The ‘Photosensitivity Model’ is ( also) a model for focal (partial) seizures

Trenité, Dorothée Kasteleijn Nolst; Genton, Pierre; Brandt, Christian; Reed, Ronald C.

doi:10.1016/j.eplepsyres.2016.11.012

Cited by 25 publications

(15 citation statements)

References 72 publications

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“…The photosensitivity model has been successful in identifying AEDs in early-phase development. 3,7 Previous studies have shown a reduction in photosensitivity with almost all effective AEDs tested, despite differences in mechanisms of action. 1,3,6,7,16,17 In this model, demonstrating a change from placebo confirms delivery of drug to the brain; therefore, it can be used as initial evidence of drug efficacy.…”

Section: Discussionmentioning

confidence: 99%

“…The photosensitivity model has been described extensively. 1–3,12,13 In this model, patients are exposed to IPS before and after placebo/AED intake at hourly intervals over a 3-day period. A standardized stimulation protocol is used to establish photosensitivity thresholds (in Hertz), which are translated into an SPR value in points.…”

Section: Methodsmentioning

confidence: 99%

“…1,2 Photosensitivity or the IPS-induced photoparoxysmal response (PPR) on EEG is commonly associated with generalized epilepsies but can also occur in patients with focal epilepsy. 3,4 Standardized assessment of the PPR can be used as a proof-of-principle model for the assessment of investigational antiepileptic drugs (AEDs) in early clinical development. 1,5,6…”

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confidence: 99%

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Suppression of the photoparoxysmal response in photosensitive epilepsy with cenobamate (YKP3089)

et al. 2019

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ObjectiveTo evaluate the effect of cenobamate in patients with photoparoxysmal-EEG response (PPR) to intermittent photic stimulation (IPS) as proof of principle of efficacy in patients with epilepsy.MethodsIn this multicenter, single-blind study, adults with photosensitive epilepsy, with/without concomitant antiepileptic drug therapy, underwent IPS under 3 eye conditions after a single dose of placebo (day −1, day 2) or cenobamate (day 1; 100, 250, or 400 mg). Complete suppression was a standardized photosensitivity range reduction to 0 over ≥1 time points for all eye conditions. Partial suppression was a ≥3-point reduction over ≥3 testing times vs the same time points on day −1 in ≥1 eye condition. Pharmacokinetics and safety were assessed.ResultsOf 6 evaluable patients, 5 reentered to receive higher doses. Cenobamate 100 mg produced partial suppression in 1 of 3 patients; 250 mg produced complete suppression in 1 of 4 and partial suppression in 4 of 4 patients; and 400 mg produced complete suppression in 1 of 4 and partial suppression in 2 of 4 patients. PPR was consistently reduced on days 1 and 2 (>24 hours after cenobamate) vs day −1 (placebo) with the 250- and 400-mg doses. Area under the plasma concentration-time curve (before dose to last measurable concentration) values between 201 and 400 μg/h/mL resulted in partial suppression in 4 of 6 (66%) patients. Most common adverse events were dizziness and somnolence.ConclusionsThis proof-of-principle study demonstrated that cenobamate is a potentially effective product for epilepsy.ClinicalTrials.gov identifierNCT00616148.Classification of evidenceThis study provides Class III evidence that, for patients with photosensitive epilepsy, cenobamate suppresses IPS-induced PPR.

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Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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confidence: 99%

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Suppression of the photoparoxysmal response in photosensitive epilepsy with cenobamate (YKP3089)

et al. 2019

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“…Studies are needed to further explore the clinical therapeutic significance of the apparent 5.5 min faster CNS penetrance with BRV. the efficacy of single oral doses of potential new ASMs in epilepsy [11][12][13][14][15]. Typically, repeated hourly electroencephalogram (EEG) photosensitivity measures (baseline placebo day, then ASM day, within-patient, separate occasions) have been used.…”

Section: Key Pointsmentioning

confidence: 99%

Rapidity of CNS Effect on Photoparoxysmal Response for Brivaracetam vs. Levetiracetam: A Randomized, Double-blind, Crossover Trial in Photosensitive Epilepsy Patients

