Genetics of epilepsy: epilepsy research foundation workshop report.

The Sixth Epilepsy Research Foundation workshop, held in Oxford in March 2006, brought together basic scientists, geneticists, epidemiologists, statisticians, pharmacologists and clinicians to consider progress, issues and strategies for harnessing genetics to improve the understanding and treatment of the epilepsies. General principles were considered, including the fundamental importance of clear study design, adequate patient numbers, defi ned phenotypes, robust statistical data handling, and follow-up of genetic discoveries. Topics where some progress had been made were considered including chromosomal abnormalities, neurodevelopment, hippocampal sclerosis, juvenile myoclonic epilepsy, focal cortical dysplasia and pharmacogenetics. The ethical aspects of epilepsy genetics were reviewed. Principles and limitations of collaboration were discussed. Presentations and their matched discussions are produced here. There was optimism that further genetic research in epilepsy was not only feasible, but might lead to improvements in the lives of people with epilepsy.     

Knee-chest vs horizontal side position during induction of spinal anaesthesia in patients undergoing lumbar disc surgery

In the prone knee-chest position the spread of plain 0.5% bupivacaine in the cerebrospinal fluid and associated haemodynamic changes may be different compared with the horizontal position. A randomized comparison was performed in 40 ASA I-II patients, aged 24-61 yr, undergoing lumbar disc surgery. Subarachnoid injection (27-gauge needle) at the L2-3 interspace with 3 ml of 0.5% bupivacaine was performed with the patient in the operative knee-chest position (prone knee-chest group, n = 20) or in the horizontal side position (supine side horizontal group, n = 20). Patients in the supine side horizontal group were turned into the horizontal supine position for 20 min, and subsequently they were placed in the operative knee-chest position. In three patients in the prone knee-chest group, the spinal needle was replaced by a larger needle (25-gauge). The final cephalad extension of sensory analgesia on skin tested by pinprick was T5 (median) in the prone knee-chest group and T6 in the supine side horizontal group. Recovery was also similar, on average 210 min from injection in both groups. The mean decrease in systolic arterial pressure was somewhat greater in the prone knee-chest group (30 mm Hg) than in the supine side horizontal group (13 mm Hg). The need for ephedrine occurred earlier in the supine side horizontal group (three patients, all within 10 min from local anaesthetic injection) than in the prone knee-chest group (six patients, all after 15 min). Four of the latter patients also required administration of an anticholinergic for bradycardia compared with two patients in the supine side horizontal group. Light sedation was given to five patients in the prone knee-chest group and to four in the supine side horizontal group because of numbness and aching in the shoulders. We conclude that spinal block was similar in the two groups but there was a tendency to more frequent episodes of haemodynamic deterioration in the knee-chest position.      

The role of the clinical laboratory in the evaluation of the tubular function of the kidneys]

Renal tubules contribute to maintenance of the body equilibrium by regulating urinary excretion of electrolytes and low molecular mass components. Many transport mechanisms for regulation of concentrations of various components of the tubular fluid are situated in the renal tubules. Studies on the specification and localization of subcellular mechanisms functioning in the renal tubules is a progressive borderline trend of investigation. A new approach has been used to solve the problems of clinical nephrology and maintenance of the body balance. Processes of calcium, sodium, and monosaccharide reabsorption in the tubular fluid are described in brief.     

Effect of Vigabatrin on the Electroencephalogram in Rats

Vigabatrin (gamma-vinyl GABA; GVG) is a new antiepileptic drug (AED) that increases the level of the inhibitory transmitter, gamma-aminobutyric acid (GABA) in the brain. We evaluated the effect of GVG on the EEG of normal rats. GVG was administered intraperitoneally (i.p.) at a dose of 100 mg/kg once a day for 12 days. EEG was recorded at baseline, on the fourth day, at the end of the 12-day GVG period and 10 days after discontinuation of GVG. GVG increased the amplitude of delta (1-4 Hz) and theta (4-8 Hz) frequency bands and resulted in slowing of the peak frequency (Fp) and mean frequency (Fm) in both the frontal and occipital cortex, especially during waking-immobility. EEG changes normalized within 10 days after the last GVG injections. The results suggest that a relationship may exist between the EEG changes and increase in GABA levels with GVG.     

