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1.  Abnormal dendrite and spine morphology in primary visual cortex in the CGG knock-in mouse model of the fragile X premutation 
Epilepsia  2012;53(0 1):150-160.
Summary
The fragile X mental retardation 1 gene (Fmr1) is polymorphic for CGG trinucleotide repeat number in the 5′-untranslated region, with repeat lengths <45 associated with typical development and repeat lengths >200 resulting in hypermethylation and transcriptional silencing of the gene and mental retardation in the fragile X Syndrome (FXS). Individuals with CGG repeat expansions between 55 and 200 are carriers of the fragile X premutation (PM). PM carriers show a phenotype that can include anxiety, depression, social phobia, and memory deficits. They are also at risk for developing fragile X–associated tremor/ataxia syndrome (FXTAS), a late onset neurodegenerative disorder characterized by tremor, ataxia, cognitive impairment, and neuropathologic features including intranuclear inclusions in neurons and astrocytes, loss of Purkinje cells, and white matter disease. However, very little is known about dendritic morphology in PM or in FXTAS. Therefore, we carried out a Golgi study of dendritic complexity and dendritic spine morphology in layer II/III pyramidal neurons in primary visual cortex in a knock-in (KI) mouse model of the PM. These CGG KI mice carry an expanded CGG trinucleotide repeat on Fmr1, and model many features of the PM and FXTAS. Compared to wild-type (WT) mice, CGG KI mice showed fewer dendritic branches proximal to the soma, reduced total dendritic length, and a higher frequency of longer dendritic spines. The distribution of morphologic spine types (e.g., stubby, mushroom, filopodial) did not differ between WT and KI mice. These findings demonstrate that synaptic circuitry is abnormal in visual cortex of mice used to model the PM, and suggest that such changes may underlie neurologic features found in individuals carrying the PM as well as in individuals with FXTAS.
doi:10.1111/j.1528-1167.2012.03486.x
PMCID: PMC4316681  PMID: 22612820
Golgi impregnation; Pyramidal neurons; Visual cortex; Dendritic spines; Fragile X; Fragile X mental retardation protein; Fragile X premutation; FXTAS; Synapse; Circuitry
2.  [No title available] 
PMCID: PMC3945279  PMID: 24447124
3.  [No title available] 
PMCID: PMC4045634  PMID: 24447031
4.  [No title available] 
PMCID: PMC4103687  PMID: 24417694
5.  [No title available] 
PMCID: PMC4104491  PMID: 24483230
6.  A potassium leak channel silences hyperactive neurons and ameliorates status epilepticus 
Epilepsia  2013;55(2):203-213.
Objective
To develop a constitutively active K+ leak channel using TREK-1 (TWIK-related potassium channel 1; TREK-M) that is resistant to compensatory down-regulation by second messenger cascades, and to validate the ability of TREK-M to silence hyperactive neurons using cultured hippocampal neurons. To test if adenoassociated viral (AAV) delivery of TREK-M could reduce the duration of status epilepticus and reduce neuronal death induced by lithium-pilocarpine administration.
Methods
Molecular cloning techniques were used to engineer novel vectors to deliver TREK–M via plasmids, lentivirus, and AAV using a cytomegalovirus (CMV)-enhanced GABRA4 promoter. Electrophysiology was used to characterize the activity and regulation of TREK–M in human embryonic kidney (HEK-293) cells, and the ability to reduce spontaneous activity in cultured hippocampal neurons. Adult male rats were injected bilaterally with self-complementary AAV particles composed of serotype 5 capsid into the hippocampus and entorhinal cortex. Lithium-pilocarpine was used to induce status epilepticus. Seizures were monitored using continuous video–electroencephalography (EEG) monitoring. Neuronal death was measured using Fluoro-Jade C staining of para-formaldehyde-fixed brain slices.
Results
TREK-M inhibited neuronal firing by hyperpolarizing the resting membrane potential and decreasing input resistance. AAV delivery of TREK-M decreased the duration of status epilepticus by 50%. Concomitantly it reduced neuronal death in areas targeted by the AAV injection.
Significance
These findings demonstrate that TREK-M can silence hyperexcitable neurons in the brain of epileptic rats and treat acute seizures. This study paves the way for an alternative gene therapy treatment of status epilepticus, and provides the rationale for studies of AAV-TREK-M’s effect on spontaneous seizures in chronic models of temporal lobe epilepsy.
doi:10.1111/epi.12472
PMCID: PMC4161023  PMID: 24299204
Potassium currents; Gene therapy; Hippocampus; Status epilepticus; T-type calcium channel; Temporal lobe epilepsy
7.  High Resolution Molecular Genomic Autopsy Reveals Complex SUDEP Risk Profile 
Epilepsia  2013;55(2):e6-12.
SUMMARY
Advanced variant detection in genes underlying risk of sudden unexpected death in epilepsy (SUDEP) can uncover extensive epistatic complexity and improve diagnostic accuracy of epilepsy related mortality. However, the sensitivity and clinical utility of diagnostic panels based solely on established cardiac arrhythmia genes in the molecular autopsy of SUDEP is unknown.
We applied the established clinical diagnostic panels, followed by sequencing and a high density copy number variant (CNV) detection array of an additional 253 related ion channel subunit genes to analyze the overall genomic variation in a SUDEP of the three year old proband with severe myoclonic epilepsy of infancy (SMEI).
