Photosensitivity in generalized epilepsies

YEBEH-05131; No of Pages 9 Epilepsy & Behavior xxx (2016) xxx–xxx

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Targeted Review

Photosensitivity in generalized epilepsies☆ Shervonne Poleon ⁎, Jerzy P. Szaflarski University of Alabama at Birmingham, Department of Neurology and UAB Epilepsy Center, Birmingham, AL, USA

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Article history: Received 27 September 2016 Revised 26 October 2016 Accepted 29 October 2016 Available online xxxx Keywords: Photosensitivity Photoparoxysmal response IGE JME Treatment

a b s t r a c t Photosensitivity, which is the hallmark of photosensitive epilepsy (PSE), is described as an abnormal EEG response to visual stimuli known as a photoparoxysmal response (PPR). The PPR is a well-recognized phenomenon, occurring in 2–14% of patients with epilepsy but its pathophysiology is not clearly understood. PPR is electrographically described as 2–5 Hz spike, spike-wave, or slow wave complexes with frontal and paracentral prevalence. Diagnosis of PPR is confirmed using intermittent photic stimulation (IPS) as well as video monitoring. The PPR can be elicited by certain types of visual stimuli including flicker, high contrast gratings, moving patterns, and rapidly modulating luminance patterns which may be encountered during e.g., watching television, playing video games, or attending discotheques. Photosensitivity may present in different idiopathic (genetic) epilepsy syndromes e.g. juvenile myoclonic epilepsy (JME) as well as non-IGE syndromes e.g. severe myoclonic epilepsy of infancy. Consequently, PPR is present in patients with diverse seizure types including absence, myoclonic, and generalized tonic-clonic (GTC) seizures. Across syndromes, abnormalities in structural connectivity, functional connectivity, cortical excitability, cortical morphology, and behavioral and neuropsychological function have been reported. Treatment of photosensitivity includes antiepileptic drug administration, and the use of nonpharmacological agents, e.g. tinted or polarizing glasses, as well as occupational measures, e.g. avoidance of certain stimuli. © 2016 Elsevier Inc. All rights reserved.

1. Introduction The 1997 “Pokémon® incident” in Japan, which resulted in 685 seizures among viewers, has been integral in reviving general interest and research in photosensitive epilepsy (PSE) [1]. The seizure-provoking scene featured high-contrast, high-flicker, and high-luminance imagery that led to complaints of blurred vision, nausea, headaches, and seizures in both children and adults [1,2]. Although the most widely noted account of seizures provoked by photic stimulation, the “Pokémon® incident” is hardly the first; among the earliest is that of a US television program, “Captain Powers”, which was reported to induce seizures in a male viewer in the 1980s [3]. Photosensitivity (the hallmark of PSE) is characterized by an abnormal EEG response to visual stimuli known as a photoparoxysmal response (PPR). The PPR can, in turn, be described as a pattern of generalized spikes, spike waves, or slow waves predominantly in frontal and paracentral head regions [2,4]. Photoparoxysmal responses are most readily elicited by stimuli containing high-frequency

☆ Support: Division of Epilepsy/UAB Epilepsy Center, University of Alabama at Birmingham. ⁎ Corresponding author at: University of Alabama at Birmingham (UAB) and the UAB Epilepsy Center, Civitan International Research Center, Birmingham, AL, USA. E-mail address: [email protected] (S. Poleon).

flicker (16–25 Hz), high-contrast gratings, and high-luminance color modulation [2,3]. Phtosensitive epilepsy is not an epilepsy syndrome per se, as photosensitivity may present in different clinical conditions including Dravet syndrome, eyelid myoclonia with absences (Jeavons syndrome), juvenile myoclonic epilepsy (JME), and idiopathic occipital photosensitive epilepsy (IOPE) [5]. The PPR has been reported to occur in 0.5–8.9% of healthy individuals; however, the majority of all PPRs are associated with epilepsy [5,6]. Onset of photosensitivity is generally around puberty and it has been found to be 5 times as common in 7- to 19-year-olds when compared to all other age groups [7]. Photosensitivity is 1.5- to 2-times more common in females and such preponderance suggests the influence of genetics and hormones on the pathophysiology of PSE [2,8,9]. Fisher et al. reported the prevalence of photosensitivity to be between 0.3 and 3% of the population, with patients with epilepsy having a 2–14% chance of developing photic-induced seizures [2,10]. Variability among reported values for the prevalence of photosensitivity among patients and healthy individuals has been attributed to a bias in referral populations as well as lack of a strict definition of the condition being reported [2]. According to one study, the highest prevalence of photosensitivity was reported in JME (30.5%), childhood absence epilepsy, CAE (18%), and in West and Lennox-Gastaut syndromes (17.1%) [10]. Considering the dominant role of vision in everyday perception, and current advancements in optics, video game technology, television graphics, and

