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1.  Time to pediatric epilepsy surgery is related to disease severity and nonclinical factors 
Neurology  2013;80(13):1231-1239.
Objective:
To identify clinical and nonclinical factors associated with time from epilepsy onset to surgical evaluation and treatment among a cohort of children having epilepsy surgery.
Methods:
Data were abstracted from records of 430 children (younger than 18 years) who had epilepsy neurosurgery at the University of California, Los Angeles from 1986 to 2010. Multivariable Cox proportional hazards models were used to analyze unique associations of clinical severity, pre-referral brain MRI, and sociodemographic characteristics with time to surgery.
Results:
Shorter time to surgery was associated with active (hazard ratio [HR] 5.67, 95% confidence interval [CI] 3.74–8.70) and successfully treated infantile spasms (HR 2.20, 95% CI 1.63–2.96); daily or more seizures (HR 2.09, 95% CI 1.58–2.76); MRI before referral regardless of imaging findings (HR 1.95, 95% CI 1.47–2.58); private insurance (HR 1.54, 95% CI 1.14–2.09); and Hispanic ethnicity (HR 1.38, 95% CI 1.01–1.87). There were race/ethnicity by insurance interactions (log-rank p = 0.049) with shortest time to surgery for Hispanic children with private insurance.
Conclusions:
Shorter intervals to surgical treatment were associated with greater epilepsy severity and insurance type, consistent with existing literature. However, associations of shorter times to treatment with having a brain MRI before referral and Hispanic ethnicity were unexpected and warrant further investigation. More knowledgeable referring providers and parents with greater help-seeking capability may explain obtaining an MRI before referral. Shorter intervals to surgery among Hispanic children may relate to the same factors yielding an increased volume of Hispanic children receiving surgery at the University of California, Los Angeles since 2000.
doi:10.1212/WNL.0b013e3182897082
PMCID: PMC3691779  PMID: 23468549
2.  Sociodemographic changes over 25 years of pediatric epilepsy surgery at UCLA 
Journal of neurosurgery. Pediatrics  2013;11(3):10.3171/2012.11.PEDS12359.
Object
Low income, government insurance, and minority status are associated with delayed treatment for neurosurgery patients. Less is known about the influence of referral location and how socioeconomic factors and referral patterns evolve over time. For pediatric epilepsy surgery patients at the University of California, Los Angeles (UCLA), this study determined how referral location and sociodemographic features have evolved over 25 years.
Methods
Children undergoing epilepsy neurosurgery at UCLA (453 patients) were classified by location of residence and compared with clinical epilepsy and sociodemographic factors.
Results
From 1986 to 2010, referrals from Southern California increased (+33%) and referrals from outside of California decreased (−19%). Over the same period, the number of patients with preferred provider organization (PPO) and health maintenance organization (HMO) insurance increased (+148% and +69%, respectively) and indemnity insurance decreased (−96%). Likewise, the number of Hispanics (+117%) and Asians (100%) increased and Caucasians/whites decreased (−24%). The number of insurance companies decreased from 52 carriers per 100 surgical patients in 1986–1990 to 19 per 100 in 2006–2010. Patients living in the Eastern US had a younger age at surgery (−46%), shorter intervals from seizure onset to referral for evaluation (−28%) and from presurgical evaluation to surgery (−61%) compared with patients from Southern California. The interval from seizure onset to evaluation was shorter (−33%) for patients from Los Angeles County compared with those living in non-California Western US states.
Conclusions
Referral locations evolved over 25 years at UCLA, with more cases coming from local regions; the percentage of minority patients also increased. The interval from seizures onset to surgery was shortest for patients living farthest from UCLA but still within the US. Geographic location and race/ethnicity was not associated with differences in becoming seizure free after epilepsy surgery in children.
doi:10.3171/2012.11.PEDS12359
PMCID: PMC3832187  PMID: 23331214
socioeconomic disparity; seizure; craniotomy; health inequity; epilepsy
3.  Interleukin-1beta Causes Fluoxetine Resistance in an Animal Model of Epilepsy-Associated Depression 
Neurotherapeutics  2012;9(2):477-485.
Depression represents a common comorbidity of epilepsy and is frequently resistant to selective serotonin reuptake inhibitors (SSRI). We tested the hypothesis that the SSRI resistance in epilepsy associated depression may be a result of a pathologically enhanced interleukin-1β (IL1-β) signaling, and consequently that the blockade of IL1-β may restore the effectiveness of SSRI. Epilepsy and concurrent depression-like impairments were induced in Wistar rats by pilocarpine status epilepticus (SE). The effects of the 2-week long treatment with fluoxetine, interleukin-1 receptor antagonist (IL-1ra), and their combination were examined using behavioral, biochemical, neuroendocrine, and autoradiographic assays. In post-SE rats, depression-like impairments included behavioral deficits indicative of hopelessness and anhedonia; the hyperactivity of the hypothalamo-pituitary-adrenocortical axis; the diminished serotonin output from raphe nucleus; and the upregulation of presynaptic serotonin 1-A (5-HT1A) receptors. Fluoxetine monotherapy exerted no antidepressant effects, whereas the treatment with IL-1ra led to the complete reversal of anhedonia and to a partial improvement of all other depressive impairments. Combined administration of fluoxetine and IL-1ra completely abolished all hallmarks of epilepsy-associated depressive abnormalities, with the exception of the hyperactivity of the hypothalamo-pituitary-adrenocortical axis, the latter remaining only partially improved. We propose that in certain forms of depression, including but not limited to depression associated with epilepsy, the resistance to SSRI may be driven by the pathologically enhanced interleukin-1β signaling and by the subsequent upregulation of presynaptic 5-HT1A receptors. In such forms of depression, the use of interleukin-1β blockers in conjunction with SSRI may represent an effective therapeutic approach.
