Differential transcriptional control as the major molecular event in generating Otx1-/- and Otx2-/- divergent phenotypes. (1/4971)

Otx1 and Otx2, two murine homologs of the Drosophila orthodenticle (otd) gene, show a limited amino acid sequence divergence. Their embryonic expression patterns overlap in spatial and temporal profiles with two major exceptions: until 8 days post coitum (d.p.c. ) only Otx2 is expressed in gastrulating embryos, and from 11 d.p.c. onwards only Otx1 is transcribed within the dorsal telencephalon. Otx1 null mice exhibit spontaneous epileptic seizures and multiple abnormalities affecting primarily the dorsal telencephalic cortex and components of the acoustic and visual sense organs. Otx2 null mice show heavy gastrulation abnormalities and lack the rostral neuroectoderm corresponding to the forebrain, midbrain and rostral hindbrain. In order to define whether these contrasting phenotypes reflect differences in expression pattern or coding sequence of Otx1 and Otx2 genes, we replaced Otx1 with a human Otx2 (hOtx2) full-coding cDNA. Interestingly, homozygous mutant mice (hOtx2(1)/hOtx2(1)) fully rescued epilepsy and corticogenesis abnormalities and showed a significant improvement of mesencephalon, cerebellum, eye and lachrymal gland defects. In contrast, the lateral semicircular canal of the inner ear was never recovered, strongly supporting an Otx1-specific requirement for the specification of this structure. These data indicate an extended functional homology between OTX1 and OTX2 proteins and provide evidence that, with the exception of the inner ear, in Otx1 and Otx2 null mice contrasting phenotypes stem from differences in expression patterns rather than in amino acid sequences.  (+info)

Characterization of nodular neuronal heterotopia in children. (2/4971)

Neuronal heterotopia are seen in various pathologies and are associated with intractable epilepsy. We examined brain tissue from four children with subcortical or periventricular nodular heterotopia of different aetiologies: one with severe epilepsy following focal brain trauma at 17 weeks gestation, one with hemimegalencephaly and intractable epilepsy, one with focal cortical dysplasia and intractable epilepsy, and one dysmorphic term infant with associated hydrocephalus and polymicrogyria. The connectivity of nodules was investigated using histological and carbocyanine dye (DiI) tracing techniques. DiI crystal placement adjacent to heterotopic nodules revealed numerous DiI-labelled fibres within a 2-3 mm radius of the crystals. Although we observed labelled fibres closely surrounding nodules, the majority did not penetrate them. Placement of DiI crystals within nodules also identified a limited number of projections out of the nodules and in one case there was evidence for connectivity between adjacent nodules. The cellular and neurochemical composition of nodules was also examined using immunohistochemistry for calretinin and neuropeptide Y (NPY), which are normally expressed in GABAergic cortical interneurons. Within heterotopic nodules from all cases, numerous calretinin-positive neurons were identified, along with a few cell bodies and many processes positive for NPY. Calretinin-positive neurons within nodules were less morphologically complex than those in the cortex, which may reflect incomplete differentiation into an inhibitory neuronal phenotype. There were also abnormal clusters of calretinin-positive cells in the overlying cortical plate, indicating that the migratory defect which produces heterotopic nodules also affects development of the cortex itself. Thus, heterotopic nodules consisting of multiple neuronal cell types are associated with malformation in the overlying cortical plate, and have limited connectivity with other brain regions. This abnormal development of connectivity may affect neuronal maturation and consequently the balance of excitation and inhibition in neuronal circuits, leading to their epileptogenic potential.  (+info)

Oligodendroglial vacuolar degeneration in the bilateral motor cortices and astrocytosis in epileptic beagle dogs. (3/4971)

We performed a pathologic examination of the brains of three dogs in an epileptic beagle colony. Histologically, all the cases had diffuse astrocytosis in the cerebral cortex and basal ganglia as well as the hippocampus, whereas they showed acute nerve cell change in the hippocampus and some other areas of the cerebrum. One of these animals showed laminar myelin pallor associated with the presence of many vacuoles in the IV to VI layers of the bilateral motor cortices. Most of the vacuoles contained fine granules stained with luxol-fast-blue stain. Ultrastructural examination revealed that some oligodendrocytes and perineuronal satellite oligodendrocytes in the bilateral cerebral motor cortices of the two affected dogs had many vacuoles surrounded by myelin-like lamellar structures. These findings suggest a possibility that astrocytosis in the cerebrum and vacuolar degeneration of oligodendrocytes in the cerebral motor cortex may be, at least in part, related to the occurrence or development of seizures.  (+info)

Onchocerciasis and epilepsy: a matched case-control study in the Central African Republic. (4/4971)

