The disease complex Chiari-like malformation (CM) and syringomyelia (SM) has been associated with... more The disease complex Chiari-like malformation (CM) and syringomyelia (SM) has been associated with the development of neuropathic pain (NeP), and commonly affects Cavalier King Charles spaniels (CKCS). This prospective cohort study followed 48 CKCSs with CM and/or SM and clinical signs suggestive of NeP for a period of 39 (±14.3) months from diagnosis.
Materials and Methods Medical records at two UK referral hospitals for the period 2000–2009 were ... more Materials and Methods Medical records at two UK referral hospitals for the period 2000–2009 were searched for dogs and cats that had MR imaging of the brain and/or spinal cord and a diagnosis of primary or secondary CNS lymphoma based either on cytologic evidence of neoplastic cells (lymphoblasts) in the CSF and/or histopathologic examination.
PRESENTATION AND LESION LOCALISATION: Seven adult domestic shorthair cats were presented with a 1... more PRESENTATION AND LESION LOCALISATION: Seven adult domestic shorthair cats were presented with a 1-to 6-day history of progressive neurological signs. A focal skin puncture and subcutaneous swelling over the dorsal part of the head were detected on physical examination. Neurological examination indicated lesion (s) in the right forebrain in four cats, multifocal forebrain in one cat, left forebrain in one cat, and multifocal forebrain and brainstem in the remaining cat.
Reliance on history and description of episodes of collapse to differentiate seizures from syncop... more Reliance on history and description of episodes of collapse to differentiate seizures from syncope can be misleading. Syncope can have features of seizures or can be the cause of seizures. Clinical and neurologic examinations can also be misleading. High-grade atrioventricular (AV) block can be intermittent in cats and interictal neurologic examination can be normal in patients with epilepsy. In this report we describe highgrade AV dysfunction that mimicked epilepsy in 3 cats.
Abstract Previous research in Cavalier King Charles Spaniels (CKCS) has found that Chiari-like ma... more Abstract Previous research in Cavalier King Charles Spaniels (CKCS) has found that Chiari-like malformation and syringomyelia (CM/SM) are associated with a volume mismatch between the caudal cranial fossa (CCF) and the brain parenchyma contained within.
Zusammenfassung Die Epilepsie ist durch wiederkehrende Anfälle gekennzeichnet und mit einer Präva... more Zusammenfassung Die Epilepsie ist durch wiederkehrende Anfälle gekennzeichnet und mit einer Prävalenz von 0, 5–5, 7% die häufigste chronische neurologische Funktionsstörung des Hundes. Sie manifestiert sich aufgrund abnormaler elektrischer Aktivität des Großhirns. Jedes Gehirn besitzt die Voraussetzung für eine epileptische Aktivität.
Background Disk-associated cervical spondylomyelopathy (DA-CSM) is a multifactorial neurological ... more Background Disk-associated cervical spondylomyelopathy (DA-CSM) is a multifactorial neurological disorder in which progressive caudal cervical spinal cord compression is mainly caused by one or more intervertebral disk protrusions. The Doberman pinscher breed seems predisposed for this condition. The underlying cause and pathophysiology of DA-CSM are currently unknown. Recently, wider intervertebral disks have been put forward as a risk factor for development of clinically relevant DA-CSM.
Background Understanding the pathogenesis of the chiari-like malformation in the Cavalier King Ch... more Background Understanding the pathogenesis of the chiari-like malformation in the Cavalier King Charles Spaniel (CKCS) is incomplete, and current hypotheses do not fully explain the development of syringomyelia (SM) in the spinal cords of affected dogs. This study investigates an unconventional pathogenetic theory for the development of cerebrospinal fluid (CSF) pressure waves in the subarachnoid space in CKCS with SM, by analogy with human diseases.
Multidrug transporter over-expression is considered to limit access of antiepileptic drugs to the... more Multidrug transporter over-expression is considered to limit access of antiepileptic drugs to the epileptic focus region and to be one cause of intractable epilepsy. To reach further proof for this multidrug transporter hypothesis, we compared P-glycoprotein expression rates in subgroups of Wistar rats which are sensitive or resistant to the anticonvulsant effect of the antiepileptic drug phenytoin in the amygdala-kindling model of temporal lobe epilepsy. In the electrode-implanted amygdala of phenytoin-resistant rats, the area labelled for P-glycoprotein was more than twice as large than that in phenytoin-sensitive rats. The data indicate that P-glycoprotein expression levels in the kindled focus have a critical impact on the anticonvulsant response to antiepileptic drugs.
