R.D.C. Elwes

Intracerebral propagation of interictal activity in partial epilepsy: implications for source localisation.

The hypothesis that focal scalp EEG and MEG interictal epileptiform activity can be modelled by single dipoles or by a limited number of dipoles was examined. The time course and spatial distribution of interictal activity recorded simultaneously by surface electrodes and by electrodes next to mesial temporal structures in 12 patients being assessed for epilepsy surgery have been studied to estimate the degree of confinement of neural activity present during interictal paroxysms, and the degree to which volume conduction and neural propagation take part in the diffusion of interictal activity. Also, intrapatient topographical correlations of ictal onset zone and deep interictal activity have been studied. Correlations between the amplitudes of deep and surface recordings, together with previous reports on the amplitude of scalp signals produced by artificially implanted dipoles suggest that the ratio of deep to surface activity recorded during interictal epileptiform activity on the scalp is around 1:2000. This implies that most such activity recorded on the scalp does not arise from volume conduction from deep structures but is generated in the underlying neocortex. Also, time delays of up to 220 ms recorded between interictal paroxysms at different recording sites show that interictal epileptiform activity can propagate neuronally within several milliseconds to relatively remote cortex. Large areas of archicortex and neocortex can then be simultaneously or sequentially active via three possible mechanisms: (1) by fast association fibres directly, (2) by fast association fibres that trigger local phenomena which in turn give rise to sharp/slow waves or spikes, and (3) propagation along the neocortex. The low ratio of deep-to-surface signal on the scalp and the simultaneous activation of large neocortical areas can yield spurious equivalent dipoles localised in deeper structures. Frequent interictal spike activities can also take place independently in areas other than the ictal onset zone and their interictal propagation to the surface is independent of their capacity to trigger seizures. It is concluded that: (1) the deep-to-surface ratios of electromagnetic fields from deep sources are extremely low on the scalp; (2) single dipoles or a limited number of dipoles are not adequate for surgical assessment; (3) the correct localisation of the onset of interictal activity does not necessarily imply the onset of seizures in the region or in the same hemisphere. It is suggested that, until volume conduction and neurophysiological propagation can be distinguished, semiempirical correlations between symptomatology, surgical outcome, and detailed presurgical modeling of the neocortical projection patterns by combined MEG, EEG, and MRI could be more fruitful than source localization with unrealistic source models.

The Prognosis for Seizure Control in Newly Diagnosed Epilepsy

We assessed the prognosis for seizure control in 106 patients who were referred to an adult neurology clinic with previously untreated tonic-clonic, partial, or mixed seizures and were followed prospectively for a median of 66 months (range, 6 to 96). Twenty-six patients remained completely free of seizures for as long as they were followed. Actuarial analysis showed that 35 per cent of patients could be expected to enter a seizure-free period of at least two years at the start of treatment, 73 per cent would have had a two-year seizure-free period at the end of four years, and 82 per cent would have had a two-year seizure-free period at the end of eight years. Of 79 patients whose seizures were completely controlled for at least two years, 51 subsequently remained seizure-free. If seizures continued for up to two years after the start of treatment, the probability of subsequent seizure control fell by half. The presence of partial seizures; a high frequency of tonic-clonic seizures before treatment; a neurologic, social, or psychiatric handicap; and a family history of epilepsy each indicated a worse prognosis. We conclude that the long-term pattern of seizure control is largely established during the first two years of treatment.

Phenobarbitone, phenytoin, carbamazepine, or sodium valproate for newly diagnosed adult epilepsy: a randomised comparative monotherapy trial

Recent studies have shown that most newly diagnosed epileptic patients can be satisfactorily treated with a single antiepileptic drug. We therefore undertook a prospective randomised pragmatic trial of the comparative efficacy and toxicity of four major antiepileptic drugs, utilised as monotherapy in newly diagnosed epileptic patients. Between 1981 and 1987 243 adult patients aged 16 years or over, newly referred to two district general hospitals with a minimum of two previously untreated tonic-clonic or partial with or without secondary generalised seizures were randomly allocated to treatment with phenobarbitone, phenytoin, carbamazepine, or sodium valproate. The protocol was designed to conform with standard clinical practice. Efficacy was assessed by time to first seizure after the start of treatment and time to enter one year remission. The overall outcome with all of the four drugs was good with 27% remaining seizure free and 75% entering one year of remission by three years of follow up. No significant differences between the four drugs were found for either measure of efficacy at one, two, or three years of follow up. The overall incidence of unacceptable side effects, necessitating withdrawal of the randomised drug, was 10%. For the individual drugs phenobarbitone (22%) was more likely to be withdrawn than phenytoin (3%), carbamazepine (11%), and sodium valproate (5%). In patients with newly diagnosed tonic-clonic or partial with or without secondary generalised seizures, the choice of drug will be more influenced by considerations of toxicity and costs.

