Individual Seizure Research Articles

Treatment of epilepsy in the multiply handicapped.

The medical management of epilepsy in the multi-handicapped patient requires careful evaluation, classification, and pharmacologic treatment. It is estimated that 20-40% of patients with mental retardation and cerebral palsy have epilepsy. This review reports the clinical trial data and personal experience related to the use of newer AEDs in the chronic management of epilepsy syndromes in children and adults, as well as information available on the treatment of seizures in individuals with mental retardation and associated handicaps. Furthermore, clusters of seizures, prolonged seizures and status epilepticus are more commonly seen in the multiply handicapped and mentally retarded population and require special attention. The new antiepileptic drugs felbamate, gabapentin, lamotrigine, levetiracetam, oxcarbazepine, tiagabine, topiramate, vigabatrin and zonisamide show specific advantage in some multiply handicapped patients, be it for seizure control or medication tolerance. Furthermore, new modalities of treatment for prolonged seizures allow better efficacy both outside of hospital and within hospital facilities. The treatment of epilepsy in multi-handicapped and retarded adults and children has significantly advanced in the past few years, and much of this improvement can be attributed to improved knowledge and monitoring of new antiepileptic drugs. Conventional anticonvulsants remain first line therapy for most clinicians, but newer AEDs must broaden the therapeutic option and do allow improved therapy for some multiply handicapped patients.

The diversity of seizures related to alcohol use. A study of consecutive patients.

The aim of this study was to investigate the influence of hazardous alcohol drinking on the occurrence of epileptic seizures, the semiology of such seizures, and the extent of the problem. A consecutive sample of 142 acute seizure patients (78 male and 64 female, mean age 46 (16-79) years) was studied. Control groups were 185 consecutive sciatica patients and 254 healthy individuals. Subjects with a hazardous alcohol drinking level were identified by a score >8 in the Alcohol Use Disorders Identification Test (AUDIT). Seizures in AUDIT-positive individuals occurring within 72 h of the last drink were considered to be related to alcohol withdrawal. Generalized or partial onset seizures were classified on the basis of history, electroencephalographic (EEG) and neuroradiological findings. Thirty-five percent of seizure patients were AUDIT-positive, whereas conversely 27% were abstainers. Two-thirds of AUDIT-positive seizure patients met the criteria for withdrawal seizures. Indications of partial onset seizures were found in 25 (51%) of AUDIT-positive patients, all secondarily generalized seizures. Sixty percent of generalized onset seizure patients were AUDIT-positive. In conclusion, seizure patients included significantly more AUDIT-positive subjects, as well as abstainers, than healthy Norwegian controls and consecutive sciatica patients from our hospital. Partial onset seizures are more frequent among hazardous drinkers than hitherto recognized. A generalized onset seizure in adults warrants a high suspicion of alcohol as a provoking factor. Routine screening of acute seizure admissions with the Alcohol Use Disorders Identification Test is recommended.

Epilepsy education in schools

The objective of this study was to assess the effect of an epilepsy education initiative on the management of epilepsy in Southampton schools. A self-completion questionnaire survey was undertaken of staff in 19 Southampton primary schools and ten secondary schools. Changes in knowledge and management of seizures in children with epilepsy were measured following an education session and a recommended implementation of an individual seizure protocol for children with epilepsy. There were significant changes in some areas of seizure management and knowledge. Only a small number (three) of primary schools had a protocol in place. Two primary and four secondary schools were in the process of putting the protocol in place. An improvement in knowledge and seizure management has been demonstrated. Further work is needed to implement an individual seizure protocol for all children with epilepsy.

The Comparative Effectiveness of Fixed and Stimulus Dosing Forms of Electroconvulsive Therapy for the Treatment of Unipolar Depression: A ‘Quality Assurance’ Study

While the necessity for suprathreshold dosing has become widely accepted as the most effective means of administering ECT, there are differing schools of thought regarding the utilisation of this approach in day-to-day clinical practice. Abrams [ 1 , 2 ] and Fink [ 3 ] support fixed dosing whereby patients receive a fixed dose of about 2.5 times the average population seizure threshold (approximately 375–500 mC). On the other hand, Sackeim [ 4 ] developed the technique of stimulus dosing with which individual seizure thresholds and suprathreshold doses are determined. Both the American, and Australian and New Zealand Psychiatric Associations [ 5 , 6 ] view both fixed and stimulus dosing in ECT as appropriate and acceptable alternatives. This has also been endorsed in recent literature [ 7 ].

