Medial temporal lobe functional connectivity predicts stimulation-induced theta power.

Focal electrical stimulation of the brain incites a cascade of neural activity that propagates from the stimulated region to both nearby and remote areas, offering the potential to control the activity of brain networks. Understanding how exogenous electrical signals perturb such networks in humans is key to its clinical translation. To investigate this, we applied electrical stimulation to subregions of the medial temporal lobe in 26 neurosurgical patients fitted with indwelling electrodes. Networks of low-frequency (5-13 Hz) spectral coherence predicted stimulation-evoked increases in theta (5-8 Hz) power, particularly when stimulation was applied in or adjacent to white matter. Stimulation tended to decrease power in the high-frequency broadband (HFB; 50-200 Hz) range, and these modulations were correlated with HFB-based networks in a subset of subjects. Our results demonstrate that functional connectivity is predictive of causal changes in the brain, capturing evoked activity across brain regions and frequency bands.

Widespread theta synchrony and high-frequency desynchronization underlies enhanced cognition.

The idea that synchronous neural activity underlies cognition has driven an extensive body of research in human and animal neuroscience. Yet, insufficient data on intracranial electrical connectivity has precluded a direct test of this hypothesis in a whole-brain setting. Through the lens of memory encoding and retrieval processes, we construct whole-brain connectivity maps of fast gamma (30-100 Hz) and slow theta (3-8 Hz) spectral neural activity, based on data from 294 neurosurgical patients fitted with indwelling electrodes. Here we report that gamma networks desynchronize and theta networks synchronize during encoding and retrieval. Furthermore, for nearly all brain regions we studied, gamma power rises as that region desynchronizes with gamma activity elsewhere in the brain, establishing gamma as a largely asynchronous phenomenon. The abundant phenomenon of theta synchrony is positively correlated with a brain region's gamma power, suggesting a predominant low-frequency mechanism for inter-regional communication.

Mesial temporal lobe epilepsy with childhood febrile seizure.

OBJECTIVES: To evaluate the demographic and clinical manifestations of patients with mesial temporal sclerosis and temporal lobe epilepsy (MTS-TLE) with childhood febrile seizure (FS) and establishing the potential differences as compared to those without FS. We also investigated the surgery outcome in these two groups of patients. MATERIALS AND METHODS: In this retrospective study, all patients with a clinical diagnosis of drug-resistant TLE due to mesial temporal sclerosis, who underwent epilepsy surgery at Jefferson Comprehensive Epilepsy Center, were recruited. Patients were prospectively registered in a database from 1986 through 2014. Postsurgical outcome was classified into two groups; seizure-free or relapsed. Clinical manifestations and outcome were compared between patients with MTS-TLE with FS and those without FS. RESULTS: Two hundred and sixty-two patients were eligible for this study. One hundred and seventy patients (64.9%) did not have FS in their childhood, while 92 patients (35.1%) reported experiencing FS in their childhood. Demographic and clinical characteristics of these two groups of patients were not different. Postoperative seizure outcome was not statistically different between these two groups of patients (P = 0.19). CONCLUSIONS: When MTS is the pathological substrate of TLE, clinical manifestations and response to surgical treatment of patients are very similar in patients with history of febrile seizure in their childhood compared to those without such an experience. In other words, when the subgroup of patients with MTS-TLE and drug-resistant seizures is examined history of childhood febrile seizure loses its value as a distinguishing factor in characteristics or predictive factor for surgery outcome.

Seasonality of birth in patients with temporal lobe epilepsy.

OBJECTIVES: We investigated the seasonal pattern in births of patients with temporal lobe epilepsy and mesial temporal sclerosis. We hypothesized that the seasonal pattern in births of these patients is different from that in the general population. MATERIALS AND METHODS: In this retrospective study, all patients who were evaluated for epilepsy surgery at Jefferson Comprehensive Epilepsy Center, Thomas Jefferson, Philadelphia, USA, between 1986 and 2014 and had a diagnosis of mesial temporal sclerosis (made by definite imaging findings of atrophy and/or sclerosis) were included. The seasonality in births of patients was compared with the seasonal pattern in the live births of the general population from Pennsylvania State. RESULTS: Two hundred and eighty-two patients (146 females and 136 males) were studied. The seasonality pattern in birth of patients was not statistically different from that in the general population. CONCLUSIONS: The observed contradictory findings among various studies indicate the need for further studies to elucidate whether season of birth brings the possibility of acquiring various epilepsy syndromes in the future. To investigate any possible association between season of birth and epilepsy, we suggest avoid pooling all patients with epilepsy together.

