Long-term outcome of vagus nerve stimulation for drug-resistant epilepsy using continuous assessment, with a note on mortality.

PURPOSE: To examine the outcome of vagus nerve stimulation (VNS) for drug-resistant epilepsy using data from a National Health Service VNS clinic. METHODS: Clinical records of patients implanted with VNS for epilepsy between1995 and 2010 were examined. Patients were selected for study who had at least one year of therapeutic stimulation (minimum 1 mA stimulator current) and follow-up by our service with analysable electronic records, providing continuous assessment of seizure control during available follow-up. Seizure status at each attendance was assessed and graded 1-4 (1=seizure free or <5 seizures/year; 2 =≥50%reduction in seizure frequency; 3=<50% reduction; 4=no improvement compared to baseline). Responders were those whose grades improved consistently (Grades 1,2 and 3). RESULTS: Of 464 patients, 171 fulfilled the inclusion criteria and were divided into three groups: a) Responders (n = 81); b) non-responders (n = 80) and c) others (n = 10), the latter showing a late step-wise change (six improved; four deteriorated). After initial ramping up of current, groups were very stable over subsequent periods varying from one to 12 years (median 3.8 years). Sixteen patients died, 10 of non-epilepsy causes with 6 epilepsy-related deaths. There was a significant relation between epilepsy-related deaths and response (p < 0.00001). Patients with longer time as non-responders had more likelihood of suffering an epilepsy death than responders, though numbers were small. CONCLUSION: This study shows that meaningful data can be obtained retrospectively from routine clinic records. In this cohort about half of patients treated with VNS responded and the response generally remaining stable over time.

Mortality and SUDEP in epilepsy patients treated with vagus nerve stimulation.

OBJECTIVE: The risk of premature death is increased in patients with intractable epilepsy. The effect of vagus nerve stimulation (VNS) on mortality remains unclear. In a previous study by Annegers et al., mortality was raised, comparable to similar intractable cohorts. Our aim was to calculate standardized mortality ratios (SMRs), identify epilepsy-related deaths, and estimate sudden unexpected death in epilepsy (SUDEP) rates in patients treated with VNS for epilepsy. METHODS: All United Kingdom patients undergoing VNS between January 1, 1995 and December 31, 2010 at King's College Hospital, London were flagged through the national Medical Research Information Service. Analysis was performed in relation to all deaths occurring by December 31, 2010. Deceased patients were identified from the national death register, and additional information on cause and circumstances of death sought where appropriate to allow for classification of deaths. RESULTS: The cohort consisted of 466 patients, with 2993.83 person-years of follow-up and a median observation period of 5.9 years. Twenty-nine deaths occurred, 27 with the device active. SMR was 7.1 (95% confidence interval [CI] 4.8-10.3) for the active device; 12 deaths were considered epilepsy related, including 10 definite or probable SUDEP and one fatal near SUDEP. Definite/probable and fatal near SUDEP occurred at a rate of 3.7/1,000 person-years. SMRs decreased from 10.5 (5.6-19.5) in the first 2 years after implantation to 5.9 (3.7-9.5) thereafter, although CIs overlapped. SUDEP rates did not alter over time. SIGNIFICANCE: SMRs and SUDEP rate in this study are comparable to other cohorts with intractable epilepsy, with SUDEP an important cause of death. VNS does not appear to lower the risk of premature death overall. There was a clear trend with lower SMR after 2 years of implantation, although CIs overlapped. SUDEP rates, however, did not change.

Preoperative estimation of seizure control after resective surgery for the treatment of epilepsy.