We uncovered complex combinations of single nucleotide polymorphisms and CNVs in genes expressed in both neuro-cardiac and respiratory control pathways, including SCN1A, KCNA1, RYR3, and HTR2C.
Our findings demonstrate the importance of comprehensive high resolution variant analysis in the assessment of personally relevant SUDEP risk. In this case, the combination of de novo SNPs and CNVs in the SCN1A and KCNA1 genes respectively is suspected to be the principal risk factor for both epilepsy and premature death. However, consideration of the overall biologically relevant variant complexity with its extensive functional epistatic interactions reveals potential personal risk more accurately.
doi:10.1111/epi.12489
PMCID: PMC4195652  PMID: 24372310
SUDEP; SMEI; Epileptic Encephalopathy; Dravet Syndrome; Gene; Risk; Molecular Autopsy
8.  Treatment of infantile spasms with very high dose prednisolone before high dose ACTH 
Epilepsia  2013;55(1):103-107.
Summary
Objective
This study investigated the short-term response to a standardized hormonal therapy protocol for treatment of infantile spasms.
Methods
Twenty-seven children with video-EEG confirmed infantile spasms received very high dose (8 mg/kg/day, max 60 mg/day) oral prednisolone for 2 weeks. Response (absence of both hypsarrhythmia and spasms) to prednisolone was ascertained by repeat overnight video-EEG. Responders were tapered off over 2 weeks and non-responders were immediately transitioned to high dose (150 IU/m2/day) intramuscular ACTH for 2 additional weeks. Response was again determined by overnight video-EEG after ACTH therapy.
Results
Sixty-three percent (17/27) of patients responded completely to prednisolone. Subsequently, 40% (4/10) of prednisolone non-responders exhibited a complete response after an additional 2-week course with ACTH. Among 27 subjects with median follow-up of 13.5 months (interquartile range 4.8-25.9), 12% (2/17) of prednisolone responders and 50% (2/4) of ACTH responders experienced a relapse between 2 and 9 months after initial response.
Significance
Very high dose prednisolone demonstrated significantly higher efficacy than previously reported for lower doses in prior studies. High dose ACTH may be superior to very high dose prednisolone, and in lieu of a definitive clinical trial, the choice between prednisolone and ACTH for initial treatment of infantile spasms remains controversial.
doi:10.1111/epi.12460
PMCID: PMC3904676  PMID: 24446954
hypsarrhythmia; corticotropin; ACTHar; corticosteroids; West syndrome
9.  Diagnostic delays in children with early-onset epilepsy: impact, reasons, and opportunities to improve care 
Epilepsia  2013;55(1):123-132.
Purpose
Delayed diagnosis of early-onset epilepsy is a potentially important and avoidable complication in epilepsy care. We examined the frequency of diagnostic delays in young children with newly presenting epilepsy, their developmental impact, and reasons for delays.
Methods
Children who developed epilepsy before their third birthday were identified in a prospective community-based cohort. An interval ≥1 month from second seizure to diagnosis was considered a delay. Testing of development at baseline and for up to three years after and of IQ 8–9 years later was performed. Detailed parental baseline interview accounts and medical records were reviewed to identify potential reasons for delays. Factors associated with delays included the parent, child, pediatrician, neurologist, and scheduling.
Results
Diagnostic delays occurred in 70/172 (41%) children. Delays occurred less often if children had received medical attention for the first seizure (p<0.0001), previously had neonatal or febrile seizures (p=0.02), had only convulsions before diagnosis (p=0.005) or had a college-educated parent (p=0.01). A ≥1 month diagnostic delay was associated with an average 7.4 point drop (p=0.02) in the Vineland Scales of Adaptive Behavior motor score. The effect was present at diagnosis, persisted for at least three years, and was also apparent in IQ scores 8–9 years later which were lower in association with a diagnostic delay by 8.4 points (p=0.06) for processing speed up to 14.5 points (p=0.004) for full scale IQ, after adjustment for parental education and other epilepsy-related clinical factors. Factors associated with delayed diagnosis included parents not recognizing events as seizures (N=47), pediatricians missing or deferring diagnosis (N=15), neurologists deferring diagnosis (N=7), and scheduling problems (N=11).
Significance
Diagnostic delays occur in many young children with epilepsy. They are associated with substantial decrements in development and IQ later in childhood. Several factors influence diagnostic delays and may represent opportunities for intervention and improved care.
doi:10.1111/epi.12479
PMCID: PMC3946922  PMID: 24313635
Health Services; Barriers to care; pediatrics; development
10.  FUNCTIONAL CONNECTIVITY OF HIPPOCAMPAL NETWORKS IN TEMPORAL LOBE EPILEPSY 
Epilepsia  2013;55(1):137-145.
Summary
Objective
Temporal Lobe Epilepsy (TLE) affects brain areas beyond the temporal lobes due to connections of the hippocampi and other temporal lobe structures. Using functional connectivity MRI, we determined the changes of hippocampal networks in TLE to assess for a more complete distribution of abnormality.