A comparison of occipital and temporal lobe epilepsies.

PURPOSE: Differentiating between occipital lobe epilepsy (OLE) and temporal lobe epilepsy (TLE) is often challenging. This retrospective case-control study compares OLE to TLE and explores markers that suggest the diagnosis of OLE. METHODS: We queried the Jefferson Epilepsy Center surgery database for patients who underwent a resection that involved the occipital lobe. For each patient with OLE, three sequential case-control patients with TLE were matched. Demographic characteristics, symptoms, electrophysiological findings, imaging findings, and surgical outcome were compared. RESULTS: Nineteen patients with OLE and 57 patients with TLE were included in the study. Visual symptoms were unique to patients with OLE (8/19) and were not reported by patients with TLE (P < 0.0001). Occipital interictal spikes (IIS) were found only in one-third of the patients with OLE (6/19) and in no patients with TLE (P < 0.0001). IIS in the posterior temporal lobe were found in five of 19 patients with OLE vs one of 57 patients with TLE (P = 0.003). IIS involved more than one lobe of the brain in most patients with OLE (11/19) but only in nine of 57 the TLE group. (P = 0.0003) Multilobar resection was needed in most patients with OLE (15/19), typically including the temporal lobe, but in only one of the patients with TLE (P < 0.0001). CONCLUSION: Occipital lobe epilepsy is difficult to identify and may masquerade as temporal lobe epilepsy. Visual symptoms and occipital findings in the EEG suggest the diagnosis of OLE, but absence of these features, does not exclude the diagnosis. When posterior temporal EEG findings or multilobar involvement occurs, the diagnosis of OLE should be considered.

Methods for implantation of micro-wire bundles and optimization of single/multi-unit recordings from human mesial temporal lobe.

OBJECTIVE: The authors report methods developed for the implantation of micro-wire bundles into mesial temporal lobe structures and subsequent single neuron recording in epileptic patients undergoing in-patient diagnostic monitoring. This is done with the intention of lowering the perceived barriers to routine single neuron recording from deep brain structures in the clinical setting. APPROACH: Over a 15 month period, 11 patients were implanted with platinum micro-wire bundles into mesial temporal structures. Protocols were developed for (A) monitoring electrode integrity through impedance testing, (B) ensuring continuous 24-7 recording, (C) localizing micro-wire position and 'splay' pattern and (D) monitoring grounding and referencing to maintain the quality of recordings. MAIN RESULTS: Five common modes of failure were identified: (1) broken micro-wires from acute tensile force, (2) broken micro-wires from cyclic fatigue at stress points, (3) poor in vivo micro-electrode separation, (4) motion artifact and (5) deteriorating ground connection and subsequent drop in common mode noise rejection. Single neurons have been observed up to 14 days post-implantation and on 40% of micro-wires. SIGNIFICANCE: Long-term success requires detailed review of each implant by both the clinical and research teams to identify failure modes, and appropriate refinement of techniques while moving forward. This approach leads to reliable unit recordings without prolonging operative times, which will help increase the availability and clinical viability of human single neuron data.

Progesterone vs placebo therapy for women with epilepsy: A randomized clinical trial.

OBJECTIVE: To assess progesterone treatment of intractable seizures in women with partial epilepsy. METHODS: This randomized, double-blind, placebo-controlled, phase III, multicenter, clinical trial compared the efficacy and safety of adjunctive cyclic natural progesterone therapy vs placebo treatment of intractable seizures in 294 subjects randomized 2:1 to progesterone or placebo, stratified by catamenial and noncatamenial status. It compared treatments on proportions of ≥50% responders and changes in seizure frequency from 3 baseline to 3 treated menstrual cycles. RESULTS: There was no significant difference in proportions of responders between progesterone and placebo in the catamenial and noncatamenial strata. Prespecified secondary analysis showed that the level of perimenstrual seizure exacerbation (C1 level) was a significant predictor of responders for progesterone but not placebo. With increasing C1 levels, responders increased from 21% to 57% with progesterone vs 19% to 20% with placebo. Reductions in seizure frequency correlated with increasing C1 levels for progesterone but not placebo, progressing from 26% to 71% for progesterone vs 25% to 26% for placebo. A prespecified clinically important separation between progesterone and placebo responders (37.8% vs 11.1%; p = 0.037) was realized among 21.4% of women who had C1 level ≥3. CONCLUSION: There was no difference in the primary outcome of ≥50% responder rates between progesterone vs placebo for catamenial or noncatamenial groups. Post hoc findings suggest that the level of perimenstrual seizure exacerbation is a significant predictor of responder rate with progesterone and that progesterone may provide clinically important benefit for a subset of women with perimenstrually exacerbated seizures. CLASSIFICATION OF EVIDENCE: This study provides Class III evidence that cyclic progesterone is ineffective in women with intractable partial epilepsy. Post hoc analysis identified a subset of women with higher levels of perimenstrual seizure exacerbation that were responsive to treatment.

