Photosensitivity and self-induction in patients aged 50 and older.

OBJECTIVE: Photosensitivity is known to occur predominantly in children and adolescents and with a clear female predominance. Little is known on the prevalence of photosensitivity in older patients (50+) and its phenotypical appearance. METHODS: A retrospective observational study was performed investigating the prevalence of a photoparoxysmal EEG response (PPR) on at least one EEG during the period 2015-2021. Data were gathered from patients aged 50 years and older by retrieving clinical and EEG characteristics from existing medical records. Data on photosensitivity-related symptoms in daily life were gathered with telephone interviewing. RESULTS: In 248 patients a PPR had been elicited, of whom 16 patients (6.5%) were 50 years or older. In older patients, photosensitivity was a persistent feature of childhood-onset epilepsy (n = 8), of adult-onset epilepsy (n = 7), or an incidental finding (n = 1). In the 50+ group, 56% of photosensitive patients was female, whereas 72% in the total PPR-group. In six of 16 older patients, eye closure sensitivity was observed; two of these patients reported self-induction. Symptoms of photosensitivity in daily life were present in eight out of nine patients who consented in a telephone interview. For seven of these patients, wearing sunglasses was helpful. SIGNIFICANCE: Female preponderance for photosensitivity was not found in epilepsy patients of 50 years and older. In 44% of the older photosensitive patients in this series, the PPR was a feature of adult-onset epilepsy. Symptoms of photosensitivity in daily life in older patients with epilepsy seem comparable to those in younger patients, and thus worthwhile to diagnose and treat them equally.

"Headache and epilepsy"--how are they connected?

The relationship between headache and seizures is a complicated one, since these two conditions are related in numerous ways. Although the nature of this association is unclear, several plausible explanations exist: the two disorders coexist by chance; headache is part (or even the sole ictal phenomenon) of seizures or the post-ictal state; both disorders share a common underlying etiology; and epilepsy mimics the symptoms of migraine (as in benign childhood epilepsy). Seizures and headaches as well as their respective primary syndromes (epilepsy and headache/migraine) share several pathophysiological mechanisms. These mechanisms especially involve neurotransmitter and ion channel dysfunctions. Also, photosensitivity seems to play a role in the connection. In order to improve the care for patients with a clinical connection between migraine and epilepsy, it is necessary to try to understand more accurately the exact pathophysiological point of connection between these two conditions. Both experimental and clinical measures are required to better understand this relationship. The development of animal models, molecular studies defining more precise genotype/phenotype correlations, and multicenter clinical studies with revision of clinical criteria for headache/epilepsy-related disorders represent the start for planning future translational research. In this paper, we review the relationship between migraine and epilepsy in terms of epidemiology and pathophysiology with regard to translational research and clinical correlations and classification.

Ictal headache and visual sensitivity.

Migrainous headache is reported by patients with photosensitive epilepsy, whereas their relatives complain more often about headache than the relatives of patients with other types of epilepsy. We therefore investigated whether headache itself could be an epileptic symptom related to photosensitivity. Four probands with headache and photosensitive epilepsy were selected. Their first-degree family members were studied using video-EEG with extensive intermittent photic stimulation and pattern stimulation. Nine of the 12 subjects (10 female and two male, mean age 30 years, range 14-46 years) proved to be photosensitive with either focal (n = 5) or generalized (n = 4) epileptiform discharges. In two subjects an ictal recording of headache occurred after visual stimulation. We found evidence that, in specific patients, headache could be an ictal sign of epilepsy. Photic stimulation during EEG recording can contribute to correct diagnosis and lead to the best care and management of the patient.

Photosensitivity in epilepsy. Electrophysiological and clinical correlates.

