Metabolic networks in epilepsy by MR spectroscopic imaging.

OBJECTIVE: The concept of an epileptic network has long been suggested from both animal and human studies of epilepsy. Based on the common observation that the MR spectroscopic imaging measure of NAA/Cr is sensitive to neuronal function and injury, we use this parameter to assess for the presence of a metabolic network in mesial temporal lobe epilepsy (MTLE) patients. MATERIALS AND METHODS: A multivariate factor analysis is performed with controls and MTLE patients, using NAA/Cr measures from 12 loci: the bilateral hippocampi, thalami, basal ganglia, and insula. The factor analysis determines which and to what extent these loci are metabolically covarying. RESULTS: We extract two independent factors that explain the data's variability in control and MTLE patients. In controls, these factors characterize a 'thalamic' and 'dominant subcortical' function. The MTLE patients also exhibit a 'thalamic' factor, in addition to a second factor involving the ipsilateral insula and bilateral basal ganglia. CONCLUSIONS: These data suggest that MTLE patients demonstrate a metabolic network that involves the thalami, also seen in controls. The MTLE patients also display a second set of metabolically covarying regions that may be a manifestation of the epileptic network that characterizes limbic seizure propagation.

Long-term association between seizure outcome and depression after resective epilepsy surgery.

OBJECTIVE: This study explored the association between long-term epilepsy surgery outcome and changes in depressive symptoms. METHODS: Adults were enrolled between 1996 and 2001 in a multicenter prospective study to evaluate outcomes of resective epilepsy surgery. The extent of depressive symptoms and depression case status (none, mild, or moderate/severe) were assessed using the Beck Depression Inventory (BDI) preoperatively and 3, 12, 24, 48, and 60 months postoperatively. A mixed-model repeated-measures analysis was performed, adjusting for covariates of seizure location, gender, age, race, education, and seizure control. RESULTS: Of the total 373 subjects, 256 were evaluated at baseline and 5 years after surgery. At baseline, 164 (64.1%) were not depressed, 34 (13.3%) were mildly depressed, and 58 (22.7%) had moderate to severe depression. After 5 years, 198 (77.3%) were not depressed, 20 (7.8%) were mildly depressed, and 38 (14.8%) were moderately to severely depressed. Five years after surgery, the reduction in mean change from baseline in BDI score was greater in subjects with excellent seizure control than in the fair and poor seizure control groups (p = 0.0006 and p = 0.02 respectively). Those with good seizure control had a greater reduction in BDI score than the poor seizure control group (p = 0.02) and borderline significant reduction compared with the fair seizure control group (p = 0.055). CONCLUSION: Although study participants had initial improvement in depressive symptoms, on average, after resective surgery, only patients with good or excellent seizure control had sustained long-term improvement in mood.

Intracranial EEG power and metabolism in human epilepsy.

EEG power and high frequency activity in the seizure onset zone has been increasingly considered for its relationship with seizures in animal and human studies of epilepsy. We examine the relationship between quantitative EEG measures and metabolic imaging in epilepsy patients undergoing intracranial EEG (icEEG) analysis for seizure localization. Patients with mesial temporal lobe epilepsy (MTLE) and neocortical epilepsy (NE) were studied. Metabolic imaging was performed with MR spectroscopic imaging using N-acetyl aspartate (NAA) and creatine (Cr). All data were acquired from the mesial temporal lobe such that a direct comparison of the same anatomical regions between the two groups could be performed. While no difference was seen in the total power recorded from the mesial temporal lobe, the MTLE group had significantly greater power in the high frequency bands. There was a significant positive exponential relationship between total icEEG power with NAA/Cr in MTLE, R=+0.84 and p<0.001, which was not seen in NE. There was also a significant negative relationship between fractional gamma power with NAA/Cr in MTLE, R=-0.66 and p<0.02, also not seen in NE. These data argue that within the seizure onset zone, the tight correlation between total power and NAA/Cr suggests that total electrical output is powered by available mitochondrial function. These data are also consistent with the hypothesis that high frequency activity is an abnormal manifestation of tissue injury.

Clinical use of ictal SPECT in secondarily generalized tonic-clonic seizures.

