Susan S. Spencer

Neural networks in human epilepsy: evidence of and implications for treatment.

A considerable amount of compelling evidence exists, predominantly from animal models and experimental paradigms, for the existence of specific cortical and subcortical networks in the genesis and expression of partialand generalized-onset seizures (1–13). My goal is to present the concept of human epilepsy as a disorder of large neural networks and to support through several lines of reasoning how applicable the observations from experimental models are to localization-related seizures in the human disorder. I do not attempt to define specifically every possible operational human network or even all the limits or components of those that I do address, but I hope to show in a compelling way that the evidence we already have is not consistent with any other explanation. This is a new way of understanding, diagnosing, and potentially treating the various forms of human epilepsy. In this context, I consider a network to be a functionally and anatomically connected, bilaterally represented, set of cortical and subcortical brain structures and regions in which activity in any one part affects activity in all the others. The essential operational component of this definition is the observation that vulnerability to seizure activity in any one part of the network is influenced by activity everywhere else in the network, and that the network as a whole is responsible for the clinical and electrographic phenomena that we associate with human seizures. Implicit in this idea is that the seizures may entrain this large neural network from any given part, such that it becomes irrelevant to discuss the “onset” of seizures in any specific part of the network. In other words, the electrical hyperexcitability associated with seizure activity reverberates within the neural structures of the network, which operate together and inextricably to culminate in the eventual expression of seizures. A singular concept is the distinction between the anatomic structures involved in seizure propagation, and those belonging to the neural network that underlies a specific patient’s epilepsy. The network structures are connected functionally and structurally; they are essential to the development of the seizure and thus the existence and maintenance of the epileptic disorder. Independently, seizures propagate in a variably extensive way that might involve any region or neural structure with anatomic connections to the primary seizure network; seizures can propagate to many more regions than those that are involved in the network. Important corollaries that derive from these ideas are that interruption of the network, in a structural sense, or modification of network activity by electrical, biochemical, or metabolic influences in any part of the network will alter seizure expression or its occurrence. The corollaries have the greatest implications for treatment, as we will see later. Based on extensive experience with a great number and diversity of human epilepsy patients with intractable seizures, I describe and support the evidence for three specific large human epilepsy networks. Many others are likely, but the data are not so extensive. The first is the network associated with the most common human intractable epilepsy, and the one about which we have the most information: the medial temporal/limbic network. The medial temporal/limbic network is bilateral, cortical, and subcortical, and includes the hippocampi, the amygdalae, the entorhinal cortices, lateral temporal neocortices, and extratemporal components of the medial thalamus and the inferior frontal lobes. The other two networks are less commonly identified, even in their component parts: the medial occipital/lateral temporal network and the superior parietal/medial frontal network. Two additional networks, for which evidence is highly suggestive, but which I do not discuss in detail, include the bifrontal/ pontine/subthalamic network and the parietal/medial temporal network. The lines of evidence that support the existence and importance of these networks in the genesis of human epilepsy are clinical observations, intracranial EEG, functional neuroimaging, anatomic observations, and the response of seizures to specific invasive treatments. Accepted December 7, 2001. Address correspondence and reprint requests to Dr. S.S. Spencer at Department of Neurology, Yale University School of Medicine, P.O. Box 208018, New Haven, CT 06520-8018, U.S.A. E-mail: susan.spencer@yale.edu Epilepsia, 43(3):219–227, 2002 Blackwell Publishing, Inc.

Outcomes of epilepsy surgery in adults and children

Surgery is widely accepted as an effective therapy for selected individuals with medically refractory epilepsy. Numerous studies in the past 20 years have reported seizure freedom for at least 1 year in 53-84% of patients after anteromesial temporal lobe resections for mesial temporal lobe sclerosis, in 66-100% of patients with dual pathology, in 36-76% of patients with localised neocortical epilepsy, and in 43-79% of patients after hemispherectomies. Reported rates for non-resective surgery have been less impressive in terms of seizure freedom; however, the benefit is more apparent when reported in terms of significant seizure reductions. In this Review, we consider the outcomes of surgery in adults and children with epilepsy and review studies of neurological and cognitive sequelae, psychiatric and behavioural outcomes, and overall health-related quality of life.

Entorhinal-Hippocampal Interactions in Medial Temporal Lobe Epilepsy

Summary: Experimental studies suggest important interactions between hippocampus and entorhinal cerebral cortex in generation of temporal lobe seizure activity. We studied electrical expression of spontaneous temporallobe ictal activity in hippocampus and entorhinal cortex in 9 medically refractory epileptic patients who had intracranial depth and subdural electrodes implanted during surgical evaluation. All 9 patients subsequently under‐went anteromedial temporal lobectomy with hippocam‐pectomy, all had >50% decrease in neuronal cell density in hippocampal CA1 and CA3, and all had good to excellent seizure outcome after operation. Two to 10 spontaneous seizures were analyzed per patient (total 41 seizures). Nine patients had variable onset of seizure activity recorded in hippocampus, entorhinal cortex, or both simultaneously. Low‐voltage fast activity was observed in either location and varied among seizures in an individual patient. Periodic preictal spikes, when present, were often synchronous in both locations, but were noted independently only in hippocampus. Our data suggest that preictal spikes and low‐voltage fast seizure discharges have anatomically distinct origins, and that some syndromes of medial temporal lobe epilepsy involve interactions between entorhinal and hippocampal regions that act together to produce and propagate the seizures in such patients.

