Disparities in adherence and emergency department utilization among people with epilepsy: A machine learning approach.

PURPOSE: We used a machine learning approach to identify the combinations of factors that contribute to lower adherence and high emergency department (ED) utilization. METHODS: Using Medicaid claims, we identified adherence to anti-seizure medications and the number of ED visits for people with epilepsy in a 2-year follow up period. We used three years of baseline data to identify demographics, disease severity and management, comorbidities, and county-level social factors. Using Classification and Regression Tree (CART) and random forest analyses we identified combinations of baseline factors that predicted lower adherence and ED visits. We further stratified these models by race and ethnicity. RESULTS: From 52,175 people with epilepsy, the CART model identified developmental disabilities, age, race and ethnicity, and utilization as top predictors of adherence. When stratified by race and ethnicity, there was variation in the combinations of comorbidities including developmental disabilities, hypertension, and psychiatric comorbidities. Our CART model for ED utilization included a primary split among those with previous injuries, followed by anxiety and mood disorders, headache, back problems, and urinary tract infections. When stratified by race and ethnicity we saw that for Black individuals headache was a top predictor of future ED utilization although this did not appear in other racial and ethnic groups. CONCLUSIONS: ASM adherence differed by race and ethnicity, with different combinations of comorbidities predicting lower adherence across racial and ethnic groups. While there were not differences in ED use across races and ethnicity, we observed different combinations of comorbidities that predicted high ED utilization.

Racial and Ethnic Differences in Antiseizure Medications Among People With Epilepsy on Medicaid: A Case of Potential Inequities.

Background and Objectives: Being on a newer, second-, and third-generation antiseizure medication (ASM) may represent an important marker of quality of care for people with epilepsy. We sought to examine whether there were racial/ethnic differences in their use. Methods: Using Medicaid claims data, we identified the type and number of ASMs, as well as the adherence, for people with epilepsy over a 5-year period (2010-2014). We used multilevel logistic regression models to examine the association between newer-generation ASMs and adherence. We then examined whether there were racial/ethnic differences in ASM use in models adjusted for demographics, utilization, year, and comorbidities. Results: Among 78,534 adults with epilepsy, 17,729 were Black, and 9,376 were Hispanic. Overall, 25.6% were on older ASMs, and being solely on second-generation ASMs during the study period was associated with better adherence (adjusted odds ratio: 1.17, 95% confidence interval [CI]: 1.11-1.23). Those who saw a neurologist (3.26, 95% CI: 3.13-3.41) or who were newly diagnosed (1.29, 95% CI: 1.16-1.42) had higher odds of being on newer ASMs. Importantly, Black (0.71, 95% CI: 0.68-0.75), Hispanic (0.93, 95% CI: 0.88-0.99), and Native Hawaiian and Other Pacific Island individuals (0.77, 95% CI: 0.67-0.88) had lower odds of being on newer ASMs when compared with White individuals. Discussion: Generally, racial and ethnic minoritized people with epilepsy have lower odds of being on newer-generation ASMs. Greater adherence by people who were only on newer ASMs, their greater use among people seeing a neurologist, and the opportunity of a new diagnosis point to actionable leverage points for reducing inequities in epilepsy care.

A framework for health equity in people living with epilepsy.

Epilepsy is a disease where disparities and inequities in risk and outcomes are complex and multifactorial. While most epilepsy research to date has identified several key areas of disparities, we set out to provide a multilevel life course model of epilepsy development, diagnosis, treatment, and outcomes to highlight how these disparities represent true inequities. Our piece also presents three hypothetical cases that highlight how the solutions to address inequities may vary across the lifespan. We then identify four key domains (structural, socio-cultural, health care, and physiological) that contribute to the persistence of inequities in epilepsy risk and outcomes in the United States. Each of these domains, and their core components in the context of epilepsy, are reviewed and discussed. Further, we highlight the connection between domains and key areas of intervention to strive towards health equity. The goal of this work is to highlight these domains while also providing epilepsy researchers and clinicians with broader context of how their work fits into health equity.