Electronic supplementary material
The online version of this article (doi:10.1007/s13311-012-0110-4) contains supplementary material, which is available to authorized users.
doi:10.1007/s13311-012-0110-4
PMCID: PMC3337012  PMID: 22427156
Epilepsy; depression; comorbidity; cytokines; selective serotonin reuptake inhibitors
4.  Neuroprotective and antiepileptogenic effects of combination of anti-inflammatory drugs in the immature brain 
Background
Inflammatory signaling elicited by prolonged seizures can be contributory to neuronal injury as well as adverse plasticity leading to the development of spontaneous recurrent seizures (epilepsy) and associated co-morbidities. In this study, developing rat pups were subjected to lithium-pilocarpine status epilepticus (SE) at 2 and 3 weeks of age to study the effect of anti-inflammatory drugs (AID) on SE-induced hippocampal injury and the development of spontaneous seizures.
Findings
We selected AIDs directed against interleukin-1 receptors (IL-1ra), a cyclooxygenase-2 (COX-2) inhibitor (CAY 10404), and an antagonist of microglia activation of caspase-1 (minocycline). Acute injury after SE was studied in the 2-week-old rats 24 h after SE. Development of recurrent spontaneous seizures was studied in 3-week-old rats subjected to SE 4 months after the initial insult.
None of those AIDs were effective in attenuating CA1 injury in the 2-week-old pups or in limiting the development of spontaneous seizures in 3-week-old pups when administered individually. When empiric binary combinations of these drugs were tried, the combined targeting of IL-1r and COX-2 resulted in attenuation of acute CA1 injury, as determined 24 h after SE, in those animals. The same combination administered for 10 days following SE in 3-week-old rats, reduced the development of spontaneous recurrent seizures and limited the extent of mossy fiber sprouting.
Conclusions
Deployment of an empirically designed ‘drug cocktail’ targeting multiple inflammatory signaling pathways for a limited duration after an initial insult like SE may provide a practical approach to neuroprotection and anti-epileptogenic therapy.
doi:10.1186/1742-2094-10-30
PMCID: PMC3599749  PMID: 23442201
Epilepsy; Anti-epileptogenesis; Hippocampus; Status epilepticus; Inflammation; IL-1β; COX-2
5.  Plasticity of Presynaptic and Postsynaptic Serotonin 1A Receptors in an Animal Model of Epilepsy-Associated Depression 
Neuropsychopharmacology  2011;36(6):1305-1316.
Depression is a common comorbidity of temporal lobe epilepsy and has highly negative impact on patients' quality of life. We previously established that pilocarpine-induced status epilepticus (SE) in rats, concurrently with chronic epilepsy leads to depressive impairments, and that the latter may stem from the dysregulation of hypothalamo–pituitary–adrenocortical (HPA) axis and/or diminished raphe–hippocampal serotonergic transmission. We examined possible involvement of presynaptic and postsynaptic serotonin 1A (5-HT1A) receptors in epilepsy-associated depression. Based on their performance in the forced swim test (FST), post-SE animals were classified as those with moderate and severe depressive impairments. In moderately impaired rats, the activity of the HPA axis (examined using plasma corticosterone radioimmunoassay) was higher than in naive subjects, but the functional capacity of presynaptic 5-HT1A receptors (measured in raphe using autoradiography) remained unaltered. In severely depressed animals, both the activity of the HPA axis and the function of presynaptic 5-HT1A receptors were increased as compared with naive and moderately depressed rats. Pharmacological uncoupling of the HPA axis from raphe nucleus exerted antidepressant effects in severely impaired rats, but did not modify behavior in both naive and moderately depressed animals. Further, the function of postsynaptic 5-HT1A receptors was diminished in the hippocampus of post-SE rats. Pharmacological activation of postsynaptic 5-HT1A receptors improved depressive deficits in epileptic animals. We suggest that under the conditions of chronic epilepsy, excessively hyperactive HPA axis activates presynaptic 5-HT1A receptors, thus shifting the regulation of serotonin release in favor of autoinhibition. Downregulation of postsynaptic 5-HT1A receptors may further exacerbate the severity of epilepsy-associated depression.
doi:10.1038/npp.2011.18
PMCID: PMC3077437  PMID: 21346733
epilepsy; depression; comorbidity; serotonin 1A receptors; dorsal raphe; hypothalamo–pituitary–adrenocortical axis; mood / anxiety / stress disorders; serotonin; animal models; neurology; epilepsy; comorbidity; dorsal aphe; hippocampus; serotonin 1A receptors
6.  Neurobiology of Depression as a Comorbidity of Epilepsy 
Epilepsia  2010;51(s5):81-.