Access to the Posterior Medial Temporal Lobe Structures in the Surgical Treatment of Temporal Lobe Epilepsy

The authors describe a surgical technique that allows access to the posterior temporal horn of the lateral ventricle with preservation of the most functional lateral temporal cortex. Development of the technique was stimulated by the need to resect posteromedial temporal lobe structures in patients with intractable complex partial epilepsy and well-identified unilateral posterior hippocampal foci. This technique has also been of value in the resection of some lateral ventricular and posteromedial temporal lobe masses. The operation consists of three steps. No more than 4.5 cm of the anterolateral temporal lobe is removed en bloc such that the most anterior aspect of the temporal horn is entered. An incision is carried from the floor of the temporal horn through the inferior longitudinal fasciculus to the middle fossa dura mater and posteriorally into the lateral ventricular atrium. The lateral temporal cortex and white matter are then elevated with a self-retaining retractor. This exposes the posteromedial temporal horn or intraaxial mass for excision or allows en bloc resection of the entire hippocampus and medial temporal lobe structures while preserving the functional association areas of the lateral temporal cortex, including speech and visual spatial function.

The Relative Contributions of MRI, SPECT, and PET Imaging in Epilepsy

Summary: Functional and structural neuroimaging techniques are increasingly indispensable in the evaluation of epileptic patients for localization of the epileptic area as well as for understanding pathophysiology, propagation, and neurochemical correlates of chronic epilepsy. Although interictal single photon emission computed tomography (SPECT) imaging of cerebral blood flow is only moderately sensitive, ictal SPECT markedly improves yield. Positron emission tomography (PET) imaging of interictal cerebral metabolism is more sensitive than measurement of blood flow in temporal lobe epilepsy. Furthermore, PET has greater spatial resolution and versatility in that multiple tracers can image various aspects of cerebral function. Interpretation of all types of functional imaging studies is difficult and requires knowledge of time of most recent seizure activity and structural correlates. Only magnetic resonance imaging (MRI) can image the structural changes associated with the underlying epileptic process, and quantitative evidence of hippocampal volume loss has been highly correlated with seizure onset in medial temporal structures. Improved resolution and interpretation have made quantitative MRI more sensitive in temporal lobe epilepsy, as judged by pathology. When judged by electroencephalography (EEG), ictal SPECT and interictal PET have the highest sensitivity and specificity for temporal lobe epilepsy; these neuroimaging techniques have lower sensitivity and higher specificity for extratemporal EEG abnormalities. Regardless of the presence of structural abnormalities, functional imaging by PET or SPECT provides complementary information. Ideally these techniques should be used and interpreted together to improve the localization and understanding of epileptic brain.

Predicting long-term seizure outcome after resective epilepsy surgery The Multicenter Study

Background: In a seven-center prospective observational study of resective epilepsy surgery, the authors examined probability and predictors of entering 2-year remission and the risk of subsequent relapse. Methods: Patients aged 12 years and over were enrolled at time of referral for epilepsy surgery, and underwent standardized evaluation, treatment, and follow-up procedures. The authors defined seizure remission as 2 years completely seizure-free after hospital discharge with or without auras, and relapse as any seizures after 2-year remission. The authors examined type of surgery, seizure, clinical and demographic variables, and localization study results with respect to prediction of seizure remission or relapse, using χ2 and proportional hazards analysis. Results: Of 396 operated patients, 339 were followed over 2 years, and 223 (66%) experienced 2-year remission, not significantly different between medial temporal (68%) and neocortical (50%) resections. In multivariable models, only absence of generalized tonic-clonic seizures and presence of hippocampal atrophy were significantly and independently associated with remission, and only in the medial temporal resection group. Fifty-five patients relapsed after 2-year remission, again not significantly different between medial temporal (25%) and neocortical (19%) resections. Only delay to remission predicted relapse, and only in medial temporal patients. Conclusion: Hippocampal atrophy and a history of absence of generalized tonic clonic seizures were the sole predictors of 2-year remission, and only for medial temporal resections.

Combined depth and subdural electrode investigation in uncontrolled epilepsy

We used both depth and subdural electrodes to obtain localization of the seizure focus in 47 medically refractory epileptic patients. Seizures were localized in 33 patients. Onset was consistently localized by the depth electrodes in 23 patients, was variable or simultaneous in depth and subdural electrodes in 6 (in the same lobe), and was consistently localized to subdural electrodes in 4. All patients localized with subdural electrodes were extratemporal and 3 of the 4 had lesions on imaging studies which helped guide location of electrode placement. Eighty-seven percent of temporal lobe seizures began in hippocampus (recorded by the depth electrode), and 80% were eventually propagated to the ipsilateral temporal neocortex (recorded by the subdural electrode). In 8 patients with bilateral temporal depth and subdural recording, seizures never spread to the contralateral neocortex before the ipsilateral neocortex. Subdural electrodes were 20% less sensitive than depth electrodes in detection of seizures beginning in hippocampus but were accurate when lateralized. Variable or simultaneous unilateral neocortical versus hippocampal temporal lobe seizure onset, determined by the combined study, was significantly correlated with less favorable seizure control after anteromedial temporal lobectomy and hippocampectomy.

