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SC-13504 was given intravenously to baboons with photosensitive epilepsy, Papio papio, with and without prior administration of allylglycine. Plasma levels of the drug were determined by differential pulse polarography and correlated with behavioural changes and the anticonvulsant action of the drug. Protection against photically induced seizures or self-sustaining myoclonic responses was seen 30 to 120 min after SC-13504, 4-8 mg/kg (when plasma levels were 1 mug/ml or greater). EEG and neurological signs of toxicity were seen after SC-13504 8 mg/kg but not after 4-6 mg/kg.

Controversy has existed as to the nature of the visual evoked potential in photosensitive epilepsy. Early literature reported that the VEP in photosensitive patients was similar to that seen in other epilepsies1; that it was abnormal and of high amplitude2,3, even when patients’ EEGs were normal4. However, others noted that the presence of seizure activity altered VEP morphology5,6. Chatrianet al 7. found normal responses in 2 pattern-sensitive epileptics during the absence of spike and wave discharge.

Of the 605 patients seen since 1973, 336 patients have been treated with sodium valproate (VPA) alone or in combination with drugs other than carbamazepine (CBZ). Of these 336, 240 have been on monotherapy, of whom 200 are seizure-free. Follow up has been longer than 3 years in 78%. Complete control of seizures has been achieved in more than 80% of patients with absence, myoclonic, and primary tonic-clonic seizures, in 72% of those with photosensitive epilepsy including eyelid myoclonia, and in 47% of partial epilepsies, for which carbamazepine was the initial drug of choice. Only 21% of those with myoclonic astatic epilepsy have become free from seizures. At first VPA was given twice daily, but in recent years it was given once daily, as this was more effective. Reasons for failure of VPA therapy are given. Side effects in 436 patients (100 more patients were added for this assessment only) were uncommon, though where they did occur, weight increase was the most frequent. Platelets were reduced without clinical problems. There were no severe hepatic disorders. Serum levels were assessed in seizure-free patients, and the optimum level was between 60 and 120 mg/L (most patients received between 20 and 30 mg/kg). VPA was given during 30 pregnancies, and there was no evidence of teratogenicity on monotherapy. VPA is most effective in primary generalized epilepsy, especially if given as the sole antiepileptic drug. If the daily dose does not exceed 40 mg/kg or 2.5 g, it is singularly free from serious side effects.

The photoconvulsive effect of photic stimulation on various eye states has been studied, in patients suffering from photosensitive epilepsy as well as in patients with epilepsy and photoconvulsive responses evoked by intermittent photic stimulation (IPS). Particular emphasis has been given to the state of eye-closure i.e. the state immediately following the closure of the eyes. Our findings indicate that IPS is more potent in eliciting photoconvulsive responses during the eye-closure state. IPS with the eyes open is more provocative than with the eyes closed or with monocular stimulation. Electroencephalographic abnormalities induced on eye-closure in the resting EEG are not evoked when eye-closure is performed in darkness, thus indicating that the light is the important factor in the causation of the above EEG abnormalities.

2 observations: enfants atteints d'epilepsie photosensitive, provoquant eux memes les crises convulsives en mettant le feu a des objets et en regardant les flammes

Photosensitivity is the most common mode of seizure precipitation. It is age-related, more frequent in females, and most often found in generalised epilepsies. Little is known about its relation to individual epileptic syndromes. This study on 1062 epileptic patients who had 4007 split screen video EEG investigations revealed that the relation to generalised epilepsy is even more close than generally believed. Versive seizures with visual hallucinations was the only focal seizure type related to photosensitivity. Of the syndromes of generalised epilepsy, only childhood absence epilepsy, juvenile myoclonic epilepsy, and epilepsy with grand mal on awakening were related to photosensitivity. The closest correlation was with juvenile myoclonic epilepsy. This is confirmed by a relation to the poly-spike wave pattern, and by an increase of myoclonic seizures by intermittent light stimuli. No relation was found with early childhood syndromes of generalised epilepsy, or generalised tonic-clonic seizures in the evening, or, most remarkably, with juvenile absence epilepsy. In generalised epilepsies with onset around puberty, photosensitivity could thus act as a pathoplastic factor. The female preponderance in both childhood absences and photosensitivity could be due to the same unknown factor.