It has previously been shown that prolonged (60-min) low-intensity electrical stimulation of a ki... more It has previously been shown that prolonged (60-min) low-intensity electrical stimulation of a kindled focus in the basolateral nucleus of the amygdala (BLA) of Wistar rats resulted in the development of self-sustained status epilepticus (SSSE) with predominantly partial seizures and subsequent brain damage in the ipsilateral hemisphere. In the present study, using high-intensity (700 microA) pulsed-train electrical stimulation of the BLA for 25 min, SSSE was induced in both kindled and non-kindled Wistar rats, demonstrating that under these experimental conditions prior kindling is not necessary to induce SSSE. Thus, all subsequent experiments were done in non-kindled rats of different strains (Wistar, Sprague-Dawley) and genders. Three distinct behavioral types of SSSE were observed: (1) continuous partial seizures; (2) continuous partial seizures, repeatedly interrupted by generalized convulsive seizures; and (3) continuous generalized convulsive seizures. These three forms of SSSE were seen in both strains and genders, although the percentage of rats in each strain and gender developing a specific type of SSSE differed. Rats spontaneously recovered from SSSE after between 3 and 8h on average, the SSSE duration depending on SSSE type, rat strain and gender. Following SSSE, rats were monitored with a video- and EEG-recording system for occurrence of spontaneous recurrent seizures (SRS). Overall, about 80% of the rats developed epilepsy with SRS after SSSE, but the proportion of rats developing SRS depended on the type of SSSE. Only 33% of the rats developed SRS after a partial SSSE, compared to >90% in case of either type 2 or type 3 SSSE with generalized convulsive seizures. Interruption of different forms of SSSE with diazepam after 90 min prevented development of epilepsy, while a generalized SSSE duration of 4h consistently produced epilepsy in >90% of rats. Histologic analysis of rat brains after the different SSSE types indicated that neuronal loss after partial SSSE was much more regionally restricted and less severe compared to neuronal damage after SSSE with generalized convulsive seizures, which was similar to the brain damage seen in the kainate and pilocarpine models of temporal lobe epilepsy. These experiments establish that prolonged electrical stimulation of the BLA induces different forms of SSSE that resemble nonconvulsive and convulsive types of SE in humans. These different forms of SSSE induce epilepsy with SRS and brain pathology reminiscent of temporal lobe epilepsy with hippocampal sclerosis. The rat model provides a new tool to mimic different types of SE and investigate the pathogenesis underlying their long-term complications.
Multidrug resistance proteins (MRPs; symbol ABCC) are membrane glycoproteins that mediate the ATP... more Multidrug resistance proteins (MRPs; symbol ABCC) are membrane glycoproteins that mediate the ATP-dependent export of a wide range of substrates from cells and thereby affect the bioavailability and disposition of many drugs. MRP2 (ABCC2) is expressed on the apical domain of hepatocytes, enterocytes of the proximal small intestine, and proximal renal tubular cells, but its location in the brain is a matter of debate. Most previous studies failed to determine MRP2 mRNA or protein in the brain or cell preparations from the brain of different species including humans. Based on our previous experience with the drug efflux transporter P-glycoprotein, we evaluated whether the immunohistochemical determination of MRP2 expression is sensitive to fixation and staining variables. Furthermore, we examined whether the MRP2 protein is overexpressed after experimentally induced seizures in rats, using the pilocarpine model of temporal lobe epilepsy. The MRP2 expression in the liver was used as positive control. MRP2 deficient TR- rats were used as negative controls. Despite various modifications in tissue fixation and immunohistochemical staining as well as use of different commercially available MRP2 antibodies, we never observed any unequivocal MRP2 staining in the brain of normal rats. However, after a pilocarpine-induced convulsive status epilepticus, clear MRP2 staining became visible in brain capillary endothelial cells and, less frequently, perivascular astroglia and neurons in various brain regions. In view of our recent data on brain access of antiepileptic drugs in MRP2 deficient TR- rats, seizure-induced over-expression of MRP2 in the blood-brain barrier is likely to impair drug penetration into the brain, thereby contributing to drug resistance in epilepsy.
