Age‐dependent consequences of seizures: Relationship to seizure frequency, brain damage, and circuitry reorganization

Lado, Fred A.; Sankar, Raman; Lowenstein, DH; Moshé, Solomon L.

doi:10.1002/1098-2779(2000)6:4<242::aid-mrdd3>3.3.co;2-n

Cited by 12 publications

(15 citation statements)

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“…Nevertheless, several studies have shown that the immature brain is resistant to seizure-induced hippocampal neuronal cell loss (9-12) and synaptic reorganization (11,13,14). Despite hippocampal resistance to neuronal Address correspondence and reprint requests to Dr. A. V. Silva at Lab Neurologia Experimental UNIFESP-EPM, Rua Botucatú, 862, CEP 04023-900 São Paulo, SP, Brazil.…”

Section: Resultsmentioning

confidence: 99%

Disruption of Cortical Development as a Consequence of Repetitive Pilocarpine‐induced Status Epilepticus in Rats

et al. 2005

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Summary: Purpose:The aim of the present study was to observe possible cortical abnormalities after repetitive pilocarpineinduced status epilepticus (SE) in rats during development.Methods: Wistar rats received intraperitoneal injection of pilocarpine hydrochloride 2% (380 mg/kg) at P7, P8, and P9. All experimental rats displayed SE after pilocarpine injections. Rats were killed at P10 and P35, and immunocytochemistry procedures were performed on 50-µm vibratome sections, by using antibodies against nonphosphorylated neurofilament (SMI-311), parvalbumin (PV), calbindin (CB), calretinin (CR), and glutamate decarboxylase (GAD-65). Selected sections were used for the TUNEL method and double-labeling experiments, with different mixtures of the same markers. Results:The major findings of the present work were (a) altered intracortical circuitry development; (b) anticipation of PV immunoreactivity in neocortical interneurons; (c) increased GAD-65 immunoreactivity; and (d) reduced neocortical apoptotic process.Conclusions: From these results, we suggest that previously healthy brain, without genetic abnormalities, might develop an "acquired" disruption of cortical development whose evolution reproduces some characteristics of the childhood epilepsies associated with cognitive impairment. Key Words: Immature brain-Early insult-Apoptosis-Neocortex-Interneurons.In humans, the incidence of seizures is higher in the first year of life and decreases until adulthood (1,2). Although most of the early-life seizures are inherently benign, symptomatic febrile or hypoxic seizures are present in the history of many patients with temporal lobe epilepsy (TLE) and are believed to be associated with an underlying progressive epileptogenic process (3). Despite increasing knowledge of basic epileptology, the role of early-life seizures in the development of TLE remains an open question.In rats, neonatal seizures induce a range of hippocampal changes, such as glia activation and cytokine increase (4), altered glutamate and γ -aminobutyric acid (GABA)(A)-receptor gene immunoreactivity (5), persistent changes in intrinsic properties of CA1 cells (6), long-term behavioral deficits (7), and reduced hippocampal neurogenesis (8). Nevertheless, several studies have shown that the immature brain is resistant to seizure-induced hippocampal neuronal cell loss (9-12) and synaptic reorganization (11,13,14). Despite hippocampal resistance to neuronal Address correspondence and reprint requests to Dr. A. V. Silva at Lab Neurologia Experimental UNIFESP-EPM, Rua Botucatú, 862, CEP 04023-900 São Paulo, SP, Brazil. E-mail: valotta.nexp@epm.br damage during early development, Santos and colleagues (15,16) recently demonstrated that multiple episodes of pilocarpine-induced status epilepticus (SE) in developing rats (P7-P9) led to progressive neocortical/hippocampal epileptiform activity, persistent in vitro hyperexcitability, increased hippocampal/thalamic apoptosis, and severe cognitive impairment in adulthood.In contrast to adult rats that develop hippocam...

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Section: Resultsmentioning

confidence: 99%

Disruption of Cortical Development as a Consequence of Repetitive Pilocarpine‐induced Status Epilepticus in Rats

et al. 2005

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“…Consistent with the results we have observed for the metabolic mutants investigated here, it appears that distinct metabolic changes can result both in increased seizure susceptibility and neurodegeneration (Kunz 2002) and that impaired neuronal viability may be independent of actual seizures. These results further link seizures and neurodegeneration and suggest that in human patients affected by certain seizure disorders effective therapeutic intervention may require amelioration of the metabolic deficit in addition to controlling seizures (Lado et al 2000;Pitkänen 2002;Sutula 2002;Trojnar et al 2002).…”

