Publications by authors named "Gary W Mathern"

130 Publications

Clonally Focused Public and Private T Cells in Resected Brain Tissue From Surgeries to Treat Children With Intractable Seizures.

Front Immunol 2021 6;12:664344. Epub 2021 Apr 6.

Department of Neurosurgery, David Geffen School of Medicine at the University of California, Los Angeles, CA, United States.

Using a targeted transcriptomics approach, we have analyzed resected brain tissue from a cohort of 53 pediatric epilepsy surgery cases, and have found that there is a spectrum of involvement of both the innate and adaptive immune systems as evidenced by the differential expression of immune-specific genes in the affected brain tissue. The specimens with the highest expression of immune-specific genes were from two Rasmussen encephalitis cases, which is known to be a neuro-immunological disease, but also from tuberous sclerosis complex (TSC), focal cortical dysplasia, and hemimegalencephaly surgery cases. We obtained T cell receptor (TCR) Vβ chain sequence data from brain tissue and blood from patients with the highest levels of T cell transcripts. The clonality indices and the frequency of the top 50 Vβ clonotypes indicated that T cells in the brain were clonally restricted. The top 50 Vβ clonotypes comprised both public and private (patient specific) clonotypes, and the TCR Vβ chain third complementarity region (CDR3) of the most abundant public Vβ clonotype in each brain sample was strikingly similar to a CDR3 that recognizes an immunodominant epitope in either human cytomegalovirus or Epstein Barr virus, or influenza virus A. We found that the frequency of 14 of the top 50 brain Vβ clonotypes from a TSC surgery case had significantly increased in brain tissue removed to control recurrent seizures 11 months after the first surgery. Conversely, we found that the frequency in the blood of 18 of the top 50 brain clonotypes from a second TSC patient, who was seizure free, had significantly decreased 5 months after surgery indicating that T cell clones found in the brain had contracted in the periphery after removal of the brain area associated with seizure activity and inflammation. However, the frequency of a public and a private clonotype significantly increased in the brain after seizures recurred and the patient underwent a second surgery. Combined single cell gene expression and TCR sequencing of brain-infiltrating leukocytes from the second surgery showed that the two clones were CD8 effector T cells, indicating that they are likely to be pathologically relevant.
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http://dx.doi.org/10.3389/fimmu.2021.664344DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8056262PMC
April 2021

Hemispherectomy Outcome Prediction Scale: Development and validation of a seizure freedom prediction tool.

Epilepsia 2021 May 13;62(5):1064-1073. Epub 2021 Mar 13.

Department of Pediatrics, BC Children's Hospital and University of British Columbia, Vancouver, British Columbia, Canada.

Objective: To develop and validate a model to predict seizure freedom in children undergoing cerebral hemispheric surgery for the treatment of drug-resistant epilepsy.

Methods: We analyzed 1267 hemispheric surgeries performed in pediatric participants across 32 centers and 12 countries to identify predictors of seizure freedom at 3 months after surgery. A multivariate logistic regression model was developed based on 70% of the dataset (training set) and validated on 30% of the dataset (validation set). Missing data were handled using multiple imputation techniques.

Results: Overall, 817 of 1237 (66%) hemispheric surgeries led to seizure freedom (median follow-up = 24 months), and 1050 of 1237 (85%) were seizure-free at 12 months after surgery. A simple regression model containing age at seizure onset, presence of generalized seizure semiology, presence of contralateral 18-fluoro-2-deoxyglucose-positron emission tomography hypometabolism, etiologic substrate, and previous nonhemispheric resective surgery is predictive of seizure freedom (area under the curve = .72). A Hemispheric Surgery Outcome Prediction Scale (HOPS) score was devised that can be used to predict seizure freedom.

Significance: Children most likely to benefit from hemispheric surgery can be selected and counseled through the implementation of a scale derived from a multiple regression model. Importantly, children who are unlikely to experience seizure control can be spared from the complications and deficits associated with this surgery. The HOPS score is likely to help physicians in clinical decision-making.
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http://dx.doi.org/10.1111/epi.16861DOI Listing
May 2021

Novel tonometer device distinguishes brain stiffness in epilepsy surgery.

Sci Rep 2020 12 1;10(1):20978. Epub 2020 Dec 1.

Department of Neurosurgery, David Geffen School of Medicine at UCLA, 300 Stein Plaza, Suite 525, Los Angeles, CA, 90095-6901, USA.

Complete surgical resection of abnormal brain tissue is the most important predictor of seizure freedom following surgery for cortical dysplasia. While lesional tissue is often visually indiscernible from normal brain, anecdotally, it is subjectively stiffer. We report the first experience of the use of a digital tonometer to understand the biomechanical properties of epilepsy tissue and to guide the conduct of epilepsy surgery. Consecutive epilepsy surgery patients (n = 24) from UCLA Mattel Children's Hospital were recruited to undergo intraoperative brain tonometry at the time of open craniotomy for epilepsy surgery. Brain stiffness measurements were corrected with abnormalities on neuroimaging and histopathology using mixed-effects multivariable linear regression. We collected 249 measurements across 30 operations involving 24 patients through the pediatric epilepsy surgery program at UCLA Mattel Children's Hospital. On multivariable mixed-effects regression, brain stiffness was significantly associated with the presence of MRI lesion (β = 32.3, 95%CI 16.3-48.2; p < 0.001), severity of cortical disorganization (β = 19.8, 95%CI 9.4-30.2; p = 0.001), and recent subdural grid implantation (β = 42.8, 95%CI 11.8-73.8; p = 0.009). Brain tonometry offers the potential of real-time intraoperative feedback to identify abnormal brain tissue with millimeter spatial resolution. We present the first experience with this novel intraoperative tool for the conduct of epilepsy surgery. A carefully designed prospective study is required to elucidate whether the clinical application of brain tonometry during resective procedures could guide the area of resection and improve seizure outcomes.
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http://dx.doi.org/10.1038/s41598-020-77888-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7708453PMC
December 2020

Recurrent limbic seizures do not cause hippocampal neuronal loss: A prolonged laboratory study.

Neurobiol Dis 2021 01 15;148:105183. Epub 2020 Nov 15.

Department of Neurology, University of Virginia, Charlottesville, Virginia, United States of America. Electronic address:

Purpose: It remains controversial whether neuronal damage and synaptic reorganization found in some forms of epilepsy are the result of an initial injury and potentially contributory to the epileptic condition or are the cumulative affect of repeated seizures. A number of reports of human and animal pathology suggest that at least some neuronal loss precedes the onset of seizures, but there is debate over whether there is further damage over time from intermittent seizures. In support of this latter hypothesis are MRI studies in people that show reduced hippocampal volumes and cortical thickness with longer durations of the disease. In this study we addressed the question of neuronal loss from intermittent seizures using kindled rats (no initial injury) and rats with limbic epilepsy (initial injury).

Methods: Supragranular mossy fiber sprouting, hippocampal neuronal densities, and subfield area measurements were determined in rats with chronic limbic epilepsy (CLE) that developed following an episode of limbic status epilepticus (n = 25), in kindled rats (n = 15), and in age matched controls (n = 20). To determine whether age or seizure frequency played a role in the changes, CLE and kindled rats were further classified by seizure frequency (low/high) and the duration of the seizure disorder (young/old).