More than one third of patients with epilepsy have inadequate control of seizures with drug thera... more More than one third of patients with epilepsy have inadequate control of seizures with drug therapy, but mechanisms of intractability are largely unknown. Because of this large number of pharmacoresistant patients with epilepsy, the existing process of antiepileptic drug (AED) discovery and development must be reevaluated with a focus on preclinical models of therapy-resistant epilepsy syndromes such as mesial temporal lobe epilepsy (TLE). However, although various rodent models of TLE are available, the pharmacoresponsiveness of most models is not well known. In the present study, we used a post-status epilepticus model of TLE to examine whether rats with spontaneous recurrent seizures (SRSs) differ in their individual responses to phenobarbital (PB). Status epilepticus was induced in Sprague-Dawley rats by prolonged electrical stimulation of the basolateral amygdala. Once the rats had developed SRSs, seizure frequency and severity were determined by continuous EEG/video recording over a 6-week period (i.e., a predrug control period of 2 weeks, followed by PB treatment for 2 weeks, and a postdrug control period of 2 weeks). PB was administered twice daily at maximal tolerated doses. Analysis of plasma drug concentrations showed that drug concentrations within the therapeutic range (10-40 microg/ml) were maintained in all rats throughout the period of treatment. In six (55%) of 11 rats, complete control of seizures was achieved, and another rat exhibited a >90% reduction of seizure frequency. These seven rats were considered responders. The remaining four (36%) rats showed either no response at all (n=3) or only moderate reduction in seizure frequency and were therefore considered nonresponders. Plasma drug concentrations did not differ between these two groups of rats. These data demonstrate that, similar to patients with epilepsy, rats with SRSs markedly differ in their individual responses to AED treatment. Pharmacoresistant rats selected by prolonged drug treatment from groups of rats with SRSs may provide a unique model to study mechanisms of pharmacoresistance and to identify novel AEDs for treating seizures of patients currently not controlled with existing therapies.
The disabling seizures associated with mesial temporal lobe epilepsy (TLE) are often resistant to... more The disabling seizures associated with mesial temporal lobe epilepsy (TLE) are often resistant to antiepileptic drugs (AEDs). The biological basis of this refractoriness is unknown but may include alterations in AED targets in the epileptogenic brain tissue, reduced AED penetration to the seizure focus, and neuropathological brain alterations such as hippocampal sclerosis typically found in patients with refractory TLE. In the present study, we used a rat model of TLE to examine whether AED responders differ from non-responders in their structural alterations and GABA(A) receptor characteristics in the hippocampal formation. In this model, spontaneous recurrent seizures develop after a status epilepticus induced by prolonged electrical stimulation of the basolateral amygdala. The frequency of these seizures was recorded by continuous video/EEG monitoring before, during, and after daily treatment with phenobarbital, which was given at maximum tolerated doses for 2 weeks. Based on their individual response to phenobarbital, rats were grouped into responders and non-responders. The severity or duration of the initial brain insult (the status epilepticus) did not differ between responders and non-responders, indicating that the difference between the two subgroups is genetically determined. Subsequent histological examination showed a significant loss of neurons in the CA1, CA3c/CA4, and dentate hilus of non-responders, whereas responders did not differ in this respect from non-epileptic controls. The morphological alterations in the non-responders were associated with striking alterations in autoradiographic imaging of diazepam-sensitive and diazepam-insensitive GABA(A) receptor binding in the dentate gyrus with a significant shift to enhanced diazepam-insensitive binding. The present data indicate that neurodegeneration and associated GABA(A) receptor changes in the dentate gyrus are critically involved in the mechanisms underlying refractoriness of seizures in TLE.