Photosensitivity is a rare phenomenon found, often more or less accidentally, in approximately 5% of epileptic patients. Its pathophysiology still remains largely unsolved and the clinical significance of photosensitivity is controversial. The literature on the subject is impressive, yet predominantly anecdotal. In this thesis we describe the results of an extensive and standardized study of 100 consecutive photosensitive patients with special emphasis on the clinical history, the seizure history and the electrophysiological findings. These are then compared to identical data of an age and sex matched control group, obtained from the same population of epileptic patients, referred to a special (tertiary care) epilepsy clinic. In chapter I, the literature is reviewed and photosensitivity as a special form of "reflex epilepsy" is discussed. A distinction is made between normal and abnormal reactions on intermittent photic stimulation (IPS) during electroencephalographic (EEG) registrations and the criteria of true photosensitivity are formulated. The relation between the presence of photosensitivity during EEG examination and the occurrence of visually-induced epileptic seizures in daily life is discussed. As self-induction of seizures has been associated with photosensitivity, an extensive review, including a special reference list (see appendix A), is given concerning such self-inducing behaviour in photosensitive patients. A review of photosensitivity as a genetic marker and model of epilepsy concludes this chapter. In chapter II the aims of this study are outlined. Some general conceptions about photosensitive epilepsy have become widely accepted in clinical practice without much scientific support, i.e., the idea that the finding of photosensitivity is synonym with the diagnosis of primary generalized epilepsy. Furthermore, photosensitivity is generally believed to be a genetically determined, benign type of epilepsy in childhood and adolescence but when associated with self-inducing behaviour is interpreted as a sign of mental subnormality. Whether or not these conceptions are valid and whether photosensitivity is or is not a special subtype of epilepsy remains unsolved. In this study we thus set out to answer the following questions: A. Are photosensitive epileptic patients different from non-photosensitive patients with epilepsy, with respect to clinical history and, more specifically, to seizure history and family history for seizures? B. Is the degree of photosensitivity, established as photosensitivity range, predictive for the liability to visually-induced seizures in daily life? Are detailed laboratory findings concerning sensitivity to television and black-and-white striped patterns of clinically predictive value, e.g. can patients, liable to TV epilepsy or pattern-induced seizures, be identified by EEG investigations?

Epilepsy provoked by television and video games: safety of 100-Hz screens.

Television (TV) and video games (VG) can provoke seizures in patients with photosensitive epilepsies. Flicker frequency is the most important factor in screen activation. We tested conventional 50-Hz versus 100-Hz monitors during TV viewing and VG playing in 30 photosensitive subjects, 23 of whom had a history of TV or VG seizures or both. Fifteen subjects' discharges were activated by 50-Hz TV; 17 by 50-Hz VG; and one by a 100-Hz screen. Thus, 100-Hz screens protect against screen activation.

Dispensing epilepsy medication: a method of determining the frequency of symptomatic individuals with seizures.

We estimated the prevalence and incidence of epilepsy in The Netherlands using drug-dispensing information from the PHARMO database, containing medication histories of nearly 300,000 individuals. An algorithm based on antiepileptic drug prescription records was used to identify patients with epilepsy requiring medication for seizure control. The algorithm was validated by comparing positive algorithm identifications to medical diagnoses from general practitioners and hospital records. In 1990-1991, the algorithm revealed 1158 patients with "certain" epilepsy, and 451 patients with "probable" epilepsy. Epilepsy was present in 93% of patients on polytherapy, and 58% on monotherapy. Clonazepam monotherapy was non-specific for epilepsy. The use of carbamazepine monotherapy for epilepsy was age-dependent. After correcting the algorithm for these drugs, and standardizing to the Dutch population, the point prevalence of epilepsy was 4.8/1000 (95% CI: 4.5-5.0). The incidence rate was 0.72/1000 person-years (95% CI: 0.65-0.79). Using drug-dispensing data for epilepsy medication, it is possible to make valid estimations of the number of epilepsy patients requiring drug therapy.

Photosensitive epilepsy: a model to study the effects of antiepileptic drugs. Evaluation of the piracetam analogue, levetiracetam.

