ORIGINAL ARTICLE

Diffusion tensor imaging abnormalities in photosensitive juvenile myoclonic epilepsy €gera, J. Geithnerb, Z. I. Wangc, A. V. Khawa,d, A. Angermaiera, B. Gaidaa, F. von Podewilsa, U. Rungea, S. Kru M. Domine, C. Kesslera and S. Langnere a

EUROPEAN JOURNAL OF NEUROLOGY

Department of Neurology, Epilepsy Center, University Medicine Greifswald, Greifswald; bEpilepsie-Zentrum Berlin-Brandenburg, Ev. Krankenhaus K€ onigin Elisabeth Herzberge, Berlin, Germany; cEpilepsy Center, Neurological Institute, Cleveland Clinic Foundation, Cleveland, OH, USA; dDepartment of Clinical Neurosciences, Schulich School of Medicine and Dentistry, London Health Sciences Centre, University of Western Ontario, London, ON, Canada; and eCenter for Diagnostic Radiology and Neuroradiology, University Medicine Greifswald, Greifswald, Germany

Keywords:

diffusion tensor imaging, juvenile myoclonic epilepsy, microstructural abnormalities, photosensitivity Received 20 September 2014 Accepted 26 February 2015 European Journal of Neurology 2015, 22: 1192–1200 doi:10.1111/ene.12725

Background and purpose: Multiple structural white matter abnormalities have been described in patients with juvenile myoclonic epilepsy (JME). In the present study, the question of whether microstructural variations exist between the two subgroups of JME, with and without photoparoxysmal responses (PPR positive and negative), was addressed using diffusion tensor imaging. Methods: A selection of 18 patients (eight PPR positive) from a tertiary epilepsy center diagnosed with JME and 27 healthy controls was studied. The following regions of interest were investigated: the ascending reticular activating system, lateral geniculate nucleus, genu of the internal capsule, ventromedial thalamus and inferior cerebellar peduncle. Results: Widespread white matter microstructural abnormalities in JME and in particular in PPR positive cases were identified. PPR positive patients demonstrated increased fractional anisotropy in the ascending reticular activating system and ventromedial thalamus compared to PPR negative patients and healthy controls. Reduced fractional anisotropy of the lateral geniculate nucleus was observed in the entire JME group compared to healthy controls. Conclusions: Several microstructural variations between PPR positive and negative JME patients have been identified. Our findings highlight the pivotal role of the thalamus in the pathophysiology of primary generalized seizures and suggest that thalamo-premotor connections are both an essential part of epileptic networks and important in the pathogenesis of photosensitivity.

Introduction Juvenile myoclonic epilepsy (JME), a common idiopathic generalized epilepsy (IGE) syndrome with a prevalence of 5%–11% amongst all patients with epilepsy [1–3], is characterized by bilateral myoclonic seizures (BMS) alone or combined with generalized tonic clonic seizures (GTCS) and/or absence seizures (ABS) [2,4]. As a specific electroclinical syndrome it is characterized by generalized spikes and poly-spikes Correspondence: F. von Podewils, Department of Neurology, Epilepsy Center, University Medicine Greifswald, Sauerbruchstrasse, 17489 Greifswald, Germany (tel.: +49 3834 866815; fax: +49 3834 866875; e-mail: [email protected]).

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≥3 Hz on interictal electroencephalography (EEG) [5,6]. Approximately 30% of patients with JME show photoparoxysmal responses (PPR) [7], defined as the occurrence of spikes, poly-spike waves or repetitive spikes in response to intermittent photic stimulation (PS) [8,9]. Prior studies revealed functional and structural frontal abnormalities in JME patients that are considered to be associated with impairment of frontal lobe functions and seizure severity [6,10–12]. Amongst functional imaging modalities, diffusion tensor imaging (DTI) is a non-invasive magnetic resonance imaging (MRI) based technique to depict and quantify white matter (WM) fiber tracts of the brain and to give valuable information about their orienta-

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DTI AND PHOTOSENSITIVITY IN JME

tion and integrity in vivo. Common parameters derived from DTI are fractional anisotropy (FA) and mean diffusivity (MD) [13]. Both the thalamus and thalamo-cortical networks have been reported to play an important role in the pathophysiology of JME [14,15]. Recent studies revealed a bilateral reduction of FA in the anterior limb of the internal capsule and thalamo-cortical WM fibers [16,17]. Vollmar et al. reported that structural alterations in the medial frontal region were responsible for functional hyperconnectivity, which might be essential in the pathophysiology of JME. Additionally, an increased connectivity between the supplementary motor area and occipital cortex was shown in PPR positive patients, which was considered to be a reason for the provocative effect of PS to generate frontocentral discharges and seizures [12]. The aim of this study was to identify inter-cortical, thalamo-cortical and reticulo-thalamic structural abnormalities in JME compared to healthy controls using DTI. Furthermore, our aim was to determine potential microstructural variations between the two subgroups of JME PPR positive (pPPR) and PPR negative (nPPR) cases.

