Antiepileptic drug treatment strategies in neonatal epilepsy.

The highest risk of seizures across the lifespan is in the neonatal period. The enhanced excitability of the immature brain compared to the mature brain is related to the sequential development and expression of essential neurotransmitter signaling pathways. During the neonatal period there is an overabundance of excitatory receptors, and γ-amino-butyric acid (GABA) is potentially depolarizing, as opposed to hyperpolarizing in the older brain. While this enhanced excitability is required for regulation of activity-dependent synapse formation and refining of synaptic connections that are necessary for normal brain development, enhanced excitability predisposes the immature brain to seizures. In addition to being common, neonatal seizures are very difficult to treat; antiepileptic drugs used in older children and adults are less efficacious, and possibly detrimental to brain development. In an effort to target the unique features of neurotransmission in the neonate, bumetanide, an NKCC1 inhibitor which reduces intraneuronal Cl(-) and induces a significant shift of EGABA toward more hyperpolarized values in vitro, has been used to treat neonatal seizures. As the understanding of the pathophysiology of genetic forms of neonatal epilepsy has evolved there have been a few successful attempts to pharmacologically target the mutated protein. This approach, while promising, is challenging due to the findings that the genetic syndromes presenting in infancy demonstrate genetic heterogeneity in regard to both the mutated gene and its function.

Contribution of protease-activated receptor 1 in status epilepticus-induced epileptogenesis.

Clinical observations and studies on different animal models of acquired epilepsy consistently demonstrate that blood-brain barrier (BBB) leakage can be an important risk factor for developing recurrent seizures. However, the involved signaling pathways remain largely unclear. Given the important role of thrombin and its major receptor in the brain, protease-activated receptor 1 (PAR1), in the pathophysiology of neurological injury, we hypothesized that PAR1 may contribute to status epilepticus (SE)-induced epileptogenesis and that its inhibition shortly after SE will have neuroprotective and antiepileptogenic effects. Adult rats subjected to lithium-pilocarpine SE were administrated with SCH79797 (a PAR1 selective antagonist) after SE termination. Thrombin and PAR1 levels and neuronal cell survival were evaluated 48h following SE. The effect of PAR1 inhibition on animal survival, interictal spikes (IIS) and electrographic seizures during the first two weeks after SE and behavioral seizures during the chronic period was evaluated. SE resulted in a high mortality rate and incidence of IIS and seizures in the surviving animals. There was a marked increase in thrombin, decrease in PAR1 immunoreactivity and hippocampal cell loss in the SE-treated rats. Inhibition of PAR1 following SE resulted in a decrease in mortality and morbidity, increase in neuronal cell survival in the hippocampus and suppression of IIS, electrographic and behavioral seizures following SE. These data suggest that the PAR1 signaling pathway contributes to epileptogenesis following SE. Because breakdown of the BBB occurs frequently in brain injuries, PAR1 inhibition may have beneficial effects in a variety of acquired injuries leading to epilepsy.

Cognitive impairment in temporal lobe epilepsy: role of online and offline processing of single cell information.

Cognitive impairment is a common comorbidity in temporal lobe epilepsy (TLE) and is often considered more detrimental to quality of life than seizures. While it has been previously shown that the encoding of memory during behavior is impaired in the pilocarpine model of TLE in rats, how this information is consolidated during the subsequent sleep period remains unknown. In this study, we first report marked deficits in spatial memory performance and severe cell loss in the CA1 layer of the hippocampus lower spatial coherence of firing in TLE rats. We then present the first evidence that the reactivation of behavior-driven patterns of activity of CA1 place cells in the hippocampus is intact in TLE rats. Using a template-matching method, we discovered that real-time (3-5 s) reactivation structure was intact in TLE rats. Furthermore, we estimated the entropy rate of short time scale (∼250 ms) bursting activity using block entropies and found that significant, extended temporal correlations exist in both TLE and control rats. Fitting a first-order Markov Chain model to these bursting time series, we found that long sequences derived from behavior were significantly enriched in the Markov model over corresponding models fit on randomized data confirming the presence of replay in shorter time scales. We propose that the persistent consolidation of poor spatial information in both real time and during bursting activity may contribute to memory impairments in TLE rats.

Altered short-term plasticity in the prefrontal cortex after early life seizures.