Levetiracetam (LEV) is a structurally novel antiepileptic drug (AED) which has demonstrated a bro... more Levetiracetam (LEV) is a structurally novel antiepileptic drug (AED) which has demonstrated a broad spectrum of anticonvulsant activities both in experimental and clinical studies. Previous experiments in the kindling model suggested that LEV, in addition to its seizure-suppressing activity, may possess antiepileptogenic or disease-modifying activity. In the present study, we evaluated this possibility by using a rat model in which epilepsy with spontaneous recurrent seizures (SRS), behavioral alterations, and hippocampal damages develop after a status epilepticus (SE) induced by sustained electrical stimulation of the basal amygdala. Two experimental protocols were used. In the first protocol, LEV treatment was started 24h after onset of electrical amygdala stimulation without prior termination of the SE. In the second protocol, the SE was interrupted after 4h by diazepam, immediately followed by onset of treatment with LEV. Treatment with LEV was continued for 8 weeks (experiment #1) or 5 weeks (experiment #2) after SE, using continuous drug administration via osmotic minipumps. The occurrence of SRS was recorded during and after treatment. In addition, the rats were tested in a battery of behavioral tests, including the elevated-plus maze and the Morris water maze. Finally, the brains of the animals were analyzed for histological lesions in the hippocampal formation. With the experimental protocols chosen for these experiments, LEV did not exert antiepileptogenic or neuroprotective activity. Furthermore, the behavioral alterations, e.g., behavioral hyperexcitability and learning deficits, in epileptic rats were not affected by treatment with LEV after SE. These data do not support the idea that administration of LEV after SE prevents or reduces the long-term alterations developing after such brain insult in rats.
This information is being used in a study on the molecular basis of canine epilepsies, funded by ... more This information is being used in a study on the molecular basis of canine epilepsies, funded by the American Kennel Club. The study is based on the hypothesis that the genetic basis of canine epilepsies may be similar to genetic epilepsies that have recently been identified ...
A seizure is defined as the clinical manifestation(s) of excessive and/or hypersynchronous, usual... more A seizure is defined as the clinical manifestation(s) of excessive and/or hypersynchronous, usually self-limit-ing, neuronal discharges (Engel 2001). Different types of seizures can occur (see box on the right). Seizure activity is almost solely due to cerebral cortex dysfunc-tion but can ...
The disease complex Chiari-like malformation (CM) and syringomyelia (SM) has been associated with... more The disease complex Chiari-like malformation (CM) and syringomyelia (SM) has been associated with the development of neuropathic pain (NeP), and commonly affects Cavalier King Charles spaniels (CKCS). This prospective cohort study followed 48 CKCSs with CM and/or SM and clinical signs suggestive of NeP for a period of 39 (±14.3) months from diagnosis.
Materials and Methods Medical records at two UK referral hospitals for the period 2000–2009 were ... more Materials and Methods Medical records at two UK referral hospitals for the period 2000–2009 were searched for dogs and cats that had MR imaging of the brain and/or spinal cord and a diagnosis of primary or secondary CNS lymphoma based either on cytologic evidence of neoplastic cells (lymphoblasts) in the CSF and/or histopathologic examination.
PRESENTATION AND LESION LOCALISATION: Seven adult domestic shorthair cats were presented with a 1... more PRESENTATION AND LESION LOCALISATION: Seven adult domestic shorthair cats were presented with a 1-to 6-day history of progressive neurological signs. A focal skin puncture and subcutaneous swelling over the dorsal part of the head were detected on physical examination. Neurological examination indicated lesion (s) in the right forebrain in four cats, multifocal forebrain in one cat, left forebrain in one cat, and multifocal forebrain and brainstem in the remaining cat.
Reliance on history and description of episodes of collapse to differentiate seizures from syncop... more Reliance on history and description of episodes of collapse to differentiate seizures from syncope can be misleading. Syncope can have features of seizures or can be the cause of seizures. Clinical and neurologic examinations can also be misleading. High-grade atrioventricular (AV) block can be intermittent in cats and interictal neurologic examination can be normal in patients with epilepsy. In this report we describe highgrade AV dysfunction that mimicked epilepsy in 3 cats.
Abstract Previous research in Cavalier King Charles Spaniels (CKCS) has found that Chiari-like ma... more Abstract Previous research in Cavalier King Charles Spaniels (CKCS) has found that Chiari-like malformation and syringomyelia (CM/SM) are associated with a volume mismatch between the caudal cranial fossa (CCF) and the brain parenchyma contained within.