Summary
The study of depression as a comorbidity of epilepsy in humans is limited by the attendant iatrogenic and psychosocial variables. In order to study the neurobiology of this clinically important phenomenon without the above-mentioned confounding factors, we have studied the behavioral and biochemical correlates of epilepsy-associated depression in two rodent models of limbic epileptogenesis. For an expanded treatment of this topic see Jasper’s Basic Mechanisms of the Epilepsies, Fourth Edition (Noebels JL, Avoli M, Rogawski MA, Olsen RW, Delgado-Escueta AV, eds) published by Oxford University Press. Available on NCBI Bookshelf.
doi:10.1111/j.1528-1167.2010.02867.x
PMCID: PMC3056239  PMID: 21415938
animal models; glucocorticoids; hypothalamus-pituitary-adrenal (HPA) axis; interleukin-1β; seizures; serotonin
7.  Plasticity of presynaptic and postsynaptic serotonin 1A receptors in an animal model of epilepsy – associated depression 
Depression is a common comorbidity of temporal lobe epilepsy and has highly negative impact on patients’ quality of life. We previously established that pilocarpine-induced status epilepticus (SE) in rats, concurrently with chronic epilepsy leads to depressive impairments, and that the latter may stem from the dysregulation of hypothalamo-pituitary-adrenocortical (HPA) axis and/or diminished raphe-hippocampal serotonergic transmission. We examined possible involvement of presynaptic and postsynaptic serotonin-1A (5-HT1A) receptors in epilepsy-associated depression. Based on their performance in the forced swim test (FST), post-SE animals were classified as those with moderate and severe depressive impairments. In moderately impaired rats, the activity of the HPA axis (examined using plasma corticosterone radioimmunoassay) was higher than in naïve subjects, but the functional capacity of presynaptic 5-HT1A receptors (measured in raphe using autoradiography) remained unaltered. In severely depressed animals, both the activity of the HPA axis and the function of presynaptic 5-HT1A receptors were increased as compared with naïve and moderately depressed rats. Pharmacological uncoupling of the HPA axis from raphe nucleus exerted antidepressant effects in severely impaired rats, but did not modify behavior in both naïve and moderately depressed animals. Further, the function of postsynaptic 5-HT1A receptors was diminished in the hippocampus of post-SE rats. Pharmacological activation of postsynaptic 5-HT1A receptors improved depressive deficits in epileptic animals. We suggest that under conditions of chronic epilepsy, excessively hyperactive HPA axis activates presynaptic 5-HT1A receptors, thus shifting the regulation of serotonin release in favor of autoinhibition. Downregulation of postsynaptic 5-HT1A receptors may further exacerbate the severity of epilepsy-associated depression.
doi:10.1038/npp.2011.18
PMCID: PMC3077437  PMID: 21346733
Epilepsy; depression; comorbidity; serotonin 1A receptors; dorsal raphe; hypothalamo-pituitary-adrenocortical axis
8.  INFLAMMATION ENHANCES EPILEPTOGENESIS IN THE DEVELOPING RAT BRAIN 
Neurobiology of disease  2010;40(1):303-310.
In many experimental systems, proinflammatory stimuli exhibit proconvulsant properties. There are also accumulating data suggesting that inflammation may contribute to epileptogenesis in experimental models as well as in humans. Using two different models (Lithium-pilocarpine induced-status epilepticus (SE) and rapid kindling), we address this issue in the developing brain. Using P14 wistar rat pups, we showed that inflammation induced by LPS results, after SE, into a more severe disease in adulthood. The main histological feature was an active gliosis that was observed only when inflammation and SE was combined. The use of a kindling model at P14, a model where seizure progress without any neurodegeneration, permits to show that systemic inflammation is responsible of an enhancement of epileptogenesis. The role of inflammation should be further explored in immature brain to identify therapeutic targets that may be relevant to clinical practice where the association of inflammation and epileptic events is common.
doi:10.1016/j.nbd.2010.06.004
PMCID: PMC2926147  PMID: 20600912
Developing brain; Epileptogenesis; Inflammation; Kindling; LPS; Status epilepticus
9.  Comorbidity between epilepsy and depression: Experimental evidence for the involvement of serotonergic, glucocorticoid and neuroinflammatory mechanisms 
Epilepsia  2010;51(Suppl 3):110-114.
