Abbreviated report of the NIH/NINDS workshop on sudden unexpected death in epilepsy.

Sudden unexpected death in epilepsy (SUDEP) is a devastating complication of epilepsy and is not rare. The NIH and National Institute of Neurological Disorders and Stroke sponsored a 3-day multidisciplinary workshop to advance research into SUDEP and its prevention. Parallel sessions were held: one with a focus on the science of SUDEP, and the other with a focus on issues related to the education of health care practitioners and people with epilepsy. This report summarizes the discussions and recommendations of the workshop, including lessons learned from investigations of sudden infant death syndrome (SIDS), sudden cardiac death, autonomic and respiratory physiology, medical devices, genetics, and animal models. Recommendations include educating all people with epilepsy about SUDEP as part of their general education on the potential harm of seizures, except in extenuating circumstances. Increasing awareness of SUDEP may facilitate improved seizure control, possibly decreasing SUDEP incidence. There have been significant advances in our understanding of the clinical and physiologic features of SIDS, sudden cardiac death, and SUDEP in both people and animals. Research should continue to focus on the cardiac, autonomic, respiratory, and genetic factors that likely contribute to the risk of SUDEP. Multicenter collaborative research should be encouraged, especially investigations with direct implications for the prevention of SUDEP. An ongoing SUDEP Coalition has been established to facilitate this effort. With the expansion of clinical, genetic, and basic science research, there is reasonable hope of advancing our understanding of SUDEP and ultimately our ability to prevent it.

Ictal SPECT statistical parametric mapping in temporal lobe epilepsy surgery.

OBJECTIVE: Although subtraction ictal SPECT coregistered to MRI (SISCOM) is clinically useful in epilepsy surgery evaluation, it does not determine whether the ictal-interictal subtraction difference is statistically different from the expected random variation between 2 SPECT studies. We developed a statistical parametric mapping and MRI voxel-based method of analyzing ictal-interictal SPECT difference data (statistical ictal SPECT coregistered to MRI [STATISCOM]) and compared it with SISCOM. METHODS: Two serial SPECT studies were performed in 11 healthy volunteers without epilepsy (control subjects) to measure random variation between serial studies from individuals. STATISCOM and SISCOM images from 87 consecutive patients who had ictal SPECT studies and subsequent temporal lobectomy were assessed by reviewers blinded to clinical data and outcome. RESULTS: Interobserver agreement between blinded reviewers was higher for STATISCOM images than for SISCOM images (kappa = 0.81 vs kappa = 0.36). STATISCOM identified a hyperperfusion focus in 84% of patients, SISCOM in 66% (p < 0.05). STATISCOM correctly localized the temporal lobe epilepsy (TLE) subtypes (mesial vs lateral neocortical) in 68% of patients compared with 24% by SISCOM (p = 0.02); subgroup analysis of patients without lesions (as determined by MRI) showed superiority of STATISCOM (80% vs 47%; p = 0.04). Moreover, the probability of seizure-free outcome was higher when STATISCOM correctly localized the TLE subtype than when it was indeterminate (81% vs 53%; p = 0.03). CONCLUSION: Statistical ictal SPECT coregistered to MRI (STATISCOM) was superior to subtraction ictal SPECT coregistered to MRI for seizure localization before temporal lobe epilepsy (TLE) surgery. STATISCOM localization to the correct TLE subtype was prognostically important for postsurgical seizure freedom.

Psychiatric co-morbidity in 75 patients undergoing epilepsy surgery: lack of correlation with pathological findings.

