Neuromodulation for Refractory Epilepsy.

Three neuromodulation therapies, all using implanted device and electrodes, have been approved to treat adults with drug-resistant focal epilepsy, namely, the vagus nerve stimulation in 1995, deep brain stimulation of the anterior nucleus of the thalamus (ANT-DBS) in 2018 (2010 in Europe), and responsive neurostimulation (RNS) in 2014. Indications for VNS have more recently extended to children down to age of 4. Limited or anecdotal data are available in other epilepsy syndromes and refractory/super-refractory status epilepticus. Overall, neuromodulation therapies are palliative, with only a minority of patients achieving long-term seizure freedom, justifying favoring such treatments in patients who are not good candidates for curative epilepsy surgery. About half of patients implanted with VNS, ANT-DBS, and RNS have 50% or greater reduction in seizures, with long-term data suggesting increased efficacy over time. Besides their impact on seizure frequency, neuromodulation therapies are associated with various benefits and drawbacks in comparison to antiseizure drugs. Yet, we lack high-level evidence to best position each neuromodulation therapy in the treatment pathways of persons with difficult-to-treat epilepsy.

The Efficacy and Use of a Pocket Card Algorithm in Status Epilepticus Treatment.

OBJECTIVE: To determine whether a pocket card treatment algorithm improves the early treatment of status epilepticus and to assess its utilization and retention in clinical practice. METHODS: Multidisciplinary care teams participated in video-recorded status epilepticus simulation sessions from 2015 to 2019. In this longitudinal cohort study, we examined the sessions recorded before and after introducing an internally developed, guideline-derived pocket card to determine differences in the adequacy or timeliness of rescue benzodiazepine. Simulation participants were queried 9 months later for submission of a differentiating identification number on each card to assess ongoing availability and utilization. RESULTS: Forty-four teams were included (22 before and 22 after the introduction of the pocket card). The time to rescue therapy was shorter for teams with the pocket card available (84 seconds [64-132]) compared with teams before introduction (144 seconds [100-162]) (U = 94; median difference = -46.9, 95% confidence interval [CI]: -75.9 to -21.9). The adequate dosing did not differ with card availability (odds ratio 1.48, 95% CI: 0.43-5.1). At the 9-month follow-up, 32 participants (65%) completed the survey, with 26 (81%) self-reporting having the pocket card available and 11 (34%) confirming ready access with the identification number. All identification numbers submitted corresponded to the hard copy laminated pocket card, and none to the electronic version. CONCLUSIONS: A pocket card is a feasible, effective, and worthwhile educational tool to improve the implementation of updated guidelines for the treatment of status epilepticus.

Outcomes in the treatment of psychogenic nonepileptic seizures (PNES) with CBTip: Response in seizure frequency, depression, anxiety, and quality of life.

RATIONALE: Psychogenic Nonepileptic Seizures (PNES) are seizure-like episodes without EEG abnormality, and are of psychological origin. Cognitive Behavioral Therapy (CBT), a type of psychological counseling, is known to be the best intervention to treat PNES and the underlying psychiatric symptoms. Yet, many remain untreated because of limited access to specialized counseling programs. In this study, first we intended to see if the positive outcomes of the CBTip can be replicated in our patient population using within-group comparison. We also aimed to examine the outcomes of patients who received a variable dose of treatment than the established treatment protocol. METHOD: We obtained retrospective patient reported outcomes (PRO) data from patients treated with Cognitive Behavioral Therapy-informed psychotherapy (CBT-ip) from January 2015 to January 2020 in an outpatient tertiary care epilepsy center. The CBTip program is a 12-session intervention delivered weekly by a seizure counselor. Although the program comprises 12 sessions of treatment, we included patients who attended at least 7 sessions consistent with previous research that used a similar cutoff. We had a total of 160 patient PROs included in the analysis. Outcome variables including seizure frequency, depression, anxiety, and quality of life were examined using self-report outcome scores. Demographic and other clinical and psychosocial confounding variables were controlled. RESULTS: In the first analysis in which we compared pre-treatment scores with 3-month posttreatment scores, there was no significant change in seizure frequency, depression, anxiety, and quality-of-life outcomes. In the second analysis when we compared pre- and posttreatment scores in patients who completed the treatment in longer than 3-month time, there were significant improvement in primary and secondary outcomes. For seizure frequency, 10 patients had data for "seizures per day in the last 6 months" and 5 participants (50%) improved by 50% or more in the number of seizures per day. There were also significant reductions in depression and anxiety scores but not in quality of life. IMPLICATION AND CONCLUSIONS: Our analysis showed that patients treated with CBTip with a minimum of 7 sessions in 3 months did not have significant improvement. However, attending at least 7 sessions of CBTip in longer than 3 months was effective for seizure control, depression, and anxiety. The observational and exploratory nature of our study, however, limits the generalizability of our findings outside of the single tertiary clinical care setting.