Summary
Depression represents one of the most common comorbidities of temporal lobe epilepsy (TLE), and has profound negative impact on the quality of life of TLE patients. However, causes and mechanisms of depression in TLE remain poorly understood, and its effective therapies are lacking. We examined whether a commonly used model of TLE in rats can be used as a model of comorbidity between epilepsy and depression suitable for both mechanistic studies and for the development mechanism-based antidepressant therapies. We established that animals which had been subjected to LiCl and pilocarpine status epilepticus (SE) and developed spontaneous recurrent seizures, exhibited set of impairments congruent with depressive state: behavioral equivalents of anhedonia and despair; dysregulation of the hypothalamo-pituitary adrenocortical (HPA) axis; compromised raphe-hippocampal serotonergic transmission. Pharmacological studies suggested that depressive impairments following SE develop as a result of the enhanced interleukin-1β signaling in the hippocampus, which leads to depression via inducing perturbations in the HPA axis and subsequent deficit in the raphe-hippocampal serotonergic transmission.
doi:10.1111/j.1528-1167.2010.02623.x
PMCID: PMC2909020  PMID: 20618414
Temporal lobe epilepsy; depression; comorbidity; serotonin; hypothalamo-pituitary-adrenocortical axis; interleukin-1β
10.  Inflammation induced by LPS enhances epileptogenesis in immature rat and may be partially reversed by IL1RA 
Epilepsia  2010;51(Suppl 3):34-38.
Inflammatory signaling in the CNS has been shown to exacerbate both seizure activity and seizure-induced neuronal injury. However, it has not been firmly established whether neurodegeneration is a prerequisite of proconvulsant effect of neuroinflammation, or whether the latter may facilitate seizures without involving neuronal injury. We examined effects of inflammation in the rapid kindling model, where seizure progression occurs in the absence of neurodegeneration. P14 male Wistar rats were subjected to a rapid kindling procedure –60 electrical stimulations of the hippocampus delivered every five minutes at the current that had been established to induce afterdischarge. LPS was injected (50μg/kg i.p. 2h prior the RKP); IL-1Ra was injected (25mg/kg i.p. 2h prior the RKP). The effects of treatments were examined on baseline hippocampal excitability; on the progression of rapid kindling; and on the retention of rapid kindling. LPS increased baseline hippocampal excitability evident as the decrease of hippocampal ADT. LPS also increased kindling progression. 24 hrs after the completion of kindling procedure, LPS treated animals exhibited increased excitability as compared with saline-treated kindling controls. The kindling progression was blocked by IL1RA when given combination with LPS. IL1RA was able to reverse the effect of LPS on ADD while IL1RA alone decrease ADT. We showed that inflammation provoked by LPS enhanced rapid kindling epileptogenesis in immature rat brains. IL1RA was also able to mitigate this augmentation of epileptogenesis enhanced by LPS.
doi:10.1111/j.1528-1167.2010.02606.x
PMCID: PMC2910518  PMID: 20618397
Developing brain; IL1RA; Inflammation; Kindling; LPS; Seizure; Rat
11.  Evaluation of development-specific targets for antiepileptogenic therapy using rapid kindling 
Epilepsia  2010;51(Suppl 3):39-42.
We used the method of rapid hippocampal kindling to assess the potential antiepileptogenic efficacy of a number of anticonvulsant medications. This method afforded a higher throughput than methods based on traditional kindling or post-status epilepticus models of epileptogenesis. This “compressed epileptogenesis” model also permitted the study of age-dependent pharmacologic targets, and distinguished among AEDs based on their age-specific antiepileptogenic efficacy. We found retigabine to be the most effective anticonvulsant therapy during early development. Topiramate seemed most effective further along development, while some drugs did not demonstrate an age-specific effect. The method also reproduced some of the paradoxical pharmacologic findings previously shown with lamotrigine. While the utility of this model for screening the antiepileptogenic therapies requires further validation it introduces the ability to undertake development-specific testing and a more rapid throughput than conventional methods.
doi:10.1111/j.1528-1167.2010.02607.x
PMCID: PMC2912152  PMID: 20618398
Epileptogenesis; development; rapid kindling; hippocampus
12.  Language and Brain Volumes in Children with Epilepsy 
Epilepsy & behavior : E&B  2010;17(3):402-407.
This study compared the relationship of language skill with fronto-temporal volumes in 69 medically treated epilepsy subjects and 34 healthy children, aged 6.1-16.6 years. It also determined if the patients with linguistic deficits had abnormal volumes and atypical associations between volumes and language skills in these brain regions. The children underwent language testing and magnetic resonance imaging scans at 1.5 Tesla. Brain tissue was segmented and fronto-temporal volumes were computed. Higher mean language scores were significantly associated with larger inferior frontal gyrus, temporal lobe, and posterior superior temporal gyrus gray matter volumes in the epilepsy group and in the children with epilepsy with average language scores. Increased total brain and dorsolateral prefrontal gray and white matter volumes, however, were associated with higher language scores in the healthy controls. Within the epilepsy group, linguistic deficits were related to smaller anterior superior temporal gyrus gray matter volumes and a negative association between language scores and dorsolateral prefrontal gray matter volumes. These findings demonstrate abnormal development of language related brain regions, and imply differential reorganization of brain regions subserving language in children with epilepsy with normal linguistic skills and in those with impaired language.
doi:10.1016/j.yebeh.2010.01.009
PMCID: PMC2892796  PMID: 20149755
Language; epilepsy; development; MRI; frontal lobe; temporal lobe
13.  Comorbidity between epilepsy and depression: role of hippocampal interleukin-1β 
Neurobiology of disease  2009;37(2):461.
