Long-term open multicentre, add-on trial of vigabatrin in adult resistant partial epilepsy. The Canadian Vigabatrin Study Group.

Vigabatrin (VGB) has been shown in a number of clinical trials with varying designs to be effective and well-tolerated as both add-on therapy and monotherapy in epilepsy with partial seizures with or without secondary generalization as well as in infantile spasms. The present study is an open, long-term (1 year) extension of a randomized double-blind placebo-controlled multicentre Canadian trial of VGB in resistant partial adult epilepsy. The present study was designed to examine the safety and long-term efficacy of VGB. Completers of the preceding double-blind study had their dose of VGB titrated to 4 g/day over 3 weeks. Patients were evaluated every 2-4 weeks and at week 14 were allowed to continue only if they achieved a 50% seizure reduction compared with pre-VGB baseline. In addition to neurological and physical examinations, safety was assessed by a cognitive psychosocial test battery, visual and somatosensory evoked potentials and MRI scans. Ninety-seven of 100 eligible patients entered the study, 53 of whom completed the 52 weeks. Fifty-eight percent of the patients had a greater than 50% seizure reduction in seizures vs. pre-VGB baseline. Seizure reductions of 56% and 45%, respectively, were seen in the VGB and placebo groups from the preceding study. Fifty-four percent of patients were judged by the investigators to have experienced at least a moderate therapeutic effect. Discontinuations were 29% for lack of efficacy and 12% for adverse effects. There was a mean weight gain of 3.7 +/- 0.2 kg by end of study. Neurologica/psychiatric side effects were the most common reason for withdrawal including three behavioral reactions attributed to the drug which required temporary hospitalization. There were no abnormalities on laboratory or special tests and there was a tendency for improvement on most tests of cognitive function and mood. Vigabatrin, as an add-on agent, is well-tolerated and can be of long-term benefit in a substantial proportion of patients with intractable partial epilepsy.

Vigabatrin as add-on therapy for adult complex partial seizures: a double-blind, placebo-controlled multicentre study. The Canadian Vigabatrin Study Group.

Vigabatrin (VGB) is a novel antiepileptic drug effective as adjunctive therapy in patients with partial seizures. In this study, the efficacy and tolerability of VGB as adjunctive therapy were evaluated in patients with refractory epilepsy. Adult patients with a definite diagnosis of complex partial seizures and/or partial seizures secondarily generalized were recruited from 10 Canadian centres. Patients were randomized to receive either active medication or placebo in a double- blind fashion and entered a 36-week titration and maintenance phase with regularly scheduled visits. Both efficacy parameters and safety assessments were monitored. Clinical laboratory, evoked potential studies, MRI, and neuropsychological tests were also performed. Forty-eight percent of VGB-treated patients vs. 26 percent of placebo-treated patients had a 50 percent or greater reduction in the frequency of complex partial seizures and partial seizures secondarily generalized. Vigabatrin was well tolerated by the majority of patients. Minor neurological side effects were observed in a number of patients in both treatment groups. No serious systemic toxicity was observed. No changes in evoked potential studies or MRI findings were noted. Vigabatrin was found to be an effective and well-tolerated antiepileptic drug when used as adjunctive therapy in patients with difficult to control complex partial seizures and for partial seizures secondarily generalized. Vigabatrin is a selective irreversible inhibitor of the GABA- degradating enzyme GABA transaminase and has shown efficacy in a number of clinical trials in patients with difficult to control partial seizures. Vigabatrin has been found most effective against complex partial and secondarily generalized tonic-clonic seizures in both adults and children. Vigabatrin has also been shown to reduce infantile spasms secondary to various aetiologies and is most effective in spasms associated with tuberous sclerosis. The aim of this study was to further extend the clinical experience with VGB as adjunctive therapy in the treatment of adult patients with difficult to control complex partial seizures and/or partial seizures secondarily generalized. In addition to the assessments of efficacy and tolerability to VGB, neuropsychological evaluations were also carried out.

Gabapentin as adjunctive therapy for partial seizures.

The safety, tolerability, and efficacy of gabapentin as adjunctive therapy were assessed in epileptic patients who had experienced up to four complex partial seizures per month while receiving phenytoin and/or carbamazepine. This was a multicenter, open-label prospective study, with the treatment period lasting 20 weeks. The gabapentin dosage was titrated to effective tolerated dose up to 2400 mg/day. Quality of life was evaluated with the QOLIE-10 questionnaire. A total of 141 patients were enrolled; 114 patients were evaluated for efficacy analysis. The mean maintenance dose of gabapentin was 1600 mg/day. Seventy-one percent of patients (81 patients) experienced a 50% or greater reduction in seizure frequency and 46% (52 patients) became seizure free. The most frequent adverse effects included drowsiness (16%), dizziness (9%), and asthenia (6%). Sixteen patients (11%) discontinued the study prematurely because of adverse events. A significant improvement was observed in five of the 10 questions of the QOLIE-10.