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Please cite this article as: Poleon S, Szaflarski JP, Photosensitivity in generalized epilepsies, Epilepsy Behav (2016), http://dx.doi.org/10.1016/ j.yebeh.2016.10.040

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pyrotechnics, it is imperative that PSE continue to be a prime target for basic, clinical, and translational research. In this targeted review we pose the following questions: 1. What are the discrete mechanisms underlying photosensitivity in epilepsy? 2. What is the contribution of neuroimaging to our understanding of photosensitive epilepsies? 3. What are the behavioral and psychiatric phenotypes associated with the photosensitive epilepsies? 4. What novel insights into etiology and pathophysiology of photosensitivity are now being made possible through the use of advanced research and analytical techniques? 5. How do these new insights impact or improve the current treatment of photosensitive epilepsies? 2. What are the discrete mechanisms underlying photosensitivity in epilepsy? The precise mechanisms which underscore photosensitivity remain unclear; however, aberrant visual processing of stimuli, cortical excitability, genetics, and structural abnormalities are major factors that contribute to the pathogenesis of PSE [11–18]. Sleep deprivation, alcohol consumption, and emotional stress have also been found to lower seizure threshold and contribute to greater seizure frequency – a phenomenon that is sometimes called pseudo-resistance [19–21]. In the human retina, photoreceptors encode visual stimuli and provide input to bipolar cells (BC) and retinal ganglion cells (RGC). The RGC receptive field center and surround, as depicted in Fig. 1, can be spatially mapped to the photoreceptors which encode chromatic, luminance, and temporal information about the environment [22]. Photoreceptors providing input to the RGC receptive field center and surround have different spectral sensitivities and, thus, respond differently when presented with the same stimuli. This physiological dichotomy in RGC receptive fields is known as an antagonistic centersurround structure [23]. The antagonistic functionality of RGC receptive fields allows for spatiotemporal specificity when processing stimuli containing contrast, flicker, color, and motion. Retinal ganglion neurons responding to stimuli that excite photoreceptors in both the center and surround (different spectral sensitivities) have a diminished response when compared to stimuli that excite photoreceptors in the center only or surround only (same spectral sensitivities) [23]. This diminished response is referred to as center- surround inhibition. Cortical inhibition has been suggested to act as a control mechanism to prevent the spread of epileptic activity in visual cortex, and defective inhibition has been posited to underlie the origin of PPR [24]. Stimuli containing certain patterns, be they chromatic (color), temporal (flicker), or luminance (brightness and contrast) are considered “strong” and consistently trigger high-amplitude VEPs during photic stimulation [25]. Wilkins [26] argued that gratings forming regular

a

b

Fig. 1. Schematic of RGC receptive field center (inner circle) and surround (annulus). There is a greater response to a stimulus that excites photoreceptors at the receptive field center only (a) when compared to a stimulus that excites photoreceptors at the center and surround (b).

patterns contributed to synchronicity in neural responses by eliciting regular responses in large numbers of neurons high-amplitude neuronal synchronicity has in turn, been considered an integral event in epileptogenesis [25]. The thalamus is also believed to play a significant role in the synchronization, regulation, and generalization of neural oscillations [27–30]. Microstructural abnormalities in the thalamus and other key cerebral structures, e.g. putamen, have also been reported in several studies, further underscoring the contribution of structural architecture to photosensitivity [13,16,31]. Moeller et al. found significant thalamic activity, but only when the PPR was associated with generalized tonicclinic seizures (GTCS) [32]. According to the cortical focus theory, the ictogenic focus, once established in the cortex, quickly becomes generalized via thalamic connections as larger neural networks become entrained in the rhythmic oscillatory activity [33–35]. Meldrum et al. proposed that the spread of ictal activity from the seizure locus was facilitated by the compromise of pyramidal cell inhibitory processes secondary to immense excitation, highlighting the role of cortical excitability [36]. In line with this finding, transcranial magnetic stimulation (TMS) studies aimed at elucidating the etiology of PPR reported greater cortical excitability in groups of IGE patients exhibiting PPR when compared to groups of IGE patients not exhibiting the PPR, as well as greater motor excitability in the group exhibiting positive PPR when compared to the control group [12,17]. Genetic studies have found that voltage-gated chloride and sodium channelopathies occur in many IGE syndromes and contribute to hyperexcitability [37], and genes encoding ion channels and other neuronal structures have been implicated in photosensitivity as well. Thus, these studies indicate that genetics play a considerable role in PSE etiology. 3. What is the contribution of neuroimaging to our understanding of photosensitive epilepsies? Neuroimaging studies have provided significant insights into changes in functional connectivity, structural connectivity, blood flow and energy metabolism associated with photosensitivity. In diffusion tensor MRI studies, reduced fractional anisotropy (FA) values reflect impaired microstructural integrity in white matter tracts, reduced fiber density, and reduced myelin integrity [39–42]. Diffusion tensor MRI studies of patients with JME and other IGE syndromes have found FA reductions in key white matter networks including thalamo-frontal regions, corpus callosum, lateral geniculate nucleus, and supplementary motor area [13,16,31,40,43–45]. Furthermore, studies of photosensitive patients revealed increased FA in the ventromedial thalamus and in the ascending limb of the reticular activating system when compared to healthy controls and patients who did not exhibit PPR [44]. Increases in mean diffusivity (MD) have been reported in the genu and body of corpus callosum, as well as bilateral anterior and superior corona radiata [31]. All of the these structures play prominent roles in mediating consciousness, cognitive integration, and sensorimotor integration, and may be involved in other IGE syndromes with high incidences of photosensitivity like JME and CAE [46–48]. A voxel based morphometry (VBM) study of patients with JME and photosensitivity revealed reduced occipital bilateral gray matter volume when compared to patients with JME but without photosensitivity, as well as reduced frontal gyrus and hippocampal volume [49]. However, Hanganu et al. reported greater bilateral thickness in occipital, frontal, and parietal cortices in patients who exhibited PPR compared to patients who did not [50]. Though divergent, the aforementioned findings highlight the variability in anatomical irregularities reported within the photosensitive population [49]. In addition to structural abnormalities, altered functional connectivity has been observed in patients with photosensitive epilepsy [33,35, 51–56]. Resting state fMRI analyses in patients with IGEs have shown reduced functional connectivity between medial prefrontal cortex and posterior cingulate cortex within the DMN when compared to healthy controls [55,57]. The DMN functions to maintain a baseline non-task