Zusammenfassung Die Epilepsie ist durch wiederkehrende Anfälle gekennzeichnet und mit einer Präva... more Zusammenfassung Die Epilepsie ist durch wiederkehrende Anfälle gekennzeichnet und mit einer Prävalenz von 0, 5–5, 7% die häufigste chronische neurologische Funktionsstörung des Hundes. Sie manifestiert sich aufgrund abnormaler elektrischer Aktivität des Großhirns. Jedes Gehirn besitzt die Voraussetzung für eine epileptische Aktivität.
Background Disk-associated cervical spondylomyelopathy (DA-CSM) is a multifactorial neurological ... more Background Disk-associated cervical spondylomyelopathy (DA-CSM) is a multifactorial neurological disorder in which progressive caudal cervical spinal cord compression is mainly caused by one or more intervertebral disk protrusions. The Doberman pinscher breed seems predisposed for this condition. The underlying cause and pathophysiology of DA-CSM are currently unknown. Recently, wider intervertebral disks have been put forward as a risk factor for development of clinically relevant DA-CSM.
Background Understanding the pathogenesis of the chiari-like malformation in the Cavalier King Ch... more Background Understanding the pathogenesis of the chiari-like malformation in the Cavalier King Charles Spaniel (CKCS) is incomplete, and current hypotheses do not fully explain the development of syringomyelia (SM) in the spinal cords of affected dogs. This study investigates an unconventional pathogenetic theory for the development of cerebrospinal fluid (CSF) pressure waves in the subarachnoid space in CKCS with SM, by analogy with human diseases.
Multidrug transporter over-expression is considered to limit access of antiepileptic drugs to the... more Multidrug transporter over-expression is considered to limit access of antiepileptic drugs to the epileptic focus region and to be one cause of intractable epilepsy. To reach further proof for this multidrug transporter hypothesis, we compared P-glycoprotein expression rates in subgroups of Wistar rats which are sensitive or resistant to the anticonvulsant effect of the antiepileptic drug phenytoin in the amygdala-kindling model of temporal lobe epilepsy. In the electrode-implanted amygdala of phenytoin-resistant rats, the area labelled for P-glycoprotein was more than twice as large than that in phenytoin-sensitive rats. The data indicate that P-glycoprotein expression levels in the kindled focus have a critical impact on the anticonvulsant response to antiepileptic drugs.
It has previously been shown that prolonged (60-min) low-intensity electrical stimulation of a ki... more It has previously been shown that prolonged (60-min) low-intensity electrical stimulation of a kindled focus in the basolateral nucleus of the amygdala (BLA) of Wistar rats resulted in the development of self-sustained status epilepticus (SSSE) with predominantly partial seizures and subsequent brain damage in the ipsilateral hemisphere. In the present study, using high-intensity (700 microA) pulsed-train electrical stimulation of the BLA for 25 min, SSSE was induced in both kindled and non-kindled Wistar rats, demonstrating that under these experimental conditions prior kindling is not necessary to induce SSSE. Thus, all subsequent experiments were done in non-kindled rats of different strains (Wistar, Sprague-Dawley) and genders. Three distinct behavioral types of SSSE were observed: (1) continuous partial seizures; (2) continuous partial seizures, repeatedly interrupted by generalized convulsive seizures; and (3) continuous generalized convulsive seizures. These three forms of SSSE were seen in both strains and genders, although the percentage of rats in each strain and gender developing a specific type of SSSE differed. Rats spontaneously recovered from SSSE after between 3 and 8h on average, the SSSE duration depending on SSSE type, rat strain and gender. Following SSSE, rats were monitored with a video- and EEG-recording system for occurrence of spontaneous recurrent seizures (SRS). Overall, about 80% of the rats developed epilepsy with SRS after SSSE, but the proportion of rats developing SRS depended on the type of SSSE. Only 33% of the rats developed SRS after a partial SSSE, compared to >90% in case of either type 2 or type 3 SSSE with generalized convulsive seizures. Interruption of different forms of SSSE with diazepam after 90 min prevented development of epilepsy, while a generalized SSSE duration of 4h consistently produced epilepsy in >90% of rats. Histologic analysis of rat brains after the different SSSE types indicated that neuronal loss after partial SSSE was much more regionally restricted and less severe compared to neuronal damage after SSSE with generalized convulsive seizures, which was similar to the brain damage seen in the kainate and pilocarpine models of temporal lobe epilepsy. These experiments establish that prolonged electrical stimulation of the BLA induces different forms of SSSE that resemble nonconvulsive and convulsive types of SE in humans. These different forms of SSSE induce epilepsy with SRS and brain pathology reminiscent of temporal lobe epilepsy with hippocampal sclerosis. The rat model provides a new tool to mimic different types of SE and investigate the pathogenesis underlying their long-term complications.
