Seizure 35 (2016) 36–40
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Optical coherence tomography parameters in patients with photosensitive juvenile myoclonic epilepsy Yasemin Bicer Gomceli *, Berna Dogan, Fatma Genc, Elif Uygur, Deniz Turgut Coban, Abidin Erdal, Muhammed Kazım Erol Uncalı mah. 30. Cad. Binbirgece konakları E blok No:7, Konyaaltı, Antalya, Turkey
A R T I C L E I N F O
A B S T R A C T
Article history: Received 23 October 2015 Received in revised form 23 December 2015 Accepted 25 December 2015
Purpose: Juvenile myoclonic epilepsy (JME) is commonly associated with photoparoxysmal response (PPR) with a reported prevalence of 25–42%. In this study, we aim to explore the relationship between the PPR and Optical Coherence Tomography (OCT) parameters in order to determine whether optic nerve fiber layer or other structural differences have a pathophysiological role of photosensitivity in patients with JME. Methods: We studied 53 consecutive patients with Juvenile myoclonic epilepsy (JME) at our outpatient department. The interictal electroencephalogram (EEG) findings for each patient were analyzed for the presence of photoparoxysmal features. The peripapillary Retina Nerve Fiber Layer (RNFL) thickness, ganglion cell thickness, macular thickness and choroid thickness levels were analyzed using OCT. Results: We classified the patients into two groups as those with PPR (Group 1) and those without PPR (Group 2). There were statistically significant differences in the average RNFL thickness values of the left eye between the two groups (p < 0.001). Although the RNFL thickness of the right eye was higher in Group 1, no statistically significant difference was observed between the two groups. The RFNL thickness of the superior quadrants both in the right and the left eyes was significantly higher in Group 1 patients (p < 0.001). Macular thickness of the right and left eyes were significantly thinner in Group 1 patients (p < 0.001). Choroid thickness of the left eye was significantly higher in Group 1 than in Group 2 patients (p < 0.001). Although the choroid thickness of the right eye was higher in Group 1 patients, no statistically significant difference was observed between the two groups. Conclusion: This is the first study to our knowledge which has investigated the relation between the OCT parameters and photosensitivity in patients with JME. We concluded that these microstructural features may be related to photosensitivity in patients with JME. ß 2015 British Epilepsy Association. Published by Elsevier Ltd. All rights reserved.
Keywords: Retinal Nerve Fiber Layer EEG Photoparoxysmal EEG response Generalized epilepsy.
1. Introduction JME is a hereditary, generalized form of epilepsy and is estimated to account for approximately 10% of all epilepsies, with a range of 4–11% [1]. Seizures have an age-related onset and are characterized by the triad of myoclonic jerks on awakening, generalized tonic–clonic seizures (GTC) and typical absence seizures. Photosensitivity or photoparoxysmal response (PPR) is defined as the presence of an abnormal response to intermittent
Abbreviations: OCT, optical coherence tomography; RNFL, retina nerve fiber layer; JME, juvenile myoclonic epilepsy; PPR, photoparoxysmal response. * Tel.: +90 505 575 77 34; fax: +90 242 249 44 62. E-mail address: [email protected] (Y.B. Gomceli).
photic stimulation (IPS) during an EEG [2] and [3]. Different patterns of PPR were determined as ranging from a localized form of occipital spikes (Grade 1) to the generalized spikes-and-waves or polyspike waves (Grade 4) [4–6] (Table 1). The context of photosensitivity and epilepsy reveals diverse clinical situations. Patients may have seizures that are entirely (or predominantly) visually stimulated, which is sometimes described as ‘‘pure photosensitive epilepsy’’ [7]. By way of alternative, the patient may reveal photosensitivity as an EEG response to IPS in the laboratory and the epilepsy may be with or without visually induced seizures [8]. Among the various syndromes, JME is commonly associated with PPR with a reported prevalence of 25– 42% [9]. OCT is a non-invasive technique for cross-sectional imaging of the retinal microstructure and it has been used to evaluate retinal
http://dx.doi.org/10.1016/j.seizure.2015.12.014 1059-1311/ß 2015 British Epilepsy Association. Published by Elsevier Ltd. All rights reserved.
Y.B. Gomceli et al. / Seizure 35 (2016) 36–40 Table 1 The different patterns of photoparoxysmal response.a Grade
Type of PPR
Grade 1 Grade 2 Grade 3
Spikes within the occipital rhythm Parieto-occipital spikes with a biphasic slow wave Parieto-occipital spikes with a biphasic slow wave and spread to the frontal region Generalized spikes and waves or polyspikes and waves
Grade 4
PPR: photoparoxysmal response. a Refs. [4–6].