Please cite this article as: Poleon S, Szaflarski JP, Photosensitivity in generalized epilepsies, Epilepsy Behav (2016), http://dx.doi.org/10.1016/ j.yebeh.2016.10.040

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attention state as well as consciousness [28,29,46,53]. In absence seizures, GSWD onset is believed to be the key factor in the attenuation of the DMN and this deactivation has been correlated to the changes in attention and consciousness that characterize absence seizures [4,48,58]. Recent studies have reported BOLD increments in frontoparietal areas (most particularly the precuneus-posterior cingulate region) up to 10 s prior to GSWD onset [4,52], as well as BOLD decrements in the DMN after onset [4,51,52,58]. In addition to the DMN, IPS-induced BOLD signal changes were noted in thalami and primary somatosensory cortex (SM1) following early positive responses in the putamen and SM1 [51]. Finally, at least two studies noted variable thalamic nuclei involvement in response to GSWDs: Tyvaert et al. demonstrated centromedian and parafascicular nuclei involvement prior to anterior thalamic nucleus involvement in GSWD generation and Kay et al. documented variable thalamic connectivity with the paracingulate cortex, an area that shows structural differences between patients with IGEs and healthy controls and involvement of which may be associated with poor treatment response [54,60]. Based on these findings, studies have purported that the PPR is a pathogenic phenomenon involving the striato-thalamo-cortical system, and that disruptions in functional organization between motor and other cortical networks could underlie JME and associated clinical conditions. In line with their assertions, Moeller et al., found that occipital, parietal, and frontal networks were indeed involved in the PPR and that the thalamus was involved in the disruption of DMN functionality in absence seizures [32]. Other imaging techniques including positron emission tomography (PET), single photon emission computed tomography (SPECT), and MR spectroscopy have also been used in PSE studies. Baseline SPECT analyses in PSE patients revealed relative hypoperfusion in bilateral frontal, prefrontal, fronto-parietal, and parietal regions in 6 out of 7 patients [61]. During activation, however, all 7 patients showed hyperperfusion in the aforementioned areas alluding to their roles in PPR pathophysiology. In another study, Chiappa et al. using EEG-fMRI combined with MR spectroscopy found elevated baseline lactate levels in occipital cortex, and greater areas of cortical activation in response to intermittent photic stimulation (IPS) in subjects exhibiting PSE when compared to non-PSE controls [62,63]. During IPS, BOLD signal attenuation was reported in perirolandic regions, as well as a decrement in signal intensity in visual cortical areas and posterior cingulate gyrus after completion of IPS. These data suggest abnormal interictal metabolism, as well as increased vascular reactivity, in patients exhibiting photosensitivity [62]. In line with these findings, Naquet et al., in an EEG study on the photosensitive Papio papio baboon, reported significant frontal lobe involvement during myoclonia induced by IPS, which was then followed by paroxysmal EEG discharges [64]. Da Silva et al., using [15O]-H2O PET, described photic driving response in healthy controls and photoparoxysmal response in patients with IGEs exhibiting photosensitivity at 14 Hz. The patient group showed a significant regional cerebral blood flow (rCBF) increase in the hypothalamic region inferior to the left caudate nucleus during the PPR and increased rCBF in the head of the left caudate nucleus, left hippocampus, and left insula during IPS without photoparoxysmal response [65]. Taken together, these studies point to frontal, parietal, and occipital cortical regions as playing fundamental roles in the pathophysiology of photosensitivity. 4. What are the behavioral and psychiatric phenotypes associated with the photosensitive epilepsies? The term photosensitive epilepsy refers to a heterogeneous group of epileptic conditions characterized by photic- or pattern-induced seizures (video games, flicker, TV, color modulation, IPS) [2,5]. Photosensitive epilepsy can be categorized into two broad groups: pure photosensitive epilepsy (40% PSE incidence) and epilepsy with photosensitivity (60% of PSE incidence), and can present clinically in the form of absence seizures, myoclonic seizures, tonic seizures, focal seizures, GTCS [2,6,66].