Monoamine neurotransmitters and their metabolites in the mature rabbit brain following induction of hydrocephalus.

Functional and behavioral disturbances associated with hydrocephalus may be due in part to altered neurotransmitter function in the brain. Hydrocephalus was induced in adult rabbits by injection of silicone oil into the cisterna magna. These and controls were killed 3 days, 1 and 4 weeks post-injection. Tissue concentrations of norepinephrine, epinephrine, serotonin, dopamine, and the metabolites 5-hydroxyindoleacetic acid (5-HIAA), homovanillic acid (HVA), and 3,4-dihydroxyphenylacetic acid (DOPAC) levels were determined in fifteen brain regions using HPLC. There were decreases in hypothalamic and medullary dopamine, transient decreases in basal ganglia serotonin, increases in thalamic noradrenaline, and increases in hypothalamic and thalamic epinephrine. Changes in the primary neurotransmitters may be attributable to damage of their axonal projection systems. Metabolite concentrations increased in the cerebrum. Reduced clearance of extracellular fluid which accompanies cerebrospinal fluid stasis may explain the accumulation of metabolites.

Women's issues in the treatment of epilepsy.

BACKGROUND: The management of women with epilepsy involves a number of important issues including conception control, sexual dysfunction and fertility, the effect of seizures on the fetus, possible changes in seizures frequency during pregnancy, potential teratogenic effects of antiepileptic drugs and management issues during pregnancy. The primary goal in the treatment of women with epilepsy remains optimal seizure control in the absence of unacceptable adverse effects. The advantages and disadvantages of the new antiepileptic drugs in women remain to be fully established but these new agents allow a wider choice for improved seizure control.

Efficacy of topiramate.

In controlled clinical trials, topiramate (Topamax) has demonstrated efficacy in refractory patients with complex partial seizures and secondarily generalized tonic-clonic seizures. Approximately 45 percent of 534 patients had a > or = 50 percent reduction in seizure frequency. Limited open label trials have shown that topiramate has broad spectrum activity and may be effective in patients with primary generalized epilepsies. The efficacy of topiramate compares very favourably with the efficacy of other new antiepileptic drugs recently introduced.

Outcome evaluation of gabapentin as add-on therapy for partial seizures. "NEON" Study Investigators Group. Neurontin Evaluation of Outcomes in Neurological Practice.

OBJECTIVE: The safety, tolerability, efficacy, and impact on quality of life of gabapentin (Neurontin) as adjunctive therapy to carbamazepine (CBZ) and/or phenytoin (PHT) was assessed in epileptic patients with partial seizures. METHODS: NEON (Neurontin Evaluation of Outcomes in Neurological Practice) was an open-label, prospective, multicentre study conducted in patients on a stable dose of CBZ and/or PHT and experiencing an average of up to 4 complex partial seizures with or without secondary generalization per month, with no seizure-free months. The treatment lasted 20 weeks. Gabapentin was started at 400 mg/day and was individually titrated to effective tolerable dose up to 2400 mg/day. Quality of life was evaluated using the QOLIE-10 questionnaire. RESULTS: A total of 141 patients were enrolled at 36 sites; 114 patients were evaluable for efficacy analyses. The mean maintenance dose of gabapentin was 1600 mg/day (range = 300-3200). A decrease of 50% or more in frequency of complex partial + secondary generalized seizures was observed in 81 (71%) patients (p = 0.0001). Fifty two (46%) patients were seizure-free during the last 8 weeks of treatment. A significant improvement (p < 0.05) was observed in 5 of the 10 questions of the QOLIE-10, as well as in the composite QOL score (p = 0.0002). The most frequent adverse events included somnolence (16%), dizziness (9%), and asthenia (6%). Twenty-five (18%) patients prematurely discontinued the study, 16 (11%) of them due to adverse events. CONCLUSIONS: This study indicates that treatment with gabapentin as adjunctive therapy to standard antiepileptic drugs in this group of patients not only provides significant improvement in seizure control, but also has a positive impact on quality of life. The clinical benefits in efficacy, safety and tolerability demonstrated at 20 weeks are sustained, and no tolerance develops with gabapentin in longer term use.