disease and structural optic disc damage associated with glaucoma for more than 20 years. OCT has been successfully used in many neurological conditions such as, multiple sclerosis, neuromyelitis optica, Parkinson disease and Alzheimer disease. The main findings of these studies have been damage of retinal ganglion cells which reflect degenerative changes in the brain, therefore the patterns of changes differ in some aspects [10]. Anyanwu and Ehiri have investigated the ocular defects in patients with photosensitive epilepsy using visual-evoked response (VER) [11]. They observed that since luminance variance is the factor that causes seizures in patients with photosensitive epilepsy, it is apparent that the cells in the visual system of such patients may show a negative reaction to the stimuli which have the propensity to alter the functional status of the visual system. Such changes may result in abnormalities in ocular structures and consequently have a negative impact on the clarity of vision. The correlation between the ocular abnormalities and the interpretations of the changes in the characteristics of the VEP signaled the fact that optic-related atrophies, visual defects, optic neuritis, chiasmal compression, nystagmus, migraine headache, cataracts, and amblyopia were dominant in photosensitive epileptic patients at varying degrees. The results of their study have clearly revealed that although ocular defects in photosensitive epilepsy may not be differentially obvious, VEP measurements can be employed in their diagnosis. Major structural changes of the visual system and their relation to photosensitivity in patients with epilepsy has been researched before; however, microstructural changes in the visual system and their relation to photosensitivity have previously not been documented in such patients. Our hypothesis was that the visual system in photosensitive patients with JME could display microstructural changes. For this reason, in our study we aimed at comparing the RNFL thicknesses and the other structural changes of the retina in JME patients with and without photosensitivity. There are numerous studies suggesting that PPR is related with extreme excitability and reactivity in the visual cortex [12,13]. Moreover, it has been revealed in several studies that during the PPR, functional changes and changes in the blood stream occur in the supplementary motor area (SMA), the perisylvian area and medial temporal areas, besides the occipital cortex [14–16]. Strigaro et al. documented a defective inhibition in the visual system of photosensitive patients with IGE, using a new VEP technique (Faired pulse flash – VEP) [17]. In a recent study, Vollmar et al. demonstrated in patients with JME the alterations of the mesial frontal connectivity with increased structural connectivity between the prefrontal cognitive cortex and the motor cortex [18]. They found out that the increased connectivity between the SMA and the occipital cortex, which was stronger in photosensitive patients, may explain the provocative effect of photic stimulation in order to elicit frontocentral discharges and seizures. The question here is could a structure similar to that of the increased structural connectivity between the occipital cortex and the SMA exist in the retina or in the connection between the retina and the occipital cortex as well? While being distant from providing a satisfactory answer to this question, we believe that the demonstration of the potential microstructural changes in the
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retina in photosensitive patients with JME might be a starting point. In this study we aim to explore the relationship between PPR and OCT parameters in order to determine whether RNFL or other microstructural differences have a pathophysiological role in photosensitivity in patients with JME. 2. Methods We studied 53 consecutive patients with Juvenile myoclonic epilepsy (JME) at our outpatient department. All patients were diagnosed according to the recommendations by the Commission on Classification and Terminology of the International League Against Epilepsy (ILAE) in 2010 with Genetic Generalised Epilepsy (GGE) and were classified as JME, based on the type of seizures, predominant seizure type, age of onset of seizures and EEG characteristics [19]. The EEG evaluation was performed and analyzed at the same institution. The standard placement of 10–20 electrodes was used for the EEG recordings. The standard recording phase lasted 30 min and the hyperventilation phase lasted 4 min. IPS was performed at dim room lighting, an upright position of the patient and by simultaneous video recording. We used the lamp with circular reflector that delivers flashes with an intensity of 0.70 Joule which at 30 cm from the nasion of the patient. IPS was performed with frequencies of 1, 2, 4, 8, 10, 12, 15, 18, 20, 25, 40, 50, and 60 flashes/ s, and 0.5 and 70 Hz filters were used. Each frequency was performed with an interval of at least 7 s between each frequency, and each application was continued for 10 s, during which the eye was kept open in the first five seconds and closed in the last five seconds. The interictal EEG findings for each patient were analyzed for the presence of any generalized or occipital photoparoxysmal features. Each patient underwent a complete ophthalmological examination by the same physician who was uninformed of the EEG findings of the patients. All patients underwent the best-corrected visual acuity testing, slit-lamp biomicroscopy, intraocular pressure measurement, gonioscopy, dilated funduscopic examination and refraction. The peripapillary RNFL thickness, macular thickness and ganglion cell thickness values were analyzed using OCT (Cirrus HD OCT, Carl Zeiss Meditec, Dublin, CA, USA). RNFL measurements were obtained using a circular sweep of a fixed diameter of 3.45 mm around the optic disc. The choroid thickness was analyzed using an EDI-OCT. The exclusion criteria included a best-corrected visual acuity of less than 0.8 logMAR, corneal disease, retinal disease, uveitis, optic neuropathy, glaucoma or orbital disease and previous ophthalmic surgeries. Subjects were also excluded if they presented with a spherical refractive error greater than 1D or a cylindrical error greater than 1D. The study was approved by the Ethical Committee of Antalya Education and Research Hospital. Statistical analyses were performed using Pearson Chi-square test and t-test (Independent Samples Test) to determine potentially significant differences, and a p value less than 0.05 was considered significant. 3. Results We classified the 53 patients in our study into two groups as those with generalized/type 4 PPR (Group 1, 43.4%) and those without PPR (Group 2, 56.6%). No patient’s EEG demonstrated occipital spikes. The 23 patients in Group 1 had an age range between 19 and 49 (mean: 28.4), and 18 of them were female (78%). In Group 2, there were 30 patients, of whom 18 were female (60%). The age range of these patients was 12–41 (mean: 25.4). All patients were caucasian. Most of the patients were right-handed. Two patients
Y.B. Gomceli et al. / Seizure 35 (2016) 36–40
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Table 2 Average follow-up period, types of seizures and response to treatment of Group 1 and Group 2 patients.a Variable
Group 1 (n = 23)
Group 2 (n = 30)
Average follow-up period (months)
24.5 (3–52)
22.1 (2–45)
Seizure types Myoclonic jerks only Myoclonic + GTC seizures Myoclonic + absence seizures Myoclonic + absence + GTC seizures
5 10 1 7
4 14 2 10
Response to treatment All seizure types controlled Rare myoclonic jerks with triggering factors GTC controlled, persisting myoclonic and/or absence seizures Persisting seizures
(21.7%) (43.4%) (4.3%) (30.4%)
17 (74%) 4 (17.3%)
(13.3%) (46.6%) (6.6%) (33.3%)
18 (60%) 6 (20%)
1 (4.3%)
4 (13.3%)
1 (4.3%)
2 (6.6%)
Group 1: patients with PPR, Group 2: patients without PPR. a Modified from [20].