Depression is a frequent comorbidity of temporal lobe epilepsy (TLE); however its mechanisms remain poorly understood and effective therapies are lacking. Augmentation of hippocampal interleukin-1β (IL-1β) signaling may be a mechanistic factor of both TLE and clinical depression. We examined whether pharmacological blockade of hippocampal interleukin-1 receptor exerts antidepressant effects in an animal model of comorbidity between TLE and depression, which developed in Wistar rats following pilocarpine status epilepticus (SE). In post-SE animals, depression-like state was characterized by behavioral equivalents of anhedonia and despair; dysregulation of the hypothalamo-pituitary-adrenocortical axis; compromised raphe-hippocampal serotonergic transmission. Two-week long bilateral intrahippocampal infusion of human recombinant Interleukin-1 Receptor antagonist (IL-1ra) improved all of the examined depressive impairments, without modifying spontaneous seizure frequency and without affecting normal parameters in naïve rats. These findings implicate hippocampal IL-1β in epilepsy-associated depression, and provide a rationale for the introduction of IL-1β blockers in the treatment of depression in TLE.
doi:10.1016/j.nbd.2009.11.001
PMCID: PMC2818460  PMID: 19900553
Temporal lobe epilepsy; depression; comorbidity; brain inflammation; Interleukin-1β; hippocampus
14.  Acute Neuroprotection to Pilocarpine-Induced Seizures is Not Sustained After Traumatic Brain Injury in the Developing Rat: “Neuroprotection Following Traumatic Brain Injury” 
Neuroscience  2009;164(2):862-876.
Following central nervous system injury there is a period of vulnerability when cells will not easily tolerate a secondary insult. However recent studies have shown that following traumatic brain injury (TBI), as well as hypoxic-ischemic injuries, the central nervous system may experience a period of protection termed “preconditioning.” While there is literature characterizing the properties of vulnerability and preconditioning in the adult rodent, there is an absence of comparable literature in the developing rat. To determine if there is a window of vulnerability in the developing rat, post-natal day 19 animals were subjected to a severe lateral fluid percussion injury followed by pilocarpine-induced status epilepticus at 1, 6 or 24-hours post TBI. During the first 24 hours after TBI, the dorsal hippocampus exhibited less status epilepticus-induced cell death than that normally seen following pilocarpine administration alone. Instead of producing a state of hippocampal vulnerability to activation, TBI produced a state of neuroprotection. However, in a second group of animals evaluated 20-weeks post-injury, double-injured animals were statistically indistinguishable in terms of seizure threshold, mossy fiber sprouting and cell survival when compared to those treated with pilocarpine alone. TBI, therefore, produced a temporary state of neuroprotection from seizure-induced cell death in the developing rat; however, this ultimately conferred no long-term protection from altered hippocampal circuit rearrangements, enhanced excitability or later convulsive seizures.
doi:10.1016/j.neuroscience.2009.08.021
PMCID: PMC2762013  PMID: 19695311
long-term outcome; preconditioning; secondary insult; vulnerability; hippocampus
15.  Clinical profile of vigabatrin as monotherapy for treatment of infantile spasms 
Vigabatrin, the first therapeutic agent to be approved by the Food and Drug Administration for the treatment of infantile spasms, as well as for adjunctive use in the treatment of refractory complex partial epilepsy, represents an important advance for patients with difficult-to-manage epilepsy. This review summarizes the complex history, chemistry, and pharmacology, as well as the clinical data leading to the approval of vigabatrin for infantile spasms in the US. The long path to its approval reflects the visual system and white matter toxicity concerns with this agent. This review provides a brief description of these concerns, and the regulatory safety monitoring and mitigation systems that have been put in place to enhance benefit over risk.
doi:10.2147/NDT.S5235
PMCID: PMC2987507  PMID: 21127692
vigabatrin; infantile spasms; monotherapy
16.  Bumetanide inhibits rapid kindling in neonatal rats 
Epilepsia  2009;50(9):2117-2122.
Purpose
To examine effects of bumetanide, a selective blocker of Na+-K+-2Cl− cotransporter (NKCC1), on hippocampal excitability and rapid kindling in immature rats.
Methods
Studies were performed in Wistar rats of three ages: postnatal day 11 (P11, neonatal), P14 (post-neonatal), and P21 (pre-adolescent). Bumetanide (0.2, 0.5, 2.5 mg/kg) was given intraperitoneally 20 minutes prior to the beginning of the studies. Hippocampal excitability was examined by measuring threshold and duration of afterdischarge, which had been elicited by electrical stimulation of ventral hippocampus. Kindling procedure consisted of 80 electrical stimulations of ventral hippocampus, delivered every 5 minutes.
Results
At P11, bumetanide (0.5 mg/kg) increased the baseline hippocampal afterdischarge threshold and shortened the afterdischarge duration. Bumetanide delayed the occurrence, and reduced the number of full motor seizures during kindling, and prevented the development of kindling-induced enhanced seizure susceptibility in a majority of animals. At P14 bumetanide (0.5 mg/kg) induced no significant antiepileptic effects, although suppression of hippocampal excitability and inhibition of kindling were observed in a subset of animals. At P21 bumetanide (0.2; 2.5 mg/kg) exerted no effects on hippocampal excitability and kindling progression.