Management of postcardiotomy hypertension by microcomputer-controlled administration of sodium nitroprusside

Manual administration of sodium nitroprusside in patients who have undergone cardiac operations can be associated with wide swings in mean systemic arterial pressure. Moreover, it is necessary for constant attention to be paid in order to minimize these potentially catastrophic arterial pressure changes. A microcomputer-based controller was constructed in the belief that it might improve the accuracy of systemic arterial pressure control as well as relieve the clinical staff of a time-consuming task. Comparison was made of the effectiveness of manual control versus computer control of sodium nitroprusside infusion in two groups of patients with similar clinical characteristics. In the manual control group the mean systemic arterial pressure could be maintained within 5 mm Hg of the target pressure only half (52%) of the time. In the computer-controlled group the mean systemic arterial pressure was maintained within 5 mm Hg of the target pressure 94% of the time (p less than 0.005). Thus, computerized control of sodium nitroprusside infusion eliminated the need for an intensive care unit nurse to be "locked into" the task of making frequent adjustments of infusion rate. Of even greater importance, control of mean systemic arterial pressure was more precise.     

Projections from the lateral,basal, and accessory basal nuclei of the amygdala to the entorhinal cortex in the macaque monkey

We used the anterograde tracers Phaseolus vulgaris-leucoagglutinin (PHA-L) and biotinylated dextran amine (BDA) to examine the projections from the lateral, basal, and accessory basal nuclei of the amygdaloid complex to the entorhinal cortex in Macaca fascicularis monkeys. The heaviest amygdaloid projections originate in the lateral nucleus, which innervates the rostrally situated entorhinal fields but does not project to the caudal entorhinal cortex. The most extensive projections originate in the ventral division of the lateral nucleus. Injections in this subdivision lead to moderate to heavy fiber and terminal labeling in the entorhinal cortex, rostral levels of the rostral intermediate El (ER) and lateral fields, (ELr), and light labeling in the olfactory field EO. The projections from all portions of the lateral nucleus terminate most heavily in layer III. Layer II of EO and ER also receives a substantial input from the ventral division of the lateral nucleus. Layer II of ELr receives light innervation from all portions of the lateral nucleus that project to layer III. Projections from the basal nucleus arise mainly from the parvicellular division and are light to moderate in density. Fibers terminate predominantly in ELr, ER, EO, and the caudal portion of the lateral field (Elc); only the most rostral portion of El receives projections. While fibers from the basal nucleus innervate the same layers as the projections from the lateral nucleus, they tend to have a more vertical or radial orientation within the entorhinal cortex. Electron microscopic analysis of these fibers and terminals indicates that they overwhelmingly form asymmetrical synapses onto dendrites and dendritic spines. The accessory basal nucleus provides a light projection to the same regions of the entorhinal cortex innervated by the lateral and basal nuclei.     

Projections from the amygdaloid complex to the claustrum and the endopiriform nucleus: a Phaseolus vulgaris leucoagglutinin study in the rat