of Group 1 and 3 patients of Group 2 were left-handed, 1 patient of Group 2 was both-handed. Group 1 and Group 2 were statistically comparable with respect to age, gender and antiepileptic treatment. Average follow-up period, types of seizures and response to treatment of patients were summarized in Table 2, and antiepileptic drugs, doses and combinations of patients were summarized in Table 3. The best-corrected visual acuities, anterior and posterior segment examinations and direct/indirect pupillary light reflexes were normal in both eyes of all patients. To avoid inter-eye differences in RNFL and other OCT parameters, the study was considered as one eye design. We have separately compared the right eyes and then the left eyes of the patients in the groups with each other. The average RFNL thickness of both left and right side was analyzed and compared between the two groups (Table 4). The average RNFL thickness of the left side was increased in Group 1 patients as different from that of the Group 2 patients. There was a statistically significant difference in the average RNFL thickness of the left side in the two groups (p < 0.001). Although the RNFL thickness of right side was higher in Group 1, no statistically significant difference was observed between the two groups. The RFNL thickness in each of the 908 quadrants (superior, inferior, temporal and nasal) around the optic disc was analyzed and compared between the two groups (Table 5). The RFNL thickness levels of the superior quadrants both of the right and of the left side and the nasal quadrant of the right side were significantly higher in Group 1 than in Group 2 patients (p < 0.001). The ganglion cell thickness of the left side was 84.13 7.21 mm in Group 1 patients, and 79.72 7.22 mm in Group 2 patients and the
Table 3 Antiepileptic drugs, doses and combinations of Group 1 and Group 2 patients. AED
Group 1 (n = 23)
Group 2 (n = 30)
Mean or individual doses Group1/Group 2 (mg/day)
VPA LTG LEV TPM VPA + LTG VPA + LEV LTG + LEV LTG + TPM
11 2 4 2 3 – – 1
15 6 5 – 2 1 1 –
725 275/716.6 281 183 76/170 67 1125 177/1083 140 175 35.0/– 1125 177 + 125 35/1375 176 + 125 35 –/1000 + 1000 –/200 + 1000 200 + 100/–
Group 1: patients with PPR, Group 2: patients without PPR, AED: antiepileptic drug, VPA: valproic acid, LTG: lamotrigine, LEV: levetiracetam, TPM: topiramate.
Table 4 Mean (SD) value of the average RFNL thickness of Group 1 and Group 2 patients. Sides
Group 1 (n = 23)
Group 2 (n = 30)
Range (Group 1/Group 2)
p value
Left (mm) Right (mm)
94.65 10.92 93.39 10.49
87.96 7.60 88.33 8.93
71–118/75–103 70–113/75–110
0.011* 0.064
Group 1: patients with PPR, Group 2: patients without PPR. * Statistically significant data.
right side was measured as 83.78 9.45 mm, 78.11 8.56 mm respectively. Although ganglion cell thickness measures in each of the quadrants on both the left and the right eye were higher in Group 1 than in Group 2 patients, no statistically significant difference was observed between the two groups. Macular thickness levels of the right and left eyes were significantly thinner in Group 1 than in Group 2 patients (p < 0.001). In Group 1, the choroid thickness of the left eye was significantly higher than the one in Group 2 patients (p < 0.001). Although choroid thickness of the right eye was higher in Group 1, no statistically significant difference was seen between the two groups (Table 6). Intraocular pressure (IOP) of the left and right eyes was significantly lower in Group 1 than in Group 2 patients (p < 0.001). 4. Discussion In patients with epilepsy, OCT parameters have been investigated only in a few studies. Most of these studies have related the vigabatrin-exposed epileptic patients, and the relationship between RNFL thickness and visual field loss size has been found [21–23]. In epileptic patients another OCT study investigated RNFL and macular thickness in adolescents with newly diagnosed patients with epilepsy before and during monotherapy with valproate or carbamazepine over a period of one year [24]. There was no difference in the values of RNFL and macular thickness following the use of either valproate or carbamazepine after this one year period. Dereci et al. investigated peripapillary RNFL in children with epilepsy who were receiving valproate monotheraphy [25]. Conversely, in a previous study they had found out that compared to the healthy children, in patients with epilepsy who were receiving valproate monotherapy treatment for at least one year the values of the average thickness and superior peripapillary RNFL thickness were thinner. In a recent study, Balestrini et al. have found out that retinal fiber thinning is associated with drug resistance in patients with epilepsy [26]. They observed that the Table 5 Mean (SD) value of RFNL thickness in each of the 908 quadrants around the optic disk of Group 1 and Group 2 patients. Quadrants
Group 1 (n = 23)
Group 2 (n = 30)
p value
Superior (mm) Left Right
122.43 15.35 115.17 14.99
109.20 14.63 106.83 9.77
0.002* 0.018*
Temporal (mm) Left Right
63.52 8.92 66.17 10.96
60.40 7.12 62.76 9.27
0.163 0.226
Inferior (mm) Left Right
119.21 16.15 119.52 17.85
115.56 13.19 111.90 25.32
0.369 0.225
Nasal (mm) Left Right
72.65 12.27 73.17 12.77
67.26 13.35 66.83 9.66
0.138 0.045*
Group 1: patients with PPR, Group 2: patients without PPR. * Statistically significant data.