Neurotoxicity following CD19/CD28ζ CAR T-cells in children and young adults with B-cell malignancies.

BACKGROUND: Neurotoxicity is an established toxicity of CD19 CAR T-cell therapy; however, there is little information on neurotoxicity in children, adolescents, and young adults (CAYA) receiving CD19/CD28ζ CAR T-cells for B-cell malignancies. METHODS: We analyzed neurotoxicity of CD19/CD28ζ CAR T-cells in CAYA treated on a phase I study (NCT01593696). Assessments included daily inpatient monitoring, caregiver-based neuro-symptom checklist (NSC), exploratory neurocognitive assessments, clinically-indicated imaging, CSF analysis, and systematic cytokine profiling, outcomes of which were associated with cytokine release syndrome (CRS) and treatment response postinfusion. Patients with active CNS leukemia were included. RESULTS: Amongst 52 patients treated, 13 patients had active CNS leukemia at infusion. Neurotoxicity was seen in 11/52 (21.2%) patients, with an incidence of 29.7% (11/37) in patients with CRS. Neurotoxicity was associated with the presence and severity of CRS. Those with neurotoxicity had higher levels of peak serum IL-6, IFNγ, and IL-15. Additionally, CNS leukemia was effectively eradicated in most patients with CRS. Pilot neurocognitive testing demonstrated stable-to-improved neurocognitive test scores in most patients, albeit limited by small patient numbers. The NSC enabled caregiver input into the patient experience. CONCLUSIONS: This is the first systematic analysis of neurotoxicity utilizing a CD19/CD28ζ CAR construct in CAYA, including in those with active CNS involvement. The experience demonstrates that the neurotoxicity profile was acceptable and reversible, with evidence of anti-leukemia response and CNS trafficking of CAR T-cells. Additionally, neurocognitive testing, while exploratory, provides an opportunity for future studies to employ systematic evaluations into neurotoxicity assessments and validation is needed in future studies.

Influence of Research Continuity on Physician-Scientists' Career Success.

OBJECTIVE: To determine if maintaining continuity in research topic and method from early to late career yields a greater likelihood of physician-scientists' research career success; that is, achieving research independence and producing impactful publications. METHODS: To explore the effect of maintaining continuity in research, 108 neurology residency graduates (2000-2010) from former medical scientist training programs at the highest National Institute of Neurological Disorders and Stroke- and NIH-funded institutions were identified. Through comparison of PhD dissertations with postgraduate work, research continuity was deemed present if there was evidence of continuity in research topic and method. With publicly available SCOPUS, PubMed, and NIH RePORT data, the correlation that degree of continuity had with h-indices, number of grants awarded, and R01 acquisition was examined. RESULTS: Nearly half of the graduates were classified as noncontinuous (45%), fewer than a quarter as somewhat continuous (22%), and roughly a third as very continuous (32%). The data demonstrated that research continuity increased the ability to acquire a R01, with 83% of R01 or R21 recipients having very continuous research. Very continuous graduates also had higher median number of grants received (2 [interquartile range (IQR) 1-3]) and a higher median h-index (17 [IQR 10.5-20]) compared to the somewhat continuous and noncontinuous groups. CONCLUSIONS: This study highlights research continuity as an important and modifiable variable during the training period of physician-scientists and one that may improve their career success and promote greater retention within the workforce.

Neurotoxicities associated with checkpoint inhibitors: Two case reports and a review of the literature.

We report a case of nivolumab-induced delayed-onset aseptic meningitis and a case of limbic encephalitis and peripheral nerve palsy with toxicity relapse 6 months after initial presentation. The atypical presentations contribute to our knowledge of these rare events and reinforce the necessity for vigilant monitoring and a multidisciplinary treatment approach.

Fatal encephalopathy with wild-type JC virus and ruxolitinib therapy.

