CIC Edizioni Internazionali. Could DTI alterations be different in temporal lobe epilepsy? Two case reports and a review of the literature.

Transcription

1 Review Could DTI alterations be different in temporal lobe epilepsy? Two case reports and a review of the literature Laura Mumoli 1 Angelo Labate 1 Andrea Cherubini 2 Maria Eugenia Caligiuri 2 Edoardo Ferlazzo 1 Umberto Aguglia 1 Aldo Quattrone 1 Antonio Gambardella 1 1 Institute of Neurology, Magna Græcia University, Germaneto, Catanzaro, Italy 2 Institute of Molecular Bioimaging and Physiology of the National Research Council (IBFM-CNR), Germaneto, Catanzaro, Italy Corresponding author: Angelo Labate Institute of Neurology, Magna Græcia University Viale Europa Germaneto, Catanzaro, Italy labate@unicz.it Abstract Objective: diffusion tensor imaging (DTI) studies have demonstrated bilateral temporal and extratemporal alterations in white matter tracts in patients with refractory mesial temporal lobe epilepsy (rmtle). Conversely, DTI data in patients with benign MTLE (bmtle) have not been exhaustively investigated yet. Here we described clinical and DTI features of two patients together with a review of the current literature. Methods: one patient with rmtle and one with bm- TLE are described. DTI was performed in each patient and compared to healthy volunteer. Mean diffusivity (MD) and fractional anisotropy (FA) in hippocampi and temporal lobe grey and white matter regions were measured. We also reviewed all the existing literature relevant to the understanding the role of DTI in MTLE using predefined search criteria from electronic databases (e.g., PubMed, Cochrane Library Database of Systematic Reviews). Results: here we have found in rmtle subject a FA lower in temporal white matter compared to bmtle subject. These data are very closely to the unique study of DTI performed in bmtle. Conclusions: to date the majority of DTI studies in MTLE have been performed in rmtle patients as highlighted in our review of the literature. Our two cases together with our previous DTI results in bmtle support the hypotheses that DTI features may capture differences among MTLE patients. KEY WORDS: temporal lobe epilepsy, DTI, refractoriness. Introduction Diffusion tensor imaging (DTI), a novel non-invasive imaging technique, has shown diffuse temporal and extra-temporal alterations in white matter tracts of patients with mesial temporal lobe epilepsy (MTLE), even in those without bilateral or unilateral hippocampal sclerosis (Hs) (1-3). However, all DTI findings available in the literature have been obtained in refractory MTLE (rmtle), so it is possible that the detected abnormalities could be the effect of repeated seizures, or multiple drugs use (1, 3). On the other hand these abnormalities may be correlated to congenital malformation of the temporal lobe and/or induced by an early event such as a prolonged febrile convulsions, with increased susceptibility to the development of Hs and subsequent rmtle (4). During the last years our group has focused the attention on studying a benign form of MTLE (bmtle), whose main features include onset of seizures in adult age and long-term seizure freedom (5). Furthermore, although about 1/3 of bmtle patients shows on brain MRI the presence of Hs, they display mild epilepsy (6). In the recent past, using advanced MRI techniques such as voxel-based morphometry (VBM) we showed reduction in grey matter volume of temporal and extratemporal structures in bmtle (7-9) as well as in rmtle, as previously reported, suggesting that these two phenotypes might be part of a biological continuum (5, 6). In this article, we firstly presented our data on DTI analysis in two patients with MTLE (one with rmtle and one with bmtle); secondly we reviewed the current DTI literature on MTLE. Clinical Study Methods A research ethics committee approved this study and written informed consent was obtained from participants. DTI data of two patients were compared with the ones obtained in a control group of healthy subject (matched for age and gender). In each patient, the diagnosis of MTLE was made on the basis of seizure Clinical Cases and Reviews in Epilepsy 2016; 1(1):1-5 1

