Uncontrolled Complex Partial Seizures Research Articles

Refractory Epilepsy

Refractory Epilepsy

Limbic encephalitis and hyperactive foci on PET scan

Two cases of patients with paraneoplastic limbic encephalitis, difficult to control seizures, and unilateral hippocampal hypermetabolism on positron emission tomography (PET) are described. Two women aged 33 and 61 presented with uncontrolled complex partial seizures, profound memory loss and cognitive decline. One was later diagnosed with breast cancer and the other with lung cancer. Video-EEG on the first patient recorded multifocal sharp waves and bilateral independent seizure onsets. The second patient had no epileptiform discharges and bitemporal ictal onset, even though the clinical seizures suggested a right temporal onset. Magnetic resonance imaging (MRI) was normal in both patients. PET scans obtained in the interictal state showed right hippocampal hypermetabolism in both patients. In the second patient, the lung cancer was irradiated with resolution of seizures and improvement of memory function. A PET scan six months later was normal. Subsequent seizure recurrence and worsening of memory led to the discovery of widespread metastases. Limbic encephalitis should be considered in the differential diagnosis of intractable partial epilepsy, particularly if accompanied by severe memory loss and cognitive decline. Treatment of the underlying cancer may be lead to improved seizure control. Hippocampal hypermetabolism may be a common feature on PET, and may indicate subclinical seizure activity.

Hippocampal atrophy, epilepsy duration, and febrile seizures in patients with partial seizures.

Previous studies have suggested a variety of factors that may be associated with the presence of hippocampal formation (HF) atrophy in patients with complex partial seizures (CPS), including a history of complex or prolonged febrile seizures (FS), age at seizure onset, and epilepsy duration. To determine whether epilepsy duration is related to HF atrophy. We performed MRIs on 35 patients with uncontrolled CPS who had temporal lobe ictal onset on video-EEG. None had evidence for an alien tissue lesion or extra-hippocampal seizure onset. All had a history of secondary generalization. Brain structures were drawn on consecutive images and pixel points summed from successive pictures to calculate volumes. Nine patients with a history of complex or prolonged FS had smaller ipsilateral HF volume and ipsilateral/contralateral ratio than did patients without a history of FS. Epilepsy duration had a significant relation to ipsilateral HF volume and ipsilateral/contralateral ratio. In a multivariate analysis, the effect of duration, but not age at onset or scan, was significant. Patients with a history of FS did not have earlier age at epilepsy onset or longer duration. A history of FS predicted the severity of HF atrophy in our patients. Age at onset or study was not a significant factor. Epilepsy duration, however, did have a significant effect, suggesting that, after an initial insult, progressive HF damage may occur in patients with persistent seizures.

Effect of seizures on cerebral blood flow measured with 15O-H2O and positron emission tomography.

To study quantitative alterations in regional cerebral blood flow (rCBF) accompanying seizures, and to assess the utility of ictal activation PET scanning as a noninvasive clinical tool for localization of epileptogenic foci, we used pentylenetetrazole (PTZ) to induce seizures during 15O-water positron emission tomography (PET) CBF measurement in 15 patients with uncontrolled complex partial seizures (CPS) who had been referred for surgical evaluation. Continuous EEG monitoring was performed during the PET scans. After baseline scans were obtained, each patient was injected with 150-300 mg PTZ. Two patients had generalized tonic-clonic seizures (GTCs). CBF increases were asymmetrical. Two patients (in 1 the seizure occurred spontaneously, without PTZ injection) who had CPS had bitemporal 70-80% increases in CBF. Thalamic CBF increased during both CPS and GTCS. Five patients had an increase in focal EEG interictal abnormality, accompanied by focal flow decreases in 3. PTZ injection not accompanied by clinical seizures did not increase CBF. Partial seizures may be associated with bilateral increases in CBF, and subcortical gray regions are involved in ictal activation.

Postsurgical outcome of patients with uncontrolled complex partial seizures and temporal lobe hypometabolism on 18FDG-positron emission tomography.