Methods
Regions of interest (ROIs) were defined in the right and left hippocampi in three groups of participants- left TLE (n=13), right TLE (n=11) and healthy controls (n=16). Brain regions functionally connected to these ROIs were identified by correlating resting-state low-frequency fMRI Blood Oxygenation Level Dependent (BOLD) signal fluctuations. The grouped results were compared using independent sample t-test.
Results
TLE was associated with increased hippocampal connectivity involving several key areas of the limbic network (temporal lobe, insula, thalamus), frontal lobes, angular gyrus, basal ganglia, brainstem and cerebellum along with reduced connectivity involving areas of the sensorimotor cortex (visual, somatosensory, auditory, primary motor) and the default mode network (precuneus). Left TLE had more marked connectivity changes than right TLE.
Significance
The observed connectivity changes in TLE indicate dysfunctional networks that underlie widespread brain involvement in TLE. There are identifiable differences in the connectivity of the hippocampi between left and right TLE.
doi:10.1111/epi.12476
PMCID: PMC3946924  PMID: 24313597
Temporal Lobe Epilepsy (TLE); Hippocampal networks; fMRI; Functional Connectivity; Epilepsy psychopathology; Epileptic Networks
11.  Cyclooxygenase-2 in epilepsy 
Epilepsia  2013;55(1):17-25.
Summary
Epilepsy is one of the more prevalent neurological disorders in the world, affecting approximately 50 million people of different ages and backgrounds. Epileptic seizures propagating through both lobes of the forebrain can have permanent debilitating effects on a patient's cognitive and somatosensory brain functions. Epilepsy, defined by the sporadic occurrence of recurrent seizures (SRS), is often accompanied by inflammation of the brain. Pronounced increases in the expression of key inflammatory mediators (e.g. IL-1β, TNFα, cyclooxygenase-2, CXCL10) after seizures may cause secondary damage in the brain and increase the likelihood of repetitive seizures. The cyclooxygenase-2 (COX-2) enzyme is induced rapidly during seizures. The increased level of COX-2 in specific areas of the epileptic brain can help to identify regions of seizure-induced brain inflammation. A good deal of effort has been expended to determine whether COX-2 inhibition might be neuroprotective and represent an adjunct therapeutic strategy along with antiepileptic drugs to treat epilepsy. However, the effectiveness of COX-2 inhibitors on epilepsy animal models appears to depend on the timing of administration. With all of the effort placed on making use of COX-2 inhibitors as therapeutic agents for the treatment of epilepsy, inflammation, and neurodegenerative diseases there has yet to be a selective and potent COX-2 inhibitor that has shown a clear therapeutic outcome with acceptable side effects.
doi:10.1111/epi.12461
PMCID: PMC3956447  PMID: 24446952
Seizure; Neurodegeneration; Anti-convulsant; Prostaglandin; Blood-brain Barrier; cognitive deficit; EP2; EP1
12.  Clinical features, proximate causes and consequences of active convulsive epilepsy in Africa 
Epilepsia  2013;55(1):76-85.
SUMMARY
Purpose
Epilepsy is common in sub-Saharan Africa (SSA), but the clinical features and consequences are poorly characterized. Most studies are hospital-based and few studies have compared different ecological sites in SSA. We described active convulsive epilepsy (ACE) identified in cross-sectional community-based surveys in SSA, to understand the proximate causes, features, and consequences.
Methods
We performed a detailed clinical and neurophysiological description of ACE cases identified from a community survey of 584,586 people using medical history, neurological examination and electroencephalograph (EEG) data from five sites in Africa: South Africa; Tanzania; Uganda; Kenya and Ghana. The cases were examined by clinicians to discover risk factors, clinical features, and consequences of epilepsy. We used logistic regression to determine the epilepsy factors associated with medical comorbidities.
Key findings
Half (51%) of the 2,170 people with ACE were children and 69% of seizures began in childhood. Focal features (EEG, seizure types and neurological deficits) were present in 58% of ACE cases, and varied significantly with site. Status epilepticus occurred in 25% of people with ACE. Only 36% received antiepileptic drugs (phenobarbital was the commonest drug (95%)), and the proportion varied significantly with the site. Proximate causes of ACE were adverse perinatal events (11%) for onset of seizures before 18 years; acute encephalopathy (10%) and head injury prior to seizure-onset (3%). Important comorbidities were malnutrition (15%), cognitive impairment (23%) and neurological deficits (15%). The consequences of ACE were burns (16%), head injuries (post seizures) (1%), lack of education (43%) and being unmarried (67%) or unemployed (57%) in adults; all significantly more common than those without epilepsy.
Significance
There were significant differences in the co-morbidities across sites. Focal features are common in ACE suggesting identifiable and preventable causes. Malnutrition, cognitive and neurological deficits are common in people with ACE and should be integrated into the management of epilepsy in this region. Consequences of epilepsy such as burns, lack of education, poor marriage prospects and unemployment need to be addressed.
doi:10.1111/epi.12392
PMCID: PMC4074306  PMID: 24116877
sub-Saharan Africa; clinical features; active convulsive epilepsy; co-morbidity; population-based study
13.  CPP-115, a vigabatrin analogue, decreases spasms in the multiple-hit rat model of infantile spasms 
Epilepsia  2013;55(1):94-102.