Y.B. Gomceli et al. / Seizure 35 (2016) 36–40 Table 6 Mean (SD) value of macular and choroid thickness of Group 1 and Group 2 patients. Group 1 (n = 23)
Group 2 (n = 30)
p value
Macular thickness (mm) 217.39 54.61 Left Right 215.56 58.56
251.13 24.66 249.34 23.40
0.010* 0.007*
Choroid thickness (mm) Left 387.39 66.61 Right 388.95 80.67
343.31 83.81 353.79 67.31
0.045* 0.93
Group 1: patients with PPR, Group 2: patients without PPR. * Statistically significant data.
average RNFL thickness and the thickness of each of the 908 quadrants were significantly thinner in people with epilepsy than in healthy controls. Moreover, RNFL thinning was associated with longer duration of epilepsy, presence of drug resistance and intellectual disability. Previous studies hypothesize that altered thalamo-cortical circuitry and microstructural organization may play an important role in the pathophysiology of JME [27,28]. The current understanding of the mechanisms underlying photosensitivity remains limited. Our hypothesis was that in JME patients the microstructural differences in the optic nerve fiber layer might be related with photosensitivity. Supporting this hypothesis, we indeed observed that the average RNFL thickness (especially of the left eyes) and each of quadrants (especially of the superior quadrants) of both the right and the left eyes was higher in photosensitive patients with JME. Although we could not explain why one eye was more involved, this could be related to the patient number. We thought that if more patients could be included in the study, the difference would be eliminated, which is the limitation of our study. The reason for the thicker RNFL values in photosensitive patients might result from the larger diameter values of the axons forming the RNFL layer, the bigger number of the axons or from the abnormal distributions of the axons with larger diameters. Large axons have faster conduction velocities and lower stimulus thresholds than the small fibers [29]. Indeed, the axons forming the RNFL (especially in the superior quadrant) in the group of photosensitive patients might be of larger diameter. These axons providing fast conduction and having low stimulus thresholds might have a cause or effect relationship with photosensitivity. Recent studies have demonstrated that the mean retinal ganglion axon diameter varies according to RNFL location, and on average inferior and/or nasal retinal ganglion cell (RGC) axons are larger than the superior and/or temporal axons [29]. In photosensitive patients with JME, the number of the large diameter axons might have been increased or the normally present large diameter axons might be displaying an abnormal distribution. We speculated that, these findings can be a consequence or the cause of photosensitivity. A new type of photoreceptor, intrinsically photosensitive retinal ganglion cells (ipRGCs), was described in a study in 2002 [30]. As different from rods and cones signalling within the retina with graded membrane voltages, ipRGCs signal to the brain making use of action potentials (spikes), and ipRGCs reveal spontaneous firing at moments when it is dark and when there is no synaptic activity [31]. In photosensitive epilepsy patients a potential unusual reorganization at the spontaneous firing propensity of ipRGCs might be facilitating photic sensitivity. In the study of Hattar et al. the density of melanopsin-positive RGC cells was more abundant in the superior and temporal quadrants of the rat retina [30]. In our study, RNFL thickness especially of the superior quadrants of both the right and the left eyes was higher in photosensitive patients with JME. In a study conducted by Gracitelli et al, it has been put forth that the decrease in the
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number of ipRGCs might be related to the decrease in the RNFL thickness [32]. The increase in the thickness of the RNFL we detected in our study might result from the larger number of the ipRGC in the superior quadrant. It might be the case that this physiologically existing state is present in the superior quadrant in a more exaggerated way than normal in photosensitive JME patients. In our study, macular thickness has been found to be significantly smaller in both eyes in JME patients with photosensitivity. It has been reported in a study there is a positive correlation between the increase in the macular pigment and in the foveal thickness [33]. In the light of these observations, it can be said that the macula layer thinning which we detected in photosensitive JME patients is related with the decrease in the macular pigments. Macular pigment is known to absorb visible light between the wavelengths of about 400–520 nm, with peak absorption occurring at 460 nm [34]. There are wavelengthdependent and quantity-of-light-dependent pathophysiologic mechanisms for eliciting PPRs by low-luminance IPS, and long wavelength red light may be especially provocative [35]. Even though it is known that macular pigments function as filters for the short wavelength light activity, they might have a similar function in the long wavelength light activity that cause the formation of the PPR. On the other hand, in the formation of the PPR, short wavelength light stimulant might also have a role even though it might not be so significant like that of the long wavelength light. As a result, it can be argued that the thinning of the macula which results from the reduction in the number of the macular pigments might be related to (a consequence or the cause of) photosensitivity. In our study, as different from the patients with no photosensitivity, the choroid thickness of photosensitive JME patients has been found to have increased in both eyes. The choroid is a vascular structure with multiple functions in the eye, including metabolic support of the retina and blood supply to the outer retinal layers [36]. In the group of photosensitive patients, the increase in the choroid thickness hence the vascular and metabolic changes might be related with photosensitivity. To our knowledge this is the first study which has investigated the relation between the OCT parameters and photosensitivity in patients with JME. We have concluded that microstructural differences in the optic nerve fiber layer may be a consequence or the cause of photosensitivity in patients with JME. Further studies investigating the peripheral mechanisms besides cortical mechanisms in the pathogenesis of photosensitivity are necessary.
Conflict of interest All authors have read and approved the manuscript and take for responsibility for its content. The authors have no conflicts of interest in regard to this research or its funding. None of the authors has any conflict of interest to disclose.