BACKGROUND: Psychiatric disorders may occur in patients with intractable partial epilepsy after surgical treatment. Previous reports attributed the presence of psychological adverse events to specific pathological entities such as dysembryoplastic neuroepithelial tumors (DNETs) and gangliogliomas. The rationale for the present study is to evaluate the importance of the surgical pathology in individuals undergoing epilepsy surgery. METHODS: The patients were separated into three groups based on the surgical pathology: group I ganglioglioma (N=25), group II DNETs (N=25), and group III mesial temporal sclerosis (N=25). Thirteen of the 75 patients (17.3%) had a preexisting psychiatric disorder. The most common preoperative psychiatric diagnosis was depression (N=4). Sixty-three of the lesions (84%) were restricted to the temporal lobe. The operative strategy included resection of the lesion and epileptogenic cortex. Sixty-two of the 75 patients (83%) were rendered seizure-free. RESULTS: Eight of the 75 patients (10.7%) had an acquired psychiatric illness following surgical treatment. A mood disorder developed in three patients after surgery. No statistical difference emerged in preoperative psychiatric co-morbidity (no group difference; p=1.0) or in newly diagnosed postoperative psychiatric disease (group I vs. II, p=0.67; group I vs. III, p=1.0; and group II vs. III, p=0.67) within the three surgical pathology groups. CONCLUSION: This study indicates that the presence of psychiatric disease before and after surgery for intractable partial epilepsy, predominantly of temporal lobe origin, was independent of the pathological findings.

Resective reoperation for failed epilepsy surgery: seizure outcome in 64 patients.

OBJECTIVE: To determine the surgical outcome and factors of predictive value in patients undergoing reoperation for intractable partial epilepsy. METHODS: The authors retrospectively studied the operative outcome in 64 consecutive patients who underwent reoperation for intractable partial epilepsy. Demographic data, results of comprehensive preoperative evaluations, and the seizure and neurologic outcome after reoperation were determined. All patients were followed a minimum of 1 year subsequent to their last operative procedure. RESULTS: Fifty-three patients had two surgeries, and 11 patients had three or more operations. The first surgery involved a lesionectomy (n = 33), "nonlesional" temporal lobe resection (n = 28), and a "nonlesional" extratemporal resection (n = 3). The mean duration between the first and second procedure was 5.5 years. Fifty-five patients underwent an intralobar reoperation, whereas nine had a resection of a different lobe. After reoperation, 25 patients (39%) were free of seizure, 6 patients (9%) had rare seizures, 12 patients (19%) had a worthwhile improvement, and 21 patients (33%) failed to respond to surgery. Predictors of seizure-free outcome were age at seizure onset >15 years (p = 0.01), duration of epilepsy < or =5 years at the time of initial surgery (p = 0.03), and focal interictal discharges in scalp EEG (p = 0.03). Using a logistic regression model, two significant predictors emerged: duration of epilepsy < or =5 years (odds ratio, 3.18; p = 0.04) and preoperative focal interictal discharge (odds ratio, 4.45; p = 0.02). Complications of reoperation included visual field deficits (n = 9), wound infection (n = 2), subdural hematoma (n = 1), and hemiparesis (n = 1). CONCLUSION: Reoperation may be an appropriate alternative form of treatment for selected patients with intractable partial epilepsy who fail to respond to initial surgery.

Peri-ictal SPECT and surgical treatment for intractable epilepsy related to schizencephaly.

The authors evaluated four patients with schizencephaly who underwent subtraction ictal SPECT coregistered to MRI (SISCOM) prior to epilepsy surgery. Three patients had a SISCOM alteration that was concordant with the epileptic brain tissue. Two of these patients were rendered seizure-free and one individual experienced a significant reduction in seizures. The patient with an indeterminate SISCOM had an unfavorable outcome. SISCOM is useful in evaluating patients with schizencephaly for epilepsy surgery.

Injuries due to seizures in persons with epilepsy: a population-based study.

BACKGROUND: Previous studies of injuries due to epileptic seizures predominantly involved patients with intractable epilepsy. These studies may have overestimated the risk of injuries in persons with epilepsy. METHODS: Patients consisted of 247 Rochester, MN, residents who were diagnosed with epilepsy between 1975 and 1984. Seizure-related injuries were defined as any injury, other than orolingual trauma, resulting from a seizure, sufficient for the patient to seek medical attention or for injury occurrence to be determined during the course of medical care. To identify risk factors for injury, characteristics of patients with seizure-related injury were compared with those without injury. RESULTS: During a total of 2,714 patient-years of follow-up, 62 seizure-related injuries were identified in 39 patients (16%, one injury in every 44 person-years). Most injuries involved cranial soft tissue contusions or lacerations (79%). The majority of seizure-related injuries (82%) occurred during generalized convulsive seizures. Univariate analyses identified five potential risk factors for seizure-related injury: greater number of antiepileptic drugs used, less independent living situation, higher Rankin score, history of generalized convulsive seizures or drop attacks, and higher seizure frequency score. Seizure frequency, however, was the only significant risk factor identified by multivariate analysis (p < 0.001; relative risk, 1.33). CONCLUSIONS: This population-based study shows that seizure-related injuries are infrequent and generally of minor severity. In most epilepsy patients, excessive restriction of daily activities to avoid injury is unnecessary. Effective seizure control reliably reduces the risk of seizure-related injuries.