Materials and methods Patients

The local Institutional Review Board approved this study. The study was conducted amongst the inhabitants of the catchment area of a tertiary care epilepsy center (total population 500 000). Due to the rural structure of the population and the condition that the hospital provides the only neurological care in the whole catchment area, all patients were referred to this epilepsy center either to perform the diagnostics in newly diagnosed epilepsies or to optimize the medication in drug-nonresponsive cases. Eighteen patients with JME and 27 age and gender matched healthy controls (mean age 28.4 years; standard deviation (SD) 4.29 years, 21–35, 13 females) were prospectively recruited from the inpatient and outpatient clinic between January 2012 and August 2013. Inclusion criteria were (i) a diagnosis of JME, (ii) normal neurological examination and overall intelligence, (iii) at least one abnormal routine EEG (International 10–20 system of electrode placement) showing normal background and generalized abnormalities, and (iv) normal clinical MRI. Exclusion criteria were a history of epilepsy syndromes other than JME and severe brain trauma. Healthy controls had no history of neurological disease and brain trauma, a normal clinical MRI and routine EEG, and no family history of epi-

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lepsy. Diagnostic criteria of JME included a history of BMS with or without additional GTCS and/or ABS. The diagnosis of JME was made by experienced epileptologists (UR, FvP, JG) on the basis of the patients’ medical history and the patients’ EEG. Patients were considered as pPPR if epileptiform discharges and/or seizures only occurred in response to intermittent PS. PPRs were classified according to Waltz et al. [18]. Due to the lack of data on reflex epileptic traits other than PPR in our patient group further subgroup analysis was not part of our study protocol. Clinical data were collected by reviewing the medical records and during the interview. Data acquisition

Imaging was performed using a 3 T MR scanner (Magnetom Verio, Siemens Medical System, Erlangen, Germany) with a 32-channel head coil. A three-dimensional T1-weighted magnetization-prepared rapid gradient echo data set with 1 mm isotropic voxels was acquired. Additional imaging parameters were TR 1690 ms, TE 2.52 ms, TI 900 mm, 176 slices with an acquisition time of 3:50 min. DTI was performed using a spin-echo echo planar imaging sequence with 1.8 mm isotropic voxels and 64 gradient directions. Further imaging parameters were TR 15 300 ms and TE 107 ms, 80 slices. The acquisition time was 17:22 min. For imaging analysis a region of interest (ROI) for the ascending reticular activating system (ARAS) and for both hemispheres for the lateral geniculate nucleus (LGN), the genu of the internal capsule (GIC) and the ventromedial thalamus (VMT) was drawn based on the Montreal Neurological Institute (MNI) neuroanatomical template. The ROI for the inferior cerebellar peduncle (ICP) was based on the Johns Hopkins University WM labels. Data sets underwent a standard preprocessing procedure as proposed by the FSL Analysis Group (Analysis Group, FMRIB, Oxford, UK), including eddy_correct for eddy current correction and correction for subject motion, bet for skull stripping for improved co-registration and FLIRT for linear co-registration. For further data evaluations the diffusion data within the individual space were used to avoid data modification by a normalization process. An inverse warp of the previously found nonlinear transformation into MNI space using FLIRT was calculated using the FSL tool invwarp. DTI was performed with in-house developed software (JAVATM DTI, Center for Diagnostic Radiology and Neuroradiology, University Medicine Greifswald, Greifswald, Germany). For all ROIs the number of voxels in the denormalized brain and the diffusion parameters FA

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and MD were calculated. Fiber-tracking was performed with each ROI as seed point and the number of fibers was evaluated. Three-dimensional tract reconstruction was based on the Fiber Assignment by Continuous Tracking (FACT) algorithm [19]. Tracking parameters were a minimum fiber length of 25 mm, angle 30° and an FA threshold of 0.2. Statistics

