Contrasting effects of zonisamide and acetazolamide on amygdaloid kindling in rats.

PURPOSE: Zonisamide (ZNS) and acetazolamide (AZM) are two antiepileptic drugs (AEDs) that differ in clinical efficacy. To elucidate the mechanisms of action of these compounds, we investigated their therapeutic and prophylactic effects in rats by using a kindling model of partial epilepsy. METHODS: Electrodes were implanted into the left amygdala of adult male Wistar rats. The animals were stimulated at the afterdischarge threshold until five stage 5 seizures were induced. The generalized seizure threshold was then determined. Therapeutic effects were examined in rats manifesting successive convulsions with near-threshold stimulation. To test prophylactic effects, drugs were administered intraperitoneally before daily kindling stimulation until the animal had a stage 5 seizure or reached day 18. RESULTS: ZNS (10-40 mg/kg; n=6) suppressed kindled seizures in a dose-dependent manner. Repeated administration for 7 days produced tolerance to anticonvulsive effects. AZM (25-200 mg/kg; n=7) showed limited therapeutic effect, alleviating only the clonic convulsion in stage 5 seizures and reducing afterdischarge duration. Secondary generalization was not significantly suppressed during repeated treatment (50-200 mg/kg; n=6). ZNS, 25 or 40 mg/kg (n=8), significantly retarded seizure development; 15.0 or 17.0 daily stimulations were required to produce a stage 5 seizure. AZM, 50-200 mg/kg (n=6), also retarded seizure development, with 14.0-14.8 stimulations required. CONCLUSIONS: ZNS exhibited modest therapeutic and prophylactic effects, whereas AZM showed mainly prophylactic effects. Hypotheses are presented that may explain the mechanisms of action of these drugs.

Activation of the dorsal premotor cortex and pre-supplementary motor area of humans during an auditory conditional motor task.

Using functional magnetic resonance imaging (fMRI), we measured regional blood flow to examine which motor areas of the human cerebral cortex are preferentially involved in an auditory conditional motor behavior. As a conditional motor task, randomly selected 330 or 660 Hz tones were presented to the subjects every 1. 0 s. The low and high tones indicated that the subjects should initiate three successive opposition movements by tapping together the right thumb and index finger or the right thumb and little finger, respectively. As a control task, the same subjects were asked to alternate the two opposition movements, in response to randomly selected tones that were presented at the same frequencies. Between the two tasks, MRI images were also scanned in the resting state while the tones were presented in the same way. Comparing the images during each of the two tasks with images during the resting state, it was observed that several frontal motor areas, including the primary motor cortex, dorsal premotor cortex (PMd), supplementary motor area (SMA), and pre-SMA, were activated. However, preferential activation during the conditional motor task was observed only in the PMd and pre-SMA of the subjects' left (contralateral) frontal cortex. The PMd has been thought to play an important role in transforming conditional as well as spatial visual cues into corresponding motor responses, but our results suggest that the PMd along with the pre-SMA are the sites where more general and extensive sensorimotor integration takes place.

Electrical stimulation of the contralateral mesial temporal structure induces an ipsilateral seizure pattern in mesial temporal lobe epilepsy.

PURPOSE: We examined the mode of seizure development induced by electrical stimulation in patients with mesial temporal lobe epilepsy. METHODS: Of 25 patients undergoing intracranial EEG evaluation and electrical stimulation ipsilateral to the presumed site of habitual seizure origin, 17 patients had additional stimulation studies on the contralateral temporal lobe. RESULTS: Fourteen of the 25 patients had seizures induced with ipsilateral stimulation, and two of the 17 patients had seizures with contralateral stimulation. Seizures induced by ipsilateral stimulation started in the ipsilateral temporal lobe, whereas those induced by contralateral stimulation originated from the ipsilateral temporal lobe structure and were identical to the habitual seizures. CONCLUSIONS: Electrical stimulation of the temporal lobe structure opposite the site of habitual seizure origin is said to induce a seizure rarely. However, according to our preliminary results, if contralateral stimulation elicits a habitual seizure in the ipsilateral temporal lobe, it might be considered additional confirmatory evidence of seizure lateralization.