Automated analysis of cortical volume loss predicts seizure outcomes after frontal lobectomy.

OBJECTIVE: Patients undergoing frontal lobectomy demonstrate lower seizure-freedom rates than patients undergoing temporal lobectomy and several other resective interventions. We attempted to utilize automated preoperative quantitative analysis of focal and global cortical volume loss to develop predictive volumetric indicators of seizure outcome after frontal lobectomy. METHODS: Ninety patients who underwent frontal lobectomy were stratified based on seizure freedom at a mean follow-up time of 3.5 (standard deviation [SD] 2.5) years. Automated quantitative analysis of cortical volume loss organized by distinct brain region and laterality was performed on preoperative T1-weighted magnetic resonance imaging (MRI) studies. Univariate statistical analysis was used to select potential predictors of seizure freedom. Backward variable selection and multivariate logistical regression were used to develop models to predict seizure freedom. RESULTS: Forty-eight of 90 (53.3%) patients were seizure-free at the last follow-up. Several frontal and extrafrontal brain regions demonstrated statistically significant differences in both volumetric cortical volume loss and volumetric asymmetry between the left and right sides in the seizure-free and non-seizure-free cohorts. A final multivariate logistic model utilizing only preoperative quantitative MRI data to predict seizure outcome was developed with a c-statistic of 0.846. Using both preoperative quantitative MRI data and previously validated clinical predictors of seizure outcomes, we developed a model with a c-statistic of 0.897. SIGNIFICANCE: This study demonstrates that preoperative cortical volume loss in both frontal and extrafrontal regions can be predictive of seizure outcome after frontal lobectomy, and models can be developed with excellent predictive capabilities using preoperative MRI data. Automated quantitative MRI analysis can be quickly and reliably performed in patients with frontal lobe epilepsy, and further studies may be developed for integration into preoperative risk stratification.

Highlights From the Annual Meeting of the American Epilepsy Society 2018.

The American Epilepsy Society Meeting in New Orleans attracted more than 5900 attendees. There was a lively exchange of new science, innovation, education, clinical practice, and many other items related to epilepsy. Educational symposia were a major part of the meeting and explored varying topics of interest for all types of epilepsy professionals. This article reviews highlights of the meeting presented in major symposia. Topics ranged from how to treat varying aspects of epilepsy as a consultant in the hospital to finding the scientific underpinning of the interaction between sleep and epilepsy. Pros and cons of novel antiseizure medications, dietary, and stimulation treatments were discussed. Epilepsy may impair memory and we need to learn what is the pathophysiologic relationship. Febrile status epilepticus may have severe consequences for a later life with seizures. Epilepsy professionals should be very well aware of the ethical implications of devasting seizures and their associated disability. These are just a few select topics of the many that we need to study further to archive the final goal to improve the lives of patients with epilepsy.

Effect of invasive EEG monitoring on cognitive outcome after left temporal lobe epilepsy surgery.