Advances in computer-assisted single-photon emission computed tomography (SPECT) for epilepsy surgery in children.

Epilepsy surgery has emerged as an important option in the treatment of children with epilepsy that is refractory to antiepileptic drug management. The cornerstone of successful surgery is accurate localization of the brain region of seizure onset. Traditional techniques of seizure onset localization, e.g. surface electroencephalography (EEG) recording and magnetic resonance imaging (MRI), allow accurate localization in a significant number of patients. When the focus of seizure onset is not apparent from these non-invasive techniques, other methods of localization, e.g. intracranial EEG recording, may be needed before resection of the focus. Single-photon emission computed tomography (SPECT) is a nuclear medicine blood-flow technique that has been used to identify a region of epileptogenic brain associated with low blood flow in the resting state (interictal SPECT) or increased blood flow at the time of seizure activity (ictal SPECT). This report describes the validation and utility of a computer-assisted method of subtracting the interictal from the ictal SPECT scans and co-registering the difference image on the MRI. This method, called subtraction ictal SPECT co-registered on MRI (SISCOM), is used in guiding the location and the extent of intracranial electrode implantation, or in obviating the need for the implantation in some cases.

Comparative diagnostic utility of 1H MRS and DWI in evaluation of temporal lobe epilepsy.

OBJECTIVE: To compare the ability of diffusion-weighted MRI (DWI) and (1)H MRS to lateralize to the temporal lobe of seizure onset and to predict postoperative seizure control in patients with temporal lobe epilepsy (TLE). METHODS: Forty TLE patients who subsequently underwent epilepsy surgery and 20 normal subjects were studied with (1)H MRS and DWI. Medial parietal and temporal lobe N-acetylaspartate (NAA)/creatine (Cr) ratios and hippocampal and temporal stem apparent diffusion coefficients (ADC) were obtained. Lateralization to either temporal lobe with each MR measurement was based on the threshold values derived from +/-1-SD right/left ratios of normal subjects. RESULTS: Temporal lobe NAA/Cr lateralized to the operated temporal lobe in 18 of 40 (45%), hippocampal ADC in 32 of 40 (80%), and temporal stem ADC in 26 of 40 (65%) patients. Almost all of the cases that lateralized to the surgical side with NAA/Cr ratios (94%) had an excellent postoperative seizure control (p = 0.01). Lateralization to the side of surgery was not associated with surgical outcome with hippocampal and temporal stem ADC (p > 0.05). CONCLUSION: (1)H MRS and DWI complement each other in the clinical setting. DWI more frequently lateralized to the operated side, and (1)HMRS was a better predictor of postoperative seizure control.

Rapidly progressive hippocampal atrophy: evidence for a seizure-induced mechanism.

Hippocampal formation atrophy (HFA) developed in an adult, who did not have epilepsy previously, after the occurrence of new-onset partial seizures from acute thrombosis of an ipsilateral parietal venous angioma. There was no evidence of hippocampal injury, and the patient had only one brief, generalized tonic-clonic seizure. Although HFA progressed rapidly over 5.5 months, the partial seizures did not become prolonged or secondarily generalized. Evidence from the patient indicates that partial seizure activity can cause rapid and progressive hippocampal atrophy.

Significance of epileptiform discharges in patients without epilepsy in the community.