SUMMARY
Objective
Infantile spasms (IS) have poor outcomes and limited treatment options, including vigabatrin, a GABA aminotransferase inactivator. Vigabatrin has been associated with retinal toxicity. A high affinity vigabatrin analogue (CPP-115, Catalyst Pharmaceutical Partners) has shown lower risk of retinal toxicity. Here, we test the efficacy of CPP-115 in reducing spasms and its tolerability in the multiple-hit rat model of IS, in which daily vigabatrin reduced spasms only for one day, but was not well tolerated.
Methods
Male rats were treated with the protocol of the multiple-hit model of IS at postnatal day 3 (PN3). Using a randomized, blinded, vehicle-controlled, dose-response study design, CPP-115 [0.1, 1, or 5 mg/kg intraperitoneally (i.p.)] or vehicle were given daily (PN4-12) or as single injection (PN7) after spasms onset. Intermittent video- or video-EEG monitoring was done. Secondary endpoints included: daily weights, survival, performance on open field activity, surface righting time, and negative geotaxis (PN3-20), horizontal bar (PN13-20), Barnes maze (PN16-19). Statistics used a linear mixed model of raw or normalized log-transformed data, taking into account the repeated observations on each animal.
Results
The lower CPP-115 doses (0.1–1 mg/kg/day, PN4-12) reduced spasms between PN6-7 without increasing mortality. CPP-115 at 5 mg/kg/day (PN4-12) reduced spasms earlier (PN5), but was eventually lethal. A single CPP-115 injection (1mg/kg i.p.) decreased electroclinical spasms acutely but transiently. CPP-115 transiently improved the probability to >50% reduction of spasms, but did not accelerate spasms cessation. CPP-115 did not alter neurodevelopmental outcomes or visuospatial learning.
Significance
We provide proof-of-concept evidence that CPP-115, a vigabatrin analogue, decreases spasms in the multiple-hit rat model of IS at considerably lower and better tolerated doses than vigabatrin did in our previous studies. Further optimization of the treatment protocol is needed. CPP-115 may be a promising new candidate treatment for IS with better tolerability than vigabatrin.
doi:10.1111/epi.12424
PMCID: PMC4102583  PMID: 24321005
Epilepsy; seizure; lipopolysaccharide; doxorubicin; GABA aminotransferase; neurodevelopmental reflexes; learning; memory
14.  Bilateral frontoparietal polymicrogyria, Lennox-Gastaut syndrome, and GPR56 gene mutations  
Epilepsia  2008;50(6):1344-1353.
Summary
Purpose
Bilateral frontoparietal polymicrogyria (BFPP) has been reported in sporadic patients and in recessive pedigrees. Eleven mutations in GPR56, a gene encoding an evolutionarily dynamic G-protein–coupled receptor, have been identified in 29 patients from 18 families. The clinical features of BFPP include severe mental retardation, motor and language impairment, and epilepsy. No detailed description of the epilepsy is available for the patients reported to date. We report three consanguineous families in which four affected individuals with BFPP and GPR56 mutations had Lennox-Gastaut syndrome.
Methods
Family studies, brain magnetic resonance imaging (MRI), electroencephalography (EEG)-video recordings, and mutation analysis.
Results
In Family 1, with one affected proband, we found an R565W change in the second extracellular loop of GPR56, involving a highly conserved aminoacidic residue. In Family 2, with one affected proband, we found an R79X change affecting the protein N-terminus and predicted to cause a premature truncation with loss of the G-protein–coupled receptor proteolytic site. In family 3, with two affected siblings, we found an R33P substitution in the protein N-terminus, involving a highly conserved aminoacidic residue. Epilepsy, present in all four patients, had started between ages 1 and 8 years, with infantile spasms in one patient and with de novo Lennox-Gastaut syndrome in the remaining three. All patients had Lennox-Gastaut syndrome when last observed, at ages 13 to 32 years.
Discussion
Several genes, when mutated, can cause malformations of cortical development that have been associated with the Lennox-Gastaut syndrome. BFPP caused by GPR56 mutations represents an additional, although rare, genetically determined cause of Lennox-Gastaut syndrome.
doi:10.1111/j.1528-1167.2008.01787.x
PMCID: PMC4271835  PMID: 19016831
Polymicrogyria; Epilepsy; Lennox-Gastaut; GPR56
15.  Genetic malformations of the human frontal lobe 
Epilepsia  2010;51(0 1):13-16.
doi:10.1111/j.1528-1167.2009.02435.x
PMCID: PMC4271974  PMID: 20331705
16.  AMPA Receptor antagonist NBQX attenuates later-life epileptic seizures and autistic-like social deficits following neonatal seizures 
Epilepsia  2013;54(11):1922-1932.
Summary
Purpose
To determine whether AMPA receptor (AMPAR) antagonist NBQX can prevent early mTOR pathway activation and long-term sequelae following neonatal seizures in rats, including later-life spontaneous recurrent seizures, CA3 mossy fiber sprouting, and autistic-like social deficits.
