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Research Article| Volume 35, P36-40, February 2016

Optical coherence tomography parameters in patients with photosensitive juvenile myoclonic epilepsy

Open ArchivePublished:December 30, 2015DOI:https://doi.org/10.1016/j.seizure.2015.12.014

      Highlights

      • Understanding of the mechanisms underlying photosensitivity is still limited.
      • Differences in the OCT parameters might be related with photosensitivity.
      • The RNFL and choroid thickness was found as increased in people with JME and a PPR.
      • Macular thickness was decreased in people with JME and a PPR.
      • Further studies investigating the peripheral mechanisms of PPR are necessary.

      Abstract

      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.

      Keywords

      Abbreviations:

      OCT (optical coherence tomography), RNFL (retina nerve fiber layer), JME (juvenile myoclonic epilepsy), PPR (photoparoxysmal response)

      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% [
      • Loddenkemper T.
      • Benbadis S.R.
      • Serratosa J.M.
      • Berkovic S.F.
      Idiopathic generalized epilepsy syndromes of childhood and adolescence.
      ]. 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 photic stimulation (IPS) during an EEG [
      • Covanis A.
      Photosensitivity in idiopathic generalised epilepsies.
      ] and [
      • Verrotti A.
      • Fiori F.
      • Coppola G.
      • Franzoni E.
      • Parisi P.
      • Chiarelli F.
      Idiopathic generalised tonic-clonic epilepsy and photosensitivity: a long-term follow-up study.
      ]. 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) [
      • Waltz S.
      • Christen H.J.
      • Doose H.
      The different patterns of the photoparoxysmal response-a genetic study.
      ,
      • Lu Y.
      • Waltz S.
      • Stenzel K.
      • Muhle H.
      • Stephani U.
      Photosensitivity in epileptic syndromes of childhood and adolescence.
      ,
      • Verrotti A.
      • Beccaria F.
      • Fiori F.
      • Montagnini A.
      • Capovilla G.
      Photosensitivity: epidemiology, genetics, clinical manifestations, assessment, and management.
      ] (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” [
      • Covanis A.
      • Stodieck S.R.
      • Wilkins A.J.
      Treatment of photosensitivity.
      ]. 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 [
      • Guerrini R.
      • Genton P.
      Epileptic syndromes and visually induced seizures.
      ]. Among the various syndromes, JME is commonly associated with PPR with a reported prevalence of 25–42% [
      • Appleton R.
      • Beirne M.
      • Acomb B.
      Photosensitivity in juvenile myoclonic epilepsy.
      ].
      Table 1The different patterns of photoparoxysmal response.
      Refs. [4–6].
      GradeType of PPR
      Grade 1Spikes within the occipital rhythm
      Grade 2Parieto-occipital spikes with a biphasic slow wave
      Grade 3Parieto-occipital spikes with a biphasic slow wave and spread to the frontal region
      Grade 4Generalized spikes and waves or polyspikes and waves
      PPR: photoparoxysmal response.
      a Refs.
      • Waltz S.
      • Christen H.J.
      • Doose H.
      The different patterns of the photoparoxysmal response-a genetic study.
      ,
      • Lu Y.
      • Waltz S.
      • Stenzel K.
      • Muhle H.
      • Stephani U.
      Photosensitivity in epileptic syndromes of childhood and adolescence.
      ,
      • Verrotti A.
      • Beccaria F.
      • Fiori F.
      • Montagnini A.
      • Capovilla G.
      Photosensitivity: epidemiology, genetics, clinical manifestations, assessment, and management.
      .
      OCT is a non-invasive technique for cross-sectional imaging of the retinal microstructure and it has been used to evaluate retinal 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 [
      • Jindahra P.
      • Hedges T.R.
      • Mendoza-Santiesteban C.E.
      • Plant G.T.
      Optical coherence tomography of the retina: applications in neurology.
      ].
      Anyanwu and Ehiri have investigated the ocular defects in patients with photosensitive epilepsy using visual-evoked response (VER) [
      • Anyanwu E.C.
      • Ehiri J.
      Ocular defects in photosensitive epilepsy.
      ]. 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 [
      • Parra J.
      • Kalitzin S.N.
      • Iriarte J.
      • Blanes W.
      • Velis D.N.
      • Lopes da Silva F.H.
      Gamma-band phase clustering and photosensitivity: is there an underlying mechanism common to photosensitive epilepsy and visual perception?.
      ,
      • Wilkins A.J.
      • Bonanni P.
      • Porciatti P.
      • Guerrini R.
      Physiology of human photosensitivity.
      ]. 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 [
      • Chiappa K.H.
      • Hill R.A.
      • Huang-Hellinger F.
      • Jenkins B.G.
      Photosensitive epilepsy studied by functional magnetic resonance imaging and magnetic resonance spectroscopy.