Effects of Blocking GABA Degradation on Corticotropin‐Releasing Hormone Gene Expression in Selected Brain Regions

The gamma-aminobutyric acid (GABA) degradation blocker gamma-vinyl-GABA (VGB) is used clinically to treat seizures in both adult and immature individuals. The mechanism by which VGB controls developmental seizures is not fully understood. Specifically, whether the anticonvulsant properties of VGB arise only from its elevation of brain GABA levels and the resulting activation of GABA receptors, or also from associated mechanisms, remains unresolved. Corticotropin-releasing hormone (CRH), a neuropeptide present in many brain regions involved in developmental seizures, is a known convulsant in the immature brain and has been implicated in some developmental seizures. In certain brain regions, it has been suggested that CRH synthesis and release may be regulated by GABA. Therefore we tested the hypothesis that VGB decreases CRH gene expression in the immature rat brain, consistent with the notion that VGB may decrease seizures also by reducing the levels of the convulsant molecule, CRH. VGB was administered to immature, 9-day-old rats in clinically relevant doses, whereas littermate controls received vehicle. In situ hybridization histochemistry demonstrated a downregulation of CRH mRNA levels in the hypothalamic paraventricular nucleus but not in other limbic regions of VGB-treated pups compared with controls. In addition, VGB-treated pups had increased CRH peptide levels in the anterior hypothalamus, as shown by radioimmunoassay. These findings are consistent with a reduction of both CRH gene expression and secretion in the hypothalamus, but do not support an indirect anticonvulsant mechanism of VGB via downregulation of CRH levels in limbic structures. However, the data support a region-specific regulation of CRH gene expression by GABA.

Efficacy of lamotrigine in idiopathic generalized epilepsy syndromes: a video‐EEG‐controlled, open study

ABSTRACT Purpose This prospective, open, video‐EEG‐controlled study examined the efficacy of lamotrigine (LTG) as add‐on and monotherapy in idiopathic generalized epilepsy (IGE). Methods 47 patients received LTG either because of insufficient seizure control (n = 35) or serious side effects of prior antiepileptic drugs (AED). Long‐term video‐EEG recordings were performed before and after the introduction of LTG. The mean follow‐up time was 25.5 months. Results Of 12 patients with refractory childhood absence epilepsy, 9 became seizure free; in one child with absences with eyelid myoclonia, absence frequency was reduced > 50%; in 2 children with absences with a mild atonic component, seizure reduction was only transient. Of 12 patients with juvenile absence epilepsy, 10 became seizure‐free and, in 2, a > 50% reduction was obtained. In 15 patients with juvenile myoclonic epilepsy, complete seizure control was achieved in 7 patients, in 6 patients myoclonia persisted. In one patient generalized tonic‐clonic seizures also persisted and another patient developed a rash, LTG was therefore stopped. Of 5 patients with grand‐mal on awakening, 3 became seizure‐free, and a reduction of > 50% was obtained in one patient; LTG was stopped in one patient because of poor compliance. Three patients with pure photosensitive epilepsy became seizure‐free. At the end of the study, 11 patients were seizure‐free on LTG monotherapy, and in most other patients concomitant AED dosage could be substantially reduced. Conclusions Lamotrigine was effective and well tolerated in patients with various IGE syndromes, although differences were observed between individual syndromes and seizure types.

Kinetics of serum neuron-specific enolase and prolactin in patients after single epileptic seizures.