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Optical coherence tomography parameters in patients with photosensitive juvenile myoclonic epilepsy Yasemin Bicer Gomceli *, Berna Dogan, Fatma Genc, Elif Uygur, Deniz Turgut Coban, Abidin Erdal, Muhammed Kazım Erol Uncalı mah. 30. Cad. Binbirgece konakları E blok No:7, Konyaaltı, Antalya, Turkey
A R T I C L E I N F O
A B S T R A C T
Article history: Received 23 October 2015 Received in revised form 23 December 2015 Accepted 25 December 2015
Purpose: Juvenile myoclonic epilepsy (JME) is commonly associated with photoparoxysmal response (PPR) with a reported prevalence of 25–42%. In this study, we aim to explore the relationship between the PPR and Optical Coherence Tomography (OCT) parameters in order to determine whether optic nerve fiber layer or other structural differences have a pathophysiological role of photosensitivity in patients with JME. Methods: We studied 53 consecutive patients with Juvenile myoclonic epilepsy (JME) at our outpatient department. The interictal electroencephalogram (EEG) findings for each patient were analyzed for the presence of photoparoxysmal features. The peripapillary Retina Nerve Fiber Layer (RNFL) thickness, ganglion cell thickness, macular thickness and choroid thickness levels were analyzed using OCT. Results: We classified the patients into two groups as those with PPR (Group 1) and those without PPR (Group 2). There were statistically significant differences in the average RNFL thickness values of the left eye between the two groups (p < 0.001). Although the RNFL thickness of the right eye was higher in Group 1, no statistically significant difference was observed between the two groups. The RFNL thickness of the superior quadrants both in the right and the left eyes was significantly higher in Group 1 patients (p < 0.001). Macular thickness of the right and left eyes were significantly thinner in Group 1 patients (p < 0.001). Choroid thickness of the left eye was significantly higher in Group 1 than in Group 2 patients (p < 0.001). Although the choroid thickness of the right eye was higher in Group 1 patients, no statistically significant difference was observed between the two groups. Conclusion: This is the first study to our knowledge which has investigated the relation between the OCT parameters and photosensitivity in patients with JME. We concluded that these microstructural features may be related to photosensitivity in patients with JME. ß 2015 British Epilepsy Association. Published by Elsevier Ltd. All rights reserved.
Keywords: Retinal Nerve Fiber Layer EEG Photoparoxysmal EEG response Generalized epilepsy.
1. Introduction JME is a hereditary, generalized form of epilepsy and is estimated to account for approximately 10% of all epilepsies, with a range of 4–11% [1]. Seizures have an age-related onset and are characterized by the triad of myoclonic jerks on awakening, generalized tonic–clonic seizures (GTC) and typical absence seizures. Photosensitivity or photoparoxysmal response (PPR) is defined as the presence of an abnormal response to intermittent
Abbreviations: OCT, optical coherence tomography; RNFL, retina nerve fiber layer; JME, juvenile myoclonic epilepsy; PPR, photoparoxysmal response. * Tel.: +90 505 575 77 34; fax: +90 242 249 44 62. E-mail address: [email protected] (Y.B. Gomceli).
photic stimulation (IPS) during an EEG [2] and [3]. Different patterns of PPR were determined as ranging from a localized form of occipital spikes (Grade 1) to the generalized spikes-and-waves or polyspike waves (Grade 4) [4–6] (Table 1). The context of photosensitivity and epilepsy reveals diverse clinical situations. Patients may have seizures that are entirely (or predominantly) visually stimulated, which is sometimes described as ‘‘pure photosensitive epilepsy’’ [7]. By way of alternative, the patient may reveal photosensitivity as an EEG response to IPS in the laboratory and the epilepsy may be with or without visually induced seizures [8]. Among the various syndromes, JME is commonly associated with PPR with a reported prevalence of 25– 42% [9]. OCT is a non-invasive technique for cross-sectional imaging of the retinal microstructure and it has been used to evaluate retinal
http://dx.doi.org/10.1016/j.seizure.2015.12.014 1059-1311/ß 2015 British Epilepsy Association. Published by Elsevier Ltd. All rights reserved.
Y.B. Gomceli et al. / Seizure 35 (2016) 36–40 Table 1 The different patterns of photoparoxysmal response.a Grade
Type of PPR
Grade 1 Grade 2 Grade 3
Spikes within the occipital rhythm Parieto-occipital spikes with a biphasic slow wave Parieto-occipital spikes with a biphasic slow wave and spread to the frontal region Generalized spikes and waves or polyspikes and waves
Grade 4
PPR: photoparoxysmal response. a Refs. [4–6].