The occurrence of epileptic seizures during onchocercal infestation has been suspected. Epidemiologic studies are necessary to confirm the relation between onchocerciasis and epilepsy. A matched case-control study was conducted in dispensaries of three northwestern towns of the Central African Republic. Each epileptic case was matched against two nonepileptic controls on the six criteria of sex, age (+/-5 years), residence, treatment with ivermectin, date of last ivermectin dose, and the number of ivermectin doses. Onchocerciasis was defined as at least one microfilaria observed in iliac crest skin snip biopsy. A total of 561 subjects (187 cases and 374 controls) were included in the study. Of the epileptics, 39.6% had onchocerciasis, as did 35.8% of the controls. The mean dermal microfilarial load was 26 microfilariae per mg of skin (standard deviation, 42) in the epileptics and 24 microfilariae per mg of skin (standard deviation, 48) in the controls. This matched case-control study found some relation (odds ratio = 1.21, 95% confidence interval 0.81-1.80), although it was nonstatistically significant.  (+info)

Adjunctive therapy in epilepsy: a cost-effectiveness comparison of two AEDs. (5/4971)

The objective of this study was to compare the relative cost-effectiveness of two AEDs by a prospective clinical audit. Patients starting on the adjunctive therapies lamotrigine and topiramate were recruited from the out-patient epilepsy clinics at Queen Square. Three interview were scheduled: baseline; three months follow-up and six months from baseline. Of the 81 patients recruited, a total of 73 patients completed all three interviews. An intention to treat analysis was performed on the data. Seizure severity and frequency were assessed using the National Hospital Seizure Severity Scale. Side-effects, adverse events and reasons for stopping medication were also recorded. At the third interview, a total of 47/73 (64%) were still on the prescribed adjunctive drug. Outcome was assessed by two methods: the > 50% seizure reduction cited in the literature and a more stringent assessment of patient 'satisfaction' which we defined operationally on clinical criteria. Using this definition, a total of 10/73 (14%) patients were 'satisfied'. The relative costs of starting patients on each of the two AEDs were calculated, both drug costs and the costs of adverse events (the latter were defined as events requiring urgent medical attention). The costs of the two drugs were compared. A number of methodological issues relating to cost comparison are discussed. Outcome and pharmaco-economic studies need to assess more than reduction in number of seizures. They should take into account variables important for quality of life including side-effects and adverse events.  (+info)

Willingness to pay: a feasible method for assessing treatment benefits in epilepsy? (6/4971)

Contingent valuation using willingness to pay (WTP) is one of the methods available for assessing the value of a new technology or treatment for a disease in monetary terms. Experience with this method is lacking in epilepsy. The objectives of this study were to assess the acceptability of the WTP method in epilepsy, the level of the responses, and to investigate its validity by comparison with other non-monetary preference measures. Among 397 patients with epilepsy responding to a comprehensive questionnaire, 82 were randomly selected for an interview. They were asked about their WTP for an imaginary new technology which could permanently cure their epilepsy. Fifty-nine patients participated and 57 completed the interview (32 women; mean age 44 years), the majority with well-controlled epilepsy. The patients indicated a median WTP of Norwegian Kroner (NOK) 150,000 (USD 20,000; GBP 11,800), interquartile range NOK 50,000-350,000 (USD 6, 667-46, 667; GBP 3,937-27,559) for this cure. Non-response was low, indicating high acceptability of this method. There was little association between WTP and other preference measures; the Spearman rank correlation coefficient was -0.09 and -0.12 with time trade-off and standard gamble respectively, questioning the validity of this method.  (+info)

Outcome of pregnancies in epileptic women: a study in Saudi Arabia. (7/4971)

We studied the outcome of 79 pregnancies in 44 Saudi women who had epilepsy. Their mean age was 28+/-6.5 years and the number of pregnancies studied varied from one to six. Nineteen subjects had generalized seizures, 16 had partial seizures and nine were unclassified. The commonest drug prescribed was carbamazepine and the majority of the women (61%) were on monotherapy. The seizures were controlled in 53 pregnancies (67%). Spontaneous vertex deliveries were the commonest. The indications for intervention by lower segment Caesarean section, forceps or ventouse were foetal distress, pre-eclamptic toxaemia (PET), eclampsia, breech presentation and prolonged labour. The most frequent adverse outcome in the babies was low birth weight (<2.5 kg) in nine pregnancies. The frequency of congenital malformation was 2.5%. Low birth weight was associated with prematurity, PET, congenital malformation and polytherapy. Avoidance of polytherapy appears to be the most feasible intervention in reducing the frequency of low birth-weight children by epileptic mothers.  (+info)

Information exchange in an epilepsy forum on the World Wide Web. (8/4971)

The Partners Healthcare Epilepsy Service hosts an epilepsy 'Webforum'. In this paper, we describe our observations regarding who uses it, what kind of information is exchanged, how much misinformation is present and how we can better serve our patients. We examined a sample of 155 posts to the forum and 342 responses to those posts. The individual making the post and the type of questions were categorized. We also determined whether any information was objectively inaccurate. The principal users were care-givers (49%) and patients (34%). Eighty percent of the primary posts were questions. Answers were given largely by patients (38%) and care-givers (34%). The most commonly asked questions were about treatment options (31%) and the natural history of the illness (28%). In 20% of the questions, the user incidentally remarked that a health-care provider had not met their information needs. Six percent of the information was objectively inaccurate. The Web can serve as an effective means for the exchange of information between individuals with a common medical condition. We found that a small amount of misinformation is exchanged and that health-care providers are sometimes perceived as unable or unwilling to supply important health-related information.  (+info)