To investigate and compare the temporal profile of serial levels of neuron-specific enolase (NSE) and prolactin in serum from patients after single epileptic seizures. Measurement of NSE and prolactin by sensitive immunoassays in 21 patients with complex partial seizure (CPSs: n = 11) and secondarily generalized tonic-clonic seizures (SGTCSs; n = 10) during continuous video-EEG monitoring at four different time points (1, 3, 6, and 24 h after ictal event). Statistical analysis was performed by using a repeated-measures analysis of variance (ANOVA) model. Mean+/-SD values for NSE levels (ng/ml) were 12.5 +/-4.4 (1 h), 10.8+/-3.8 (3 h), 11.1+/-4.9 (6 h), and 8.2+/-1.9 (24 h). The corresponding prolactin levels (mU/L) were 1,311+/-1,034, 232+/-158, 237+/-175, and 251+/-98. There was a significant decrease of NSE and prolactin levels over time (p < 0.001). The pair-wise comparison of NSE levels showed significant differences between the time points 1 vs. 24 h (p < 0.001), 3 vs. 24 h (p = 0.007), and 6 vs. 24 h (p = 0.009). In contrast, serum prolactin levels showed a significant difference between 1 vs. 3 h (p < 0.001) only. Most of the NSE levels remained normal after CPSs and SGTCSs. At 1 h after the seizure, only 33% of the subjects had increased NSE, whereas abnormal prolactin levels occurred with a sensitivity of 80%. In contrast to prolactin, serum NSE is not a sensitive marker of individual seizures. Only some individuals showed an increase of NSE beyond the prolactin-sensitive time frame after a single seizure, and mean NSE levels were not significantly increased compared with those of normal controls.

Blood concentrations of vasopressin, neuropeptide FF and prolactin are increased by high-dose right unilateral ECT

Electroconvulsive therapy (ECT) is known to stimulate subcortical brain regions and release hormones from the anterior and the posterior pituitary. To enhance the subcortical effect of ECT and the neuroendocrinological response we used high dose right unilateral ECT (RUL-ECT) in 11 depressive patients and studied its effect on the release of vasopressin, prolactin and neuropeptide FF. The RUL ECT stimulus for all studied patients was 5 times the individual seizure threshold and it led to immediate release of vasopressin in all studied patients. The release of prolactin was less uniform, however in accordance with results from earlier studies. The ECT also stimulated a NPFF secretion peak that came approximately 5 min after ECT stimulus and preceded the prolactin peak. The maximal elevations in circulating vasopressin and prolactin concentrations were 680% and 950%, respectively. The neuropeptide FF concentration increased by 100% after ECT. There was a second rise in NPFF concentration at 25 min after the ECT treatment. The increases in all peptide concentrations were significant, but were not correlated with each other. The neuropeptide FF concentration returned to baseline level at 10 min and the vasopressin concentration at 25 min after ECT. The prolactin concentration remained increased during the 30 min follow up period. Our results complete earlier finding on ECT stimulated vasopressin and prolactin release and show that high intensity RUL-ECT releases neuropeptide FF into human blood. The modest rise of circulating NFFF most likely represents leakage from the CNS.

Epileptic aphasia: a consequence of regional hypometabolic encephalopathy?

A series of 25 children, 13 females and 12 males, who had an acquired communication disorder together with epilepsy, but did not fulfil the strict criteria of the Landau-Kleffner syndrome, was studied. All children had a clinical neurological evaluation, speech and language assessment, an awake and sleep EEG, cranial MRI, SPET scan, and audiometry. Clinical seizures were most often polymorphic in type (17 of 25). Atypical absences were the commonest individual seizure type occurring in 15 cases. All patients had an unequivocal epileptiform EEG. Normal sleep phenomena were only observed in 10 cases, enhancement of epileptiform activity in sleep was seen in 16. Cranial MRI was abnormal in six and normal in 19 cases. The SPET scans were abnormal in 22 of 25 children. The language deficits were classified neurologically as receptive aphasia, 24 of 25; expressive aphasia, 20 of 25; nominal aphasia, eight of 25; articulatory dyspraxia, 10 of 25; and auditory agnosia, nine of 25. It is hypothesized that the loss of communication skills is due to an encephalopathy secondary to the persistent epileptic discharge and manifests as a hypometabolic area on the SPET scan.

