Epileptogenic Developmental Venous Anomaly: Insights From Simultaneous EEG/fMRI

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Epileptogenic Developmental Venous Anomaly: Insights From Simultaneous EEG/fMRI Olivier Scheidegger, Roland Wiest, Kay Jann, Thomas König, Klaus Meyer and Martinus Hauf Clin EEG Neurosci 2013 44: 157 originally published online 7 February 2013 DOI: 10.1177/1550059412464463 The online version of this article can be found at: http://eeg.sagepub.com/content/44/2/157

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Article

Epileptogenic Developmental Venous Anomaly: Insights From Simultaneous EEG/fMRI

Clinical EEG and Neuroscience 44(2) 157-160 ª EEG and Clinical Neuroscience Society (ECNS) 2013 Reprints and permission: sagepub.com/journalsPermissions.nav DOI: 10.1177/1550059412464463 eeg.sagepub.com

Olivier Scheidegger1, Roland Wiest1, Kay Jann2, Thomas Ko¨nig2, Klaus Meyer3, and Martinus Hauf1

Abstract Developmental venous anomalies (DVAs) are associated with epileptic seizures; however, the role of DVA in the epileptogenesis is still not established. Simultaneous interictal electroencephalogram/functional magnetic resonance imaging (EEG/fMRI) recordings provide supplementary information to electroclinical data about the epileptic generators, and thus aid in the differentiation of clinically equivocal epilepsy syndromes. The main objective of our study was to characterize the epileptic network in a patient with DVA and epilepsy by simultaneous EEG/fMRI recordings. A 17-year-old woman with recently emerging generalized tonic–clonic seizures, and atypical generalized discharges, was investigated using simultaneous EEG/fMRI at the university hospital. Previous high-resolution MRI showed no structural abnormalities, except a DVA in the right frontal operculum. Interictal EEG recordings showed atypical generalized discharges, corresponding to positive focal blood oxygen level dependent (BOLD) correlates in the right frontal operculum, a region drained by the DVA. Additionally, widespread cortical bilateral negative BOLD correlates in the frontal and parietal lobes were delineated, resembling a generalized epileptic network. The EEG/fMRI recordings support a right frontal lobe epilepsy, originating in the vicinity of the DVA, propagating rapidly to both frontal and parietal lobes, as expressed on the scalp EEG by secondary bilateral synchrony. The DVA may be causative of focal epilepsies in cases where no concomitant epileptogenic lesions can be detected. Advanced imaging techniques, such as simultaneous EEG/fMRI, may thus aid in the differentiation of clinically equivocal epilepsy syndromes. Keywords developmental venous anomaly, DVA, EEG, EEG/fMRI, epilepsy Received January 13, 2012; accepted August 11, 2012.

Introduction DVAs, formerly called venous angiomas, are congenital variations in the transmedullar venous drainage of white and gray matter. During embryologic development of intracranial blood vessels, a developmental arrest of medullary veins results in the persistence of a large primitive embryonic deep white matter vein. Diagnosis is made on structural magnetic resonance imaging (MRI) studies, by identifying an enlarged subependymal draining vein, with associated radially oriented medullary veins (caput medusae) surrounded by normal brain tissue. DVAs are the most prevalent intracranial vascular malformation at autopsy,1 and population-based studies showed a prevalence on magnetic resonance (MR) scans of 1.7%.2 A recent systematic review and prospective population-based study concluded that DVAs usually have a benign presentation, mostly being incidental findings with rare symptoms due to non-hemorrhagic focal neurological deficits, symptomatic hemorrhage, epileptic seizures, and infarction, and that they have a benign clinical course as well.3 The exact clinical significance of DVA

still remains controversial, as most symptoms are assumed to be related to associated pathologies.4 In symptomatic DVAs, up to 4% of patients presented with epileptic seizures as the initial symptom.3,5 Despite this association, DVAs are rarely found in the presumed epileptogenic zone, in contrast to other vascular malformations such as 1 Support Center for Advanced Neuroimaging (SCAN), Institute for Diagnostic and Interventional Neuroradiology, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland 2 Department of Psychiatric Neurophysiology, University Hospital of Psychiatry, University of Bern, Bern, Switzerland 3 Bethesda Epilepsy Center, Tschugg, Switzerland

