Bleeding risk assessment in hemophilia A carriers from Dakar, Senegal.

: Hemophilia A carriers have an abnormal X chromosome with a molecular abnormality of FVIII gene. These carriers, long considered to be free of bleeding risk, could have the same symptoms as mild hemophiliacs. This study aim to assess bleeding risk of hemophilia A carriers monitored at the Clinical Hematology Department of Dakar. This is a prospective study of a period of 6 months including 22 hemophilia A carriers aged between 8 and 48 years. Hemophilia carriers were recruited using the genealogical tree of hemophiliacs followed in the service. Their diagnosis was carried out by long range PCR and Sanger sequencing method searching the molecular abnormality responsible for hemophilia in their family. Bleeding risk was determined using a questionnaire consisting of different bleeding symptoms quoted from -1 to 4 according to the severity. Total of different values allow to determine the bleeding score which was pathological if it was greater than or equal to 1. Medium age was 22.5 years (8-48) (SD = 9.28). Four hemophilia A carriers (18.1%) presented bleeding symptoms and had a bleeding score at least 1 (P = 0.02). Menorrhagia was predominant (13.6%) followed by epistaxis (9%), gingivorrhagia (9%), and prolonged bleeding after tooth extraction (9%). Factor VIII level was lower in hemophilia carriers who presented bleeding (42 ±â€Š8.61 UI/l) versus hemophilia carriers without bleeding (100 ±â€Š50.95 UI/l) (P = 0.001). There was no significant correlation between bleeding occurrence and age (P = 0.81), activated patial thromboplastin time value (P = 0.97) and FVIII/Von Willebrand Factor ratio (P = 0.12). One in five hemophilia carriers presented bleeding and the questionnaire was effective to identify hemophilia carriers who had a risk of bleeding.

Unusual evolutionary mechanisms to escape effector-triggered immunity in the fungal phytopathogen Leptosphaeria maculans.

Leptosphaeria maculans is the fungus responsible for the stem canker disease of oilseed rape (Brassica napus). AvrLm3 and AvrLm4-7, two avirulence effector genes of L. maculans, are involved in an unusual relationship: AvrLm4-7 suppresses the Rlm3-mediated resistance. Here, we assessed AvrLm3 polymorphism in a collection of 235 L. maculans isolates. No field isolates exhibited deletion or inactivating mutations in AvrLm3, as observed for other L. maculans avirulence genes. Eleven isoforms of the AvrLm3 protein were found. In isolates virulent towards both Rlm3 and Rlm7 (a3a7), the loss of the Rlm3-mediated resistance response was due to two distinct mechanisms. First, when AvrLm4-7 was inactivated (deletion or inactivating mutations), amino acid substitutions in AvrLm3 generated virulent isoforms of the protein. Second, when only point mutations were observed in AvrLm4-7, a3a7 isolates still contained an avirulent allele of AvrLm3. Directed mutagenesis confirmed that some point mutations in AvrLm4-7 were sufficient for the fungus to escape Rlm7-mediated resistance while maintaining the suppression of the AvrLm3 phenotype. Signatures of positive selection were also identified in AvrLm3. The complex evolutionary mechanisms enabling L. maculans to escape Rlm3-mediated resistance while preserving AvrLm3 integrity, along with observed reduced aggressiveness of isolates silenced for AvrLm3, serves to emphasize the importance of this effector in pathogenicity towards B. napus. While the common response to resistance gene pressure is local selection of isolates depleted in the cognate avirulence gene, this example contributes to complexify the gene-for-gene concept of plant-pathogen evolution with a 'camouflaged' model allowing retention of nondispensable avirulence effectors.

Lennox-Gastaut syndrome: a consensus approach to differential diagnosis.

Lennox-Gastaut syndrome (LGS) is a severe epileptic encephalopathy that shares many features and characteristics of other treatment-resistant childhood epilepsies. Accurate and early diagnosis is essential to both prognosis and overall patient management. However, accurate diagnosis of LGS can be clinically challenging. This article summarizes key characteristics of LGS and areas of overlap with other childhood epilepsies. Drawing upon input from a committee of established LGS experts convened in June 2012 in Chicago, Illinois, the authors highlight key diagnostic tests for making the differential diagnosis and propose a diagnostic scheme for people with suspected LGS.

