Biomedical subjects
Publications and source records attributed to A J Wilensky.
Automatisms are commonly seen in epilepsy, either ictally or postictally. However, most automatisms are simple, with hand movements, mouth smacking, nose-rubbing, repetition of a single word, or coughing, grunting, or screeching. Complex automatisms are less common and striking. The authors report two cases of seizure-associated singing where song expression may be recognizable.
OBJECTIVES: To evaluate the significance of exclusively unifocal, unilateral, interictal epileptiform patterns on scalp electroencephalography (EEG) in surgical candidates with medically intractable extratemporal epilepsy. METHODS: We reviewed 126 patients with refractory extratemporal partial seizures who underwent epilepsy surgery at our center. All were followed for at least 2 years after resections. Surgery was based on ictal EEG recordings. We examined ictal onsets and surgical outcome in subjects whose preoperative, interictal scalp EEGs during long-term monitoring (LTM) demonstrated only unilateral, well-defined focal discharges, and outcome in patients whose interictal EEGs during LTM showed bilateral, non-localized, or multifocal epileptiform patterns. RESULTS: We found that 26 subjects exhibited only unilateral, unifocal, interictal epileptiform patterns. In all 26 cases (100%) clinical seizures arose from the regions expected by the interictal findings (P<0.0001, Sign test). At last follow-up 77% (20/26) of these patients were seizure-free, while 23% (6/26) had >75% reduction in seizures. This compares to the remaining patients, of whom 34% (34/100) were seizure-free, 41% (41/100) had >75% reduction in seizures, and 25% (25/100) had <75% reduction in seizures (P=0.0001, Fisher's Exact test). CONCLUSIONS: Strictly unifocal, interictal epileptiform patterns on scalp EEG, though seen in a minority of subjects, may be an important, independent factor in evaluating subjects with intractable extratemporal, localization-related epilepsy for surgical therapy. This finding is highly predictive of both ictal onsets and successful postsurgical outcome.
Our purpose is to determine predictors of outcome in patients with refractory temporal lobe epilepsy and normal high resolution magnetic resonance imaging (MRI) who undergo surgical therapy. We identified 23 patients who underwent temporal lobectomy and had normal pre-operative MRI, including surface coil phased array temporal lobe imaging. All were followed at least 2 years after surgery. We graded outcome as seizure-free, > 75% reduction in seizures, or < 75% reduction in seizures. We examined pre-operative interictal and ictal electroencephalographic (EEG) findings, age of onset, gender, duration of epilepsy, risk factors, family history, physical findings, age at operation, side of operation, and pathology of resected tissue in order to determine if any of these factors were associated with outcome. Overall, 48% (11/23) of patients were seizure-free, 39% (9/23) had > 75% reduction in seizures, while 13% (3/23) had < 75% reduction in seizures. Only the EEG findings were useful in predicting outcome. When ictal onsets arose from basal-temporal regions, 61% (11/18) of patients were seizure-free, while none (0/5) were seizure-free when seizures arose from mid-posterior temporal regions (P = 0.04). Interictally, if all epileptiform patterns were localized exclusively to one basal-temporal region, a finding that invariably correlated with ictal onsets, 78% (7/9) of patients were seizure-free, while only 29% (4/14) were seizure-free if discharges were bilateral or multifocal (P = 0.04). We conclude that surgery may be a reasonable treatment for some patients with intractable temporal lobe seizures and normal MRI. The best outcomes occur when seizure onsets and interictal epileptiform patterns are exclusive to one basal-temporal region. Unfavorable outcomes are most likely to occur when ictal origins are from mid-posterior temporal regions and when interictal discharges are bitemporal or multifocal in distribution.
Advances in neuroimaging techniques, particularly high-resolution magnetic resonance imaging (MRI), have proved invaluable in identifying structural brain lesions in patients with epilepsy. The assumption that such focal lesions invariably predict the site of seizure origin may not be correct, however. We report a series of 20 adults with medically intractable partial epilepsy, where high-resolution brain MRI disclosed a unilateral, focal, hippocampal, or neocortical lesion as the only abnormality in each case; nevertheless, based on electroencephalographic (EEG) recordings, ictal onsets arose from a completely different location than that of the MRI lesion. All patients underwent epilepsy surgery, with the operations based on ictal EEG findings, and all were followed at least 2 years after the resection. After the most recent follow-up examination, 50% (10/20) of the patients were completely seizure-free, 35% (7/20) had at least a 75% reduction in the number of seizures, and 15% (3/20) had less than a 75% reduction in the number of seizures. We conclude that the identification of a focal, structural, hippocampal, or neocortical lesion on brain MRI is not always indicative of the site of seizure origin in partial epilepsy. Furthermore, in cases of discordance between MRI and EEG data, a good outcome after epilepsy surgery is possible if EEG ictal onsets are definitive.