Predictors of outcome and pathological considerations in the surgical treatment of intractable epilepsy associated with temporal lobe lesions.

OBJECTIVES To evaluate the influence of clinical, investigative, and pathological factors on seizure remission after temporal lobectomy for medically intractable epilepsy associated with focal lesions other than hippocampal sclerosis. METHODS From a series of 234 consecutive “en bloc” temporal resections for medically intractable epilepsy performed between 1976 and 1995, neuropathological examination disclosed a focal lesion in 80. The preoperative clinical, neuropsychological, interictal EEG, and neuroimaging characteristics of these patients were assembled in a computerised database. The original neuropathological material was re-examined for lesion classification and completeness of removal. The presence of additional cortical dysplasia and mesial temporal sclerosis was also noted. Survival analysis was performed using Kaplein-Meier curves and actuarial statistics. Logistic regression analysis was used to establish the independent significance of the clinical variables. RESULTS The probability of achieving a 1 year seizure remission was 71% by 5 years of follow up. Factors predicting a poor outcome on multivariate analysis included the need for special schooling and a long duration of epilepsy. Generalised tonic-clonic seizures, interictal EEG discharges confined to the resected lobe, demonstration of the lesion preoperatively on CT, and complete histological resection of the lesion were not predictive of outcome. Neuropsychological tests correctly predicted outcome in left sided cases but apparently congruent findings in right sided resections were associated with a poor outcome. Pathological reclassification established the dysembryoplastic neuroepithelial tumour as the commonest neoplasm (87%) in this series, with a significantly better seizure outcome than for developmental lesions, such as focal cortical dysplasia. CONCLUSIONS The findings highlight the importance of dysembryoplastic neuroepithelial tumour in the pathogenesis of medically refractory lesional temporal lobe epilepsy and the prognostic significance of preoperative duration of epilepsy emphasises the need for early recognition and surgical treatment. Cognitive and behavioural dysfunction, however, is associated with a lower seizure remission rate, independent of duration of epilepsy.

Multiple subpial transection: a review of 21 cases.

Multiple subpial transection (MST) is a novel technique in surgery for epilepsy, employed in patients where some or all of the epileptogenic zone cannot be resected because it lies in a vital cortical area. Twenty one patients subjected to MST were reviewed. Eighteen patients had medically intractable epilepsy and three patients had Landau-Kleffner syndrome. Their ages ranged from 6 to 47 (mean 15-9) and duration of epilepsy ranged from 0.33 to 42 (mean 8.6) years. Preoperative MRI showed focal abnormalities in eight cases. Detailed electrophysiological examination was carried out on all patients. Brain resection was performed in addition to MST in 12 patients. A further six patients underwent brain biopsy. Three patients with Landau-Kleffner syndrome were subjected neither to resection nor to biopsy. Histopathological examination showed Rasmussens syndrome in six patients, cortical dysplasia in six, cerebral tumour in one, and non-specific changes in five. Multiple subpial transection was carried out mainly in precentral and postcentral regions. Eighteen patients have been followed up for one to five years, and three for 10 months. The three patients with Landau-Kleffner syndrome were mute before operation and have shown substantial recovery of speech. Of the other 18, 11 showed a worthwhile decrease in seizure frequency. None of the patients developed chronic neurological deficits attributable to MST. It is concluded that MST leads to worthwhile seizure control without major neurological deficit in patients who would otherwise be inoperable.

WHY DOES EPILEPSY BECOME INTRACTABLE - PREVENTION OF CHRONIC EPILEPSY

Community-based and our own hospital-based studies suggest that the prognosis for seizure control is very good in most patients with epilepsy. However, chronic epilepsy develops in about 25%. The pattern of chronicity is established early in the course of treatment. Factors associated with a high risk of chronicity include additional neurological, psychological, and social handicaps and also partial seizures. In addition a process of evolution of chronic epilepsy may occur by a mechanism proposed by Gowers a century ago. Chronic epilepsy is very difficult to control and may best be prevented by more effective treatment at the onset of the disorder.

