In the treatment of the patient with epilepsy not only seizure control but quality of life issues are important aspects of management. Aspects that have an impact on the quality of life include seizure frequency and severity, social functioning, psychological well-being, disease specific measures, and general health status.

Background: Calmodulin-dependent cyclic nucleotide phosphodiesterase (CaMPDE) has been extensively studied and characterized in normal mammalian tissues; however very little is known about this enzyme in human brain tumors. It has been established that high levels of this enzyme exist in non-central nervous system tumors, PDE inhibitors or cAMP analogues have been used to treat them. This study has examined the levels of CaMPDE in glioblastoma multiforme from six patients and has compared these to the levels of CaMPDE in four patients with normal cerebral tissue. In addition, an enzyme immune assay method (EIA) was developed in this study for the detection of CaMPDE in human cerebral tissue. This method is proposed to be used as an adjunct to the spectrophotometric method presently utilized. This would be beneficial in cases where small tissue samples, for example in stereotactic biopsy, are available. Methods: The CaMPDE activity and corresponding levels of expression in cerebral tissue from temporal lobectomies and both surgical extraction or stereotactic biopsy in patients with primary tumors were determined by spectophotometric and EIA, respectively. The EIA was developed from the production of a polyclonal antibody against bovine brain 60 kDa CaMPDE isozyme. Cross reactivity of the antibody with human was confirmed using transblot and immunohistochemistry. Results: Utilising the EIA, there was found to be significant reduction in both catalytic activity (p < 0.001) and in quantitative protein expression (p < 0.001) in glioblastoma multiforme from patients when compared to normal cerebral cortex. Immunoblotting experiments and immunohistochemistry demonstrated that CaMPDE in glioblastoma multiforme failed to react with a polyclonal antibody raised against bovine brain 60 kDa CaMPDE isozyme, whereas the enzyme from normal tissue reacted with antibody. Conclusions: Contrary to other studies on non-CNS tumors, the catalytic activity and the protein expression of CaMPDE is reduced in glioblastoma multiforme. The EIA method is a more sensitive in detecting CaMPDE than in the spectrophotometric method, especially when a small amount of tissue is available. Immunohistochemistry and the EIA may be useful in the future to use as markers for other types of brain tumors and not for glioblastoma multiforme as demonstrated.

The term epileptic seizures is used to describe a variety of paroxysmal signs and symptoms resulting from a large number of underlying pathological processes. Generalized tonic-clonic convulsions, therefore, reflect entirely different basic neuronal mechanisms than those of typical absences. Animal research suggests that the former result from disturbances that involve disinhibilion, whereas the abnormality giving rise to the latter requires intact, if not enhanced, inhibition in order to sustain hypersynchronous neuronal discharges. Investigations in human mesial temporal lobe epilepsy and chronic experimental animal models indicate that partial seizures can also reflect multiple underlying mechanisms, with some disinhibitory in type, while others appear to be hypersynchronous and associated with enhanced inhibition. Just as more than one epileptogenic disturbance can result in transition to ictus, it is likely that more than one mechanism can be engaged to terminate epileptic seizures, that these diverse processes could result in different postictal manifestations, and that they could conceivably contribute differently to the development of interictal behavioral disturbances. An appreciation for the fact that epilepsy is not merely an increase in excitation and/or a decrease in inhibition, but a variety of complicated neuronal interactions in different patients, or even at different times in the same patient or same seizure, is essential to the development of effective treatments to control epileptic seizures and prevent their consequences.

Background: Chronic liver failure is associated with high signal abnormalities in the basal ganglia on Tl-weighted magnetic resonance imaging of the brain. These abnormalities are strikingly similar to those seen following manganese intoxication. As dietary manganese is normally cleared by the liver, we hypothesize that hepatic dysfunction could lead to manganese overload and account for the MR1 abnormalities seen in patients with chronic liver disease. Methods: We measured blood manganese concentrations in eleven patients with biopsy-proven hepatic cirrhosis and eleven healthy age and sex-matched controls. We also performed semi-quantitative measures of Tl signal abnormalities on MRI in the patients with chronic liver disease. Results: Patients with cirrhosis had significantly higher blood manganese concentrations (20.6 ± 10.2 mcg/L) than controls (7.2 ± 2.7, p = .0013). In addition, semi-quantitative scores of TI-weighted signal hyperintensity on MRI correlated with blood manganese concentration in patients with cirrhosis (r = .65, p = .029). Conclusions: These findings demonstrate that chronic liver disease is associated with manganese overload and suggest that manganese is responsible for the Tl-weighted signal hyperintensity seen on MRI of patients with liver disease. As manganese intoxication is known to cause parkinsonism and an encephalopathy similar to those which occur with chronic liver disease, it is possible that manganese toxicity contributes to the development of these symptoms in liver damaged patients and that therapies which prevent or reduce manganese overload may have clinical benefit.

