Cognitive impairment following status epilepticus and recurrent seizures during early development: support for the "two-hit hypothesis"

Prolonged seizures in immature rats result in minimal behavioral consequences when the animals are studied later in life. Likewise, early-onset seizures are associated with minimal morphological changes. However, it is known that seizures early in life result in changes in the brain that make it more vulnerable to subsequent seizure-induced injury (the so-called two-hit hypothesis). Whether this heightened vulnerability occurs immediately after the first seizure is not known. In this study, immature rats were exposed to status epilepticus (SE) followed by a series of 25 flurothyl-induced seizures, SE alone, 25 flurothyl-induced seizures alone, or no seizures. Rats exposed to SE and flurothyl seizures performed significantly poorer in the water maze 2 weeks following the last seizure compared with the other groups. No histological lesions were seen in any of the four groups. This study suggests that SE renders the immature brain vulnerable to further seizure-induced injury and this enhanced vulnerability occurs very quickly after the SE.     

Early life seizures cause long-standing impairment of the hippocampal map

Children with seizures are at risk for long-term cognitive deficits. Similarly, recurrent seizures in developing rats are associated with deficits in spatial learning and memory. However, the pathophysiological bases for these deficits are not known. Hippocampal place cells, cells that are activated selectively when an animal moves through a particular location in space, provides the animal with a spatial map. We hypothesized that seizure-induced impairment in spatial learning is a consequence of the rat's inability to form accurate and stable hippocampal maps. To directly address the cellular concomitants of spatial memory impairment, we recorded the activity of place cells from hippocampal subfield CA1 in freely moving rats subjected to 100 brief flurothyl-induced seizures during the first weeks of life and then tested them in the Morris water maze and radial-arm water maze followed by place cell testing. Compared to controls, rats with recurrent seizures had marked impairment in Morris water maze and radial-arm water maze. In parallel, there were substantial deficits in action potential firing characteristics of place cells with two major defects: i) the coherence, information content, center firing rate, and field size were reduced compared to control cells; and ii) the fields were less stable than those in control place cells. These results show that recurrent seizures during early development are associated with significant impairment in spatial learning and that these deficits are paralleled by deficits in the hippocampal map. This study thus provides a cellular correlate for how recurrent seizures during early development lead to cognitive impairment.     

氯化锂预处理时间的改变对锂-匹鲁卡品诱导大鼠痫性发作的影响

目的在锂-匹鲁卡品癫痫大鼠模型中探讨氯化锂的预处理时间的最佳变化范围.方法改变氯化锂的预处理时间表,观察其对大鼠痫性发作、潜伏期、痫性发作的程度和致死率的影响,同时行组织学观察.结果当氯化锂预处理时间范围在2～24 h内变化时,大鼠痫性发作率为100%,并且氯化锂的预处理时间与大鼠痫性发作的程度呈线性关联(P＜0.0001);当氯化锂提前48和72 h时,大鼠的痫性发作率下降到40%和0.结论根据试验需要和条件可以选择合适的氯化锂预处理时间(在2～24 h之间)来诱导相应的癫痫大鼠模型.     

Cognitive dysfunction after experimental febrile seizures

While the majority of children with febrile seizures have an excellent prognosis, a small percentage are later discovered to have cognitive impairment. Whether the febrile seizures produce the cognitive deficits or the febrile seizures are a marker or the result of underlying brain pathology is not clear from the clinical literature. We evaluated hippocampal and prefrontal cortex function in adult rats with a prior history of experimental febrile seizures as rat pups. All of the rat pups had MRI brain scans following the seizures. Rats subjected to experimental febrile seizures were found to have moderate deficits in working and reference memory and strategy shifting in the Morris water maze test. A possible basis for these hippocampal deficits involved abnormal firing rate and poor stability of hippocampal CA1 place cells, neurons involved in encoding and retrieval of spatial information. Additional derangements of interneuron firing in the CA1 hippocampal circuit suggested a complex network dysfunction in the rats. MRI T2 values in the hippocampus were significantly elevated in 50% of seizure-experiencing rats. Learning and memory functions of these T2-positive rats were significantly worse than those of T2-negative cohorts and of controls. We conclude that cognitive dysfunction involving the hippocampus and prefrontal cortex networks occur following experimental febrile seizures and that the MRI provides a potential biomarker for hippocampal deficits in a model of prolonged human febrile seizures.     