Methods
Long-Evans rats experienced hypoxia-induced neonatal seizures (HS) at postnatal day (P)10. NBQX (20 mg/kg) was administered immediately following HS (every 12h x 4 doses). 12h post-HS, we assessed mTOR activation marker phosphorylated p70-S6 kinase (p-p70S6K) in hippocampus and cortex of vehicle (HS+V) or NBQX-treated post-HS rats (HS+N) versus littermate controls (C+V). Spontaneous seizure activity was compared between groups by epidural cortical electroencephalography (EEG) at P70-100. Aberrant mossy fiber sprouting was measured using Timm staining. Finally, we assessed behavior between P30-38.
Key findings
Post-seizure NBQX treatment significantly attenuated seizure-induced increases in p-P70S6K in the hippocampus (p<0.01) and cortex (p<0.001). While spontaneous recurrent seizures increased in adulthood in HS+V rats compared to controls (3.22±1seizures/hour; p=0.03), NBQX significantly attenuated later-life seizures (0.14±0.1 seizures/hour; p=0.046). HS+N rats showed less aberrant mossy fiber sprouting (115±8.0%) than vehicle-treated post-HS rats (174±10%, p=0.004), compared to controls (normalized to 100%). Finally, NBQX treatment prevented alterations in later-life social behavior; post-HS rats showed significantly decreased preference for a novel over a familiar rat (71.0±12 sec) compared to controls (99.0±15.6 sec; p<0.01), while HS+N rats showed social novelty preference similar to controls (114.3±14.1 sec).
Significance
Brief NBQX administration during the 48 hours post-seizure in P10 Long-Evans rats suppresses transient mTOR pathway activation and attenuates spontaneous recurrent seizures, social preference deficits and mossy fiber sprouting observed in vehicle-treated adult rats after early-life seizures. These results suggest that acute AMPAR antagonist treatment during the latent period immediately following neonatal HS can modify seizure-induced activation of mTOR, reduce the frequency of later-life seizures, and protect against CA3 mossy fiber sprouting and autistic-like social deficits.
doi:10.1111/epi.12378
PMCID: PMC4262152  PMID: 24117347
Hypoxic/ischemic encephalopathy; epileptogenesis; autistic-like behavior; AMPA receptor antagonists; early-life seizures
17.  Neurobehavioral comorbidities of pediatric epilepsies are linked to thalamic structural abnormalities 
Epilepsia  2013;54(12):2116-2124.
Summary
Purpose
Neurobehavioral comorbidities are common in pediatric epilepsy with enduring adverse effects on functioning, but their neuroanatomical underpinning is unclear. Striatal and thalamic abnormalities have been associated with childhood-onset epilepsies, suggesting that epilepsy-related changes in the subcortical circuit might be associated with the combordities of children with epilepsy. We aimed to compare subcortical volumes and their relationship with age in children with complex partial seizures (CPS), childhood absence epilepsy (CAE), and healthy controls (HC). We examined the shared versus unique structural-functional relationships of these volumes with behavior problems, intelligence, language, peer interaction, and epilepsy variables in these two epilepsy syndromes.
Methods
We investigated volumetric differences of caudate, putamen, pallidum, and thalamus in children with CPS (N= 21), CAE (N=20), and HC (N=27). Study subjects underwent structural MRI, intelligence, and language testing. Parent-completed Child Behavior Checklists provided behavior problem and peer interaction scores. We examined the association of age, IQ, language, behavioral problems, and epilepsy variables with subcortical volumes that were significantly different between the children with epilepsy and HC.
Results
Both children with CPS and CAE exhibited significantly smaller left thalamic volume compared to HC. In terms of developmental trajectory, greater thalamic volume was significantly correlated with increasing age in children with CPS and CAE but not in HC. With regard to the comorbidities, reduced left thalamic volumes were related to more social problems in children with CPS and CAE. Smaller left thalamic volumes in children with CPS were also associated with poor attention, lower IQ and language scores, and impaired peer interaction.
Significance
Our study is the first to directly compare and detect shared thalamic structural abnormalities in children with CPS and CAE. These findings highlight the vulnerability of the thalamus and provide important new insights on its possible role in the neurobehavioral comorbidities of childhood-onset epilepsy.
doi:10.1111/epi.12428
PMCID: PMC4259153  PMID: 24304435
18.  Gene Markers in Brain Tumors – What the Epileptologist Should Know 
Epilepsia  2013;54(0 9):10.1111/epi.12439.
Summary
Gene markers or biomarkers can be used for diagnostic or prognostic purposes for all different types of complex disease, including brain tumors. Prognostic markers can be useful to not only explain differences in overall survival but also for differences in response to treatment and for development of targeted therapies. Multiple genes with specific types of alterations have now been identified that are associated with improved response to chemotherapy and radiotherapy, such as o6-methylguanine methyltranferase (MGMT) or loss of chromosomes 1p and/or 19q. Other alterations have been identified that are associated with improved overall survival, such as mutations in isocitrate dehydrogenase 1 (IDH1) and/or isocitrate dehydrogenase 2 (IDH2) or having the glioma CpG island DNA methylator phenotype (G-CIMP). There are many biomarkers that may have relevance in brain tumor associated epilepsy that does not respond to treatment. Given the rapidly changing landscape of high throughput “omics” technologies, there is significant potential for gaining further knowledge via integration of multiple different types of high genome wide data. This knowledge can be translated into improved therapies and clinical outcomes for brain tumor patients.
doi:10.1111/epi.12439
PMCID: PMC3868995  PMID: 24328868
Biomarker; Epilepsy; Brain tumor; MGMT; IDH1; IDH2; LEAT; G-CIMP
19.  Neuroimaging Characteristics of MRI-negative Orbitofrontal Epilepsy with Focus on Voxel-based Morphometric MRI Post-processing 
Epilepsia  2013;54(12):2195-2203.