PURPOSE: To determine the frequency of recording epileptiform discharges (EDs) in patients without epilepsy in the community and to assess their risk of seizure disorders subsequently developing. METHODS: We identified all outpatient and inpatient EEGs that were recorded in persons residing in Rochester, Minnesota, from 1979 to 1988. Patients with a history of unprovoked seizure disorders before the index EEG were excluded. Periodic lateralized EDs (PLEDs) were not evaluated, because of their well-established association with seizure disorders. RESULTS: Five hundred twenty-one patients in the community had no history of unprovoked seizure disorders before their EEG. Sixty-four (12.3%) patients had EDs; neither isolated unprovoked seizure nor epilepsy developed during 230.8 person-years of follow-up. Forty-seven (73.4%) of the 64 patients had acute or progressive cerebral disorders when EEG detected EDs. Seizures that were acutely provoked by the underlying disorder (enlarging brain tumor, cerebral infarct, or bilateral subdural hematoma, in one patient each) subsequently developed in three (6.3%) of the 64 patients. Seizures of any type did not develop in the 17 patients without acute or progressive cerebral disorders. CONCLUSIONS: In a community setting, EDs are sometimes observed in patients without epilepsy. However, nearly three fourths have underlying acute or progressive cerebral disorders. Acutely provoked seizures may develop in a small proportion of patients. Although none of our patients developed isolated unprovoked seizures or epilepsy, a longer period of follow-up is needed to determine their risks relative to the general population.

The relationship between quantitative T2 relaxometry and memory in nonlesional temporal lobe epilepsy.

PURPOSE: We investigated the relationship between preoperative quantitative magnetic resonance imaging (MRI) T2 relaxometry and volumetry of the hippocampi and pre- and postoperative verbal memory in temporal lobectomy patients who had nonlesional temporal lobe epilepsy. METHODS: Pre- and postoperative memory data based on the Logical Memory (LM) subtest of the Wechsler Memory Scale-Revised (WMS-R) and the 30-min delayed recall trial of the Rey Auditory Verbal Learning Test (AVLT) were obtained from 26 left and 15 right temporal lobectomy patients. Coronal MRI T2 maps were generated for these 41 temporal lobectomy patients as well as 61 control patients. Hippocampal T2 relaxation times and hippocampal volumes, converted to z scores using control group data, were correlated with neuropsychological performance in the patients. RESULTS: In left temporal lobe-onset patients, high T2 in the left hippocampal body predicted higher LM performance after surgery. Asymmetrically high T2 in the left hippocampal body (i.e., the right-minus-left difference), compared with the right hippocampal body, also predicted higher LM performance after surgery. In right temporal lobe-onset patients, high T2 in the left hippocampal body predicted relatively lower AVLT performance after surgery. Multiple regression analysis in left temporal-onset patients revealed that high T2 in the left hippocampal body together with higher preoperative LM performance predict higher postoperative LM performance. CONCLUSIONS: Our findings suggest that elevated (i.e., abnormal) hippocampal T2 signal is associated with memory ability (or hippocampal functional capacity) independent of MRI-determined hippocampal atrophy. Therefore, our findings support the use of quantitative T2 relaxometry as an independent predictor of verbal memory outcome in both left and right TLE patients who are candidates for temporal lobectomy.

Video-EEG monitoring in patients with hippocampal atrophy.

OBJECTIVES: To analyze the value of ictal EEG recordings in patients with unilateral magnetic resonance imaging (MRI)-identified hippocampal atrophy and concordant interictal epileptiform discharges (IEDs). MATERIAL AND METHODS: The ictal EEG patterns in 84 patients with pharmaco resistant epilepsy undergoing an anterior temporal lobectomy between 1992 and 1995 were reviewed. The concordance between the ictal EEG and MRI and the IEDs was examined. RESULTS: Two-hundred-and-thirty seizures (76.4%) were concordant and 11 seizures (3.7%) were discordant with the atrophic temporal lobe. Sixty seizures (19.9%) were indeterminate in localization. Sixty-three of the 69 patients (91.3%) with confirmatory and 14 of the 15 patients (93%) with non-confirmatory ictal EEG recordings, respectively, experienced an excellent operative outcome (P=0.629, Fisher's exact test). CONCLUSIONS: Patients with unilateral hippocampal atrophy and concordant IEDs are excellent surgical candidates even when video-EEG monitoring shows discordant or non-localizing seizures.

Subtraction peri-ictal SPECT is predictive of extratemporal epilepsy surgery outcome.