OBJECTIVES: The objective of this cohort study was to compare neuropsychological outcomes following left temporal lobe resection (TLR) in patients with epilepsy who had or had not undergone prior invasive monitoring. METHODS: Data were obtained from an institutional review board-approved, neuropsychology registry for patients who underwent epilepsy surgery at Cleveland Clinic between 1997 and 2013. A total of 176 patients (45 with and 131 without invasive EEG) met inclusion criteria. Primary outcome measures were verbal memory and language scores. Other cognitive outcomes were also examined. Outcomes were assessed using difference in scores from before to after surgery and by presence/absence of clinically meaningful decline using reliable change indices (RCIs). Effect of invasive EEG on cognitive outcomes was estimated using weighting and propensity score adjustment to account for differences in baseline characteristics. Linear and logistic regression models compared surgical groups on all cognitive outcomes. RESULTS: Patients with invasive monitoring showed greater declines in confrontation naming; however, when RCIs were used to assess clinically meaningful change, there was no significant treatment effect on naming performance. No difference in verbal memory was observed, regardless of how the outcome was measured. In secondary outcomes, patients with invasive monitoring showed greater declines in working memory, which were no longer apparent using RCIs to define change. There were no outcome differences on other cognitive measures. CONCLUSIONS: Results suggest that invasive EEG monitoring conducted prior to left TLR is not associated with greater cognitive morbidity than left TLR alone. This information is important when counseling patients regarding cognitive risks associated with this elective surgery.

Incorporating patient-reported outcome measures into the electronic health record for research: application using the Patient Health Questionnaire (PHQ-9).

PURPOSE: Electronic health records (EHRs) present an opportunity to access large stores of data for research, but mapping raw EHR data to clinical phenotypes is complex. We propose adding patient-reported data to the EHR to improve phenotyping performance and describe a retrospective cohort study demonstrating a test case in depressive disorder. METHODS: We compared four EHR-phenotyping methods based on International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) codes, medication records, and the Patient Health Questionnaire 9 (PHQ-9) regarding the ability to identify cases with depression and characteristics of patients identified with depression. Our sample included 168,884 patients seen (2007-2013) at our neurological institute. We assessed the diagnostic performance in a subset of 225 patients who had a reference standard measurement available. RESULTS: ICD-9-CM codes identified the fewest number of patients as depressed (4,658), followed by PHQ-9 (46,565), and medication data (50,505). The presence of at least one of these criteria identified the largest number (78,322). The PHQ-9 identified a higher proportion of elderly, disabled, Medicaid, and rural patients, as compared to ICD-9-CM codes. ICD-9-CM codes were least sensitive (6.7% sensitivity), whereas the method using at least one of the criteria identified the highest number of truly depressed patients (93.3% sensitivity); however, specificity dropped from 97.7 to 58.1%. CONCLUSIONS: The choice of phenotyping method may disproportionately exclude patient groups from research. Patient-reported data hold potential to improve sensitivity while maintaining an acceptable loss of specificity, depending on the context. Researchers should consider including patient-reported data in EHR-driven phenotyping methods.

Reducing versus stopping antiepileptic medications after temporal lobe surgery.

OBJECTIVE: To study the safety of antiepileptic drug (AED) withdrawal after temporal lobe epilepsy (TLE) surgery. METHODS: We reviewed patients who underwent TLE surgery from 1995 to 2011, collecting data on doses, dates of AED initiation, reduction, and discontinuation. Predictors of seizure outcome were defined using Cox-proportional hazard modeling and adjusted for, while comparing longitudinal seizure-freedom in patients for whom AEDs were unchanged after resection as opposed to reduced or stopped. RESULTS: A total of 609 patients (86% adults) were analyzed. Follow-up ranged from 0.5 to 16.7 years. Most (64%) had hippocampal sclerosis. Overall, 229 patients had remained on their same baseline AEDs, while 380 patients stopped (127 cases) or reduced (253 cases) their AEDs. Mean timing of the earliest AED change was shorter in patients with recurrent seizures (1.04 years) compared to those seizure-free at last follow-up (1.44 years; P-value 0.03). Whether AEDs were withdrawn 12 or 24 months after surgery, there was a 10-25% higher risk of breakthrough seizures within the subsequent 2 years. However, 70% of patients with seizure recurrence after AED discontinuation reachieved remission, as opposed to 50% of those whose seizures recurred while reducing AEDs (P = 0.0001). Long-term remission rates were similar in both AED discontinuation and "unchanged" groups (82% remission for AEDs withdrawn after 1 year and 90% for AEDs withdrawn after 2 years), while only 65% of patients whose recurrences started during AED reduction achieved a 2-year remission by last follow-up. INTERPRETATION: AED withdrawal increases the short-term risk of breakthrough seizures after TLE surgery, and may alter the long-term disease course in some patients.