SPSS 22.0 (IBM Co., Armonk, NY, USA) was used for statistical processing of the data. Inter-group differences for FA and MD were assessed using univariate analyses of variance (ANOVA) with Duncan’s post hoc test and the Mann–Whitney U test (non-parametric test). The percentage change of FA and MD between controls and patients was calculated according to the formula used by Keller et al.: (b a)/a 9 100 (where a is the control value and b is the patient value) [17]. The relationship between FA/MD and clinical parameters was assessed using the eta correlation (g). Statistical significance was defined as a P value ≤0.05. The Bonferroni-corrected P value is ≤0.004.

Eighteen patients (12 female) were enrolled [mean age 29.9 years (SD 8.91, 20–49); mean age of epilepsy onset (first recognized seizure) 13.94 years (SD 5.30, 3–21); mean duration of epilepsy 16.06 years (SD 10.56, 3–36)]. Eight of them (44.4%) were pPPR (all of them were classified as PPR type III or IV) [18]. No significant difference between pPPR and nPPR patients was found with regard to sex (P = 0.308), epilepsy onset (P = 0.968), epilepsy duration (P = 0.968) and types of occurring seizures (P = 0.503). No significant EEG changes during hyperventilation were observed. Eta coefficients (g) for relationships between clinical data and both FA and MD are given in Table 2. The strongest correlations were found for lower mean FA values in the VMT and both early epilepsy onset (≤15 years of age) (left VMT g = 0.909; right VMT g = 0.827) and a longer duration of epilepsy (≥15 years) (left VMT g = 0.985; right VMT g = 0.991). Furthermore, early epilepsy onset correlated with lower mean FA values in the ARAS (g = 0.785). In all of the investigated ROIs low correlations were found between FA/ MD and both the occurring seizure types and the occurrence of status epilepticus.

Results Tractography: FA Patient demographics and clinical characteristics

Fractional anisotropy values for all patients and controls are given in Table 3. Inter-group comparisons

Details of all study patients are given in Table 1. Table 1 Detailed clinical data of all patients included in the study Patient no.

Age

Sex

EO (years)

ED (years)

Seizure types

First seizure

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18

42 21 26 28 40 35 27 24 24 23 20 28 49 41 25 41 21 24

F F M F F F F M M F M F F F F M F M

8 18 16 6 19 15 12 21 21 3 12 12 14 14 19 15 7 19

36 3 10 21 21 20 15 3 3 20 8 16 35 27 6 26 14 5

3 2 2 2 1 1 2 0 1 2 2 2 2 3 0 1 2 1

ABS ABS/BMS u ABS BMS BMS BMS BMS BMS ABS u GTCS ABS ABS BMS BMS ABS u

PPR (type)a

+ (III) + (IV) + (IV)

GTCS preceded by BMS

SE

BMS in series

+

+

u u u

u u u

+ (IV) + (III)

+ (ABS)

+ + (IV) + (IV) + (III)

u

AED responseb i ii ii i ii iii i i i iii iii iii i ii i iii i i

ABS, absence seizures; AED, antiepileptic drug; BMS, bilateral myoclonic seizures; ED, epilepsy duration; EO, epilepsy onset; F, female; GTCS, generalized tonic clonic seizures; M, male; PPR, photoparoxysmal response; SE, status epilepticus. Seizure types: 0 BMS, 1 BMS + GTCS, 2 BMS + GTCS + ABS, 3 BMS + ABS. +, yes; , no; u, unknown. a Type of PPR according to the classification of Waltz et al. [18]. bAED response: i, responsive to the first AED trial or in the case of side effects the second AED; ii, failure of the first AED, responsive to the second AED trial; iii, hard to control (failure of ≥ two AEDs or polytherapy).