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• Among photosensitive patients, GTCS are the most common occurring in nearly 100% of pure photosensitive epilepsy patients and 80% of photosensitive individuals [5]. • Absence seizures induced by IPS may show no overt symptoms besides seemingly blank stares and/or eyelid myoclonus [5]. • Myoclonus or myoclonic seizures may be unilateral, bilateral, focal, synchronous, asymmetrical or symmetrical. • Tonic seizures induced by IPS are rare and may either lead to GTCS or may be limited to head jerking or versive posture of the head and eyes [5]. In pure photosensitive epilepsy, seizures exclusively occur in response to photic stimulation as opposed to epilepsy with photosensitivity, where seizures may be spontaneous as well as elicited by photic stimulation [2,5,6]. Pure photosensitive epilepsy includes idiopathic photosensitive occipital lobe epilepsy (IPOE), and photosensitive benign myoclonic epilepsy of infancy has also been suggested to be a part of this group [6]. • Idiopathic occipital lobe photosensitive epilepsy (IOPE) IPOE is a focal onset epilepsy with a prevalence of 0.4%. In IOPE, patients either have only GTCS, or GTCS combined with absence/myoclonic seizures [5,6]. Age at onset ranges from 5 years to 17 years and patients have normal intelligence, neurological examination, structural brain imaging, and EEG background [67]. Ictal symptoms of IOPE include aura (typically colorful moving spots in periphery), blurred vision, nausea, vomiting, deviation of eyes and head, unresponsiveness and epigastric discomfort [67,68]. Distinction between IOPE and photosensitive IGE syndromes is made on the basis of predominant occipital epileptiform activity, as well as occipital aura [67]. • Photosensitive benign myoclonic epilepsy of infancy (BMEI) A 2007 study aimed at characterizing photosensitive BMEI found that age of onset was between 11 and 38 months and that the photosensitive range was generally wide (8–30 Hz). Neuroradiological and psychomotor examinations were generally unremarkable, and clinical manifestations varied from upward deviation of the eyes to myoclonic jerks of the upper torso (shoulders, head) in 2 cases. Interictal EEGs were typified by rare, abrupt GSWD during the awake state (75%) and during sleep (25%) [69]. In epilepsy with photosensitivity, photosensitivity occurs in several syndromes with positive response to IPS reported to range from ≥7.5% in JME to 100% in pure photosensitive epilepsy [5]. • Juvenile myoclonic epilepsy (JME) The most characteristic clinical manifestation of JME is upper body myoclonus, usually within 15–30 min after awakening. They are described as arrhythmic movements which result in dropped objects or simple accidents [5]. A recent study on JME subsyndromes reported that myoclonic seizures were the first seizure type reported (68%), followed by myoclonic seizures preceded by GTCS (30%) in JME probands [70]. Covanis, in a 2005 study, reported that among JME patients, GTCS, absence, seizures, and PPRs occurred in 60%, 48%, and 75% of patients, with onset between 5 and 16 years [5]. Guerrini, however, cites more modest numbers (30–35%) of patients as photosensitive [71]. A neuropsychological study of patients with JME described poorer patient performance in language tasks (both semantic and phonemic word fluency) when compared to healthy controls and siblings [72]. This study also reported that patients with JME were more likely than asymptomatic siblings and controls to report low mood and express traits associated with executive dysfunction. Furthermore, psychological assessment of patients with JME indicated 35% prevalence of one or more psychiatric disorders (19% axis I and 23% personality disorders). In total, 47% of study participants were reported to have a psychiatric disorder during the course of their lives [73].

Please cite this article as: Poleon S, Szaflarski JP, Photosensitivity in generalized epilepsies, Epilepsy Behav (2016), http://dx.doi.org/10.1016/ j.yebeh.2016.10.040