Multidrug resistance proteins (MRPs; symbol ABCC) are membrane glycoproteins that mediate the ATP... more Multidrug resistance proteins (MRPs; symbol ABCC) are membrane glycoproteins that mediate the ATP-dependent export of a wide range of substrates from cells and thereby affect the bioavailability and disposition of many drugs. MRP2 (ABCC2) is expressed on the apical domain of hepatocytes, enterocytes of the proximal small intestine, and proximal renal tubular cells, but its location in the brain is a matter of debate. Most previous studies failed to determine MRP2 mRNA or protein in the brain or cell preparations from the brain of different species including humans. Based on our previous experience with the drug efflux transporter P-glycoprotein, we evaluated whether the immunohistochemical determination of MRP2 expression is sensitive to fixation and staining variables. Furthermore, we examined whether the MRP2 protein is overexpressed after experimentally induced seizures in rats, using the pilocarpine model of temporal lobe epilepsy. The MRP2 expression in the liver was used as positive control. MRP2 deficient TR- rats were used as negative controls. Despite various modifications in tissue fixation and immunohistochemical staining as well as use of different commercially available MRP2 antibodies, we never observed any unequivocal MRP2 staining in the brain of normal rats. However, after a pilocarpine-induced convulsive status epilepticus, clear MRP2 staining became visible in brain capillary endothelial cells and, less frequently, perivascular astroglia and neurons in various brain regions. In view of our recent data on brain access of antiepileptic drugs in MRP2 deficient TR- rats, seizure-induced over-expression of MRP2 in the blood-brain barrier is likely to impair drug penetration into the brain, thereby contributing to drug resistance in epilepsy.
More than one third of patients with epilepsy have inadequate control of seizures with drug thera... more More than one third of patients with epilepsy have inadequate control of seizures with drug therapy, but mechanisms of intractability are largely unknown. Because of this large number of pharmacoresistant patients with epilepsy, the existing process of antiepileptic drug (AED) discovery and development must be reevaluated with a focus on preclinical models of therapy-resistant epilepsy syndromes such as mesial temporal lobe epilepsy (TLE). However, although various rodent models of TLE are available, the pharmacoresponsiveness of most models is not well known. In the present study, we used a post-status epilepticus model of TLE to examine whether rats with spontaneous recurrent seizures (SRSs) differ in their individual responses to phenobarbital (PB). Status epilepticus was induced in Sprague-Dawley rats by prolonged electrical stimulation of the basolateral amygdala. Once the rats had developed SRSs, seizure frequency and severity were determined by continuous EEG/video recording over a 6-week period (i.e., a predrug control period of 2 weeks, followed by PB treatment for 2 weeks, and a postdrug control period of 2 weeks). PB was administered twice daily at maximal tolerated doses. Analysis of plasma drug concentrations showed that drug concentrations within the therapeutic range (10-40 microg/ml) were maintained in all rats throughout the period of treatment. In six (55%) of 11 rats, complete control of seizures was achieved, and another rat exhibited a >90% reduction of seizure frequency. These seven rats were considered responders. The remaining four (36%) rats showed either no response at all (n=3) or only moderate reduction in seizure frequency and were therefore considered nonresponders. Plasma drug concentrations did not differ between these two groups of rats. These data demonstrate that, similar to patients with epilepsy, rats with SRSs markedly differ in their individual responses to AED treatment. Pharmacoresistant rats selected by prolonged drug treatment from groups of rats with SRSs may provide a unique model to study mechanisms of pharmacoresistance and to identify novel AEDs for treating seizures of patients currently not controlled with existing therapies.