The effects of dl -allylglycine, an inhibitor of GABA synthesis, on the responses to photic stimulation were studied in the cat kindled in the lateral geniculate body (GL). For 3 to 8 h after the injection of dl -allylglycine at a subconvulsant dose (30 or 40 mg/kg, i.v.), the kindled cat showed a stable level of photosensitivity without any toxic effects and responded with various degrees of myoclonus or a generalized tonicclonic convulsion when photic stimulation was repeated at hourly intervals. The incidence of photically induced myoclonus reached its plateau during this period. Our results suggest that photosensitivity of the lateral geniculate-kindled cat is related to the modification of GABAergic mechanisms, and that when the GL-kindled cat is pretreated with dl -allylglycine it is a reliable model of photosensitive epilepsy.

Since 1968, annual EEG recordings during photic stimulation using a standardised technique have been made on photosensitive patients and siblings. In 1983, 72 were aged greater than or equal to 20 years and 14 were aged 16-19 years. Mean duration of follow-up was 9.8 +/- 4.8 years. Seventy-five patients were treated with sodium valproate (VPA), which was withdrawn in 15 but restarted in eight because of return of photosensitivity. Eighty-two patients had seizures at some time; at follow-up 58 were receiving monotherapy with VPA, seven were receiving comedication, and three were taking other drugs. Fifty-four of them were seizure free, as were 10 of the 15 who were not being treated with drugs. Photosensitivity disappeared in 44 of 65 patients at a mean dosage of VPA at 21.5 +/- 6 mg/kg day. In 55 of 86 patients photosensitivity was no longer present at follow-up; in 18, slight abnormality was evoked by intermittent photic stimulation, and in 13, photoconvulsive responses were still present. Eighteen patients were not receiving drugs, 10 of them being no longer photosensitive at the mean age of 24.5 +/- 4.9 years. Thirty-one treated and untreated patients were still photosensitive at age 21.5 +/- 3.4 years. Photosensitivity disappeared earlier in those treated with VPA than in the untreated. Spontaneous remission in the treated cases may have occurred at 22.9 +/- 2.5 years of age. Photosensitivity appears around puberty and may disappear around 24 years of age. Photosensitive epilepsy is easily and rapidly controlled by VPA.

Photosensitive epilepsy is interesting partly because it is the most common form of reflex epilepsy, and the discovery of techniques for preventing seizures may be of practical significance, and partly because the visual system is better understood than other sensory systems, and inferences about physiological mechanisms can therefore be made. As will be shown in this chapter, the inferences may help explain not only seizures but also the visual discomfort experienced by people who do not have epilepsy.

Red-coloured flicker is claimed to be more epileptogenic than white or that of other colours matched for subjective intensity. A feature of the colour opponent system is that the response of luminosity-sensitive cortical units to stimulation of ganglion cells of a particular spectral sensitivity is reduced when cells of other sensitivities are simultaneously stimulated. We hypothesized that the apparent effect of colour on photosensitivity was not a property of red light per se but arose simply from the fact that, with commercially available filters a light can be provided to stimulate only red sensitive cones, but owing to the overlap of the absorption spectra of the visual pigments it is difficult to stimulate only green or blue sensitive cones. Such stimulation of a single cone population can be achieved by the 'silent substitution method' which has been used for evoked response studies. In 12 photosensitive epileptic patients we find that, using stimulus intensities (less than 20 nits) at which white flicker is without effect, stimulation of either red or green cones by the silent substitution method may produce epileptiform discharges, there being a slight (and not significant) excess of patients showing a greater sensitivity for green than for red cone stimulation. The findings are considered to support the hypothesis set out above.

The effects of the intravenous or intracerebroventricular injection of the stereoisomers, and the racemic mixture, of allyglycine (2-amino-pent-4-enoic acid) have been studied in baboons, Papio papio , with photosensitive epilepsy. Enhancement of the natural syndrome of photosensitive epilepsy is seen 1–12 h (maximally at 3–8 h) after l -allylglycine, 100 mg/kg, intravenously, or d,l -allyglycine, 200 mg/kg intravenously. Such enhancement is seen with a slower onset, and to a lesser, and more variable, extent after d -allylglycine, 500–750 mg/kg, intravenously. Brief focal or generalised seizures occured (in the absence of intermittent photic stimulation) after l -allylglycine, 150–200 mg/kg, intravenously. This effect is similar to that previously observed after d,l -allylglycine, 300–400 mg/kg. d -Allylglycine, 780 mg/kg, intravenously produced episodes of vertical nystagmus with increased extensor motor tone, but no ‘spontaneous’ seizures. Intracerebroventricuar injection of l -allylglycine, d -allylglycine or d,l -allylglycine, 100 mg in 1 ml saline, did not modify the natural syndrome of photosensitive epilepsy. d -allylglycine, or d,l -allylglycine, 100 mg intracerebroventricularly, after 1–2 h gave rise to a syndrome with vomiting, sustained vertical nystagmus, and intermittent extensor spasms. The results are interpreted in terms of regional differences in the metabolism of the two isomers to active compounds that can inhibit glutamic acid decarboxylase. d -Allylglycine is active only at the brain stem and cerebellum because d -amino acid oxidase is largely confined to these brain areas.