Results: Overall there was no evidence for progressive neuronal loss from recurrent seizures. Compared with control and kindled rats, CLE animals showed increased mossy fiber sprouting, decreased neuronal numbers in multiple regions and regional atrophy. In CLE, but not kindled rats: 1) Higher seizure frequency was associated with greater mossy fiber sprouting and granule cell dispersion; and 2) greater age with seizures was associated with decreased hilar densities, and increased hilar areas. There was no evidence for progressive neuronal loss, even with more than 1000 seizures.

Conclusion: These findings suggest that the neuronal loss associated with limbic epilepsy precedes the onset of the seizures and is not a consequence of recurrent seizures. However, intermittent seizures do cause other structural changes in the brain, the functional consequences of which are unclear.
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http://dx.doi.org/10.1016/j.nbd.2020.105183DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7855788PMC
January 2021

Effect of Gene Mutation on Seizures in Surgery for Tuberous Sclerosis Complex.

Can J Neurol Sci 2021 May 28;48(3):327-334. Epub 2020 Aug 28.

Department of Neurosurgery, University of California Los Angeles, Los Angeles, CA, USA.

Background: Tuberous sclerosis complex (TSC) is a rare genetic disorder that commonly leads to drug-resistant epilepsy in affected patients. This study aimed to determine whether the underlying genetic mutation (TSC1 vs. TSC2) predicts seizure outcomes following surgical treatments for epilepsy.

Methods: We retrospectively assessed TSC patients using the TSC Natural History Database core registry. Data review focused on outcomes in patients treated with surgical resection or vagus nerve stimulation.

Results: A total of 42 patients with a TSC1 mutation, and 145 patients with a TSC2 mutation, were identified. We observed a distinct clinical phenotype: children with TSC2 mutations tended to be diagnosed with TSC at a younger age than those with a TSC1 mutation (p < 0.001), were more likely to have infantile spasms (p < 0.001), and to get to surgery at a later age (p = 0.003). Among this TSC2 cohort, seizure control following resective epilepsy surgery was achieved in less than half (47%) the study sample. In contrast, patients with TSC1 mutations tended to have more favorable postsurgical outcomes; seizure control was achieved in 66% of this group.

Conclusion: TSC2 mutations result in a more severe epilepsy phenotype that is also less responsive to resective surgery. It is important to consider this distinct clinical disposition when counseling families preoperatively with respect to seizure freedom. Larger samples are required to better characterize the independent effects of genetic mutation, infantile spasms, and duration of epilepsy as they relate to seizure control following resective or neuromodulatory epilepsy surgery.
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http://dx.doi.org/10.1017/cjn.2020.185DOI Listing
May 2021

Long-Term Patient-Reported Outcomes of Visual Field Defects and Compensatory Mechanisms in Patients After Cerebral Hemispherectomy.

J Neuroophthalmol 2021 Jun;41(2):147-153

Perelman School of Medicine (EAM), University of Pennsylvania, Philadelphia, Pennsylvania; University of California Los Angeles School of Medicine (MFC), Los Angeles, California; CEO (MJ), Brain Recovery Project Childhood Epilepsy Surgery Foundation, Los Angeles, California; Brain Research Institute (GWM), University of California Los Angeles School of Medicine, Los Angeles, California; Neurological Surgery and Pediatric Neurological Surgery (GWM), Santa Monica UCLA Medical Center, Ronald Reagan UCLA Medical Center, Los Angeles, California; and Department of Ophthalmology (SLP), Stein Eye Institute, University of California Los Angeles, California.

Background: In cases of intractable epilepsy resistant to drug therapy, hemispherectomy is often the only treatment option to mitigate seizures; however, the true long-term subjective visual outcomes are relatively unexplored. In this study, we sought to determine and characterize patient-reported visual function years after hemispherectomy.

Methods: This was an observational study conducted on a large cohort of children with seizure disorder treated with cerebral hemispherectomy. An online survey was sent to parents with questions to assess subjective visual function with a variety of questions from presence of visual field defects after hemispherectomy, to improvement over time, compensatory mechanisms used, and development of strabismus.

Results: This survey was emailed to 248 parents of previously evaluated children who agreed to be re-surveyed, 48 (20%) of which responded. The average age at hemispherectomy was approximately 5 (±4) years, and the average time after hemispherectomy was 7 (±5) years. Thirty-nine patients (81%) were seizure-free after 1 surgery and 85% (n = 41) were seizure-free after ≥1 surgeries. Thirty-four (71%) experienced a visual field defect after surgery, but 25 (52%) experienced subjective improvement over time. Thirty-eight (79%) used compensatory mechanisms, such as head tilting, with 16 (33%) patients experiencing subjective improvement over time. Twenty-seven (56%) patients experienced a decrease in visual acuity after surgery with 12 (25%) experiencing subjective improvement over time.

Conclusion: In a large cohort examining patient-reported visual outcomes years after hemispherectomy, most patients experienced strabismus and/or visual field defects. However, more than half reported improvements and compensatory mechanisms (exotropic strabismus and ipsilateral esotropic strabismus) over time, presumably to enhance visual field function. By exploring subjective visual and cognitive function, this paper uniquely characterizes patient-reported improvements over time, and provides motivation for larger longitudinal studies using more quantitative measures of visual function and improvement after hemispherectomy.
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http://dx.doi.org/10.1097/WNO.0000000000000998DOI Listing
June 2021

Epilepsy surgery for Rasmussen encephalitis: the UCLA experience.

J Neurosurg Pediatr 2020 Jul 17:1-9. Epub 2020 Jul 17.

Departments of1Neurosurgery.

Objective: Rasmussen encephalitis (RE) is a rare inflammatory neurological disorder typically involving one hemisphere and resulting in drug-resistant epilepsy and progressive neurological decline. Here, the authors present seizure outcomes in children who underwent epilepsy surgery for RE at a single institution.

Methods: The records of consecutive patients who had undergone epilepsy surgery for RE at the UCLA Mattel Children's Hospital between 1982 and 2018 were retrospectively reviewed. Basic demographic information, seizure history, procedural notes, and postoperative seizure and functional outcome data were analyzed.

Results: The cohort included 44 patients, 41 of whom had sufficient data for analysis. Seizure freedom was achieved in 68%, 48%, and 22% of the patients at 1, 5, and 10 years, respectively. The median time to the first seizure for those who experienced seizure recurrence after surgery was 39 weeks (IQR 11-355 weeks). Anatomical hemispherectomy, as compared to functional hemispherectomy, was independently associated with a longer time to postoperative seizure recurrence (HR 0.078, p = 0.03). There was no statistically significant difference in postoperative seizure recurrence between patients with complete hemispherectomy and those who had less-than-hemispheric surgery. Following surgery, 68% of the patients could ambulate and 84% could speak regardless of operative intervention.