disease and structural optic disc damage associated with glaucoma for more than 20 years. OCT has been successfully used in many neurological conditions such as, multiple sclerosis, neuromyelitis optica, Parkinson disease and Alzheimer disease. The main findings of these studies have been damage of retinal ganglion cells which reflect degenerative changes in the brain, therefore the patterns of changes differ in some aspects [10]. Anyanwu and Ehiri have investigated the ocular defects in patients with photosensitive epilepsy using visual-evoked response (VER) [11]. They observed that since luminance variance is the factor that causes seizures in patients with photosensitive epilepsy, it is apparent that the cells in the visual system of such patients may show a negative reaction to the stimuli which have the propensity to alter the functional status of the visual system. Such changes may result in abnormalities in ocular structures and consequently have a negative impact on the clarity of vision. The correlation between the ocular abnormalities and the interpretations of the changes in the characteristics of the VEP signaled the fact that optic-related atrophies, visual defects, optic neuritis, chiasmal compression, nystagmus, migraine headache, cataracts, and amblyopia were dominant in photosensitive epileptic patients at varying degrees. The results of their study have clearly revealed that although ocular defects in photosensitive epilepsy may not be differentially obvious, VEP measurements can be employed in their diagnosis. Major structural changes of the visual system and their relation to photosensitivity in patients with epilepsy has been researched before; however, microstructural changes in the visual system and their relation to photosensitivity have previously not been documented in such patients. Our hypothesis was that the visual system in photosensitive patients with JME could display microstructural changes. For this reason, in our study we aimed at comparing the RNFL thicknesses and the other structural changes of the retina in JME patients with and without photosensitivity. There are numerous studies suggesting that PPR is related with extreme excitability and reactivity in the visual cortex [12,13]. Moreover, it has been revealed in several studies that during the PPR, functional changes and changes in the blood stream occur in the supplementary motor area (SMA), the perisylvian area and medial temporal areas, besides the occipital cortex [14–16]. Strigaro et al. documented a defective inhibition in the visual system of photosensitive patients with IGE, using a new VEP technique (Faired pulse flash – VEP) [17]. In a recent study, Vollmar et al. demonstrated in patients with JME the alterations of the mesial frontal connectivity with increased structural connectivity between the prefrontal cognitive cortex and the motor cortex [18]. They found out that the increased connectivity between the SMA and the occipital cortex, which was stronger in photosensitive patients, may explain the provocative effect of photic stimulation in order to elicit frontocentral discharges and seizures. The question here is could a structure similar to that of the increased structural connectivity between the occipital cortex and the SMA exist in the retina or in the connection between the retina and the occipital cortex as well? While being distant from providing a satisfactory answer to this question, we believe that the demonstration of the potential microstructural changes in the
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retina in photosensitive patients with JME might be a starting point. In this study we aim to explore the relationship between PPR and OCT parameters in order to determine whether RNFL or other microstructural differences have a pathophysiological role in photosensitivity in patients with JME. 2. Methods We studied 53 consecutive patients with Juvenile myoclonic epilepsy (JME) at our outpatient department. All patients were diagnosed according to the recommendations by the Commission on Classification and Terminology of the International League Against Epilepsy (ILAE) in 2010 with Genetic Generalised Epilepsy (GGE) and were classified as JME, based on the type of seizures, predominant seizure type, age of onset of seizures and EEG characteristics [19]. The EEG evaluation was performed and analyzed at the same institution. The standard placement of 10–20 electrodes was used for the EEG recordings. The standard recording phase lasted 30 min and the hyperventilation phase lasted 4 min. IPS was performed at dim room lighting, an upright position of the patient and by simultaneous video recording. We used the lamp with circular reflector that delivers flashes with an intensity of 0.70 Joule which at 30 cm from the nasion of the patient. IPS was performed with frequencies of 1, 2, 4, 8, 10, 12, 15, 18, 20, 25, 40, 50, and 60 flashes/ s, and 0.5 and 70 Hz filters were used. Each frequency was performed with an interval of at least 7 s between each frequency, and each application was continued for 10 s, during which the eye was kept open in the first five seconds and closed in the last five seconds. The interictal EEG findings for each patient were analyzed for the presence of any generalized or occipital photoparoxysmal features. Each patient underwent a complete ophthalmological examination by the same physician who was uninformed of the EEG findings of the patients. All patients underwent the best-corrected visual acuity testing, slit-lamp biomicroscopy, intraocular pressure measurement, gonioscopy, dilated funduscopic examination and refraction. The peripapillary RNFL thickness, macular thickness and ganglion cell thickness values were analyzed using OCT (Cirrus HD OCT, Carl Zeiss Meditec, Dublin, CA, USA). RNFL measurements were obtained using a circular sweep of a fixed diameter of 3.45 mm around the optic disc. The choroid thickness was analyzed using an EDI-OCT. The exclusion criteria included a best-corrected visual acuity of less than 0.8 logMAR, corneal disease, retinal disease, uveitis, optic neuropathy, glaucoma or orbital disease and previous ophthalmic surgeries. Subjects were also excluded if they presented with a spherical refractive error greater than 1D or a cylindrical error greater than 1D. The study was approved by the Ethical Committee of Antalya Education and Research Hospital. Statistical analyses were performed using Pearson Chi-square test and t-test (Independent Samples Test) to determine potentially significant differences, and a p value less than 0.05 was considered significant. 3. Results We classified the 53 patients in our study into two groups as those with generalized/type 4 PPR (Group 1, 43.4%) and those without PPR (Group 2, 56.6%). No patient’s EEG demonstrated occipital spikes. The 23 patients in Group 1 had an age range between 19 and 49 (mean: 28.4), and 18 of them were female (78%). In Group 2, there were 30 patients, of whom 18 were female (60%). The age range of these patients was 12–41 (mean: 25.4). All patients were caucasian. Most of the patients were right-handed. Two patients
Y.B. Gomceli et al. / Seizure 35 (2016) 36–40
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Table 2 Average follow-up period, types of seizures and response to treatment of Group 1 and Group 2 patients.a Variable
Group 1 (n = 23)
Group 2 (n = 30)
Average follow-up period (months)
24.5 (3–52)
22.1 (2–45)
Seizure types Myoclonic jerks only Myoclonic + GTC seizures Myoclonic + absence seizures Myoclonic + absence + GTC seizures
5 10 1 7
4 14 2 10
Response to treatment All seizure types controlled Rare myoclonic jerks with triggering factors GTC controlled, persisting myoclonic and/or absence seizures Persisting seizures
(21.7%) (43.4%) (4.3%) (30.4%)
17 (74%) 4 (17.3%)
(13.3%) (46.6%) (6.6%) (33.3%)
18 (60%) 6 (20%)
1 (4.3%)
4 (13.3%)
1 (4.3%)
2 (6.6%)
Group 1: patients with PPR, Group 2: patients without PPR. a Modified from [20].