OBJECTIVES: To determine whether localization of extratemporal epilepsy with subtraction ictal SPECT coregistered with MRI (SISCOM) is predictive of outcome after resective epilepsy surgery, whether SISCOM images provide prognostically important information compared with standard tests, and whether blood flow change on SISCOM images is useful in determining site and extent of excision required. BACKGROUND: The value of SISCOM in predicting surgical outcome for extratemporal epilepsy is unknown, especially if MRI findings are nonlocalizing. METHODS: SISCOM images in 36 consecutive patients were classified by blinded reviewers as "localizing and concordant with site of surgery," "localizing but nonconcordant with site of surgery," or "nonlocalizing." SISCOM images were coregistered with postoperative MRI, and reviewers visually determined whether cerebral cortex underlying the SISCOM focus had been completely resected, partially resected, or not resected. RESULTS: Twenty-four patients (66.7%) had localizing SISCOM, including 13 (76.5%) of those without a focal MRI lesion. Eleven of 19 patients (57.9%) with localizing SISCOM concordant with the surgical site, compared with 3 of 17 (17.6%) with nonlocalizing or nonconcordant SISCOM, had an excellent outcome (p < 0.05). With logistic regression analysis, SISCOM findings were predictive of postsurgical outcome, independently of MRI or scalp ictal EEG findings (p < 0.05). The extent of resection of the cortical region of the SISCOM focus was significantly associated with the rate of excellent outcome (100% with complete resection, 60% with partial resection, and 20% with nonresection, p < 0.05). CONCLUSION: SISCOM images may be useful in guiding the location and extent of resection in extratemporal epilepsy surgery.

Postictal central apnea as a cause of SUDEP: evidence from near-SUDEP incident.

While undergoing video-EEG monitoring, a 20-year-old woman had a 56-second convulsive seizure, after which she developed persistent apnea. The rhythm of the electrocardiogram complexes was unimpaired for approximately 10 seconds, after which it gradually and progressively slowed until it stopped 57 seconds later. Evaluation after successful cardio-respiratory resuscitation showed no evidence of airway obstruction or pulmonary edema. The patient had a previous cardio-respiratory arrest after a complex partial seizure without secondary generalization. Although epileptic seizures are known to be potentially arrhythmogenic to the heart, our observations strongly suggest that one probable mechanism of sudden unexplained death in epilepsy is the marked central suppression of respiratory activity after seizures.

Significance of cerebellar atrophy in intractable temporal lobe epilepsy: a quantitative MRI study.

PURPOSE: To determine the incidence of cerebellar atrophy (CA) in patients with intractable temporal lobe epilepsy, whether any clinical factors are significantly associated with CA, whether CA is unilateral or asymmetric and whether this feature has any relationship to the side of epileptogenicity, and whether the presence of CA is related to epilepsy surgery outcome. METHODS: We developed a magnetic resonance imaging method of measuring the presurgical volumes of the cerebellar hemispheres of 185 patients who underwent temporal lobectomy for intractable epilepsy and of 80 control subjects. In addition, cerebellar volumes were normalized to the total brain volumes. CA was determined as being present when the measured volume was smaller than two standard deviations from the mean value found in control subjects. RESULTS: Both absolute and normalized cerebellar volumes were found to be significantly reduced in the epilepsy patients compared with the control subjects. Without normalization of the cerebellar volumes, CA was present in 25.9% of the epilepsy patients; with normalization, it was present in only 16.2%. The atrophy was symmetric between the cerebellar hemispheres, and there was no significant difference in volume between the hemisphere ipsilateral and the hemisphere contralateral to the side of the temporal lobectomy. The duration of epilepsy was significantly longer and the age at onset of epilepsy was younger in patients with CA than in those without CA. The presence of CA was not associated with the outcome of temporal lobectomy. CONCLUSIONS: CA is symmetric and common in patients with intractable temporal lobe epilepsy. However, the results suggest that the atrophy in one third of patients with CA also proportionately affects the cerebral hemispheres. The duration of epilepsy and the age at onset of epilepsy are associated with the occurrence of CA. Seizure control after temporal lobectomy is not influenced by the presence of CA.

Integration of EEG, MRI, and SPECT in localizing the seizure focus for epilepsy surgery.