Conclusions: A large proportion of RE patients will have seizure relapse after surgery, though patients with anatomical hemispherectomies may have a longer time to postoperative seizure recurrence. Overall, the long-term data in this study suggest that hemispheric surgery can be seen as palliative treatment for seizures rather than a cure for RE.
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http://dx.doi.org/10.3171/2020.4.PEDS2098DOI Listing
July 2020

Paroxysmal Discharges in Tissue Slices From Pediatric Epilepsy Surgery Patients: Critical Role of GABA Receptors in the Generation of Ictal Activity.

Front Cell Neurosci 2020 20;14:54. Epub 2020 Mar 20.

IDDRC, Semel Institute for Neuroscience and Human Behavior, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, United States.

In the present study, we characterized the effects of bath application of the proconvulsant drug 4-aminopyridine (4-AP) alone or in combination with GABA and/or GABA receptor antagonists, in cortical dysplasia (CD type I and CD type IIa/b), tuberous sclerosis complex (TSC), and non-CD cortical tissue samples from pediatric epilepsy surgery patients. Whole-cell patch clamp recordings in current and voltage clamp modes were obtained from cortical pyramidal neurons (CPNs), interneurons, and balloon/giant cells. In pyramidal neurons, bath application of 4-AP produced an increase in spontaneous synaptic activity as well as rhythmic membrane oscillations. In current clamp mode, these oscillations were generally depolarizing or biphasic and were accompanied by increased membrane conductance. In interneurons, membrane oscillations were consistently depolarizing and accompanied by bursts of action potentials. In a subset of balloon/giant cells from CD type IIb and TSC cases, respectively, 4-AP induced very low-amplitude, slow membrane oscillations that echoed the rhythmic oscillations from pyramidal neurons and interneurons. Bicuculline reduced the amplitude of membrane oscillations induced by 4-AP, indicating that they were mediated principally by GABA receptors. 4-AP alone or in combination with bicuculline increased cortical excitability but did not induce seizure-like discharges. Ictal activity was observed in pyramidal neurons and interneurons from CD and TSC cases only when phaclofen, a GABA receptor antagonist, was added to the 4-AP and bicuculline solution. These results emphasize the critical and permissive role of GABA receptors in the transition to an ictal state in pediatric CD tissue and highlight the importance of these receptors as a potential therapeutic target in pediatric epilepsy.
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http://dx.doi.org/10.3389/fncel.2020.00054DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7099654PMC
March 2020

Pathological high frequency oscillations associate with increased GABA synaptic activity in pediatric epilepsy surgery patients.

Neurobiol Dis 2020 02 17;134:104618. Epub 2019 Oct 17.

Division of Pediatric Neurology, Mattel Children's Hospital, David Geffen School of Medicine at University of California Los Angeles, Los Angeles, CA, USA.

Pathological high-frequency oscillations (HFOs), specifically fast ripples (FRs, >250 Hz), are pathognomonic of an active epileptogenic zone. However, the origin of FRs remains unknown. Here we explored the correlation between FRs recorded with intraoperative pre-resection electrocorticography (ECoG) and spontaneous synaptic activity recorded ex vivo from cortical tissue samples resected for the treatment of pharmacoresistant epilepsy. The cohort included 47 children (ages 0.22-9.99 yr) with focal cortical dysplasias (CD types I and II), tuberous sclerosis complex (TSC) and non-CD pathologies. Whole-cell patch clamp recordings were obtained from pyramidal neurons and interneurons in cortical regions that were positive or negative for pathological HFOs, defined as FR band oscillations (250-500 Hz) at ECoG. The frequency of spontaneous excitatory and inhibitory postsynaptic currents (sEPSCs and IPSCs, respectively) was compared between HFO+ and HFO- regions. Regardless of pathological substrate, regions positive for FRs displayed significantly increased frequencies of sIPSCs compared with regions negative for FRs. In contrast, the frequency of sEPSCs was similar in both regions. In about one third of cases (n = 17), pacemaker GABA synaptic activity (PGA) was observed. In the vast majority (n = 15), PGA occurred in HFO+ areas. Further, fast-spiking interneurons displayed signs of hyperexcitability exclusively in HFO+ areas. These results indicate that, in pediatric epilepsy patients, increased GABA synaptic activity is associated with interictal FRs in the epileptogenic zone and suggest an active role of GABAergic interneurons in the generation of pathological HFOs. Increased GABA synaptic activity could serve to dampen excessive excitability of cortical pyramidal neurons in the epileptogenic zone, but it could also promote neuronal network synchrony.
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http://dx.doi.org/10.1016/j.nbd.2019.104618DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6980668PMC
February 2020

Etiology and Age Modifies Subjective Visual Function After Cerebral Hemispherectomy.

J Child Neurol 2019 07 7;34(8):446-451. Epub 2019 Apr 7.

1 Stein Eye Institute, Department of Ophthalmology, University of California, Los Angeles, CA, USA.

Background: Cerebral hemispherectomy is typically used to treat patients with pharmacoresistant epilepsy. Visual-related outcomes are relatively unstudied in this population, aside from the knowledge that patients develop a complete homonymous hemianopia contralateral to the side of the hemispherectomy. The purpose of this study was to determine and characterize parent-reported functional visual, oculomotor, and postural changes in a large population of patients following cerebral hemispherectomy.

Methods: An online survey was sent to parents of children who had undergone hemispherectomy for seizure control. Families were recruited by the Brain Recovery Project: Childhood Epilepsy Surgery Foundation. Parent-reported subjective visual function was assessed by the presence of peripheral field defects, ocular misalignment and anomalous head posture.

Results: A total of 196 (12.5%) participants responded. Postoperative follow-up was 92±78 months (range: 1-382). Ninety-three percent of parents reported the child had difficulties with peripheral vision. Torticollis was present postoperatively in 122 (62%) patients. Strabismus was noted in 93 (49%). Fifty-five (59%) of the strabismus patients demonstrated exotropia with the majority of exotropia patients demonstrating the exo-deviated eye in the direction contralateral to the hemispherectomy (74.5%). Both torticollis and strabismus were most frequently seen immediately after surgery. Sixty-six patients (34%) underwent strabismus treatment. Patients with younger age of seizure onset, younger age of surgery, and certain epilepsy etiologies (hemimegencephaly, Sturge-Weber syndrome) were more likely to develop strabismus and torticollis.

Conclusions: Torticollis and strabismus are common after hemispherectomy and appear to be influenced by etiology and age at surgery. Preoperative discussion with parents and patients regarding those compensatory mechanisms is recommended, and postoperative ophthalmologic assessments are also encouraged.
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http://dx.doi.org/10.1177/0883073819834430DOI Listing
July 2019

Physical Growth of the Contralateral Cerebrum is Preserved After Hemispherotomy in Childhood.

Pediatr Neurol 2019 07 13;96:48-52. Epub 2019 Feb 13.

Department of Radiology, UCLA Medical Center, David Geffen School of Medicine at UCLA, Los Angeles, California. Electronic address:

Background: Hemispherotomy can be an effective treatment for refractory childhood epilepsy. However, the extent of postoperative brain development after hemispherotomy remains incompletely understood. This study aims to provide an anatomic foundation in assessing development of the contralateral hemisphere, by measuring volumetric growth after hemispherotomy.