Long-term effects of status epilepticus in the immature brain are specific for age and model

PURPOSE: Status epilepticus (SE) is more common in children than adults and has a high mortality and morbidity rate. SE in adult rats results in long-term disturbances in learning and memory, as well as an enhanced seizure susceptibility to further seizures. In contrast, a number of studies suggest that the immature brain is less vulnerable to the morphologic and physiologic alterations after SE. The goal of this study was to determine whether the long-term consequences of SE during development on hippocampal plasticity and cognitive function are age and model specific. METHODS: We used lithium-pilocarpine (Li-PC) to induce SE at different age points during development (P12, P16, P20) and evaluated the effects of this abnormal neural activity on spatial memory performance and seizure susceptibility in the animals beginning at P55, corresponding to young adulthood. RESULTS: We demonstrated that SE at P12 did not result in any structural or functional changes detectable in adulthood, whereas SE at both P16 and P20 induced cell loss and mossy fiber sprouting within the hippocampus and cognitive impairment when the animals were tested as adults. CONCLUSIONS: Whereas the seizure threshold to generalized seizures was not altered, animals with SE at P20 showed an increased susceptibility to kindling in adulthood.     

Substantia nigra is an anticonvulsant site of action of topiramate in the focal pilocarpine model of limbic seizures

PURPOSE: The substantia nigra pars reticulata (SNR) is known to play a role in gating and control of seizures. Prompted by the observation that intrahippocampal topiramate (TPM) administration does not suppress limbic seizures in the focal pilocarpine model, we investigated the role of the SNR in the anticonvulsant mechanism of action of TPM. METHODS: Limbic seizures were evoked in freely moving rats by intrahippocampal administration of pilocarpine via a microdialysis probe. Changes in hippocampal extracellular (EC) glutamate and GABA concentrations were monitored. Effects of intraperitoneal (10-200 mg/kg), intrahippocampal (1-5 mM), and bilateral intranigral (100-300 nmol) TPM administration on pilocarpine-induced seizures and neurochemical changes were evaluated. Effects of TPM administration alone on hippocampal and nigral EC amino acid concentrations were also studied. RESULTS: Systemic and intranigral, but not intrahippocampal TPM administration suppressed pilocarpine-induced seizures and neurochemical changes. Nigral GABA(A) receptor blockade by picrotoxin abolished the anticonvulsant effect of TPM in SNR. Systemic TPM administration increased hippocampal glutamate and decreased GABA. Intranigral TPM administration increased hippocampal glutamate, but not GABA. Intrahippocampal TPM increased hippocampal glutamate and GABA, but only at high concentrations. CONCLUSIONS: In the focal pilocarpine model, TPM does not exert its anticonvulsant effect at the site of seizure initiation. We identified the SNR as a site of action of TPM, and showed that the nigral GABA-ergic system is central to TPM's anticonvulsant effect in SNR. Anticonvulsant effects and neurochemical changes in hippocampus following intranigral TPM administration suggest the existence of a nigro-hippocampal circuit, which may be involved in the control of limbic seizures.     

大鼠出生前后胆碱补充对癫痫发作后认知功能的影响

目的 探讨出生前后胆碱补充或缺乏对癫痫发作后认知功能的影响。方法 3组大鼠自受孕后第11天至子鼠出生后第7天分别给予胆碱丰富、胆碱缺乏和正常胆碱含量的饮食。子鼠出生后第42天，海人酸诱导癫痫发作。癫痫发作10d后，用Morris水迷宫对大鼠空间学习记忆能力进行测试并测量海马中胆碱乙酰转移酶和乙酰胆碱酯酶的活性。结果 出生前后用胆碱丰富食物饲养的大鼠较胆碱缺乏饮食和服碱正常饮食饲养的大鼠在水迷宫测试中有较好表现。经胆碱缺乏饮食饲养的大鼠海马中胆碱乙酰转移酶的活性较对照组低18．8％，较胆碱补充组低21．3％。结论 出生前后饮食中补充胆碱可以减轻癫痫发作引起的认知功能损害，这一作用可能与海马内胆碱乙酰转移酶的水平有关。     