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• Childhood absence epilepsy (CAE) CAE accounts for 10–17% of all childhood-onset epilepsies and is characterized by frequent daily absence seizures in otherwise healthy children. It is more frequent in girls and seizure onset is primarily between the ages of 5 and 7 [74]. Eighteen percent of patients with CAE experience photosensitivity [10] and in some cases, myoclonic jerks may follow absences [75–77]. Despite being previously considered benign, studies have reported CAE-associated cognitive and behavioral deficits [78] particularly in memory, visual attention, and visuospatial skills [79]. Hermann et al. reported diffuse neuropsychological deficits in language, attention, intelligence, executive function, and psychomotor ability in new-onset absence epilepsy, regardless of syndrome [80]. • Juvenile absence epilepsy (JAE) Juvenile absence epilepsy is an IGE syndrome considered to be milder than CAE in that there are fewer absences per day, onset is less abrupt, and there is less profound loss of consciousness [5]. Age of onset is near or at puberty (10–17 years) and patients have unremarkable neurological examinations [74]. Juvenile absence epilepsy is characterized by abrupt, brief, and severe absences accompanied by marked unresponsiveness, and at least 7.5% of patients with JAE have been reported to be photosensitive. Distinction between CAE and JAE is often made on the basis of video and EEG evaluation, as manifestations between the two syndromes are similar due to overlapping features. Neuropsychological distinction between JAE and CAE can be made based on the later seizure onset and less severe cognitive deficits in JAE [74]. Absence status epilepticus (ASE) may occur in 20% of patients with JAE and is, in turn, associated with impairments in memory, awareness, and higher cognitive functions [81]. • Early-onset absence seizures The mean age of onset is 2.3 ± 0.7 years. Early-onset absence seizures may be further categorized into myoclonic (63%) and non-myoclonic absence seizures (37%), and 60% of patients in the myoclonic group are photosensitive [5]. There is a great degree of heterogeneity among absence epilepsies of early onset, however one study reported neuropsychological and behavioral difficulties in 80% of patients including hyperactivity, as well as deficits in attention, language, and visuospatial performance [82]. • Jeavons syndrome (EMA) Eyelid myoclonia is a marked characteristic of Jeavons syndrome, often with upward eye deviation [83]. Spike-and-wave discharges are often irregular and occur immediately after eye closure or IPS [84]. Absences in EMA may present as a transient glare or may also be seen without eyelid myoclonia [5]. Covanis reported that myoclonic jerks other than eyelid myoclonia occur in 34% and 54.5% of children and adults respectively, while GTCS occur in 50% of children and are the most common referral symptom. Photosensitivity, however, was seen in 92% of the study population [5]. Neurocognitive function in EMA has not been well described. In a recent study, EMA patients displayed less-than-average performance in global IQ, processing speed, and verbal learning, but had average performance on nonverbal reasoning and sustained attention neuropsychological tasks [85]. • Epilepsy with GTCS on awakening (or epilepsy with GTCS alone) In this epilepsy syndrome, GTCS characteristically occur during states of awakening, drowsiness, relaxation, and excessive alcohol intake. Age of onset may be from early childhood to adolescence, peaking at or near puberty. Studies report the incidence of PPRs ranged from 13% to 62.5% [5,86]. One study reported no development, cognitive or neurological deficits in their study population, but suggested possible cognitive impairment associated with GSWD onset [87]. • Dravet syndrome (severe myoclonic epilepsy of infancy; SMEI) Dravet syndrome is a rare genetic epileptic encephalopathy in which approximately 30–50% of patients experience photosensitivity [88]. De novo genetic mutations involving ion channels have been found in 80% of cases, and seizure onset commonly occurs before the age of 1. Electroencephalograms and MRIs are typically unremarkable and

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infants are considered to have normal development until onset [89]. Generalized tonic-clonic seizures are often the first seizures reported. However, myoclonic seizures have been found to occur in 85% of children aged 1–5 years. Children suffering from Dravet syndrome develop developmental disabilities, with these disabilities typically showing signs of improvement or stability at or near the age of 6 [89]. Patients with SMEI typically display severe impairment of cognitive functions which are followed by progressive neurological deficits such as ataxia, and paroxysmal movement disorders may also occur [90]. Primary reading epilepsy Primary (idiopathic) reading epilepsy is classified as a localizationrelated form of epilepsy, with age of onset usually 12–19 years [78]. Seizures are elicited by reading (silently or aloud) and in rare cases may be accompanied by alexia and dysphasia [91]. Primary reading epilepsy is also considered to be closely related to JME, and b 10% of patients experience PPRs in response to photic or pattern stimulation [71]. Epilepsy with myoclonic–astatic seizures Also referred to as Doose syndrome, epilepsy with myoclonic-astatic seizures accounts for 1–2% of childhood-onset epilepsies, and onset typically occurs between 7 months to 6 years. However, in 94% of cases, onset occurs before the age of 5 [92]. PPR frequently accompanies astatic seizures and is reported to occur in 11% of patients [5]. In general, especially initially, patients maintain normal cognitive function despite high seizure frequency although severe intellectual disability occurs in some cases. Benign myoclonic epilepsy of infancy This is considered to be the earliest presenting form of IGE characterized by photosensitivity. Onset is often before the age of 1 year and GSWDs are associated with myoclonic jerks. About 10% of children are photosensitive, and this syndrome differs from photosensitive BMEI in that the latter is considered to be a purely photosensitive variant [5,69]. Progressive myoclonic epilepsies (PME) In PMEs, photosensitivity is associated with high-amplitude somatosensory and visual evoked potentials. These epilepsies include myoclonus epilepsy and ragged red fibers (MERRF), Lafora body disease, neuronal ceroid lipofuscinoses (NCLFs), and Unverricht-Lundborg disease. Lafora disease and MERFF are associated with spontaneous occipital seizures and broad sensitivity spectrums respectively, while visual sensitivity in Unverricht-Lundborg disease tends to abate by the second to third decades of life. Visual sensitivity may be characterized by a PPR, but is mostly associated with high-amplitude responses to flicker and flash, and patients with NCLFs may also experience vision loss [71]. Progressive myoclonic epilepsies are associated with behavioral abnormalities such as dementia and ataxia in MERRF, as well as in Lafora body disease [93].