Several modalities are now available for detecting the structural and the functional abnormalities of a seizure focus. This article discusses the principles and techniques that can be used to integrate the data derived from different test modalities in delineating the seizure focus in epilepsy surgery candidates. An approach in integrating EEG, MRI, and SPECT abnormalities is described to demonstrate how the spatial relationships among them can be precisely determined by coregistering images of the abnormalities on the MRI. The recently developed technique of subtraction ictal SPECT coregistered to MRI (SISCOM) can reveal a discrete hyperperfusion focus with its relationship to the cerebral anatomy. The SISCOM focus can also serve as a target for intracranial electrode implantation and for subsequent surgical resection. This can be achieved by using a computer-based system of relating the image space to the surgical field. The limitations of each test in localizing the surgical seizure focus must be recognized when the value of each test is interpreted relative to those of other tests. In many patients, not all tests will show localizing abnormalities, and the foci determined by different tests may be incongruent. When the location of the focus is not compatible with the possible origin of the patient's habitual seizures, further evaluation with other tests, including intracranial EEG recordings, is necessary. The decision in determining which tests and how many to employ for localizing the surgical focus must be individualized for each patient.

Factors predictive of the outcome of frontal lobe epilepsy surgery.

PURPOSE: To identify factors that predict the outcome in seizure control after frontal lobe epilepsy surgery (FLES). FLES is the second most frequent type of epilepsy surgery, but the results are generally not as good as those after anterior temporal lobectomy. METHODS: Our cohort consisted of 68 consecutive patients whose first epilepsy surgery involving the frontal lobe occurred between 1987 and 1994. Clinical history and results of imaging and electroencephalographic studies were reviewed in detail. Excellent outcome was defined as being seizure free or having only nondisabling seizures at last follow up. RESULTS: Forty of the 68 patients (58.8%) had an excellent outcome; none of the patients with a history of childhood febrile seizures had an excellent outcome, whereas outcome was excellent in 63% of those without that history (p

Subtraction ictal SPECT coregistered to MRI for seizure focus localization in partial epilepsy.

Peri-ictal single-photon emission computed tomography (SPECT) of the brain is increasingly used in localizing the seizure focus in presurgical evaluation of patients with partial epilepsy. However, traditional side-by-side visual interpretation of ictal and interictal SPECT films is hampered by differences in slice location and tracer activity. Precise correlation of the seizure focus with a high-quality image of the underlying brain anatomy can improve the physician's understanding of seizure neurophysiology and assist in surgical planning. Computer-based methods have been developed for aligning, normalizing, and subtracting digital ictal and interictal SPECT images of the patient's brain to produce a map of the blood flow changes occurring between the seizure and resting states. These maps are then aligned with a high-resolution magnetic resonance image (MRI) of the patient's brain anatomy and fused to identify anatomical regions involved in the seizure. The purpose of this article is to review the technical components and clinical implementation of subtraction ictal SPECT, as well as to discuss recent technological advances that could extend and improve the diagnostic and localizing capacity of this method.

The EEG evaluation of single photon emission computed tomography abnormalities in epilepsy.

Single photon emission computed tomography (SPECT) has increasingly been used as a diagnostic procedure for localizing epileptic seizure foci and as a research tool for investigating the physiologic mechanisms underlying seizure activity. With increasing use of SPECT in localizing the seizure focus for epilepsy surgery, there arises a need to critically assess its current role in the evaluation of patients for epilepsy surgery, especially as it relates to other clinical and laboratory data used in presurgical evaluation. Ictal EEG discharge has traditionally been used as the "gold standard" against which SPECT studies are compared in assessing the latter's localizing value. However, this practice presents a major challenge because SPECT studies are often reserved for patients with nonlocalizing EEG or magnetic resonance imaging findings. Nonetheless, SPECT studies in evaluation for epilepsy surgery should always be performed with the knowledge of the patient's EEG activity preceding, during, and after the injection of the radiotracer. The advent of techniques such as subtraction SPECT with co-registration on magnetic resonance imaging (SISCOM) and computer image-guided surgery has great potential in enhancing the clinical electrophysiologic evaluation of SPECT-detected abnormalities in epilepsy. These techniques permit accurate spatial correlation between intracranial EEG activity and SPECT perfusion patterns. The techniques can also be used to evaluate the effect of the extent of EEG focus resection compared with that of SISCOM focus resection to determine which has more prognostic importance in postsurgical control of seizures. Both animal and human studies are warranted to advance our knowledge of the electrophysiology associated with the various SPECT perfusion patterns.