Ictal SPECT findings in typical absence seizures

Single photon emission computed tomography (SPECT) is known to reveal localized hyperperfusion during partial seizures, but is rarely performed in idiopathic generalized epilepsies. We report the ictal SPECT findings in a typical absence seizure. This 35-year-old woman with childhood absence epilepsy underwent prolonged electroencephalogram (EEG)-video monitoring, during which many stereotyped typical absence seizures were recorded. These consisted of brief staring spells with arrest of activity, associated with generalized 3 Hz spike-wave complexes on EEG. Following intravenous (i.v.) injection of 17.6 millicuries of Tc-99m Bicisate, SPECT was performed. The injection was performed during hyperventilation that induced a typical absence. Compared to the baseline SPECT scan that was normal, the ictal scan showed a generalized reduction in cortical activity. These findings do not support the “cortical” theory of typical absence seizures and the genesis of the 3 Hz spike-wave complexes. They may indeed support the subcortical or “centrencephalic” hypothesis.     

Exacerbation of typical absence seizures by progesterone.

Variation of seizure frequency during the menstrual cycle has been attributed in part to an antiepileptic action of progesterone reducing seizure frequency during the luteal phase, but studies have not distinguished patients with primary generalized, secondary generalized and absence epilepsies. We describe a patient whose absence seizure frequency increased when she was administered progesterone. This indicates that, in contrast to secondarily generalized seizures, progesterone may exacerbate absence seizures.     

Open comparative long-term study of vigabatrin vs carbamazepine in newly diagnosed partial seizures in children.

OBJECTIVE: To compare vigabatrin with carbamazepine as monotherapy in newly diagnosed children with partial epilepsy in order to evaluate the efficacy and tolerability of both drugs. DESIGN: Open and randomized with a 2-year follow-up period. SETTING: The Infantile Neuropsychiatric Division of the Regional Pediatric Hospital, Ancona, Italy. PATIENTS: Seventy children with newly diagnosed partial epilepsy were treated with vigabatrin (38 patients) or carbamazepine (32 patients). INTERVENTION: Vigabatrin, 50 to 60 mg/kg per day, or carbamazepine, 15 to 20 mg/kg per day, split into twice-a-day doses. OUTCOME MEASURES: The efficacy and tolerability of vigabatrin were compared with those of the standard treatment (carbamazepine) for this patient group. RESULTS: The efficacy of vigabatrin and carbamazepine was similar, with the suggestion of a better side effect profile with vigabatrin. CONCLUSIONS: Vigabatrin monotherapy should be considered as a monotherapeutic treatment option in patients with newly diagnosed epilepsy. However, more studies are needed to evaluate other issues of concern, such as the cognitive and behavioral adverse effects of antiepileptic drugs, to determine the most suitable therapy.     

Lamotrigine as an add-on drug in typical absence seizures

Introduction - Lamotrigine is licenced in many countries for use in patients with partial seizures. Evidence suggests that it may also be effective in generalised epilepsies. Material & methods - We analysed retrospectively our patients with idiopathic generalised epilepsy with refractory absences. Results - Fifteen patients with idiopathic generalised epilepsies were identified who had been treated with lamotrigine for 3 months or more. All patients were also treated with sodium valproate. Fourteen patients had active absences. Nine (64%) had a total or virtual cessation of absences and in a further patient they became milder and less frequent. One patient reported an increase in seizures. The effective dose of lamotrigine was 1.6-3.0 mg/kg/day in children and 25-50 mg/day in adults. Patients who responded did so after the first or second dose. Lamotrigine was well tolerated. Conclusion - Low-dose lamotrigine added to sodium valproate appears to be effective in typical absence seizures. A therapeutic interaction of the two drugs seems likely.     

The utility of ambulatory EEG monitoring in typical absence seizures

In this study 8 hours ambulatory EEG monitoring (A/EEG) was performed in 25 outpatients with electroclinical evidence of absence attacks, in order to evaluate the possibility of objective quantification of the epileptic discharges, their distribution during the daytime and their relationship with evident behavioral correlates. A comparison between data obtained by A/EEG and standard EEG (S/EEG) was also made. The results have shown that: 1) it was possible to perform real quantification of the epileptic discharges only through the A/EEG test; 2) the two peaks of a greater incidence of the epileptic discharges corresponded to the execution of relaxing activities and ones requiring a low level of attentiveness; 3) a large number of epileptic generalized discharges did not exhibit a signal pattern like that of a "seizure", although they were of long duration; and 4) in six patients who showed the normalization of S/EEG and the disappearance of the absences after one month of valproate therapy, A/EEG revealed the persistence of epileptic discharges. These data demonstrate that A/EEG is a very useful technique for the quantification of paroxysmal discharges and that it may be of importance in the management of this kind of epileptic disorder.     