et al. 2020

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Introduction Both levetiracetam (LEV) and brivaracetam (BRV) eliminate the electroencephalogram photoparoxysmal response (PPR) in the human phase IIa photosensitivity model of epilepsy. The physiochemical properties of BRV differ from those of LEV, having higher potency and lipophilicity plus 10-to 15-fold greater affinity for synaptic vesicle glycoprotein 2A. Objective We compared the rapidity of the effects of both drugs in the central nervous system (CNS) of patients with photosensitive epilepsy using time to PPR elimination post-intravenous infusion as a pharmacodynamic endpoint. Methods Using a randomized, double-blind, two-period, balanced, crossover design, we tested patients with photosensitive epilepsy with equipotent milligram doses of intravenous LEV 1500 mg versus BRV 100 mg post-15-min intravenous infusion (part 1) and post-5-min intravenous infusion (part 2, same doses). Eight patients per part were deemed sufficient with 80% power to determine a 70% reduction for intravenous BRV:LEV intrapatient time ratio to PPR elimination, with a 0.05 two-sided significance level. Plasma antiseizure medicine concentrations were measured using liquid chromatography/ mass spectrometry. Results Nine patients [six women; mean age 27.8 years (range 18-42)] completed the study; seven of these participated in both parts 1 and 2. In 31 of 32 instances, patients experienced PPR elimination. In mixed-effects model time analysis, BRV eliminated PPRs more quickly than did LEV (median 2 vs. 7.5 min, respectively). However, no statistically significant difference in BRV:LEV time ratio to PPR elimination was observed for two of our multiple primary outcomes: for the 15-min infusion alone (p = 0.22) or the 5-min infusion alone (p = 0.11). However, BRV was faster when we excluded an outlier patient in part 1 (p = 0.0016). For our remaining primary outcome, parts 1 and 2 data combined, the median intrapatient BRV:LEV time ratio was 0.39 [95% confidence interval (CI) 0.16-0.91], i.e., PPR elimination was 61% faster with BRV, p = 0.039. PPR was completely eliminated in ≤ 2 min in 11 patients with BRV and in four patients with LEV. No period or carryover effects were seen. No serious or severe adverse effects occurred. At PPR elimination (n = 16), median plasma [BRV] was 250 ng/mL (range 30-4100) and median plasma [LEV] was 28.35 μg/mL (range 1-86.7). Conclusion Outcome studies directly comparing LEV and BRV are needed to define the clinical utility of the response with BRV, which was several minutes faster than that with LEV. Clinical trials ClinTrials.gov Identifier = NCT03580707; registered 07-09-18

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“…In clinical practice, a prevailing notion remains that photosensitivity in CWE suggests that the clinical diagnosis is idiopathic generalized epilepsy [5], but photosensitivity may occur in association with different epilepsy syndromes and various seizure types [1]. The study of Kasteleijn-Nolst Trenite et al found that PPRs are described in association with focal epilepsy and that clinical signs and symptoms during PPRs can be focal [6].…”

Section: Introductionmentioning

confidence: 99%

A study of the significance of photoparoxysmal responses and spontaneous epileptiform discharges in the EEG in childhood epilepsy

Win

Barnes

Ferrier

et al. 2020

Epilepsy & Behavior

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In clinical practice, there is a prevailing notion that photosensitivity mostly occurs in children with epilepsy (CWE) with idiopathic generalized epilepsy. We investigated the distribution of epilepsy types and etiology in photosensitive children and the associations with specific clinical and electroencephalogram (EEG) variables. Methods: In this retrospective cohort study, clinical data were acquired from all children that showed photosensitivity during systematic intermittent photic stimulation (IPS), over a 10-year interval at a tertiary level Children's Hospital, Winnipeg. Patient demographics, EEG findings, and clinical data and symptoms during IPS were abstracted. Classification of diagnoses using the International League Against Epilepsy (ILAE) 2017 guidelines was done by an expert panel. Results: Seventy-eight photosensitive children were identified. Forty (51.3%) had generalized epilepsy (idiopathic: 27, structural: 2, other: 11) compared with 19 (24.4%) focal (idiopathic: 1, structural: 2, other: 16), 8 (10.3%) combined focal and generalized (structural: 4, other: 4), and 11 (14.1%) unknown epilepsy (other: 11); (χ 2 (3) = 32.1, p = .000). Self-sustaining or outlasting photoparoxysmal responses (PPRs) occurred in association with all epilepsy types; however, the EEGs of focal CWE without treatment comprised almost solely of PPRs which outlasted the stimulus (8/10), in contrast to only 8/17 of focal CWE with treatment and to 13/26 of generalized epilepsy without treatment. Most frequency intervals in individual patients were less under treatment: a decrease in standardized photosensitivity range (SPR) was seen in 5 CWE, an increase in 2, and no change in 1 during treatment. Both CWE with focal and generalized epilepsy showed abnormal activity on EEG during hyperventilation (40% vs 65.7%). Thirteen out of 14 CWE with clinical signs during IPS had independent spontaneous epileptiform discharges (SEDs) in the EEG recording. Conclusion: Photosensitivity occurs in all types of epilepsy rather than in idiopathic generalized epilepsy alone. Surprisingly, there is a tendency for focal epilepsy to be associated with self-sustaining PPRs, especially when no treatment is used. Treatment tends to make the PPR more self-limiting and decrease the SPR. There is a tendency that clinical signs during IPS occur in EEGs in individuals with SEDs.

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The ‘Photosensitivity Model’ is ( also) a model for focal (partial) seizures

Cited by 25 publications

References 72 publications

Suppression of the photoparoxysmal response in photosensitive epilepsy with cenobamate (YKP3089)

Suppression of the photoparoxysmal response in photosensitive epilepsy with cenobamate (YKP3089)

Rapidity of CNS Effect on Photoparoxysmal Response for Brivaracetam vs. Levetiracetam: A Randomized, Double-blind, Crossover Trial in Photosensitive Epilepsy Patients

A study of the significance of photoparoxysmal responses and spontaneous epileptiform discharges in the EEG in childhood epilepsy

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