Discussion
The obtained results provide further evidence that bumetanide may be beneficial for treating neonatal seizures, and that NKCC1 represents a potential target for antiepileptic interventions in the immature brain.
doi:10.1111/j.1528-1167.2009.02048.x
PMCID: PMC2732750  PMID: 19260939
Epilepsy; kindling; Na+-K+-2Cl− cotransporter; bumetanide
17.  Elevated plasma corticosterone level and depressive behavior in experimental temporal lobe epilepsy 
Neurobiology of disease  2009;34(3):457-461.
Depression is frequently reported in epilepsy patients; however, mechanisms of co-morbidity between epilepsy and depression are poorly understood. An important mechanism of depression is disinhibition within the hypothalamo-pituitary-adrenocortical (HPA) axis. We examined the functional state of the HPA axis in a rat model of co-morbidity between temporal lobe epilepsy and depression. Epilepsy was accompanied by the interictal elevation of plasma corticosterone, and by the positive combined dexamethasone/corticotropin releasing hormone test. The extent of the HPA hyperactivity was independent of recurrent seizures, but positively correlated with the severity of depressive behavior. We suggest that the observed hyperactivity of the HPA axis may underlie co-morbidity between epilepsy and depression.
doi:10.1016/j.nbd.2009.02.018
PMCID: PMC2683188  PMID: 19285131
Epilepsy; depression; co-morbidity; hypothalamo-pituitary-adrenocortical axis; chronic stress
18.  Antiepileptogenic and antiictogenic effects of retigabine under conditions of rapid kindling: an ontogenic study 
Epilepsia  2008;49(10):1777-1786.
SUMMARY
Purpose
To examine antiepileptogenic and antiictogenic potential of retigabine under conditions of rapid kindling epileptogenesis during different stages of development.
Methods
The experiments were performed in postnatal day 14 (P14), P21 and P35 male Wistar rats. After stereotaxic implantation of hippocampal stimulating and recording electrodes, the effects of retigabine on baseline afterdischarge properties were studied. Next, the animals underwent rapid kindling (sixty 10 second trains, bipolar 20 Hz square wave pulses delivered every five minutes). The progression of seizures (kindling acquisition), and responses to test stimulations after kindling (retention) were compared between retigabine and vehicle-treated rats. Additionally, the effects of retigabine on the severity of seizures in previously kindled animals were examined.
Results
When administered intraperitoneally in doses that induced only mild, or no motor deficits, retigabine significantly dampened brain excitability, evident as the increase of afterdischarge threshold and shortening of afterdischarge duration. During kindling, retigabine delayed the development of focal seizures in P14 rats, and prevented the occurrence of full limbic seizures at all three ages. At P14 and P21, but not at P35, pretreatment with retigabine prevented the establishment of kindling-induced enhanced seizure susceptibility. Administration of retigabine to kindled animals decreased the severity of seizures induced by test stimulation. The effect was most prominent at P14.
Discussion
Retigabine exerted both antiepileptogenic and antiictogenic effects under conditions of rapid kindling model. These effects were apparent during post-neonatal, early childhood and adolescent stages of development.
doi:10.1111/j.1528-1167.2008.01674.x
PMCID: PMC2577127  PMID: 18503560
Antiepileptic drugs; development; epileptogenesis; kindling; retigabine
19.  Thought disorder and frontotemporal volumes in pediatric epilepsy 
Epilepsy & behavior : E&B  2008;13(4):593-599.
The aim of this study was to determine if volumes of frontotemporal regions associated with language were related to thought disorder in 42 children, aged 5–16 years, with cryptogenic epilepsy, all of whom had complex partial seizures (CPS). The children with CPS and 41 age- and gender-matched healthy children underwent brain MRI scans at 1.5 T. Tissue was segmented, and total brain, frontal lobe, and temporal lobe volumes were computed. Thought disorder measures, IQ, and seizure information were collected for each patient. The subjects with CPS had more thought disorder, smaller total gray matter and orbital frontal gray matter volumes, as well as larger temporal lobe white matter volumes than the control group. In the CPS group, thought disorder was significantly related to smaller orbital frontal and inferior frontal gray matter volumes, increased Heschl’s gyrus gray matter volumes, and smaller superior temporal gyrus white matter volumes. However, significantly larger orbital frontal gyrus, superior temporal gyrus, and temporal lobe gray matter volumes and decreased Heschl’s gyrus white matter volumes were associated with thought disorder in the control group. These findings suggest that thought disorder might represent a developmental disability involving frontotemporal regions associated with language in pediatric CPS.
doi:10.1016/j.yebeh.2008.06.021
PMCID: PMC2746463  PMID: 18652915
Thought disorder; Complex partial seizures; Development; Brain volumes; Childhood; Language
20.  Depression after status epilepticus: behavioural and biochemical deficits and effects of fluoxetine 
Brain  2008;131(8):2071-2083.