We describe the clinical features of a family with photosensitive epilepsy, followed for 13 years. Generalized paroxysmal discharges induced by photic stimulation appeared in all 9 siblings. Generalized seizures, myoclonic jerks, and absences appeared in variable combination in 7 of them who on clonazepam remained free from seizures for a seven-year follow-up period. On EEG the paroxysmal abnormalities induced by photic stimulation abated during clonazepam medication.

Antagonists of excitation induced by dicarboxylic amino acids have been evaluated for acute anticonvulsant activity in baboons, Papio papio, with photosensitive epilepsy. 2-Amino-7-phosphonoheptanoic acid, 1 mmol/kg, i.v., abolishes myoclonic responses for 5 h. Less prolonged protection is seen after cis-2,3-piperidine-dicarboxylic acid, 1-3.3 mmol/kg; 2-amino-5-phosphonovaleric acid, 1-3.3 mmol/kg; or glutamic acid diethyl ester, 1-3.3 mmol/kg. Toxic side-effects are prominent after the latter two compounds. Antagonists of excitation due to N-methyl-D-aspartate possess acute anticonvulsant activity in a wider range of models epilepsy.

beta-Carboline-3-carboxylic acid ethyl ester (beta-CCE) was tested on two models of epilepsy in the baboon: kainic acid-induced limbic status epilepticus and photosensitive epilepsy. Beta-CCE, at very low doses ranging from 8 to 100 microgram/kg (i.v.), induced a reactivation of the limbic focus and photomyoclonic and generalized seizures in photosensitive and non-photosensitive baboons. The proconvulsant effect of beta-CCE may be associated with its binding to a particular subclass of benzodiazepine receptors.

Senegalese baboons (Papio papio), with a natural syndrome of photosensitive epilepsy, consistently show generalized myoclonic jerks if stimulated stroboscopically at hourly intervals, two to eight hours after the intravenous administration of allylglycine, 200 mg/kg. This provides a model for testing the acute antiepileptic effects of established or new drugs. The relationship between concentration of drug, antiepileptic action, and acute neurological toxic effects can be studied. Pnehobarbital (15 mg/kg) and diazepam (0;5 to 1.5 mg/kg) were highly effective in the absence of signs of toxic reaction (plasma levels: phenobarbital sodium, 0.7 to 1.7 mg/100 ml; diazepam, greater than 0.5 mug/ml). After administration of carbamazepine (30 to 40 mg/kg) and diphenylhydantoin sodium (40 to 50 mg/kg), antiepileptic action was seen, but was accompanied by severe toxic signs (nystagmus and ataxia). Sulthiame (20 to 125 mg/kg) and ethosuximide (50 to 100 mg/kg) had little antiepileptic activity and no acute toxic effects. This primate model may aid the identification of new drugs that are active against grand mal seizures and status epilepticus.

Corpus Callosum Organization and Development: Development of Corpus Callosum H.P. Killackey. The Organization of Callosal Connections in Primates J.H. Kaas. Organization and Development of Interhemispheric Connections of the Prefrontal Cortex in Rhesus Monkey M.L. Schwartz. Ontogeny of Visual Callosal Projections in Primates H. Kennedy, C. Dehay. Experimental Epilepsy: Midline Subcortical Structures for Transhemispheric Ictal and Interictal Transmission J.A. Wada. Forebrain Commissures and Limbic Kindling D.C. McIntyre. Callosal and Thalamic Transection: Effects on Spontaneous and Pentylenetetrazolinduced Absence Seizures in Rats M. Vergnes, C. Marescaux. Role of the Corpus Callosum in the Photosensitive Epilepsy of Baboons Ch. Menini, et al. Clinical Epilepsy: Some Historical Aspects of Callosotomy for Epilepsy J.E. Bogen. Corpus Callosum Section: Preoperative Evaluation P.D. Williamson. EEG Selection for Corpus Callosotomy J.R. Gates. Seizure Types: Results of Partial and Complete Callosotomy in Adults S.S. Spencer, D.D. Spencer. Neuropsychology: Hemispheric Specialization and Interhemispheric Integration: Insights from Experiments with Commissurotomy Patients M.J. Tramo, et al. 14 additional articles. Index.