Myoclonic, atonic, and absence seizures following institution of carbamazepine therapy in children

Five children, aged 3 to 11 years, treated with carbamazepine for epilepsy, had an acute aberrant reaction characterized by the onset of myoclonic, atypical absence and/or atonic (minor motor) seizures within a few days. When the carbamazepine was discontinued, two of the children returned to their former state very quickly, two had the minor motor seizures resolve in 3 and 6 months, and one had the seizures persist. The child in whom the seizures persisted was later found to have ceroid lipofuscinosis. The other children are doing well on other anticonvulsants.     

Simultaneous EEG,fMRI, and behavior in typical childhood absence seizures

Purpose: Absence seizures cause transient impairment of consciousness. Typical absence seizures occur in children, and are accompanied by 3–4‐Hz spike–wave discharges (SWDs) on electroencephalography (EEG). Prior EEG–functional magnetic resonance imaging (fMRI) studies of SWDs have shown a network of cortical and subcortical changes during these electrical events. However, fMRI during typical childhood absence seizures with confirmed impaired consciousness has not been previously investigated. Methods: We performed EEG‐fMRI with simultaneous behavioral testing in 37 children with typical childhood absence epilepsy (CAE). Attentional vigilance was evaluated by a continuous performance task (CPT), and simpler motor performance was evaluated by a repetitive tapping task (RTT). Results: SWD episodes were obtained during fMRI scanning from 9 patients among the 37 studied. fMRI signal increases during SWDs were observed in the thalamus, frontal cortex, primary visual, auditory, somatosensory, and motor cortex, and fMRI decreases were seen in the lateral and medial parietal cortex, cingulate gyrus, and basal ganglia. Omission error rate (missed targets) with SWDs during fMRI was 81% on CPT and 39% on RTT. For those seizure epochs during which CPT performance was impaired, fMRI changes were seen in cortical and subcortical structures typically involved in SWDs, whereas minimal changes were observed for the few epochs during which performance was spared. Discussion: These findings suggest that typical absence seizures involve a network of cortical–subcortical areas necessary for normal attention and primary information processing. Identification of this network may improve understanding of cognitive impairments in CAE, and may help guide development of new therapies for this disorder.     

Ictal and interictal perfusion variations measured by SISCOM analysis in typical childhood absence seizures.

Single photon emission computed tomography (SPECT) is currently used in the presurgical evaluation of medically intractable partial epilepsies, but not very often, in generalized epilepsy. In the present study, we used the SISCOM procedure, which represents the fusion of MRI and ictal-interictal difference SPECT images using (99m)Tc-ECD, to study cerebral blood flow changes during the ictal and postictal phases of typical childhood absence seizures. The study was performed on four children with typical, difficult to treat absence seizures, aged 10-13 years at the time of scan. The delay between the onset of absence seizures and the injection of (99m)Tc-ECD was carefully noted. One scan was performed during the ictal phase and showed diffuse blood flow decreases, while the three other scans performed during the postictal phase, showed generalized blood flow increase. These data are consistent with most previous data reporting generalized changes in functional activity, not limited to the thalamo-cortical circuit in which absence seizures originate, and a decrease in cerebral blood flow during the ictal phase. Our data are concordant with the hypothesis that neuronal activity underlying the occurrence of spike-and-wave discharges does not seem to require an increase in metabolic demand and blood flow rates. [Published with videosequences].     

Ictal cerebral haemodynamic characteristics during typical absence seizures,compared to focal seizures with brief alteration of awareness

Aims. To investigate ictal cerebral haemodynamic characteristics during spontaneous typical absence seizures (TAS) and hyperventilation‐evoked absence seizures in paediatric patients, relative to brief complex partial seizures (BCPS). Methods. All children diagnosed with seizures using real‐time transcranial doppler ultrasonography (TCD) and sleep‐deprived video‐EEG (vEEG) from 2015 to 2017 in our hospital were included. The seizures were diagnosed based on the video and EEG findings. Mean cerebral blood flow velocity (CBFV_m) of the unilateral middle cerebral artery was measured using TCD. TCD and vEEG data were integrated for a synchronous assessment of CBFV_m changes and epileptic status. Baseline and peak CBFV_m for TAS and BCPS were compared by T‐test. Results. Six children (two boys and four girls) with TAS and two girls with BCPS were enrolled. A total of 15 spontaneous TAS, 14 hyperventilation‐evoked absence seizures, and six BCPS were recorded using real‐time TCD‐vEEG monitoring. During spontaneous TAS, whether awake or asleep, the CBFV_m decreased by 20–40% compared to baseline. During hyperventilation‐evoked absence seizures and BCPS, the CBFV_m increased by 50–150% and 20–30% over baseline levels, respectively. Conclusions. The haemodynamic characteristics during TAS and BCPS are distinct, and thus our results may provide a new method to diagnose typical absence seizures using dynamic CBFV_m curves. Ictal cerebral haemodynamic characteristics during spontaneous typical absence seizures and hyperventilation‐evoked absence seizures may reflect different pathophysiological mechanisms and networks compared with BCPS.     