The experimental antiepileptic drug, levetiracetam (UCB L059), a piracetam analogue has been investigated in photosensitive patients in the "photosensitivity model", an early phase II study. A total of 12 patients (10 females, 2 males) with a mean age of 21.5 years (range 13-38) were investigated during a 3 day period in 3 centres (France, The Netherlands, Germany), using the same standardised method. The subjects were either treated with a single oral dose of 250 mg, 500 mg, 750 mg or 1,000 mg. In addition, 4 patients took 250 mg b.i.d. for 3-5 days, after which they were re-examined. In 9 of 12 photosensitive patients (75%) a clear suppression (3 patients) or abolishment (6 patients) of IPS evoked photoparoxysmal EEG responses was found. This effect appeared to be dose-dependent, the higher the dose the greater the effect; complete abolishment was only seen at dosages of 750 mg and 1,000 mg, occurring at peak plasma levels and lasting between 6 and 30 h. There was no indication of pharmacokinetic interaction with concomitant antiepileptic drugs such as valproic acid, ethosuximide or phenobarbitone. No serious side-effects were seen and some patients reported enhancement of their mood. Two patients with myoclonic jerks noticed a clear reduction of their myoclonus, although this was not one of the objectives of the study. In conclusion, levetiracetam showed a clear antiepileptic effect in the photosensitivity model.

Interactions of epileptiform EEG discharges and cognition.

Interactions of subclinical epileptiform EEG discharges and cognitive functioning were studied in 91 patients with epilepsy, under video monitoring, to exclude overt clinical ictal phenomena during the investigations. A short-term memory test was presented as an engaging television game, in two versions, using spatial, or verbal material. Transitory cognitive impairment (TCI) was demonstrated during EEG discharges, either generalised or focal, in half the patients. Right-sided discharges were associated with impairment of the spatial task and left-sided with errors on the verbal version. TCI was demonstrable only when the discharge occurred during presentation of the material to be recalled. Increasing task difficulty, up to the patients' limit of performance, was associated with increasing susceptibility to TCI. Sixteen patients showed a significant effect of task on discharge rate, but in some this increased during the stimulus and in others while responding. There are thus complex interactions of epileptiform EEG activity on cognitive function and vice versa.

Psychological effects of subclinical epileptiform EEG discharges. I. Scholastic skills.

The possible effects of subclinical epileptiform EEG discharges on educational skills have been studied. Twenty children with proven or suspected epilepsy and known subclinical EEG discharges underwent telemetric EEG and video monitoring during standard tasks of reading, mental arithmetic and manual dexterity, and at rest. The discharge rate was significantly lower at rest than during execution of a task. For both reading and arithmetic, the discharge rate was higher when the child was presented with material appropriate to his own level of ability than when easier or more difficult material was given. High discharge rates were associated with low test performance particularly for arithmetic. Reading speed was significantly increased during the discharges, but overall reading efficiency was significantly reduced with respect to the non-discharge condition. The decrement of reading efficiency was greater for longer than for shorter discharges. The findings confirm that otherwise subclinical EEG discharges may be accompanied by momentary impairment of scholastic skills. The interaction between discharges and cognitive function is, however, complex and the nature and level of difficulty of the task in turn affects the rate of EEG discharge.

Psychological effects of subclinical epileptiform EEG discharges in children. II. General intelligence tests.

Twenty-one children with suspected or proven epilepsy and subclinical epileptiform EEG discharges in the waking state were studied. The EEG was telemetered and behaviour recorded by closed-circuit television during performance of a general intelligence test (RAKIT, shortened version) which comprised 6 subtests. Mean total IQ was below that of control populations and the subtests profile was abnormal, due particularly to impaired performance on a subtest concerned with verbal short-term memory. This effect was accounted for by that subgroup of children who exhibited discharges during the test; those who did not show discharges at that time were unimpaired. Performance of 3 of the subtests was impaired when discharges occurred during presentation of the test item or between presentation and response. The findings suggest that cognitive impairment found in people with epilepsy may not only represent a more or less static disability, due to drugs, cerebral pathology, etc., but may in part be an intermittent process related to the occurrence of subclinical epileptiform discharges. These preliminary findings need to be amplified but have implications both for interpretation of neuropsychological studies in persons with epilepsy and also for the drug treatment of those who continue to exhibit subclinical EEG discharges when overt seizures have been controlled.

Transient cognitive impairment during subclinical epileptiform electroencephalographic discharges.