OBJECTIVE: JC virus (JCV) infection is a lytic infection of oligodendrocytes in progressive multifocal leukoencephalopathy; less common forms of central nervous system manifestations associated with JCV infection include granule cell neuronopathy, encephalopathy, and meningitis. Presented is the first case of fatal JCV encephalopathy after immunosuppressive therapy that included ruxolitinib. METHODS: Postmortem analysis included next generation sequencing, Sanger sequencing, tissue immunohistochemistry, and formalin-fixed hemisphere 7T magnetic resonance imaging. RESULTS: JCV DNA isolated from postmortem tissue samples identified a novel 12bp insertion that altered the transcription site binding pattern in an otherwise "wild-type virus," which has long been thought to be the nonpathogenic form of JCV. Anti-VP1 staining demonstrated infection in cortical neurons, hippocampal neurons, and glial and endothelial cells. INTERPRETATION: This expands the spectrum of identified JCV diseases associated with broad-spectrum immunosuppression, including JAK-STAT inhibitors, and sheds light on an additional neurotropic virus strain of the archetype variety. ANN NEUROL 2019;86:878-884.

Future Directions of Training Physician-Scientists: Reimagining and Remeasuring the Workforce.

In academic medicine, the attrition of the physician-scientist workforce has been significantly discussed for the past three decades, with substantial attention and funding targeted to stop this attrition and attempt to reinvigorate the workforce. Despite these concerns and efforts, the attrition has not been stopped or even significantly slowed, and thus a further understanding of the physician-scientist workforce is needed with a closer look at how this workforce is measured and quantified. Through reviewing three methods by which physician-scientists are identified and understood, limitations in these definitions arise, leading to the basic question: Who qualifies to be a physician-scientist? Answering this question may lead to developing more comprehensive and less restrictive approaches when qualifying and measuring the physician-scientist workforce and appreciating the varying contributions physicians make to research. Through suggesting an expanded appreciation of these research contributions, recognition of collaboration, and funding models that support both of these aspects, the authors hope to add to the conversation by challenging traditional approaches and encouraging movement toward forward-looking definitions that encourage and promote all physicians to engage with research. This reimagining of physician-scientists will result not just in a remeasuring of the workforce but, subsequently, in strengthening the clinical and translational research continuum as well.

Convection-Enhanced Delivery of Muscimol in Patients with Drug-Resistant Epilepsy.

BACKGROUND: Minimally invasive therapies for drug-resistant epilepsy (DRE) have been advocated. A study of convection-enhanced delivery (CED) of muscimol, a GABAA receptor agonist, was previously completed in non-human primates. OBJECTIVE: To investigate the safety and anti-epileptic effects of intracerebral muscimol infusion into the epileptic focus of patients with DRE. METHODS: In this phase 1 clinical trial, 3 adult patients with DRE underwent CED into the seizure focus of artificial CSF vehicle followed by muscimol for 12 to 24 h each using a crossover design. Basic pathophysiology of the epileptic focus was examined by assessing the infusions' effects on seizure frequency, electroencephalogram (EEG) spike-wave activity, and power-spectral EEG frequency. RESULTS: Inter-ictal neurological function remained normal in all patients. Pathological examination of resected specimens showed no infusion-related brain injuries. Seizure frequency decreased in 1 of 3 patients during muscimol infusion but was unchanged in all patients during vehicle infusion. Mean beta frequencies did not differ significantly before, during, or after infusion periods. Infused fluid provided insufficient MRI-signal to track infusate distribution. In the 2 yr after standard epilepsy surgery, 1 patient had temporary reduction in seizure frequency and 2 patients were seizure-free. CONCLUSION: CED of muscimol into the epileptic focus of patients with DRE did not damage adjacent brain parenchyma or adversely affect seizure surgery outcome. This study did not confirm that intracerebral muscimol infusion effectively suppressed seizures. A surrogate tracer is recommended to track infusion distribution to the epileptic focus and surrounding structures in future studies using CED to suppress the seizure focus.

Physician-scientists in neurology: Research contributions of a cohort of neurologists.