Depression represents one of the most common comorbidities in patients with epilepsy. However, the mechanisms of depression in epilepsy patients are poorly understood. Establishment of animal models of this comorbidity is critical for both understanding the mechanisms of the condition, and for preclinical development of effective therapies. The current study examined whether a commonly used animal model of temporal lobe epilepsy (TLE) is characterized by behavioural and biochemical alterations involved in depression. Male Wistar rats were subjected to LiCl and pilocarpine status epilepticus (SE). The development of chronic epileptic state was confirmed by the presence of spontaneous seizures and by enhanced brain excitability. Post-SE animals exhibited increase in immobility time under conditions of forced swim test (FST) which was indicative of despair-like state, and loss of taste preference in saccharin solution consumption test which pointed to the symptomatic equivalence of anhedonia. Biochemical studies revealed compromised serotonergic transmission in the raphe-hippocampal serotonergic pathway: decrease of serotonin (5-HT) concentration and turnover in the hippocampus, measured by high performance liquid chromatography, and decrease of 5-HT release from the hippocampus in response to raphe stimulation, measured by fast cyclic voltammetry. Administration of fluoxetine (FLX, 20 mg/kg/day for 10 days) to naive animals significantly shortened immobility time under conditions of FST, and inhibited 5-HT turnover in the hippocampus. In post-SE rats FLX treatment led to a further decrease of hippocampal 5-HT turnover; however, performance in FST was not improved. At the same time, FLX reversed SE-induced increase in brain excitability. In summary, our studies provide initial evidence that post-SE model of TLE might serve as a model of the comorbidity of epilepsy and depression. The finding that behavioural equivalents of depression were resistant to an antidepressant medication suggested that depression in epilepsy might have distinct underlying mechanisms beyond alterations in serotonergic pathways.
doi:10.1093/brain/awn117
PMCID: PMC2587254  PMID: 18559371
comorbidity; depression; epilepsy; hippocampus; serotonin
21.  The Ketogenic Diet in a Pill: Is this Possible? 
Epilepsia  2008;49(Suppl 8):127-133.
Summary
Over the past decade, much progress has been made in understanding the mechanisms of ketogenic diet (KD) action. From the complex systemic and metabolic changes induced by the KD have emerged innovative hypotheses attempting to link biochemical adaptations to its clinical effects. Despite such developments, the fundamental question of how the KD works remains as elusive as ever. At present, it is unclear which of many potential mechanisms proposed thus far are directly relevant to the clinical effects of the KD. It is unlikely that these numerous hypotheses can be unified into a single mechanism (or a final common pathway). Nevertheless, it may be instructive to consider each of these putative mechanisms in turn and ask the following question: If the mechanism or target in question is a critical determinant of the anticonvulsant efficacy of the KD, then would a similar intervention known to be based on that mechanism yield a comparable effect? Perhaps answering this question for each mechanistic speculation might help substantiate (or invalidate) that particular hypothesis. Can the KD be packaged into a pill? At present, the answer is likely “no.” We have yet to discover a “magic bullet” that completely mirrors the anticonvulsant (and potential neuroprotective) effects of the KD. However, without a clearer understanding of the mechanistic elements comprising the complex metabolic puzzle posed by the KD, we would be left only with empiric observations, and to wonder curiously how a high-fat diet can exert such profound clinical effects.
doi:10.1111/j.1528-1167.2008.01857.x
PMCID: PMC2692867  PMID: 19049610
ketogenic diet; mechanism; GABA; ketone; mitochondria; reactive oxygen species; calorie restriction; glycolysis; fatty acids
22.  Depression after status epilepticus: behavioral and biochemical deficits, and effects of fluoxetine 
Brain : a journal of neurology  2008;131(Pt 8):2071-2083.
Summary
Depression represents one of the most common comorbidities in patients with epilepsy. However, the mechanisms of depression in epilepsy patients are poorly understood. Establishment of animal models of this comorbidity is critical for both understanding the mechanisms of the condition, and for preclinical development of effective therapies. The current study examined whether a commonly used animal model of temporal lobe epilepsy (TLE) is characterized by behavioral and biochemical alterations involved in depression. Male Wistar rats were subjected to LiCl and pilocarpine status epilepticus (SE). The development of chronic epileptic state was confirmed by the presence of spontaneous seizures and by enhanced brain excitability. Post-SE animals exhibited increase in immobility time under conditions of forced swim test (FST) which was indicative of despair-like state, and loss of taste preference in saccharin solution consumption test which pointed to the symptomatic equivalence of anhedonia. Biochemical studies revealed compromised serotonergic transmission in the raphe-hippocampal serotonergic pathway: decrease of serotonin (5-HT) concentration and turnover in the hippocampus, measured by high performance liquid chromatography, and decrease of 5-HT release from the hippocampus in response to raphe stimulation, measured by fast cyclic voltammetry. Administration of fluoxetine (FLX, 20 mg/kg/day for 10 days) to naïve animals significantly shortened immobility time under conditions of FST, and inhibited 5-HT turnover in the hippocampus. In post-SE rats FLX treatment led to a further decrease of hippocampal 5-HT turnover; however, performance in FST was not improved. At the same time, FLX reversed SE-induced increase in brain excitability. In summary, our studies provide initial evidence that post-SE model of TLE might serve as a model of the comorbidity of epilepsy and depression. The finding that behavioral equivalents of depression were resistant to an antidepressant medication suggested that depression in epilepsy might have distinct underlying mechanisms beyond alterations in serotonergic pathways.