5. What novel insights into etiology and pathophysiology of photosensitivity are now being made possible through the use of advanced research and analytical techniques? Intermittent photic stimulation (IPS) is a standard clinical diagnostic EEG technique for determining photosensitivity [94]. Waltz, in early EEG studies, devised a scale to characterize the ictal abnormalities in response to IPS now referred to as the Waltz classification [95] and diagrammed in Table 1. EEG studies have also highlighted the role of steroid sex hormones in photosensitivity, which have been found to significantly modulate neuronal excitability [96]. In particular, estrogens have been linked to increased seizure susceptibility in catamenial epilepsy, and increments and decrements in photic driving have been recorded during the luteal and pre-ovulatory phases of the menstrual cycle, respectively [96,97]. These findings (role of estrogens) may account for the higher preponderance of PSE in women. Many studies have employed other techniques including optical coherence tomography (OCT), visual evoked potentials (VEP), genome

Please cite this article as: Poleon S, Szaflarski JP, Photosensitivity in generalized epilepsies, Epilepsy Behav (2016), http://dx.doi.org/10.1016/ j.yebeh.2016.10.040

S. Poleon, J.P. Szaflarski / Epilepsy & Behavior xxx (2016) xxx–xxx Table 1 Waltz classification of the photoparoxysmal response (PPR). Waltz type

Description

Type 1

Spikes limited to the occipital lobe and phase locked to stimulus frequency, non-self-sustaining Parieto-occipital spikes with a biphasic slow wave Spikes an slow waves propagating to frontal areas Generalized 2–5 Hz discharges with frontal and paracentral predominance

Type 2 Type 3 Type 4

sequencing, magnetoencephalography (MEG), and transcranial magnetics stimulation (TMS) to study the PPR. In one particular study, TMS was used to induce phosphenes so as to gauge cortical excitability; this study reported that patients who exhibited PPR had lower phosphene thresholds than non-PPR patients [17]. A later study also reported the appearance of phosphenes more frequently among patients with photosensitive IGE when compared to non-photosensitive controls (87.5% vs 46%), and that IGE-photosensitive patients had greater motor and occipital excitability than non-photosensitive controls [12]. Another study concluded that abnormal visuo-motor integration greatly contributed to PPR pathophysiology after findings showed increased motor evoked potential (MEPs) in PPR-positive patients than in controls in response to visual paired associative stimulation (VPAS) [98]. Furthermore, a similar study found that IGE patients who exhibited PPR showed deficits in physiologic inhibition between visual and motor cortices when compared to both healthy controls patients with PPR-negative IGE [99]. This decrement in cortical inhibition is believed to be linked to or the result of cortical excitability in photosensitive patients. Transcranial magnetic stimulation has been used to study and quantify the contribution of cortical excitability in photosensitivity, and genomic sequencing has similarly been applied to illuminate the role of genes in the pathophysiology of IGEs, particularly genes that encode receptors and ion channels. Waltz et al. performed familial studies on 41 patients with photosensitivity and found that 50% of siblings with at least one photosensitive parent were themselves photosensitive [100]. Similarly, Takahashi performed EEGs on siblings of 17 photosensitive patents and also found that 24% of siblings had generalized PPRs in response to stimulation [101]. These findings highlight the genetic contribution to PSE, which may manifest in the form of single nucleotide polymorphisms as reported by Yavuz et al. [18]. A more recent study employed gene sequencing to elucidate the relationship between the CHD2 gene and photosensitivity [15]. The CHD2 gene encodes a chromatin helicase DNA binding protein, which plays a role in chromatin remodeling and mediation of gene expression. Studies found roughly 5 times as many CHD2 variants in photosensitive patients vs healthy controls (95% vs. 19%), with the highest incidence of CHD2 variants being found in patients with Jeavons syndrome. Additionally, the BRD2 gene, which encodes the Bromodomain containing protein-2, has been linked to photosensitivity, as were gene loci 7q32 [102] and 16p13 [103]. In short, photosensitivity is believed to have an autosomal dominant inheritance pattern with age-dependent penetrance, although no major photosensitivity gene has been identified, and meta-analyses have suggested that there is no unique genetic locus responsible for the PPR trait [6,104,105]. Other techniques including magnetoencephalography (MEG) have several advantages including greater ability to localize the sources of EEG activity which allow for its use in epilepsy studies [106,107]. Using this technique, researchers found enhanced gamma band phase synchrony in response to photic stimulation [108]. The gamma band neural oscillations were harmonically related to the IPS frequency, and were thus considered the result of repetitive stimulation and firing of a subset of cortical neurons. The enhancement in gamma band phase synchrony was found to precede PPRs, but was significantly different from the neural activity that preceded non PPR events. Another study was able to differentiate between ictal events that later progressed