1. Background 1.1. Characteristics of the EEG in photosensitive epilepsy 1.2. Stimulus parameters 1.2.1. Intermittent light 1.2.2. Pattern sensitivity 1.2.3. Intermittent light vs pattern 2. Photosensitivity as a model of epilepsy 2.1. Advantages of photosensitivity as a model of epilepsy 2.2. Outline of the physiology of the visual system 2.3. Experimental methods in the investigation of photosensitivity 3. Where is the paroxysmal activity triggered? 3.1. Movement of the retinal image 3.2. Stimuli that induced binocular rivalry 3.3. A comoarison of plaid patterns and stripes 3.4. Varying stripe orientation across the visual field 3.5, Alternate stimulation of the two eyes 4. How is paroxysmal activity triggered? 4.1. Varying pattern radius 4.2. Varying sector size 4.3. Varying central and peripheral stimulation separately 4.4. Pattern contrast 4.5. Excitation within a hemisphere 5. A synthesis 5.1. Underlying pathology 5.2. An hypothesis 5.3. Limitations of the hypothesis 5.4. Relationship with other models 5.5. Implications for vision 6. Clinical aspects of photosensitivity 6.1. Television epilepsy 6.2. Pattern-induced seizures 6.3. Self-induced seizures 6.4. Anticonvulsant therapy 7. Conclusion Acknowledgements References

Kindling is traditionally viewed as a chronic, focal epilepsy model which consistently induces complex partial seizures from limbic structures in animals. This study revealed that primary or exceedingly rapid secondary generalized seizures could also be kindled when stimulation was applied to the lateral geniculate nucleus, a thalamic region involved in sleep regulation and possibly also photosensitive epilepsy. Two experiments were conducted in cat. Experiment 1 compared the development of generalized tonic-clonic convulsions and associated sleep disorders following electrical stimulation of the lateral geniculate nucleus ( N = 4) and the amygdala ( N = 4). Experiment 2 described the effects of intermittent light stimulation on seizure thresholds in both groups. Three primary findings distinguished the epileptogenic process in those two brain regions. First, generalized electroencephalographic and clinical seizures accompanied the first afterdischarge obtained with thalamic stimulation. In contrast, focal seizures with secondary generalization appeared during a 3- to 4-week period of afterdischarge elicitations from the amygdala. Second, amygdala-kindled cats showed fewer sleep spindles during slow-wave sleep whereas cats kindled in the lateral geniculate nucleus had abnormal sleep spindles approaching spike wave-like activity. Third, only the latter cats showed reduced seizure thresholds in response to photic stimulation. Based on the anatomic substrates involved, the clinical and electrographic profiles observed during kindling and the type of sleep disturbance shown, we concluded that lateral geniculate nucleus kindling may represent primary generalized epilepsy, possibly of a photosensitive nature; alternatively, the rapid propagation of abnormal discharge was also consistent with the important role of the thalamus in secondary seizure generalization.

Three hundred sixty-two epileptic patients were examined clinically and electroencephalographically to determine the proportion with photosensitive epilepsy or showing photoconvulsive responses to intermittent photic stimulation (IPS). Also, 102 nonepileptic patients had an EEG done to find out the proportion showing photoconvulsive responses to IPS. Ten epileptic patients (2.76%) had photosensitive epilepsy, and six patients (1.6%) showed photoconvulsive responses to IPS. The nonepileptic patients showed no photoconvulsive responses to IPS. The relative rarity of photosensitive epilepsy and the greater incidence of nonreaction to photic stimulation in black African epileptics and nonepileptics compared with Caucasians indicate that black Africans are less photosensitive than Caucasians.

Clonazepam was added to the treatment of patients with poorly controlled epilepsy in a double-blind trial and an open trial. Considerable improvement occurred with patients with myoclonic jerks and tonic-clonic convulsions, and with photosensitive epilepsy. Patients with atypical petit mal and focal epilepsies also improved. Drowsiness was initially common but lasted only a short time. No evidence was found for an action of clonazepam on the metabolism of other drugs, but treatment with phenobarbitone lowered serum concentrations of clonazepam. We conclude that clonazepam is particularly valuable in epilepsy with associated myoclonsu and in photosensitive epilepsy.

Fluorescent tubes flash at twice the mains frequency (100 Hz in Europe). With aging, 50-Hz brightness modulation appears. A survey of tubes used in our institute showed that 42% exhibited brightness modulation up to a depth of 20% or occasionally 30%. The effects of fluorescent lighting on the EEGs of 20 patients with photosensitive epilepsy have been studied. In no patient did the 100-Hz flicker of normally functioning tubes elicit paroxysmal activity. In 8 of 13 subjects sensitive to 50 Hz, IPS paroxysmal discharges were evoked by 50-Hz brightness modulation, but only at modulation depths of 50% or more. It is concluded that as paroxysmal activity could not be elicited by normally functioning tubes nor at those depths of modulation occurring in practice, fluorescent lighting is unlikely to present a hazard to photosensitive patients.