PURPOSE: Predicting seizure control after epilepsy surgery is difficult. The objectives of this work are: (a) to estimate the value of surgical procedure, presence of neuroimaging abnormalities, need for intracranial recordings, resection lobe, pathology, durations of epilepsy and follow-up period to predict postsurgical seizure control after epilepsy surgery and (b) to provide empirical estimates of successful outcome after different combinations of the above factors in order to aid clinicians in advising patients presurgically about the likelihood of success under their patients' individual circumstances. METHODS: We report postsurgical seizure control from all 243 patients who underwent resective surgery for epilepsy at King's College Hospital between 1999 and 2011. Among the 243 patients, 233 had lobar or sub-lobar resections, 8 had multilobar resections and 2 had excision of a hypothalamic hamartoma. We examined the relation between postsurgical seizure control and type of surgical procedure, presence of neuroimaging abnormalities, pathology, resection lobe and the need of intra-cranial electrodes to identify seizure onset. RESULTS: Among the 243 patients, 126 (52%) enjoyed outcome grade I, 40 (16%) had grade II, 51 (21%) had grade III and 26 (11%) had grade IV (mean follow-up 41.1 months). Normal neuroimaging or need for intracranial recordings was not associated with poorer outcome. Patients undergoing temporal resections showed better outcome than those with frontal resections, due to the poor outcome seen in frontal patients with normal neuroimaging. Among temporal resections, there was no difference in outcome between patients with and without neuroimaging abnormalities. Among patients with lesions on imaging, temporal and frontal resections showed similar outcomes. Likelihood of favourable outcome under the patient's individual circumstances was estimated by the tables provided. There was an 8-9% decrease in the percentage of grade I between follow-up at 12 and >36 months. CONCLUSION: Overall, nearly 70% of patients undergoing resective surgery enjoy favourable post-surgical seizure control. Normal neuroimaging should not discourage surgery in temporal patients but is a negative prognostic sign in normal MRI frontal patients. There were no statistical differences in outcome between patients with neuroimaging lesions in frontal or temporal lobes.

Mortality after temporal lobe epilepsy surgery.

PURPOSE: To report mortality, after a longer interval, in a cohort of patients with drug-resistant epilepsy treated by temporal lobe surgery between 1975 and 1995. A previous audit of these patients ending December 1, 1997 observed a standardized mortality ratio (SMR) of 4.5. METHODS: We analyzed mortality in a cohort of 306 patients with temporal lobe epilepsy (TLE) who underwent temporal lobe resections between December 1, 1975 and December 1, 1995. Deaths occurring after December 1,1997 and until December 1, 2009 were evaluated. Medical records, death certificates, postmortem examination reports, coroner officer's reports, and coroner's inquest reports were sought, and causes of death were ascertained. Sudden unexpected death in epilepsy (SUDEP) cases were identified. KEY FINDINGS: In 3,569 person-years of follow-up 19 deaths occurred, [SMR 2.00, 95% confidence interval (CI) 1.27-3.13], 14 men (SMR 2.01, 95% CI 1.19-3.39) and 5 women (SMR 1.68, 95% CI 0.70-4.03). On analysis of subgroups, SMRs were significantly elevated in patients with mesial temporal sclerosis (MTS) (SMR 2.50, 95% CI 1.38-4.51), men with MTS (SMR 3.12, 95% CI 1.56-6.25), men with nonspecific lesions (SMR 2.68, 95% CI 1.00-7.09), and right-sided resections in MTS (SMR 3.33, 95% CI 1.39-8.00). During follow-up, six SUDEP cases were observed with a rate of 1/595 person-years. SIGNIFICANCE: In this cohort, the risk for premature death in patients undergoing TLE surgery decreased over time but remained above the standard population. Men had a slightly higher risk than women, as did right-sided resections in MTS, confirming this observation in the original cohort. Although lower, the risk of SUDEP remained. Without up-to-date information on seizure outcome, we were unable to directly relate this to mortality.

Value of scalp delayed rhythmic ictal transformation (DRIT) in presurgical assessment of temporal lobe epilepsy.

OBJECTIVES: To estimate the localising and lateralising value of delayed rhythmic ictal transformation (DRIT) on the scalp EEG during presurgical assessment for temporal lobe epilepsy. METHODS: Two hundred and eighty eight seizures recorded simultaneously with scalp and foramen ovale (FO) electrodes were studied retrospectively in 110 patients. DRIT was defined as sustained regular rhythmic waveforms seen on scalp recordings after scalp seizure onset. The incidence and laterality of scalp DRIT was evaluated by comparison to FO electrodes. RESULTS: Scalp DRIT was seen in 192 seizures, 65% of which showed focal mesial temporal onset (FMTO) recorded by FO electrodes. FMTO onset was seen in 73% of the 122 seizures showing unilateral scalp DRIT, in 32% of the 62 seizures showing bilateral asymmetrical scalp DRIT, and in 14% of the seven seizures showing bilateral symmetrical DRIT on the scalp. Among the 89 seizures showing unilateral scalp DRIT and FMTO, both were ipsilateral in 70 seizures (79%). Among the 38 seizures showing bilateral asymmetrical DRIT and FMTO, the largest amplitude of scalp DRIT was ipsilateral to the FO onset in 27 seizures (71%). CONCLUSION: Two thirds of seizures showed unilateral scalp DRIT, which had a lateralising value of up to 79%. SIGNIFICANCE: Scalp DRIT is a reliable marker to lateralise seizure focus in patients without a focal seizure onset on the scalp EEG.