Multiple Kainic Acid Seizures in the Immature and Adult Brain: Ictal Manifestations and Long–Term Effects on Learning and Memory

Summary: Purpose: While there is increasing evidence that the adverse effects of prolonged seizures are less pronounced in the immature than in the mature brain, there have been few investigations of the long-term effects of recurrent seizures during development. This study examined the effects of multiple administrations of the convulsant kainic acid (KA) on seizure characteristics and spatial learning as a function of brain development. Method: To determine the long-term effects of serial KA seizures during ontogeny, saline or convulsant doses of KA were given intraperitoneally 4 times, at 2-day intervals. Immature rats were given KA on P20, P22, P24 and P26; adult rats got KA on P60, P62, P64 and P66. Ictal characteristics and EEGs were recorded. To examine the effects of multiple KA seizures on the retention of spatial learning, water maze testing was performed before (immature group: from P16–19, adult group: from P56–P59) and after (immature: from P60–P63, adult: from P1OO–Pl03) KA injections. Finally, histology was performed to compare KA-induced damage at each age. Results: In immature animals, serial KA administration resulted in seizures with a progressively longer onset latency anddecreased severity. In contrast, KA serially administered to adult rats caused severe seizures after each of the 4 injections. In immature rats, epileptiform EEG changes were most prominent after the first KA injection, whereas in adults, prolonged paroxysmal EEG patterns were seen after all 4 KA injections. Before KA, both rat pups and adults acquired place learning in the water maze. One month after the final KA injection, there was no deficit in spatial learning retention in the immature group, whereas the adult group had profound impairment compared to age-matched, saline-injected controls. Histology revealed no lesions in immature rats treated multiple times with KA but profound cell loss in hippocampal fields CA4, CA3 and CAI in rats treated serially with KA as adults. Conclusions: Previous studies have shown that a single KA injection causes prolonged status epilepticus (which persists for several hours), leading to severe histologic and behavioral sequelae in adult rats but not in pups. Our study extends those findings, demonstrating that immature rats are spared the cognitive and pathological sequelae of multiple injections of convulsant doses of KA as well.     

Frequency and significance of acute postoperative seizures following epilepsy surgery in children and adolescents

PURPOSE: To determine the frequency and prognostic features of acute postoperative seizures (APOSs), within the first postoperative week, in a group of children undergoing surgery for the treatment of medically refractory epilepsy. METHODS: Patients younger than 18 years who underwent surgery for the relief of medically intractable epilepsy at the Mayo Clinic between 1985 and 1998 with a minimum of 12 months of follow-up were eligible. A retrospective chart review was conducted to abstract information regarding demographics, epilepsy history, and preoperative, intraoperative, and postoperative risk factors, APOSs, and outcome. A multivariate analysis was conducted to control for confounding variables. RESULTS: The study group was composed of 148 patients (mean age at surgery, 13 years; range, 5 months to 18 years). Twenty-five percent of patients experienced APOSs. Risk factors associated with a statistically significant (p < 0.05) greater likelihood of experiencing APOS were non-complex partial seizure type, extratemporal surgery, postoperative fever, non-temporal lobe epilepsy, and postoperative interictal epileptiform activity. At last follow-up, patients who did not experience APOSs had a significantly greater chance of being seizure free (80 vs. 51%; p < 0.001). With a multivariate analysis, APOS was found to be an independent predictor of outcome. CONCLUSIONS: This study indicates that APOSs are predictive of a less favorable outcome in the pediatric postsurgical patient; however, 51% remained seizure free at last follow-up. Finally, the effects of APOSs on outcome were shown to be stable over a 12-month follow-up period.     