Corresponding Author: Martinus Hauf, Support Center for Advanced Neuroimaging (SCAN), Institute for Diagnostic and Interventional Neuroradiology, Inselspital, University of Bern, Freiburgstrasse, 3010 Bern, Switzerland. Email: [email protected] Full-color figures are available online at http://eeg.sagepub.com

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cavernomas.6 In patients with epilepsy and solely DVA as a vascular malformation, To¨pper et al7 found a topographic concordance between DVA and the epileptic focus on the scalp EEG in only 1 of 15 patients, whereas no concordance was found in a study of Morioka et al.8 Seizures in the frontal lobe, corresponding to the predominant localization of DVA, are difficult to evaluate using a standard diagnostic workup. Prevailing secondary bilateral synchronous discharges on scalp EEG do not allow a differentiation between idiopathic generalized epilepsies and focal epilepsy syndromes of frontal origin.9 Ictal single photon emission computed tomography studies,10 stereotactic EEG,11 or magnetoencephalography12 have been applied to differentiate focal versus primary generalized onset in patients with bilateral synchrony on the scalp EEG. A promising method for localization of the epileptic generators combines scalp EEG with simultaneously recorded fMRI during seizure-free periods. In difficult clinical evaluation of frontal lobe epilepsies, a recent study highlighted the clinical use of EEG/fMRI,13 that may be further improved by standardized analysis strategies of EEG/fMRI data.14 Here, we present EEG/fMRI data in a case of frontal lobe epilepsy and provide evidence of the epileptogenicity of a DVA, commonly considered asymptomatic. The study was approved by the local ethics committee, and informed consent was obtained from the patient.

Report of a Case A 17-year-old female patient, without prior medical illness or family history for epilepsy, suffered 2 witnessed generalized epileptic seizures within half a day. Both seizures were generalized tonic–clonic with postictal slowing on the right hemisphere. Routine physical examination and blood tests that day were normal. Interictal standard EEG recordings disclosed repetitive, predominantly bifrontal atypical generalized discharges. Using high-resolution structural MRI (performed according to the guidelines of the International League Against Epilepsy [ILAE]), a DVA was disclosed in the right frontal operculum with a typical ‘‘caput medusae’’ sign ending in a large vein draining centripetally to the inferior sagittal sinus (Figure 1A). No other structural brain abnormalities were noticed. One month later, neurological workup was performed at an epilepsy clinic. During hospital stay, 2 further non-provoked generalized epileptic seizures occurred, starting with a tonic posture of the left arm. A postictal right frontal slowing was observed on the scalp EEG. Five days later, the patient was referred to our institution for EEG/fMRI, before anticonvulsive treatment was initiated. The scalp EEG displayed paroxysmal focal delta discharges over Fp2 and F8 preceded by 1-second generalized slow-wave discharges with frontal predominance (Figure 1B). EEG/fMRI was performed, as published previously.14,15 In summary, a surface EEG, with 92 electrodes, was performed in the interictal state outside and inside an MR scanner at 3 T with simultaneous BOLD fMRI data acquisition of 16 minutes duration. Post-processing comprised artifact removal of EEG data and scanner artifacts as well as standard

fMRI preprocessing steps using BrainVoyagerQX 1.10.2. (Brain Innovation, the Netherlands). An independent component (IC) analysis of the scalp EEG was performed and the IC factor coding for the time varying interictal epileptic discharges (IED; Figure 1C) was convoluted with a hemodynamic response function to predict the fMRI BOLD signal. Interpretation was done at a peak activation criterion (ie, the threshold that results in 1 single cluster of BOLD correlates to the IED, in that case P < 10e-5, t(df 443) ¼ 4.5), and the BOLD correlates to the IED were located in the inferior gyrus of the frontal lobe adjacent to the centripetally draining vein of the DVAs (Figure 1D). At an individual threshold of P < .003 (t(df 443) ¼ 3.0) to visualize additional BOLD clusters, widespread negative cortical BOLD correlates in the frontal and parietal lobes of both the hemispheres were delineated (Figure 1E). Following this comprehensive diagnostic workup, anticonvulsive treatment was initiated with lamotrigine 150 mg/d, which resulted in a seizure-free follow-up for 2 years.