EEG latency analysis for hemispheric lateralisation in Landau-Kleffner syndrome.

OBJECTIVE: To determine the reliability of latency analysis in lateralising the origin of epileptiform discharges in pre-surgical assessment of Landau-Kleffner syndrome (LKS). METHODS: A computer aided-method was developed to identify leading regions and measure inter-hemispheric latencies before and after averaging discharges. Scalp and intracranial EEG recordings were studied from seven patients undergoing surgical treatment. The laterality suggested by latency analysis was compared with that suggested by pharmacological tests. RESULTS: Latency analysis of bilateral discharges showed a consistent leading hemisphere. The earliest low-amplitude deflections were located in temporal regions in all patients. Contralateral low-amplitude deflections, and ipsilateral and contralateral earliest large negative peaks were recorded in temporal and less frequently in parasagittal regions. Presurgical inter-hemispheric latencies ranged between 8 and 48 ms for the deflections and between 4 and 30 ms for the peaks. The leading hemisphere identified by latency analysis of the earliest low-amplitude deflections coincided with that suggested by pharmacological tests in all 7 patients, whereas latency of later components coincided in 6. CONCLUSIONS: Latency analysis appears to be a reliable method to estimate the hemisphere driving bilateral discharges in LKS. SIGNIFICANCE: It can be carried out non-invasively and could be used to confirm, and eventually replace, results from pharmacological tests.

Single pulse electrical stimulation for identification of structural abnormalities and prediction of seizure outcome after epilepsy surgery: a prospective study.

BACKGROUND: Abnormal late responses to single pulse electrical stimulation (SPES) in patients with intracranial recordings can identify epileptogenic cortex. We aimed to investigate the presence of neuropathological abnormalities in abnormal SPES areas and to establish if removal of these areas improved postsurgical seizure control. METHODS: We studied abnormal responses to SPES during chronic intracranial recordings in 40 consecutive patients who were thereafter operated on because of refractory epilepsy and had a follow-up period of at least 12 months. FINDINGS: 22 patients had abnormal responses to SPES exclusively located in resected regions (96% with favourable outcome), seven had abnormal responses to SPES located in resected and non-resected regions (71% with favourable outcome), three had abnormal responses to SPES exclusively outside the resected region (none with favourable outcome), and eight did not have abnormal responses to SPES (62.5% with favourable outcome). Surgical outcome was significantly better when areas with abnormal responses to SPES were completely resected compared with partial or no removal of abnormal SPES areas (p=0.006). Neuropathological examination showed structural abnormalities in the abnormal SPES areas in 26 of the 29 patients in whom these regions were resected, despite the absence of clear MRI abnormalities in nine patients. INTERPRETATION: Abnormal responses to SPES are functional markers of epileptogenic structural abnormalities, and can identify epileptogenic cortex and predict surgical outcome, especially when a frontal or temporal focus is suspected.

Interictal temporal delta activity in temporal lobe epilepsy: correlations with pathology and outcome.

PURPOSE: To determine the characteristics and the clinical significance of focal slow activity and its association with focal epileptogenesis in patients with temporal lobe epilepsy (TLE). METHODS: We analyzed the interictal EEGs of 141 patients who had temporal lobe resections for intractable focal seizures and correlated the findings with pathologic changes and outcome. The pathologic changes were categorized into medial temporal sclerosis, tumors, and nonspecific changes. RESULTS: Lateralized slow activity was found in 66% of the patients, and it was mainly temporal, of delta frequency and irregular morphology. None of its characteristics, including quantity and reactivity to eye opening, was substrate specific. It was highly concordant with temporal spiking (60%), without any difference across the three groups, but provided additional information in 19 (15%) patients who had no lateralizing spikes. The effect of sleep also was similar in all three groups and included transition of slow waves into spikes. Lateralized slow activity to the side of the operation was significantly associated with favorable outcome only in the group with nonspecific pathology (p = 0.008), regardless of the presence, laterality, or topography of spikes. CONCLUSIONS: Our findings suggest that in patients with TLE whose brain magnetic resonance imaging (MRI) is either normal or suggestive of medial temporal sclerosis, interictal temporal slow activity has a lateralizing value similar to that of temporal spiking. Its association with a favorable outcome in patients with nonspecific pathology also suggests that candidates with lateralizing temporal delta and normal MRI should not be barred from further preoperative assessment.