The purpose of this study was to determine predictors of probable outcome following reoperation for medically intractable partial epilepsy. We reviewed outcome at least 1 year after reoperation in 21 patients with intractable seizures, for whom an earlier operation had failed. We examined age of onset of epilepsy, duration of seizures, gender, details of the history and clinical examination, pre-operative magnetic resonance (MRI) findings, electroencephalographic (EEG) studies obtained before and after the failed surgery, presence or absence of lateralizing neuro-psychological deficits, sites of operation and pathology of resected tissue to identify the factors associated with outcome. We found two factors that were significantly related to outcome: (1) no individual with a history of central nervous system (CNS) infection which predated the onset of epilepsy had a seizure-free outcome after reoperation (P = 0.04). (2) Reoperations that extended previous resections, based on new ictal EEG recordings that were concordant with both EEG ictal onsets and MRI findings obtained before the first, failed surgery resulted in a seizure-free outcome or >95% reduction in seizures for 100% (7/7) of such patients. This compares to 29% (4/14) of the remaining individuals without such concordance who had a similar outcome (P = 0.009). Site of operation (temporal or extratemporal) did not, in and of itself, predict outcome. A portion of patients who fail surgery for intractable partial seizures will achieve significant improvement following reoperation. Furthermore, we may be able to identify those individuals most likely to have an excellent result from a second operation.
The urinary ratio of 6-beta-hydroxycortisol/cortisol has been used as a noninvasive probe for human cytochrome P450 3A4 isoforms (CYP3A4). Ethnic-related differences in the ratio have not been evaluated. The aim of this study was to determine if there are differences in the ratio between Asian and Caucasian women over a menstrual cycle. First-morning urine samples were collected every other day starting from the second day of menstruation for a complete menstrual cycle from 15 Asians and 16 Caucasian women who were 18 to 40 years old, healthy, nonsmoking, and alcohol and drug free, including oral contraceptives. Urine concentrations of 6-beta-hydroxycortisol and cortisol were measured by high-pressure liquid chromatography (HPLC). For statistical analysis, three phases of the menstrual cycle were evaluated: menstruation (days 1-4), follicular or postmenstruation (days 6-10), and the luteal phase (days 21-24) based on the average menstrual cycle (28 days). Statistical analysis was performed by an independent sample t-test using the Bonferroni correction for repeated measures. Large intersubject and intrasubject variations of the 6-beta-hydroxycortisol/cortisol ratios were observed during the menstrual cycles in both ethnic groups. Asian women had a statistically significant lower ratio than Caucasian women did for all three phases of the menstrual cycle: 2.2 +/- 1.1 versus 5.1 +/- 3.5, 2.1 +/- 1.1 versus 6.0 +/- 4.9, and 2.8 +/- 1.6 versus 5.6 +/- 3.0 for the menstruation, follicular, and luteal phases, respectively. The two- to threefold lower 6-beta-hydroxycortisol/cortisol ratios in Asian women suggest that Asian women may have a lower CYP3A activity compared with Caucasian women. Differences in ethnicity may mask potential gender-related effects if ethnic background is not evaluated as a contributing factor.