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Table 2 Eta values of clinical parameters LGN ARAS

EO ED Seizure type SE

GIC

L

R

ICP

L

R

VMT

L

R

L

R

FA

MD

FA

MD

FA

MD

FA

MD

FA

MD

FA

MD

FA

MD

FA

MD

FA

MD

0.785 0.816 0.400

0.736 0.749 0.390

0.755 0.799 0.353

0.787 0.882 0.393

0.604 0.829 0.317

0.923 0.814 0.234

0.560 0.844 0.400

0.857 0.909 0.369

0.388 0.903 0.343

0.742 0.871 0.545

0.645 0.829 0.387

0.685 0.815 0.408

0.582 0.822 0.247

0.651 0.846 0.278

0.909 0.985 0.372

0.819 0.784 0.515

0.827 0.991 0.335

0.798 0.887 0.474

0.021

0.091

0.423

0.520

0.328

0.111

0.215

0.288

0.033

0.033

0.123

0.052

0.056

0.026

0.086

0.082

0.074

0.273

ARAS, ascending reticular activating system; ED, epilepsy duration (in years); EO, epilepsy onset (in years); FA, fractional anisotropy; GIC, genu internal capsule; ICP, inferior cerebellar peduncle; L, left; LGN, lateral geniculate nucleus; MD, mean diffusivity; R, right; SE, status epilepticus; VMT, ventromedial thalamus.

showed no significant FA differences between controls and the JME overall group, each JME subgroup (pPPR/nPPR) and between the subgroups. However, compared to controls several aspects with regard to percentage differences in FA amongst the JME subgroups were identified. ROI analysis showed mean FA differences in the ARAS and the VMT. FA was higher in pPPR JME in both ROIs (ARAS 4.26%; VMT 3.04%) than in nPPR patients (ARAS 0.19%; VMT 0.55%) or JME patients overall (ARAS 1.94%; VMT 1.66%). The percentage differences between the two subgroups were 3.90% (ARAS) and 2.41% (VMT), respectively. Tractography: MD

Mean diffusivity values for all patients and controls are given in Table 4. Inter-group comparisons showed no significant differences between controls and the JME overall group, and each subgroup. Nevertheless, when comparing controls with the JME group, ROI analysis revealed mean MD changes in the ARAS (9.98%), LGN (5.07%) and ICP (4.43%). Differences of MD were found in the ARAS with clearly lower values amongst JME patients compared to controls (9.98%); however, subgroup comparison (pPPR versus nPPR) showed only marginal differences between the two groups (1.77%). In contrast, compared to controls, mean MD values in the VMT were lower in pPPR patients ( 4.13%), whereas MD values were found to be higher in nPPR patients (+2.31%) (difference between the two subgroups 6.72%). Furthermore, compared to controls, JME patients showed increased MD values in the LGN, with highest values amongst pPPR patients (+7.08%) (nPPR +3.47%).

Discussion The goal of this prospective study was to identify potential inter-cortical, thalamo-cortical and reticulo-

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thalamic structural abnormalities in JME compared to healthy controls and between the two JME subgroups of pPPR and nPPR cases. To our knowledge, this is the first study in the challenging group of JME patients to examine microstructural differences in pPPR and nPPR groups. Both DTI-derived parameters (FA and MD) were described as being sensitive to identify WM abnormalities in patients with neurological and psychiatric disorders and were previously investigated in patients with JME [6,12,16,17,20–22]. An FA decrease reflects an impaired microstructural integrity within WM tracts caused by reduced membrane and myelin integrity and fiber density [6,23]. Several recent studies on WM integrity changes in JME reported FA reductions in the thalamo-frontal network [6,16,17], the supplementary motor area [11,20] and the corpus callosum as well as frontal executive dysfunctions, suggesting a key role of frontal lobe abnormalities in the pathogenesis of JME [20]. Compared to healthy controls and nPPR patients, our results reveal an increased FA and decreased MD amongst pPPR JME patients in the ARAS and the VMT. In contrast, the whole JME group had reduced FA and increased MD in the LGN compared to healthy controls, whereas in the GIC FA was reduced only in the pPPR group. Although the fundamental pathogenesis underlying IGE is not completely understood, the majority of prior studies pointed to the thalamus as playing a crucial role in the generation of generalized epileptic discharges and seizures, which is supported by our results [17,22,24,25]. In contrast to the mean FA increase in the VMT, a reduction was demonstrated of the mean FA in the GIC indicating an alteration of thalamo-frontal connections. This is consistent with findings of prior studies that focused on microstructural abnormalities in the internal capsule [6,16,17,22]; however, this is the first study showing a clear mean FA reduction in the

0.366 (0.317–0.420)

0.358 (0.308–0.421)

0.362

0.550 (0.397–0.628)

0.545 (0.380–0.630)

0.548

0.538 (0.452–0.604)

0.544 (0.474–0.644)