The acute effect of oral administration of a single dose of vigabatrin, a new antiepileptic drug which acts by irreversible enzyme-activated inhibition of the brain enzyme, GABA-aminotransferase, on the photoconvulsive response in patients with photosensitive epilepsy, was compared with that of the established antiepileptic drug, sodium valproate. Both drugs significantly suppressed the photoconvulsive response in 3 out of 6 subjects. This result was interpreted as further evidence of vigabatrin's potential value in the future treatment of patients with epilepsy.

Patients with photosensitive epilepsy were asked to view normally functioning 625-line televisions while the EEG was monitored. In the first of two studies paroxysmal EEG activity was reliably induced by television at a viewing distance related to a patient's sensitivity to intermittent photic stimulation (IPS); patients who were sensitive to diffuse IPS at 50 Hz were sensitive to the television at greater viewing distances than those who were not. No such relationship was obtained with patterned IPS. On the other hand, patterned IPS was generally more epileptogenic than diffuse IPS with the same luminance. In the second study, where the angular subtense of the television screen and the subtense of its lines were manipulated independently, the convulsive response was found to be a function of both factors, the relative contribution of each depending on the viewing distance at which the patient was sensitive. For patients sensitive at normal viewing distances, where 50 Hz diffuse flicker appeared to be responsible for the induction of paroxysmal activity, the probability with which paroxysmal activity was induced was closely related to the subtense of the screen. For patients sensitive only at closer viewing distances the probability was influenced not by the subtense of the screen but by the subtense of its lines, suggesting that the paroxysmal activity was induced by the 25 Hz pattern alternation produced by the scan. A television with a small screen was considerably less epileptogenic than one with a large screen for all patients, presumably due to the reduced contribution of both diffuse flicker and pattern alternation.

1. Evidence relating to the role of GABA in the pathogenesis of epilepsy is reviewed. 2. Impaired GABAergic function appears to contribute to seizure susceptibility in a variety of genetically-determined syndromes in animals, e.g. genetically epilepsy prone rats showing sound-induced seizures, gerbils with genetically determined epilepsy, and baboons, Papio papio, with photosensitive epilepsy. 3. In epilepsy secondary to a cerebral insult there is some morphological and biochemical evidence for impaired GABAergic function in experimental situations, but little definitive evidence in man. 4. Pharmacological approaches to enhancing GABAergic inhibition include the use of GABA agonists (or prodrugs), GABA-transaminase inhibition, GABA uptake inhibition, and action at the GABA/benzodiazepine allosteric site. 5. Experimental data suggest that the best prospect for potent anticonvulsant action with fewest side effects (myoclonus, sedation, ataxia) is at present offered by GABA-transaminase inhibitors or novel agents acting on the benzodiazepine receptor site.

Sodium valproate has been in clinical use for the treatment of epilepsy in Great Britain since 1973 and in the United States since 1978. It is chemically quite different from the existing antiepileptic drugs. Although most authorities concentrate on its modification of GABAergic inhibitory transmission in the central nervous system, its mechanism of action remains obscure. It has been shown to be an effective antiepileptic drug in a wide variety of seizure types, but clinically, its major use to date has been in generalized seizures. It is particularly effective in photosensitive epilepsy and myoclonus. Most adverse reactions to sodium valproate are mild and reversible, but with increasing experience, the drug's rare, idiosyncratic, adverse effects are becoming apparent, particularly hepatotoxicity and teratogenicity. The role of therapeutic drug monitoring in the management of patients taking sodium valproate is controversial.

PATIENTS suffering from photosensitive epilepsy show generalized discharges in their electroencephalogram (EEG) during intermittent photic stimulation. In some patients, these discharges are preceded by occipital spikes, suggesting a focal onset. Hishikawa et al.1 have reported that the occipital spikes obtained in photo-sensitive epileptics have the same latency as some components of the visual evoked responses (VER), and suggested, that this might explain the origin of the occipital spikes in photosensitive epilepsy. The spikes were, however, obtained at flash rates of 10–16 s−1 (that is, the interval between the flashes was limited to a range of 63–100 ms) and the comparison of the occipital spikes was made not with the VER of the individual patient, but with VERs of a normal population. Further, the latencies for positive and negative components of the VER, as given by the authors, show a very wide range and in fact overlap. The relatively small interval between the flashes and the wide range of the VER components could result in a fortuitous relationship between occipital spikes and VER components. It has also been reported by Rodin et al.2 that spikes preceding generalized seizures, induced by ‘Megimide’ during intermittent photic stimulation, were related to normal VERs and consisted of a marked exaggeration of the secondary VER components. Their report, however, is concerned with normal animals (cats); and no details of the photic stimuli and the spikes are given. For these reasons we felt that we should re-examine the problem. The existence of a relationship between abnormal and “normal” responses would be critical to any theory attempting to explain the genesis of the occipital “epileptogenic” spikes.