Is it worth pursuing surgery for epilepsy in patients with normal neuroimaging

Objective: To determine whether it is worth pursuing surgery for the treatment of epilepsy in patients with normal neuroimaging. Methods: Two patient populations were studied: (1) 136 consecutive patients who were surgically treated; (2) 105 consecutive patients assessed with chronically implanted intracranial electrodes within the same period. Sixty patients belonged to both groups, and included all 21 patients who had normal neuroimaging. Results: There were no differences in the proportion of patients with favourable outcome between those with normal and those with abnormal neuroimaging, irrespective of whether intracranial recordings were required. Among the 19 operated patients with normal neuroimaging, 74% had a favourable outcome (Engel’s seizure outcome grades I and II), and among the 93 patients with abnormal neuroimaging, 73% had favourable outcome (p = 0.96). In patients with temporal resections, 92% of the 13 patients with normal neuroimaging had a favourable outcome, whereas among the 70 patients with abnormal neuroimaging, 80% had a favourable outcome (p = 0.44). In patients with extratemporal resections, two of the six patients with normal neuroimaging had a favourable outcome, while 12 of the 23 patients with abnormal neuroimaging had a favourable outcome (p = 0.65). Among the 105 patients studied with intracranial electrodes, five suffered transitory deficits as a result of implantation, and two suffered permanent deficits (one hemiplegia caused by haematoma and one mild dysphasia resulting from haemorrhage). Conclusions: It is worth pursuing surgery in patients with normal neuroimaging because it results in good seizure control and the incidence of permanent deficits associated with intracranial studies is low.

A Comparative Study of the Cognitive Effects of Phenytoin and Carbamazepine in New Referrals with Epilepsy

Summary: This study compares cognitive function in new referrals with epilepsy well‐controlled on single drug therapy with either phenytoin or carbamazepine with that in an untreated control group. Patients receiving phenytoin performed consistently less well on memory tasks than did those untreated or receiving carbamazepine. Although patients on phenytoin overall showed a trend towards poorer performance on a tracking task, higher blood levels of this drug were correlated with better tracking performance. The correlation between blood levels of carbamazepine and tracking performance was the opposite from that of phenytoin. Blood levels of carbamazepine were negatively correlated with measures of anxiety, depression, and fatigue. These findings have implications for the choice of drug in the management of epilepsy and also for the reported claims of a psychotropic effect of carbamazepine.

A study of mortality after temporal lobe epilepsy surgery

Objective: To determine early and late mortality in a cohort of 305 consecutive patients who had temporal lobe epilepsy (TLE) surgery over a 20-year period. Methods: Survival status, cause of death, and postoperative clinical details of those who died were ascertained in a cohort of 305 patients who had TLE surgery. Mortality was related to postoperative seizure status, operative pathology, and side of resection. Results: The survival status of 299 patients was established. Twenty deaths occurred. Mortality was 1 per 136 person-years, with a standardized mortality ratio (SMR) of 4.5 (95% confidence interval [CI], 3.2 to 6.6). Six deaths were sudden and unexpected (SUDEP). The SUDEP rate was 1 per 455 person-years. The overall death and SUDEP rates were lower than those reported for similar patient populations with chronic epilepsy. Mortality in patients who had right-sided resections for mesial temporal sclerosis (MTS) remained considerably elevated with a mortality rate of 1 per 54 person-years, an SMR of 32.0 (95% CI, 24.7 to 40.5), and a SUDEP rate of 1 per 134 person-years. These patients had significantly lower seizure remission rates than left-sided patients, but the excess mortality was not simply explained by those patients whose partial seizures were uninfluenced by surgery. Patients who died had more severe or convulsive seizures despite an overall reduction in seizure frequency. Conclusions: The present findings confirm previous reports that TLE surgery lowers but does not normalize the overall mortality associated with chronic epilepsy. In patients with right-sided MTS, however, the postoperative mortality has remained similar to other groups with medically intractable seizures.

Prognosis after a first untreated tonic-clonic seizure.

The prognosis for seizure recurrence was assessed in 133 patients who presented at a median of 1 day after a first-ever tonic-clonic seizure. The cumulative probability of recurrence was 20% by 1 month, 28% by 2 months, 32% by 3 months, 46% by 6 months, 62% by 1 year, and 71% by 3 and 4 years. After a first seizure epilepsy is likely to develop in the majority of patients.