Ependymal development, proliferation, and functions: a review.

A survey of the literature shows that proliferation of ependyma occurs largely during the embryonic and early postnatal periods of development in most species. Differentiation of these cells proceeds along particular regional and temporal gradients as does the expression of various cytoskeletal (vimentin, cytokeratins, glial fibrillary acidic protein) and secretory proteins (S-100). Turnover declines significantly postnatally, and only low levels of residual activity persist into adulthood under normal conditions. Although the reported response of ependyma to injury is somewhat equivocal, only limited regenerative capacity appears to exist and to varying degrees in different regions of the neuraxis. Proliferation has been most often observed in response to spinal cord injury. Indeed, the ependyma plays a significant role in the initiation and maintenance of the regenerative processes in the spinal cord of inframammalian vertebrates. In the human, however, ependyma appears never to regenerate at any age nor re-express cytoskeletal proteins characteristic of immature cells. The functions of ependyma including tanycytes, a specialized form of ependymal cell that persists into adulthood within circumscribed regions of the nervous system, are still largely speculative. Fetal unlike mature ependyma is believed to be secretory and is believed to play a role in neurogenesis, neuronal differentiation/axonal guidance, transport, and support. In the adult brain, mature ependyma is not merely an inert lining but may regulate the transport of ions, small molecules, and water between the cerebrospinal fluid and neuropil and serve an important barrier function that protects neural tissue from potentially harmful substances by mechanisms that are still incompletely understood.

Gabapentin.

Gabapentin is a novel antiepileptic drug that has recently been introduced in Canada. Although its mechanism of action remains to be defined gabapentin is effective in a number of seizure models which predict its efficacy in partial and tonic-clonic seizures. Clinical studies support the clinical efficacy of gabapentin as adjunctive therapy in adults with epilepsy with partial and secondarily generalized tonic-clonic seizures. Gabapentin has a favorable pharmacokinetic profile and is generally well tolerated. More clinical data are required on the role of gabapentin in children and additional monotherapy experience is required before the role of gabapentin in the overall treatment of epilepsy can be better defined.

Heightened interference on implicit, but not explicit, tests of negative transfer: evidence from patients with unilateral temporal lobe lesions and normal old people.

The present research investigated alternative explanations of heightened interference in AB-AC learning in individuals with memory loss related to medial temporal lobe dysfunction. In Experiment 1, patients with left or right temporal lobectomy and control subjects were administered the standard AB-AC test. Relative to the other groups, left temporal patients exhibited significant negative transfer that was characterized by large numbers of response intrusion errors. In Experiment 2, groups of community-dwelling old and young adults were administered the standard test and an implicit version in which, during AC testing, subjects were instructed to provide the first word that comes to mind in response to stimulus words. There were no differences between groups on either version. Of particular interest was that both groups made significantly more intrusion errors on the implicit test and did not differ on this measure. It was concluded that exaggerated interference in AB-AC learning, as reflected by response intrusion errors, is related to the use of implicit memory processes rather than a failure of inhibitory mechanisms. Memory-impaired individuals, who have a selective loss of explicit memory, are vulnerable on this task because they rely excessively on implicit memory processes.

Antiepileptic drug selection and adverse effects: an overview.

In choosing an antiepileptic drug, not only efficacy but also potential adverse effects have to be considered. Adverse effects that have to be taken into account include acute and chronic systemic toxicity, cognitive side effects, and teratogenesis. Acute toxicity may be dose-related, allergic or an idiosyncratic reaction. Chronic toxicity may involve the nervous system or other organs. In determining the role of new antiepileptic drugs such as lamotrigine, vigabatrin, felbamate, and gabapentin a proper evaluation of both efficacy and adverse effects is required.

Improved screening for benzodiazepine metabolites in urine using the Triage Panel for Drugs of Abuse.

Screening for benzodiazepines is an important component of many drug testing programs. Current immunochemical methods are limited by a lack of sensitivity to many of the 35 forms of benzodiazepines available and because the antibodies used are insensitive to the glucuronic acid conjugates that constitute the major metabolites in urine. The Triage Panel for Drugs of Abuse (Biosite Diagnostics), a new screening device, is a competitive immunoassay containing monoclonal antibodies directed against glucuronide metabolites of benzodiazepines. We tested this device on 326 urine specimens, which were also tested by two other immunoassay methods (FPIA and EMIT) and by GC/MS. We found a sensitivity of 97.5% and a specificity of 94.3% for the Triage assay when it was applied to a population in which approximately 50% of the specimens were positive; a distribution of eight different benzodiazepines was found in the positive samples. Other immunoassays performed with lower sensitivity or specificity or both. We found no significant difference between two analysts using the Triage test. We conclude that the Triage method represents a superior method for benzodiazepine screening when compared with other immunoassay methods.