Photosensitive epilepsies and pathophysiologic mechanisms of the photoparoxysmal response.

OBJECTIVE: To identify the pathophysiologic mechanisms of the photoparoxysmal response (PPR) in various photosensitive epilepsy syndromes, and to discuss the relation between these pathophysiologic mechanisms and the classification of epilepsies and epileptic syndromes. BACKGROUND: The authors found two types of pathophysiologic mechanisms of PPRs (wavelength-dependent PPRs and quantity-of-light-dependent PPRs) in patients with idiopathic generalized epilepsy and hereditary dentatorubral-pallidoluysian atrophy. METHODS: Intermittent photic stimulation with wavelength-specific optical filters was performed in photosensitive epileptic patients: six patients had severe myoclonic epilepsy in infancy (SMEI), eight had localization-related epilepsy (LRE), and seven had symptomatic generalized epilepsy (SGE). RESULTS: Four of the six photosensitive SMEI patients had quantity-of-light-dependent PPRs. Five of the eight photosensitive LRE patients had wavelength-dependent PPRs. Four of the seven photosensitive SGE patients had wavelength-dependent PPRs, and two had quantity-of-light-dependent PPRs. CONCLUSIONS: The type of pathophysiologic mechanism for eliciting PPRs by low-luminance photic stimulation was closely related to the classification of the epilepsy syndrome.

Wavelength dependence of photoparoxysmal responses in photosensitive patients with epilepsy.

PURPOSE: We tried to specify the relation between the photoparoxysmal response (PPR) and the wavelength spectra of flashing light in various photosensitive epileptic syndromes in the physiologic state. METHODS: Intermittent photic stimulation (IPS) by a Grass PS22 photic stimulator was performed with wavelength-specific optical filters in photosensitive patients with epilepsy (idiopathic generalized epilepsy, IGE; hereditary dentatorubral-pallidoluysian atrophy, DRPLA) and photosensitive subjects without epilepsy. RESULTS: Five of 19 normal trichromat patients with IGE and an IGE patient with deuteranomaly showed wavelength-dependent PPRs. The wavelength-dependent PPRs were elicited only by IPS containing wavelength spectra approximately 700 nm in the normal trichromat patients. Two of four patients with DRPLA showed wavelength-dependent PPRs, and two other DRPLA patients showed quantity-of-light-dependent PPRs. Quantity-of-light-dependent PPRs are elicited by IPS containing more than a certain quantity of light, independent of the wavelength composition of the flashing light. Two of five subjects without epilepsy showed wavelength-dependent PPRs. CONCLUSIONS: There are wavelength-dependent and quantity-of-light-dependent pathophysiologic mechanisms for eliciting PPRs by low-luminance IPS. Consideration of the quantity and wavelength composition of light from electronic screens will lead to the prevention of photosensitive seizures induced by electronic screen games.

Antiepileptic effects of topiramate on amygdaloid kindling in rats.

We examined the antiepileptic properties of topiramate (TPM) in amygdaloid (AM) kindling in rats. Electrodes were implanted into the left AM of adult male Wistar rats. The animals were kindled at the after-discharge (AD) threshold. After the completion of kindling, the generalized seizure triggering threshold was determined. The drugs were administered intraperitoneally in animals which showed stable generalized convulsions at near-threshold stimulation. Intraperitoneal administration of TPM at doses of 25 mg/kg or more produced an anticonvulsive effect, but did not readily suppress limbic seizures. Complete suppression of AD was observed in only 3/8 rats at the highest dose of 200 mg/kg, which was not statistically significant. On the other hand, TPM at 100 and 200 mg/kg significantly delayed AM kindling. Thus, TPM showed modest therapeutic properties of conventional antiepileptic drugs in kindling model, those of TPM more closely resemble those of phenobarbital and the benzodiazepines than those of phenytoin and carbamazepine.