Methods: Eleven patients with hemimegalencephaly, Rasmussen's encephalitis, and cerebral infarction who underwent hemispherotomy before age 12 years, an immediate preoperative magnetic resonance imaging, and at least three years of follow-up magnetic resonance imagings were retrospectively analyzed. The volume of the contralateral hemisphere was measured before and after surgery. Growth curves were compared with those of healthy individuals from an open database. The growth rate relative to the healthy individuals ("catch-up rate") was calculated.

Results: A positive volumetric growth of the contralateral hemisphere was observed across all pathologies. The hemimegalencephaly subgroup underwent hemispherotomy at the earliest time and had the largest postoperative growth rate, which exceeded that of healthy individuals. The Rasmussen subgroup underwent surgery at the second earliest time and had an intermediate growth rate, which was similar to that of healthy individuals. The infarction subgroup underwent surgery at the latest time and had the slowest growth rate, which was less than that of healthy individuals.

Conclusions: The contralateral hemisphere continues to increase in volume after hemispherotomy in childhood. Further studies with a larger sample size and correlation with cognitive outcomes may aid in characterizing the prognosis after hemispherotomy.
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http://dx.doi.org/10.1016/j.pediatrneurol.2019.02.007DOI Listing
July 2019

Evidence for Innate and Adaptive Immune Responses in a Cohort of Intractable Pediatric Epilepsy Surgery Patients.

Front Immunol 2019 29;10:121. Epub 2019 Jan 29.

Department of Neurosurgery, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, United States.

Brain-infiltrating lymphocytes (BILs) were isolated from resected brain tissue from 10 pediatric epilepsy patients who had undergone surgery for Hemimegalencephaly (HME) ( = 1), Tuberous sclerosis complex (TSC) ( = 2), Focal cortical dysplasia (FCD) ( = 4), and Rasmussen encephalitis (RE) ( = 3). Peripheral blood mononuclear cells (PBMCs) were also isolated from blood collected at the time of the surgery. Cells were immunostained with a panel of 20 antibody markers, and analyzed by mass cytometry. To identify and quantify the immune cell types in the samples, an unbiased clustering method was applied to the entire data set. More than 85 percent of the CD45 cells isolated from resected RE brain tissue comprised T cells; by contrast NK cells and myeloid cells constituted 80-95 percent of the CD45 cells isolated from the TSC and the FCD brain specimens. Three populations of myeloid cells made up >50 percent of all of the myeloid cells in all of the samples of which a population of HLA-DR CD11b CD4 cells comprised the vast majority of myeloid cells in the BIL fractions from the FCD and TSC cases. CD45RA HLA-DR CD11b CD16 NK cells constituted the major population of NK cells in the blood from all of the cases. This subset also comprised the majority of NK cells in BILs from the resected RE and HME brain tissue, whereas NK cells defined as CD45RA HLA-DR CD11b CD16 cells comprised 86-96 percent of the NK cells isolated from the FCD and TSC brain tissue. Thirteen different subsets of CD4 and CD8 αβ T cells and γδ T cells accounted for over 80% of the CD3 T cells in all of the BIL and PBMC samples. At least 90 percent of the T cells in the RE BILs, 80 percent of the T cells in the HME BILs and 40-66 percent in the TSC and FCD BILs comprised activated antigen-experienced (CD45RO HLA-DR CD69) T cells. We conclude that even in cases where there is no evidence for an infection or an immune disorder, activated peripheral immune cells may be present in epileptogenic areas of the brain, possibly in response to seizure-driven brain inflammation.
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http://dx.doi.org/10.3389/fimmu.2019.00121DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6362260PMC
January 2020

Cellular antiseizure mechanisms of everolimus in pediatric tuberous sclerosis complex, cortical dysplasia, and non-mTOR-mediated etiologies.

Epilepsia Open 2018 Dec 2;3(Suppl Suppl 2):180-190. Epub 2018 Sep 2.

Division of Pediatric Neurology Mattel Children's Hospital David Geffen School of Medicine at University of California Los Angeles Los Angeles California U.S.A.

The present study was designed to examine the potential cellular antiseizure mechanisms of everolimus, a mechanistic target of rapamycin (mTOR) pathway blocker, in pediatric epilepsy cases. Cortical tissue samples obtained from pediatric patients (n = 11, ages 0.67-6.75 years) undergoing surgical resections for the treatment of their pharmacoresistant epilepsy were examined electrophysiologically in ex vivo slices. The cohort included mTOR-mediated pathologies (tuberous sclerosis complex [TSC] and severe cortical dysplasia [CD]) as well as non-mTOR-mediated pathologies (tumor and perinatal infarct). Bath application of everolimus (2 μm) had practically no effect on spontaneous inhibitory postsynaptic activity. In contrast, long-term application of everolimus reduced spontaneous excitatory postsynaptic activity, burst discharges induced by blockade of γ-aminobutyric acid A (GABA) receptors, and epileptiform activity generated by 4-aminopyridine, a K channel blocker. The antiseizure effects were more pronounced in TSC and CD cases, whereas in non-mTOR-mediated pathologies, the effects were subtle at best. These results support further clinical trials of everolimus in mTOR pathway-mediated pathologies and emphasize that the effects require sustained exposure over time.
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http://dx.doi.org/10.1002/epi4.12253DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6293070PMC
December 2018

Does Adult Neurogenesis Persist in the Human Hippocampus?

Cell Stem Cell 2018 12;23(6):780-781

Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, University of California, San Francisco, San Francisco, CA 94143, USA; Department of Neurological Surgery, University of California, San Francisco, San Francisco, CA 94143, USA. Electronic address:

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http://dx.doi.org/10.1016/j.stem.2018.11.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6800191PMC
December 2018

Removing high-frequency oscillations: A prospective multicenter study on seizure outcome.

Neurology 2018 09 17;91(11):e1040-e1052. Epub 2018 Aug 17.

From the Department of Neuropediatrics and Muscular Diseases (J.J., M.M.) and Epilepsy Center (J.J., A.S.-B.), Medical Center-University of Freiburg, Faculty of Medicine, University of Freiburg, Germany; Division of Pediatric Neurology (J.Y.W., G.W.M.), David Geffen School of Medicine and Mattel Children's Hospital UCLA, Los Angeles, CA; and Montreal Neurological Institute (P.P., R.Z., F.D., J.G.), McGill University, Quebec, Canada.

Objective: To evaluate the use of interictal high-frequency oscillations (HFOs) in epilepsy surgery for prediction of postsurgical seizure outcome in a prospective multicenter trial.

Methods: We hypothesized that a seizure-free outcome could be expected in patients in whom the surgical planning included the majority of HFO-generating brain tissue while a poor seizure outcome could be expected in patients in whom only a few such areas were planned to be resected. Fifty-two patients were included from 3 tertiary epilepsy centers during a 1-year period. Ripples (80-250 Hz) and fast ripples (250-500 Hz) were automatically detected during slow-wave sleep with chronic intracranial EEG in 2 centers and acute intraoperative electrocorticography in 1 patient.