OBJECTIVE: The objective of this study was to evaluate the methods by which neurology physician-scientists are quantified through applying author-level metrics to commonly used definitions when discussing funding efforts aimed at the attrition of the physician-scientist workforce. METHODS: Neurology residency alumni from institutions with the highest National Institute of Neurological Disorders and Stroke funding were identified for 2003-2005, and their funding records, publishing history, and impact factor (h-index) were obtained via the NIH Research Portfolio Online Reporting Tools and Scopus Author Profile. The group differences of total publications, yearly publication rate, and h-index between R01-funded, non-R01-funded, and nonfunded individuals were analyzed via analysis of variance models, and a publications-per-research hour rate was calculated and similarly compared across groups. RESULTS: From 15 programs, and from a total of 252 neurologists, 186 were identified as having demonstrated an interest in research. The mean h-index, yearly publication rate, and cumulative number of publications were significantly higher in those who eventually received an R01 grant compared to those without R01 funding and those with no research funding. Within the top 50 performers by yearly publication rate, there was an equal mix of the 3 groups of neurologists: R01 (19, 38%), non-R01 (15, 30%), and nonfunded (16, 32%). Those who were nonfunded (10% research effort) had an estimated 4.9 publications per 1,000 research hours compared to 3.0 for those with non-R01 (40% research effort) funding and 3.2 for those with R01 funding (80% research effort). CONCLUSIONS: While eventual R01 grant and early career funding pathways were confirmed as important components of higher h-index and larger publication numbers, the classic definition of a physician-scientist was questioned through these findings. Those presumed to be without funding and generally excluded from the physician-scientist pool because of lack of protected research time, in some instances, outperformed their R01-funded colleagues and had a higher publications-per-research hour than those with an R01 and those with non-R01 funding, when estimating a 10% research effort. This reflects a potentially erroneous assumption and indicates the important contribution of these neurologists.

Prospective longitudinal overnight video-EEG evaluation in Phelan-McDermid Syndrome.

OBJECTIVE: Phelan-McDermid Syndrome (PMS) is a rare genetic condition associated with loss of function mutations, including deletions, in the chromosome 22q13 region. This PMS phenotype includes intellectual disability, often minimal to absent verbal skills, and other neurologic features including autism spectrum disorder and seizures. Reports indicate seizures and abnormal electroencephalograms (EEGs) in this population, but previous studies do not describe EEG findings during sleep or prognostic value of abnormal EEG over any time period. METHODS: During a natural history study, 16 consecutively enrolled participants (mean age 10years) with PMS underwent both routine (approximately 25min) and overnight (average 9.65h) video-EEG, in addition to genetic testing, neurodevelopmental assessment, neurological examination, and epilepsy phenotyping. Over 240h of EEG, data was recorded. Comparison of findings from the routine EEG was made with prolonged EEG acquired during awake and sleep the same night. In a subset of nine participants, the overnight EEG was repeated one or more years later to observe the natural evolution and prognostic value of any abnormalities noted at baseline. RESULTS: A history of epilepsy, with multiple seizure types, was confirmed in seven of the 16 participants, giving a prevalence of 43.8% in this cohort. All but one EEG was abnormal (15 of 16), and 75% (12 of 16) showed epileptiform activity. Of these, only 25% of participants (3 of 12) showed definitive epileptiform discharges during the routine study. Overnight EEGs (sleep included) did not show any clinical events consistent with seizures or electrophic seizures, however, overnight EEG showed either more frequent and/or more definitive epileptiform activity in 68.75% (11 of 16) participants. All seven of the 16 participants who had previously been diagnosed with epilepsy showed epileptiform abnormalities. In addition to a wide range of epileptiform activity observed, generalized slowing with poor background organization was frequently noted. Follow-up EEG confirmed persistence of abnormal discharges, but none of the abnormal EEGs showed evolution to electrographic seizures. Clinically, there was no emergence of epilepsy or significant developmental regression noted in the time frame observed. CONCLUSIONS: This is the first and most abundant prolonged awake and sleep video-EEG data recorded in a PMS cohort to date. The importance of overnight prolonged EEGs is highlighted by findings from this study, as they can be used to document the varied topographies of EEG abnormalities in conditions such as PMS, which are often missed during routine EEG studies. While the long-term significance of the EEG abnormalities found (beyond 1year) remains uncertain despite their persistence over time, these findings do underscore the current clinical recommendation that overnight prolonged EEG studies (with sleep) should be conducted in individuals with PMS.