2 L. Mumoli et al. semiology, typical mesio-temporal auras, interictal and ictal EEG (10, 11). Epileptiform discharges were diagnosed in the presence of focal spikes or sharp waves followed by slow waves always involving the temporal regions. Any suggestion of seizure onset outside the mesial temporal structures, by semiology or EEG findings, was an exclusion criterion. The only accepted MRI sign was Hs, which was based on the characteristic MRI abnormalities (12). Conventional coronal FLAIR and IR images were visually inspected for the presence of Hs. The MRI diagnosis of Hs was based on the occurrence of at least one of the neuroimaging alterations that are considered reliable indicators of Hs: the presence of atrophy on T1 weighted, an increased mesial temporal signal intensity alteration on FLAIR or T2 images, or both. None of our patients had mental retardation. Based on the convergence of clinical, EEG and imaging investigation these MTLE patients were classified in: bmtle and rmtle. In particular a diagnosis of bmtle was made if patients were seizure-free for at least 24 months with or without antiepileptic drugs. The definition of rmtle fulfilled the ILAE criteria for drug-resistant epilepsy as persistent seizures despite trials of two or three adequately tolerated and appropriate antiepileptic drugs (13). Both patients underwent 3 Tesla MR750 GE MRI scanner with an eight channel head coil. MRI protocol including: whole-brain 3D T1-weighted SPGR (BRA- VO, voxel size of 1x1x1 mm 3 ); Diffusion Tensor Imaging (DTI) (voxel size 2x2x2 mm 3, 27 directions with gradients at a b-value of s x mm 2 and 4 b=0 images); 3D FLAIR (CUBE, voxel size of 1x1x1 mm 3 ); conventional T2-weighted and Inversion Recovery images. Image processing was performed using the tool FSL and Matlab software (14). The presence/absence of hippocampal sclerosis was assessed using the automated procedure described by Huppertz et al. (15) using the 3D FLAIR and T1-weighted volumes, and verified by a neuroradiologist blinded to the electroclinical data, based on the occurrence of at least one of the neuroimaging alterations which are widely considered reliable indicators of Hs (16). Results Patient 1 (rmtle) A 19-year-old man had simple febrile seizure every 3 to 6 months from the age of 8 months until 70 months. At the age of 13 years, he began to have, almost every 2-3 months, focal complex seizures characterized by behavioural arrest, some lip smacking and gestural automatisms, or nocturnal secondary generalized motor seizures. Seizures continued despite treatment with carbamazepine plus topiramate at a dosage of 1200 and 400 mg/day, respectively. Over the years, he also began to experience epigastric nausea with some experiential phenomena prior to the loss of awareness. Interictal EEG recording showed bilateral interictal antero-mesiotemporal epileptiform spikes, which strongly predominated (>70%) on the right side. Typical seizures with onset in the right tem- poral region were also recorded. An MRI study showed a right Hs, (seen as a reduction of volume of the right hippocampus plus an abnormally high signal intensity on FLAIR sequence). Despite polytherapy with carbamazepine, phenobarbital and topiramate, he remained refractory to treatment. He further refused a surgical evaluation. Patient 2 (bmtle) A young 22-year-old man had simple febrile seizures from the age of 5 months to the age of 70 months. When he was 11 years old he started to have twice a month focal seizures of temporal origin characterized by vegetative symptoms, loss of consciousness, head and eyes deviation to the right, gestural automatisms and cyanosis. He also had very rare nocturnal secondary generalized motor seizures. Interictal EEG recording showed left temporal spikes. An MRI study of the brain was normal. He was referred to our clinic at the age of 17 and afterwards he was started with a low dose of carbamazepine (600 mg daily). He is now seizure free since 5 years. DTI analysis The analysis of DTI measurements showed a lower FA in temporal white matter in the rmtle subject (Fig. 1) compared to the bmtle patient (Fig. 2). On the basis of these data, fractional anisotropy (FA) could be considered a possible biomarker for discriminating patients with rmtle from those with bmtle. Systematic literature search Methods For this review, published studies were identified using pre-defined search criteria that included the following key words: diffusion tensor imaging, DTI, white matter abnormalities and their combinations with temporal lobe epilepsy, refractory temporal lobe epilepsy, benign temporal lobe epilepsy, hippocampal sclerosis, in the PubMed and Cochrane