Discussion Using EEG/fMRI, we have delineated the epileptogenic zone in a patient with frontal lobe epilepsy caused by a DVA in the right frontal operculum. Previous population-based studies demonstrated that DVAs are usually asymptomatic,3 and if DVA and epilepsy are associated, the causative role of DVAs in the epileptogenesis is not established. Other concurrent vascular malformations and hemorrhage commonly complicate the determination of the epileptogenicity of the DVAs. Our patient presented with generalized epileptic seizures. Clinical semiology and postictal EEG findings pointed to a right frontal seizure onset, and besides the right frontal DVA, no other epileptogenic lesion has been detected. Using EEG/ fMRI, we have demonstrated the co-localization of interictal epileptic activity with the DVAs indicating a focal epilepsy syndrome of frontal origin. The absence of visible cortical dysplasia adjacent to the DVA does not rule out the presence of alterations beyond the spatial resolution of the used 3-T MR scanner. Possible non-lesional mechanisms for seizure onset could be related to local mechanical irritation or flow dysregulation caused by decelerated venous outflow resulting in local edema,4 although no signs of cortical or subcortical swelling were detected by high-resolution MRI. Additionally, comprehensive analysis of the EEG/fMRI recordings revealed widespread cortical negative BOLD correlates in the frontal and parietal lobes, as previously described during generalized spike and wave discharges in idiopathic generalized epilepsy16 (Figure 1E). This observation suggests that the pattern of widespread negative BOLD corresponds to a common pathway of epileptic networks in rapidly generalizing epileptic activity and to the findings of the scalp EEG showing generalized bifrontal IED. The preceding right frontal delta discharge on the scalp EEG (Figure 1E, arrow) may retrospectively correspond to the epileptic activity in the frontal operculum as localized by the EEG/fMRI analysis. EEG/fMRI, using IC analysis to extract continuously fluctuating epileptic

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Figure 1. Structural MRI, EEG, and results from the simultaneous EEG/fMRI study. A, The structural MRI shows the ‘‘caput medusae’’ of the DVAs in the right frontal operculum with the dilated, centripetally draining, collecting vein (arrow). B, Scalp EEG (average reference montage) outside the scanner shows atypical generalized slow-wave discharges preceded by a paroxysmal delta activity over FP2 and F8 (arrows). C, IC factor, obtained from the EEG data set, coding for the interictal epileptic activity and applied in the EEG/fMRI analysis. D, Peak activation (see text) shows 1 cluster of positive BOLD correlates to the IEDs adjacent to the DVA in the right operculum. E, In addition to (D) widespread cortical negative BOLD correlates are found in the frontal and parietal lobes, representing second generalized epileptic activity at an individual significance threshold. MRI indicates magnetic resonance imaging; EEG, electroencephalogram; EEG/fMRI, electroencephalogram/functional magnetic resonance imaging; DVAs, developmental venous anomalies; BOLD, blood oxygen level dependent; IC, independent component; IED, interictal epileptic discharges.

activity, has proven to be more sensitive than manually identifying interictal epileptic disorders (IED) on the scalp EEG15 by giving continuous and more detailed information on epileptic activity.17

Two main points stand out from our study: (1) DVAs may cause focal epilepsies in cases where no typical structural lesions can be detected with structural MRI and (2) atypical generalized discharges on the surface EEG may not necessarily

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preclude a focal origin of epilepsy. Advanced imaging techniques, such as simultaneous EEG/fMRI, may aid in the differentiation of clinically equivocal epilepsy syndromes. Conflict of interest The authors declared no conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding This study was supported in part by grant 33CM30-124089/140332 ‘‘Imaging large scale networks in epilepsy’’ from the Swiss National Science Foundation.

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