Results: There was a correlation between the removal of HFO-generating regions and seizure-free outcome at the group level for all patients. No correlation was found, however, for the center-specific analysis, and an individual prognostication of seizure outcome was true in only 36 patients (67%). Moreover, some patients became seizure-free without removal of the majority of HFO-generating tissue. The investigation of influencing factors, including comparisons of visual and automatic analysis, using a threshold analysis for areas with high HFO activity, and excluding contacts bordering the resection, did not result in improved prognostication.

Conclusions: On an individual patient level, a prediction of outcome was not possible in all patients. This may be due to the analysis techniques used. Alternatively, HFOs may be less specific for epileptic tissue than earlier studies have indicated.
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http://dx.doi.org/10.1212/WNL.0000000000006158DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6140372PMC
September 2018

Depressive, inflammatory, and metabolic factors associated with cognitive impairment in patients with epilepsy.

Epilepsy Behav 2018 09 2;86:49-57. Epub 2018 Aug 2.

Centro de Ciências da Saúde, Departamento de Neuropsiquiatria, Universidade Federal de Santa Maria, RS, Brazil; Centro de Ciências Naturais e Exatas, Programa de Pós-graduação em Ciências Biológicas: Bioquímica Toxicológica, Universidade Federal de Santa Maria, RS, Brazil; Centro de Educação Física e Desportos, Departamento de Métodos e Técnicas Desportivas, Laboratório de Bioquímica do Exercício (BIOEX), Universidade Federal de Santa Maria, RS, Brazil; Centro de Ciências da Saúde, Programa de Pós-Graduação em Farmacologia, Universidade Federal de Santa Maria, RS, Brazil. Electronic address:

Purpose: The purpose of this study was to examine the cognitive function and depressive traits most frequently associated with the clinical assessment of patients with epilepsy and if these clinical parameters are linked to glycolipid levels and inflammatory and apoptotic markers.

Methods: Patients with epilepsy (n = 32) and healthy subjects (n = 41) were recruited to participate in this study. Neuropsychological evaluation was performed in both groups through a battery of cognitive tests. Inflammatory markers, apoptotic factors, and deoxyribonucleic acid (DNA) damage were measured in blood samples. Additionally, the metabolic markers total cholesterol (CHO), low-density lipoprotein (LDL), high-density lipoprotein (HDL), triglyceride (TG), and glucose (GLU) levels were analyzed.

Results: Statistical analyses showed that patients with epilepsy presented decreased scores in memory, attention, language, and executive function tests compared with the control group. Analysis revealed that there was negative correlation in epilepsy for seizure duration vs. oral language (R = -0.4484, p < 0.05) and seizure duration vs. problem solving (executive functions) (R = -0.3995, p < 0.05). This was also observed when comparing depression with temporal-spatial orientation (TSO) (R = -0.39, p < 0.05). Furthermore, we observed a higher depression score in patients with epilepsy than in the healthy ones. Statistical analyses showed higher acetylcholinesterase (AChE) (p < 0.05), interleukin 1β (IL-1β, p < 0.001), and tumor necrosis factor-alpha (TNF-α) (p < 0.001) levels compared with those in the control group. Moreover, patients with epilepsy had significantly higher serum levels of caspase 3 (CASP 3) (p < 0.001) and Picogreen (p < 0.001) compared with the control subjects. Regarding the metabolic markers, higher glycolipid levels were observed in the patients with epilepsy (CHO < 0.05*, LDL < 0.0001*, TG < 0.05*, GLU p < 0.05). High-density lipoprotein levels were not significant. The patients with epilepsy had significant correlation when comparing total language with TNF-α (R = -0.4, p < 0.05), praxes with CASP 3 (R = -0.52, p < 0.01), total CHO with total language (R = -0.48, p < 0.05), TG with semantic memory (R = -0.54, p < 0.05), TG with prospective memory (R = -0.2165, p < 0.02), TG with total memory (R = -0.53, p < 0.02), and GLU with total attention (R = -0.62, p < 0.002).

Conclusion: This study supports the evidence of a distinct neuropsychological profile between patients with epilepsy and healthy subjects. Furthermore, our findings suggest that inflammatory pathway, glycolipid profile, and depressive factors may be associated with cognitive dysfunction in patients with epilepsy.
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http://dx.doi.org/10.1016/j.yebeh.2018.07.007DOI Listing
September 2018

Applying participatory action research in traumatic brain injury studies to prevent post-traumatic epilepsy.

Neurobiol Dis 2019 03 18;123:137-144. Epub 2018 Jul 18.

Saul R. Korey Department of Neurology, Dominick P. Purpura Department of Neuroscience and Department of Pediatrics, Albert Einstein College of Medicine and Montefiore Medical Center, 1410 Pelham Parkway South, K-312, Bronx, NY 10461, USA.

The increased focus on stakeholder engagement in determining the aims, design, conduct of research and dissemination of results is substantially changing the biomedical research paradigm. In this era of patient-centered care, incorporating participatory action research methodology into large-scale multi-center studies is essential. The adoption of community engagement facilitates meaningful contribution to the design and implementation of clinical studies. Consequently, encouraging citizen participation and involving key organizations may guide the effective development of future clinical research protocols. Here, we discuss our experience in engaging individuals, their caregivers, as well as scientific and consumer organizations in public outreach and knowledge transfer to assist in the development of effective strategies for recruitment and retention in a future post-traumatic epilepsy prevention randomized controlled trial within the National Institute of Neurologic Disorders and Stroke Center Without Walls, Epilepsy Bioinformatics Study for Antiepileptogenic Therapy (EpiBioS4Rx). The study includes a Public Engagement Core with a diverse consortium of stakeholder partners. Based on the Core's ongoing experience, it is recommended that multicenter studies integrate a participatory action research based approach to harness the benefits of a collective inquiry. The blueprint created by the EpiBioS4Rx Public Engagement Core is a resource that could be applied in other areas of biomedical research.
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http://dx.doi.org/10.1016/j.nbd.2018.07.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6338533PMC
March 2019

Human hippocampal neurogenesis drops sharply in children to undetectable levels in adults.

Nature 2018 03 7;555(7696):377-381. Epub 2018 Mar 7.

Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, University of California San Francisco, San Francisco, California 94143, USA.

New neurons continue to be generated in the subgranular zone of the dentate gyrus of the adult mammalian hippocampus. This process has been linked to learning and memory, stress and exercise, and is thought to be altered in neurological disease. In humans, some studies have suggested that hundreds of new neurons are added to the adult dentate gyrus every day, whereas other studies find many fewer putative new neurons. Despite these discrepancies, it is generally believed that the adult human hippocampus continues to generate new neurons. Here we show that a defined population of progenitor cells does not coalesce in the subgranular zone during human fetal or postnatal development. We also find that the number of proliferating progenitors and young neurons in the dentate gyrus declines sharply during the first year of life and only a few isolated young neurons are observed by 7 and 13 years of age. In adult patients with epilepsy and healthy adults (18-77 years; n = 17 post-mortem samples from controls; n = 12 surgical resection samples from patients with epilepsy), young neurons were not detected in the dentate gyrus. In the monkey (Macaca mulatta) hippocampus, proliferation of neurons in the subgranular zone was found in early postnatal life, but this diminished during juvenile development as neurogenesis decreased. We conclude that recruitment of young neurons to the primate hippocampus decreases rapidly during the first years of life, and that neurogenesis in the dentate gyrus does not continue, or is extremely rare, in adult humans. The early decline in hippocampal neurogenesis raises questions about how the function of the dentate gyrus differs between humans and other species in which adult hippocampal neurogenesis is preserved.
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http://dx.doi.org/10.1038/nature25975DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6179355PMC
March 2018

Noninflammatory Changes of Microglia Are Sufficient to Cause Epilepsy.

