited symptoms characterized behavior and affect of the mother while the daughter displayed a variety of inhibited symptoms. As a result, behavioral and cognitive findings in these patients do not support the prevailing view of a global mental retardation as a cardinal feature of Gillespie syndrome but primarily reflect cerebellar induced neurobehavioral dysfunctions following disruption of the cerebrocerebellar anatomical circuitry.

Primary objective. To describe clinical experience using botulinum toxin type A (BTX-A) in children with acquired brain injury.Research design. Single centre, open label, pilot study.Methods and procedures. Twenty-one patients were randomized to three groups according to impairment severity and treatment objectives.Experimental interventions. Group 1: Spastic quadriparesis patients with impaired consciousness treated with the primary goal of improving comfort and well-being; Group 2: Patients with upper limb spasticity treated with the primary goal of improving arm functioning; Group 3: Lower limb spasticity patients treated with the primary goal of improving leg function.Outcomes and results. Baseline, 1, 3 and 5-month post-treatment assessments were carried out using joint goniometry, Modified Ashworth Scale and video-observations. All groups demonstrated initial improvements, with patients in Group 2 showing a positive effect at least 5 months post-treatment.Conclusions. With a good outlining of treatm...

Severe myoclonic epilepsy in infancy, or Dravet syndrome, is one of the catastrophic epilepsy syndromes. In the past, treatment was mainly based on valproate and phenobarbital. Recently, some of the new antiepilepsy drugs, such as topiramate and stiripentol, have been shown to be promising in the treatment of this epilepsy syndrome. The treatment regimen of 12 children with Dravet syndrome and proven mutations in the alpha subunit of the sodium channel SCN1A is reported here. Five patients on the “traditional” treatment regimen are compared with seven children on an “optimal” treatment regimen based on a combination of valproate and topiramate. With respect to the literature and our own experience, we propose guidelines for “optimal” treatment of children with severe myoclonic epilepsy in infancy. This includes prevention of hyperthermia, rigorous treatment of fever, avoiding stressful situations, maintenance treatment based on a combination of only two antiepilepsy drugs (ie, valproate and topiramate), and a strict acute seizure treatment based on benzodiazepines. To prevent long-lasting periods of status epilepticus, this acute seizure treatment must be taught to parents and caregivers. ( J Child Neurol 2004;19:516—521).

'Severe myoclonic epilepsy in infancy' or Dravet syndrome is a clear example of the impact of severe epilepsy on the developing child. Presenting with febrile seizures in infancy, children later on develop a severe epileptic syndrome with mental retardation. Nearly all children have life-threatening status epilepticus during the first two years of life. The clinical diagnosis can now be confirmed by DNA-analysis in a majority of patients. Most patients have a de novo mutation in the alfa subunit of the neuronal sodium channel SCN1A. In the past few years' treatment of severe myoclonic epilepsy in infancy has changed. Prevention of seizures, avoiding anti-epileptic drugs which only block sodium channels, a simple combination of two major anti-epileptic drugs (sodium valproate and topiramate) and a strict acute seizure treatment significantly improve the quality of life for these patients. Long-term follow up is necessary to evaluate if we can also improve the development possibilities for these children.

Mutations in the alpha-subunit of the first neuronal sodium channel gene SCN1A have been described in isolated patients with severe myoclonic epilepsy in infancy or Dravet syndrome and in families with generalized epilepsy with febrile seizures plus. To find phenotype/genotype correlations, we reviewed all published cases of mutations in SCN1A in addition to four new patients reported here. A total of 60 mutations were observed. Approximately 52% (31/60) are truncating mutations correlating with de novo cases of classical Dravet syndrome in 32 of 34 (94%) patients. Missense mutations in the pore-forming part constitute 27% (16/60) and correspond to a classical type in 12 of 16 (75%) patients. Missense mutations in the voltage sensor were present in 12% (7/60) and correlate with a clinical picture ranging from febrile seizures plus to severe myoclonic epilepsy in infancy. Outside these regions missense mutations are rare and account for only 10% (6/60), corresponding mostly with febrile seizures plus. These results illustrate that the clinical spectrum of SCN1A mutations ranges from febrile seizures, febrile seizures plus, over a milder type to the classical form of severe myoclonic epilepsy in infancy, and confirm the clinical experience that severe myoclonic epilepsy in infancy is the most severe form on this spectrum.