Preoperative prediction of temporal lobe epilepsy surgery outcome.

PURPOSE: There is controversy about relative contributions of ictal scalp video EEG recording (vEEG), routine scalp outpatient interictal EEG (rEEG), intracranial EEG (iEEG) and MRI for predicting seizure-free outcomes after temporal lobectomy. We reviewed NIH experience to determine contributions at specific time points as well as long-term predictive value of standard pre-surgical investigations. METHODS: Raw data was obtained via retrospective chart review of 151 patients. After exclusions, 118 remained (median 5 years follow-up). MRI-proven mesial temporal sclerosis (MTSr) was considered a separate category for analysis. Logistic regression estimated odds ratios at 6-months, 1-year, and 2 years; proportional hazard models estimated long-term comparisons. Subset analysis of the proportional hazard model was performed including only patients with commonly encountered situations in each of the modalities, to maximize statistical inference. RESULTS: Any MRI finding, MRI proven MTS, rEEG, vEEG and iEEG did not predict two-year seizure-free outcome. MTSr was predictive at six months (OR=2.894, p=0. 0466), as were MRI and MTSr at one year (OR=10.4231, p=0. 0144 and OR=3.576, p=0. 0091). Correcting for rEEG and MRI, vEEG failed to predict outcome at 6 months, 1year and 2 years. Proportional hazard analysis including all available follow-up failed to achieve significance for any modality. In the subset analysis of 83 patients with commonly encountered results, vEEG modestly predicted long-term seizure-free outcomes with a proportional hazard ratio of 1.936 (p=0.0304). CONCLUSIONS: In this study, presurgical tools did not provide unambiguous long-term outcome predictions. Multicenter prospective studies are needed to determine optimal presurgical epilepsy evaluation.

A comparison of continuous video-EEG monitoring and 30-minute EEG in an ICU.

AIM: To determine whether there is added benefit in detecting electrographic abnormalities from 16-24 hours of continuous video-EEG in adult medical/surgical ICU patients, compared to a 30-minute EEG. METHODS: This was a prospectively enroled non-randomized study of 130 consecutive ICU patients for whom EEG was requested. For 117 patients, a 30-minute EEG was requested for altered mental state and/or suspected seizures; 83 patients continued with continuous video-EEG for 16-24 hours and 34 patients had only the 30-minute EEG. For 13 patients with prior seizures, continuous video-EEG was requested and was carried out for 16-24 hours. We gathered EEG data prospectively, and reviewed the medical records retrospectively to assess the impact of continuous video-EEG. RESULTS: A total of 83 continuous video-EEG recordings were performed for 16-24 hours beyond 30 minutes of routine EEG. All were slow, and 34% showed epileptiform findings in the first 30 minutes, including 2% with seizures. Over 16-24 hours, 14% developed new or additional epileptiform abnormalities, including 6% with seizures. In 8%, treatment was changed based on continuous video-EEG. Among the 34 EEGs limited to 30 minutes, almost all were slow and 18% showed epileptiform activity, including 3% with seizures. Among the 13 patients with known seizures, continuous video-EEG was slow in all and 69% had epileptiform abnormalities in the first 30 minutes, including 31% with seizures. An additional 8% developed epileptiform abnormalities over 16-24 hours. In 46%, treatment was changed based on continuous video-EEG. CONCLUSION: This study indicates that if continuous video-EEG is not available, a 30-minute EEG in the ICU has a substantial diagnostic yield and will lead to the detection of the majority of epileptiform abnormalities. In a small percentage of patients, continuous video-EEG will lead to the detection of additional epileptiform abnormalities. In a sub-population, with a history of seizures prior to the initiation of EEG recording, the benefits of continuous video-EEG in monitoring seizure activity and influencing treatment may be greater.

Oral cysteamine bitartrate and N-acetylcysteine for patients with infantile neuronal ceroid lipofuscinosis: a pilot study.