Cell Rep 2018 02;22(8):2080-2093

Department of Neuroscience and Experimental Therapeutics, Albany Medical College, Albany, NY 12208, USA. Electronic address:

Microglia are well known to play a critical role in maintaining brain homeostasis. However, their role in epileptogenesis has yet to be determined. Here, we demonstrate that elevated mTOR signaling in mouse microglia leads to phenotypic changes, including an amoeboid-like morphology, increased proliferation, and robust phagocytosis activity, but without a significant induction of pro-inflammatory cytokines. We further provide evidence that these noninflammatory changes in microglia disrupt homeostasis of the CNS, leading to reduced synapse density, marked microglial infiltration into hippocampal pyramidal layers, moderate neuronal degeneration, and massive proliferation of astrocytes. Moreover, the mice thus affected develop severe early-onset spontaneous recurrent seizures (SRSs). Therefore, we have revealed an epileptogenic mechanism that is independent of the microglial inflammatory response. Our data suggest that microglia could be an opportune target for epilepsy prevention.
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http://dx.doi.org/10.1016/j.celrep.2018.02.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5880308PMC
February 2018

Somatic Mutations Activating the mTOR Pathway in Dorsal Telencephalic Progenitors Cause a Continuum of Cortical Dysplasias.

Cell Rep 2017 12;21(13):3754-3766

Division of Genetics and Genomics, Manton Center for Orphan Disease, and Howard Hughes Medical Institute, Boston Children's Hospital, Boston, MA 02115, USA; Departments of Pediatrics and Neurology, Harvard Medical School, Boston, MA 02115, USA; Broad Institute of MIT and Harvard, Cambridge, MA, 02142, USA. Electronic address:

Focal cortical dysplasia (FCD) and hemimegalencephaly (HME) are epileptogenic neurodevelopmental malformations caused by mutations in mTOR pathway genes. Deep sequencing of these genes in FCD/HME brain tissue identified an etiology in 27 of 66 cases (41%). Radiographically indistinguishable lesions are caused by somatic activating mutations in AKT3, MTOR, and PIK3CA and germline loss-of-function mutations in DEPDC5, NPRL2, and TSC1/2, including TSC2 mutations in isolated HME demonstrating a "two-hit" model. Mutations in the same gene cause a disease continuum from FCD to HME to bilateral brain overgrowth, reflecting the progenitor cell and developmental time when the mutation occurred. Single-cell sequencing demonstrated mTOR activation in neurons in all lesions. Conditional Pik3ca activation in the mouse cortex showed that mTOR activation in excitatory neurons and glia, but not interneurons, is sufficient for abnormal cortical overgrowth. These data suggest that mTOR activation in dorsal telencephalic progenitors, in some cases specifically the excitatory neuron lineage, causes cortical dysplasia.
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http://dx.doi.org/10.1016/j.celrep.2017.11.106DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5752134PMC
December 2017

Corticospinal tract atrophy and motor fMRI predict motor preservation after functional cerebral hemispherectomy.

J Neurosurg Pediatr 2018 01 3;21(1):81-89. Epub 2017 Nov 3.

4Neurological Surgery.

OBJECTIVE The potential loss of motor function after cerebral hemispherectomy is a common cause of anguish for patients, their families, and their physicians. The deficits these patients face are individually unique, but as a whole they provide a framework to understand the mechanisms underlying cortical reorganization of motor function. This study investigated whether preoperative functional MRI (fMRI) and diffusion tensor imaging (DTI) could predict the postoperative preservation of hand motor function. METHODS Thirteen independent reviewers analyzed sensorimotor fMRI and colored fractional anisotropy (CoFA)-DTI maps in 25 patients undergoing functional hemispherectomy for treatment of intractable seizures. Pre- and postoperative gross hand motor function were categorized and correlated with fMRI and DTI findings, specifically, abnormally located motor activation on fMRI and corticospinal tract atrophy on DTI. RESULTS Normal sensorimotor cortical activation on preoperative fMRI was significantly associated with severe decline in postoperative motor function, demonstrating 92.9% sensitivity (95% CI 0.661-0.998) and 100% specificity (95% CI 0.715-1.00). Bilaterally robust, symmetric corticospinal tracts on CoFA-DTI maps were significantly associated with severe postoperative motor decline, demonstrating 85.7% sensitivity (95% CI 0.572-0.982) and 100% specificity (95% CI 0.715-1.00). Interpreting the fMR images, the reviewers achieved a Fleiss' kappa coefficient (κ) for interrater agreement of κ = 0.69, indicating good agreement (p < 0.01). When interpreting the CoFA-DTI maps, the reviewers achieved κ = 0.64, again indicating good agreement (p < 0.01). CONCLUSIONS Functional hemispherectomy offers a high potential for seizure freedom without debilitating functional deficits in certain instances. Patients likely to retain preoperative motor function can be identified prior to hemispherectomy, where fMRI or DTI suggests that cortical reorganization of motor function has occurred prior to the operation.
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http://dx.doi.org/10.3171/2017.7.PEDS17137DOI Listing
January 2018

Intraoperative fast ripples independently predict postsurgical epilepsy outcome: Comparison with other electrocorticographic phenomena.

Epilepsy Res 2017 09 16;135:79-86. Epub 2017 Jun 16.

Division of Pediatric Neurology, David Geffen School of Medicine and Mattel Children's Hospital UCLA,Los Angeles, CA, United States.