托吡酯对癫痫大鼠认知功能及海马组织中NCAM的mRNA表达影响

目的研究托吡酯（TPM）对癫痫大鼠认知功能的影响以及使用TPM后大鼠海马组织中神经细胞粘附分子（NCAM）的mRNA表达变化。方法将大鼠随机分成生理盐水（NS）组、癫痫（EP）组、癫痫＋托吡酯治疗1周（TPM1周）组和癫痫＋托吡酯治疗4周（TPM4周）组,建立匹罗卡品诱导癫痫大鼠模型和TPM干预模型,观察大鼠的行为学改变,通过Morris水迷宫实验测试大鼠的学习记忆能力,并通过Real—TimePCR检测大鼠海马组织中NCAM的mRNA表达水平。结果EP组大鼠的逃避潜伏期大于NS组,原平台象限游泳时间百分比小于NS组,海马NCAM的mRNA表达水平高于NS组（P〈0．01）;TPM1周组和TPM4周组大鼠的逃避潜伏期大于EP组,原平台象限游泳时间百分比小于EP组,海马NCAM的mRNA表达水平低于EP组（P〈0.01）;TPM4周组大鼠的逃避潜伏期大于TPM1周组,原平台象限游泳时间百分比小于TPM1周组,海马NCAM的mRNA表达水平低于TPMI周组（P〈0.05）。结论大鼠产生癫痫持续状态后认知功能明显下降,海马NCAM的mRNA表达上调;使用大剂量TPM短期治疗后其认知功能进一步下降,海马NCAM的mRNA表达受抑,且下降与受抑程度与TPM的持续使用时间有关。     

Children with Epilepsy: The Effect of Seizures, Syndromes, and Etiological Factors on Cognitive Functioning

Summary: Overall, children with epilepsy have poorer concentration and mental processing and are less alert than age-matched controls. The relationship between cognitive functioning and epilepsy is complex, however, with widely differing degrees of intellectual impairment–ranging from minimal to severe and progressive–related to diverse types of epileptic seizures, syndromes, and etiological factors. Prolonged and frequently repeated seizures are typically associated with more severe effects on cognitive functioning, particularly if epilepsy is symptomatic, i.e., secondary to a demonstrable brain lesion. A combination of such factors may contribute to the mental deterioration seen in many children suffering from severe epilepsy.     

Effect of orally administered guanosine on seizures and death induced by glutamatergic agents

Intraperitoneal guanosine has been shown to prevent quinolinic acid-induced seizures in mice. In this study, we investigated the effect of orally administered guanosine on seizures induced by the glutamate agonists quinolinic acid and kainate, and the endogenous glutamate releaser α-dendrotoxin. Guanosine (7.5 mg/kg, per os), administered 75 min in advance, prevented 70% of seizures induced by i.c.v. quinolinic acid, being as efficient as the NMDA channel blocker MK-801 administered intraperitoneally. Guanosine was ineffective against kainate-induced seizures, but significantly reversed the potentiation of seizures and death caused by the concomitant injection of MK-801. Guanosine also significantly prevented seizures and death induced by i.c.v. α-dendrotoxin, whereas MK-801 and phenobarbital only prevented death. Altogether, our findings underscore the therapeutic potential of oral administration of guanosine for treating diseases involving glutamatergic excitotoxicity, including epilepsy.     

Effect of topiramate on cognitive function and single units from hippocampal place cells following status epilepticus

Topiramate, an antiepileptic drug with multiple mechanisms of action, was assessed as a neuroprotective agent following status epilepticus. We administered topiramate or normal saline chronically beginning 1 hour after cessation of lithium pilocarpine-induced status epilepticus. Control animals not subjected to status epilepticus were also treated with topiramate or normal saline. Following completion of the topiramate treatment, animals were tested in the water maze to assess spatial learning and underwent in vivo single-cell place cell recordings. Spontaneous seizure frequency following status epilepticus in the topiramate-treated rats was similar to that in the rats treated with saline. Following status epilepticus, rats had profound deficits in water maze performance and place cell function. Rats subjected to status epilepticus and treated with topiramate were also severely impaired in the water maze, but performed slightly better than rats treated with saline. Following status epilepticus, topiramate-treated rats did not differ from rats treated with normal saline in the platform switch, a test of prefrontal function. Although place cell firing patterns were similar in both the topiramate- and saline-treated rats, rats treated with topiramate had higher information content scores than rats treated with saline. Topiramate-treated animals had less supragranular sprouting following status epilepticus than nontreated rats. Control animals treated with topiramate did not differ from saline-treated controls on any measures. Taken together, this study shows that topiramate administered following status epilepticus has modest neuroprotective effects.     