Seizures during development are a relatively common occurrence and are often associated with poor cognitive outcomes. Recent studies show that early life seizures alter the function of various brain structures and have long-term consequences on seizure susceptibility and behavioral regulation. While many neocortical functions could be disrupted by epileptic seizures, we have concentrated on studying the prefrontal cortex (PFC) as disturbance of PFC functions is involved in numerous co-morbid disorders associated with epilepsy. In the present work we report an alteration of short-term plasticity in the PFC in rats that have experienced early life seizures. The most robust alteration occurs in the layer II/III to layer V network of neurons. However short-term plasticity of layer V to layer V network was also affected, indicating that the PFC function is broadly influenced by early life seizures. These data strongly suggest that repetitive seizures early in development cause substantial alteration in PFC function, which may be an important component underlying cognitive deficits in individuals with a history of seizures during development.

Neuro-QOL: brief measures of health-related quality of life for clinical research in neurology.

OBJECTIVE: To address the need for brief, reliable, valid, and standardized quality of life (QOL) assessment applicable across neurologic conditions. METHODS: Drawing from larger calibrated item banks, we developed short measures (8-9 items each) of 13 different QOL domains across physical, mental, and social health and evaluated their validity and reliability. Three samples were utilized during short form development: general population (Internet-based, n = 2,113); clinical panel (Internet-based, n = 553); and clinical outpatient (clinic-based, n = 581). All short forms are expressed as T scores with a mean of 50 and SD of 10. RESULTS: Internal consistency (Cronbach α) of the 13 short forms ranged from 0.85 to 0.97. Correlations between short form and full-length item bank scores ranged from 0.88 to 0.99 (0.82-0.96 after removing common items from banks). Online respondents were asked whether they had any of 19 different chronic health conditions, and whether or not those reported conditions interfered with ability to function normally. All short forms, across physical, mental, and social health, were able to separate people who reported no health condition from those who reported 1-2 or 3 or more. In addition, scores on all 13 domains were worse for people who acknowledged being limited by the health conditions they reported, compared to those who reported conditions but were not limited by them. CONCLUSION: These 13 brief measures of self-reported QOL are reliable and show preliminary evidence of concurrent validity inasmuch as they differentiate people based upon number of reported health conditions and whether those reported conditions impede normal function.

Randomized, controlled, dose-ranging trial of carisbamate for partial-onset seizures.

OBJECTIVE: To evaluate the efficacy, safety, and tolerability of carisbamate (CRS), an investigational drug, as adjunctive treatment for partial-onset seizures in adults. METHODS: A randomized, double-blind, placebo-controlled, multicenter, dose-ranging study was conducted in 12 countries. Patients counted seizures during an 8-week baseline period, and then, if eligible, entered a double-blind phase consisting of a 4-week dose-titration period (target CRS doses: 100, 300, 800, or 1,600 mg/d or placebo in two divided doses) and a 12-week maintenance period. The primary efficacy variable was percent reduction in partial-onset seizure frequency during the double-blind phase compared with pretreatment baseline. Safety data and responder rates were also assessed. RESULTS: Five hundred thirty-seven patients were randomized, and 82% completed the study. In the intent-to-treat population (n = 533), CRS at doses of > or =300 mg/d (p < or = 0.006) reduced the frequency of partial-onset seizures vs placebo: 6% (placebo) vs 24% (300 mg/d), 21% (800 mg/d), and 29% (1,600 mg/d) for CRS. Adverse events consisted primarily of CNS effects, and led to discontinuation of drug in 8% of the placebo group vs 5% (100 mg/d), 6% (300 mg/d), 12% (800 mg/d), and 19% (1,600 mg/d) of the CRS groups. CONCLUSIONS: Carisbamate at doses of 300, 800, and 1,600 mg/d was effective as adjunctive therapy for reducing the frequency of partial-onset seizures.

Pregnancy registries in epilepsy: a consensus statement on health outcomes.

Most pregnant women with epilepsy require antiepileptic drug (AED) therapy. Present guidelines recommend optimizing treatment prior to conception, choosing the most effective AED for seizure type and syndrome, using monotherapy and lowest effective dose, and supplementing with folate. The Epilepsy Therapy Project established the international Health Outcomes in Pregnancy and Epilepsy (HOPE) forum to learn more about the impact of AEDs on the developing fetus, particularly the role of pregnancy registries in studying AED teratogenicity. The primary outcome of interest in these registries is the occurrence of major congenital malformations, with some data collected on minor malformations. Cognitive and behavioral outcomes are often beyond the timeframe for follow-up of these registries and require independent study. The HOPE consensus report describes the current state of knowledge and the limitations to interpretations of information from the various sources. Data regarding specific risks for both older and newer AEDs need to be analyzed carefully, considering study designs and confounding factors. There is a critical need for investigations to delineate the underlying mechanisms and explain the variance seen in outcomes across AEDs and within a single AED.