of Group 1 and 3 patients of Group 2 were left-handed, 1 patient of Group 2 was both-handed. Group 1 and Group 2 were statistically comparable with respect to age, gender and antiepileptic treatment. Average follow-up period, types of seizures and response to treatment of patients were summarized in Table 2, and antiepileptic drugs, doses and combinations of patients were summarized in Table 3. The best-corrected visual acuities, anterior and posterior segment examinations and direct/indirect pupillary light reflexes were normal in both eyes of all patients. To avoid inter-eye differences in RNFL and other OCT parameters, the study was considered as one eye design. We have separately compared the right eyes and then the left eyes of the patients in the groups with each other. The average RFNL thickness of both left and right side was analyzed and compared between the two groups (Table 4). The average RNFL thickness of the left side was increased in Group 1 patients as different from that of the Group 2 patients. There was a statistically significant difference in the average RNFL thickness of the left side in the two groups (p < 0.001). Although the RNFL thickness of right side was higher in Group 1, no statistically significant difference was observed between the two groups. The RFNL thickness in each of the 908 quadrants (superior, inferior, temporal and nasal) around the optic disc was analyzed and compared between the two groups (Table 5). The RFNL thickness levels of the superior quadrants both of the right and of the left side and the nasal quadrant of the right side were significantly higher in Group 1 than in Group 2 patients (p < 0.001). The ganglion cell thickness of the left side was 84.13 7.21 mm in Group 1 patients, and 79.72 7.22 mm in Group 2 patients and the
Table 3 Antiepileptic drugs, doses and combinations of Group 1 and Group 2 patients. AED
Group 1 (n = 23)
Group 2 (n = 30)
Mean or individual doses Group1/Group 2 (mg/day)
VPA LTG LEV TPM VPA + LTG VPA + LEV LTG + LEV LTG + TPM
11 2 4 2 3 – – 1
15 6 5 – 2 1 1 –
725 275/716.6 281 183 76/170 67 1125 177/1083 140 175 35.0/– 1125 177 + 125 35/1375 176 + 125 35 –/1000 + 1000 –/200 + 1000 200 + 100/–
Group 1: patients with PPR, Group 2: patients without PPR, AED: antiepileptic drug, VPA: valproic acid, LTG: lamotrigine, LEV: levetiracetam, TPM: topiramate.
Table 4 Mean (SD) value of the average RFNL thickness of Group 1 and Group 2 patients. Sides
Group 1 (n = 23)
Group 2 (n = 30)
Range (Group 1/Group 2)
p value
Left (mm) Right (mm)
94.65 10.92 93.39 10.49
87.96 7.60 88.33 8.93
71–118/75–103 70–113/75–110
0.011* 0.064
Group 1: patients with PPR, Group 2: patients without PPR. * Statistically significant data.
right side was measured as 83.78 9.45 mm, 78.11 8.56 mm respectively. Although ganglion cell thickness measures in each of the quadrants on both the left and the right eye were higher in Group 1 than in Group 2 patients, no statistically significant difference was observed between the two groups. Macular thickness levels of the right and left eyes were significantly thinner in Group 1 than in Group 2 patients (p < 0.001). In Group 1, the choroid thickness of the left eye was significantly higher than the one in Group 2 patients (p < 0.001). Although choroid thickness of the right eye was higher in Group 1, no statistically significant difference was seen between the two groups (Table 6). Intraocular pressure (IOP) of the left and right eyes was significantly lower in Group 1 than in Group 2 patients (p < 0.001). 4. Discussion In patients with epilepsy, OCT parameters have been investigated only in a few studies. Most of these studies have related the vigabatrin-exposed epileptic patients, and the relationship between RNFL thickness and visual field loss size has been found [21–23]. In epileptic patients another OCT study investigated RNFL and macular thickness in adolescents with newly diagnosed patients with epilepsy before and during monotherapy with valproate or carbamazepine over a period of one year [24]. There was no difference in the values of RNFL and macular thickness following the use of either valproate or carbamazepine after this one year period. Dereci et al. investigated peripapillary RNFL in children with epilepsy who were receiving valproate monotheraphy [25]. Conversely, in a previous study they had found out that compared to the healthy children, in patients with epilepsy who were receiving valproate monotherapy treatment for at least one year the values of the average thickness and superior peripapillary RNFL thickness were thinner. In a recent study, Balestrini et al. have found out that retinal fiber thinning is associated with drug resistance in patients with epilepsy [26]. They observed that the Table 5 Mean (SD) value of RFNL thickness in each of the 908 quadrants around the optic disk of Group 1 and Group 2 patients. Quadrants
Group 1 (n = 23)
Group 2 (n = 30)
p value
Superior (mm) Left Right
122.43 15.35 115.17 14.99
109.20 14.63 106.83 9.77
0.002* 0.018*
Temporal (mm) Left Right
63.52 8.92 66.17 10.96
60.40 7.12 62.76 9.27
0.163 0.226
Inferior (mm) Left Right
119.21 16.15 119.52 17.85
115.56 13.19 111.90 25.32
0.369 0.225
Nasal (mm) Left Right
72.65 12.27 73.17 12.77
67.26 13.35 66.83 9.66
0.138 0.045*
Group 1: patients with PPR, Group 2: patients without PPR. * Statistically significant data.