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into PPRs and those that did not by analyzing the latencies of the visually-induced responses (phase clustering) [107]. This technique has been used in other studies as well, and could potentially be used as an index for ictal transition in PSE [108]. In line with prior studies on the etiology and localization of ictal changes related to PPR [3], Inoue et al. showed that in patients with electronic screen-induced spikes there was posterior predominance of source dipoles, and additional dipoles were also recorded in the medial temporal lobe as well as supplementary motor area of patients without a history of electronic screen-induced seizures [109]. VEP and OCT studies have also focused on ocular abnormalities within the photosensitive population. Anyanwu and Ehiri studied 212 photosensitive patients to identify ocular abnormalities including optic nerve atrophy (16–17%) as well as optic neuritis (12%) [110]. Similarly, Gomceli et al. reported increased binocular retinal fiber nerve layer thickness in superior ocular quadrants in PPR-sensitive groups when compared to healthy controls [111]. Binocular macular and binocular choroid thickness were found to be significantly decreased in the PPR-positive group. Studies of ocular abnormalities have not been able to link specific structural aberrations to increased incidence of photosensitivity, but findings summarily reiterate the multifactorial nature of photosensitivity. 6. How do these new insights impact or improve the current treatment of photosensitive epilepsies? It is well-established that the larger the IPS sensitivity range, the greater the likelihood of eliciting seizures [20]. Consequently, it is important to employ both clinical and practical approaches to the diagnosis and management of photosensitive epilepsies (Fig. 2). Practical recommendations for persons suffering from PSE include avoidance of rapidly changing lights (e.g., discos or night clubs), excessive alcohol consumption, and sleep deprivation, which have been conclusively linked to greater chance of seizure recurrence in photosensitive persons [6,20]. In many cases, visually-induced seizures are reported when patients are too close to television screens or other visual interfaces. The viewing distance may be increased to a minimum of 3 times the screen width to reduce seizure incidence. Additionally, TV monitors with higher refresh and frame rates (100 Hz as opposed to 50 Hz) may help to reduce sensitivity as 100-Hz flicker rates have been deemed less likely to induce PPRs [8,112]. Monocular occlusion techniques have been shown to reduce stimulus epileptogenicity and can be performed by covering at least one eye so as to reduce the area of the retina involved in stimulus processing. It should be noted that the tendency to close both eyes actually increases the epileptogenicity of the stimulus (especially flicker) as light may diffuse through the eyelids and the area of the stimulated retina may be increased [20,94,113]. Specially designed lens and glasses have also been used to allow for normal television viewing in photosensitive persons. These contain crossed-polarized lenses which are combined with a polarizing sheet over the TV screen- the result of which is that only one eye “sees” the television, while other objects in the environment can be freely observed [20]. Cross polarizing glasses have been used as a nonpharmacological treatment method for PSE, as Kepecs et al. reported that they helped to suppress seizures in 2 out of 3 patients [114]. Blue lenses have also been used in the treatment of photosensitivity, although there is still controversy as to whether they are the most effective color or whether the color of the lens needs to be specific to each individual [20]. Besides using specifically colored lenses, the specially designed Z1 lens which is made of very dark material can be used, as it has been found to abolish PPRs in 76% of patients and reduce them in an additional 18% [115]. In addition to non-pharmacological means, pharmaceuticals e.g. valproic acid (VPA) and levetiracetam (LEV) have been used in the treatment of photosensitivity with varying degrees of success [6,20]. The Birmingham (UK) group of clinicians, after years of research with visual sensitivity, recommended VPA as the drug of choice for treatment of PSE [20,86]. VPA effectiveness has been demonstrated by

Please cite this article as: Poleon S, Szaflarski JP, Photosensitivity in generalized epilepsies, Epilepsy Behav (2016), http://dx.doi.org/10.1016/ j.yebeh.2016.10.040

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Fig. 2. Schematic approach to the diagnosis and treatment of patients with photosensitive epilepsies. BMEI – benign myoclonic epilepsy of infancy; CAE – childhood absence epilepsy; IOPE – idiopathic occipital lobe photosensitive epilepsy; JME – juvenile myoclonic epilepsy; PME – progressive myoclonic epilepsies; PPR – photoparoxysmal response; PSE – photosensitive epilepsy; VI – visually induced.