Summary
Purpose
The orbitofrontal (OF) region is one of the least explored regions of the cerebral cortex. There are few studies on patients with electrophysiologically and surgically confirmed OF epilepsy and a negative MRI. We aimed to examine the neuroimaging characteristics of MRI-negative OF epilepsy with the focus on a voxel-based morphometric MRI post-processing technique.
Methods
We included 6 patients with OF epilepsy, who met the following criteria: surgical resection of the OF lobe with/without adjacent cortex, seizure-free for ≥ 12 months, invasive video-EEG monitoring showing ictal onset from the OF area, and pre-operative MRI regarded negative. Patients were investigated in terms of their image postprocessing and functional neuroimaging characteristics, electroclinical characteristics obtained from noninvasive and invasive evaluations, and surgical pathology. MRI postprocessing on T1-weighted high-resolution scans was implemented with a Morphometric Analysis Program (MAP) in MATLAB SPM5.
Key findings
Single MAP+ abnormalities were found in 4 patients; three were in the OF region and one in the ipsilateral mesial frontal area. These abnormalities were included in the resection. One patient had bilateral MAP+ abnormalities in the OF region, with the ipsilateral one completely removed. The MAP+ foci were concordant with invasive electrophysiological data in the majority of MAP+ patients (4 of 5). The localization value of FDG-PET and ictal SPECT is low in this cohort. Surgical pathology included focal cortical dysplasia, remote infarct, rosenthal fiber formation and gliosis.
Significance
Our study highlights the importance of MRI post-processing in the process of presurgical evaluation of patients with suspected orbitofrontal epilepsy and “normal” MRI. Using MAP, we were able to positively identify subtle focal abnormalities in the majority of the patients. MAP results need to be interpreted in the context of their electroclinical findings and can provide valuable targets in the process of planning invasive evaluation.
doi:10.1111/epi.12390
PMCID: PMC3982614  PMID: 24116733
epilepsy; MRI; presurgical evaluation; MRI post-processing; MRI-negative epilepsy; voxel-based morphometry; orbitofrontal epilepsy; focal cortical dysplasia
20.  Burden of epilepsy in rural Kenya measured in disability-adjusted life years 
Epilepsia  2014;55(10):1626-1633.
Objectives
The burden of epilepsy, in terms of both morbidity and mortality, is likely to vary depending on the etiology (primary [genetic/unknown] vs. secondary [structural/metabolic]) and with the use of antiepileptic drugs (AEDs). We estimated the disability-adjusted life years (DALYs) and modeled the remission rates of active convulsive epilepsy (ACE) using epidemiologic data collected over the last decade in rural Kilifi, Kenya.
Methods
We used measures of prevalence, incidence, and mortality to model the remission of epilepsy using disease-modeling software (DisMod II). DALYs were calculated as the sum of Years Lost to Disability (YLD) and Years of Life Lost (YLL) due to premature death using the prevalence approach, with disability weights (DWs) from the 2010 Global Burden of Disease (GBD) study. DALYs were calculated with R statistical software with the associated uncertainty intervals (UIs) computed by bootstrapping.
Results
A total of 1,005 (95% UI 797–1,213) DALYs were lost to ACE, which is 433 (95% UI 393–469) DALYs lost per 100,000 people. Twenty-six percent (113/100,000/year, 95% UI 106–117) of the DALYs were due to YLD and 74% (320/100,000/year, 95% UI 248–416) to YLL. Primary epilepsy accounted for fewer DALYs than secondary epilepsy (98 vs. 334 DALYs per 100,000 people). Those taking AEDs contributed fewer DALYs than those not taking AEDs (167 vs. 266 DALYs per 100,000 people). The proportion of people with ACE in remission per year was estimated at 11.0% in males and 12.0% in females, with highest rates in the 0–5 year age group.
Significance
The DALYs for ACE are high in rural Kenya, but less than the estimates of 2010 GBD study. Three-fourths of DALYs resulted from secondary epilepsy. Use of AEDs was associated with 40% reduction of DALYs. Improving adherence to AEDs may reduce the burden of epilepsy in this area.
doi:10.1111/epi.12741
PMCID: PMC4238788  PMID: 25131901
Burden; Disability-adjusted life years; Epilepsy; Remission; Treatment gap
21.  Thalamotemporal impairment in temporal lobe epilepsy: A combined MRI analysis of structure, integrity, and connectivity 
Epilepsia  2014;55(2):306-315.
Objective
Thalamic abnormality in temporal lobe epilepsy (TLE) is well known from imaging studies, but evidence is lacking regarding connectivity profiles of the thalamus and their involvement in the disease process. We used a novel multisequence magnetic resonance imaging (MRI) protocol to elucidate the relationship between mesial temporal and thalamic pathology in TLE.