The claustrum and the endopiriform nucleus contribute to the spread of epileptiform activity from the amygdala to other brain areas. Data of the distribution of pathways underlying the information flow between these regions are, however, incomplete and controversial. To investigate the projections from the amygdala to the claustrum and the endopiriform nucleus, we injected the anterograde tracer Phaseolus vulgaris leucoagglutinin into various divisions of the amygdaloid complex, including the lateral, basal, accessory basal, central, anterior cortical and posterior cortical nuclei, the periamygdaloid cortex, and the amygdalohippocampal area in the rat. Analysis of immunohistochemically processed sections reveal that the heaviest projections to the claustrum originate in the magnocellular division of the basal nucleus. The projection is moderate in density and mainly terminates in the dorsal aspect of the anterior part of the claustrum. Light projections from the parvicellular and intermediate divisions of the basal nucleus terminate in the same region, whereas light projections from the accessory basal nucleus and the lateral division of the amygdalohippocampal area innervate the caudal part of the claustrum. The most substantial projections from the amygdala to the endopiriform nucleus originate in the lateral division of the amygdalohippocampal area. These projections terminate in the central and caudal parts of the endopiriform nucleus. Lighter projections originate in the anterior and posterior cortical nuclei, the periamygdaloid cortex, the medial division of the amygdalohippocampal area, and the accessory basal nucleus. These data provide an anatomic basis for recent functional studies demonstrating that the claustrum and the endopiriform nucleus are strategically located to synchronize and spread epileptiform activity from the amygdala to the other brain regions. These topographically organized pathways also provide a route by means of which the claustrum and the endopiriform nucleus have access to inputs from the amygdaloid networks that process emotionally significant information.     

Antidepressant efficacy and quality of life in depression: a double-blind study with moclobemide and fluoxetine

The efficacy of moclobemide (300–450 mg7sol;day) was compared with fluoxetine (20–40 mg/day) in a double-blind, multicentre study in 209 patients with new episodes of depression selected from 612 consecutive depressed patients representative of those consulting psychiatric services in Finland. Antidepressant efficacy was assessed with the Hamilton Depression Rating Scale (HDRS), Montgomery-Åsberg Depression Rating Scale and Clinical Global Impression (CGI). The Medical Outcome Study Short-form General Health Survey (SF-20) and 15D Measure of Quality of Life were used to measure effectiveness in terms of health-related quality of life. Efficacy was evident with both drug treatments, with 67% in the moclobemide group and 57% in the fluoxetine group having a reduction in HDRS of more than 50%. Similarly, 77% of the patients in the moclobemide group and 67% in the fluoxetine group were assessed on the CGI as much better or very much better after 6 weeks of treatment. The most commonly reported adverse events were nausea, other gastrointestinal symptoms, nervousness, dizziness and sleep disorders. Nausea was significantly more common in the fluoxetine group and was found especially in women. Premature terminations of treatment were 18% in the moclobemide and 21% in the fluoxetine group. A significant change for the better in quality of life was found in both treatment groups, even at week 2 but especially after 6 weeks of treatment. Improvement was not only seen in dimensions measuring depression or mental health but also in other dimensions.     

Administration of diazepam during status epilepticus reduces development and severity of epilepsy in rat

Prevention of epileptogenesis after brain insults, such as status epilepticus (SE), head trauma, or stroke, remains a challenge. Even if epilepsy cannot be prevented, it would be beneficial if the pathologic process could be modified to result in a less severe disease. We examined whether early discontinuation of SE reduces the risk of epilepsy or results in milder disease. Epileptogenesis was triggered with SE induced by electrical stimulation of the amygdala. Animals (n = 72) were treated with vehicle or diazepam (DZP, 20 mg/kg) 2 h or 3 h after the beginning of SE. Electrode-implanted non-stimulated rats served as controls for histology. All animals underwent continuous long-term video-electroencephalography monitoring 7-9 weeks and 11-15 weeks later to detect the occurrence and severity of spontaneous seizures. As another outcome measure, the severity of hippocampal damage was assessed in histologic sections. In the vehicle group, 94% of animals developed epilepsy. DZP treatment reduced the percentage of epileptic animals to 42% in the 2-h DZP group and to 71% in the 3-h DZP group (p < 0.001 and p < 0.05 compared to the vehicle group, respectively). If epilepsy developed, the seizures were less frequent in DZP-treated animals compared to the vehicle group (median 16.4 seizures/day), particularly in the 2-h DZP group (median 0.4 seizures/day). Finally, if DZP treatment was started 2 h, but not 3 h after SE, the severity of hippocampal cell loss was milder and the density of mossy-fiber sprouting was lower than in the vehicle group. These data indicate that treatment of SE with DZP within 2 h reduces the risk of epilepsy later in life, and if epilepsy develops, it is milder.