Drug treatment of partial epilepsy.
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Animals↗
Biomedical subjects
R H Mattson
Publications and source records attributed to R H Mattson.
Comparison of bitemporal and unitemporal epilepsy defined by depth electroencephalography.
Of 166 consecutive patients studied with depth electroencephalography (EEG), 87 had seizures arising from one temporal lobe and 23 had seizures arising independently from each temporal lobe. We retrospectively reviewed and compared those patients with unitemporal and those with bitemporal seizures. There was no statistically significant differences between the two groups in terms of age at onset of seizures, duration of epilepsy, localization of scalp EEG abnormalities, surgical results, or pathological findings. The bitemporal group, however, had significantly fewer patients with a history of febrile seizures (p less than 0.025). Two patients with bitemporal seizures were later found to have extratemporal lesions, and one an extrahippocampal temporal lesion, on magnetic resonance scans; one patient's extratemporal lesion was resected and all habitual seizures stopped. These findings suggest that a single pathophysiological process accounts for unitemporal and some bitemporal epilepsy, but that independent onset of seizures from each temporal lobe detected by depth EEG may also indicate extratemporal foci.
Adolescent↗
Temporal lobectomy in patients with bitemporal epilepsy defined by depth electroencephalography.
Patient selection for temporal lobectomy was reviewed for 23 patients with seizures that arose independently from each temporal lobe as detected by depth electroencephalography (EEG). Although neuropsychological testing, interictal EEG findings, imaging studies, and subclinical seizures were also considered, all patients offered temporal lobectomy had (1) at least 50% of the clinical seizures originating from the lobe to be resected, (2) adequate contralateral memory on testing with amobarbital, and (3) no clear evidence of an extratemporal focus. Eleven patients underwent temporal lobectomy. Pathological findings were considered positive in all nine specimens reviewed. Nine patients had no seizures, one had greater than 75% reduction in seizure frequency, and 1 had 50 to 75% reduction. Pathological features and clinical outcome were similar in the 6 patients with fewer than 80% and the 5 patients with at least 80% of seizures originating from the resected lobe. Thus, having fewer than 80% of seizures originate from one temporal lobe should not be an absolute contraindication for temporal lobectomy.
Adolescent↗
A method for prediction of phenytoin levels in the acute clinical setting.
Phenytoin (PHT) administration is complicated by saturation kinetics within the therapeutic range, causing marked changes in drug concentration with small changes in dose. The "half-life" increases with concentration, varying from 8-24 hr up to weeks, making it difficult to obtain the steady state levels needed by most prediction algorithms and nomograms. A Bayesian prediction program (Epidose) is presented which explicitly models PHT absorption and elimination kinetics in the non-steady state. The algorithm accounts for the interdependency of closely spaced sequential samples. Estimates of future PHT concentration were made on 20 hospital inpatients, most of whom were acutely ill and received other medications. Future (mean = 4 day) PHT concentrations were predicted over a range from 4 to 22 micrograms/ml (mean 13.9 micrograms/ml) with a median absolute error of 1.0 microgram/ml. These data demonstrate that the program can be used for accurate PHT concentration predictions in sick patients.
Adult↗
Feeling-of-knowing in temporal lobe epilepsy: monitoring knowledge inaccessible to conscious recall.
Feeling-of-Knowing was compared in left temporal, right temporal, and control subjects. Seizure patients, like controls, demonstrate knowledge of information that is not accessible to conscious recall, but they are less accurate in FOK judgements. Furthermore, there are significant differences between seizure patients and controls in the relationship between Feeling-of-Knowing and object level memory scores: (1) Controls spend more time searching memory for inaccessible information that is correctly identified on a later recognition test than they do for information that is incorrectly recognized. (2) Latency of correct recognition decreases as strength of FOK increases among controls, suggesting that controls correctly anticipate the outcome of memory search. These patterns of performance, which are consistent with an efficient memory search termination device, were not observed among seizure patients. The findings suggest that inaccurate Feeling-of-Knowing may play a role in inefficient memory search mechanisms in temporal lobe epilepsy.
Adult↗
Multicenter long-term safety and efficacy study of vigabatrin for refractory complex partial seizures: an update.
We followed 66 patients with refractory complex partial seizures and a favorable initial response to vigabatrin for 5 to 72 (median, 43) months. Thirty-seven patients discontinued vigabatrin for the following reasons: benefit-to-risk evaluation, 8; seizure breakthrough, 6; adverse events, 6; seizure breakthrough and adverse events, 5; moved or lost, 4; no longer eligible for study, 2; non-drug-related death, 2; narcotic abuse, 1; and patient request, three. There were no clinically significant abnormalities in laboratory studies including SMA 12, complete blood count, ECG, EEG, and visual evoked response testing, and no toxicity other than reversible, dose-dependent side effects. Based on this and other long-term data, clinical trials of vigabatrin have resumed in the United States and Canada.