Registered computed tomography images as an alternative to postimplantation magnetic resonance imaging in the assessment of subthalamic electrode placement.

Magnetic resonance imaging (MRI) after implantation of electrodes in the subthalamic nuclei is currently performed at a number of sites, but a recent adverse incident and changes in MRI technology may heighten safety concerns. In this report, it is demonstrated that given whole-head image data, registration of postimplantation computed tomography to preimplantation MRI can enable verification of the position of electrodes to an accuracy of 2 mm. This registration technique can remove the need for potentially risky postoperative MRI.

Characteristics of scalp electrical fields associated with deep medial temporal epileptiform discharges.

OBJECTIVE: To determine scalp characteristics of epileptiform discharges arising from medial temporal structures (MT). METHODS: Signal-to-noise ratio was increased by averaging simultaneous recordings from intracranial and scalp electrodes synchronised on discharges recorded by foramen ovale (FO) electrodes. The topography, amplitude and distribution of averaged scalp signals were analysed. RESULTS: Four thousand three hundred and twenty-seven discharges from 20 patients were averaged into 77 patterns. Before averaging, only 9% of discharges were detectable on the scalp without the need of simultaneous FO recordings (SED). A further 72.3% of discharges fell into averaged patterns that could be detected on the scalp as small transients before or after averaging (STBA or STAA). In 18.7% of discharges, no scalp signal was seen after averaging. Whereas most SED patterns had largest amplitude on the scalp at anterior temporal electrodes, STBA and STAA patterns showed greater variability and more widespread scalp fields, suggesting a deeper source. Dipole source localisation modelled the majority of SED patterns as radial dipoles located just behind the eye. In contrast, dipoles corresponding to STBA or STAA patterns showed greater variability in location and orientation and tended to be located at MT. CONCLUSIONS: SED patterns seem to arise from widespread subtemporal and/or superficial neocortical activation, generating EEG fields that are distorted by the high electrical conductivity of anterior cranial foramina. In contrast, STBA and STAA patterns represent electrical fields from neuronal activity more restricted to MT, that reach the scalp highly attenuated by volume-conduction and less distorted by cranial foramina. SIGNIFICANCE: Low amplitude scalp signals can be related to MT activity and must be taken into consideration for the diagnosis of temporal lobe epilepsy, pre-surgical assessment and for valid modelling of deep sources from the scalp EEG and magnetoencephalogram.

Clinical outcome of epilepsy surgery.

PURPOSE OF REVIEW: The outcome from current surgical methods of treating drug-resistant epilepsy will be considered, looking at changes in classical resective surgery and new methodology being introduced in the functional treatment of these patients. RECENT FINDINGS: There is now class I evidence that temporal lobe surgery is effective. Sophisticated and appropriate magnetic resonance imaging sequences, together with an assessment of the electroclinical syndrome, allow patients to be assessed for resective surgery. The concept of 'surgically remediable syndromes' determines the type of procedure that is effective for particular patients. Technical advances such as neuronavigation techniques and intra-operative magnetic resonance imaging have improved the effectiveness of these procedures. Other techniques of disconnection, such as multiple subpial transection, and stimulation both indirectly using the vagus nerve and directly using various intracranial targets, are currently effective and have potential for future development. SUMMARY: This review will demonstrate that current surgical techniques are safe and effective in relieving drug-resistant epilepsy.

Material-specific recognition memory deficits elicited by unilateral hippocampal electrical stimulation.