Library databases. Included were primary peer-reviewed articles that had been published until 10 th November Data extraction: eligibility for inclusion in the review was determined on abstract screening using the following inclusion criteria: (1) original investigation on DTI in mesial temporal lobe epilepsy focusing attention on rmtle and bmtle, (2) reviews on DTI in temporal lobe epilepsy with or without Hs. We intentionally excluded case reports, studies performed in secondary temporal lobe epilepsy due to cortical dysplasia or other neurodevelopmental disorders, connectome studies and studies focused on application of DTI in surgical fields. Results Literature search 31 studies were initially identified using our search strategy (all in PubMed, none in the Cochrane). Only 2 Clinical Cases and Reviews in Epilepsy 2016; 1(1):1-5

3 Could DTI alterations be different in temporal lobe epilepsy? Two case reports and a review of the literature Figure 1 - DTI and volumetric findings in patient with rmtle. Figure 2 - DTI and volumetric findings in patient with bmtle. 7 out of 31 matched our inclusion criteria and only 1 of these was conducted in bmtle. Discussion From 2002 to 2015 many groups have analysed DTI abnormalities in MTLE, the majority of them performed in refractory patients (17). Although these studies in rmtle were very heterogeneous, they generally showed widespread and often bilateral white matter abnormalities especially in patients with TLE and unilateral Hs (18); these patterns were less extensive and severe in patients with MTLE without evidence of Hs. The observed DTI abnormalities in MTLE were not confined only in the hippocampus and temporal lobe white matter but involved various brain structures such as corpus callosum, frontal lobe, supporting the idea that a diffuse epileptic network underlies MTLE s pathogenesis. Furthermore, the age at onset of MTLE could be an important factor responsible of different patterns of DTI abnormalities detected in children compared to adults in MTLE patients. In fact Grovindam et al. (19) reported in children with rm- TLE decreased FA in the arcuate, uncinate and internal longitudinal fasciculus, whereas Nilsson et al. reported (20) normal FA with an increased mean diffusivity (MD). A possible explanation of these conflicting data may be related to the heterogeneity of aetiologies in children with MTLE compared to adults and Clinical Cases and Reviews in Epilepsy 2016; 1(1):1-5 3

4 L. Mumoli et al. secondly because of the intrinsic white matter properties at the early stage of MTLE (19, 20). However whether white matter alterations are secondary to seizure activity or to the duration of epilepsy remains still unclear. There is no longitudinal follow-up study in these populations to draw definite hypothesises. On the other hand, a recent meta-analysis of DTI investigations in MTLE subjects without Hs revealed a pattern of white matter alterations also in their asymptomatic siblings (albeit attenuated), suggesting that DTI findings may be at least in part, under genetic control (21) creating further confusion in the current literature. Another important issue is how white matter networks contribute to cognitive morbidity and post-operative cognitive decline in patients with epilepsy, and how adaptive changes in white matter networks may allow for inter- and intra- hemispheric reorganization of function. Although a possible correlation between white matter abnormalities detected on DTI and cognitive functions in TLE patients have been investigated, the results of these studies are controversial and not conclusive (22). A chance to better understand white matter alterations in patients with MTLE regardless the presence of Hs could be to study patients with drug-responsive MTLE. For this reason our group has recently published the first study on such patients (23) showing a significant reduction of FA and increases in MD within the temporal lobe only in patients with rmtle. This important result suggests the importance of FA as the only parameter capable to discriminate patients with bmtle from those with rmtle. As expected, there was a trend in favour of a loss of volume within the hippocampi in both groups, which is greater in patients with rmtle (p=0.0057). In conclusion, the DTI literature has demonstrated very interesting findings mainly in rmtle; therefore, as highlighted in our recent publication on benign MTLE and in the two cases presented here, DTI might be considered a promising tool to find biomarkers of drug refractoriness. Disclosure or conflict of interest All Authors have no conflicts of interest. We confirm that we have read the Journal s position on issues involved in ethical publication and affirm that this report is consistent with those guidelines. References 1. Concha L, Beaulieu C, Collins DL, Gross DW. White-matter diffusion abnormalities in temporal-lobe epilepsy with and without mesial temporal sclerosis. J Neurol Neurosurg Psychiatry. 