Surgery for intractable epilepsy due to unilateral brain disease: a retrospective study comparing hemispherectomy techniques.

BACKGROUND: Hemispherectomy is a surgical procedure used to treat medically intractable epilepsy in children with severe unilateral cortical disease secondary to acquired brain or congenital lesions. The major surgical approaches for hemispherectomy are anatomic hemispherectomy, traditional functional hemispherectomy, and peri-insular hemispherotomy. We describe the epilepsy outcome, including the need for reoperation, after hemispherectomy in patients with brain malformations or acquired brain lesions who underwent hemispherectomy for refractory epilepsy. METHODS: We conducted a retrospective observational study at Children's Hospital Boston. Cases were ascertained from a research database of patients who underwent epilepsy surgery from 1997 to 2011. Data were obtained from electronic medical records and office charts. Outcome after surgery was defined as improvement in seizures (quantity and severity) represented by the Engel classification score measured at last follow-up, with a minimum of 12 months of follow-up. The need for reoperation for completion of hemispheric disconnection. We also examined whether placement of ventriculoperitoneal shunt was required after hemispherectomy was a secondary outcome. RESULTS: We identified 36 patients who underwent hemispherectomy for severe, medically intractable epilepsy. Group 1 (n = 14) had static acquired lesions, and group 2 (n = 22) had malformations of cortical development. Mean age at surgery for group 1 was 9 years (S.D. 5.5) and 2.77 years for group 2 (S.D. 4.01; P < 0.001). The seizure outcome was good in both groups (Engel score I for 25, II for three, III for six, and IV for two patients) and did not differ between the two groups. In group 1, five patients underwent anatomic hemispherectomy (one had prior focal resection), four underwent functional hemispherectomy, and five underwent peri-insular hemispherotomy; none required a second procedure. In group 2, a total of 14 patients had anatomic hemispherectomy (of these, three had had limited prior focal resection), five had functional hemispherectomy, and three had peri-insular hemispherotomy. Among the patients in group 2 who had had functional hemispherectomy, one required reoperation to complete the disconnection and one required peri-insular hemispherotomy because of persistent seizures. In group 1, three patients underwent a ventriculoperitoneal shunt, and from these patients two underwent anatomic hemispherectomy and one had functional hemispherectomy. In group 2, 12 patients had ventriculoperitoneal shunt, and all of them had anatomic hemispherectomy as a first or second procedure. CONCLUSION: Seizure outcome after hemispherectomy is good in patients with acquired lesions and with developmental malformations. Although the seizure outcome was similar in the three procedures, the complication rate was higher with anatomic hemispherectomy than with the more recent functional hemispherectomy and peri-insular hemispherotomy. The group with cortical malformations generally had surgery at a younger age; two patients with malformations of cortical development who underwent functional hemispherectomy required second surgeries. The need for reoperation in these cases may reflect the anatomic complexity of developmental hemispheric malformations, which may lead to incomplete disconnection.

Safety and retention rate of rufinamide in 300 patients: a single pediatric epilepsy center experience.

OBJECTIVE: Reports of studies evaluating rufinamide as an add-on therapy in children and adolescents with refractory epilepsy are restricted to a few publications. Prospective multicenter studies including children and adults have yielded important information about several types of epilepsies and syndromes. We evaluated the use of rufinamide in a single pediatric center with a large cohort and long-term follow-up period. METHODS: We retrospectively included patients taking rufinamide from November 2008 to March 2013. Response was defined by a seizure reduction of ≥50% compared to baseline. RESULTS: Three hundred patients with a median age of 9.1 years (range 0.4-29.6 years) were reviewed. Median follow-up was 9 months (range 1-37 months). Epilepsy etiology was classified as genetic (23.7%), structural/metabolic (41%), and unknown cause (35.3%). Overall, rufinamide treatment led to a median seizure frequency reduction of 59.2% from responders to baseline. Seizure reduction was greater in patients with genetic etiology compared to structural/metabolic (66.2% vs. 45.5% responders, p = 0.005). Rufinamide was discontinued in 110 (36.7%) of 300 patients: 63 (21%) due to unsatisfactory response, 47 (15.7%) due to side effects, and in 18 (6%) of those due to both. Most common adverse effects were sleepiness, vomiting, mood changes, nausea, and loss of appetite. Median time to loss of efficacy was 11.6 months (range 3-28 months). SIGNIFICANCE: Rufinamide provides satisfactory seizure reduction as an adjunctive treatment in refractory epilepsy. Results need to be interpreted in the setting of data acquisition, including inherent biases of retrospective studies. Patients with a known genetic etiology may have better responses than patients with structural/metabolic etiology.