Partial seizures produce increased cerebral blood flow in the region of seizure onset. These regional cerebral blood flow increases can be detected by single photon emission computed tomography (ictal SPECT), providing a useful clinical tool for seizure localization. However, when partial seizures secondarily generalize, there are often questions of interpretation since propagation of seizures could produce ambiguous results. Ictal SPECT from secondarily generalized seizures has not been thoroughly investigated. We analysed ictal SPECT from 59 secondarily generalized tonic-clonic seizures obtained during epilepsy surgery evaluation in 53 patients. Ictal versus baseline interictal SPECT difference analysis was performed using ISAS (http://spect.yale.edu). SPECT injection times were classified based on video/EEG review as either pre-generalization, during generalization or in the immediate post-ictal period. We found that in the pre-generalization and generalization phases, ictal SPECT showed significantly more regions of cerebral blood flow increases than in partial seizures without secondary generalization. This made identification of a single unambiguous region of seizure onset impossible 50% of the time with ictal SPECT in secondarily generalized seizures. However, cerebral blood flow increases on ictal SPECT correctly identified the hemisphere (left versus right) of seizure onset in 84% of cases. In addition, when a single unambiguous region of cerebral blood flow increase was seen on ictal SPECT, this was the correct localization 80% of the time. In agreement with findings from partial seizures without secondary generalization, cerebral blood flow increases in the post-ictal period and cerebral blood flow decreases during or following seizures were not useful for localizing seizure onset. Interestingly, however, cerebral blood flow hypoperfusion during the generalization phase (but not pre-generalization) was greater on the side opposite to seizure onset in 90% of patients. These findings suggest that, with appropriate cautious interpretation, ictal SPECT in secondarily generalized seizures can help localize the region of seizure onset.

Cortical and subcortical networks in human secondarily generalized tonic-clonic seizures.

Generalized tonic-clonic seizures are among the most dramatic physiological events in the nervous system. The brain regions involved during partial seizures with secondary generalization have not been thoroughly investigated in humans. We used single photon emission computed tomography (SPECT) to image cerebral blood flow (CBF) changes in 59 secondarily generalized seizures from 53 patients. Images were analysed using statistical parametric mapping to detect cortical and subcortical regions most commonly affected in three different time periods: (i) during the partial seizure phase prior to generalization; (ii) during the generalization period; and (iii) post-ictally. We found that in the pre-generalization period, there were focal CBF increases in the temporal lobe on group analysis, reflecting the most common region of partial seizure onset. During generalization, individual patients had focal CBF increases in variable regions of the cerebral cortex. Group analysis during generalization revealed that the most consistent increase occurred in the superior medial cerebellum, thalamus and basal ganglia. Post-ictally, there was a marked progressive CBF increase in the cerebellum which spread to involve the bilateral lateral cerebellar hemispheres, as well as CBF increases in the midbrain and basal ganglia. CBF decreases were seen in the fronto-parietal association cortex, precuneus and cingulate gyrus during and following seizures, similar to the 'default mode' regions reported previously to show decreased activity in seizures and in normal behavioural tasks. Analysis of patient behaviour during and following seizures showed impaired consciousness at the time of SPECT tracer injections. Correlation analysis across patients demonstrated that cerebellar CBF increases were related to increases in the upper brainstem and thalamus, and to decreases in the fronto-parietal association cortex. These results reveal a network of cortical and subcortical structures that are most consistently involved in secondarily generalized tonic-clonic seizures. Abnormal increased activity in subcortical structures (cerebellum, basal ganglia, brainstem and thalamus), along with decreased activity in the association cortex may be crucial for motor manifestations and for impaired consciousness in tonic-clonic seizures. Understanding the networks involved in generalized tonic-clonic seizures can provide insights into mechanisms of behavioural changes, and may elucidate targets for improved therapies.

Expectations prior to epilepsy surgery: an exploratory comparison of men and women.

Although the clinical goal of resective epilepsy surgery is seizure freedom, patients have a wide set of expectations for this invasive procedure. The goal of this study was to evaluate potential gender differences in expectations among patients undergoing resective epilepsy surgery. Ratings of the importance of 12 potential impacts ("expectations") of resective surgery were analyzed in a seven-center cohort study including 389 adults aged 16 and older who underwent resective epilepsy surgery. Men and women both ranked anticipated changes in driving and memory as the most important presurgical expectations. Women rated driving, physical activity limitations, and economic worries as less important, and fatigue and pregnancy concerns as more important than did men (p's< or =0.05). Exploratory factor analysis indicated a different pattern of associations among the 12 importance items for men and women. Whether gender differences in presurgical values are associated with outcomes needs exploration.