The course of convulsive disease in 195 photosensitive children was analysed. Of these, 168 were suffering from cerebral seizures and 27 from various other disorders. Only four of the patients occasionally exhibited photogenic seizures. In all the other cases the cerebral seizures occurred independently of intermittent light stimuli. 1. The clinical picture of photosensitive epilepsy varies widely. Virtually all known forms of seizures and courses of illness may be seen. In the group investigated, febrile and afebrile grand mal attacks predominated. Focal seizures and petit mal followed in third and fourth place respectively. 2. Photosensitive epilepsies are more common in females than in males. 3. The course of photosensitive epilepsy is often highly malignant. This applies especially when focal symptoms are present and when the onset of the disease took place after the fifth year of life. 4. A total of 67 per cent of the patients first suffered seizures before the sixth year of life, i.e. before the age of maximum penetrance of photosensitivity. 5. Investigation of the family histories of the patients indicated that the appearance of the disease in early childhood was affected by additional genetic factors, probably independent of photosensitivity itself. 6. Photosensitivity is to be regarded as a symptom of a gene-dependent functional disorder. The activability of this via optic afferents is markedly age-linked.

The responses to intermittent photic stimulation (IPS) at rates of 1–10 fl/sec were studied in seventy-two subjects, eighteen being normal controls, thirty-eight having photosensitive epilepsy and sixteen having epilepsy which was not clinically photosensitive. All patients showed abnormal responses to IPS. In most of the patients photic stimulation evoked negative occipital spikes with or without photoconvulsive responses. Comparison was made between the occipital spikes and the VERs in the same patient. This showed that there was no simple time relation between occipital spikes and components of the VERs. The VERs of the normal subjects showed no component with a latency corresponding to that of the negative occipital spikes seen in the patients. It is suggested that the non-specific thalamo-cortical system may be responsible for the genesis of the “epileptogenic” occipital spikes and that increased sensitivity of the occipital cortex is present in most photosensitive patients.

1.1. Drugs modifying γ-aminobutyric acid (GABA) metabolism have been administered intravenously to baboons (Papio papio) manifesting a syndrome of photosensitive epilepsy. Myoclonic and seizure responses to intermittent light stimulation (ILS) have been observed before and after drug administration and compared with epileptic phenomena directly induced by the drugs. 2.2. Isoniazid (INH), 65–80 mg/kg, increased the tendency to respond to ILS with generalized myoclonus or tonic-clonic seizures. ILS given 30–60 min after isoniazid 100 mg/kg induced seizures which commonly originated asymmetrically in the occipital cortex whereas in animals without drug treatment seizures usually originated in the fronto-rolandic cortex. Seizures occurred spontaneously (i.e., in the absence of ILS) 7–70 min after isoniazid 130–150 mg/kg. Apart from changes associated with the seizures, no acute effects on behaviour were observed and there were no modifications in the background EEG rhythms. 3.3. Enhanced responsiveness to ILS was observed 1–6 h after thiosemicarbazide (TSC), 4–5 mg/kg. Spontaneous seizures with very variable cortical points of origin were observed 1–4 h after thiosemicarbazide 7.5–10 mg/kg. After either TSC or INH it was possible to induce seizures with ILS repeatedly at intervals of a few minutes. 4.4. Pyridoxine administered acutely in doses of 50–250 mg/kg did not diminish the tendency of photosensitive baboons to respond to ILS with generalized myoclonus. Thus the natural syndrome is not due to a dietary deficiency of pyridoxine or to a metabolic disorder leading to an abnormal requirement for pyridoxine. Pyridoxine, 150–300 mg/kg, given before isoniazid, did not modify its seizure-promoting effect. Pyridoxine, 200–250 mg/kg, completely blocked both the spontaneous and the ILS-induced seizures normally produced by thiosemicarbazide, 10 mg/kg. 5.5. Amino-oxyacetic acid (AOAA) (5–15 mg/kg) had a marked protective effect against myoclonus induced by ILS. This effect began 30–40 min after AOAA administration and lasted up to 24 h. Spontaneous or ILS-induced cortical spikes or spikes and waves were not diminished by AOAA. A larger dose of AOAA (20 mg/kg) had a toxic effect, producing convulsions after 15–30 min. 6.6. Drugs lowering brain GABA turnover (INH and TSC) enhance myoclonic responses to ILS and one which raises the brain GABA content (AOAA) blocks myoclonic responses. However, the occurrence of multiple seizures and the shift to an occipital point of origin for the seizures after INH and TSC suggest that it is unlikely that the same biochemical derangement is responsible for the photically-induced and drug-induced seizures. The persistence of spontaneous spikes and waves after AOAA suggests that this drug does not correct the primary abnormality but modifies its clinical expression.