Pro-epileptic changes in synaptic function can be accompanied by pro-epileptic changes in neuronal excitability

Repetitive sensory input, stroboscopic lights or repeated sounds can induce epileptic seizures in susceptible individuals. In order to understand the process we have to consider multiple factors. The output of a set of neurones is determined by the amount of excitatory synaptic input, the degree of positive feedback and their inherent electrical excitability, which can be modified by synaptic inhibition. Recent research has shown that it is possible to separate these phenomena, and that they do not always behave in unison.

Epilepsies with partial seizures in childhood.

Individual seizures are described as either partial (localization related) or generalized depending on whether a localized area of cerebral cortex is symptomatically involved sufficient to impart to the seizure a focal signature or whether sufficient cortex is involved sufficiently rapidly to appear as if generalized from the outset. This distinction is of some diagnostic and therapeutic importance. However, it has become evident that the prognosis of the patient's epilepsy is less a function of the seizure type than it is of the etiology and of the nature of the syndrome that the seizures represent. This approach is stressed in this chapter as is the regret that there is frequently a delay in the acknowledgment of the usefulness of a new drug in childhood epilepsies, as exemplified by lamotrigine.

Does neuroanatomy predict ECT response?

1. 1. Structural neuropathologic abnormalities have been associated with severe psychiatric illnesses, including bipolar disorder, major depressive disorder, and schizophrenia. In the latter, ventricular enlargement has been variably associated with symptom severity and poor treatment response. In patients with severe depressive disorders, the relationship between cortical and subcortical pathology and ventricle enlargement, symptom severity, and response to treatment is far from clear. 2. 2. The present study investigated the relationship between structural CNS pathology, symptom severity and treatment response in patients undergoing ECT. It was hypothesized that patients with greater neuroanatomic abnormalities would demonstrate greater initial symptom severity and poorer response to ECT. 3. 3. The subjects were 57 patients with unipolar or bipolar depression admitted for ECT treatment. Symptom severity was quantified using the Hamilton Depression Rating Scale (HRSD) at baseline and post-ECT. 4. 4. Lateral and third ventricle-brain ratio (LVBR, 3VBR) were determined from CT scans and cortical atrophy was rated by a faculty neuroradiologist. 5. 5. Contrary to our first hypothesis, structural pathology was not associated with baseline symptom severity. In terms of treatment response, the number of treatments required to achieve benefit was correlated with larger 3VBR; CT variables were not related to total post-treatment or change in HRSD score. Third ventricle enlargement may be an index of generalized pathology or regional brainstem abnormalities that influence ECT response rate by limiting individual seizure efficacy or neurochemical responsiveness, thereby necessitating a greater number of ECT treatments, without significant impact on overall response.

Randomized, controlled trial of high-dose intravenous pyridoxine in the treatment of recurrent seizures in children

To determine the efficacy of pyridoxine in treating seizures, 90 infants and children with recurrent convulsions primarily due to acute infectious diseases were enrolled in the present study. Forty patients were treated with high-dose pyridoxine (30 or 50 mg/kg/day) by intravenous infusion, and 50 subjects served as controls. Antiepileptic drugs and other therapies were similar in the two groups except for pyridoxine. Clinical efficacy criteria were based on the frequency of convulsions per day and on the duration of individual seizures after therapy was initiated. The results indicated that total response rates in the pyridoxine group and control group were 92.5% and 64%, respectively (chi-square = 14.68, P < .001). After initiation of therapy, seizures resolved after 2.4 ± 1.4 days in the pyridoxine group and after 3.7 ± 2.0 days in the control group (t = 3.67, P < .001). No adverse effects of pyridoxine were apparent during the observation period. We conclude that pyridoxine is an effective, safe, well-tolerated, and relatively inexpensive adjunct to routine antiepileptic drugs for treatment of recurrent seizures in children.

Effects of NMDA antagonists on seizure thresholds induced by intrahippocampal microdialysis of picrotoxin in freely moving rats

The role of N-methyl- d-aspartate (NMDA) receptors on individual variations in animal seizure threshold induced by picrotoxin microperfusion in the hippocampus of freely moving rats was analyzed by testing the effects of NMDA receptor antagonists 2-amino 5-phosphonovalerate (AP-5) and dizocilpine (MK-801) on individual seizure thresholds. We found a correlation between the increased threshold levels induced by AP-5 and control seizure levels of each individual animal. However, no correlation was found with the increased threshold level induced by MK-801. These data suggest that the individual variations in seizure threshold in different animals reflect dynamic processes of NMDA mediated activity and emphasizes the value of whole-animal models to analyze NMDA receptor functions.