      ,
      • Inoue Y.
      • Fukao K.
      • Araki T.
      • Yamamoto S.
      • Kubota H.
      • Watanabe Y.
      Photosensitive and nonphotosensitive electronic screen game-induced seizures.
      ,
      • Kapucu L.O.
      • Gücüyener K.
      • Vural G.
      • Köse G.
      • Tokçaer A.B.
      • Turgut B.
      • et al.
      Brain SPECT evaluation of patients with pure photosensitive epilepsy.
      ]. 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) [
      • Strigaro G.
      • Prandi P.
      • Varrasi C.
      • Magistrelli L.
      • Falletta L.
      • Cantello R.
      Intermittent photic stimulation affects motor cortex excitability in photosensitive idiopathic generalised epilepsy.
      ]. 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 [
      • Vollmar C.
      • O’Muircheartaigh J.
      • Symms M.R.
      • Barker G.J.
      • Thompson P.
      • Kumari V.
      • et al.
      Altered microstructural connectivity in juvenile myoclonic epilepsy. The missing link.
      ]. 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 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 [
      • Berg A.T.
      • Berkovic S.F.
      • Brodie M.J.
      • Buchhalter J.
      • Cross J.H.
      • van Emde Boas W.
      • et al.
      Revised terminology and concepts for organization of seizures and epilepsies: report of the ILAE Commission on Classification and Terminology, 2005–2009.
      ].
      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 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.
      Table 2Average follow-up period, types of seizures and response to treatment of Group 1 and Group 2 patients.
      Modified from [20].
      VariableGroup 1 (n = 23)Group 2 (n = 30)
      Average follow-up period (months)24.5 (3–52)22.1 (2–45)
      Seizure types
      Myoclonic jerks only5 (21.7%)4 (13.3%)
      Myoclonic + GTC seizures10 (43.4%)14 (46.6%)
      Myoclonic + absence seizures1 (4.3%)2 (6.6%)
      Myoclonic + absence + GTC seizures7 (30.4%)10 (33.3%)
      Response to treatment
      All seizure types controlled17 (74%)18 (60%)
      Rare myoclonic jerks with triggering factors4 (17.3%)6 (20%)
      GTC controlled, persisting myoclonic and/or absence seizures1 (4.3%)4 (13.3%)
      Persisting seizures1 (4.3%)2 (6.6%)
      Group 1: patients with PPR, Group 2: patients without PPR.
      a Modified from
      • Medina M.T.
      • Martínez-Juárez I.E.
      • Durón R.M.
      • Genton P.
      • Guerrini R.
      • Dravet C.
      • et al.
      Treatment of myoclonic epilepsies of childhood, adolescence and adulthood.
      .
      Table 3Antiepileptic drugs, doses and combinations of Group 1 and Group 2 patients.
      AEDGroup 1 (n = 23)Group 2 (n = 30)Mean or individual doses Group1/Group 2 (mg/day)
      VPA1115725 ± 275/716.6 ± 281
      LTG26183 ± 76/170 ± 67
      LEV451125 ± 177/1083 ± 140
      TPM2175 ± 35.0/–
      VPA + LTG321125 ± 177 + 125 ± 35/1375 ± 176 + 125 ± 35
      VPA + LEV1–/1000 + 1000
      LTG + LEV1–/200 + 1000
      LTG + TPM1200 + 100/–
      Group 1: patients with PPR, Group 2: patients without PPR, AED: antiepileptic drug, VPA: valproic acid, LTG: lamotrigine, LEV: levetiracetam, TPM: topiramate.
      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 90° 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).
      Table 4Mean (±SD) value of the average RFNL thickness of Group 1 and Group 2 patients.
      SidesGroup 1 (n = 23)Group 2 (n = 30)Range (Group 1/Group 2)p value
      Left (μm)94.65 ± 10.9287.96 ± 7.6071–118/75–1030.011
      Statistically significant data.
      Right (μm)93.39 ± 10.4988.33 ± 8.9370–113/75–1100.064
      Group 1: patients with PPR, Group 2: patients without PPR.
      * Statistically significant data.
      Table 5Mean (±SD) value of RFNL thickness in each of the 90° quadrants around the optic disk of Group 1 and Group 2 patients.
      QuadrantsGroup 1 (n = 23)Group 2 (n = 30)p value
      Superior (μm)
      Left122.43 ± 15.35109.20 ± 14.630.002
      Statistically significant data.
      Right115.17 ± 14.99106.83 ± 9.770.018
      Statistically significant data.
      Temporal (μm)
      Left63.52 ± 8.9260.40 ± 7.120.163
      Right66.17 ± 10.9662.76 ± 9.270.226
      Inferior (μm)
      Left119.21 ± 16.15115.56 ± 13.190.369
      Right119.52 ± 17.85111.90 ± 25.320.225
      Nasal (μm)
      Left72.65 ± 12.2767.26 ± 13.350.138
      Right73.17 ± 12.7766.83 ± 9.660.045
      Statistically significant data.
      Group 1: patients with PPR, Group 2: patients without PPR.
      * Statistically significant data.
      The ganglion cell thickness of the left side was 84.13 ± 7.21 μm in Group 1 patients, and 79.72 ± 7.22 μm in Group 2 patients and the right side was measured as 83.78 ± 9.45 μm, 78.11 ± 8.56 μm 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).
      Table 6Mean (±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 (μm)
      Left217.39 ± 54.61251.13 ± 24.660.010
      Statistically significant data.