Effect of topiramate following recurrent and prolonged seizures during early development

Topiramate, an antiepileptic drug with a number of mechanisms of action including inhibition of glutamate activity at the AMPA and KA receptors, was assessed as a neuroprotective agent following seizures. We administered topiramate, 80 mg/kg, or saline for 4 weeks following a series of 25 neonatal seizures or status epilepticus (SE) induced by lithium-pilocarpine in postnatal day 20 rats. Age-matched control rats without a history of seizures were administered topiramate or saline. Following completion of the topiramate injections, animals were tested in the water maze for spatial learning and the brains examined for cell loss and sprouting of mossy fibers. While there was a trend for improved visual-spatial performance in the water maze following topiramate therapy in rats with neonatal seizures, no differences were found in the histological examination of the hippocampus. Neonatal rats exposed to 4 weeks of topiramate did not differ from non-treated controls in water maze performance or histological examination. In weanling rats subjected to SE, topiramate provided a moderate degree of neuroprotection, with topiramate-treated rats performing better in the water maze than rats receiving saline. However, no differences in cell loss or mossy fiber sprouting were found in the histological examination of the brains. These findings demonstrate that chronic treatment with topiramate following SE improves cognitive function. In addition, long-term administration of high-dose topiramate in the normal developing rat brain does not appear to impair cognitive performance.     

The ontogeny of partial seizures in infants and young children

PURPOSE: To describe the clinical manifestations of partial seizures in the pediatric population as a function of age. METHODS: Using the database of the pediatric epilepsy monitoring unit (Children's Hospital of New York), clinical and EEG characteristics of partial seizures were distributed by age groups 0-2, 2-6, and 6+ years for 123 patients who had at least one such seizure with a clear EEG correlate during their admission. chi2 tests for trend were used to examine clinical and EEG features as a function of age. RESULTS: The frequency of aura, limb automatisms, dystonic posturing, secondary generalization, and unresponsiveness increased with age, whereas asymmetric clonus and symmetric tonic posturing decreased with age. There were no clear changes in the types of EEG ictal patterns observed with age; however, partial seizures emanating from the anterior regions of the brain tended to increase with age, whereas those from the posterior regions tended to decrease with age. CONCLUSIONS: Important differences exist in the clinical expression of seizures between young children and adults. These findings will contribute to a better understanding of ictal ontogeny that will promote more accurate classification of seizures and of the epilepsies in young patients. Such efforts can be used to identify young patients for focal epilepsy surgery and to select appropriate anticonvulsive medications.     

Familial neonatal seizures with intellectual disability caused by a microduplication of chromosome 2q24.3

A family with dominantly inherited neonatal seizures and intellectual disability was atypical for neonatal and infantile seizure syndromes associated with potassium (KCNQ2 and KCNQ3) and sodium (SCN2A) channel mutations. Microsatellite markers linked to KCNQ2, KCNQ3, and SCN2A were examined to exclude candidate locations, but instead revealed a duplication detected by observation of three alleles for two markers flanking SCN2A. Characterization revealed a 1.57 Mb duplication at 2q24.3 containing eight genes including SCN2A, SCN3A, and the 3′ end of SCN1A. The duplication was partially inverted and inserted within or near SCN1A, probably affecting the expression levels of associated genes, including sodium channels. Rare or unique microchromosomal copy number mutations might underlie familial epilepsies that do not fit within the clinical criteria for the established syndromes.     