A comparison of the group mean visual evoked potential (VEP), somato-sensory evoked potential (SEP) and electroretinographic (ERG) response was made between photosensitive epileptic subjects and age and sex-matched normal controls. The VEP of epileptic subjects was similar in wave form but differed significantly in a number of other features from that of normals. In the occipital region, components II, III, VI and VII were of larger amplitude, component VI showed a longer latency; and there was a tendency for the response to spread anteriorly to the central electrode. Midline central (vertex) responses were generally dissimilar in wave form from occipital responses and showed greater differences than did occipital potentials between the two groups, all components being of larger amplitude in photosensitive epileptic subjects. There was evidence also for alteration of the ERG in the form of an earlier a wave. The changes indicate participation in photosensitivity of: the retina; visual pathways probably of primary, secondary and associative type; unspecific diffuse projection systems projecting maximally to the vertex; or perhaps local changes of the central cortex. The possibility of contamination of cerebral responses by ERG, eye and muscle potentials was assessed by various recording techniques and, in two cases, by comparing cortex and scalp responses during diagnostic cerebral biopsy. Differential stages of sleep and states of arousal produced quite stereotyped changes of the VEP. The SEP was altered even more than the VEP. Individual components showed marked changes in amplitude, latency and distribution, some having mean amplitudes of up to 8 times normal. It is suggested that “photosensitivity”, at least in epilepsy, represents a diffuse multi-modal alteration in cerebral excitability affecting various levels of different sensory systems.

In eleven patients with photosensitive epilepsy, photosensitivity during various phases of sleep and wakefulness was investigated. During the waking state, epileptiform discharges were promptly induced by intermittent photic stimulation (IPS) in all of the patients. During non-REM sleep, five patients showed no evidence of photosensitivity. The remaining six patients showed some EEG evidence of sensitivity to IPS, but this was reduced remarkably as compared with that in the waking state in five of them. The induced discharges during non-REM sleep were usually most prominent on the anterior regions and were found only in the first cycle of nocturnal sleep. In one patient, prominent epileptiform discharges were induced during non-REM sleep both in the first and last cycles, but IPS failed to induced paroxysmal discharges during non-REM sleep in the other cycles of nocturnal sleep. During REM sleep, all patients except one who was treated with anticonvulsants showed prominent photosensitivity, although this was in many instances relatively reduced as compared with that in the waking state. In some cases the induced discharges were of larger amplitude in the posterior than in the anterior region. Possible explanations for previous conflicting reports on this subject are discussed.

Until recently the experimental study of photosensitive epilepsy was obstructed by a major difficulty, namely the absence in the experimental animal of a syndrome comparable to that in man; indeed such a syndrome could be provoked only by the injection of convulsant drugs.

BOTH central and peripheral mechanisms may be involved in the convulsive response to photic stimulation in certain epileptics. There is disagreement as to whether the abnormal response is mediated by nonspecific (diffuse projecting system) or specific visual afferents. 1,2 The suggestion has also been made that abnormalities may exist at the retinal level because red light was a more effective stimulus than blue or green and also because closing the eyes increased photosensitivity. 3,4 The visually evoked response (VER), as measured from the scalp by an averaging device, is thought to bear some relationship to the visual pathways and to the photopic and scotopic systems. 5 Some have denied any such specificity except for perhaps the earliest component of the VER. 6,7 An increase in the VER has been reported in photosensitive epileptics, especially of the later waves. 8 The electroretinogram is a measure of retinal excitability which might

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.