Aggravation of absence seizures by carbamazepine in a genetic rat model does not induce neuronal c-Fos activation

The mechanisms underlying carbamazepine aggravation of absence seizures are uncertain but are thought to involve enhancement of neuronal activity within the thalamocortical circuitry. We used c-Fos immunohistochemistry (cFos-ir) to examine patterns of neuronal activation and the relationship to seizure expression following administration of carbamazepine in a rat model of absence epilepsy (Genetic Absence Epilepsy Rats of Strasbourg, GAERS). Female ovariectomized GAERS implanted with extradural EEG electrodes received either 20 mg/kg carbamazepine or vehicle IP. Seizure expression was quantified by measuring the total number and duration of spike-wave discharges (SWD) and with the individual burst discharge lengths over a 90-minute EEG. This was correlated with cFos-ir in thalamocortical slices from rats killed 180 minutes after carbamazepine administration. Carbamazepine-treated rats (n = 5) had a significantly greater total duration of SWD than vehicle-treated rats (17.9% versus 8.8%, P = 0.04). Despite this aggravation of seizures, the level of cFos-ir did not differ between the treatment groups. A positive correlation was found between cFos-ir in the reticularis thalami (Rt) and the total seizure duration (R = 0.66, P = 0.04) and mean burst length (R = 0.68, P = 0.03) but not total number of seizures. The lack of difference in cFos activation patterns between carbamazepine and vehicle-treated animals suggests that the mechanism for carbamazepine aggravation of absence seizures may not involve neuronal activation but rather enhanced neuronal synchronization. The association between increased neuronal activation in the Rt and seizure burden in GAERS provides further support for the critical role of this structure in the maintenance, but not initiation, of absence seizure activity.     

Effects of vigabatrin on partial seizures and cognitive function.

Forty five patients with refractory partial seizures were studied in a prospective, randomised, placebo controlled, add on, parallel group, double blind trial of the new antiepileptic drug vigabatrin (1.5 g twice daily) followed by open treatment. Seizure frequency was monitored throughout an eight week baseline, 20 weeks double blind, and up to 18 months of open vigabatrin treatment. Cognitive function, including measures of memory and concentration, mood, and behaviour were assessed at baseline and again during the 20th week of treatment. Vigabatrin was associated with a significant reduction in a measure of motor speed and overall score on a design learning test in the first 20 weeks of treatment. In comparison with the baseline period, vigabatrin treatment was associated with a significant reduction in median complex partial seizure frequency four to 12 and 12 to 20 weeks after commencing vigabatrin (-66% and -69% in the vigabatrin group, +50% and +25% in the placebo group). Ten of 20 patients on vigabatrin and four of 23 on placebo showed a > 50% reduction in complex partial seizure frequency in the last eight weeks of double blind treatment. At least 60% of responders had maintained the response to vigabatrin when assessed during the open phase of the trial at 44 weeks. Two patients discontinued vigabatrin because of depression, which resolved on drug withdrawal.     

Effect of vigabatrin addition on carbamazepine blood serum levels in patients with epilepsy

Because vigabatrin (VGB) is not metabolized by liver enzymes and does not bind with serum proteins, there is little theoretical chance of it interacting with other antiepileptic drugs. However, our observations have shown that if VGB is added to carbamazepine (CBZ) monotherapy, some patients respond with adverse, toxic symptoms suggesting possible carbamazepine-vigabatrin interaction. This article presents the results of a study of 66 epileptic patients (27 women and 39 men), age 10-66 years (mean, 28.2 years), with focal seizure onset with or without secondary generalization. In these patients, in addition to CBZ therapy with an average dose of 16.7 mg/kg per day (8.6-26.8), VGB, average dose 31.1 mg/kg per day (7.1-57.9), was added. CBZ concentration was measured twice: prior to VGB introduction and 5-12 weeks after the final dose of VGB was reached. In our study 69.7% of patients responded to VGB addition with a significant increase (by at least 10%) in CBZ concentration. A correlation between the value of the increase and the initial level of CBZ prior to VGB addition was found also. Correlational analysis (Pearson's r) revealed a negative correlation between CBZ concentration and increased concentration after VGB addition (r = -0.47, df = 64, P < 0.001). This negative correlation means that if the initial CBZ level is lower, its concentration value after VGB addition is higher.     