Clinical value of magnetoencephalographic spike propagation represented by spatiotemporal source analysis: correlation with surgical outcome.

OBJECTIVE: To investigate the correlation between spike propagation represented by spatiotemporal source analysis of magnetoencephalographic (MEG) spikes and surgical outcome in patients with temporal lobe epilepsy. METHODS: Thirty-seven patients were divided into mesial (n=27) and non-mesial (n=10) groups based on the presurgical evaluation. In each patient, ten ipsilateral spikes were averaged, and spatiotemporal source maps of the averaged spike were obtained by using minimum norm estimate. Regions of interest (ROIs) were created including temporoparietal, inferior frontal, mesial temporal, anterior and posterior part of the lateral temporal cortex. We extracted activation values from the source maps and the threshold was set at half of the maximum activation at the peak latency. The leading and propagated areas of the spike were defined as those ROIs with activation reaching the threshold at the earliest and at the peak latencies, respectively. Surgical outcome was assessed based on Engel's classification. Binary variables were created from leading areas (restricted to the anterior and mesial temporal ROIs or not) and from propagation areas (involving the temporoparietal ROI or not), and for surgical outcome (Class I or not). Fisher's exact test was used for significance testing. RESULTS: In total and mesial group, restricted anterior/mesial temporal leading areas were correlated with Class I (p<0.05). Temporoparietal propagation was correlated with Class II-IV (p<0.05). For the non-mesial group, no significant relation was found. CONCLUSIONS: Spike propagation patterns represented by spatiotemporal source analysis of MEG spikes may provide useful information for prognostic implication in presurgical evaluation of epilepsy.

Initiating antiepileptic drug treatment and characteristics of drugs.

This chapter covers the main steps involved in the initiation of antiepileptic drug therapy. Aspects covered specifically include the decision whether or not to initiate treatment, the selection process of a drug of first choice for a given patient with a particular seizure type or epilepsy syndrome, and the process of initiating therapy with the selected drug of first choice. Suggested choices of antiepileptic drugs by seizure type or epilepsy syndrome are summarized in a table. In an appendix, these drugs are reviewed individually with regard to their clinical use. The emphasis is on initial dose, dosage escalation, common and serious adverse effects, baseline evaluation, monitoring of therapy, and relevant drug interactions.

Outcomes of epileptic spasms in patients aged less than 3 years: single-center United States experience.

Retrospective review was performed of children aged <3 years with epileptic spasms at our center from 2004-2010. Short-term (<6 months) and long-term (≥6 months) outcomes were assessed. We included 173 children (104 boys; median age of onset, 6.8 months) with epileptic spasms of known (62%) and unknown (38%) etiology. Treatments included adrenocorticotropic hormone (n = 103), vigabatrin (n = 82), phenobarbital (n = 34), and other agents (n = 121). Short-term treatment with adrenocorticotropic hormone and vigabatrin provided better epileptic spasm control in groups with known and unknown etiology than other agents. At follow-up (6-27 months), 54% of children manifested seizures, and 83% manifested developmental delay. Known etiology was a predictor of poor developmental outcome (P = 0.006), whereas bilateral/diffuse brain lesions predicted both poor development and seizures (P = 0.001 and 0.005, respectively). Initial presentations of epileptic spasms with hypotonia or developmental delay most strongly predicted both seizures and neurodevelopmental outcomes (P < 0.001). In a child presenting with epileptic spasms with developmental delay or hypotonia, no specific treatment may offer superior benefit.

Somatic activation of AKT3 causes hemispheric developmental brain malformations.