Temporal distributions of seizure occurrence from various epileptogenic regions.

OBJECTIVE: The aim of this study was to determine whether seizure occurrence in partial epilepsy is under the influence of circadian rhythms and rhythmic exogenous factors, and how this influence varies according to cortical brain region. For these ends, we determined and analyzed detailed temporal distributions of seizures arising from the frontal, parietal, occipital, neocortical temporal, and mesial temporal lobes. METHODS: We retrospectively analyzed intracranial EEG recordings from 131 consecutive adult subjects whose partial epilepsy was sufficiently localized for surgical resection. In all, 669 seizures were analyzed: 132 frontal, 77 parietal, 83 occipital, 217 mesial temporal, and 160 neocortical temporal. RESULTS: Seizure distribution was dependent on brain region (p < 10(-9)). Nonuniform seizure distributions were observed in the parietal (p < 10(-4)), occipital (p < 10(-7)), mesial temporal (p < 0.02), and neocortical temporal lobes (p < 0.04). Occipital and parietal seizures occurred in strong gaussian-like distributions, 180 degrees out of phase relative to each other; occipital seizure occurrence peaked between 16:00 and 19:00, whereas parietal seizures peaked between 4:00 and 7:00. Frontal lobe seizures followed a unimodal distribution, peaking between 4:00 and 7:00. Seizures from the mesial temporal lobe were distributed bimodally, with the primary peak in the late afternoon between 16:00 and 19:00 and secondary peak in the morning between 7:00 and 10:00. Neocortical temporal seizures peaked slightly before the primary peak observed in the mesial temporal lobe; however, these distributions did not differ significantly. CONCLUSIONS: Seizure occurrence in partial epilepsy is not random. Endogenous circadian rhythms and rhythmic exogenous factors likely play substantial roles in seizure occurrence. These roles vary considerably according to brain region. Frontal and parietal lobe seizures seem most likely to occur nocturnally, whereas occipital and temporal lobe seizures seem to have strong afternoon preferences.

Worsening of quality of life after epilepsy surgery: effect of seizures and memory decline.

BACKGROUND: Surgery for intractable temporal lobe epilepsy usually controls seizures and improves health-related quality of life (HRQOL), but some patients experience continued seizures, memory decline, or both. The relative impact of these unfavorable outcomes on HRQOL has not been described. METHODS: We studied seizure control, memory change, and HRQOL among 138 patients in the Multicenter Study of Epilepsy Surgery (MSES), an ongoing, prospective study of epilepsy surgery outcomes. Seizure remission at 2 years and 5 years was prospectively determined based upon regularly scheduled follow-up calls to study patients throughout the follow-up period. HRQOL was assessed annually using the Quality of Life in Epilepsy Inventory (QOLIE-89). Memory decline was determined by change in verbal delayed recall from baseline to the 2- or 5-year follow-up. RESULTS: HRQOL improved in patients who were in remission at the 2-year or 5-year follow-up, regardless of memory outcome. Among those not in remission at both 2 and 5 years (25/138, 18%), HRQOL remained stable when memory did not decline (14/138, 10%), but HRQOL declined when memory did decline (11/138, 8%). These 11 patients had baseline characteristics predictive of poor seizure or memory outcome. Declines were most apparent on HRQOL subscales assessing memory, role limitations, and limitations in work, driving, and social activities. CONCLUSIONS: After temporal resection, health-related quality of life (HRQOL) improves or remains stable in seizure-free patients despite memory decline, but HRQOL declines when persistent seizures are accompanied by memory decline. These results may be useful in presurgical counseling and identifying patients at risk for poor psychosocial outcome following surgery.

Health care costs decline after successful epilepsy surgery.