Mesial temporal versus neocortical temporal lobe seizures: Demonstration of different electroencephalographic spreading patterns by combined use of subdural and intracerebral electrodes

We investigated differences between spatiotemporal intracranial EEG characteristics of temporal lobe seizures with mesiolimbic versus neocortical onset, using both subdural and intracerebral electrodes. In 37 patients we analyzed 128 seizures, assessing time intervals from initial onset of a seizure in either mesial or neocortical temporal (NT) lobe structures to sequential ictal involvement of the contralateral mesiolimbic structures and the ipsi- and contralateral temporal and frontal neocortical areas. We noted significantly more rapid seizure spread from mesiolimbic temporal (MT) structures ipsilateral to contralateral in patients with NT versus MT seizure onset. Time values for total seizure duration and time of spread from ipsilateral limbic to contralateral limbic reliably discriminate between individual seizures of either type. Three different spreading patterns were noted in the MT group and two more were noted in the NT group. Theoretical considerations concerning routes of spread are presented. In neither the MT nor the NT group could a correlation be established between pattern of seizure spread and outcome of surgery.

Systemic administration of kainate induces marked increases of endogenous kynurenic acid in various brain regions and plasma of rats

The endogenous neuroinhibitory and neuroprotective excitatory amino acid receptor antagonist kynurenic acid has been hypothetically linked to the pathogenesis of epilepsy and several other brain disorders. In the present study, alterations in kynurenic acid levels were examined in the kainate model of temporal lobe epilepsy. Kainate was systemically injected in rats at a dose (10 mg/kg s.c.) which induces a characteristic behavioural syndrome with stereotypies and focal (limbic) and generalized seizures, eventually progressing into severe status epilepticus. Kynurenic acid was determined 3 h after kainate injection in various brain regions (olfactory bulb, frontal cortex, piriform cortex, amygdala, hippocampus, nucleus accumbens, caudate/putamen, thalamus, superior and inferior colliculus, pons and medulla, and cerebellar cortex) and in plasma, using a sensitive high-performance liquid chromatographic method. When data were analysed irrespective of individual seizure severity, significant increases in kynurenic acid were determined in all brain regions examined except the hippocampus, nucleus accumbens and pons/medulla. The most marked (200–500%) increases above controls were seen in the piriform cortex, amygdala, and cerebellar cortex. Furthermore, a significant kynurenic acid increase of about 200% above control was determined in plasma. When kynurenic acid levels were determined in subgroups of rats with different behavioural alterations in response to kainate, the most marked kynurenic acid increases were seen in subgroups with status epilepticus. Rats which only developed mild (focal) seizures or stereotyped behaviours (wet dog shakes) also exhibited significantly increased kynurenic acid levels, thus indicating that the increase in kynurenic acid in response to kainate was not solely due to sustained convulsive seizure activity. Whereas it was previously proposed that kynurenic acid is involved only in later stages of seizure disorders, the present data demonstrate that marked increases in central and peripheral kynurenic acid levels occur early after the onset of neuroexcitation, at least in the kainate model.

Distribution of parvalbumin-containing interneurons in the hippocampus of the gerbil — a qualitative and quantitative statistical analysis