Effects of in utero exposure to low dose ionizing radiation on development in the rat.

Most studies of in utero effects of ionizing irradiation involve high doses and examination at postnatal intervals. Little information is available on the effects of low levels of ionizing radiation on embryogenesis. The developmental effects of in utero exposure to 50 cGy gamma radiation on gestational day-9.5 was investigated using Sprague-Dawley rats. Irradiated rats and appropriate controls were killed at prenatal intervals of 4h, 48h and 10 days after exposure. Fetuses were examined for abnormalities and random samples of tissues were prepared for microscopic study. With the exception of the neuroepithelium, no histopathological changes were observed in embryos 4h after exposure to 50 cGy. In irradiated embryos, mitoses were reduced within the neuro-epithelium; pyknosis and some necrosis of cells were apparent at this gestational interval. Among the gross developmental abnormalities observed in embryos 48h after irradiation, excessive flexion of the embryo and abnormal flexion of the head were the only ones that appeared to be radiation-induced. The mean numerical score (42.3 +/- 0.2, controls; 42.4 +/- 0.1, irradiated) for 17 morphological parameters examined in fetuses at this gestational period compares favorably with other studies. Controls, however, showed greater variability in the extent of development of their forebrain, olfactory system, midbrain, hindbrain, and caudal neural tube. In all cases, there was evidence of slower development in these regions compared to their irradiated counterparts. At term, no significant differences in litter size or resorption rates were observed in irradiated animals compared to the controls, but there was a higher incidence of defective eye development, spinal curvature and visceral anomalies.(ABSTRACT TRUNCATED AT 250 WORDS)

Visual attention problems as a predictor of vehicle crashes in older drivers.

PURPOSE: To identify visual factors that are significantly associated with increased vehicle crashes in older drivers. METHODS: Several aspects of vision and visual information processing were assessed in 294 drivers aged 55 to 90 years. The sample was stratified with respect to age and crash frequency during the 5-year period before the test date. Variables assessed included eye health status, visual sensory function, the size of the useful field of view, and cognitive status. Crash data were obtained from state records. RESULTS: The size of the useful field of view, a test of visual attention, had high sensitivity (89%) and specificity (81%) in predicting which older drivers had a history of crash problems. This level of predictability is unprecedented in research on crash risk in older drivers. Older adults with substantial shrinkage in the useful field of view were six times more likely to have incurred one or more crashes in the previous 5-year period. Eye health status, visual sensory function, cognitive status, and chronological age were significantly correlated with crashes, but were relatively poor at discriminating between crash-involved versus crash-free drivers. CONCLUSIONS: This study suggests that policies that restrict driving privileges based solely on age or on common stereotypes of age-related declines in vision and cognition are scientifically unfounded. With the identification of a visual attention measure highly predictive of crash problems in the elderly, this study points to a way in which the suitability of licensure in the older adult population could be based on objective, performance-based criteria.

Postnatal development of the rat CNS following in utero exposure to a low dose of ionizing radiation.

In utero exposure to ionizing radiation is of importance because of its potential health risks. The developing nervous system is particularly vulnerable and the consequences of exposure to low levels of radiation (< or = 1 Gy) are not well established. The developmental effects of maternal exposure to 50 cGy gamma-radiation on gestational days (GD) 9.5, 15, and 18 were investigated in Sprague Dawley rats. Rats exposed on GD-9.5 along with appropriate controls were killed at 4 h, 48 h, and 10 days post-irradiation while those irradiated on GD-15 and GD-18 were killed postnatally (PN) on days 7 and 26. All were examined for developmental anomalies and representative samples of brains were processed for microscopic study. No significant developmental differences were observed between irradiated and control embryos killed 48 h after irradiation on GD 9.5. However, in irradiated fetuses a larger number of developmental anomalies were observed at term. Defects of the eye and of spinal curvature were the most common malformations encountered. Mitoses were reduced within the neuroepithelium of embryos irradiated on GD-9.5 and evidence of pyknosis and necrosis was seen 4 h after irradiation. The capacity of surviving primitive neural cells for repair, however, was such that by 48 h after exposure the irradiated nervous system no longer differed from controls. Rats irradiated on GD-15 and GD-18 and examined on PN-26 exhibited clusters of small, dark, pyknotic neurons within the hippocampal and dentate gyri, often bilaterally.(ABSTRACT TRUNCATED AT 250 WORDS)

The effects of intracerebroventricular versus intravenous administration of vasopressin on intracranial pressure in the rat.