New-onset epilepsy in the elderly: challenges for the internist.

New-onset epilepsy in the elderly is difficult to diagnose, owing to atypical presentation, concomitant cognitive impairment, similarities with other common disorders, and nonspecific changes on electroencephalography (EEG). Its management is also challenging because of its deranging physiology, comorbidities, and polypharmacy. Antiepileptic drugs must be carefully chosen and closely monitored. Support of the patient and caregiver is key.

Validation of the Patient Health Questionnaire-9 (PHQ-9) for depression screening in adults with epilepsy.

OBJECTIVE: This study aimed to assess the accuracy and operating characteristics of the Patient Health Questionnaire-9 (PHQ-9) for depression screening in adults with epilepsy. METHODS: Tertiary epilepsy center patients served as the study population, with 237 agreeing to structured interview using the Mini-International Neuropsychiatric Interview (MINI), a "gold standard" instrument developed for rapid diagnosis of neuropsychiatric disorders, including major depressive disorder (MDD); 172 also completed the PHQ-9, and 127 completed both the PHQ-9 and the Neurological Disorders Depression Inventory for Epilepsy (NDDI-E) within two days of the MINI. Sensitivity, specificity, positive and negative predictive values, and areas under the ROC curves for each instrument were determined. Cut-points of 10 for the PHQ-9 and 15 for the NDDI-E were used, and ratings at or above the cut-points were considered screen-positive. The PHQ-9 was divided into cognitive/affective (PHQ-9/CA) and somatic (PHQ-9/S) subscales to determine comparative depression screening accuracy. RESULTS: The calculated areas under the ROC curves for the PHQ-9 (n=172) and the PHQ-9/CA and PHQ-9/S subscales were 0.914, 0.924, and 0.846, respectively, with the PHQ-9 more accurate than the PHQ-9/S (p=0.002) but not different from the PHQ-9/CA (p=0.378). At cut-points of 10 and 15, respectively, the PHQ-9 had higher sensitivity (0.92 vs 0.87) but lower specificity (0.74 vs 0.89) compared with the NDDI-E. The areas under the ROC curves of the PHQ-9 and the NDDI-E showed similar accuracy (n=127; 0.930 vs 0.934; p=0.864). SIGNIFICANCE: The PHQ-9 is an efficient and nonproprietary depression screening instrument with excellent accuracy validated for use in adult patients with epilepsy as well as multiple other medical populations.

Cerebral cavernous malformations in the setting of focal epilepsies: pathological findings, clinical characteristics, and surgical treatment principles.

Cavernous cerebral malformations (CCMs) are a well-defined epilepsy-associated pathology. They represent lesions/conglomerates of abnormally configured vessels leading to seizures either as a result of physiological changes affecting the cerebral cortex immediately surrounding the CCM (an epileptogenic mechanism that is relevant for both temporal and extratemporal lesions), or as a result of promoting epileptogenicity in remote but anatomo-functionally connected brain regions (a mechanism that is particularly relevant for temporal lobe lesions). This review details the pathological findings in CCMs and discusses the mechanisms of epileptogenicity in this context. The bulk of the review will focus on therapeutic strategies. Medical therapy using antiepileptic drugs is recommended as a first-line therapy, but surgical removal of the CCM with the surrounding cortex should be pursued if seizures prove to be drug resistant. Early timing of the resection and complete removal of any associated epileptic pathology are critical for best outcomes. In addition to reviewing the available data from prior series, we present original research from two specialized epilepsy centers targeted at answering particularly pressing clinical questions mainly related to the ideal timing and extent of surgery. Further research is needed to define the best surgical strategies in patients with temporal lobe CCMs and structurally normal hippocampi.