0.541

0.393 (0.318–0.552)

0.376 (0.349–0.421)

0.370 (0.342–0.410)

0.373

0.567 (0.490–0.620)

0.557 (0.479–0.599)

0.562

0.532 (0.464–0.616)

0.524 (0.431–0.585)

0.528

0.389 (0.351–0.427)

0.390 (0.328–0.421)

0.390

0.538 (0.449–0.603)

JME PPR +

0.363 (0.312–0.408)

0.364 (0.321–0.395)

0.364

0.565 (0.504–0.623)

0.559 (0.514–0.613)

0.562

0.538 (0.504–0.595)

0.550 (0.487–0.615)

0.544

0.349 (0.267–0.433)

0.419 (0.281–0.555)

0.384

0.517 (0.377–0.626)

JME PPR

0.369 (0.312–0.421)

0.367 (0.321–0.410)

0.368

0.566 (0.490–0.623)

0.558 (0.479–0.613)

0.562

0.535 (0.464–0.616)

0.539 (0.431–0.615)

0.537

0.367 (0.267–0.433)

0.406 (0.281–0.555)

0.386

0.526 (0.377–0.626)

JME total

0.025

0.028

0.027

0.053

0.0557

0.054

0.034

0.040

0.038

0.061

0.053

0.057

0.077

Controls

SD

0.026

0.021

0.023

0.053

0.039

0.045

0.045

0.048

0.045

0.025

0.035

0.029

0.046

PPR +

JME

0.032

0.024

0.028

0.036

0.032

0.033

0.025

0.038

0.032

0.060

0.081

0.078

0.074

PPR

JME

0.030

0.022

0.026

0.043

0.034

0.039

0.034

0.044

0.039

0.051

0.065

0.061

0.062

total

JME

2.73

3.35

3.04

3.09

2.20

2.55

1.12

3.68

2.40

1.02

4.41

2.50

4.26

controls

PPR + vs. vs.

0.82

1,68

0.55

2.73

2.57

2.55

0

1.10

0.62

11.20

2.70

4.00

0.19

controls

PPR

Percentage change

0.82

2.51

1.66

2.91

2.38

2.55

0.56

0.92

0.55

6.62

0.49

3.50

1.94

controls

JME vs.

3.46

1.62

2.41

0.35

0.36

0

1.13

4.96

3.03

10.28

7.44

1.54

3.90

PPR

PPR + vs.

0.281a

0.325a

0.438a

0.521a

0.706a

0.149a

0.083a

0.268a

0.799b

0.507a

0.917b

0.247b

0.719b

0.354b

0.694b

0.741b

0.532b

0.982b

0.889b

0.391b

0.685b

0.711b

JME totalb

PPR a

(vs. controls) (P value)

Statistical significance

ARAS, ascending reticular activating system; GIC, genu internal capsule; ICP, inferior cerebellar peduncle; JME, juvenile myoclonic epilepsy; LGN, lateral geniculate nucleus; PPR, photoparoxysmal response; SD, standard deviation; VMT, ventromedial thalamus. a Post hoc test (Duncan test); bMann–Whitney U test.

right

FA VMT

left

FA VMT

overall

FA VMT

right

FA ICP

left

FA ICP

overall

FA ICP

right

FA GIC

left

FA GIC

overall

FA GIC

right

FA LGN

left

FA LGN

0.408 (0.280–0.504)

0.400

FA LGN

overall

0.516 (0.232–0.631)

FA ARAS

Controls

Mean (min–max)

Table 3 Statistical values for fractional anisotropy (FA)

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0.806 (0.718–1.029)

0.841 (0.686–0.958)

0.823

0.786 (0.658–0.965)

0.794 (0.612–1.188)

0.790

0.713 (0.634–0.777)

0.714 (0.660–0.800)

0.714

0.714 (0.660–0.700)

0.774 (0.684–0.852)

0.804 (0.713–0.907)

0.789

0.765 (0.674–0.976)

0.747 (0.686–0.984)

0.756

0.697 (0.606–0.777)

0.711 (0.606–0.788)

0.704

0.825 (0.727–1.070)

0.780 (0.701–0.861)

0.802

0.902 (0.628–1.438)

JME PPR +

0.841 (0.702–1.214)

0.843 (0.716–1.179)

0.842

0.763 (0.687–0.827)

0.745 (0.664–0.840)

