Identifying epileptic foci on contrast-enhanced computerized tomographic scans.

There is a statistically significant association between lateralization of interictal epileptic foci and lateralization of numerical changes between enhanced and unenhanced grossly normal computerized tomographic (CT) scans in the area of the suspected focus. This CT change, lateralized to the side of the focus compared to the homologous opposite brain, is a relative increase in CT values after enhancement. This change is seen in both right or left frontal and temporal foci, and is independent of the time of the last seizure, but is not reliably present if there is a gross abnormality on the CT scan. The technique provides additional evidence of lateralization in epileptic patients without clearly lateralized EEG findings.

Unilateral focal preponderance of interictal epileptiform discharges as a predictor of seizure origin.

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.

Effect of psychotropic medications on seizure control in patients with epilepsy.

Psychiatric problems are frequently encountered in patients with epilepsy. In an adult clinic population of 2,000 patients, 219 were identified as having been treated with psychotropic medication (PTM). Of these, 59 patients had adequate documentation of seizure frequency 2 months prior to and 2 months during treatment with PTMs. Contrary to many reports, most patients experienced better seizure control on PTM therapy. This demonstrates that most patients will not have an increased frequency of seizures when psychotropic medication is used in low to moderate doses and is introduced slowly.

Effect of doxepin on seizure frequency in depressed epileptic patients.

We performed a retrospective study of the effect of antidepressant treatment with doxepin on seizure frequency. From 47 patients treated with doxepin in 3 years, a confirmed seizure disorder and adequate follow-up (mean, 6.8 months) were available for 19 patients. Comparison of mean monthly seizure frequency during equal blocks of time before and during treatment with doxepin in doses of 5 to 400 mg/day demonstrated improved seizure control in 15, no change in 2, and increased seizures in 2 patients. The reduction in seizure frequency may have been a result of a direct antiepileptic effect of doxepin, an indirect effect because of improved affective state, drug interactions, or some combination of these mechanisms.

Outcome following surgery in patients with bitemporal interictal epileptiform patterns.

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.

Clorazepate and phenobarbital as antiepileptic drugs: a double-blind study.

The antiepileptic effect of clorazepate when given with phenytoin was compared, in a randomized double-blind crossover study, to the effect of the standard regimen of phenobarbital plus phenytoin in patients with partial seizures. Thirty of 42 subjects preferred the clorazepate-phenytoin regimen (p less than 0.01). The same number of subjects had fewer seizures while taking clorazepate as had fewer seizures while taking phenobarbital. However, subjects had significantly more toxicity, objective and subjective, on the phenobarbital-phenytoin regimen (p less than 0.01 in both cases). In some subjects, increased toxicity due to phenobarbital outweighed better seizure control, so that clorazepate was preferred. As an add-on antiepileptic drug, clorazepate is well tolerated, effective, and preferred by most patients to phenobarbital.

Carbamazepine--a double-blind comparison with phenytoin.

In a double-blind crossover study, carbamazepine and phenytoin were compared as single anticonvulsants in 47 patients with focal and major generalized seizures. Each drug provided superior seizure control in about half the patients, but significantly fewer patients had objective side effects while taking carbamazepine. Neuropsychologic testing showed improved performance in cognitive function and emotional status of patients while and carbamazepine. No hematotoxic complications arose, but vigilant follow-up is advised. Mean serum level of carbamazepine was 9.3 microng per milliliter with a suggested therapeutic range of 8 to 12 microng per milliliter reached by eventual doses of 16 to 20 mg per kilogram. Carbamazepine offers an independent choice of improved seizure control with a possibility of fewer side effects.

Differences in the urinary excretion of 6-beta-hydroxycortisol/cortisol between Asian and Caucasian women.

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.

Interictal, unifocal spikes in refractory extratemporal epilepsy predict ictal origin and postsurgical outcome.

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.

Long-term treatment with gabapentin for partial epilepsy.

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.

High-resolution inter-ictal SPET and phased-array MRI in partial epilepsy: an imaging comparison with video/EEG and outcome correlation.

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.

Seizure outcome in patients undergoing temporal lobe resections for epilepsy.

This article reviews the results of surgical treatment of temporal lobe epilepsy based on retrospective reviews: more recent surveys from 91 centers on the outcomes from the surgical treatment of epilepsy and preliminary data from the authors' institution's 5-year retrospective review of nearly 100 surgical patients matched to medically treated epileptics. Surgical outcomes from resections in other areas, including extratemporal resections, and the efficacy of lesionectomy versus epilepsy surgery for structural lesions are detailed elsewhere in this issue.