Photosensitivity is a heritable abnormal cortical response to flickering light, manifesting as particular electroencephalographic changes, with or without seizures. Photosensitivity is prominent in a very rare epileptic encephalopathy due to de novo CHD2 mutations, but is also seen in epileptic encephalopathies due to other gene mutations. We determined whether CHD2 variation underlies photosensitivity in common epilepsies, specific photosensitive epilepsies and individuals with photosensitivity without seizures. We studied 580 individuals with epilepsy and either photosensitive seizures or abnormal photoparoxysmal response on electroencephalography, or both, and 55 individuals with photoparoxysmal response but no seizures. We compared CHD2 sequence data to publicly available data from 34 427 individuals, not enriched for epilepsy. We investigated the role of unique variants seen only once in the entire data set. We sought CHD2 variants in 238 exomes from familial genetic generalized epilepsies, and in other public exome data sets. We identified 11 unique variants in the 580 individuals with photosensitive epilepsies and 128 unique variants in the 34 427 controls: unique CHD2 variation is over-represented in cases overall (P = 2.17 × 10(-5)). Among epilepsy syndromes, there was over-representation of unique CHD2 variants (3/36 cases) in the archetypal photosensitive epilepsy syndrome, eyelid myoclonia with absences (P = 3.50 × 10(-4)). CHD2 variation was not over-represented in photoparoxysmal response without seizures. Zebrafish larvae with chd2 knockdown were tested for photosensitivity. Chd2 knockdown markedly enhanced mild innate zebrafish larval photosensitivity. CHD2 mutation is the first identified cause of the archetypal generalized photosensitive epilepsy syndrome, eyelid myoclonia with absences. Unique CHD2 variants are also associated with photosensitivity in common epilepsies. CHD2 does not encode an ion channel, opening new avenues for research into human cortical excitability.

Television is by nature a flickering medium. It is also designed to convey images that flash or flicker. This paper seeks to characterize the stimulus parameters of broadcast materials that have been responsible for triggering epileptic seizures. Three sources of evidence are considered: the characteristics of flicker and pattern predicted to induce seizures on the basis of clinical studies; the statistics of broadcast images; and the characteristics of video sequences that have been associated with anecdotal reports of seizures. The results of these studies have contributed to a revision, in mid-2001, of a Guidance Note issued by the Independent Television Commission (ITC) in the U.K. seeking to protect, so far as is reasonably practicable, the section of the population that is liable to photosensitive epilepsy.

YG 19-256, 4-(1,3,4,9b-tetrahydro-5 methyl-2H-indeno[1,2-c]pyridine-2-yl)-2-butanone methane sulphonate, 1-3 mg/kg i.v., abolished or reduced photically-induced myoclonic responses for 1.5-6.5 h in baboons, Papio papio, without producing signs of acute neurological toxicity.

3D television (TV) and cinema have experienced a recent surge in popularity aided in part by the success of films such as "Toy Story 3" and "Avatar". In parallel with this trend there have been increasing concerns about the safety of 3D TV and cinema for patients with photosensitive epilepsy. General practitioners, paediatricians and neurologists are being consulted about their opinions on the risk of triggering a seizure. Photosensitive epilepsy occurs in 1 in 4000 of the population but the incidence is higher in people aged 7–19 years. We found little evidence in the literature and confusing advice on various websites. We discuss this evidence in an attempt to clarify the advice that health professionals should be giving on this issue. We conclude that 3D cinema and television are only unlikely to trigger seizures in patients with non-photosensitive epilepsy. In young people with photosensitive epilepsy the risk of triggering a seizure is not greater with 3D TV or cinema than with conventional television, and we suggest means by which this risk can be minimised. We suggest removing 3D glasses when watching conventional TV to prevent the eyes from picking up flicker. Unfortunately there is currently insufficient evidence to draw more formal conclusions and clinical trials would be of great benefit.

Apomorphine, a dopamine receptor agonist, blocked epileptic photosensitivity in patients with primary corticoreticular epilepsy. This effect was not modified by naloxone, a narcotic antagonist, suggesting that apomorphine acts on cerebral dopaminergic receptors. Apomorphine did not block spontaneous spike-and-wave discharges in patients with nonphotosensitive primary corticoreticular epilepsy. The different actions of apomorphine on spontaneous and phot-ically induced spike-and-wave activity suggest that there is a selective dopaminergic mechanism in human epileptic photosensitivity.

Apomorphine, an agonist of dopamine receptors, blocks or significantly reduces photically induced seizures in the baboon (Papio papio). We therefore studied the effect of subcutaneously administered apomorphine in 11 patients with generalized photosensitive epilepsy. Visual evoked potentials were not altered by apomorphine, but in nine patients apomorphine transiently blocked the epileptic photosensitivity for an average of 45 minutes. Therefore, dopaminergic mechanisms play a role in the pathophysiology of human generalized photosensitive epilepsy.