Lamotrigine (LTG) inhibits repetitive high frequency firing in depolarised neurones by selectively prolonging slow inactivation of the sodium channel, thereby suppressing the release of excitatory amino acids. It has been shown to be effective in 11 pivotal double-blind add-on trials in patients with refractory partial seizures with or without secondary generalisation. Subsequent anecdotal data support its efficacy for typical and atypical absences, myoclonic jerks, tonic or clonic seizures, Lennox- Gastaut syndrome and infantile spasms. Most recently LTG has been compared with carbamazepine and phenytoin in double-blind trials in patients with newly diagnosed partial and primary and secondary generalised tonic-clonic seizures. At the doses used, its efficacy was similar to the older agents for all seizure types, but LTG was better tolerated than both of the older agents. The commonest sideeffects with LTG include headache, nausea, diplopia, dizziness, ataxia and tremor. Rash occurs in fewer than 5% patients. Its incidence can be reduced by starting treatment with a low dose, particularly in patients receiving concomitant sodium valproate which inhibits LTG metabolism. Enzyme inducers, such as carbamazepine, phenytoin and phenobarbital, accelerate its elimination, but LTG itself has no effect on hepatic metabolic processes. A pharmacodynamic interaction with carbamazepine necessitates a dosage reduction in some patients when LTG is introduced. LTG is a new antiepileptic agent with a long elimination half-life, a broad spectrum of activity, and a wide therapeutic ratio.

Background: Thirty-one gliosarcomas (25 nonirradiated and 6 postirradiated tumors) were selected based on the presence of two distinctive areas: a malignant gliomatous and a sarcomatous component. In all cases, the sarcomatous component appears like fibrosarcoma or malignant fibrous histiocytoma. Two tumors showed additional areas consisting of osteochondroid differentiation. Methods: All tumors were examined using antibodies against Ulex europaeus agglutinin I (UEA), glial fibrillary acidic protein (GFAP), vimentin (VM), epithelial membrane antigen (EMA), desmin, collagen IV, alpha-1-antitrypsin (a-l-AT) and smooth muscle actin (SMA). Results: While the VM highlighted the sarcomatous areas of all tumors there were only scattered spindle cells that were GFAP-positive in the same areas. The a-l-AT was diffusely reactive in the sarcomatous areas in 20 cases. Focal immunoreactivity was seen with SMA (20 tumors), UEA (8 tumors), EMA (5 tumors), collagen IV (5 tumors) and desmin (4 tumors) in the nonvascular sarcomatous cells. Conclusions: The range of immunophenotypical expression is likely to be a reflection of the capacity of a multipotential progenitor to undergo divergent differentiation. There is very little morphological difference between the postirradiated and nonirradiated tumors except that a higher proportion of postirradiated tumors are immunoreactive to SMA and desmin.

Background and Purpose: We examined the efficacy of the antioxidant LY231617 administered five hours following middle cerebral artery (MCA) occlusion in rats. Methods: The treatment was contrived for a two hour interval. Group A (n=16) was left untreated. Group B (n=16) received an intravenous infusion of LY231617. Group C (n=6) received saline (86 μI/min) by retrograde infusion of the cerebral vein (RICV). Group D (n=22) was administered LY231617 (10mg/kg/2hr) in saline (86μI/min) by RICV. Local cerebral blood flow with [14C]-iodoantipyrine and blood-brain transfer constant with 14C-α-amino-isobutyric acid were examined. Early ischemic damage was histologically examined with cresyl violet and Luxol fast blue and with triphenyl-tetrazolium chloride. Results: The results revealed a marked increase in local cerebral blood flow (over 600%, p < 0.01) after RICV with LY231617, with a significant improvement of BBB permeability in rats from group D. Ischemic brain damage measured with Luxol fast blue and triphenyl-tetrazolium chloride methods showed a significant improvement (50-91 %) of ischemic damage in group D, as compared to groups B and C. Conclusion: Retrograde infusion of the cerebral vein with LY231617 resulted in a significant amelioration at seven hours post MCA occlusion.

Objective: We report three patients with malignant rhabdoid tumor (MRT) of the brain, two children and an adult. There were three purposes to this report: to describe the clinical course in an adult with MRT; to describe the interesting histopathological metamorphosis of one of the tumors; and to report the outcome of the treatment regimens we used in order to help guide future treatment. Since these tumors are quite rare it is important to continue to try new regimens in the search for effective therapy rather than to repeat ineffective ones. Method: Report of three patients. Results: The clinical course in all three patients was typical of these aggressive neoplasms in that chemotherapy and radiotherapy were ineffective in modifying the rapid deterioration leading to death. Conclusions: MRT can occur in adults. Autopsy in one patient showed that the tumor seemed to undergo an evolution in appearance when compared with the original pathology specimen from craniotomy. Administration of systemic therapy should be prompt and include intrathecal chemotherapy.