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.

Depression and anxiety in patients with epilepsy, with or without other chronic disorders.

BACKGROUND: Most people with epilepsy lead a normal emotional and cognitive life, however neurobehavioral problems can be found in a large number of patients. This study evaluates the prevalence of depression and anxiety among patients with epilepsy and determines whether having other chronic somatic illnesses increases the prevalence. METHODS: Adults with epilepsy were recruited in either the inpatient epilepsy monitoring unit or the Outpatient Epilepsy Clinic at Thomas Jefferson University in 2006. Patients anonymously filled out a questionnaire, included data about age, sex, education, having other chronic illnesses, and degree of seizure control. The Hospital Anxiety and Depression scale was used to define the presence or absence of anxiety and depression.  RESULTS: Two hundreds patients participated, with a mean age of 40.3±16 years. Nineteen (9.5%) patients had depression and 49 (24.5%) had anxiety. Age, seizure control, and having other chronic illnesses did not have a significant relationship with either depression or anxiety. Gender was significantly related to anxiety, with females displaying greater frequency of anxiety than males. Depression was inversely related to education. CONCLUSIONS: It is probable that people with higher education use more effective ways to psychologically and physically adapt to their illness.

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.

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.

The association of mood with quality of life ratings in epilepsy.

OBJECTIVE: To determine the relative contributions of psychological (mood and anxiety), social, and seizure-related variables to quality of life (QOL) scores in epilepsy. METHODS: Outpatients (n = 435) with epilepsy completed the Quality of Life in Epilepsy 31 Inventory (QOLIE-31), Beck Depression Inventory II (BDI-II), Beck Anxiety Inventory, and a social survey. Stepwise linear regression and general linear model analyses determined the set of best predictors and the most unique predictors of composite QOLIE-31 score and subscale scores. RESULTS: A three-variable model accounted for 56% of the variance for the composite QOLIE-31 score. The BDI-II was the strongest (often by several multiples in terms of variance explained) and most consistent predictor of the composite and QOLIE subscales in both types of analytic approaches. In no case did BDI-II significantly interact with the other variables, suggesting that its effect on QOL was direct and not mediated by other factors. Throughout the results, depression had an inverse relation to scores, i.e., lower levels of depression correlated with high QOL scores. Separate correlational analyses showed that poor seizure control was associated with increased numbers of depressive symptoms. DISCUSSION: Quality of Life in Epilepsy (QOLIE) scores, reflecting both general and specific aspects of quality of life, are strongly influenced by mood state, such as depression. Factors such as seizure control exert a more limited effect on the QOLIE. Health-related quality of life measures are needed in which mood does not play such a dominant role.

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.

Positron emission tomography in Dyke-Davidoff-Masson syndrome.

Dyke-Davidoff-Masson syndrome is clinically characterized by hemiparesis, hemiplegia, seizures, mental retardation, and facial asymmetry secondary to congenital or early childhood vascular insult. A 21-year-old man with Dyke-Davidoff-Masson syndrome presented with uncontrolled seizures. The authors present the magnetic resonance (MR) and positron emission tomography (PET) findings of this syndrome.

Adult-onset epilepsy in focal cortical dysplasia of Taylor type.

Focal cortical dysplasia of Taylor type (FCDT) usually presents with seizures at an early age, whereas adult onset of epilepsy is uncommon. We reviewed the medical records of 213 patients with FCDT. In 21 patients (10%), age at seizure onset ranged from 18 to 55 years (mean 25.3). The outcome of seizures in patients with FCDT and adult-onset epilepsy seems favorable vs childhood-onset seizures.