Effect of callosal bisection on seizure development and interhemispheric transfer effects in feline motor cortical kindling.

Motor cortical (MC) kindling was carried out in 12 adult cats, seven with the corpus callosum (CC) intact and five with the CC bisected, to study interhemispheric transfer effects and the effect of callosal bisection on both seizure development and interhemispheric transfer effects. MC kindling developed from partial motor seizures to partial onset generalized convulsions. Interhemispheric negative transfer effect, but not positive, existed in secondary site kindling and primary site retest of the CC-intact group, as shown by: (i) electroencephalographically lateralized seizure development in the stimulated hemisphere; (ii) delayed generalization of partial onset generalized convulsions; and (iii) a markedly unstable generalized convulsive seizure state. The CC-bisected group showed: (i) significantly delayed seizure development from partial motor seizure stage to generalized convulsive seizure stage in primary and secondary kindling; (ii) facilitated intrahemispheric seizure development; (iii) the diminution of interhemispheric negative transfer effect; (iv) modified generalized convulsions showing extremely asymmetrical generalized convulsions shifting from contralaterally dominant convulsions to ipsilaterally dominant ones (n = 2) or alternate generalized convulsions changing from contralateral hemiconvulsions to ipsilateral ones (n = 3). The results obtained suggest that the CC plays a major role in interhemispheric seizure propagation as well as interhemispheric negative transfer effects in MC kindling and may have suppressive effect on intrahemispheric motor seizure development in MC kindling. However, interhemispheric seizure propagation and interhemispheric negative transfer effects were mediated via other structures, possibly subcortical structures, when the CC was bisected.

Effect of motor cortical kindling on subsequent ventral hippocampal kindling and the role of the corpus callosum in the cat.

The effect of bilateral motor cortical (MC) kindling on subsequent unilateral ventral hippocampal (VHIPP) kindling was studied in four cats with the corpus callosum (CC) intact and five cats with the CC bisected, compared with nine cats with unilateral VHIPP kindling. Subsequent VHIPP kindling in CC-intact cats resulted in the modified development of limbic seizures to ipsilateral, not contralateral, focal motor seizures in one of four cats, significantly greater seizure regressions from generalized convulsive seizure stage to earlier seizure stages and delayed onset of focal motor seizures and generalized convulsions in partial onset generalized convulsions. CC bisection reduced the degree of seizure regression from generalized convulsive seizure stage to earlier stages, facilitated the development of the last limbic seizure to the first generalized convulsive seizure, accentuated hemiconvulsions and asymmetrical generalized convulsions and delayed the onset of generalized convulsions in partial onset generalized convulsions. The modified seizure development was also induced in three of five CC-bisected cats. Results indicate that bilateral MC kindling induces inhibitory effects on subsequent unilateral VHIPP kindling and the modified ictal progress from the VHIPP to the contralateral hemispheric motor structures and also that CC bisection interferes with the bilateralization and synchronization of convulsions, but reduces the inhibition of previously established MC kindling against VHIPP kindling and facilitates the development of focal motor seizures to secondarily generalized convulsions.

Two different pathological conditions of photoparoxysmal responses in hereditary dentatorubral-pallidoluysian atrophy.

In order to reveal the pathophysiology of photoparoxysmal responses (PPRs) in photosensitive patients with hereditary dentatorubral-pallidoluysian atrophy (DRPLA) who had expansion of the CAG repeat in the DRPLA gene, we studied the characteristics of PPRs using optical filters with specific wavelength transmission. In two patients, the wavelength spectrum around 700 nm (670-720 nm) was apparently the only visible range essential for eliciting PPRs, and flash lights containing the essential wavelength elicited PPRs. In another patient, PPRs were elicited by flash lights above certain quantity of light and independent of the wavelength composition of the lights. These data suggest that two different pathological conditions contribute to PPRs in DRPLA patients; one condition depends on the essential wavelength spectrum around 700 nm, and the other not on the wavelength, but on the quantity of light. The condition contributing to PPRs in all three patients was not determined directly by the level of the CAG repeat expansion in the DRPLA gene.