BACKGROUND: Infantile neuronal ceroid lipofuscinosis is a devastating neurodegenerative lysosomal storage disease caused by mutations in the gene (CLN1 or PPT1) encoding palmitoyl-protein thioesterase-1 (PPT1). We have previously reported that phosphocysteamine and N-acetylcysteine mediate ceroid depletion in cultured cells from patients with this disease. We aimed to assess whether combination of oral cysteamine bitartrate and N-acetylcysteine is beneficial for patients with neuronal ceroid lipofuscinosis. METHODS: Children between 6 months and 3 years of age with infantile neuronal ceroid lipofuscinosis with any two of the seven most lethal PPT1 mutations were eligible for inclusion in this pilot study. All patients were recruited from physician referrals. Patients received oral cysteamine bitartrate (60 mg/kg per day) and N-acetylcysteine (60 mg/kg per day) and were assessed every 6-12 months until they had an isoelectric electroencephalogram (EEG, attesting to a vegetative state) or were too ill to travel. Patients were also assessed by electroretinography, brain MRI and magnetic resonance spectroscopy (MRS), and electron microscopic analyses of leukocytes for granular osmiophilic deposits (GRODs). Children also underwent physical and neurodevelopmental assessments on the Denver scale. Outcomes were compared with the reported natural history of infantile neuronal ceroid lipofuscinosis and that of affected older siblings. This trial is registered with ClinicalTrials.gov, number NCT00028262. FINDINGS: Between March 14, 2001, and June 30, 2012, we recruited ten children with infantile neuronal ceroid lipofuscinosis; one child was lost to follow-up after the first visit and nine patients (five girls and four boys) were followed up for 8 to 75 months. MRI showed abnormalities similar to those in previous reports; brain volume and N-acetyl aspartic acid (NAA) decreased steadily, but no published quantitative MRI or MRS studies were available for comparison. None of the children acquired new developmental skills, and their retinal function decreased progressively. Average time to isoelectric EEG (52 months, SD 13) was longer than reported previously (36 months). At the first follow-up visit, peripheral leukocytes in all nine patients showed virtually complete depletion of GRODs. Parents and physicians reported less irritability, improved alertness, or both in seven patients. No treatment-related adverse events occurred apart from mild gastrointestinal discomfort in two patients, which disappeared when liquid cysteamine bitartrate was replaced with capsules. INTERPRETATION: Our findings suggest that combination therapy with cysteamine bitartrate and N-acetylcysteine is associated with delay of isoelectric EEG, depletion of GRODs, and subjective benefits as reported by parents and physicians. Our systematic and quantitative report of the natural history of patients with infantile neuronal ceroid lipofuscinosis provides a guide for future assessment of experimental therapies. FUNDING: National Institutes of Health.

Characterization of atypical language activation patterns in focal epilepsy.

OBJECTIVE: Functional magnetic resonance imaging is sensitive to the variation in language network patterns. Large populations are needed to rigorously assess atypical patterns, which, even in neurological populations, are a minority. METHODS: We studied 220 patients with focal epilepsy and 118 healthy volunteers who performed an auditory description decision task. We compared a data-driven hierarchical clustering approach to the commonly used a priori laterality index (LI) threshold (LI < 0.20 as atypical) to classify language patterns within frontal and temporal regions of interest. We explored (n = 128) whether IQ varied with different language activation patterns. RESULTS: The rate of atypical language among healthy volunteers (2.5%) and patients (24.5%) agreed with previous studies; however, we found 6 patterns of atypical language: a symmetrically bilateral, 2 unilaterally crossed, and 3 right dominant patterns. There was high agreement between classification methods, yet the cluster analysis revealed novel correlations with clinical features. Beyond the established association of left-handedness, early seizure onset, and vascular pathology with atypical language, cluster analysis identified an association of handedness with frontal lateralization, early seizure onset with temporal lateralization, and left hemisphere focus with a unilateral right pattern. Intelligence quotient was not significantly different among patterns. INTERPRETATION: Language dominance is a continuum; however, our results demonstrate meaningful thresholds in classifying laterality. Atypical language patterns are less frequent but more variable than typical language patterns, posing challenges for accurate presurgical planning. Language dominance should be assessed on a regional rather than hemispheric basis, and clinical characteristics should inform evaluation of atypical language dominance. Reorganization of language is not uniformly detrimental to language functioning.