Hemimegalencephaly (HMG) is a developmental brain disorder characterized by an enlarged, malformed cerebral hemisphere, typically causing epilepsy that requires surgical resection. We studied resected HMG tissue to test whether the condition might reflect somatic mutations affecting genes critical to brain development. We found that two out of eight HMG samples showed trisomy of chromosome 1q, which encompasses many genes, including AKT3, a gene known to regulate brain size. A third case showed a known activating mutation in AKT3 (c.49G→A, creating p.E17K) that was not present in the patient's blood cells. Remarkably, the E17K mutation in AKT3 is exactly paralogous to E17K mutations in AKT1 and AKT2 recently discovered in somatic overgrowth syndromes. We show that AKT3 is the most abundant AKT paralog in the brain during neurogenesis and that phosphorylated AKT is abundant in cortical progenitor cells. Our data suggest that somatic mutations limited to the brain could represent an important cause of complex neurogenetic disease.

Experience with lacosamide in a series of children with drug-resistant focal epilepsy.

We report our pediatric experience with lacosamide, a new antiepileptic drug, approved by the US Food and Drug Administration as adjunctive therapy in focal epilepsy in patients more than 17 years old. We retrospectively reviewed charts for lacosamide use and seizure frequency outcome in patients with focal epilepsy (Wilcoxon signed rank test). Sixteen patients (7 boys) were identified (median dose 275 mg daily, 4.7 mg/kg daily; mean age 14.9 years, range 8-21 years). Patients were receiving a median of 2 antiepileptic drugs (interquartile range [IQR] 1.7-3) in addition to having undergone previous epilepsy surgery (n=3), vagus nerve stimulation (n=9), and ketogenic diet (n=3). Causes included structural (encephalomalacia and diffuse encephalitis, 1 each; stroke in 2) and genetic abnormalities (Aarskog and Rett syndromes, 1 each) or cause not known (n=10). Median seizure frequency at baseline was 57 per month (IQR 7-75), and after a median follow-up of 4 months (range 1-13 months) of receiving lacosamide, it was 12.5 per month (IQR 3-75), (P<0.01). Six patients (37.5%; 3 seizure free) were classified as having disease that responded to therapy (≥50% reduction seizure frequency) and 10 as having disease that did not respond to therapy (<50% in 3; increase in 1; unchanged in 6). Adverse events (tics, behavioral disturbance, seizure worsening, and depression with suicidal ideation in 1 patient each) prompted lacosamide discontinuation in 4/16 (25%). This retrospective study of 16 children with drug-resistant focal epilepsy demonstrated good response to adjunctive lacosamide therapy (median seizure reduction of 39.6%; 37.5% with ≥50% seizure reduction) without severe adverse events.

New onset epilepsy in Prader-Willi syndrome: semiology and literature review.

Prader-Willi syndrome is a chromosomal disorder caused by absence of expression of the paternal active genes in the 15q11∼q13 chromosome region; it is associated with an increased incidence of epilepsy and narcolepsy. Presented here is the case of a 2.5-year-old boy with Prader-Willi syndrome and a history of neonatal superior sagittal sinus thrombosis with new onset of atonic seizures with electrographic onset from the parasagittal region. It is postulated that microscarring from neonatal venous sinus thrombosis, history of febrile seizures, and Prader-Willi syndrome are factors predisposing him to epilepsy. The importance of video electroencephalography with electromyography electrodes is emphasized for Prader-Willi syndrome patients with drop episodes, to differentiate cataplexy from seizures. This being a novel report of a Prader-Willi syndrome patient with atonic seizures, the literature on seizure semiology among patients with Prader-Willi syndrome is reviewed.

Experience with rufinamide in a pediatric population: a single center's experience.

Rufinamide is a new antiepileptic drug recently approved as adjunctive treatment for generalized seizures in Lennox-Gastaut syndrome. We undertook a retrospective analysis of 77 patients with refractory epilepsy and receiving rufinamide to evaluate the drug's efficacy, tolerability, safety, and dosing schedules. It appeared efficacious in diverse epilepsy syndromes, with the highest responder rate in focal cryptogenic epilepsies (81.1% of patients with >50% response rate), and in diverse seizure types, with the highest responder rate in tonic/atonic and partial seizures (48.6% and 46.7% of patients with >50% response rate, respectively). Rufinamide was well tolerated: only 13% of patients developed side effects necessitating drug withdrawal. These findings suggest that rufinamide may possess good efficacy and tolerability, and that its efficacy may extend to epilepsy syndromes beyond Lennox-Gastaut, including both partial and generalized epilepsy syndromes.

