What is the significance of interictal water diffusion changes in frontal lobe epilepsies?

Abstract

The aim of this study was to better understand the significance of interictal changes in water molecule diffusivity defined by diffusion-weighted imaging (DWI) in frontal lobe epilepsy (FLE), as well as to test the accuracy of interictal DWI in the definition of the epileptogenic zone (EZ).

DWI was carried out in 14 patients with refractory FLE (9 negative-MRI) as well as in 25 controls. Statistical mapping analysis (SPM2) of diffusivity maps was used to detect, for each subject, significant diffusivity alterations. We then studied the relationships between diffusion and depth recorded electrical abnormalities. Clinical correlates of the extent of diffusivity changes were also tested. We found areas of significantly increased diffusivity (SID) in 13 patients. Eight had SID in the EZ, 9 within the irritative zone (IZ) and 12 outside, mainly in connected areas. We found a correlation between the extent of SID and the duration of epilepsy (p corrected = 0.026, R = 0.621). In addition, SID was significantly less widespread in negative-MRI patients (p = 0.028). However, we found no significant differences concerning either seizure frequency (p = 0.302), seizure generalization (p = 0.841), history of status (p = 0.396), or surgical outcome (p = 0.606). We suggest that SID in normal appearing areas is not a specific signature of epileptogenicity in FLE, and is more likely to reflect multifactorial and potentially evolving neuro-glial injuries.

Introduction

Frontal lobe epilepsy (FLE) is the second most common form of drug-resistant partial epilepsy referred to epilepsy surgery centres (Rosenow and Luders, 2001). However, though frequent, intractable FLEs are still poorly studied and remain ill-understood. Indeed, the epileptogenic zone (EZ) that must be surgically removed in order to cure patients is much more difficult to define in FLE than in temporal lobe epilepsy (TLE) (Chauvel et al., 1992, Chauvel et al., 1995, Jobst and Williamson, 2005, Williamson and Jobst, 2000). This may be explained by several anatomical and functional differences between FLE and TLE: (i) the size of the frontal lobe, (ii) the complexity and wide connectivity of the neural systems potentially involved in frontal lobe seizures, and (iii) the often misleading electroclinical patterns due to fast discharge spread. Therefore, intracranial recordings are frequently required in the presurgical evaluation of FLEs (Talairach et al., 1992). However, invasive investigations are still difficult to perform in such epilepsies and need to be guided. In this context, better definition of structural alterations and their epileptogenicity in vivo, are major issues. Structural changes at a cellular scale may be assessed by diffusion-weighted imaging (DWI), which is a non-invasive MR technique allowing quantification of passive water motion or diffusivity (expressed as apparent diffusion coefficient (ADC) or mean diffusivity (MD)). In the brain, this diffusivity, being mainly extra-cellular, is constrained by cell membranes and organelles, axons and myelin sheaths (Basser and Pierpaoli, 1996). Therefore, DWI measures the interactions between water molecules and cerebral structures. Thus, any cell or tissue alteration may affect water molecule motion and consequently be assessed in vivo by measuring water diffusivity.

Using DWI, animal studies have first demonstrated an early and transient diffusivity decrease during provoked status or sustained seizures (Ebisu et al., 1996, Nakasu et al., 1995, Prichard et al., 1995, Zhong et al., 1993, Zhong et al., 1997). This decrease has been interpreted as a functional cellular swelling due to the edema produced by seizure excitotoxicity (Wang et al., 1996). In human studies of status epilepticus, DWI data have shown more complex modifications comprising both decreased and increased diffusivity (Hisano et al., 2000, Wieshmann et al., 1997). Peri-ictal and post-ictal human studies using DWI or diffusion tensor imaging (DTI) (i.e. a diffusion imaging technique allowing quantification of water diffusivity as well as anisotropy) showed in some cases, transiently decreased local diffusivity, potentially in concordance with the EZ (Diehl et al., 1999, Diehl et al., 2001, Diehl et al., 2005, Hufnagel et al., 2003).

Conversely, interictal diffusion imaging is more likely to demonstrate fixed tissue changes susceptible to affect water diffusivity. Several diffusion studies have already demonstrated areas of significantly increased diffusivity (SID) in a proportion of patients with partial epilepsies during the interictal period (Arfanakis et al., 2002, Assaf et al., 2003, Eriksson et al., 2001, Rugg-Gunn et al., 2001, Rugg-Gunn et al., 2002, Sundgren et al., 2004, Thivard et al., 2005, Thivard et al., 2006, Lee et al., 2004, Kantarci et al., 2002). Numerous studies have focused on TLE demonstrating SID in mesial temporal lobe structures, predominating on the ipsilateral side in individual and group studies (Assaf et al., 2003, Lee et al., 2004, Kantarci et al., 2002, Arfanakis et al., 2002, Thivard et al., 2005). However, individual approaches have also shown SID in areas outside the temporal lobe (Arfanakis et al., 2002, Thivard et al., 2005). Rugg-Gunn et al. were the first to demonstrate areas of SID in 8 out of 30 negative-MRI patients presenting with several forms of partial epilepsy. Six SID were concordant with surface EEG abnormalities (Rugg-Gunn et al., 2001). In that study, the clinical data provided (no depth recording) showed that 8 of the 30 patients probably suffered from FLE. Three out of these 8 probable FLEs had SID compatible with the surface EEG abnormalities. In a case report, the same group reported good concordance between a single area of SID and the EZ identified by using depth electrode recording in one patient (Rugg-Gunn et al., 2002). Thivard and colleagues found areas of SID in 11 out of 16 patients, including 2 cases of FLE (Thivard et al., 2006). Performing a careful comparison between diffusivity and electrical abnormalities by using depth electrode recordings, they found congruent location in 7 out of the 11 patients (including 1 FLE). Therefore, only 3 cases of careful comparison between diffusion imaging and depth electrode recording in FLE are currently available in the literature. Although comparisons between the location of diffusivity abnormalities and epileptogenic areas have been already addressed in partial epilepsy, the significance of such abnormalities has not been fully examined in FLE.

In the present study, we aimed to better understand the relationships between interictal water diffusivity changes and electrical abnormalities in FLE. We also aimed to assess the accuracy of interictal DWI in the definition of the EZ in such epilepsies. We studied 14 patients suffering from intractable FLE (9 MRI-negative). DWI of each patient was compared to a group of 25 control subjects on a voxel-by-voxel basis to define statistically abnormal areas of diffusivity. We then compared the location of diffusivity changes with the location of depth recorded electrical abnormalities (defined by using stereo-electroencephalography (SEEG)). Based on these comparisons, we studied the specificity and sensitivity of DWI in the definition of the epileptogenic zone. We also tested whether the extent of diffusion abnormalities was correlated to clinical features.