doi:10.1093/brain/awn117
PMCID: PMC2587254  PMID: 18559371
Comorbidity; depression; epilepsy; hippocampus; serotonin
23.  Amygdala Volume and Psychopathology in Childhood Complex Partial Seizures 
Epilepsy & behavior : E&B  2008;13(1):212-217.
Purpose
This study compared amygdala volume in children with cryptogenic epilepsy, who had complex partial seizures (CPS), with age and gender matched normal children. It also examined the relationship of amygdala volumes with seizure variables and the presence of psychopathology in the patients.
Methods
28 children with cryptogenic epilepsy, all of whom had CPS, and gender matched normal children, aged 6–16 years had magnetic resonance imaging (MRI) at 1.5 Tesla. Tissue was segmented and total brain volume and amygdala volumes obtained from manual tracings were computed.
Results
There were no significant differences in the amygdala volume of the CPS and normal groups. Within the CPS group, the children with an affective/anxiety disorder had significantly larger left amygdala volumes compared to those with no psychopathology as well as greater amygdala asymmetry. Exploring the association of seizure variables to amygdala volumes yielded no significant predictors.
Conclusions
In pediatric CPS left amygdala involvement might reflect effects of the neuropathology underlying comorbid affective or anxiety disorders on amygdala development rather than effects of on-going seizures.
doi:10.1016/j.yebeh.2007.12.021
PMCID: PMC2486270  PMID: 18359276
complex partial seizure disorder; childhood; magnetic resonance imaging; amygdala; seizure variables
24.  Age-Dependent Effects of Topiramate on the Acquisition and the Retention of Rapid Kindling 
Epilepsia  2007;48(4):765-773.
Summary
Purpose
To examine antiepileptogenic, disease-modifying, and anticonvulsant effects of topiramate under conditions of rapid kindling at different stages of development.
Methods
Afterdischarge threshold (ADT) and duration (ADD) were examined in two-, three-, and five-week old Wistar rats before and after administration of topiramate (200 mg/kg). Animals underwent a rapid kindling protocol (sixty 10 second trains, bipolar 20 Hz square wave pulses delivered every five minutes). The progression of behavioral and electrographic seizures, and responses to test stimulations 24 hours after the protocol were compared between topiramate and vehicle treated control rats. In addition, rats that were previously given vehicle only prior to kindling, were then given topiramate to examine the effect on established kindled seizures.
Results
In two-week old animals, topiramate affected neither the baseline afterdischarge, nor the progression of kindled seizures. In three-week old rats, topiramate did not modify the baseline afterdischarge, but significantly delayed the occurrence of full motor seizures in response to repeated stimulations. Topiramate treatment of five-week old rats increased baseline ADT, shortened ADD, and delayed the progression of kindled seizures. Twenty four hours after the last kindling stimulation, animals of all ages exhibited a decreased ADT, an increase ADD, and developed behavioral seizures in response to threshold stimulation. Vehicle treated kindled rats that were then given topiramate displayed significantly attenuated behavioral seizures induced by the threshold stimulation.
Conclusions
Topiramate exhibited age-dependent disease-modifying effects under conditions of rapid kindling, but failed to block epileptogenesis. Topiramate also inhibited kindled seizures with equal efficacy across the three ages.
doi:10.1111/j.1528-1167.2007.00987.x
PMCID: PMC2376752  PMID: 17319916
Temporal lobe epilepsy; epileptogenesis; kindling; topiramate; antiepileptic drugs; development
25.  Kindling epileptogenesis in immature rats leads to persistent depressive behavior 
Epilepsy & behavior : E&B  2007;10(3):377-383.
Depression is a frequent comorbidity in epilepsy patients. A variety of biological factors may underlie epilepsy-associated depression. We examined whether kindling-induced chronic increase in seizure susceptibility is accompanied by behavioral symptoms of depression. Three week-old Wistar rats underwent rapid kindling - 84 initially subconvulsant electrical stimulations of ventral hippocampus delivered every five minutes - followed by depression-specific behavioral tests performed two and four weeks later. Kindled animals exhibited sustained increase in the immobility time in the forced swim test and the loss of taste preference towards calorie-free saccharin, as compared to controls. Initial loss of preference towards the intake of calorie-containing sucrose was followed by the increased consumption at four weeks. At both time points, animals exhibited enhanced seizure susceptibility upon test stimulations of the hippocampus. We conclude that neuronal plastic changes associated with kindling state are accompanied by the development of depressive behavior.
doi:10.1016/j.yebeh.2007.02.001
PMCID: PMC1958957  PMID: 17368107
Epilepsy; depression; kindling; forced swim test; taste preference; rat

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