Current dipole orientation and distribution of epileptiform activity correlates with cortical thinning in left mesiotemporal epilepsy.

To evaluate cortical architecture in mesial temporal lobe epilepsy (MTLE) with respect to electrophysiology, we analyze both magnetic resonance imaging (MRI) and magnetoencephalography (MEG) in 19 patients with left MTLE. We divide the patients into two groups: 9 patients (Group A) have vertically oriented antero-medial equivalent current dipoles (ECDs). 10 patients (Group B) have ECDs that are diversely oriented and widely distributed. Group analysis of MRI data shows widespread cortical thinning in Group B compared with Group A, in the left hemisphere involving the cingulate, supramarginal, occipitotemporal and parahippocampal gyri, precuneus and parietal lobule, and in the right hemisphere involving the fronto-medial, -central and -basal gyri and the precuneus. These results suggest that regardless of the presence of hippocampal sclerosis, in a subgroup of patients with MTLE a large cortical network is affected. This finding may, in part, explain the unfavorable outcome in some MTLE patients after epilepsy surgery.

The safety and tolerability of newer antiepileptic drugs in children and adolescents.

The newer antiepileptic drugs (AEDs) provide more therapeutic options and overall improved safety and tolerability for patients. To provide the best care, physicians must be familiar with the latest tolerability and safety data. This is particularly true in children, given there are relatively fewer studies examining the effects of AEDs in children compared with adults. Since we now have significant paediatric literature on each of these agents, we provide a comprehensive and current literature review of the newer AEDs, focusing on safety and tolerability data in children and adolescents. Because the safety profiles in children differ from those in adults, familiarity with this literature is important for child neurologists and other paediatric caregivers. We have organized the data by organ system for each AED for easier reference.

Propagation of epileptic spikes reconstructed from spatiotemporal magnetoencephalographic and electroencephalographic source analysis.

The purpose of this study is to assess the accuracy of spatiotemporal source analysis of magnetoencephalography (MEG) and scalp electroencephalography (EEG) for representing the propagation of frontotemporal spikes in patients with partial epilepsy. This study focuses on frontotemporal spikes, which are typically characterized by a preceding anterior temporal peak followed by an ipsilateral inferior frontal peak. Ten patients with frontotemporal spikes on MEG/EEG were studied. We analyzed the propagation of temporal to frontal epileptic spikes on both MEG and EEG independently by using a cortically constrained minimum norm estimate (MNE). Spatiotemporal source distribution of each spike was obtained on the cortical surface derived from the patient's MRI. All patients underwent an extraoperative intracranial EEG (IEEG) recording covering temporal and frontal lobes after presurgical evaluation. We extracted source waveforms of MEG and EEG from the source distribution of interictal spikes at the sites corresponding to the location of intracranial electrodes. The time differences of the ipsilateral temporal and frontal peaks as obtained by MEG, EEG and IEEG were statistically compared in each patient. In all patients, MEG and IEEG showed similar time differences between temporal and frontal peaks. The time differences of EEG spikes were significantly smaller than those of IEEG in nine of ten patients. Spatiotemporal analysis of MEG spikes models the time course of frontotemporal spikes as observed on IEEG more adequately than EEG in our patients. Spatiotemporal source analysis may be useful for planning epilepsy surgery, by predicting the pattern of IEEG spikes.

Magnetoencephalographic analysis in patients with vagus nerve stimulator.