      Right215.56 ± 58.56249.34 ± 23.400.007
      Statistically significant data.
      Choroid thickness (μm)
      Left387.39 ± 66.61343.31 ± 83.810.045
      Statistically significant data.
      Right388.95 ± 80.67353.79 ± 67.310.93
      Group 1: patients with PPR, Group 2: patients without PPR.
      * Statistically significant data.
      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 [
      • Lawthom C.
      • Smith P.E.
      • Wild J.M.
      Nasal retinal nerve fiber layer attenuation: a biomarker for vigabatrin toxicity.
      ,
      • Clayton L.M.
      • Dévilé M.
      • Punte T.
      • Kallis C.
      • de Haan G.J.
      • Sander J.W.
      • et al.
      Retinal nerve fiber layer thickness in vigabatrin-exposed patients.
      ,
      • Moseng L.
      • Sæter M.
      • Mørch-Johnsen G.H.
      • Hoff J.M.
      • Gajda A.
      • Brodtkorb E.
      • et al.
      Retinal nerve fibre layer attenuation: clinical indicator for vigabatrin toxicity.
      ].
      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 [
      • Lobefalo L.
      • Rapinese M.
      • Altobelli E.
      • Di Mascio R.
      • Lattanzi D.
      • Gallenga P.E.
      • et al.
      Retinal nerve fiber layer and macular thickness in adolescents with epilepsy treated with valproate and carbamazepine.
      ]. 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 [
      • Dereci S.
      • Koca T.
      • Akçam M.
      • Türkyilmaz K.
      An evaluation of peripapillary retinal nerve fiber layer thickness in children with epilepsy receiving treatment of valproic acid.
      ]. 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 [
      • Balestrini S.
      • Clayton L.M.
      • Bartmann A.P.
      • Chinthapalli K.
      • Novy J.
      • Coppola A.
      • et al.
      Retinal nerve fibre layer thinning is associated with drug resistance in epilepsy.
      ]. They observed that the average RNFL thickness and the thickness of each of the 90° 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 [
      • Gloor P.
      Generalized cortico-reticular epilepsies. Some considerations on the pathophysiology of generalized bilaterally synchronous spike and wave discharge.
      ,
      • Blumenfeld H.
      Cellular and network mechanisms of spike wave seizures.
      ]. 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 [
      • FitzGibbon T.
      • Taylor S.F.
      Mean retinal ganglion cell axon diameter varies with location in the human retina.
      ]. 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 [
      • FitzGibbon T.
      • Taylor S.F.
      Mean retinal ganglion cell axon diameter varies with location in the human retina.
      ]. 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 [
      • Hattar S.
      • Liao H.W.
      • Takao M.
      • Berson D.M.
      • Yau K.W.
      Melanopsin-containing retinal ganglion cells: architecture, projections, and intrinsic photosensitivity.
      ]. 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 [
      • Do M.T.H.
      • Kang S.H.
      • Xue T.
      • Zhong H.
      • Liao H.W.
      • Bergles D.E.
      • et al.
      Photon capture and signalling by melanopsin retinal ganglion cells.
      ]. 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 [
      • Hattar S.
      • Liao H.W.
      • Takao M.
      • Berson D.M.
      • Yau K.W.
      Melanopsin-containing retinal ganglion cells: architecture, projections, and intrinsic photosensitivity.
      ]. 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 number of ipRGCs might be related to the decrease in the RNFL thickness [
      • Gracitelli C.P.
      • Duque-Chica G.L.
      • Moura A.L.
      • Nagy B.V.
      • de Melo G.R.
      • Roizenblatt M.
      • et al.
      A positive association between intrinsically photosensitive retinal ganglion cells and retinal nerve fiber layer thinning in glaucoma.
      ]. 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 [
      • Van der Veen R.L.
      • Ostendorf S.
      • Hendrikse F.
      • Berendschot T.T.
      Macular pigment optical density relates to foveal thickness.
      ]. 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 [
      • Hammond Jr., B.R.
      • Wooten B.R.
      • Snodderly D.M.
      Individual variations in the spatial profile of human macular pigment.
      ]. There are wavelength-dependent and quantity-of-light-dependent pathophysiologic mechanisms for eliciting PPRs by low-luminance IPS, and long wavelength red light may be especially provocative [
      • Takahashi Y.
      • Fujiwara T.
      • Yagi K.
      • Seino M.
      Wavelength dependence of photoparoxysmal responses in photosensitive patients with epilepsy.
      ]. 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 [
      • Linsenmeier R.A.
      • Padnick-Silver L.
      Metabolic dependence of photoreceptors on the choroid in the normal and detached retina.
      ]. 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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