Effects of spontaneous recurrent seizures on cognitive function via modulation of SNAREs expression

Purpose: To explore whether soluble N-ethylmaleimide-sensitive factor attachment protein receptors (SNARE) complexes are involved in cognitive dysfunction induced by spontaneous recurrent seizures (SRS). Materials and methods: An animal model of epilepsy was established by intraperitoneal injection of kainic acid (KA). Following the onset of SRS, the rats were divided into control group, KA-SRS group, KA+SRS group and KA+SRS+VAP group. Morris water maze and open field test were conducted to evaluate the cognitive function. Protein and mRNA levels of SNAREs complex were measured by Western-blot and RT-PCR, respectively. Besides, the Ca²⁺ concentration in the hippocampus was also detected. Results: A delayed escape latency and a reduced number of platform crossings were found in the KA+SRS group. Meanwhile, a longer moving distance and time spent in central area were also observed during the open field test. Besides, the Ca²⁺ concentration in the hippocampus of the KA+SRS group was markedly increased. However, when compared with the KA+SRS group, all indices in the KA+SRS+VAP group were markedly improved. Moreover, the SNARE complexes in the hippocampus of the KA+SRS group were significantly increased when compared with both control group and KA+SRS+VAP group. Conclusions: Results of our study demonstrated that the cognitive dysfunction caused by SRS may be attributed to the modulation expression of SNARE complexes.     

Expressive aprosody and amusia as a manifestation of right hemisphere seizures

PURPOSE: Aprosody and amusia are disorders commonly associated with right hemisphere abnormalities. They are regarded as negative phenomena and usually seen after strokes. We report a case of a patient who had both expressive aprosody and amusia as a clinical manifestation of right temporooccipital seizures. METHODS: A 43-year-old woman had a 1-month history of monotonic speech and difficulty singing. Her examination revealed both expressive aprosody and amusia. Magnetic resonance imaging of the head was normal, but her EEG revealed several electrographic seizures of right temporooccipital origin. RESULTS: Treatment with phenytoin (PHT) almost immediately caused her speech and singing to return to baseline. A repeated EEG was normal CONCLUSIONS: Seizures of right temporooccipital origin can manifest with expressive aprosody and amusia.     

The role of interleukin-1 in seizures and epilepsy: A critical review

Interleukin-1 (IL-1) has a multitude of functions in the central nervous system. Some of them involve mechanisms that are related to epileptogenesis. The role of IL-1 in seizures and epilepsy has been investigated in both patients and animal models. This review aims to synthesize, based on the currently available literature, the consensus role of IL-1 in epilepsy.Three lines of evidence suggest a role for IL-1: brain tissue from epilepsy patients and brain tissue from animal models shows increased IL-1 expression after seizures, and IL-1 has proconvulsive properties when applied exogeneously. However, opposing results have been published as well. More research is needed to fully establish the role of IL-1 in seizure generation and epilepsy, and to explore possible new treatment strategies that are based on interference with intracellular signaling cascades that are initiated when IL-1 binds to its receptor.     

全面性癫癎伴热性惊厥附加症的临床和脑电图特征分析

目的探讨全面性癫伴热性惊厥附加症(GEFS )的临床和脑电图(EEG)特点。方法收集4个GEFS 的家系资料,通过详细的调查建立完善的家系谱,并对受累者的临床资料、EEG进行分析总结。结果4个家系共有60名成员,其中受累者20例,表现为FS者5例,FS 者7例,FS 与失神发作2例,FS 与肌阵挛发作1例,FS 与失神和肌阵挛发作1例,此例患者发作间期EEG呈现局灶性癫放电和全面性癫放电共存的现象,1例表现为FS 和部分性发作,其发作间歇期EEG呈现中央中颞棘波灶,个体诊断符合良性罗兰多区癫。另外,受累者有肯定的临床发作,但是由于不能收集到可靠的发作表现资料,无法进行发作分类者3例。受累者神经系统检查以及头颅CT或磁共振成像(MRI)检查均未见异常。结论GEFS 的正确诊断需要注重个体,立足于整个家系进行,其临床发作谱还包括部分性发作,脑电图也有局灶的癫样放电。良性罗兰多区癫也许是GEFS 的一个新表现型。