How long does it take for partial epilepsy to become intractable

Background: Much remains unknown about the natural history of intractable localization-related epilepsy, including how long it typically takes before intractability becomes evident. This information could guide the design of future studies, resolve certain discrepancies in the literature, and provide more accurate information about long-term prognosis. Methods: Individuals evaluated for resective surgery for refractory localization-related epilepsy were prospectively identified at the time of initial surgical evaluation at seven surgical centers (between 1996 and 2001). The latency time between onset of epilepsy and failure of second medication and history of remission (≥1 year seizure-free) before surgical evaluation were examined with respect to age at onset, hippocampal atrophy, febrile seizures, and surgical site. Results: In the 333 patients included in the analysis, latency time was 9.1 years (range 0 to 48) and 26% reported a prior remission before surgery. A prior remission of ≥5 years was reported by 8.5% of study participants. Younger age at onset was strongly associated with longer latency time (p < 0.0001) and higher probability of past remission (p < 0.0001). In multivariable analyses, age at onset remained as the most important explanatory variable of both latency time and prior remission. Conclusions: A substantial proportion of localization-related epilepsy may not become clearly intractable for many years after onset. This is especially true of epilepsy of childhood and early adolescent onset. If prospective studies confirm these findings and the underlying mechanisms behind these associations become understood, this raises the possibility of considering interventions that might interrupt such a process and some day prevent some forms of epilepsy from becoming intractable.

Initial outcomes in the Multicenter Study of Epilepsy Surgery

Objective: To obtain prospective data regarding seizures, anxiety, depression, and quality of life (QOL) outcomes after resective epilepsy surgery. Methods: The authors characterized resective epilepsy surgery patients prospectively at yearly intervals for seizure outcome, QOL, anxiety, and depression, using standardized instruments and patient interviews. Results: Of 396 patients who underwent resective surgical procedures, 355 were followed for at least 1 year. Of these, 75% achieved a 1-year remission at some time during follow-up; patients with medial temporal (77%) were more likely than neocortical resections (56%) to achieve remission (p = 0.01). Relapse occurred in 59 (22%) patients who remitted, more often in medial temporal (24%) than neocortical (4%) resected patients (p = 0.02). QOL, anxiety, and depression all improved dramatically within 3 months after surgery (p < 0.0001), with no significant difference based on seizure outcome. After 3 months, QOL in seizure-free patients further improved gradually, and patients with seizures showed gradual declines. By 12 and 24 months, overall QOL and its epilepsy-targeted and physical health domains were significantly different in the two outcome groups. (Anxiety and depression scores also gradually diverged, with improvements in seizure-free and declines in continued seizure groups, but differences were not significant.) Conclusion: Resective surgery for treatment of epilepsy significantly reduces seizures, most strikingly after medial temporal resection (77% 1 year remission) compared to neocortical resection (56% 1 year remission). Resective epilepsy surgery has a gradual but lasting effect on QOL, but minimal effects on anxiety and depression. Longer follow-up will be essential to determine ultimate seizure, QOL, and psychiatric outcomes of epilepsy surgery.

Morphological Patterns of Seizures Recorded Intracranially

Summary: We analyzed the frequency and morphological characteristics of the initial EEG manifestations of spontaneous seizures recorded from depth and subdural electrodes in 26patients for whom pathological analysis of the area of seizure onset was available after resective surgery. Pathological features considered to be positive findings included well‐defined structural lesions (hamartoma, neoplasm) or strictly defined mesial temporal sclerosis. Seizure onset was characterized by the frequency of the rhythmic discharge >2 Hz in the first second and by the presence or absence of periodic low‐frequency spikes (<2 Hz) preceding this stable change in background frequency. These features were correlated with the presence or absence of pathologic abnormalities in temporal and extratemporal locations. Although all patterns and frequencies of seizure onset were recorded in both medial temporal and extratemporal locations, medial temporal seizure onset was significantly more likely to have high frequency (>13 Hz, p < 0.05) and no periodic spikes before seizure onset tended to periodic spikes prior to the seizure when it was associated with medial temporal sclerosis compared to when it was not. Extratemporal seizure onset associated with abnormal pathological substrate was significantly more likely to have a lower frequency (<13 Hz, p < 0.05) and no periodic spikes before seizure onset (p < 0.00001) than extratemporal seizure onset recorded from areas without pathological findings. Variability of seizure onset frequency was a characteristic of temporal, but not extra temporal, seizures (p < 0.01). The existence of such differences between seizures of temporal and extratemporal origin suggests that the underlying anatomy may in part determine these patterns, and that interpretation of EEG records of seizures beginning in different cerebral locations requires recognition of these differences.