[Relevance of basic research to clinical data: Good answers, wrong questions!]. / La recherche fondamentale est-elle utile à la clinique? Bonnes réponses, mauvaises questions !

What conclusions can be derived from experimental data on human epilepsies? This review discusses these issues, notably concerning human temporal lobe epilepsies (TLEs) and infantile epilepsies, where important advances have been achieved in both theory and the comprehension of epileptogenic mechanisms. A wide spectrum of human and animal data converge to show that the naive network transforms to one that generates seizures spontaneously. Thus, in TLE, experimental and human data suggest that the inaugurating status generates a sequence of events that lead to the sprouting of fibers and the formation of novel excitatory synapses. This reactive plasticity constitutes a basis for the generation of novel seizures by the epileptic network. Similarly, in vitro studies indicate that in immature hippocampal formation, the propagation of high- but not low-frequency seizures can transform a naive network into one that generates further seizures, thereby, giving an indication as to the types of seizure that are epileptogenic. In conclusion, it is suggested that although animal data cannot mimic human seizures in all their complex and variable etiologies, it provides essential indications on the mechanisms that enable seizure generation.

Bilateral volume reduction of the superior temporal areas in Landau-Kleffner syndrome.

No specific anatomic abnormalities have been detected in typical Landau-Kleffner syndrome (LKS), an acquired epileptic aphasia with language regression in children. In four children with typical LKS without obvious anatomic abnormalities, the authors performed MRI volumetric analysis of various neocortical regions and subcortical substructures. Volume reduction was detected in bilateral superior temporal areas (26 to 51%), specifically in planum temporale (25 to 63%) and superior temporal gyrus (25 to 57%), where receptive language is localized.

Beneficial effects of enriched environment following status epilepticus in immature rats.

BACKGROUND: There is increasing evidence that enriching the environment can improve cognitive and motor deficits following a variety of brain injuries. Whether environmental enrichment can improve cognitive impairment following status epilepticus (SE) is not known. OBJECTIVE: To determine whether the environment in which animals are raised influences cognitive function in normal rats and rats subjected to SE. METHODS: Rats (n = 100) underwent lithium-pilocarpine-induced SE at postnatal (P) day 20 and were then placed in either an enriched environment consisting of a large play area with toys, climbing objects, and music, or in standard vivarium cages for 30 days. Control rats (n = 32) were handled similarly to the SE rats but received saline injections instead of lithium-pilocarpine. Rats were then tested in the water maze, a measure of visual-spatial memory. A subset of the rats were killed during exposure to the enriched or nonenriched environment and the brains examined for dentate granule cell neurogenesis using bromodeoxyuridine (BrdU) and phosphorylated cyclic AMP response element binding protein (pCREB) immunostaining, a brain transcription factor important in long-term memory. RESULTS: Both control and SE rats exposed to the enriched environment performed significantly better than the nonenriched group in the water maze. There was a significant increase in neurogenesis and pCREB immunostaining in the dentate gyrus in both control and SE animals exposed to the enriched environment compared to the nonenriched groups. Environmental enrichment resulted in no change in SE-induced histologic damage. CONCLUSIONS: Exposure to an enriched environment in weanling rats significantly improves visual-spatial learning. Even following SE, an enriched environment enhances cognitive function. An increase in neurogenesis and activation of transcription factors may contribute to this enhanced visual-spatial memory.

GnRH-immunoreactive fiber changes with unilateral amygdala-kindled seizures.

PURPOSE: To assess whether unilateral amygdala seizures are associated with a change in the number and lateral distribution of gonadotropin releasing hormone (GnRH)-staining fibers in the ventromedial hypothalamus of female rats. METHODS: The study compared three groups of female rats: (1) amygdala seizures induced by focal injection of kainic acid (KA); (2) saline injected controls; and (3) nai;ve controls. The animals were sacrificed at 4 weeks in the diestrus phase. GnRH fibers were counted in the ventromedial hypothalamus and compared among groups. RESULTS: GnRH fiber counts were significantly lower in KA than saline and nai;ve animals ipsilaterally but not contralaterally. CONCLUSIONS: This finding may support a potential mechanism by which (1) temporolimbic epilepsy may promote the development of reproductive endocrine disorders and (2) the laterality of the epilepsy may influence the particular nature of the reproductive endocrine disorder.

Timing of cognitive deficits following neonatal seizures: relationship to histological changes in the hippocampus.