Methods
For 23 patients with TLE and 23 healthy controls, we performed T1-weighted (for analysis of tissue structure), diffusion tensor imaging (tissue connectivity), and T1 and T2 relaxation (tissue integrity) MRI across the whole brain. We used connectivity-based segmentation to determine connectivity patterns of thalamus to ipsilateral cortical regions (occipital, parietal, prefrontal, postcentral, precentral, and temporal). We subsequently determined volumes, mean tractography streamlines, and mean T1 and T2 relaxometry values for each thalamic segment preferentially connecting to a given cortical region, and of the hippocampus and entorhinal cortex.
Results
As expected, patients had significant volume reduction and increased T2 relaxation time in ipsilateral hippocampus and entorhinal cortex. There was bilateral volume loss, mean streamline reduction, and T2 increase of the thalamic segment preferentially connected to temporal lobe, corresponding to anterior, dorsomedial, and pulvinar thalamic regions, with no evidence of significant change in any other thalamic segments. Left and right thalamotemporal segment volume and T2 were significantly correlated with volume and T2 of ipsilateral (epileptogenic), but not contralateral (nonepileptogenic), mesial temporal structures.
Significance
These convergent and robust data indicate that thalamic abnormality in TLE is restricted to the area of the thalamus that is preferentially connected to the epileptogenic temporal lobe. The degree of thalamic pathology is related to the extent of mesial temporal lobe damage in TLE.
doi:10.1111/epi.12520
PMCID: PMC4074767  PMID: 24447099
Connectivity; Brain networks; Diffusion tensor imaging; Mesial temporal lobe; Thalamus
22.  Two-year seizure reduction in adults with medically intractable partial onset epilepsy treated with responsive neurostimulation: Final results of the RNS System Pivotal trial 
Epilepsia  2014;55(3):432-441.
Objective
To demonstrate the safety and effectiveness of responsive stimulation at the seizure focus as an adjunctive therapy to reduce the frequency of seizures in adults with medically intractable partial onset seizures arising from one or two seizure foci.
Methods
Randomized multicenter double-blinded controlled trial of responsive focal cortical stimulation (RNS System). Subjects with medically intractable partial onset seizures from one or two foci were implanted, and 1 month postimplant were randomized 1:1 to active or sham stimulation. After the fifth postimplant month, all subjects received responsive stimulation in an open label period (OLP) to complete 2 years of postimplant follow-up.
Results
All 191 subjects were randomized. The percent change in seizures at the end of the blinded period was −37.9% in the active and −17.3% in the sham stimulation group (p = 0.012, Generalized Estimating Equations). The median percent reduction in seizures in the OLP was 44% at 1 year and 53% at 2 years, which represents a progressive and significant improvement with time (p < 0.0001). The serious adverse event rate was not different between subjects receiving active and sham stimulation. Adverse events were consistent with the known risks of an implanted medical device, seizures, and of other epilepsy treatments. There were no adverse effects on neuropsychological function or mood.
Significance
Responsive stimulation to the seizure focus reduced the frequency of partial-onset seizures acutely, showed improving seizure reduction over time, was well tolerated, and was acceptably safe. The RNS System provides an additional treatment option for patients with medically intractable partial-onset seizures.
doi:10.1111/epi.12534
PMCID: PMC4233950  PMID: 24621228
Cortical stimulation; Partial seizures; Focal seizures; Responsive stimulation; Neurostimulator
23.  Evaluation of Kilifi Epilepsy Education Programme: A randomized controlled trial 
Epilepsia  2014;55(2):344-352.
Objectives
The epilepsy treatment gap is largest in resource-poor countries. We evaluated the efficacy of a 1-day health education program in a rural area of Kenya. The primary outcome was adherence to antiepileptic drugs (AEDs) as measured by drug levels in the blood, and the secondary outcomes were seizure frequency and Kilifi Epilepsy Beliefs and Attitudes Scores (KEBAS).
Methods
Seven hundred thirty-eight people with epilepsy (PWE) and their designated supporter were randomized to either the intervention (education) or nonintervention group. Data were collected at baseline and 1 year after the education intervention was administered to the intervention group. There were 581 PWE assessed at both time points. At the end of the study, 105 PWE from the intervention group and 86 from the nonintervention group gave blood samples, which were assayed for the most commonly used AEDs (phenobarbital, phenytoin, and carbamazepine). The proportions of PWE with detectable AED levels were determined using a standard blood assay method. The laboratory technicians conducting the assays were blinded to the randomization. Secondary outcomes were evaluated using questionnaires administered by trained field staff. Modified Poisson regression was used to investigate the factors associated with improved adherence (transition from nonoptimal AED level in blood at baseline to optimal levels at follow-up), reduced seizures, and improved KEBAS, which was done as a post hoc analysis. This trial is registered in ISRCTN register under ISRCTN35680481.