The influence of gender on the aggravation of absence seizures by carbamazepine in the low-dose pentylenetetrazol rat model.

OBJECTIVES: To determine whether carbamazepine (CBZ) aggravates absence seizures in the low-dose pentylenetetrazol (PTZ) rat model in both male and female animals, and investigate for gender differences. METHODS: Inbred Sprague-Dawley rats were implanted with EEG electrodes. Seven days later PTZ (20 mg/kg, i.p.) was administered following pre-treatment with vehicle or CBZ (20 mg/kg, i.p.) and the occurrence of spike-and-wave discharges (SWDs) on the EEG quantified. RESULTS: The cumulative SWD for 90-minute post-PTZ was higher in the CBZ versus vehicle pre-treatment arm for both female (mean 110 seconds vs. 62 seconds; P = 0.03) and male (mean 89 seconds vs. 60 seconds; P = 0.03) rats. The increase in SWD duration in the CBZ arm was greater in female rats for the first five 15-minute intervals, but none attained statistical significance (P > 0.05). CBZ pre-treatment resulted in reductions in both SWD frequency (Hz) (male, P = 0.003; female, P < 0.0001) and latency to onset of SWD (male, P = 0.002). The frequency of SWD in CBZ pre-treated rats was lower in females (5.8 Hz vs. 6.1 Hz, P = 0.002) as was the decrease in the SWD burst duration following CBZ versus vehicle pre-treatment (-0.05 seconds vs. -0.25 seconds, P = 0.046). CONCLUSIONS: CBZ consistently aggravates absence seizures in the low-dose PTZ model in both female and male rats. However, while some gender differences were found, the results failed to support the hypothesis that females are significantly more susceptible to aggravation of the number or duration of absence seizures by CBZ.     

Clinical trials of carbamazepine for autonomic seizures with and without generalized epileptic seizures

Carbamazepine (CBZ) was used for the treatment of 52 children of autonomic seizures with and without generalized epileptic seizures. Their ages ranged from 4 to 17 years. Their autonomic seizures were recurrent episodic headaches and/or abdominal pains. EEG abnormalities were found in all cases in this study. The abnormal EEG findings consisted of diffuse paroxysmal slow dysrhythmia, generalized spike and wave complexes, focal spike and wave complexes with diffuse slow wave bursts, spike and wave complexes with 14 and 6 Hz positive spikes of 14 and 6 Hz positive spikes. Of the 40 patients with autonomic seizures only, 36 (90%) showed disappearance of pain, and of the remaining 4, 2 showed moderate improvement and 2 showed no change as far as their clinical symptoms were concerned. Of the 12 patients with both autonomic seizures and generalized epileptic seizures, 10 (83%) became free from headache and 2 improved moderately. The efficacy of CBZ was found to be very satisfactory. The effective dosage of CBZ ranged from 3.9 to 11.4 mg/kg/day (total dose, 100 to 400 mg/day) with the mean value of 7.0 mg/kg/day.     

A quantitative study of daytime sleepiness induced by carbamazepine and add-on vigabatrin in epileptic patients

Introduction – The clinical relevance of daytime sleepiness associated with carbamazepine (CBZ) and vigabatrin (VGB) was objectively assessed by the multiple sleep latency test (MSLT) and nocturnal sleep recordings. Material and methods – Twenty-six patients with partial epilepsy and mean monthly seizure frequency of 4, aged 18 to 48 years, receiving chronic monotherapy with CBZ and subsequent VGB addition for 2 months (14 patients), were compared with a group of healthy subjects. Subjective daytime sleepiness was complained by 13 patients on CBZ monotherapy and 9 patients during VGB add-on treatment. Results – No differences in nocturnal sleep parameters, but significantly shorter daytime sleep latencies at the MSLT, were detected in CBZ-treated patients as compared with healthy controls. Addition of VGB therapy did not further enhance objective daytime sleepiness. Conclusion – Some sleepiness occurs in chronically CBZ-treated epileptic patients, which can be objectively measured by the MSLT, but it is not aggravated by add-on VGB.     

Misdiagnosis of complex absence seizures

Video-EEG monitoring disclosed absence seizures in five patients who were treated for partial seizures. Analysis of the historical and video data showed the presence of several potentially misleading ictal manifestations as follows: unidirectional head and/or eye turning, symmetric clonic activity, urinary incontinence, loss of balance causing injuries, focal clonic activity, and de novo automatisms. Without EEG correlation, complex absence seizures may be difficult to differentiate from other types of seizures. When correctly diagnosed, appropriate therapy may improve seizure control.