Predicting outcome following reoperation for medically intractable epilepsy.

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.

Outcome after surgery in patients with refractory temporal lobe epilepsy and normal MRI.

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.

Quantitative dendritic and spine analyses of speech cortices: a case study.

The present case study documents an unprecedented opportunity for correlative investigation of brain structure and function by quantitatively investigating the basilar dendritic systems of supragranular pyramidal cells in several cortical areas from a subject who had undergone electrical stimulation mapping 2 years prior to death. Electrical stimulation mapping results provided valuable functional information about the cortical areas removed for postmortem histological analysis. Morphometric analyses distinguished between proximal (first, second, and third order) and ontogenetically later developing distal (fourth order and above) basilar dendritic branches. In general, perisylvian language association stimulation sites (classical Wernicke's and Broca's areas) were characterized by different dendritic patterns than motor strip sites. In primary motor strip tissue blocks, proximal segments were longer than distal segments. In "higher order" elaborative cortical zones, distal segments were longer than proximal segments. Proximal segments outnumbered distal segments in primary motor zones, but the numerical difference between proximal and distal segments was reduced in the association areas. Finally, fourth order segments had significantly more dendritic spines than third order segments in all sites. These dendritic findings suggest a somewhat later ontogenetic development in classical Broca's and Wernicke's areas than in primary motor cortex.

Natural history of drug resistant seizures: clinical aspects.

In an effort to determine the long-term efficacy of surgical therapy for epilepsy, a control group of patients was identified. Both the surgically treated and non-surgical groups were evaluated before and after 5- or 10-year follow-ups for seizure frequency in the preceding 2 years. To date 39 patients have had bona fide partial seizures, with or without secondary generalization, and EEGs with focal epileptiform patterns. Prior to first evaluation, these patients had had seizures for an average of 10 years and were treated with an average of 54 AEDs with documented therapeutic serum levels in most; one-third of the patients participated in experimental studies. After treatment for another 5 years with an average of 2.5 AEDs or 10 years with an average of 4.0 AEDs, no one was seizure free. Fifteen percent had a 75% decrease in seizure frequency and 85% continued to have no significant improvement in seizure control. Thus despite vigorous treatment, these patients who might have been considered surgical candidates continued to have uncontrolled seizures.

Treatment of epilepsy.

Seizure patterns usually reflect known functions of the involved areas of the brain. The causes of epilepsy vary with the age at onset. For the purposes of determining drug therapy, seizures are divided into three groups. Focal and tonic-clonic seizures respond to one group of drugs, and absence seizures respond to another group. Surgical therapy may be beneficial in some patients with medically intractable epilepsy.

Paradoxical intoxication--a complication of anticonvulsant administration.

A new syndrome, paradoxical intoxication, has been defined in which high levels of hydantoins, and in one instance carbamazepine, produced an increase in seizures with little or no evidence of intoxication; a decrease in these levels produced an improvement in seizure control. This syndrome occurs often but not exclusively in those people who are less astute in assessing their neurologic status and therefore may experience unexpectedly higher blood levels of their anticonvulsants. Instances have been documented with serum levels above 40 mugm/ml for phenytoin or mephenytoin alone, or above 50 mugm/ml of combined hydantoins phenytoin and mephenytoin, and when the level is in the range of 20 mugm/ml and above for carbamazepine. Possible mechanisms underlying the syndrome are reviewed. Appropriate therapy is a reduction of the dose of the drug in question.

Use of psychological and neuropsychological variables in selection of patients for epilepsy surgery.

Cortical resection surgery for epilepsy is costly, involves risk, and does not result in significant seizure relief in a number of patients. Therefore, it is important to develop methods which will as accurately as possible identify in advance those persons who will or will not be helped by this procedure. From a review of the literature and from a presentation of original data, it is concluded that psychological/neuropsychological variables are valid predictors of cessation of seizures following surgery but that they are only infrequently used. A multidisciplinary, multivariate statistical approach, using EEG findings and psychological/neuropsychological variables in combination, provides the most accurate predictions which are superior to those derived from using either EEG variables or psychological/neuropsychological variables alone. This approach also avoids much of the predictive instability encountered when single variables are evaluated. Since psychological/neuropsychological variables are obtained at low cost and are non-invasive, further evaluation of their role as predictors of seizure relief following surgery is needed.