The disabling seizures associated with mesial temporal lobe epilepsy (TLE) are often resistant to... more The disabling seizures associated with mesial temporal lobe epilepsy (TLE) are often resistant to antiepileptic drugs (AEDs). The biological basis of this refractoriness is unknown but may include alterations in AED targets in the epileptogenic brain tissue, reduced AED penetration to the seizure focus, and neuropathological brain alterations such as hippocampal sclerosis typically found in patients with refractory TLE. In the present study, we used a rat model of TLE to examine whether AED responders differ from non-responders in their structural alterations and GABA(A) receptor characteristics in the hippocampal formation. In this model, spontaneous recurrent seizures develop after a status epilepticus induced by prolonged electrical stimulation of the basolateral amygdala. The frequency of these seizures was recorded by continuous video/EEG monitoring before, during, and after daily treatment with phenobarbital, which was given at maximum tolerated doses for 2 weeks. Based on their individual response to phenobarbital, rats were grouped into responders and non-responders. The severity or duration of the initial brain insult (the status epilepticus) did not differ between responders and non-responders, indicating that the difference between the two subgroups is genetically determined. Subsequent histological examination showed a significant loss of neurons in the CA1, CA3c/CA4, and dentate hilus of non-responders, whereas responders did not differ in this respect from non-epileptic controls. The morphological alterations in the non-responders were associated with striking alterations in autoradiographic imaging of diazepam-sensitive and diazepam-insensitive GABA(A) receptor binding in the dentate gyrus with a significant shift to enhanced diazepam-insensitive binding. The present data indicate that neurodegeneration and associated GABA(A) receptor changes in the dentate gyrus are critically involved in the mechanisms underlying refractoriness of seizures in TLE.
Levetiracetam (LEV) is a structurally novel antiepileptic drug (AED) which has demonstrated a bro... more Levetiracetam (LEV) is a structurally novel antiepileptic drug (AED) which has demonstrated a broad spectrum of anticonvulsant activities both in experimental and clinical studies. Previous experiments in the kindling model suggested that LEV, in addition to its seizure-suppressing activity, may possess antiepileptogenic or disease-modifying activity. In the present study, we evaluated this possibility by using a rat model in which epilepsy with spontaneous recurrent seizures (SRS), behavioral alterations, and hippocampal damages develop after a status epilepticus (SE) induced by sustained electrical stimulation of the basal amygdala. Two experimental protocols were used. In the first protocol, LEV treatment was started 24h after onset of electrical amygdala stimulation without prior termination of the SE. In the second protocol, the SE was interrupted after 4h by diazepam, immediately followed by onset of treatment with LEV. Treatment with LEV was continued for 8 weeks (experiment #1) or 5 weeks (experiment #2) after SE, using continuous drug administration via osmotic minipumps. The occurrence of SRS was recorded during and after treatment. In addition, the rats were tested in a battery of behavioral tests, including the elevated-plus maze and the Morris water maze. Finally, the brains of the animals were analyzed for histological lesions in the hippocampal formation. With the experimental protocols chosen for these experiments, LEV did not exert antiepileptogenic or neuroprotective activity. Furthermore, the behavioral alterations, e.g., behavioral hyperexcitability and learning deficits, in epileptic rats were not affected by treatment with LEV after SE. These data do not support the idea that administration of LEV after SE prevents or reduces the long-term alterations developing after such brain insult in rats.
This information is being used in a study on the molecular basis of canine epilepsies, funded by ... more This information is being used in a study on the molecular basis of canine epilepsies, funded by the American Kennel Club. The study is based on the hypothesis that the genetic basis of canine epilepsies may be similar to genetic epilepsies that have recently been identified ...
A seizure is defined as the clinical manifestation(s) of excessive and/or hypersynchronous, usual... more A seizure is defined as the clinical manifestation(s) of excessive and/or hypersynchronous, usually self-limit-ing, neuronal discharges (Engel 2001). Different types of seizures can occur (see box on the right). Seizure activity is almost solely due to cerebral cortex dysfunc-tion but can ...
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