Introduction
Intractable partial epilepsy is a kind of seizure disorder encountered in patients with epilepsy, one of the most common chronic neurological diseases. Partial seizures are focal at onset, which means that they emerge from a localized region of the brain. In addition, more than 30 % of patients with partial seizures are refractory to antiepileptic drug medication (Berg
2008). These two features, focal localization of epileptogenic region and drug resistance, lead us to consider surgery as a possible treatment.
An accurate localization of epileptogenic focus (EF) in intractable partial epilepsy is essential to guarantee success in surgical treatment. To this end, a variety of multimodal techniques including EEG, MRI, SPECT and PET are employed. Ictal SPECT is still the only imaging modality that allows us to assess cerebral blood flow during a seizure without artifacts (Setoain et al.
2012). One of the techniques to analyze ictal SPECT is the Subtraction of Ictal SPECT Co-registered to MRI (SISCOM) (O’Brien et al.
1998a). Several authors agree that this methodology is very useful above all when there is no anatomical lesion and in cases where invasive video-EEG should be avoided (O’Brien et al.
1998b; Vera et al.
1999; Ahnlide et al.
2007; Tan et al.
2008; Matsuda et al.
2009).
SISCOM processing is commonly divided into four steps: SPECT-SPECT (S-S) registration, intensity normalization, subtraction and SPECT-MRI (S-M) registration. To perform SISCOM analysis, there are computer-aided methods such as those of general purpose in image processing (Acton and Friston
1998; Smith et al.
2004) or those that integrate a SISCOM analysis tool in a larger image software package (Robb and Hanson
1990; Papademetris et al.
2001) which are mainly addressed to researchers or image technicians rather than to clinicians.
This paper presents a multimodal application designed to aid clinicians in the analysis of intractable partial epilepsy. The application named FocusDET (focus detection) allows us to perform the SISCOM analysis by means of a user-friendly interface. The registration algorithms of FocusDET (S-S and S-M) were evaluated by assessing the accuracy of the localization of the EF. We also evaluated the relationship between registration errors and image corrections by reconstructing simulated studies using two reconstruction methods (with and without corrections).
Discussion
In the present study, FocusDET, a new application to localize the epileptogenic focus in intractable partial epilepsy using the SISCOM methodology has been presented and evaluated. We assessed the registration errors involved in the SISCOM process by using Monte Carlo SPECT simulations, including anatomical variability and epileptogenic foci positioned in several anatomical areas where they are usually located.
In clinical practice, reconstruction of SPECT images is usually performed by using FBP reconstruction with low cut-off frequencies in order to obtain a smooth image, which is useful for visual analysis. Nevertheless, after the results of Fig.
5a, the cut-off frequency recommended for the SISCOM analysis using FBP reconstruction is 0.75 cm
−1 (1/2f
N). To maintain a suitable signal-to-noise ratio for visual evaluation, a smoothing process of registered images could be applied after the registration process. For OSEM reconstruction, Fig.
5b shows that registration errors in the SISCOM process reaches the minimum after 8 iterations. Although the reconstruction with corrections (OSEM) is increasingly used, the small differences found between both reconstructions methods (with or without corrections) make the use of FBP a suitable method of reconstruction in terms of registration errors with FocusDET, especially for those centers that do not have the possibility of correcting images for these degrading effects.
SPECT-SPECT registration has been a challenging process because the better the registration, the fewer the artifacts in the final result of SISCOM analysis (Brinkmann et al.
1999). Comparing our findings (Table
1) with the results of other studies, the use of the local correlation coefficient as a cost function yields lower registration errors than other cost functions such as is NMI (Mumcuoglu et al.
2006).
As regards SPECT-MRI registration, our results show the importance of the optimization of the Gaussian kernel width and the number of samples used to compute the cost function. Thus, the registration errors are lower than the voxel size when using the optimum registration parameters and NMI–MMI as the cost functions, and very similar than other studies (Barnden et al.
2000 and Thurfjell et al.
2000).
Evaluation of registration algorithms with real cases is always problematic. In epilepsy surgery, where three studies (two SPECTs and MRI) are performed and multimodal registrations are involved, the challenge increases. In this situation, the use of fiducial markers is practically ruled out. Thus, the FocusDET facility described above is considered to be an appropriated visual tool for accepting o discarding a registration. In this way, we take advantage of the expertise of nuclear medicine physicians in evaluating images to assess the accuracy of the registration processes in a qualitative but skilled way. The excellent results obtained in the registration error using simulated studies, and in the qualitative assessment of the registration process by experts using patient studies, support the robustness of FocusDET registration algorithms.
In addition to registration assessment, the qualitative analysis of the epileptogenic focus localizations using simulation and patient studies allowed us to evaluate the entire SISCOM process. Our results show an agreement in epileptogenic focus localization in simulated studies (between theoretical and reported localizations) and patient cases (between localizations from MRI and video-EEG techniques and that reported by the expert from SISCOM output). For simulation data, false positives were improbable because there are no differences, other than focus and real noise, between ictal and interictal SPECTs. Nevertheless, false positives are likely in the case of patient studies. False positives in partial epilepsy studies have several origins, the most important one being associated with injection latency. In our set of patients, the ictal studies selected are true ictal SPECT, i.e., the tracer injection was performed close to the seizure onset and no propagation artifacts were detected in the SISCOM analysis. Besides, a localization error could be due to a registration error. The agreement between the different techniques (video-EEG, MRI and SISCOM) in each of patients studied reinforced the impression of a well performed registration given that no propagation was s observed a posteriori.
It should also be pointed out that FocusDET registration algorithms have been tested in 62 patients from the Epilepsy Unit database, and the registrations were considered to be satisfactory for the clinicians in every case. These studies have not been included as they do not fulfill the selection criteria required of patients with a well-localized epilepsy, whom we considered as a gold standard for our validation of the localization.
In summary, our findings show that SISCOM analysis with FocusDET led to small registration errors and satisfactory results in the evaluation of experts in both simulated and patient studies.
Acknowledgments
This work was supported in part by Virtual Physiological Human Toolkit (VPHTk) project of Centro de Investigación Biomédica en Red en Bioingeniería, Biomateriales y Nanomedicina (CIBER-BBN), by Talència’s grants 2009SGR-00866 and 2009SGR-1049, by Ministerio de Ciencia e Innovación (SAF2009-08076), by the European Commission VPH Network of Excellence (IST-2007-223920) and by Spain’s Ministry of Science & Innovation through CDTI-CENIT (AMIT project) and project TEC2010-21619-C04-03; Comunidad de Madrid (ARTEMIS S2009/DPI-1802), and the European Regional Development Funds (FEDER). B. Martí was awarded a PhD fellowship (App Form—Call 07-2009) of Institute for Bioengineering of Catalonia (IBEC). A.F. Frangi holds an ICREA-Academia Award from the Institució Catalana de Recerca I Estudis Avançats (ICREA).