Although the medial temporal lobe is thought to be critical for recognition memory (RM), the specific role of the hippocampus in RM remains uncertain. We investigated the effects of transient unilateral hippocampal electrical stimulation (ES), subthreshold for afterdischarge, on delayed item RM in epilepsy patients implanted with bilateral hippocampal depth electrodes. RM was assessed using a novel computer-controlled test paradigm in which ES to left or right hippocampus was either absent (baseline) or synchronized with item presentation. Subsequent yes-no RM performance revealed a double dissociation between material-specific RM and the lateralization of ES. Left hippocampal ES produced word RM deficits, whereas right hippocampal ES produced face RM deficits. Our findings provide the first demonstration in humans that selective unilateral stimulation-induced hippocampal disruption is sufficient to produce impairments on delayed RM tasks and provide support for the material-specific laterality of hippocampal function with respect to RM.

Brain stimulation in the treatment of epilepsy.

Stimulation of the brain for the treatment of epilepsy, indirectly via the vagus nerve and directly through intracranial targets, is feasible and has increased in use and complexity over the past 10 years. Vagus nerve stimulation is widely applied and the present indications and outcomes together with possible ways in which the treatment could be refined are reviewed. The application of stimulation to deep-brain targets is also reviewed along with present practice and results. Possible developments in the use of direct intracranial stimulation are also considered.

Alternative surgical procedures to help drug-resistant epilepsy - a review.

The concepts of pathophysiology of epilepsy which underly the non-resective surgical treatment of epilepsy are reviewed. The available techniques, lesioning, disconnection and stimulation are described and reviewed critically. Stereotactic lesioning, popular in the 1950's has been largely abandoned but stereotactic radiosurgery emerges as a useful technique, especially in the treatment of mesial temporal sclerosis. Disconnection by callosotomy has fewer applications than previously and multiple subpial transection (MST) has limited applications. Stimulation is a technique with increasing usefulness. Vagus nerve stimulation(VNS) is an accepted method of treatment with low morbidity and mortality, which improves seizure control in at least 30% of patients, together with concomitant improvements in QOL and economic advantages. Stimulation of deep brain targets in the thalamus, subthalamus and mesial temporal structures is practical. There are indications that this improves seizure control in groups of patients previously un helped by surgery, and this methodology has enormous potential.

Lateralising value of neuropsychological protocols for presurgical assessment of temporal lobe epilepsy.

PURPOSE: To estimate the value of neuropsychological measurements in determining the side of seizure onset for presurgical assessment in patients with temporal lobe epilepsy. The lateralising value of neuropsychological protocols was evaluated for all patients and in subpopulations depending on surgical outcome with regard to seizure control, speech dominance, neuropathology, and need for intracranial EEG recordings. METHODS: A battery of neuropsychological procedures was carried out preoperatively in 125 patients who underwent left (n = 66) or right (n = 59) temporal lobectomies. Binary logistic regression analysis was performed to find sets of variables that allowed the best prediction of the side of seizure onset (assumed to be the operated-on side). RESULTS: Combinations of noninvasive neuropsychological tests and Wada subscores showed the highest lateralising values: 80.8% for all patients, 79.4% in seizure-free patients, 86.0% in patients not rendered seizure free, 85.7% in left speech patients, 77.8% in non-left speech patients, 89.3% in patients with mesial temporal sclerosis (MTS), 78.1% in non-MTS patients, 80.3% in patients who underwent intracranial EEG recordings, and 77.3% in those who did not. CONCLUSIONS: The lateralising value (80-90%) of neuropsychological protocols appears similar to that of other tests widely accepted for lateralisation (ictal and interictal scalp EEG and neuroimaging). Attention should be paid to neuropsychological results, particularly from the Wada test, during presurgical assessment of temporal lobe epilepsy, as they can provide strong support for findings from other lateralising tests, particularly in patients with presumed MTS or in left-speech patients.

Quantitative magnetic resonance imaging of the amygdala in temporal lobe epilepsy-clinico-pathological correlations (a pilot study).