In the surgical management of epilepsy, the resection of cortex exhibiting interictal fast ripples (250-500Hz) on electrocorticography has been linked to postoperative seizure-freedom. Although fast ripples appear to accurately identify the epileptogenic zone-the minimum tissue that must be removed at surgery to achieve seizure-freedom-it has not been established that fast ripples are a superior biomarker in comparison with multimodal presurgical neuroimaging and other electrocorticography abnormalities. Hence, in the prediction of postoperative seizure-freedom, we compared the value of fast ripples with other intraoperative electocorticography abnormalities including focal slowing, paroxysmal fast activity, intermittent spike discharges, continuous epileptiform discharges, focal attenuation, and intraoperative seizures, as well as complete resection of the lesion defined by MRI and other neuroimaging. In a cohort of 60 children with lesional epilepsy and median postsurgical follow-up exceeding 4 years, who underwent resective epilepsy surgery with intraoperative electrocorticography, we evaluated the extent to which removal of each intraoperative electrocorticography abnormality impacts time to first postoperative seizure using the Kaplan-Meier method and Cox proportional hazards regression. Secondly, we contrasted the predictive value of resection of each competing electrocorticography abnormality using standard test metrics (sensitivity, specificity, positive predictive value, and negative predictive value). In contrast with all other intraoperative electrocorticography abnormalities, fast ripples demonstrated the most favorable combination of positive predictive value (100%) and negative predictive value (76%) in the prediction of postoperative seizures. Among all candidate electrocorticography features, time to first postoperative seizure was most strongly associated with incomplete resection of fast ripples (hazard ratio=19.8, p<0.001). In multivariate survival analyses, postoperative seizures were independently predicted by incomplete resection of cortex generating fast ripples (hazard ratio=25.4, 95%CI 6.71-96.0, p<0.001) and focal slowing (hazard ratio=5.79, 95%CI 1.76-19.0, p=0.004), even after adjustment for the impact of an otherwise complete resection. All children with incomplete resection of interictal FR-generating cortex exhibited postoperative seizures within six months. Notably, this cohort included many patients with large resections and thus limited opportunity to exhibit unresected fast ripples. Future study in a cohort with small resection volume, or a clinical trial in which resection margins are guided by fast ripple distribution, would likely yield a more precise estimate of the risk posed by unresected fast ripples. With a high detection rate during brief intraoperative electrocorticography and favorable positive and negative predictive value, interictal fast ripple characterization during surgery is a feasible and useful adjunct to standard methods for epilepsy surgery planning, and represents a valuable spatially-localizing biomarker of the epileptogenic zone, without the need for prolonged extraoperative electrocorticography.
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http://dx.doi.org/10.1016/j.eplepsyres.2017.06.010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5568451PMC
September 2017

AR2, a novel automatic muscle artifact reduction software method for ictal EEG interpretation: Validation and comparison of performance with commercially available software.

F1000Res 2017 10;6:30. Epub 2017 Jan 10.

Department of Neurology, Jefferson Comprehensive Epilepsy Center, Thomas Jefferson University, Philadelphia, USA.

To develop a novel software method (AR2) for reducing muscle contamination of ictal scalp electroencephalogram (EEG), and validate this method on the basis of its performance in comparison to a commercially available software method (AR1) to accurately depict seizure-onset location. A blinded investigation used 23 EEG recordings of seizures from 8 patients. Each recording was uninterpretable with digital filtering because of muscle artifact and processed using AR1 and AR2 and reviewed by 26 EEG specialists. EEG readers assessed seizure-onset time, lateralization, and region, and specified confidence for each determination. The two methods were validated on the basis of the number of readers able to render assignments, confidence, the intra-class correlation (ICC), and agreement with other clinical findings. Among the 23 seizures, two-thirds of the readers were able to delineate seizure-onset time in 10 of 23 using AR1, and 15 of 23 using AR2 (p<0.01). Fewer readers could lateralize seizure-onset (p<0.05). The confidence measures of the assignments were low (probable-unlikely), but increased using AR2 (p<0.05). The ICC for identifying the time of seizure-onset was 0.15 (95% confidence interval (CI), 0.11-0.18) using AR1 and 0.26 (95% CI 0.21-0.30) using AR2.  The EEG interpretations were often consistent with behavioral, neurophysiological, and neuro-radiological findings, with left sided assignments correct in 95.9% (CI 85.7-98.9%, n=4) of cases using AR2, and 91.9% (77.0-97.5%) (n=4) of cases using AR1. EEG artifact reduction methods for localizing seizure-onset does not result in high rates of interpretability, reader confidence, and inter-reader agreement. However, the assignments by groups of readers are often congruent with other clinical data. Utilization of the AR2 software method may improve the validity of ictal EEG artifact reduction.
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http://dx.doi.org/10.12688/f1000research.10569.2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5399961PMC
January 2017

ILAE classification of the epilepsies: Position paper of the ILAE Commission for Classification and Terminology.

Epilepsia 2017 04 8;58(4):512-521. Epub 2017 Mar 8.

Paediatric Neurosciences Research Group, Fraser of Allander Neurosciences Unit, Royal Hospital for Children, Glasgow, United Kingdom.

The International League Against Epilepsy (ILAE) Classification of the Epilepsies has been updated to reflect our gain in understanding of the epilepsies and their underlying mechanisms following the major scientific advances that have taken place since the last ratified classification in 1989. As a critical tool for the practicing clinician, epilepsy classification must be relevant and dynamic to changes in thinking, yet robust and translatable to all areas of the globe. Its primary purpose is for diagnosis of patients, but it is also critical for epilepsy research, development of antiepileptic therapies, and communication around the world. The new classification originates from a draft document submitted for public comments in 2013, which was revised to incorporate extensive feedback from the international epilepsy community over several rounds of consultation. It presents three levels, starting with seizure type, where it assumes that the patient is having epileptic seizures as defined by the new 2017 ILAE Seizure Classification. After diagnosis of the seizure type, the next step is diagnosis of epilepsy type, including focal epilepsy, generalized epilepsy, combined generalized, and focal epilepsy, and also an unknown epilepsy group. The third level is that of epilepsy syndrome, where a specific syndromic diagnosis can be made. The new classification incorporates etiology along each stage, emphasizing the need to consider etiology at each step of diagnosis, as it often carries significant treatment implications. Etiology is broken into six subgroups, selected because of their potential therapeutic consequences. New terminology is introduced such as developmental and epileptic encephalopathy. The term benign is replaced by the terms self-limited and pharmacoresponsive, to be used where appropriate. It is hoped that this new framework will assist in improving epilepsy care and research in the 21st century.
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http://dx.doi.org/10.1111/epi.13709DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5386840PMC
April 2017

Shared HLA Class I and II Alleles and Clonally Restricted Public and Private Brain-Infiltrating αβ T Cells in a Cohort of Rasmussen Encephalitis Surgery Patients.

Front Immunol 2016 19;7:608. Epub 2016 Dec 19.

Department of Neurosurgery, David Geffen School of Medicine at the University of California Los Angeles , Los Angeles, CA , USA.

Rasmussen encephalitis (RE) is a rare pediatric neuroinflammatory disease characterized by intractable seizures and unilateral brain atrophy. T cell infiltrates in affected brain tissue and the presence of circulating autoantibodies in some RE patients have indicated that RE may be an autoimmune disease. The strongest genetic links to autoimmunity reside in the MHC locus, therefore, we determined the human leukocyte antigen (HLA) class I and class II alleles carried by a cohort of 24 RE surgery cases by targeted in-depth genomic sequencing. Compared with a reference population the allelic frequency of three alleles, DQA1*04:01:01, DQB1*04:02:01, and HLA-C*07:02:01:01 indicated that they might confer susceptibility to the disease. It has been reported that HLA-C*07:02 is a risk factor for Graves disease. Further, eight patients in the study cohort carried HLA-A*03:01:01:01, which has been linked to susceptibility to multiple sclerosis. Four patients carried a combination of three HLA class II alleles that has been linked to type 1 diabetes (DQA1*05:01:01:01~DQB1*02:01:01~DRB1*03:01:01:01), and five patients carried a combination of HLA class II alleles that has been linked to the risk of contracting multiple sclerosis (DQA1*01:02:01:01, DQB1*06:02:01, DRB1*15:01:01:01). We also analyzed the diversity of αβ T cells in brain and blood specimens from 14 of these RE surgery cases by sequencing the third complementarity regions (CDR3s) of rearranged T cell receptor β genes. A total of 31 unique CDR3 sequences accounted for the top 5% of all CDR3 sequences in the 14 brain specimens. Thirteen of these sequences were found in sequencing data from healthy blood donors; the remaining 18 sequences were patient specific. These observations provide evidence for the clonal expansion of public and private T cells in the brain, which might be influenced by the RE patient's HLA haplotype.
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http://dx.doi.org/10.3389/fimmu.2016.00608DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5165278PMC
December 2016

Prospective and "live" fast ripple detection and localization in the operating room: Impact on epilepsy surgery outcomes in children.