Arginine vasopressin (AVP) in the CSF has been implicated in the control of intracranial pressure (ICP) and studies have shown that some patients with raised ICP also have elevated levels of AVP in their CSF. Evidence suggests that central AVP has a separate origin and may exert different effects than AVP in the peripheral circulation. The purpose of this study was to compare the effects of intracerebro ventricular (ICV) and intravenous (IV) injection of AVP on ICP and arterial BP. AVP was administered to anaesthetized, ventilated, S/D rats following a 30 min baseline recording period. BP and ICP were recorded continuously for 40 min post-injection. A single ICV injection of 0.125 microgram or 0.5 microgram AVP significantly (p < 0.05) reduced ICP from 5-26% or 0.2-1.0 mmHg for the duration of the recording period. This was accompanied by a corresponding increase in arterial BP of 5-44% or 4-34 mmHg. In contrast, iv injection of 4 ng or 0.05 microgram AVP produced an abrupt but transient rise in BP of 9-171 mmHg accompanied by a 5-23% increase in ICP. Intravenous injection of 0.125 microgram AVP increased BP to 156-171 mmHg exceeding the autoregulatory range and because of this ICP also increased significantly. BP and ICP exhibited a negative linear relationship following ICV administration of both doses of AVP but only after administration of the smaller dose iv. Vehicle alone administered by either route produced no significant changes in ICP of BP.(ABSTRACT TRUNCATED AT 250 WORDS)

Visual/cognitive correlates of vehicle accidents in older drivers.

Older drivers have more accidents per miles driven than any other age group and tend to have significant impairments in their visual function, which could interfere with driving. Previous research has largely failed to document a link between vision and driving in the elderly. We have taken a comprehensive approach by examining how accident frequency in older drivers relates to the visual/cognitive system at a number of levels: ophthalmological disease, visual function, visual attention, and cognitive function. The best predictor of accident frequency as recorded by the state was a model incorporating measures of early visual attention and mental status, which together accounted for 20% of the variance, a much stronger model than in earlier studies. Those older drivers with a visual attentional disorder or with poor scores on a mental status test had 3-4 times more accidents (of any type) and 15 times more intersection accidents than those without these problems.

Silicone oil-induced hydrocephalus in the rabbit.

Hydrocephalus was induced in adult rabbits by injecting silicone oil into the cisterna magna. Mean intracranial pressure was significantly elevated for approximately 36 h post-injection, during which time maximal ventricular dilatation was attained. Stretching and compression of periventricular tissue and capillaries accompanied dilation of the lateral ventricles. Ventricular dilation promoted mitotic activity among the periventricular astroglia. Ventriculomegaly altered the metabolism of the monoamine neurotransmitters in the cortex, hippocampus, diencephalon, hypothalamus, and brain-stem. Ischemic injury to neurons of the hippocampal formation, particularly the dentate gyrus, was observed when hydrocephalus had persisted for more than 4 weeks. Cerebrospinal fluid shunting effectively reversed the neuropathologic changes only when done in the early stages of hydrocephalus. When hydrocephalus persisted for 8 weeks, rapid reversal of changes in the ependyma and periventricular capillaries was prevented largely by periventricular gliosis.

Circumventricular organ origin of domoic acid-induced neuropathology and toxicology.

The neuroexcitotoxin, domoic acid, was responsible for an episode of mussel poisoning in Eastern Canada in 1987. Severe neurologic impairment and some deaths occurred. We have characterized the nature of domoate-induced neuropathology in the mouse brain. Domoic acid was administered intraperitoneally at doses of 2, 3 or 7 mg/kg to Swiss-Webster mice. Brains were examined at 0.5, 1, 24, 48 or 72 h postinjection for evidence of damage. Significant pathologic changes occurred only after the largest dose of domoic acid. Damage was confined to circumventricular organs lacking a blood-brain barrier and their environs, including the organon vasculosum of the lamina terminalis, subfornical organ, mediobasal hypothalamus and area postrema. The neural damage induced by domoic acid was evident at as early as 30 min after injection and increased by 60 min postinjection. The loci of domoic acid-induced neuropathological changes accounts for several central and peripheral effects and toxicities observed following systemic domoate treatment, these included gastroduodenal lesions, hypodipsia, analgesia, and blood pressure fluctuations.