Aminocaproates↗
A method of assessing the efficacy of memory rehabilitation techniques using a "real-world" memory task: learning a computer language.
A software program developed to assess the effectiveness of memory rehabilitation techniques is described. This project addresses current weaknesses in the research literature on memory rehabilitation: 1) remediation strategies are evaluated in terms of performance on a practical, real-world memory task, rather than a laboratory learning task; 2) the program allows maximum flexibility in assessing a wide variety of remediation strategies and training schedules; and, 3) the software, which provides sensitive outcome measures and detailed feedback about performance, is adaptable to the needs of patients with widely varying degrees of memory impairment. The results of a demonstration project are included to illustrate the use of this technology in determining the usefulness of different mnemonic strategies for patients with specific patterns of memory deficit. The importance of assessing maintenance of rehabilitation training over time is stressed.
Computer Graphics↗
Emotional effects on seizure occurrence.
Emotional factors can alter the likelihood of seizure occurrence, and they usually increase the frequency of attacks. Our case studies showed that such activation is brought about through missed medication, sleep deprivation, and hyperventilation. Less well documented is the possibility that increased excitability and seizures may be due to direct neuronal activation of limbic circuits, although such a mechanism would be quite plausible.
Adult↗
Selection of drugs for the treatment of epilepsy.
Antiepileptic drug selection is based on efficacy for specific seizure types and epileptic syndromes. For idiopathic generalized epilepsies with absence, tonic-clonic, and myoclonic seizures, the drug of choice is valproate. Secondary generalized epilepsies with tonic, atonic, and other seizure types are difficult to treat with any single drug or combination of drugs. The drugs of choice for absence seizures are ethosuximide and valproate. For control of tonic-clonic seizures, any of the other major antiepileptic drugs can be effective. If valproate cannot be used, carbamazepine, phenobarbital, phenytoin, or primidone is effective, but ethosuximide or a benzodiazepine needs to be added to control associated absence or myoclonic seizures. The drugs of first choice for partial epilepsies with partial and secondarily tonic-clonic seizures are carbamazepine and phenytoin. Increasing evidence suggests that valproate may be a third alternative. Phenobarbital and primidone are second choice selections because of side effects. A combination of two of these five major antiepileptic drugs may be necessary for inadequately controlled patients. Other epilepsy syndromes such as neonatal and infantile epilepsies, febrile epilepsy, and alcoholic epilepsy require specific drug treatment. For all these seizure types and epilepsy syndromes, treatment ultimately must be selected to provide maximal efficacy and minimal adverse effect for each individual patient.
Anticonvulsants↗
Generic substitutions for antiepileptic drugs.
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Anticonvulsants↗
In vivo determination of valproate binding constants during sole and multi-drug therapy.
Valproate (VPA) is present in humans and is largely bound to protein. Only free drug is metabolized, and antiepileptic and toxic effects are probably related to free concentrations. By measuring serial free and total serum VPA levels after routine oral doses, we have determined individual in vivo protein binding parameters for 37 patients after a total of 49 separate drug administrations. Binding site concentrations and dissociation constants were fitted using a nonlinear algorithm. On sole VPA (n = 28) the mean dissociation constant was 91 mumol/L, and the mean concentration of binding sites was 1,176 mumol/L. Evidence suggests a second, nonsaturable binding site. Fraction of unbound VPA ranged from 5.4% at low levels up to 38.7%, rising with increasing total concentration. Concurrent therapy with phenytoin (n = 7) or carbamazepine (n = 8) did not cause displacement of VPA. Changes in free fraction were consistently observed during the interdose interval. The data demonstrate that the binding changes are not a factor in decreased VPA levels during coadministration of other antiepileptic drugs.
Binding, Competitive↗
Compliance declines between clinic visits.
Adherence to prescribed drug dosing regimens declined substantially during the interval between clinic visits and drug level tests. Using microelectronic monitors to observe pill-taking habits, 20 patients averaged 88% compliance before and 86% compliance after the visit, but this dropped to 67% compliance a month later. These data indicate that spot drug levels do not represent long-term "steady-state" drug serum concentrations.
Anticonvulsants↗
How often is medication taken as prescribed? A novel assessment technique.