Effects of single and repeated administration of sulthiame on amygdaloid kindled seizures in rats.

In this study, we assessed the anti-convulsive effects of sulthiame (SUL) in amygdaloid (AM) kindled rats. Electrodes were implanted into the left AM of adult male Wistar rats. The animals were kindled at the after-discharge (AD) threshold. Upon completion of kindling, a generalized seizure triggering threshold was determined. The drugs were administered intraperitoneally in rats which reproducibly exhibited generalized convulsions at the near-threshold stimulation. Single administration of SUL (25-200 mg; n = 7-9) reduced the forelimb clonus (FCL) duration, but only the highest dose significantly regressed the secondarily generalized convulsion. During repeated administration of SUL, 50 mg/kg for 8 days, FCL duration was significantly alleviated until the fifth treatment day. With the dose of 200 mg/kg, significant suppression of secondary generalization was noted only until the second test day. On the other hand, significant reductions of FCL and AD duration were preserved afterwards. The anti-convulsive effects of SUL indicated in this study were not comparable to those of other standard anti-epileptic drugs reported from our laboratory.

Wavelength dependency of photoparoxysmal responses in photosensitive nonepileptic subjects.

Using specially made optical filters, we analyzed the wavelength dependency of photoparoxysmal responses (PPRs) in five photosensitive nonepileptic subjects. The wavelength spectrum around 700 nm (680-700 nm) was estimated as the only visible spectrum essential for eliciting PPRs in two normal trichromat nonepileptic subjects, although the effect of some wavelength spectra (360-400 nm and 520-580 nm) was uncertain. The wavelength dependency of PPRs in two photosensitive nonepileptic subjects was the same as that found in some patients with photosensitive idiopathic generalized epilepsy.

Epilepsia partialis continua of childhood involving bilateral brain hemispheres.

OBJECTIVES: Epilepsia partialis continua (Kojewnikow's syndrome) can be classified into 2 groups. The 1st group had stable neurological deficit, and the 2nd group had slowly progressive neurological deficit. The latter usually manifests not tetraplegia, but hemiplegia. We describe 3 patients with epilepsia partialis continua, rapid neurological and mental deterioration, resulting in tetraplegia and serious mental deficits within 2 to 3 years from the onset. RESULTS: Their interictal EEGs showed progressive findings of deterioration, which resulted in an inactive pattern or a pattern reminiscent of suppression-burst within several years. Their cranial CTs revealed rapid progressive atrophy of both hemispheres. Various screening tests failed to confirm a metabolic disease, a degenerative disease, or an infectious disease in the central nervous system. CONCLUSION: Frequent status epilepticus might contribute to the bilateral brain involvement and the serious neurological and mental outcomes in young patients with epileptia partialis continua.

Effects of clobazam and its active metabolite on GABA-activated currents in rat cerebral neurons in culture.