The objective of this study was to assess the feasibility of magnetoencephalography in epilepsy patients with a vagus nerve stimulator. Magnetoencephalography was performed in two patients with medically intractable epilepsy who had a vagus nerve stimulator. Because of the artifacts caused by the vagus nerve stimulator, no spikes could be identified in the original magnetoencephalographic data in either patient. The temporally extended signal space separation method was used to remove artifacts. After processing by this method, left temporoparietal spikes were clearly identified in patient 1. Equivalent current dipoles calculated from these spikes were localized in the left posterior-temporal and parietal lobes. The location of the dipoles was consistent with the spike distribution on intracranial electroencephalography. In patient 2, bilateral diffuse spikes were seen in the processed data. The contour maps demonstrated a bilateral pattern, not in agreement with a single focal source. These findings supported the diagnosis of symptomatic generalized epilepsy in this patient. Magnetoencephalography may thus be a useful option for evaluating patients with intractable epilepsy who have a vagus nerve stimulator.

In-session seizures during low-frequency repetitive transcranial magnetic stimulation in patients with epilepsy.

Low-frequency repetitive transcranial magnetic stimulation (rTMS) is emerging as a therapeutic tool for patients with intractable epilepsy. Although seizures during treatment have been reported as adverse events in some patients, the nature and severity of seizures that may be provoked by low-frequency rTMS in patients with epilepsy have not been extensively studied. Accordingly, this article documents seizures in patients (n=5) with intractable epilepsy and average seizure frequency greater than one per day who underwent 1-Hz rTMS for seizure suppression. We report three observations in the present case series: (1) in each instance the in-session seizure was typical in semiology to the patient's habitual seizures, (2) the duration of each documented seizure was either the same as or shorter than the patients' baseline seizures, and (3) the overall neurological outcome on follow-up was not affected by the in-session seizures. More data will be required for valid conclusions with respect to safety and tolerability of low-frequency rTMS in patients with epilepsy, but it is noteworthy from our perspective that seizures during rTMS in this series were similar to the patients' habitual seizures, occurred in patients with epilepsy with baseline seizure frequency exceeding one per day, and did not correlate with a poor neurological outcome or with absence of clinical response to rTMS.

A key enzyme of the Leloir pathway is involved in pathogenicity of Leptosphaeria maculans toward oilseed rape.

Agrobacterium tumefaciens-mediated random insertional mutagenesis was used to investigate pathogenicity determinants in Leptosphaeria maculans. One tagged nonpathogenic mutant, termed m186, is analyzed in detail here. Microscopic analyses of infected plant tissues revealed that m186 is specifically blocked at the invasive growth phase after an unaffected initial penetration stage and is unable to switch to the necrotrophic lifestyle. In addition, m186 exhibits an altered cell wall and seems to be affected in its ability to produce cell-wall-degrading enzymes. The T-DNA insertion occurs in the intergenic region between two head-to-tail genes, leading to a constitutive upregulation of their expression. Complementation experiments showed that only one of these two genes, Lmepi, fully accounts for the mutant phenotype. Bioinformatics and expression analyses along with functional studies suggested that the Lmepi gene encodes for the highly conserved UDP-glucose-4-epimerase, a key enzyme of the Leloir pathway involved in galactose metabolism. For the third time, this study highlights the intimate connection between primary metabolism and pathogenicity in L. maculans. This finding, along with similar data obtained from the related species Stagonospora nodorum, indicates the importance of in planta nutrition for the success of infection of plants by fungi belonging to class Dothideomycete.

Dynamic statistical parametric mapping for analyzing ictal magnetoencephalographic spikes in patients with intractable frontal lobe epilepsy.

The purpose of this study is to assess the clinical value of spatiotemporal source analysis for analyzing ictal magnetoencephalography (MEG). Ictal MEG and simultaneous scalp EEG was recorded in five patients with medically intractable frontal lobe epilepsy. Dynamic statistical parametric maps (dSPMs) were calculated at the peak of early ictal spikes for the purpose of estimating the spatiotemporal cortical source distribution. DSPM solutions were mapped onto a cortical surface, which was derived from each patient's MRI. Equivalent current dipoles (ECDs) were calculated using a single-dipole model for comparison with dSPMs. In all patients, dSPMs tended to have a localized activation, consistent with the clinically determined ictal onset zone, whereas most ECDs were considered to be inappropriate sources according to their goodness-of-fit values. Analyzing ictal MEG spikes by using dSPMs may provide useful information in presurgical evaluation of epilepsy.