Short epileptiform discharges of 10 seconds or less in children with or without epilepsy are not noticed by clinical observation of the child. These so-called subclinical discharges can however disturb cognition and influence daily performance at school and at home. Several studies have been performed to show the negative effect of these epileptiform electroencephalographic (EEG) discharges on choice reaction time tests, short term memory tests (verbal and nonverbal), and on school performance tasks such as reading, writing, and arithmetic. About one-half of children with subclinical discharges will show transient cognitive impairment during these discharges; those with predominantly left-sided discharges are poorer on reading and those with right-sided discharges are poorer on visual spatial tasks. Suppression of the EEG discharges with the antiepileptic drug valproic acid improved cognitive performance in two of six children; failure was because of side effects of the drug or insufficient suppression of the discharges. In individual cases, suppression of the epileptiform EEG discharges can be beneficial. Evaluation of this effect is necessary by standardizing EEG and cognitive performance measures. Furthermore, the phenomenon of transient cognitive impairment (TCI) must be taken into account when evaluating results of psychological tests.

Video games are exciting: a European study of video game-induced seizures and epilepsy.

BACKGROUND: Video game seizures have been reported in photosensitive and non-photosensitive patients with epilepsy. The game Super Mario World, has led to many cases of first seizures. We examined whether this game was indeed more provocative than other programs and whether playing the game added to this effect. METHODS: We prospectively investigated 352 patients in four European cities, using a standard protocol including testing of a variety of visual stimuli. We correlated historical data on provocative factors in daily life with electroencephalographic laboratory findings. RESULTS: The video game, Super Mario World proved more epileptogenic than standard TV programs and as provocative as programs with flashing lights and patterns. Most striking was the fact that video game-viewing and-playing on the 50 and 100 Hz TV was significantly more provocative than viewing the standard program (P < 0.001, P < 0.05 respectively). Playing the video game Mario World on a 50 Hz TV, appeared to be significantly more provocative than playing this game on the 100 Hz TV (P < 0.001). Of 163 patients with a history of TV-, VG- or CG-seizures, 85% of them showed epileptiform discharges in response to photic stimulation, 44% to patterns, 59% to 50 Hz TV and 29% to 100 Hz TV. CONCLUSIONS: Children and adolescents with a history of video game seizures are, in the vast majority, photosensitive and should be investigated with standardised photic stimulation. Games and programs with bright background or flashing images are specifically provocative. Playing a video game on a 100 Hz TV is less provocative [published with videosequences].

Whole-genome linkage scan for epilepsy-related photosensitivity: a mega-analysis.

Photoparoxysmal response (PPR) is considered to be a risk factor for idiopathic generalised epilepsy (IGE) and it has a strong genetic basis. Two genome-wide linkage studies have been published before and they identified loci for PPR at 6p21, 7q32, 13q13, 13q31 and 16p13. Here we combine these studies, augmented with additional families, in a mega-analysis of 100 families. Non-parametric linkage analysis identified three suggestive peaks for photosensitivity, two of which are novel (5q35.3 and 8q21.13) and one has been found before (16p13.3). We found no evidence for linkage at four previously detected loci (6p21, 7q32, 13q13 and 13q31). Our results suggest that the different family data sets are not linked to a shared locus. Detailed analysis showed that the peak at 16p13 was mainly supported by a single subset of families, while the peaks at 5q35 and 8q21 had weak support from multiple subsets. Family studies clearly support the role of PPR as a risk factor for IGE. This mega-analysis shows that distinct loci seem to be linked to subsets of PPR-positive families that may differ in subtle clinical phenotypes or geographic origin. Further linkage studies of PPR should therefore include in-depth phenotyping to make appropriate subsets and increase genetic homogeneity.

Evaluation of brivaracetam, a novel SV2A ligand, in the photosensitivity model.