In the gerbil ( Meriones unguiculatus) hippocampal formation, the calcium-binding protein parvalbumin (PV) shows a unique species-specific distribution: it is present in the perforant path from the entorhinal cortex to the stratum moleculare of the dentate area and cornu ammonis. A possible relation of this to the seizure-sensitivity of gerbils has been suggested. In addition, as in other species, PV is contained in a subpopulation of GABAergic nerve cells of the gerbil hippocampus. The characteristics of these PV-containing neurons are here described. Distribution and shape of the PV-positive neurons in general agreed with the features described for rat hippocampus with two notable exceptions: in CA2 PV-containing perikarya were densely crowded and gave rise to an intense immunoreactive plexus around the pyramidal cells and, in CAI, the number of stained neurons was variable, often much lower than in rats and occasionally not a single PV-positive neuron was present. In parasagittal brain sections of the lateralities 1.0, 1.6 and 2.2 mm from the midline, obtained from 27 male gerbils, the number of PV-containing neurons was determined. The data set obtained in CA3 and dentate area resembled unimodal distributions, while in CAI a bimodal frequency distribution was present. Since parametric and non-parametric correlation tests rely on a unimodal distribution of the data set, they gave falsely significant values in CAI. The bimodal distribution suggests that, with respect to the PV-containing interneurons in CA1, two different populations of gerbils were included in our sample, those with many positive neurons and those with only a few. Since the nerve terminal staining is preserved also in those gerbils with only a few positive perikarya in CAI, it seems possible that an unknown factor influenced PV expression and storage in the soma. Sex, age, seasonal or circadian rhythm or quality of immunocytochemical staining did not influence the outcome of the quantitative analysis. However, a relation of the expression of the high affinity calcium buffering PV in interneurons and the individual seizure sensitivity of the gerbil is considered.

Prevention as it pertains to epilepsy.

Prevention may be practiced at various levels in the hierarchy of epilepsy; at the level of epilepsy itself (epileptogenesis), the individual epileptic seizures (ictogenesis), or in the avoidance of the consequences of the epilepsies or their component seizures. Moreover, it also applies in the arena of psychosocial predicaments, the neurologic or other injurious side effects of recurrent seizures, and the unwanted side effects of drug therapy or surgery employed in management, where attention to the risk/benefit analysis of the treatment employed may greatly influence outcome not only of life itself but also its quality.

Aspartame and Seizure Susceptibility: Results of a Clinical Study in Reportedly Sensitive Individuals

The high intensity sweetener aspartame has been implicated anecdotally in seizure provocation. This possibility was investigated with a randomized, double-blind, placebo-controlled, cross-over study. After an extensive search, 18 individuals (16 adults and 2 children) who had seizures allegedly related to aspartame consumption were admitted to adult or pediatric epilepsy monitoring units where their EEG was monitored continuously for 5 days. Aspartame (50 mg/kg) or identically enpackaged placebo was administered in divided doses at 0800, 1000, and 1200 h on study days 2 and 4. All meals were uniformly standardized on treatment days. No clinical seizures or other adverse experiences were observed after aspartame ingestion. Mean plasma phenylalanine (Phe) concentrations increased significantly after aspartame ingestion (83.6 microM) as compared with placebo (52.3 microM). Results suggest that aspartame, in acute dosage of approximately 50 mg/kg, is no more likely than placebo to cause seizures in individuals who reported that their seizures were provoked by aspartame consumption.

Fractal analysis of electroencephalographic signals intracerebrally recorded during 35 epileptic seizures: evaluation of a new method for synoptic visualisation of ictal events

Traditional electroencephalography (EEG) produces a large volume display of brain electrical activity, which creates problems particularly in assessment of long periods of intracranial, stereoelectrocephalographic (SEEG) recording. A method for fractal analysis that describes 100 SEEG data points in terms of a single estimate of fractal dimension (1 < FD < 2) is reported; the central processing unit time costs amount to approximately 2 min/Mbyte of input signal (using a Sun SPARCstation LX). The diagnostic sensitivity of this method, applied to quantification and synoptic visualisation of SEEG signals recorded during 35 epileptic seizures in 7 patients, is evaluated. It is found that the method consistently defines ictal onset in terms of rapid relative increase in FD across several channels. Clinically severe seizures are characterised by more intense and generalised ictal changes in FD than clinically less severe events. For all 7 patients, and for 75% of individual seizures, “fractal diagnosis” of anatomically defined ictal onset zone coincided closely with ictal onset zone independently determined by inspection of traditional EEG displays of the same data. We conclude that the method is a computationally feasible way to achieve substantial reduction in the volume of SEEG data without undue loss of diagnostically important information in the primary signal.