OBJECT: Seizures frequently accompany moderate to severe traumatic brain injury. Phenytoin and carbamazepine are effective in preventing early, but not late, posttraumatic seizures. In this study the authors compare the safety and effectiveness of valproate with those of short-term phenytoin for prevention of seizures following traumatic brain injury. METHODS: The study was a randomized, double-blind, single-center, parallel-group clinical trial. Treatment began within 24 hours of injury. One hundred thirty-two patients at high risk for seizures were assigned to receive a 1-week course of phenytoin, 120 were assigned to receive a 1-month course of valproate, and 127 were assigned to receive a 6-month course of valproate. The cases were followed for up to 2 years. The rates of early seizures were low and similar when using either valproate or phenytoin (1.5% in the phenytoin treatment group and 4.5% in the valproate arms of the study; p = 0.14, relative risk [RR] = 2.9, 95% confidence interval [CI] 0.7-13.3). The rates of late seizures did not differ among treatment groups (15% in patients receiving the 1-week course of phenytoin, 16% in patients receiving the 1-month course of valproate, and 24% in those receiving the 6-month course of valproate; p = 0.19, RR = 1.4, 95% CI 0.8-2.4). The rates of mortality were not significantly different between treatment groups, but there was a trend toward a higher mortality rate in patients treated with valproate (7.2% in patients receiving phenytoin and 13.4% in those receiving valproate; p = 0.07, RR = 2.0, 95% CI 0.9-4.1). The incidence of serious adverse events, including coagulation problems and liver abnormalities, was similar in phenytoin- and valproate-treated patients. CONCLUSIONS: Valproate therapy shows no benefit over short-term phenytoin therapy for prevention of early seizures and neither treatment prevents late seizures. There was a trend toward a higher mortality rate among valproate-treated patients. The lack of additional benefit and the potentially higher mortality rate suggest that valproate should not be routinely used for the prevention of posttraumatic seizures.
To assess the clinical utility of high-resolution inter-ictal single photon emission tomography (SPET) of regional cerebral perfusion and high-resolution magnetic resonance imaging (MRI) of the brain with a phased-array temporal lobe coil, 35 patients with presumed partial epilepsy were evaluated prospectively by these techniques in addition to prolonged video/electroencephalographic (EEG) monitoring. Twenty of these patients had surgical treatment of partial epilepsy with outcome determinations spanning from 12 months to 3 years at follow-up. There were four categories of imaging findings as compared to scalp/sphenoidal EEG localization. Category I included 12 patients (34% of total) in whom there was complete imaging and EEG concordance. Category II included 4 patients (11%) in whom MRI and EEG were concordant but SPET was divergent or normal. Category III included 13 patients (37%) in whom SPET and EEG were concordant but MRI was divergent or normal. Category IV included 4 patients (11%) in whom neither SPET nor MRI was concordant with EEG. In this study, the relative sensitivities of SPET and MRI for localization of partial epilepsy based on prolonged scalp/sphenoidal video/EEG recordings were 76% and 49%, respectively. We conclude that these neuroimaging techniques (phased-array MRI and inter-ictal cerebral perfusion SPET) are complementary and useful in the pre-operative evaluation of patients with partial epilepsy.
OBJECTIVE: To develop a revised equation reflecting the current practice of measuring unbound phenytoin at room temperature, and to evaluate the revised Winter-Tozer method of predicting normalized total phenytoin concentrations in two groups of patients with hypoalbuminemia-elderly nursing home patients and critically ill head trauma patients. DESIGN: Albumin, unbound phenytoin, and total phenytoin concentrations were obtained from two sources: prospectively from a group of elderly nursing home patients and by a retrospective chart review of trauma patients enrolled in a previous double-blind, placebo-controlled study. SETTING: Community nursing homes; a university-affiliated urban teaching hospital. PARTICIPANTS: Elderly nursing home patients (n = 46) taking chronic phenytoin therapy and patients enrolled in a double-blind, placebo-controlled study (n = 58) evaluating the use of phenytoin to prevent posttraumatic seizures. MAIN OUTCOME MEASURES: Prediction error analysis was performed by using the methods proposed by Sheiner and Beal. Bias and precision were evaluated by calculating the mean prediction error (MPE) and root mean squared error (RMSE), respectively. RESULTS: The Winter-Tozer equation consistently overpredicted the normalized phenytoin concentration in the elderly nursing home population (MPE = 3.2, RMSE = 5.9) and the trauma patients (MPE = 3.3, RMSE = 4.8). The equation was revised to reflect the increased protein binding of phenytoin with decreased temperature and resulted in significantly decreased bias in both groups of patients. CONCLUSIONS: The revised equation is useful in predicting normalized phenytoin concentrations in both elderly nursing home patients and critically ill trauma patients.