OBJECTIVE: To assess the activity of brivaracetam, a novel SV2A ligand, in the photosensitivity model as a proof-of-principle of efficacy in patients with epilepsy. METHODS: A subject-blind placebo-controlled study in patients with photosensitive epilepsy was performed to investigate the effect of single-dose brivaracetam (10, 20, 40, or 80 mg) on photosensitive responses. Each patient was exposed to intermittent photic stimulation that evoked a generalized photoparoxysmal EEG response. Individual standard photosensitivity ranges (SPRs) were recorded post-placebo (day -1) and post-brivaracetam until return to baseline (day 1 to 3). Plasma concentrations of brivaracetam and any concomitant antiepileptic drugs were determined. RESULTS: Of the 18 evaluable patients, none achieved SPR abolishment post-placebo, whereas 14 (78%) achieved complete abolishment post-brivaracetam. Decrease in SPR was seen in 8 patients (44%) post-placebo compared to 17 (94%) post-brivaracetam. Duration of response was twice as long post-brivaracetam 80 mg (59.5 hours) compared with lower doses, although the overall effect was not dose-dependent. Time to maximal photosensitive response was dose-related with the shortest time interval observed at the highest dose (0.5 hours post-brivaracetam 80 mg). The area under the effect curve (SPR change from pre-dose vs time) appeared linearly correlated with the area under the plasma concentration curve. Brivaracetam was well tolerated. The most common adverse events were dizziness and somnolence. CONCLUSIONS: Our findings show that brivaracetam clearly suppresses generalized photoparoxysmal EEG response. As such, investigations of the antiepileptic properties and tolerability of brivaracetam are warranted in further clinical studies of patients with epilepsy.

Levetiracetam: a long-term follow-up study of efficacy and safety.

OBJECTIVES: To evaluate the efficacy and safety of long-term add-on treatment with levetiracetam 1,000-4,000 mg/day. PATIENTS AND METHODS: In this multicenter, open-label follow-up study, 505 patients, from 10 European countries, who had benefited from previous add-on treatment with levetiracetam in a clinical trial or compassionate-use program were enrolled; 274 (54.3%) stayed to the end. Most then continued levetiracetam by prescription or in a named patient program, where it was not yet commercially available. Mean treatment duration was 1,045 days (range: 24 days to >7 years). Median daily dosage was 3,000 mg/day (range: 250-6,000 mg/day), with 250 (49.5%) patients receiving levetiracetam for >3 years. RESULTS: Median total and partial seizure frequency per week over the evaluation period were 0.8 and 0.7; seizure frequency per week was generally stable over time and remained low. There was a probability of 6.6% of remaining seizure-free for the first 3 years, and of 18.9% of having a seizure-free period of at least 3 years at any time. Most adverse events were mild or moderate and unrelated to study drug. Levetiracetam was well tolerated, and provided stable seizure control during long-term treatment.

Discussion of the AED workshop.

An overview is given of the different issues that have been discussed, with subsequent recommendation. Standardisation of measurement and reporting of efficacy parameter and side-effects is essential; not only the number of patients achieving complete seizure controlled or have a decrease in seizure frequency and severity should be mentioned but also the number who dropped out and the reasons therefore. More information is needed on the teratogeneticy of a drug, either by performing control trials or by registration of all pregnancies with new anti-epileptic drugs. Appropriate bio-marker for efficacy and toxicity should be developed. Health-related quality of life scales, collecting both subjective and objective information should be developed and used as complimentary tools in understanding more about the disease. A drug that improves the quality of life but is less effective in suppressing seizures should be marketed. Finally, pharmaco-economic studies should be encouraged in the field of epilepsy.

Photic stimulation: standardization of screening methods.

PURPOSE: Differences in methodology of intermittent photic stimulation within and between countries in Europe make collaborative research and interpretation of results difficult. METHOD: Experts in the field of photic stimulation from European countries have given an overview of methods used in routine photic stimulation. A consensus meeting was organized in May 1996 in the Netherlands. RESULTS: Methodology, including specification of a photo stimulator, procedure of photic stimulation, and interpretation of EEG results, has been defined according to available scientific and clinical knowledge. CONCLUSIONS: Consensus was reached in setting up a safe, quick, simple and reliable method to determine whether or not patients are photosensitive. A specification of an international standard for intermittent photic stimulation in the routine EEG examination is given with the purpose of improving patient care and facilitating collaborative research.