BACKGROUND: Surgery is an effective, high-cost procedure used increasingly to treat refractory epilepsy. For surgery to be cost-effective, long-term cost savings from reduced health care use should provide some offset to the initial costs of evaluation and surgery. There is little information about how health care costs are affected by evaluation and surgery. OBJECTIVE: To determine whether health care costs change when seizures become controlled after surgery. METHODS: Health care costs for the 2 years prior to surgical evaluation and for 2 years afterward were calculated from medical records of 68 subjects with temporal lobe epilepsy (TLE) participating in a multicenter observational study. Costs were compared among patients who did not have surgery, patients who had persisting seizures after surgery, and patients who were seizure free after surgery. RESULTS: Antiepileptic drugs (AEDs) accounted for more than half of the costs of care in the pre-evaluation period. Total costs for seizure-free patients had declined 32% by 2 years following surgery due to less use of AEDs and inpatient care. Costs did not change in patients with persisting seizures, whether they had surgery or not. In the 18 to 24 months following evaluation, epilepsy-related costs were $2,068 to $2,094 in patients with persisting seizures vs $582 in seizure-free patients. CONCLUSIONS: Costs remain stable over 2 years post-evaluation in patients with temporal lobe epilepsy whose seizures persist, but patients who become seizure free after surgery use substantially less health care than before surgery. Further cost reductions in seizure-free patients can be expected as antiepileptic drugs are successfully eliminated.

Patient-perceived impact of resective epilepsy surgery.

OBJECTIVE: To evaluate the patient-perceived impact of resective epilepsy surgery, a key outcome to consider in evaluating such a highly invasive, elective procedure. METHODS: Impact measures obtained from 396 patients in a multicenter cohort study of resective epilepsy surgery included (1) willingness to undergo surgery if that decision could be made again and (2) the overall impact of surgery on the patient's life. Predictors of impact were analyzed using multivariate ordinal logistic regression. RESULTS: Of study participants, 73.8%, 77.4%, and 75.5% would definitely undergo surgery again and 78.2%, 80.2%, and 79.1% reported a very strong or strong positive overall impact of surgery at 3, 12, and 24 months. Multivariate ordinal logistic regression showed that seizure freedom predicted more positive perceptions at 3, 12, and 24 months (all p < 0.04). Becoming employed was uniquely associated with willingness to undergo surgery again and with overall impact at 24 months (all p < 0.05), but only a net 7% of the cohort improved their employment status. Right-sided resection (at 12 and 24 months, p < 0.005) and female gender (at 3 and 12 months, p = 0.006) were each positively associated with perceived overall impact. CONCLUSIONS: Most epilepsy surgery patients report a positive overall impact of the procedure on their lives and a high willingness to undergo surgery again if that choice could be made. Seizure-free individuals express consistently more positive perceptions of the procedure. Findings suggest that it is important to make early efforts to reintegrate epilepsy surgery patients into employment.

Validity and responsiveness of generic preference-based HRQOL instruments in chronic epilepsy.

Generic, preference-based instruments are recommended for assessing health-related quality of life (HRQOL) in cost-utility analyses (CUA). We aimed to determine which instrument is the most appropriate for CUA of epilepsy care, using established psychometric criteria. We compared validity and responsiveness of EQ5D (using both UK and US preferences), visual analog scale (VAS), Health Utilities Index Mark II (HUI-2) and Mark III (HUI-3) and SF6D in 165 adults evaluated for epilepsy surgery. SF6D had the strongest or next-strongest associations with seizure severity and seizure control. It was not associated with education or IQ. Only SF6D and HUI-3 discriminated between patients with and without seizures 2 years after baseline evaluation. SF6D was most or next-most responsive to being seizure-free for 2 years, in most responsiveness analyses. VAS was also responsive, but showed less evidence of validity. The QOLIE-89, an epilepsy-targeted profile instrument, had stronger evidence for validity and responsiveness than the preference instruments. SF6D has several key psychometric advantages over four other preference instruments in CUAs of epilepsy care. This may reflect better coverage of HRQOL dimensions affected by epilepsy, greater sensitivity at the upper end of the HRQOL continuum, or both. These findings may not generalize to other chronic conditions.

Changes in depression and anxiety after resective surgery for epilepsy.