Neonatal seizures are frequently associated with cognitive impairment and reduced seizure threshold. Previous studies in our laboratory have demonstrated that rats with recurrent neonatal seizures have impaired learning, lower seizure thresholds, and sprouting of mossy fibers in CA3 and the supragranular region of the dentate gyrus in the hippocampus when studied as adults. The goal of this study was to determine the age of onset of cognitive dysfunction and alterations in seizure susceptibility in rats subjected to recurrent neonatal seizures and the relation of this cognitive impairment to mossy fiber sprouting and expression of glutamate receptors. Starting at postnatal day (P) 0, rats were exposed to 45 flurothyl-induced seizures over a 9-day period of time. Visual-spatial learning in the water maze and seizure susceptibility were assessed in subsets of the rats at P20 or P35. Brains were evaluated for cell loss, mossy fiber distribution, and AMPA (GluR1) and NMDA (NMDAR1) subreceptor expression at these same time points. Rats with neonatal seizures showed significant impairment in the performance of the water maze and increased seizure susceptibility at both P20 and P35. Sprouting of mossy fibers into the CA3 and supragranular region of the dentate gyrus was seen at both P20 and P35. GluR1 expression was increased in CA3 at P20 and NMDAR1 was increased in expression in CA3 and the supragranular region of the dentate gyrus at P35. Our findings indicate that altered seizure susceptibility and cognitive impairment occurs prior to weaning following a series of neonatal seizures. Furthermore, these alterations in cognition and seizure susceptibility are paralleled by sprouting of mossy fibers and increased expression of glutamate receptors. To be effective, our results suggest that strategies to alter the adverse outcome following neonatal seizures will have to be initiated during, or shortly following, the seizures.

Enhanced auditory reversal learning by genetic activation of protein kinase C in small groups of rat hippocampal neurons.

The hippocampus has a central role in specific types of learning, but there is only limited evidence identifying the requisite molecular changes in ensembles of hippocampal neurons. To investigate the role of protein kinase C (PKC) pathways in hippocampal mediated learning, a constitutively active, catalytic domain of rat PKC betaII was delivered into hippocampal dentate granule neurons using a Herpes Simplex Virus (HSV-1) vector. This PKC causes a long-lasting, activation-dependent increase in neurotransmitter release from cultured cells. Activation of PKC pathways in a small percentage (< or =0.26%) of dentate granule neurons was sufficient to enhance rat auditory discrimination reversal learning. The affected neurons altered hippocampal physiology as revealed by elevated NMDA receptor densities in specific hippocampal areas. Thus, these results directly suggest that activation of PKC pathways in a specific hippocampal area alters rat auditory discrimination reversal learning. Because each rat may contain a unique pattern of affected neurons, there appears to be considerable flexibility and/or redundancy in the groups of neurons that can modify learning.

Prediction of safe duration of hypothermic circulatory arrest by near-infrared spectroscopy.

OBJECTIVE: Hypothermic circulatory arrest is widely used for adults with aortic arch disease as well as for children with congenital heart disease. At present, no method exists for monitoring safe duration of circulatory arrest. Near-infrared spectroscopy is a new technique for noninvasive monitoring of cerebral oxygenation and energy state. In the current study, the relationship between near-infrared spectroscopy data and neurologic outcome was evaluated in a survival piglet model with hypothermic circulatory arrest. METHODS: Thirty-six piglets (9.36 +/- 0.16 kg) underwent circulatory arrest under varying conditions with continuous monitoring by near-infrared spectroscopy (temperature 15 degrees C or 25 degrees C, hematocrit value 20% or 30%, circulatory arrest time 60, 80, or 100 minutes). Each setting included 3 animals. Neurologic recovery was evaluated daily by neurologic deficit score and overall performance category. Brain was fixed in situ on postoperative day 4 and examined by histologic score. RESULTS: Oxygenated hemoglobin signal declined to a plateau (nadir) during circulatory arrest. Time to nadir was significantly shorter with lower hematocrit value (P <.001) and higher temperature (P <.01). Duration from reaching nadir until reperfusion ("oxygenated hemoglobin signal nadir time") was significantly related to histologic score (r (s) = 0.826), neurologic deficit score (r (s) = 0.717 on postoperative day 1; 0.716 on postoperative day 4), and overall performance category (r (s) = 0.642 on postoperative day 1; 0.702 on postoperative day 4) (P <.001). All animals in which oxygenated hemoglobin signal nadir time was less than 25 minutes were free of behavioral or histologic evidence of brain injury. CONCLUSION: Oxygenated hemoglobin signal nadir time determined by near-infrared spectroscopy monitoring is a useful predictor of safe duration of circulatory arrest. Safe duration of hypothermic circulatory arrest is strongly influenced by perfusate hematocrit value and temperature during circulatory arrest.