We reviewed outcome at least 1 year after temporal lobectomy in 44 patients with bitemporal, independent, interictal epileptiform patterns on EEG. All 44 underwent preoperative intracranial monitoring. Twenty-two (50%) were seizure-free, 14 (32%) had at a least 75% reduction in seizures, and eight (18%) had less than a 75% reduction in seizures. We analyzed age of seizure onset, duration of epilepsy, gender, side of operation, history and clinical findings, findings on MRI, results of intracranial EEG-video monitoring, presence or absence of lateralizing neuropsychological deficits, and pathology of resected tissue to identify factors associated with outcome. Three factors emerged as independently associated with a good outcome: concordance of MRI abnormality and side of operation (p = 0.01), history of febrile seizures (p = 0.04), and 100% lateralization of intracranially recorded ictal onsets to the side of operation (p = 0.05). A seizure-free outcome was much more likely to occur if more than one of these factors was present: with at least two factors co-existing, 83% (15/18) of patients were seizure-free, while only 35% (7/20) were seizure-free with a single factor present (p = 0.0009). Of the six patients without any of the three factors, none were seizure-free. We conclude that it is possible to predict reasonably which patients with bitemporal epileptiform abnormalities will have a good outcome after surgery.
OBJECTIVE: To test the hypothesis that seizure origin may be predicted from scalp-recorded electroencephalographic interictal epileptiform patterns that occur exclusively or preponderantly over a single focal region. PATIENTS AND METHODS: Fifty-nine of 98 patients (>=16 years old) with intractable epilepsy who underwent sphenoidal/scalp electroencephalographic video monitoring were identified as having interictal epileptiform discharges preponderantly (>=75% of all discharges) or exclusively over a single unilateral region (basal-temporal, midposterior temporal, frontopolar, superior frontal, central). Ictal recordings in 48 patients could be interpreted as demonstrating focal origins, and the ictal findings were compared with the interictal findings. Eleven patients had uninterpretable ictal recordings or no seizures during monitoring and were not further considered. RESULTS: All seizures arose from the expected region in 39 of the 48 patients (Fisher's exact test, P<.001). Interictal discharges occurred exclusively over a single region in 23 of the 48 patients, and all seizures arose from the expected region in 22 of the 23 patients (P<.001). Seventeen patients among this group of 23 had exclusively unilateral basal-temporal discharges, and all seizures arose from the expected side, with the exception of one seizure that arose from the opposite side in one patient, with her other seizure arising from the expected side (P<.001). All seizures arose from the expected region in three patients who exhibited all interictal discharges arising from a single superior frontal region, in two patients with discharges only over a single midposterior temporal region, and in one patient with exclusively unilateral frontopolar discharges. CONCLUSIONS: Interictal discharges that demonstrate a consistent unilateral focal preponderance over a single region, regardless of location, generally predict seizure origin. If the discharges are exclusive to a single region, there is a greater than 95% probability that all recorded seizures will originate from the expected region.
1. One hundred and ten plasma samples were obtained from 50 patients treated with valproate for prophylaxis of post-traumatic head injuries. The samples were selected to include a wide range of albumin concentrations and were assayed for free and total valproate concentrations. Valproate binding parameters were determined from the Scatchard equation for one binding site using reweighted least squares analysis. 2. Plasma albumin concentrations were measured in 130 patients with head trauma. They started to decrease immediately after trauma, reaching a minimum at 5-7 days of approximately 24% of baseline value and did not return to normal until 1 month. 3. The free fraction of valproate varied six to seven-fold as albumin concentration ranged from 1.5 to 4.8 g 100 ml-1 (218-696 mumol l-1). The mean association constant for binding (Ka) was 0.008 mumol l(-1) and the mean number of binding sites (N) was 2.0. There values were similar to those reported for valproate in otherwise healthy patients with epilepsy. 4. Because of saturable protein binding of valproate, hypoalbuminaemia may necessitate the monitoring of free valproate concentrations to avoid toxicity when valproate is used in patients with acute head injury.
An impairment or hereditary defect in microsomal epoxide hydrolase is considered a possible risk factor for drug and chemical toxicity. However, nothing is known about variability of in vivo epoxide hydrolase activity in humans. Our objectives were to develop and test a simple pharmacokinetic approach for measuring microsomal epoxide hydrolase activity in a population. After administration of carbamazepine-10,11-epoxide (100 mg), oral clearance showed a nearly linear relationship to the log (transdihydrodiol/epoxide) urine ratio in the 24- to 36-hour interval (log metabolic ratio). Intrasubject variability was assessed by administering the epoxide twice to 13 subjects (1- to 4-month interval); the log metabolic ratio did not change significantly (mean difference, 11%; paired t test, p = 0.79). In 110 healthy white adults, the log metabolic ratio ranged from 1.28 to 2.05 (mean +/- SD, 1.68 +/- 0.155). Outliers indicating enzyme-deficient phenotypes were not observed, and the frequency distribution was unimodal normal. The log metabolic ratio detected pronounced inhibition of epoxide hydrolase by valpromide (six subjects; median ratio, 0.91) and induction by phenobarbital/phenytoin (six subjects; median ratio, 2.42). We conclude that distribution of microsomal epoxide hydrolase activity in a study group can be measured pharmacokinetically by use of carbamazepine epoxide.