Harding et al. as they showed that 85% of visually-sensitive patients became seizure-free after VPA treatment [116]. In another study, it was reported to abolish or reduce photosensitivity in 78% of study patients (abolished photosensitivity in 27 out of 50 patients, and reduced photosensitivity in 12 out of 50 patients) [2,117]. Levetiracetam (LEV) has also been found to be effective in suppressing or abolishing PPR [118], and a proof-of-concept drug trial reported that LEV 1000 mg, but not carbamazepine 400 mg, was effective in suppressing

photosensitivity [119]. Similar results were observed with carisbamate [120]. In a more recent proof-of-concept a Kv7 potassium channel agonist was found to reduce the photosensitivity range, suggesting the mitigating role of the Kv7 potassium channels in PPR onset [121]. The diversity in the mechanisms of action among AEDs emphasizes the multifactorial nature of photosensitivity and PPR in particular. In general, VPA followed by lamotrigine (LTG) are most commonly prescribed AEDs in these patients [20]. If neither drug is successful, LEV, clobazam,

Please cite this article as: Poleon S, Szaflarski JP, Photosensitivity in generalized epilepsies, Epilepsy Behav (2016), http://dx.doi.org/10.1016/ j.yebeh.2016.10.040

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or ethosuximide may be prescribed. Although not conventionally used to treat photosensitivity or epilepsy, the drug clomiphene directly addresses the effect of sex hormones in catamenial epilepsy and may be effective in select cases [9]. Care must be taken with AEDs, however, as they have been found to aggravate photosensitivity, as was the case with a young patient on phenytoin [122]. The effectiveness of various AEDs for the treatment of photosensitivity has been explored in several studies [117,119,120,123–125]. For example, Striano et al. reported that in patients with SMEI, there was a reduction in seizure frequency with LEV when compared to baseline [125]. In comparison to carbamazepine (CBZ) in French's study, patients who received LEV had the lowest mean PPR when compared with both placebo and CBZ treatment groups [119]. Additionally, there was no evidence of a significant change in PPR after CBZ or placebo treatment. Another study compared the effects of VPA and vigabatrin, and revealed that both drugs were able to suppress the photoconvulsive response in 50% of patients studied (3 out of 6) [124]. Carisbamate has been reported to be effective in the treatment of PSE [120]. Trenite et al. posited that the effect of carisbamate was dose dependent as photosensitivity was abolished or suppressed in 50% of patients at 500 mg (2 out of 4), 75% of patients at 750 mg (3 out of 4) and 100% of patients at 1000 mg (5 out of 5); photosensitivity was abolished in 77% of all patients (total of 10 out of 13). In short, in patients with spontaneous and photic-induced seizures, AEDs should be evaluated and prescribed accordingly, and use of lenses may be recommended. For patients without epileptic seizures, AEDs are not recommended, but photoprotection (lenses, screens) may be used [6]. Key questions answered 1. What are the discrete mechanisms underlying photosensitivity in epilepsy? Increased cortical excitability, and defective cortical inhibition, as well as thalamic entrainment secondary to spread of ictal activity from seizure locus are are believed to primarily underlie the PPR. These mechanisms in turn, may be rooted in structural and genetic aberrations, as well as exacerbated by factors like sleep deprivation and alcohol consumption. 2. What is the contribution of neuroimaging to our understanding of photosensitive epilepsies? Neuroimaging studies have summarily revealed changes in cortical thickness, as well as reduced white matter tract integrity and DMN functionality in photosensitive patients. Additionally, these studies have highlighted the role of frontal, occipital and parietal cortical regions in the onset and spread of ictal activity associated with photosensitivity. 3. What are the behavioral and psychiatric phenotypes associated with the photosensitive epilepsies? The epileptic syndromes are associated with varying neuropsychiatric phenotypes such as hyperactivity, ataxia, and paroxysmal movement disorders. Deficits in memory, attention, language processing, executive function, and mood have also been reported in patients regardless of syndrome. 4. What novel insights into etiology and pathophysiology of photosensitivity are now being made possible through the use of advanced research and analytical techniques? Transcranial magnetic stimulation has been integral in demonstrating and quantifying both the increased excitability and decreased inhibition believed to mediate photosensitivity, while OCT studies have revealed changes in ocular structure and retinal nerve fiber integrity. Genetic studies have also highlighted gene modifications, and specific gene loci, which may account for PSE incidence, when taken together with the inheritance patterns established by early EEG studies. 5. How do these new insights impact or improve the current treatment of photosensitive epilepsies? Treatment for photosensitivity is primarily through the use of AEDs which help to reduce excitability. VPA, followed by LTG, are the

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first drugs of choice, but nonpharmacological methods may also be undertaken, e.g. use of polarized glasses, darkened Z1 lenses and careful avoidance of certain environmental triggers.

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Please cite this article as: Poleon S, Szaflarski JP, Photosensitivity in generalized epilepsies, Epilepsy Behav (2016), http://dx.doi.org/10.1016/ j.yebeh.2016.10.040