Y.B. Gomceli et al. / Seizure 35 (2016) 36–40 Table 6 Mean (SD) value of macular and choroid thickness of Group 1 and Group 2 patients. Group 1 (n = 23)
Group 2 (n = 30)
p value
Macular thickness (mm) 217.39 54.61 Left Right 215.56 58.56
251.13 24.66 249.34 23.40
0.010* 0.007*
Choroid thickness (mm) Left 387.39 66.61 Right 388.95 80.67
343.31 83.81 353.79 67.31
0.045* 0.93
Group 1: patients with PPR, Group 2: patients without PPR. * Statistically significant data.
average RNFL thickness and the thickness of each of the 908 quadrants were significantly thinner in people with epilepsy than in healthy controls. Moreover, RNFL thinning was associated with longer duration of epilepsy, presence of drug resistance and intellectual disability. Previous studies hypothesize that altered thalamo-cortical circuitry and microstructural organization may play an important role in the pathophysiology of JME [27,28]. The current understanding of the mechanisms underlying photosensitivity remains limited. Our hypothesis was that in JME patients the microstructural differences in the optic nerve fiber layer might be related with photosensitivity. Supporting this hypothesis, we indeed observed that the average RNFL thickness (especially of the left eyes) and each of quadrants (especially of the superior quadrants) of both the right and the left eyes was higher in photosensitive patients with JME. Although we could not explain why one eye was more involved, this could be related to the patient number. We thought that if more patients could be included in the study, the difference would be eliminated, which is the limitation of our study. The reason for the thicker RNFL values in photosensitive patients might result from the larger diameter values of the axons forming the RNFL layer, the bigger number of the axons or from the abnormal distributions of the axons with larger diameters. Large axons have faster conduction velocities and lower stimulus thresholds than the small fibers [29]. Indeed, the axons forming the RNFL (especially in the superior quadrant) in the group of photosensitive patients might be of larger diameter. These axons providing fast conduction and having low stimulus thresholds might have a cause or effect relationship with photosensitivity. Recent studies have demonstrated that the mean retinal ganglion axon diameter varies according to RNFL location, and on average inferior and/or nasal retinal ganglion cell (RGC) axons are larger than the superior and/or temporal axons [29]. In photosensitive patients with JME, the number of the large diameter axons might have been increased or the normally present large diameter axons might be displaying an abnormal distribution. We speculated that, these findings can be a consequence or the cause of photosensitivity. A new type of photoreceptor, intrinsically photosensitive retinal ganglion cells (ipRGCs), was described in a study in 2002 [30]. As different from rods and cones signalling within the retina with graded membrane voltages, ipRGCs signal to the brain making use of action potentials (spikes), and ipRGCs reveal spontaneous firing at moments when it is dark and when there is no synaptic activity [31]. In photosensitive epilepsy patients a potential unusual reorganization at the spontaneous firing propensity of ipRGCs might be facilitating photic sensitivity. In the study of Hattar et al. the density of melanopsin-positive RGC cells was more abundant in the superior and temporal quadrants of the rat retina [30]. In our study, RNFL thickness especially of the superior quadrants of both the right and the left eyes was higher in photosensitive patients with JME. In a study conducted by Gracitelli et al, it has been put forth that the decrease in the
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number of ipRGCs might be related to the decrease in the RNFL thickness [32]. The increase in the thickness of the RNFL we detected in our study might result from the larger number of the ipRGC in the superior quadrant. It might be the case that this physiologically existing state is present in the superior quadrant in a more exaggerated way than normal in photosensitive JME patients. In our study, macular thickness has been found to be significantly smaller in both eyes in JME patients with photosensitivity. It has been reported in a study there is a positive correlation between the increase in the macular pigment and in the foveal thickness [33]. In the light of these observations, it can be said that the macula layer thinning which we detected in photosensitive JME patients is related with the decrease in the macular pigments. Macular pigment is known to absorb visible light between the wavelengths of about 400–520 nm, with peak absorption occurring at 460 nm [34]. There are wavelengthdependent and quantity-of-light-dependent pathophysiologic mechanisms for eliciting PPRs by low-luminance IPS, and long wavelength red light may be especially provocative [35]. Even though it is known that macular pigments function as filters for the short wavelength light activity, they might have a similar function in the long wavelength light activity that cause the formation of the PPR. On the other hand, in the formation of the PPR, short wavelength light stimulant might also have a role even though it might not be so significant like that of the long wavelength light. As a result, it can be argued that the thinning of the macula which results from the reduction in the number of the macular pigments might be related to (a consequence or the cause of) photosensitivity. In our study, as different from the patients with no photosensitivity, the choroid thickness of photosensitive JME patients has been found to have increased in both eyes. The choroid is a vascular structure with multiple functions in the eye, including metabolic support of the retina and blood supply to the outer retinal layers [36]. In the group of photosensitive patients, the increase in the choroid thickness hence the vascular and metabolic changes might be related with photosensitivity. To our knowledge this is the first study which has investigated the relation between the OCT parameters and photosensitivity in patients with JME. We have concluded that microstructural differences in the optic nerve fiber layer may be a consequence or the cause of photosensitivity in patients with JME. Further studies investigating the peripheral mechanisms besides cortical mechanisms in the pathogenesis of photosensitivity are necessary.
Conflict of interest All authors have read and approved the manuscript and take for responsibility for its content. The authors have no conflicts of interest in regard to this research or its funding. None of the authors has any conflict of interest to disclose.
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