PURPOSE: We carried out a pilot study of quantitative volumetric MRI of the amygdala in patients undergoing surgery for intractable temporal lobe epilepsy. We wished to explore whether amygdala volume correlated with pre-operative clinical variables and post-operative outcome. METHODS: Ten patients had detailed volumetric measurements of their amygdala and hippocampus according to operationalised anatomical criteria from an optimised MRI imaging sequence. A ratio of volumes from the unoperated to operated side was calculated. Surgical specimens were examined histologically for astrocytosis. RESULTS: The volumes of the amygdala and hippocampus on the operated side were significantly smaller than on the unoperated side. More severe astrocytosis appeared to go along with smaller volume ratios but the relationship was not significant. There were few significant correlations between volumes measures and clinical or outcome variables. CONCLUSION: Reductions in amygdala volume in the to-be-operated temporal lobe in patients with medically intractable epilepsy can be reliably detected using volumetric MRI. Accurate amygdala volume measures do not appear to exert a significant effect on clinical presentation and outcome in the presence of hippocampal volumes reductions, but may be useful in confirming bilateral pathology. Larger studies examining clinico-pathological correlations are recommended.

Resective surgery for hypothalamic hamartoma.

Hypothalamic hamartoma presents with precocious puberty, epilepsy or both. There are two epileptic syndromes, one presenting initially in infancy with gelastic seizures evolving rapidly into a syndrome with multiple seizures, developmental delay and a moderate to severe behaviour disorder. The other presents later with a milder epileptic syndrome, again usually including gelastic seizures, but with normal intellect and behaviour. Magnetic resonance imaging identifies and gives a detailed anatomical picture of these lesions. Direct surgery, using microsurgical techniques and neuronavigation guidance has been used for these lesions. Three surgical approaches have been used, one lateral pterional, another midline frontal through the lamina terminalis and a third is a transcallosal interforniceal approach. In addition a disconnection procedure, usually pterional, aims to disconnect the lesion without the risks of major resection. The transcallosal interforniceal approach is the most successful with 69% of patients seizure-free. There are complications in about 24% of patients, the same as other approaches, but the complications are milder and include fewer neurological deficits than the other routes. Alternate strategies include stereotactic radiosurgery and radiofrequency ablation under stereotactic control.

Internal carotid-inferior petrosal sinus fistula complicating foramen ovale telemetry: successful treatment with detachable coils: case report and review.

OBJECTIVE AND IMPORTANCE: Iatrogenic internal carotid artery-cavernous sinus fistula complicating percutaneous foramen ovale (FO) instrumentation (e.g., retrogasserian rhizotomy for trigeminal neuralgia) has been reported in only four patients to date. To our knowledge, no case of fistula has previously been reported either to complicate FO telemetry or to involve the inferior petrosal sinus (IPS); moreover, most patients have presented within 48 hours. We present a case of internal carotid artery-IPS fistula that complicated FO telemetry in which the clinical syndrome was delayed by 4 weeks. CLINICAL PRESENTATION: Four weeks after undergoing bilateral FO telemetry during Phase 2 investigations for surgery for epilepsy, a 37-year-old man suddenly developed a painful bilateral pupil-sparing oculomotor palsy, poor visual acuity, proptosis, conjunctival suffusion, and an audible bruit over the right frontotemporal region. INTERVENTION: Cerebral angiography demonstrated a high-flow arteriovenous fistula between the junction of the petrous and laceral portions of the right internal carotid artery and right IPS, with rapid filling of both cavernous sinuses. Successful obliteration was obtained with Guglielmi detachable coils, followed by complete resolution of the bilateral ocular abnormality. CONCLUSION: This is the first reported case of iatrogenic fistula formation to either involve the IPS or to complicate FO telemetry. In addition, symptomatology was anomalously delayed. This case highlights the importance of noting FO anatomic asymmetries before FO instrumentation and of routinely inquiring for "swooshing" noises after electrode withdrawal.

Neuropsychological Outcome and the Extent of Resection in the Unilateral Temporal Lobectomy.

Thirty-eight patients who had undergone either a right (RTL, n = 19) or left (RTL, n = 19) en bloc unilateral temporal lobectomy were scanned using magnetic resonance imaging, and the extent of removal of the superior lateral (SL), inferolateral (IL), basal, parahippocampal, and hippocampal regions was rated using semiautomated analysis. Brain regional ratings were correlated against pre- versus postoperative changes in memory functioning. The results showed overall significant postoperative decline in verbal memory only in the LTL group. Despite this, in the RTL group basal and hippocampal region removal was correlated with visuospatial memory outcome. In the LTL group, IL and basal region removal was correlated with Performance Intelligence outcome. In each case, more resection was associated with worse functioning and vice versa. It was concluded that variability in neuropsychological outcome can be explained in part by variations in the extent of tissue removal within the en bloc operation.