The purpose of this study is to evaluate the relation between a focus of temporal lobe hypometabolism, including comparison between mesial and lateral asymmetry on fluorine-18-labeled-deoxyglucose-positron emission tomography (18FDG-PET) and surgical outcome in patients with uncontrolled partial seizures. Case histories, electroencephalogram (EEG) findings, radiographic findings, and surgical outcome (36 +/- 11 months of follow-up) were reviewed in 38 consecutive patients who had a interictal 18FDG-PET scan and subsequent temporal resection. Among the 36 patients who had a temporal lobe focus of hypometabolism (more than 15% asymmetry to contralateral side), 61% (22 of 36) became seizure-free, 33% (12 of 36) markedly improved and 6% (2 of 36) did not improve. The focus of hypometabolism on PET was in agreement with the epileptic focus on the noninvasive EEG in 30 of 36 patients and in 19 of the 22 patients who underwent an invasive EEG. The asymmetry index for the mesial temporal lobe was significantly higher in the group of patients who became seizure-free compared with the other patients. This study confirms that a focus of interictal temporal hypometabolism on PET is associated with marked improvement of seizure control after surgery in 94% (34 of 36) of the patients. Hypometabolism in the mesial temporal lobe appears to be associated with a seizure-free outcome.

A double-blind, placebo-controlled study of Vigabatrin three g/day in patients with uncontrolled complex partial seizures

This study compared the efficacy and tolerability of vigabatrin 3/day as add-on therapy with that of placebo in patients with focal epilepsy whose complex partial seizures were difficult to control with established antiepilepsy drug therapy. We enrolled 203 patients; 182 (90 placebo; 92 vigabatrin) received drug therapy under double-blind conditions. We increased the daily dosage to 2.5 g/day during a 4-week titration segment and maintained it at 3 g/day during the 12-week maintenance segment. By analyses we found a statistically significant lower frequency of seizures (complex seizures plus partial seizures secondarily generalized) at the end of the study for patients receiving vigabatrin than for those receiving placebo. The median monthly frequency was reduced by three seizures per 28 days in the placebo group (baseline, 8.3; end of study, 7.5) (p = 0.0002). Therapeutic success (a 50% reduction from baseline in mean monthly seizure frequency) was attained in 40 of the vigabatrin patients (43%) compared with 17 of those treated with placebo (19%) (p < 0.001). Vigabatrin significantly increased the mean number of seizure-free days per 28 days (2.2 days) compared with placebo (0.5 days) (p = 0.0024). Mean trough serum vigabatrin concentration during therapy was 8.6 +/- 7.7 micrograms/ml. The oral clearance of vigabatrin was determined to be 7.8 L/hr, and the elimination half-life was 8.4 hours. No clinically important changes in MRI, evoked potential, or other laboratory tests were noted during vigabatrin treatment. The results of this study indicate that 3 g/day vigabatrin is more effective than placebo as add-on therapy. Vigabatrin was well tolerated, compliance was high with twice-daily administration, and therapy did not result in clinically relevant drug interactions.

Positron emission tomographic measurement of cerebral blood flow and temporal lobectomy

We used positron emission tomography (PET) and bolus injection of H2(15O) to measure interictal cerebral blood flow (CBF) in 32 patients who had temporal lobectomy for uncontrolled complex partial seizures. Seizure focus localization was confirmed by ictal video-electroencephalographic (video-EEG) telemetry, and patients who had imaging findings suggesting the presence of a tumor were excluded. PET-CBF studies were interpreted using a standard template by raters blinded to EEG and clinical data, and were not used in surgical planning. After surgery, patients were followed for 32 +/- 18 months. Twenty-six patients were seizure free and 6 had persistent seizures. Mean lateral temporal hypoperfusion was 8 +/- 14% in patients who became seizure free and 9 +/- 6% in patients with persistent seizures. Fourteen patients had at least 15%, and 11 at least 20% hypoperfusion, but were not more likely to be seizure free. Three additional patients had 15 to 20% hypoperfusion in the temporal lobe contralateral to their EEG focus. PET measurement of CBF using bolus H2(15O) should not be used to help select patients for temporal lobectomy.