PURPOSE: The antiepileptic effects of clobazam, a 1,5-benzodiazepine, have been well documented in animal experiments and clinical trials. However, the drug's mechanisms of antiepileptic actions are still undetermined. The purpose of this study was to learn how clobazam and its active metabolite modulate gamma-aminobutyric acid (GABA)-activated currents in rat cerebral neurons in culture. METHODS: Whole-cell voltage-clamp recordings were performed on cultured cerebral neurons of the rat. Clobazam or its metabolite N-desmethylclobazam was dissolved in the extracellular solution and applied for 2 s by pressure ejection from a micropipette. To maintain GABA-activated currents, 2 mM Mg adenosine triphosphate (ATP) was added to the intracellular solution. RESULTS: GABA elicited outward currents that were mediated by GABAA receptor-coupled Cl- channels. Applying clobazam with 10 microM GABA elicited enhanced outward currents. Flumazenil, an antagonist of the benzodiazepine receptor, inhibited the enhancing effect of clobazam. The enhancement ratio increased as much as 2.28-fold in a dose-dependent manner at a concentration of 3 microM clobazam. However, it started to decrease at a concentration of 10 microM clobazam. The metabolite N-desmethylclobazam was tested in the same manner, and exhibited an identical dose-dependent enhancement of GABA-activated currents. CONCLUSIONS: The antiepileptic effects of the 1,5-benzodiazepines are attributed to the enhancement of GABAergic inhibitory neurotransmission. The antiepileptic effects of clobazam are thought to depend mainly on its active metabolite N-desmethylclobazam, which is present in high concentrations in patients who receive long-term clobazam. Clobazam's enhancement of GABA-activated currents was most marked on weaker GABA currents. We therefore infer that clobazam acts more efficiently on tissues in which the release of GABA is diminished.

Recommendation of early surgery from the viewpoint of daily quality of life.

We surveyed pre- and postoperative levels of satisfaction with a range of the daily quality-of-life (QOL) domains in 132 sets of epilepsy surgery patients and their families. All patients underwent resective surgery for temporal lobe epilepsy and were monitored for > 2 years. Patient and family assessments showed patients' overall QOL markedly improves after surgery, depending on freedom from seizures. However, factors such as social contacts, family relations, or financial status improved little. Some families and patients were not satisfied with the postsurgical status, despite freedom from seizures. Patients who had surgery at a later age were not so satisfied with their postsurgical status as were patients who had surgery at a younger age, particularly on the QOL domains of role activities, memory function, leisure activities, or emotional well-being. This lower satisfaction level in older patients likely results from a variety of problems affecting patients during the long-lasting epileptic process; social handicaps, psychologic conflicts, and deterioration of cognitive/behavioral functions. Based on each case, we recommend that investigations start at an early stage of the illness, so that surgical intervention may be considered as early as possible.

Can absence status epilepticus be of frontal lobe origin?

Five women with an unclassifiable nonconvulsive status epilepticus (NCSE) characterized by young age at onset, prolonged confusions, focal motor seizures, and both generalized spike-and-wave discharges and focal epileptic discharges on the EEG were studied with video-EEG monitoring. Electrographically, the NCSE originated from the left frontal lobe in 4 patients, and the left hemisphere with multifocal seizure discharges in 1 patient. Focal motor seizures seemed to originate from the left hemisphere in all 5 patients, particularly from its anterior part in 3 of them. Results show that the NCSE is complex partial status epilepticus of frontal lobe origin electroclinically mimicking absence status epilepticus once it reaches a full-blown phase.

Wavelength specificity of photoparoxysmal responses in idiopathic generalized epilepsy.

Using optic filters, we analyzed the wave-length specificity of photoparoxysmal responses (PPR) in photosensitive patients with idiopathic generalized epilepsy (IGE). We specified the wavelength spectrum approximately 700 nm (660-720 nm) as the only visible spectrum essential for eliciting PPR in some normal trichromat IGE patients and showed that any flashing lights containing this essential wavelength spectrum could elicit PPR independent of the number of stimulated cones. Absorption of the wavelength spectrum approximately 700 nm by optic filters eliminated PPR in normal trichromat IGE patients. In an IGE patient with deuteranomaly, intermittent flashing lights containing a part of the wavelength spectrum from 580 to 700 nm elicited PPR. These data suggest a new interpretation of wavelength specificity of PPR: Flashing lights containing the wavelength spectrum that does not produce antagonistic cone interactions at the level of retinal ganglion cells can elicit PPR in some photosensitive IGE patients.