OBJECTIVE: To determine changes in depression and anxiety after resective surgery. METHODS: Data from subjects enrolled in a prospective multicenter study of resective epilepsy surgery were reviewed with the Beck Psychiatric Symptoms Scales (Beck Depression Inventory [BDI] and Beck Anxiety Inventory [BAI]) and Composite International Diagnostic Interview (CIDI) up to a 24-month period. chi2 analyses were used to correlate proportions. RESULTS: A total of 358 presurgical BDI and 360 BAI results were reviewed. Moderate and severe levels of depression were reported in 22.1% of patients, and similar levels of anxiety were reported by 24.7%. Postoperative rates of depression and anxiety declined at the 3-, 12-, and 24-month follow-up periods. At the 24-month follow-up, moderate to severe levels of depression symptoms were reported in 17.6 and 14.7% of the patients who continued to have postoperative seizures. Moderate to severe depression and anxiety were found in 8.2% of those who were seizure-free. There was no relationship, prior to surgery, between the presence or absence of depression and anxiety and the laterality or location of the seizure onset. There were no significant relationships between depression or anxiety at 24-month follow-up and the laterality or location of the surgery. CONCLUSIONS: Depression and anxiety in patients with refractory epilepsy significantly improve after epilepsy surgery, especially in those who are seizure-free. Neither the lateralization nor the localization of the seizure focus or surgery was associated with the risk of affective symptoms at baseline or after surgery.

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 chi2 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.

Ictal neocortical slowing in temporal lobe epilepsy.

BACKGROUND: Temporal lobe epilepsy (TLE) may affect brain regions outside the temporal lobe, causing impaired neocortical function during seizures. METHODS: The authors selected 11 consecutive patients with mesial TLE and hippocampal sclerosis who underwent intracranial EEG monitoring and had no seizures during a follow-up period of at least 1 year after temporal lobe resection. Secondarily generalized seizures were excluded, and up to three seizures were analyzed per patient (31 seizures total). Electrode contacts were assigned to one of nine cortical regions based on MRI surface reconstructions. EEG during seizures was analyzed for specific patterns including low-voltage fast (LVF), rhythmic polyspike, spike-wave, irregular slowing, and postictal suppression. RESULTS: Mesial and lateral temporal contacts on the side of seizure onset showed significant increases in ictal patterns such as LVF and polyspike activity, followed by postictal suppression. Bilateral frontal and ipsilateral parietal cortex exhibited large amplitude irregular slow waves during seizures. This frontoparietal slowing persisted into the postictal period. Perirolandic and occipital cortex were relatively spared. These EEG patterns were accompanied by bland staring, minor automatisms, and unresponsiveness or amnesia in the majority of patients studied. CONCLUSIONS: Prominent irregular slowing occurs in bilateral frontal and ipsilateral parietal association cortex during and after temporal lobe seizures. EEG slowing in the frontoparietal association cortex may signify physiologic impairment that contributes to widespread altered cerebral function during partial seizures.

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.

Long-term seizure outcome in patients initially seizure-free after resective epilepsy surgery.

OBJECTIVE: To evaluate the likelihood of and risk factors for seizure recurrence in patients initially seizure-free after resective surgery for intractable epilepsy. METHODS: One hundred seventy-five patients who underwent lobectomy between 1972 and 1992 and were seizure-free during the first postoperative year were retrospectively studied. Outcome was measured by relapse risk, presence of auras in otherwise seizure-free patients, and seizure frequency among relapsers. Factors significant in bivariate or Kaplan-Meier analysis or considered potentially predictive a priori were included in multivariate models. RESULTS: Of the 175 patients (mean follow-up 8.4 years), 63% never relapsed. The likelihood of being seizure-free was 83 +/- 6% 3 years after surgery, 72 +/- 7% after 5 years, and 56 +/- 9% after 10 years. After adjusting for age at surgery, duration of preoperative epilepsy, and resection site, normal pathology was associated with increased risk of relapse compared to mesial temporal sclerosis or other pathology (p = 0.036; hazard ratio [HR] 2.38; 95% CI 1.06 to 5.34). Among patients otherwise seizure-free, preoperative illness of > or =20 years was associated with increased risk of postoperative auras (p = 0.040; HR 3.55; 95% CI 1.06 to 11.90). Among relapsers, 51% experienced one or fewer seizures per year. Normal pathology and earlier relapse were associated with higher postoperative seizure frequency. CONCLUSIONS: In patients seizure-free during the first year after resective epilepsy surgery, the likelihood of remaining seizure-free declined to 56% over 10 years, but half of patients who relapsed had at most one seizure per year. Longer preoperative illness and normal pathology predicted poorer outcome.