PET of serotonin 1A receptors and cerebral glucose metabolism for temporal lobectomy.

UNLABELLED: The objective of this study was to compare 5-hydroxytryptamine receptor 1A (5-HT(1A)) PET with cerebral metabolic rate of glucose (CMRglc) PET for temporal lobectomy planning. METHODS: We estimated 5-HT(1A) receptor binding preoperatively with (18)F-trans-4-fluoro-N-2-[4-(2-methoxyphenyl) piperazin-1-yl]ethyl-N-(2-pyridyl) cyclohexane carboxamide ((18)F-FCWAY) PET and CMRglc measurement with (18)F-FDG in regions drawn on coregistered MRI after partial-volume correction in 41 patients who had anterior temporal lobectomy with at least a 1-y follow-up. Surgery was tailored to individual preresection evaluations and intraoperative electrocorticography. Mean regional asymmetry values and the number of regions with asymmetry exceeding 2 SDs in 16 healthy volunteers were compared between seizure-free and non-seizure-free patients. (18)F-FCWAY but not (18)F-FDG and MRI data were masked for surgical decisions and outcome assessment. RESULTS: Twenty-six of 41 (63%) patients seizure-free since surgery had significantly different mesial temporal asymmetries, compared with 15 non-seizure-free patients for both (18)F-FCWAY (F(1,39) = 5.87; P = 0.02) and (18)F-FDG PET (F(1,38) = 5.79; P = 0.021). The probability of being seizure-free was explained by both (18)F-FDG and (18)F-FCWAY PET, but not MRI, with a significant additional (18)F-FCWAY effect (chi(2)(2) = 9.8796; P = 0.0072) after the probability of being seizure-free was explained by (18)F-FDG. Although MRI alone was not predictive, any combination of 2 lateralizing imaging studies was highly predictive of seizure freedom. CONCLUSION: Our study provides class III evidence that both 5-HT(1A) receptor PET and CMRglc PET can contribute to temporal lobectomy planning. Additional studies should explore the potential for temporal lobectomy based on interictal electroencephalography and minimally invasive imaging studies.

Cerebral blood flow and fMRI BOLD auditory language activation in temporal lobe epilepsy.

PURPOSE: Blood oxygen level-dependent (BOLD) functional magnetic resonance imaging (fMRI), an important research and clinical tool, depends on relatively greater transient increases in (regional cerebral blood flow) rCBF than cerebral metabolic rate for oxygen during neural activity. We investigated whether reduced resting rCBF in patients with temporal lobe epilepsy affects BOLD signal during fMRI language mapping. METHODS: We used [(15)O] water positron emission tomography (PET) to measure rCBF, and 3 Tesla echo planar imaging (EPI) BOLD fMRI with an auditory description decision task in 33 patients with temporal lobe epilepsy (16 men; mean age 33.6 ± standard deviation [SD] 10.6 years; epilepsy onset 14.8 ± 10.6 years; mean duration 18.8 ± 13.2 years; 23 left focus, 10 right focus). Anatomic regions drawn on structural MRI, based on the Wake Forest Pick Atlas, included Wernicke's area (WA), inferior frontal gyrus (IFG), middle frontal gyrus (MFG), and hippocampus (HC). Laterality indices (LIs), and asymmetry indices (AIs), were calculated on coregistered fMRI and PET. KEY FINDINGS: Twelve patients had mesial temporal sclerosis (seven on the left), two patients had a tumor or malformation of cortical development (both left), one patient a right temporal cyst, and 18 patients had normal MRI (14 left). Decreasing relative left WA CBF correlated with decreased left IFG voxel activation and decreasing left IFG LI. However, CBF WA AI was not related to left WA voxel activation itself or WA LI. There was a weak positive correlation between absolute CBF and fMRI activation in left IFG, right IFG, and left WA. Patients with normal and abnormal MRI did not differ in fMRI activation or rCBF AIs. SIGNIFICANCE: Reduced WA rCBF is associated with reduced fMRI activation in IFG but not WA itself, suggesting distributed network effects, but not impairment of underlying BOLD response. Hypoperfusion in TLE does not affect fMRI clinical value.