Results
There was no significant difference in adherence to AEDs based on detectable drug levels (odds ratio [OR] 1.46, 95% confidence interval [95% CI] 0.74–2.90, p = 0.28) or by self-reports (OR 1.00, 95% CI 0.71–1.40, p = 1.00) between the intervention and nonintervention group. The intervention group had significantly fewer beliefs about traditional causes of epilepsy, cultural treatment, and negative stereotypes than the nonintervention group. There was no difference in seizure frequency. A comparison of the baseline and follow-up data showed a significant increase in adherence—intervention group (36–81% [p < 0.001]) and nonintervention group (38–74% [p < 0.001])—using detectable blood levels. The number of patients with less frequent seizures (≤3 seizures in the last 3 months) increased in the intervention group (62–80% [p = 0.002]) and in the nonintervention group (67–75% [p = 0.04]). Improved therapeutic adherence (observed in both groups combined) was positively associated with positive change in beliefs about risks of epilepsy (relative risk [RR] 2.00, 95% CI 1.03–3.95) and having nontraditional religious beliefs (RR 2.01, 95% CI 1.01–3.99). Reduced seizure frequency was associated with improved adherence (RR 1.72, 95% CI 1.19–2.47). Positive changes in KEBAS were associated with having tertiary education as compared to none (RR 1.09, 95% CI 1.05–1.14).
Significance
Health education improves knowledge about epilepsy, but once only contact does not improve adherence. However, sustained education may improve adherence in future studies.
doi:10.1111/epi.12498
PMCID: PMC4233970  PMID: 24447063
Epilepsy; Education intervention; Adherence; Beliefs about epilepsy; Seizure frequency
24.  Health-related quality of life, mood, and patient satisfaction after epilepsy surgery in Sweden—A prospective controlled observational study 
Epilepsia  2014;55(6):878-885.
Objective
To evaluate health-related quality of life (HRQOL), mood, and patient satisfaction in epilepsy surgery candidates before and 2 years after epilepsy surgery or presurgical investigation.
Methods
In this prospective study of 141 patients, 96 underwent surgery and 45 did not. Questionnaires at baseline and at 2-year follow-up included the generic 36-item Short Form Health Survey (SF-36), the Hospital Anxiety and Depression scale (HAD), and operated patients answered patient satisfaction questions. SF-36 scores were compared with scores from a matched sample from the Swedish norm population. Numbers were calculated of patients achieving a minimum important change (MIC) in the SF-36 Physical Composite Summary (PCS) and Mental Composite Summary (MCS).
Results
At baseline, patients had significantly lower values than the norm on all SF-36 domains. At follow-up, operated patients were divided into seizure-free (International League Against Epilepsy [ILAE] class 1 and 2, n = 53) or with continued seizures (n = 43). No differences in baseline HAD or SF-36 values were found between these groups. Seizure-free patients reached the same levels as the norm in all SF-36 domains except Social Function. Operated patients with continued seizures and nonoperated patients had unchanged scores. Fifty-one percent of seizure-free patients had an improvement reaching MIC for PCS and 45% for MCS. Corresponding results for patients with continued seizures were 28% in PCS and 28% in MCS, for nonoperated 33% in PCS and 29% in MCS. HAD anxiety scores improved significantly in only the seizure-free patients. Of all operated patients, 80% were satisfied with having had surgery and 86% considered that they had benefited, whereas 20% thought that surgery caused some harm.
Significance
In patients who were seizure-free after epilepsy surgery HRQOL normalized and anxiety decreased. Operated patients overwhelmingly considered epilepsy surgery to be beneficial. Nonetheless, only about half of the seizure-free patients achieved important HRQOL improvements, suggesting that seizure freedom does not in and of itself guarantee improved patient well-being.
doi:10.1111/epi.12616
PMCID: PMC4232909  PMID: 24701994
Quality of life; Patient satisfaction; Mood; Epilepsy surgery
25.  Modeling Seizure Self-Prediction: An E-Diary Study 
Epilepsia  2013;54(11):10.1111/epi.12355.
Purpose
A subset of patients with epilepsy successfully self-predicted seizures in a paper diary study. We conducted an e-diary study to ensure that prediction precedes seizures, and to characterize the prodromal features and time windows that underlie self-prediction.
Methods
Subjects 18 or older with LRE and ≥3 seizures/month maintained an e-diary, reporting AM/PM data daily, including mood, premonitory symptoms, and all seizures. Self-prediction was rated by, “How likely are you to experience a seizure [time frame]”? Five choices ranged from almost certain (>95% chance) to very unlikely. Relative odds of seizure (OR) within time frames was examined using Poisson models with log normal random effects to adjust for multiple observations.
Key Findings
Nineteen subjects reported 244 eligible seizures. OR for prediction choices within 6hrs was as high as 9.31 (1.92,45.23) for “almost certain”. Prediction was most robust within 6hrs of diary entry, and remained significant up to 12hrs. For 9 best predictors, average sensitivity was 50%. Older age contributed to successful self-prediction, and self-prediction appeared to be driven by mood and premonitory symptoms. In multivariate modeling of seizure occurrence, self-prediction (2.84; 1.68,4.81), favorable change in mood (0.82; 0.67,0.99) and number of premonitory symptoms (1,11; 1.00,1.24) were significant.
Significance
Some persons with epilepsy can self-predict seizures. In these individuals, the odds of a seizure following a positive prediction are high. Predictions were robust, not attributable to recall bias, and were related to self awareness of mood and premonitory features. The 6-hour prediction window is suitable for the development of pre-emptive therapy.
doi:10.1111/epi.12355
PMCID: PMC3833277  PMID: 24111898
Seizure prediction; self-prediction; localization-related epilepsy; seizure diary; electronic diary; premonitory symptoms; seizure precipitants

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