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.

Future directions for epilepsy research.

The authors propose that epilepsy research embark on a revitalized effort to move from targeting control of symptoms to strategies for prevention and cure. The recent advances that make this a realistic goal include identification of genes mutated in inherited epilepsy syndromes, molecular characterization of brain networks, better imaging of sites of seizure origin, and developments in seizure prediction by quantitative EEG analysis. Research directions include determination of mechanisms of epilepsy development, identification of genes for common epilepsy syndromes through linkage analysis and gene chip technology, and validation of new models of epilepsy and epileptogenesis. Directions for therapeutics include identification of new molecular targets, focal methods of drug delivery tied to EEG activity, gene and cell therapy, and surgical and nonablative therapies. Integrated approaches, such as coupling imaging with electrophysiology, are central to progress in localizing regions of epilepsy development in people at risk and better seizure prediction and treatment for people with epilepsy.

Training clinical researchers in neurology: we must do better.

The pace of scientific discoveries, the increasing complexity of managing patients, and the runaway cost of neurological services have created an urgent need for a wide range of clinical research in neurology. Despite increasing recognition of this need and recent increases in funding for training clinical investigators, neurologists conducting cellular and molecular investigations are more likely to join faculties, maintain research careers, and attain academic advancement. Because academic departments of neurology are successful in producing and nurturing basic science researchers, why aren't they just as triumphant in spawning clinical investigators? This crisis in the preparation of clinical investigators has been brought about by many factors: competing time demands for clinical service, lack of methodologically rigorous training in the disciplines necessary to conduct clinical research, and lack of mentorship. Neurology residents contemplating a clinical research career may observe junior faculty who lack career guidance, are ill-prepared as independent investigators, and must juggle patient demands while trying to write a research grant or conduct a study. Already burdened by medical school debts, is it any wonder that our neurology graduates don't leap to a career with a future that seems so insecure? Academic departments of neurology must develop full-scale clinical research training programs if they are to meet the pressing need for clinical research. As a starting point, they must free themselves from their dependence on providing clinical services to generate income. Following the model which has produced successful basic researchers, much greater effort must be given to establishing rigorous methodological training in collaboration with other departments, creating senior role models, and protecting time for clinical investigators to conduct research. Unless we create incentives to careers in clinical research, we will never answer the growing number of clinical research questions we face today.

Interictal 99mTc-HMPAO SPECT in temporal lobe epilepsy: relation to clinical variables.

PURPOSE: Factors affecting blood flow observed by interictal single-photon emission computed tomography (SPECT) images in temporal lobe epilepsy (TLE) have not been systematically studied or consistently demonstrated. We evaluated interictal SPECT results with respect to many clinical variables in a large population of TLE patients, all of whom underwent temporal lobectomy. METHODS: Interictal 99mTc-HMPAO SPECT scans from 61 TLE patients were obtained before an anterior temporal lobectomy. SPECT was analyzed using a region of interest analysis (ROI) in the cerebellum, anterior temporal lobe, lateral temporal lobe, mesial temporal lobe, whole temporal lobe, and inferior frontal lobe. Asymmetry indices (AIs) were calculated. Correlative analysis of AIs and clinical variables was performed. RESULTS: The AIs from TLE patients differed significantly from those of controls in the anterior temporal (p < 0.01), lateral temporal (p < 0.001), and whole temporal (p < 0.01) regions. No consistent overall correlation between the AIs and clinical variables existed. In right TLE (RTLE) only, AIs in the lateral and whole temporal lobe were positively correlated with age of onset (r = 0.470, p < 0.05; r = 0.548, p < 0.01, respectively). Similarly, in RTLE only, duration of epilepsy was negatively correlated with the anterior (r = -0.395, p < 0.05) and mesial (r = -0.45, p < 0.05) temporal lobe AI. No correlations were found between clinical variables and AIs in left TLE (LTLE) patients. CONCLUSIONS: Significant correlation of age at onset and duration of epilepsy with AIs in RTLE but not LTLE suggests physiologic processes may be determined in part by laterality of TLE. Clinical applications are problematic.