0.754

0.721 (0.644–0.874)

0.710 (0.649–0.805)

0.715

0.822 (0.601–1.117)

0.728 (0.586–0.888)

0.775

0.918 (0.696–1.262)

JME PPR

0.811 (0.684–1.214)

0.826 (0.713–1.179)

0.818

0.764 (0.674–0.976)

0.746 (0.664–0.984)

0.755

0.710 (0.606–0.874)

0.711 (0.606–0.805)

0.710

0.823 (0.601–1.117)

0.751 (0.586–0.888)

0.787

0.911 (0.628–1.438)

JME total

0.069

0.073

0.073

0.089

0.129

0.110

0.033

0.036

0.034

0.109

0.092

0.100

0.385

Controls

SD

0.062

0.064

0.063

0.112

0.103

0.104

0.051

0.059

0.054

0.113

0.061

0.091

0.281

PPR +

JME

0.150

0.133

0.138

0.047

0.056

0.050

0.061

0.052

0.056

0.140

0.087

0.123

0.196

PPR

JME

0.121

0.107

0.113

0.078

0.078

0.077

0.057

0.054

0.054

0.125

0.079

0.110

0.230

total

JME

3.97

4.40

4.13

2.67

5.92

4.30

2.24

0.42

1.40

15.55

5.98

7.08

10.87

controls

PPR + vs.

Change in % PPR

vs.

4.34

0.24

2.31

2.93

6.17

4.56

1.12

0.56

0.14

15.13

1.09

3.47

9.29

controls

0.62

1.78

0.61

2.80

6.05

4.43

0.42

0.42

0.56

15.27

2.04

5.07

9.98

controls

JME vs.

8.66

4.85

6.72

0.26

0.26

0.26

3.44

0.14

1.56

0.36

6.67

3.37

1.77

PPR

PPR + vs.

0.107

0.327

0.545

0.333

0.230

0.852

0.235

0.184

0.470

PPR a

0.677

0.237

0.624

0.465

0.164

0.674

0.660

0.720

0.826

0.071

0.445

0.632

0.342

JME totalb

(vs. controls) (P value)

Statistical significance

ARAS, ascending reticular activating system; GIC, genu internal capsule; ICP, inferior cerebellar peduncle; JME, juvenile myoclonic epilepsy; LGN, lateral geniculate nucleus; PPR, photoparoxysmal response; SD, standard deviation; VMT, ventromedial thalamus. a Post hoc test (Duncan test); bMann–Whitney U test.

right

MD VMT

left

MD VMT

overall

MD VMT

right

MD ICP

left

MD ICP

overall

MD ICP

right

MD GIC

left

MD GIC

overall

MD GIC

right

MD LGN

left

MD LGN

0.736 (0.587–0.911)

0.749

MD LGN

overall

1.012 (0.594–2.544)

MD ARAS

Controls

Mean (min–max)

Table 4 Statistical values for mean diffusivity (MD)

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GIC in pPPR JME patients in contrast to the nPPR group when compared to healthy controls. The GIC predominantly contains motor fibers between the thalamus and the premotor cortex including the supplementary motor area [26]. Geithner et al. suggested photosensitive JME to be a JME subtype with a higher seizure risk, which makes antiepileptic drug (AED) treatment indispensable in these patients [27]. Additionally, in contrast to ABS, BMS and GTCS are predominantly characterized by motor symptoms and reported to be the most common seizure types induced by PS [8,28]. Therefore, different underlying epileptic mechanisms and pathways of generalized seizures can be suggested, especially with regard to PS as a provocative factor. Taking this into consideration, (i) it can be assumed that thalamo-frontal connections are an essential component of the propagation network of generalized seizures as previously suggested [29,30] and (ii) it is quite likely that microstructural abnormalities of thalamo-frontal (thalamo-premotor) connections in the GIC associate with an increased susceptibility to external stimuli in photosensitive cases, and may even reflect an increased epileptogenicity with a lower threshold to generate generalized seizures, notably those with predominantly motor symptoms. It should be noted that this study was not designed to investigate the effects of AEDs in JME; however, both the need for long-term AED treatment and the predominance of motor seizures in photosensitive JME implies that WM structures may be one target of AED effects. Kim et al. [6] reported reduced FA and increased MD to be suggestive for degradations of the microstructural organization of WM tracts in JME. Another recent study on microstructural changes in JME revealed increased FA and volume alterations in the putamen relative to healthy controls [17], possibly caused by alterations of the local iron concentration, which are reported to associate with FA variations in the putamen [31]. Additionally, Keller et al. [17] showed correlations between increased putamen FA and decreased thalamo-cortical WM FA. Conclusively, the involvement of both structures (putamen and thalamo-cortical connections) may support the existence of an executive network as reported previously [17,32,33]. The important role of thalamo-cortical circuitry as a pathological factor in IGE was shown previously [29,30], and reduced thalamo-cortical WM FA and thalamic volume loss was found especially in JME [30,34]. The LGN is part of the thalamus and receives afferences from retinal ganglion cells and the ARAS. Efferences go to the primary visual cortex with feedback connections back to the LGN. How-