Gabapentin was studied as an open-label 'add-on' antiepileptic drug in 35 patients with partial seizures. Follow-up at 6 months, 12 months, 18 months, and 24 months is reported. There was a trend toward improvement in simple (SPS) and complex partial seizures with it reaching significance for SPS at 12 and 24 months and for the weighted combination of seizures at 3 months. Five of nine patients were subsequently successfully converted to gabapentin monotherapy. Of those five, one is now seizure free and three are significantly improved since baseline. One remains with unchanged seizure frequency compared to baseline, but is experiencing less toxicity than at that time. This long-term observation suggests that the short-term effect demonstrated in blinded studies continues and that indeed some patients with refractory epilepsy can be maintained on gabapentin alone. Based on these findings, double-blind monotherapy trials of this drug are presently being conducted.
BACKGROUND: Antiepileptic drugs are commonly used to prevent seizures that may follow head trauma. However, previous controlled studies of this practice have been inconclusive. METHODS: To study further the effectiveness of phenytoin (Dilantin) in preventing post-traumatic seizures, we randomly assigned 404 eligible patients with serious head trauma to treatment with phenytoin (n = 208) or placebo (n = 196) for one year in a double-blind fashion. An intravenous loading dose was given within 24 hours of injury. Serum levels of phenytoin were maintained in the high therapeutic range (3 to 6 mumol of free phenytoin per liter). Follow-up was continued for two years. The primary data analysis was performed according to the intention to treat. RESULTS: Between drug loading and day 7, 3.6 percent of the patients assigned to phenytoin had seizures, as compared with 14.2 percent of patients assigned to placebo (P less than 0.001; risk ratio, 0.27; 95 percent confidence interval, 0.12 to 0.62). Between day 8 and the end of year 1, 21.5 percent of the phenytoin group and 15.7 percent of the placebo group had seizures; at the end of year 2, the rates were 27.5 percent and 21.1 percent, respectively (P greater than 0.2 for each comparison; risk ratio, 1.20; 95 percent confidence interval, 0.71 to 2.02). This lack of a late effect could not be attributed to differential mortality, low phenytoin levels, or treatment of some early seizures in patients assigned to the placebo group. CONCLUSIONS: Phenytoin exerts a beneficial effect by reducing seizures only during the first week after severe head injury.
The incidence of valproic acid hepatotoxicity has been reported to increase in patients who are receiving polytherapy. A minor valproic acid metabolite, 2-propyl-4-pentenoic acid (4-ene-VPA), formed by a cytochrome P450-mediated reaction, has been shown to be a potent inducer of microvesicular steatosis in rats. This study tested the hypothesis that formation of 4-ene-VPA would be increased in patients taking valproic acid with carbamazepine or with phenytoin but decreased with coadministration of an inhibitor of cytochrome P450 (the antiepileptic drug stiripentol in 300 to 1200 mg daily doses) in healthy subjects. Blood and urine samples in the studies were collected during a dosing interval at steady state. Valproic acid was assayed in plasma by capillary gas chromatography; valproic acid and 15 metabolites were measured in urine by gas chromatography/mass spectrometry. The formation clearance (CLf) of 4-ene-VPA was increased twofold in the valproic acid-carbamazepine and valproic acid-phenytoin groups. In the valproic acid/stiripentol studies, the CLf of 4-ene-VPA decreased by 32% in the 1200 mg/day stiripentol study. Similar findings were obtained at 600 and 300 mg/day stiripentol. These findings provide evidence supporting a role for cytochrome P450 in the formation of the hepatotoxic metabolite, 4-ene-VPA, in humans. The increased formation of 4-ene-VPA associated with carbamazepine and phenytoin is striking in relation to the epidemiologic finding of increased incidence of valproic acid-related hepatotoxicity during polytherapy with P450 inducers.
Mental ability changes following status epilepticus (SE) are explored. With respect to the studies reviewed, it is noted that (1) most dealt with children, (2) few utilized any formal psychologic assessment, (3) most were retrospective, (4) earlier studies tended to disclose greater losses in mental ability than later studies, and (5) most investigators described at least a few adverse changes attributable to SE rather than to underlying neurologic disease. An original prospective study is also reported.