Epilepsy Res 2016 11 23;127:344-351. Epub 2016 Sep 23.

Division of Pediatric Neurology, Mattel Children's Hospital UCLA, Los Angeles, CA, United States. Electronic address:

Objective: Fast ripples (FR, 250-500Hz) are proposed biomarkers of the epileptogenic zone on the basis of several retrospective reports linking postoperative seizure freedom to their complete resection. There are no clinical trials or prospective reports validating the use of FR as characterized by electrocorticography (ECoG), to guide the scope of epilepsy surgery, and to inform prognosis thereafter. We set out to prospectively evaluate the utility of FR resection to predict postoperative epilepsy outcomes, and examine the feasibility of "live" intraoperative FR ascertainment.

Methods: FR were prospectively reviewed in 30 consecutive pediatric cases including 11 reviewed "live" during surgery. Intraoperative ECoG studies were recorded at 2000Hz sampling rate, interpreted conventionally to guide surgical resection, and visually inspected for FR. Seizure outcome was tallied for all 30 children.

Results: Median age at surgery was 9.1 years (interquartile range [IQR] 4.7-13.2), median ECoG duration was 10.5min (IQR 8.0-13.2), and median postoperative follow-up was 58.4 months (IQR 25.7-79.0). FR were identified in 24 of 30 ECoG studies. The incomplete resection of FR was strongly linked to postoperative seizures (hazard ratio 11.6, p=0.005). "Live" ECoG review in the operating room to ascertain FR proved feasible and did not differ from conventional FR ascertainment.

Significance: In a prospective fashion, including "live" review, FR were detected in 80% of pediatric ECoG studies, and incomplete resection of FR cortex predicted postoperative seizures. These findings extend the notion that interictal FR are surrogate markers of the epileptogenic zone, and that their intraoperative localization could be used to inform prognosis and guide surgical resections in children.
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http://dx.doi.org/10.1016/j.eplepsyres.2016.09.017DOI Listing
November 2016

Cost-utility analysis of competing treatment strategies for drug-resistant epilepsy in children with Tuberous Sclerosis Complex.

Epilepsy Behav 2016 10 31;63:79-88. Epub 2016 Aug 31.

Department of Neurosurgery, David Geffen School of Medicine at University of California Los Angeles, Los Angeles, CA, USA; Brain Research Institute, University of California Los Angeles, Los Angeles, CA, USA.

Background: The management of drug-resistant epilepsy in children with Tuberous Sclerosis Complex (TSC) is challenging because of the multitude of treatment options, wide range of associated costs, and uncertainty of seizure outcomes. The most cost-effective approach for children whose epilepsy has failed to improve with first-line medical therapy is uncertain.

Methods: A review of MEDLINE from 1990 to 2015 was conducted. A cost-utility analysis, from a third-party payer perspective, was performed for children with drug-resistant epilepsy that had failed to improve with 2 antiseizure drugs (ASDs) and that was amenable to resective epilepsy surgery, across a time-horizon of 5years. Four strategies were included: (1) resective epilepsy surgery, (2) vagus nerve stimulator (VNS) implantation, (3) ketogenic diet, and (4) addition of a third ASD (specifically, carbamazepine). The incremental cost per quality-adjusted life year (QALY) gained was analyzed.

Results: Given a willingness-to-pay (WTP) of $100,000 per QALY, the addition of a third ASD ($6600 for a gain of 4.14 QALYs) was the most cost-effective treatment strategy. In a secondary analysis, if the child whose epilepsy had failed to improve with 3 ASDs, ketogenic diet, addition of a fourth ASD, and resective epilepsy surgery were incrementally cost-effective treatment strategies. Vagus nerve stimulator implantation was more expensive yet less effective than alternative strategies and should not be prioritized.

Conclusions: The addition of a third ASD is a universally cost-effective treatment option in the management of children with drug-resistant epilepsy that has failed to improve with 2 ASDs. For children whose epilepsy has failed to improve with 3 ASDs, the most cost-effective treatment depends on the health-care resources available reflected by the WTP.
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http://dx.doi.org/10.1016/j.yebeh.2016.07.034DOI Listing
October 2016

Knowledge translation of an online tool to determine candidacy for epilepsy surgery evaluation.

Neurol Clin Pract 2016 Aug;6(4):304-314

Department of Clinical Neurosciences & Hotchkiss Brain Institute (KMS, SW, LC, NJ), Department of Community Health Sciences & O'Brien Institute for Public Health (KMS, JH-L, SW, HQ, NJ), Department of Medicine (JH-L), Department of Family Medicine (HA), and Ward of the 21st Century (JS), Cumming School of Medicine, University of Calgary, Alberta, Canada; UCL Institute of Child Health & Great Ormond Street Hospital for Children (JHC), London, UK; and Department of Neurosurgery, Ronald Reagan UCLA Medical Center, University of California (GWM), Los Angeles.

Background: Guidelines recommend that surgery be considered in patients with drug-resistant epilepsy, yet delays to epilepsy surgery still exist. A Web-based, evidence-informed clinical decision tool (www.toolsforepilepsy.com) was developed to help physicians determine which patients are appropriate for an epilepsy surgery evaluation. We evaluated the usability and feasibility of the tool with the intended end users in order to improve implementation into practice.

Methods: Usability testing was conducted with relevant end users. After the tool was modified based on usability results, another group of end users trialed the tool in their clinical practice. This latter group of end users then participated in focus groups and semi-structured interviews to address barriers and facilitators to tool implementation. Finally, a stakeholder meeting was held with domain experts and end users to discuss further changes to the tool and implementation strategies.

Results: Six overall themes were identified through usability testing, and an additional 11 themes were identified through the focus groups and interviews. The tool was modified based on these findings, which were then presented at the stakeholder meeting of experts and end users for further refinement. The findings were also used to guide discussions of potential implementation strategies at the meeting.

Conclusion: This study provides guidance on how to improve the usability of clinical decision tools by engaging end users, experts, and other key stakeholders. The modifications to the tool should facilitate its implementation in clinical practice and ultimately enhance the quality of care persons with epilepsy receive.
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http://dx.doi.org/10.1212/CPJ.0000000000000250DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4987121PMC
August 2016