Subtelomeric rearrangements are responsible for 5% to 10% of cases of unexplained mental retardation. Despite their clinical relevance, methods to screen for these cytogenetically invisible abnormalities on a routine base are scarce. We screened patients with idiopathic mental retardation for subtelomeric aberrations using multiplex ligation-dependent probe amplification (MLPA). This recently developed technique is based on PCR amplification of ligated probes hybridized to chromosome ends. Currently, 41 telomeres can be screened in just two multiplex reactions. Four subtelomeric rearrangements (5.3%) were detected in a group of 75 patients with mild to severe mental retardation in combination with dysmorphic features and/or a familial history of mental retardation: two terminal 1p deletions, a terminal 1q deletion, and a terminal 3p deletion. Deletions could be verified by FISH and marker analysis. In one case the MLPA indicated a terminal 21q deletion due to a 3-bp deletion at the site of the probe, giving a false-positive rate of 1.3%. This study demonstrates that MLPA is a fast and reliable screening method, potentially suitable for use in routine diagnostics. Hum Mutat 23:17–21, 2004. © 2003 Wiley-Liss, Inc.

Generalized epilepsy with febrile seizures plus (GEFS+) is a clinically and genetically heterogeneous syndrome with childhood onset, characterized by febrile seizures (FS) and a variety of afebrile epileptic seizure types. The authors performed a mutational analysis of SCN1B on 74 unrelated probands with GEFS+, FS, or FS plus (FS+). In a family with FS+ and early-onset absence epilepsy, a mutation was identified that predicts a deletion of five amino acids in the extracellular immunoglobulin-like domain of SCN1B and potential loss of function. SCN1B mutations are associated with GEFS+ and may have a role in the elicitation of absence seizures.

Severe myoclonic epilepsy of infancy (SMEI or Dravet syndrome) is a rare disorder occurring in young children often without a family history of a similar disorder. The earliest disease manifestations are usually fever-associated seizures. Later in life, patients display different types of afebrile seizures including myoclonic seizures. Arrest of psychomotor development occurs in the second year of life and most patients become ataxic. Patients are resistant to antiepileptic drug therapy. Recently, we described de novo mutations of the neuronal sodium channel alpha-subunit gene SCN1A in seven isolated SMEI patients. To investigate the contribution of SCN1A mutations to the etiology of SMEI, we examined nine additional SMEI patients. We observed eight coding and one noncoding mutation. In contrast to our previous study, most mutations are missense mutations clustering in the S4-S6 region of SCN1A. These findings demonstrate that de novo mutations in SCN1A are a major cause of isolated SMEI.

Shaken-baby syndrome (SBS) is a type of child abuse caused by violent shaking of an infant, with or without impact, and characterized by subdural hematomas, retinal hemorrhages, and occult bone fractures. Parenchymal brain lesions in SBS may be missed or underestimated on CT scans, but can be detected at an earlier stage with diffusion-weighted MRI (DW-MRI) as areas of restricted diffusion. We demonstrate the value of DW-MRI in a 2-month-old baby boy with suspected SBS. The pattern of diffusion abnormalities indicates that the neuropathology of parenchymal lesions in SBS is due to hypoxic-ischemic brain injuries, and not to diffuse axonal injury.

Dissection of a cerebral blood vessel is a rare complication of acute neurotrauma with a high incidence of morbidity and mortality. We report on a case of a pediatric patient with severe neurological symptoms in whom angiography showed evidence of a basilar artery dissection. The patient was heparinized and recovered uneventfully.

Inleiding: Atypische koortsconvulsies kunnen het eerste teken zijn van severe myoclonic epilepsy in infancy (smei) of ernstige myoclone epilepsie van het jonge kind. Het betreft hier een ernstig epileptisch syndroom met zowel veralgemeende als partiele aanvallen, frequent, vaak door koorts geprovoceerde status epilepticus. Deze aandoening is erg therapieresistent en gaat gepaard met een progressieve mentale retardatie.

We describe two female siblings with similar clinical features consisting of hydrocephalus, scaphocephaly, hypotonia, mongoloid eye slant, blepharophimosis, micrognathia, supernumerary mouth frenula and mental retardation. Routine cytogenetic studies in the elder patient did not reveal any abnormality, and initially it was assumed that the syndrome had an autosomal recessive inheritance. However, a slightly larger chromosome 13 was seen in routine G-banded metaphases of the mother and the youngest of the two siblings. A shorter chromosome 15 was detected in the mother only. High resolution banding showed that the abnormal chromosome 13 contained an extra G-positive band at 13q12. The short chromosome 15 in the mother appeared to have a deletion of band q12. Fluorescence in situ hybridization using DNA markers specific to chromosomes 13 and 15 unequivocally showed that the mother was a carrier of a balanced reciprocal translocation t(13;15)(q12;q13), whereas the youngest sibling's karyotype was 46,XX,-13,+der(15)t(13;15)(q12;q13)mat, resulting in partial monosomy 13pter----q12 and partial trisomy 15pter----q13. The proband is thus trisomic for the critical region responsible for Prader-Willi syndrome and Angelman syndrome; this was confirmed by DNA analysis demonstrating one paternal and two maternal alleles from multiallelic marker loci mapping to 15q11-q13. This report illustrates the sensitivity and specificity offered by fluorescence in situ hybridization and its usefulness in the diagnosis and delineation of subtle chromosomal rearrangements.