Section: Dts1mentioning

confidence: 95%

Neuropathology in Drosophila Mutants With Increased Seizure Susceptibility

et al. 2008

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Genetic factors are known to contribute to seizure susceptibility, although the long-term effects of these predisposing factors on neuronal viability remain unclear. To examine the consequences of genetic factors conferring increased seizure susceptibility, we surveyed a class of Drosophila mutants that exhibit seizures and paralysis following mechanical stimulation. These bang-sensitive seizure mutants exhibit shortened life spans and age-dependent neurodegeneration. Because the increased seizure susceptibility in these mutants likely results from altered metabolism and since the Na 1 /K1 ATPase consumes the majority of ATP in neurons, we examined the effect of ATPa mutations in combination with bang-sensitive mutations. We found that double mutants exhibit strikingly reduced life spans and age-dependent uncoordination and inactivity. These results emphasize the importance of proper cellular metabolism in maintaining both the activity and viability of neurons. (Bittigau et al. 2002). Such links suggest that among the genetic components underlying epilepsy and neurodegeneration, certain risk factors may be shared.These neurological diseases have been extensively modeled and studied in the genetically tractable system of Drosophila. In addition to the availability of numerous seizure mutants, many mutants have been isolated, exhibiting pronounced age-dependent neurodegeneration (reviewed by Bilen and Bonini 2005;Celotto and Palladino 2005;Kretzschmar 2005). Bang-sensitive mutants exhibit behavioral seizures and paralysis following mechanical stimulation that usually become more severe with age. It was proposed that these mutants were associated with defects leading to increased membrane excitability (Benzer 1971;Ganetzky and Wu 1982). This idea is further supported by the reduced threshold for electrically induced seizures in these mutants (Kuebler and Tanouye 2000). Molecular identification of several of these mutants has suggested that they result from defects in mitochondrial metabolism (Royden et al. 1987;Zhang et al. 1999;Fergestad et al. 2006a To examine the long-term effects of genetic perturbations conferring increased seizure susceptibility, we performed aging and histological analyses on these seizure mutants alone and in combination with ATPa mutations. Our studies of bang-sensitive seizure mutants revealed reduced life spans and appearance of age-dependent spongiform-like degeneration in the nervous system. Strong genetic interactions were identified between bang-sensitive mutations and dominant mutations affecting ATPa, the Na 1 /K 1 ATPase a-subunit, known to cause conditional seizures, neurodegeneration, and early death, supporting a model in which metabolic perturbations result in both altered neuronal activity and neurodegeneration. MATERIALS AND METHODSFly strains: Fly stocks were cultured on cornmeal-molasses agar medium at 22-25°. Strains used in this study include tko 25t , We dedicate this article to the memory of Seymour Benzer, mentor, friend, and father of our field.

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“…Several pathologies (Mathern et al, 1995;Lado et al, 2000), including mesial temporal sclerosis (MTS), may account for associations between prolonged FS and later epilepsy, but the scarcity of data limit conclusions. While there have been two studies of magnetic resonance imaging (MRI) in febrile status epilepticus (SE) 765 766 D. C. Hesdorffer et al (VanLandingham et al, 1998;Scott et al, 2003), MRI studies are lacking in cohorts with simple and complex FS of shorter duration, where such studies could contribute to understanding why children experience FS.…”

Section: Objective: Whether Magnetic Resonance Imaging (Mri) Is Informentioning

confidence: 99%

Are MRI‐detected brain abnormalities associated with febrile seizure type?

et al. 2008

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SUMMARY Objective: Whether magnetic resonance imaging (MRI) is informative in febrile seizures (FS) is unknown. We undertook a study to determine the frequency of MRI-detected brain abnormalities andFebrile seizures (FS) are common, affecting 2-5% of children by 6 years of age (van den Berg & Yerushalmy, 1969;Verity et al., 1985) and are associated with an increased risk of subsequent epilepsy. Epilepsy develops in 2-4% of children with a history of FS, four times more fre- (Nelson & Ellenberg, 1978;Annegers et al., 1979;Verity et al., 1985).Computed tomography (CT) scans are not recommended in FS (NIH, 1980;Al-Qudah, 1995), although preexisting brain abnormality has been proposed (Annegers et al., 1987) to explain the observation that complex, but not simple, FS are associated with increased risk for focal epilepsy. Several pathologies (Mathern et al., 1995;Lado et al., 2000), including mesial temporal sclerosis (MTS), may account for associations between prolonged FS and later epilepsy, but the scarcity of data limit conclusions. While there have been two studies of magnetic resonance imaging (MRI) in febrile status epilepticus (SE) 765 766 D. C. Hesdorffer et al. (VanLandingham et al., 1998;Scott et al., 2003), MRI studies are lacking in cohorts with simple and complex FS of shorter duration, where such studies could contribute to understanding why children experience FS.We undertook a prospective study of children with first FS (1) to determine the proportion with MRI-detected brain abnormalities, and (2) to evaluate whether these abnormalities were more common among children with complex FS than among those with simple FS or were associated with specific features of complex FS. METHODS Study subjectsIn this prospective cohort study, we identified children, aged 6 months to 5 years, with first FS by daily screening of The Morgan Stanley Children's Hospital of New YorkPresbyterian Pediatric Emergency Department log and by review of pediatric hospital discharges with an ICD-9 code of 780.3 between March 1999 and April 2004. We defined FS as seizures occurring among children with a rectal temperature of at least 101• Fahrenheit (38.3 o C), in the absence of a history of unprovoked seizures or concurrent central nervous system infection (NIH, 1980). Children with prior neonatal seizure were included.Upon identification, we contacted the child's primary care physician to request permission for the study team to contact the child's parents or guardians. After obtaining permission from the parent, the physician notified the study team and the family was contacted to explain the study and offer participation. Measures and proceduresIf initial screening confirmed the first FS, we obtained informed consent and the child received an MRI of the brain within 1 week of the FS. Within 1 month, parents were interviewed regarding the child's medical history, demographics, and family history of FS and epilepsy in firstdegree relatives. At the parent interview, children received a neurological examination, which was classifie...

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Age‐dependent consequences of seizures: Relationship to seizure frequency, brain damage, and circuitry reorganization

Cited by 12 publications

References 123 publications

Disruption of Cortical Development as a Consequence of Repetitive Pilocarpine‐induced Status Epilepticus in Rats

Disruption of Cortical Development as a Consequence of Repetitive Pilocarpine‐induced Status Epilepticus in Rats

Neuropathology in Drosophila Mutants With Increased Seizure Susceptibility

Are MRI‐detected brain abnormalities associated with febrile seizure type?

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