Predictive factors for controlling seizures using a behavioural approach

A behavioural approach using EEG biofeedback for controlling complex-partial seizures has been successful at the Andrews/Reiter Epilepsy Research Program. Records for a random sample of 83 patients with uncontrolled seizures, one third of those receiving care between 1980 and 1985, document that 69 (83%) achieved control by completion of the programme. Additional data about initial age of seizure onset, number of years seizures had been uncontrolled and seizure frequency when treatment started were collected to determine whether these factors predicted seizure control. Only frequency was significantly related to whether seizures were controlled when treatment ended. Further study using discriminant analysis showed that earlier onset age and higher seizure frequency were associated with a significantly greater number of treatment sessions required. Thus, these two factors predicted difficulty in controlling seizures, as measured by number of sessions, although onset age did not predict whether control was eventually achieved. Since even the subgroup achieving the lowest rate of control (i.e., patients having daily seizures when treatment started) had 67% success, these results suggest that a behavioural approach can be useful for many people with currently uncontrolled complex-partial seizures regardless of their characteristics on factors examined in this study.

Cerebral activation during speech discrimination in temporal lobe epilepsy

Eight patients with uncontrolled complex partial seizures underwent positron emission tomography with 18-fluoro-2-deoxyglucose both at rest and during an auditory order discrimination task using speech syllables. Eight age-matched controls were scanned under identical conditions; an additional 18 normal subjects were scanned only at rest. No consistent task-related changes were seen in control subjects. For the 3 patients with left temporal epileptogenic foci, left inferior temporal lobe hypometabolism was more evident during the activated than during the resting scan. Activation procedures may augment the diagnostic yield of metabolic scanning in epilepsy.

Balance and Cognitive Impairment in Two Epileptic Patients Before and After Vagal Nerve Stimulation

Balance and cognition were assessed in two patients with uncontrolled complex partial seizures. The patients were on anticonvulsant medications and were treated with left vagal stimulation. Balance and cognition were assessed before and after vagal stimulation, and the results were compared with age matched controls and older patients with Parkinson's disease. Severe impairments of function were found in the epileptic patients, and such negative effects of medication make vagal stimulation a potentially practical alternative treatment for uncontrolled epilepsy.

Focal medial temporal lobe spike-wave complexes evoked by a memory task.

Several factors are known to modulate the occurrence of interictal spike-wave complexes (SWC). During performance of a recent memory task by a patient with uncontrolled complex partial seizures and implanted electrodes, visually presented stimuli consistently evoked focal medial temporal lobe interictal SWC with an average latency of 228 +/- 29 ms. The SWC were more often lateralized to the left medial temporal lobe. No consistent change in interictal spike rate was observed during performance of several other cognitive tasks during which visual or auditory stimuli were presented. This suggests that performance of specific cognitive tasks--in this case, recognition memory of words--can trigger interictal SWC.

Disposition of mephenytoin and its metabolite, nirvanol, in epileptic patients.

We investigated the conversion of mephenytoin to nirvanol in five patients with uncontrolled complex partial seizures. After a 50-mg single oral dose, mean peak mephenytoin level was 0.48 microgram/ml and nirvanol 0.37 microgram/ml. After 400 mg, peak mephenytoin level was 3.9 micrograms/ml and nirvanol 2.5 micrograms/ml. On 400 mg daily, mephenytoin reached a mean steady-state level of 1.5 micrograms/ml. Nirvanol mean steady-state level was 18 micrograms/ml. Mean plasma half-life was 17 hours for mephenytoin and 114 hours for nirvanol. Two patients had reduced seizures during mephenytoin therapy and one a transient increase during drug withdrawal. No toxicity was seen, but mephenytoin was not more effective than phenytoin.