Background: Patient outcomes in multiple sclerosis (MS) have generally been measured by their neurological impairment using specific scales such as the Kurtzke Expanded Disability Status Scale (EDSS). However, this scale does not measure the multiple dimensions of health-related quality of life (HRQOL) such as functional status and general well-being, which are also important outcomes along with disease-specific measurements. Methods: HRQOL was measured in a group of 97 MS patients using the RAND 36-item Health Survey 1.0. The EDSS score was assigned by the clinic neurologist. Additional data were collected from the clinical record for each patient. Results: MS patients scored poorly in a number of HRQOL domains such as physical and role functioning and energy or vitality. Disability as quantified by the EDSS correlated only with the physical functioning domain. Regression models were developed to measure the relationship between patient characteristics (independent variables) and HRQOL domains (dependent variables). Discussion: A number of patient characteristics were associated with higher or lower scores on the HRQOL domains. Of particular interest is the finding that a family history of MS was associated with poorer physical and social functioning as well as more pain and less vitality. The occurrence of seizures had a negative impact on role functioning, social functioning and general health perceptions. HRQOL gives caregivers a broader measure of disease burden than the EDSS alone, and should be useful in planning and monitoring interventions.

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.

Background: Using a population-based register of the Saguenay-Lac-Saint-Jean region (Quebec, Canada), the genealogical reconstruction of 533 individuals with intracranial aneurysm (IA) showed a familial aggregation (the presence of aneurysm in two or more first- to third-degree relatives) for 159 (29.8%) of them; this proportion is much higher than reported elsewhere. Objective: As part of an ongoing project to assess a genetic predisposition to intracranial aneurysms in the Saguenay-Lac-Saint-Jean population, the objective of the present study was to determine whether age-specific rates of ruptured cerebral aneurysms were higher than in other populations. Design: A retrospective study of cases of proven ruptured I As which were hospitalized during the 1973 to 1992 period was conducted. Age-adjusted rates were computed and compared to those reported in the Helsinki population. Results: We identified 412 cases of ruptured aneurysms. The age-adjusted incidence rate was 7.2/100,000/year (6.2 for men, 8.1 for women), which is similar to the incidence rates reported in other studies. Although the mean age at time of rupture was younger (46.6 years ± 13.8) than usually reported, no increase in age-specific incidence rates was detected. Conclusions: The results of this epidemiological study neither support nor reject the hypothesis of a genetic predisposition to intracranial aneurysms in the Saguenay-Lac-Saint-Jean population.

Vigabatrin (VGB) is a recently-released antiepileptic drug which works by a clearlydefined mechanism of action: inhibition of GABA transaminase leading to an elevation of brain GABA concentration. It has been proven effective, mainly as an add-on agent, in complex partial and secondarily generalized seizures in both adults and children as well as in infantile spasms in both short and long-term controlled studies. World-wide experience now includes over 150,000 patients exposed to the drug. VGB has a favorable pharmacokinetic profile since it has little protein-binding, is mainly excreted unchanged by the kidney and has a long effective half-life allowing once or twice daily dosing. It is generally well-tolerated with very few cognitive effects but may cause significant behavioral side effects such as agitation, irritability, depression or psychosis in approximately 2-4% of cases. Mild weight gain and possible exacerbation of absence and myoclonic seizures are other reported adverse effects. The role of VGB in other childhood epileptic syndromes apart from West syndrome is still being defined.

Background: When H-reflexes are recorded during movement in human subjects, the stimulator current output is not a good indicator of sensory stimulation efficacy because of unavoidable nerve movement relative to the stimulus electrodes. Therefore, the M-wave amplitude has been used by researchers as an indicator of the efficacy of the stimulus. In this study we have examined the general validity of the hypothesis that the M-wave amplitude is directly proportional to the group I sensory afferent volley evoked by the stimulus. Methods: A nerve recording cuff, stimulating electrodes, and EMG recording electrodes were implanted in cats. Nerve cuff recordings of centrally propagating volleys evoked by electrical stimuli were directly compared to M-waves produced by the same stimuli. Compound action potentials (CAPs) recorded in the sciatic nerve were compared with soleus M-waves during either tibial nerve or soleus muscle nerve stimulation. CAPs in the ulnar nerve were correlated with flexor carpi ulnaris M-waves during ulnar nerve stimulation. Results and Conclusions: Our findings indicate that for mixed nerve stimulation (e.g., tibial or ulnar nerve) the M-wave can be a reliable indicator of the centrally propagating sensory volley. Due to the high correlation between CAP and M-wave amplitude in these nerves, a small number of M-waves can give a good estimate of the size of the group I sensory volley. On the other hand, when nerves with only partially overlaping fibre diameter populations are stimulated (e.g., the soleus muscle nerve), the M-wave is not well correlated with the group I sensory volley and thus may not be used as a measure of the size of the input volley for H-reflex studies.