Topiramate and metabolic acidosis in pediatric epilepsy.

PURPOSE: Topiramate (TPM) has been widely used as an adjunctive therapy for treating epilepsy. TPM is reported to have multiple mechanisms of action, including inhibition of carbonic anhydrase, which may result in metabolic acidosis from decreased serum bicarbonate (HCO3-). METHODS: Clinical data from 30 children who received TPM as adjunctive therapy for medically refractory epilepsy were reviewed at Children's Hospital, Boston. Serum HCO3- levels were assessed before, during, and after discontinuing TPM (n = 9). When multiple data were available, mean values were used for analysis. RESULTS: Of the 30 patients, 21 had a >10% decrease in HCO3- levels. The mean decrease in HCO3- among the 21 patients was 4.7 mEq/L, and maximum was 10 mEq/L. No clinical symptoms occurred, and HCO3- supplement was not needed, except for one patient who developed tachypnea from worsened acidosis after prolonged status epilepticus during a suspected viral illness. Among the 21 patients, TPM was discontinued in seven children because of a lack of efficacy, and in two because of anorexia. After discontinuing TPM, the serum HCO3- returned to the previous level before starting TPM in all nine. CONCLUSIONS: Decreased HCO3- levels occurred in the majority of patients reviewed, usually only to a small to moderate extent, but by 8 and 10 mEq/L in two cases. In patients at risk for acidosis, the decrease in HCO3- may cause significant consequences, such as severe acidosis or renal calculi. Monitoring HCO3- levels before and during TPM therapy may be indicated, especially with conditions that predispose to acidosis.

Recurrent neonatal seizures: relationship of pathology to the electroencephalogram and cognition.

Seizures in preterm infants are associated with a high risk of neurological sequelae. In the neonatal rat recurrent seizures have been associated with long-term changes in cerebral excitability and cognition as well as sprouting of mossy fiber terminals in the granule cell layer of the dentate gyrus and hippocampal CA3 subfield. To evaluate the relationship between seizure-induced morphological changes and cognitive function we subjected newborn rats to 55 seizures with flurothyl during the first 12 days of life. During adolescence rats with prior recurrent seizures were compared with controls in electroencephalographic power and performance in the Morris water maze and open field test. Rats subjected to recurrent seizures had marked impairment in water maze performance and never reached the level of learning seen in controls despite a total of 54 trials. Recurrent seizures were also associated with an overall reduction in spectral power which was most pronounced in the theta range. On histological examination rats with recurrent neonatal seizures had sprouting of mossy fiber terminals in CA3 and the granule cell layer of the dentate gyrus without any accompanying cell loss. Sprouting in CA3, but not the granule cell layer of the dentate gyrus, correlated with water maze performance. This study demonstrates that recurrent neonatal seizures can result in profound impairment of water maze performance and reduction of electroencephalographic power despite the lack of discernible cell loss and that this cognitive impairment correlates with mossy fiber sprouting in CA3.

Reduced neurogenesis after neonatal seizures.

Although neonatal seizures are quite common, there is controversy regarding their consequences. Despite considerable evidence that seizures may cause less cell loss in young animals compared with mature animals, there are nonetheless clear indications that seizures may have other potentially deleterious effects. Because it is known that seizures in the mature brain can increase neurogenesis in the hippocampus, we studied the extent of neurogenesis in the granule cell layer of the dentate gyrus over multiple time points after a series of 25 flurothyl-induced seizures administered between postnatal day 0 (P0) and P4. Rats with neonatal seizures had a significant reduction in the number of the thymidine analog 5-bromo-2'-deoxyuridine-5'-monophosphate- (BrdU) labeled cells in the dentate gyrus and hilus compared with the control groups when the animals were killed either 36 hr or 2 weeks after the BrdU injections. The reduction in BrdU-labeled cells continued for 6 d after the last seizure. BrdU-labeled cells primarily colocalized with the neuronal marker neuron-specific nuclear protein and rarely colocalized with the glial cell marker glial fibrillary acidic protein, providing evidence that a very large percentage of the newly formed cells were neurons. Immature rats subjected to a single seizure did not differ from controls in number of BrdU-labeled cells. In comparison, adult rats undergoing a series of 25 flurothyl-induced seizures had a significant increase in neurogenesis compared with controls. This study indicates that, after recurrent seizures in the neonatal rat, there is a reduction in newly born granule cells.