2009;80: Focke NK, Yogarajah M, Bonelli SB, Bartlett PA, Symms MR, Duncan JS. Voxel-based diffusion tensor imaging in patients with mesial temporal lobe epilepsy and hippocampal sclerosis. Neuroimage. 2008;40: Gross DW. Diffusion tensor imaging in temporal lobe epilepsy. Epilepsia. 2011;52(Suppl. 4):S Gloor P. Mesial temporal sclerosis: historical background and an overview from a modern perspective. In: Luders H, ed. Epilepsy Surgery. New York: Raven Press. 1991; Labate A, Gambardella A, Andermann E, et al. Benign Mesial Temporal Lobe Epilepsy. Nature Reviews Neurology. 2011;7: Labate A, Ventura P, Gambardella A, et al. MRI evidence of mesial temporal sclerosis in sporadic benign temporal lobe epilepsy. Neurology. 2006;66: Labate A, Cerasa A, Aguglia U, Mumoli L, Quattrone A, Gambardella A. Voxel-based-morphometry of sporadic epileptic patients with mesio-temporal sclerosis. Epilepsia. 2010;51: Labate A, Cerasa A, Gambardella A, Aguglia U, Quattrone A. Hippocampal and thalamic atrophy in mild temporal lobe epilepsy: a VBM study. Neurology. 2008;71: Labate A, Cerasa A, Aguglia U, Mumoli L, Quattrone A, Gambardella A. Neocortical thinning in benign mesial temporal lobe epilepsy. Epilepsia. 2011;52: Cendes F, Li LM,Watson C, Andermann F, Dubeau F, Arnold DL. Is ictal recording mandatory in temporal lobe epilepsy? Not when the interictal electroencephalogram and hippocampal atrophy coincide. Arch Neurol. 2000;57: Berg AT, Berkovic SF, Brodie MJ, Buchhalter J, Cross JH, 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, Epilepsia. 2010;51(4): Jackson GD, Berkovic SF, Duncan JS, Connelly A. Optimizing the diagnosis of hippocampal sclerosis using MR imaging. AJNR Am J Neuroradiol. 1993;14: Kwan P, Arzimanoglou A, Berg AT, Brodie MJ, Allen Hauser W, Mathern G, et al. Definition of drug resistant epilepsy: consensus proposal by the ad hoc Task Force of the ILAE Commission on Therapeutic Strategies. Epilepsia. 2010;51: Jenkinson M, Beckmann CF, Behrens TE, Woolrich MW, Smith SM. FSL. NeuroImage. 2010;62: Huppertz HJ, Wagner J, Weber B, House P, Urbach H. Automated quantitative FLAIR analysis in hippocampal sclerosis. Epilepsy Res. 2011;97(1-2): Jackson GD, Connelly A, Duncan JS, et al. Optimizing the diagnosis of hippocampal sclerosis using MR imaging. AJNR Am J Neuroradiol. 1993;14: Gross DW. Diffusion tensor imaging in temporal lobe epilepsy. Epilepsia. 2011;52: Concha L, Beaulieu C, Collins DL, Gross DW. White matter abnormalities in temporal-lobe epilepsy with or whithout mesial temporal sclerosis. J Neurol Neurosurg Psychiatry. 2009;80: Govindan RM, Makki MI, Sundaram SK, Juhasz C, Chugani HT. Diffusion tensor analysis of temporal and extra-temporal lobe tracts in temporal lobe epilepsy. Epilepsy Res. 2008;80: Nilsson D, Go C, Rutka JT, Rydenhag B, Mabbott DJ, Snead OC III, Ray- Baud CR, Widjaja E. Bilateral diffusion tensor abnormalities of temporal lobe and cingulate gyrus white matter in children with temporal lobe epilepsy. Epilepsy Res. 2008;81: Whelan CD, Alhusaini S, O Hanlon E, Cheung M, Iyer PM, Meaney JF, Fagan AJ, Boyle G, Delanty N, Doherty CP, Cavalleri GL. White matter alterations in patients with MRInegative temporal lobe epilepsy and their asymptomatic siblings. Epilepsia. 2015;56(10): Clinical Cases and Reviews in Epilepsy 2016; 1(1):1-5

5 Could DTI alterations be different in temporal lobe epilepsy? Two case reports and a review of the literature 22. Leyden KM, Kucukboyaci NE, Puckett OK, Lee D, Loi RQ, Paul B, McDonald CR. What does diffusion tensor imaging (DTI) tell us about cognitive networks in temporal lobe epilepsy? Quant Imaging Med Surg. 2015;5(2): Labate A, Cherubini A, Tripepi G, Mumoli L, Ferlazzo E, Aguglia U, Quattrone A, Gambardella A. White matter abnormalities differentiate severe from benign temporal lobe epilepsy. Epilepsia. 2015;56(7): Clinical Cases and Reviews in Epilepsy 2016; 1(1):1-5 5