The evaluation of the efficacy of medication is confounded when patients do not adhere to prescribed regimens. Overdosing, underdosing, and erratic dosing intervals can diminish drug action or cause adverse effects. Using a new method with epilepsy as a model, we assessed compliance with long-term medications among newly treated and long-term patients. Medication Event Monitor Systems (Aprex Corporation, Fremont, Calif) are standard pill bottles with micro-processors in the cap to record every bottle opening as a presumptive dose. Compliance rates averaged 76% during 3428 days observed: 87% of the once daily, 81% of the twice daily, 77% of the three times a day, and 39% of the four times a day dosages were taken as prescribed. Coefficients of variation of drug serum concentrations had no significant relationship to compliance rates. Pill counts overestimated compliance increasingly as compliance with the prescribed regimen declined. Neither drug serum concentrations nor pill counts would have identified the frequency of missed doses that were revealed with continuous dose observations.
Adult↗
A multicentre study of vigabatrin for drug-resistant epilepsy.
1. Vigabatrin (GVG) was given in a single-blind fashion to 89 patients with complex partial seizures (CPS) refractory to conventional drugs. 2. The median number of CPS per month decreased from 11.0 to 5.0 after addition of GVG, and 51% of patients had a 50% or greater decrease in CPS frequency (P less than 0.001). 3. Side effects (principally drowsiness, ataxia, headache) occurred mainly during the initiation of therapy and decreased during therapy. After 12 weeks on GVG side effects significantly interfered with functioning in only 13% of patients, and the efficacy: toxicity ratio warranted continued administration in 74% of patients. 4. Co-administration of GVG resulted in a mean decrease of 20% in phenytoin serum concentration (P less than 0.001). 5. Sixty-six patients having a favourable response to GVG during the single-blind study have been followed for 6-54 (median 33) months on GVG. Only 17 patients have dropped out of long-term follow-up due to break through seizures and/or side effects. No serious systemic or neurological toxicity has been detected.
Adult↗
Improvement in cognitive functioning and mood state after conversion to valproate monotherapy.
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Affect↗
Barbiturate-related connective tissue disorders.
Development of Dupuytren's contractures, frozen shoulder, Ledderhose's syndrome, Peyronie's disease, fibromas, and general joint pain has been linked in retrospective studies and case reports to the use of antiepileptic drugs. We undertook a prospective survey of the incidence of connective tissue disorders in 622 patients newly treated with carbamazepine, phenobarbital, phenytoin sodium, or primidone. Ten of the 406 patients who were treated for 6 months or more developed connective tissue disorders. All affected patients were taking a barbiturate (primidone, 4 patients; phenobarbital, 6 patients). Seven of the 10 problems occurred during the first year of treatment. These data are prospective evidence of a statistically significant relationship between barbiturate use and the development of connective tissue disorders, and timing of appearance.
Adult↗
Crossover from polytherapy to monotherapy in primary generalized epilepsy.
Patients with primary generalized tonic-clonic seizures can obtain equal or superior seizure control and fewer side effects when managed with valproate than when taking multiple antiepileptic drugs. The conversion from polytherapy to valproate monotherapy must be done carefully if side effects and seizure exacerbation are to be avoided. A gradual crossover, often requiring several months, is usually necessary. A well-developed plan and understanding by the patient, coupled with close follow-up, are essential. The major improvement in quality of life that results for the majority of patients after completing such a conversion fully warrants the extra time and effort required.
Adult↗
Can categorization of patient background problems be used to determine early termination in a clinical trial?
Many patients entering a long-term clinical study are unable to remain active in the trial (taking medication as prescribed and attending clinic as scheduled) for up to 6 years. We studied a group of 622 patients entering an antiepileptic drug study with maximum possible follow-up period of 6 years. A centralized case validation system was used in this VA Epilepsy Cooperative Study to note problems in patients entering the study. The categories established for pre-entry case status were associated with events occurring during the course of the study that led to noncompletion of the study. The data were reviewed to determine whether pre-entry status can be used to suggest the likelihood that an individual patient will remain in the study to completion or become a non-drug-related loss. Over one-half of all losses were related to failure to return to clinic. Medical problems (18%), medication noncompliance (14%), and psychiatric problems (12%) accounted for the remainder of losses. Pre-entry issues often were the same reason for early loss. However, many patients with problems known at entry were maintained in the study when targeted for extra support. We found some groups of patients had considerably more early terminations whereas others had less loss to the trial than we predicted originally. Thus, case categorization at entry can be used to estimate the likelihood of early termination from a clinical trial.
Actuarial Analysis↗