Serotonin 1A receptors, depression, and memory in temporal lobe epilepsy.

PURPOSE: Memory deficits and depression are common in patients with temporal lobe epilepsy (TLE). Previous positron emission tomography (PET) studies have shown reduced mesial temporal 5HT1A-receptor binding in these patients. We examined the relationships among verbal memory performance, depression, and 5HT1A-receptor binding measured with 18F-trans-4-fluoro-N-2-[4-(2-methoxyphenyl)piperazin-1-yl]ethyl-N-(2-pyridyl) cyclohexane carboxamide (18FCWAY) PET in a cross-sectional study. METHODS: We studied 40 patients (24 male; mean age 34.5 ± 10.7 years) with TLE. Seizure diagnosis and focus localization were based on ictal video-electroencephalography (EEG) recording. Patients had neuropsychological testing with Wechsler Adult Intelligence Score III (WAIS III) and Wechsler Memory Score III (WMS III) on stable antiepileptic drug (AED) regimens at least 24 h since the last seizure. Beck Depression Inventory (BDI) scores were obtained. We performed interictal PET with 18FCWAY, a fluorinated derivative of WAY 100635, a highly specific 5HT1A ligand, and structural magnetic resonance imaging (MRI) scans to estimate partial volume and plasma free fraction corrected 18FCWAY volume of distribution (V/f1). KEY FINDINGS: Hippocampal V/f1 was significantly lower in area ipsilateral than contralateral to the epileptic focus (73.7 ± 27.3 vs. 95.4 ± 28.4; p < 0.001). We found a significant relation between both left hippocampal 18FCWAY V/f1 (r = 0.41; p < 0.02) and left hippocampal volume (r = 0.36; p < 0.03) and delayed auditory memory score. On multiple regression, there was a significant effect of the interaction of left hippocampal 18FCWAY V/f1 and left hippocampal volume on delayed auditory memory, but not of either alone. High collinearity was present. In an analysis of variance including the side of the seizure focus, the effect of left hippocampal 18FCWAY V/f1 but not focus laterality retained significance. Mean BDI was 8.3 ± 7.0. There was a significant inverse relation between BDI and 18FCWAY V/f1 ipsilateral to the patient's epileptic focus (r = 0.38 p < 0.02). There was no difference between patients with a right or left temporal focus. There was no relation between BDI and immediate or delayed auditory memory. SIGNIFICANCE: Our study suggests that reduced left hippocampal 5HT1A-receptor binding may play a role in memory impairment in patients with TLE.

Interictal spikes in developing rats cause long-standing cognitive deficits.

Frequent interictal spikes are a common finding in the electroencephalograms of children with epileptic encephalopathies. While it is well recognized that interictal spikes are a biological marker of seizures and can lead to transitory cognitive impairment, whether interictal spikes can result in long-standing adverse effects on learning and memory in children is not known. Here we investigated the consequences of interictal spikes in rat pups without seizures on long-term learning and memory. Rat pups were given a low dose of flurothyl for 4h for 10 days during continuous electroencephalographic monitoring. Rats developed interictal spikes without seizures while age-matched controls under similar testing conditions had few interictal spikes. When rats were tested as adults, there was impairment in reference memory in the probe test of the Morris water maze, reference memory impairment in the four-trial radial-arm water maze and impaired long-term potentiation. Early-life interictal spikes resulted in impaired new cell formation and decreased cell counts in the hippocampus but did not cause an increase in apoptosis. This study, for the first time demonstrates that interictal spikes in rat pups without seizures can result in long-standing spatial cognitive impairment. Our findings suggest that suppressing IIS may be as important as treating seizures during brain development.