ever, the pathological significance of the LGN in JME has not been investigated to date. Our findings of reduced FA and increased MD in the LGN in the JME group are suggestive of involvement in the epileptogenesis of JME. Assuming the LGN to be a filter for information coming from retinal ganglion cells and the ARAS, microstructural abnormalities in the LGN amongst patients with JME may be one explanation for the association of seizures with awakening [1,28], as both the thalamus and ARAS are known to be crucial in circadian rhythm regulation [35]. Additionally, our findings support the hypothesis that photosensitivity is a network dysfunction involving both cortical (primary visual cortex) and subcortical (ARAS, thalamus, thalamo-cortical connections) structures. Our findings of both FA reduction in the JME group compared to healthy controls and maximum MD increase in pPPR JME compared to nPPR JME and healthy controls may suggest a pivotal role of the LGN for the generation of PPR within this network. Recently, Kim et al. showed a greater reduction of the thalamo-cortical functional connectivity in relation to increasing disease duration, assuming that thalamoprefrontal network abnormalities may be the consequence of long-standing disease burden [22]. This is consistent with our results of strong correlations between lower mean FA in the VMT and early epilepsy onset (≤15 years of age). Furthermore, our study identified that lower mean FA and higher MD values in the ARAS correlate with both early epilepsy onset and a longer duration of epilepsy (≥15 years). Other recent investigations on WM abnormalities in JME patients (corona radiata, corpus callosum, frontal WM tracts) showed a significant negative correlation between FA and the frequency of GTCS [6]. In contrast, no correlation of FA and/or MD alterations with occurring seizure types was found in our study, which could be due to different patient selection criteria. Several limitations need to be considered. This study is a single center study with a relatively small group of 18 patients and therefore the possibility of type 2 statistical errors should be considered, particularly with regard to further subgroup analyses. Furthermore, inter-subject reliability of ROI position was achieved by registration in MNI space. To avoid the effects of normalization on DTI parameters, denormalization was performed prior to analysis for each individual subject. This may lead to inter-individual variations of the ROI size. This has to be considered in the interpretation of the statistical analysis of DTI parameters, which showed no statistically significant results but a trend. These limitations are also shared by other studies [9,11,12].

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DTI AND PHOTOSENSITIVITY IN JME

Despite the above limitations, our results corroborate the heterogeneity of JME as an electroclinical epilepsy syndrome and indicate microstructural abnormalities in JME compared to healthy controls. Additionally, this study reveals microstructural variations between pPPR and nPPR JME patients. Our findings are consistent with those of prior studies showing altered thalamo-cortical connectivity in JME patients; additionally, our results show both impaired microstructural integrity in the LGN in JME and microstructural abnormalities of (i) thalamo-premotor connections in the GIC, (ii) the ARAS and (iii) the VMT only in the group of photosensitive JME cases. These results are suggestive of a key role of the ARAS, the thalamic areas LGN and VMT, and thalamo-premotor connections in the increased susceptibility of generalized seizures to external stimuli in photosensitive JME, notably seizures with predominantly motor symptoms. Although no statistically significant correlations were found, our findings may help to generate hypotheses about structural and network connectivity in JME and contribute to a better understanding of the pathophysiology and epileptic networks of photosensitivity. Our results may therefore help in the planning of future prospective studies with larger study groups of patients with JME as well as other IGE syndromes.

Acknowledgements We gratefully acknowledge the assistance of Professor Dr med. G. Rabending and Dr rer. nat. P. Kolyschkow, University of Greifswald, Germany.

Disclosure of conflicts of interest The authors declare no financial or other conflicts of interest.

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