Effects of surgical side and site on mood and behavior outcome in children with pharmacoresistant epilepsy.

Children with epilepsy have a high rate of mood and behavior problems; yet few studies consider the emotional and behavioral impact of surgery. No study to date has been sufficiently powered to investigate effects of both side (left/right) and site (temporal/frontal) of surgery. One hundred patients (aged 6-16) and their families completed measures of depression, anxiety, and behavioral function as part of neuropsychological evaluations before and after surgery for pharmacoresistant epilepsy. Among children who had left-sided surgeries (frontal = 16; temporal = 38), there were significant interactions between time (pre to post-operative neuropsychological assessment) and resection site (frontal/temporal) on anhedonia, social anxiety, and withdrawn/depressed scales. Patients with frontal lobe epilepsy (FLE) endorsed greater pre-surgical anhedonia and social anxiety than patients with temporal lobe epilepsy (TLE) with scores normalizing following surgery. While scores on the withdrawn/depressed scale were similar between groups before surgery, the FLE group showed greater symptom improvement after surgery. In children who underwent right-sided surgeries (FLE = 20; TLE = 26), main effects of time (patients in both groups improved) and resection site (caregivers of FLE patients endorsed greater symptoms than those with TLE) were observed primarily on behavior scales. Individual data revealed that a greater proportion of children with left FLE demonstrated clinically significant improvements in anhedonia, social anxiety, and aggressive behavior than children with TLE. This is the first study to demonstrate differential effects of both side and site of surgery in children with epilepsy at group and individual levels. Results suggest that children with FLE have greater emotional and behavioral dysfunction before surgery, but show marked improvement after surgery. Overall, most children had good emotional and behavioral outcomes, with most scores remaining stable or improving.

Surgical outcomes in patients with extratemporal epilepsy and subtle or normal magnetic resonance imaging findings.

BACKGROUND: Surgery is an important therapeutic option in patients with medically refractory epilepsy. The combination of an extratemporal epileptic focus and nonlesional magnetic resonance imaging (MRI) was often believed to portend a poor outcome. OBJECTIVE: To investigate the outcome and analyze potential prognostic predictors in patients without lesions on MRI who underwent extratemporal resections. METHODS: Clinical, presurgical evaluation, invasive monitoring, and postoperative data of patients with high-resolution MRI that was initially reported as nonlesional were reviewed. Patients were reclassified as MRI-positive if an MRI abnormality related to the epilepsy was revealed at the multidisciplinary presurgical patient management conference, or as MRI-negative if imaging remained normal or revealed incidental findings. RESULTS: Sixty patients were identified; 72% were MRI-negative. In the original cohort, the median seizure-free duration was 1.32 years (95% confidence interval [CI], 0.16-2.0); probability of seizure freedom at 2 years was 36% (95% CI, 30%-43%). In the MRI-negative group, the median seizure-free duration was 1.52 years (95% CI, 0.12-5.17); probability of seizure freedom at 2 years was 42% (95% CI, 33%-50%). Complete resection of ictal onset areas and absence of acute postoperative seizures were significantly associated with longer seizure freedom (risk ratio 4.9, P = .004; 95% CI, 1.6-16.7 and 22.1, P < .001; 95% CI, 5.9-94.7, respectively). CONCLUSION: Among patients with medically refractory MRI nonlesional extratemporal epilepsy, detailed evaluation and subsequent resection leads to seizure freedom in 42% of patients at 2 years.