Pharmaco-resistance

Despite a well conducted therapy with antiepileptic drugs, around 30% of patients suffering from epilepsy will endure recurring seizures despite multiple anti-epileptic drug (AED) treatments (Kwan&Brodie 2000). The introduction of the first anti-epileptic drug will lead to seizure freedom in 47% with the first drug, 30% with the second drug, 10%

with the third and 5% with the fourth. Pharmaco-resistance is defined as the persistence of seizures despite a well conducted anti-epileptic drug treatment with at least two drugs during at least 2 years.

9 1.2

Epilepsy surgery

1.2.1

Background

In some carefully selected patients, epilepsy surgery, consisting in removing the cortical zone necessary for the initiation of epileptic seizures (the epileptogenic zone), can lead to seizure freedom or significant improvement of the seizure control. The determination of which brain structures should be targeted by surgery is tailored to the individual patients after a comprehensive presurgical evaluation, in order to remove the estimated epileptogenic zone, while sparing the eloquent cortex. Epilepsy surgery can consist in the resection of a radiological lesion (lesionectomy), removal of epileptogenic cortex (cortectomy), partial or total resection of a lobe (lobectomy) or multiple lobectomies.

Disconnective surgery can also be performed in specific cases to interrupt major white matter tracts responsible for the propagation of epileptic activity and the severity of the seizures. Callosotomy (section of the corpus callosum) or functional hemispherectomy (disconnection of a whole hemisphere) are the main examples of disconnective surgery.

1.2.2

Non-invasive presurgical evaluation

The recording of clinical and electrical manifestations of seizures with long-term video-EEG (telemetry) represents the core of the presurgical evaluation. Consistent electro-clinical patterns across several seizures are needed to ensure that the epilepsy is unifocal. However, scalp video-EEG per se is not sufficient to delineate which brain structures need to be surgically removed and additional structural/functional imaging is needed to find concordant areas of tissue damage or dysfunction.

Magnetic Resonance Imaging (MRI) is currently the gold standard for structural imaging in patients with epilepsy as it detects lesions in 75% of patients with pharmaco-resistant epilepsy. The most common lesions are hippocampal sclerosis, malformation of cerebral development such as focal cortical dysplasia or heterotopia, low grade tumors, cavernoma, traumatic or ischemic lesions, parasitic lesions such as cysticercosis (Duncan 2010).

In addition, neuropsychological and psychiatric assessments are needed to characterise the cognitive and affective disorders associated with epilepsy and stratify the risk of post-operative cognitive and psychiatric outcome.

10 1.2.3

Intracranial EEG recordings

In some patients, the non-invasive tests do not allow an unequivocal decision to be made on whether surgery is possible and intracranial EEG recordings are needed to clarifiy the localisation and extent of the epileptogenic tissue and their spatial relation with the eloquent cortex (Seeck&Spinelli 2004). This can be done with depth electrodes implanted into the brain via a stereotactic procedure (StereoEEG, SEEG) or with subdural electrodes laid on the cortex after craniotomy. Telemetry is then performed to record seizures and interictal activity with these invasive electrodes.

The number and position of electrodes and contacts is limited both by surgical considerations (vascular anatomy) and number of available channels of EEG recording systems (typically 64-128 channels). This highlights the limited spatial sampling of intracranial EEG recordings. Therefore, prior hypotheses about the possible localisation of the epileptic focus are critically needed in order to select the brain regions which need to be recorded with intracranial electrodes.

1.2.4

Additional imaging tools

A variety of imaging techniques can been applied to help detect structural lesions or abnormal brain function to better understand epileptic networks in individual patients, guide the placement of intracranial electrodes and tailor epilepsy surgery.

Isotopic imaging techniques such as ¹⁸F-Fluoro-Deoxy-Glucose Positron Emission Tomography (FDG-PET) and Single Photon Emission Computerised Tomography (SPECT) are based on the intravenous injection of radio-labeled tracers and can be used as functional imaging tools to help localise the epileptic focus via focal interictal hypometabolism on FDG-PET, interictal hypoperfusion or ictal hyperperfusion on SPECT. Magnetic Resonance Spectroscopy can detect focal disturbances of neuronal and glial metabolism and MRI volummetry can quantitatively identify structural abnormalities that had escaped visual detection (Duncan 2010).

Functional imaging of epileptic activity itself is mostly performed in the interictal state and therefore maps the irritative zone, Electric (Magnetic) Source Imaging, and EEG-fMRI can be used for that purpose and are presented in detail in chapter 2. Previous studies and experimental studies in this work suggest that the mapping of the clinically relevant

11 part of the irritative zone based on meaningful epileptic spikes is a good surrogate of the localisation of the epileptogenic zone to be removed.

In parallel, functional imaging of brain function allows localising the eloquent cortical and subcortical networks to tailor surgical resections and predict neurological and cognitive oucome. Currently, functional imaging is increasingly based on functional MRI to localise motor, sensory, language and memory functions and the techniques are progressively being translated from the research labs to the clinical setting. Finally, the mapping of white matter connections with Diffusion Tensor imaging is also a promising techniques with growing clinical applications, notably in the context of epilepsy surgery (Duncan 2010).

1.2.5

Post-operative seizure outcome

In temporal lobe epilepsy with hippocampal sclerosis, the most frequent pharmaco-resistant epileptic syndrome in adults, anterior temporal lobectomy can lead to seizure freedom in up to 85% of patients, at one-year follow-up (Spencer&Huh 2008). In a proportion of patients, seizures tend however to recur with time and seizure-freedom after a follow-up of 10 years is around 40% (McIntosh et al. 2004). Epilepsy surgery therefore is largely superior to the continuation of medical therapy in patients with pharmaco-resistant epilepsy, as confirmed by a randomised (Wiebe et al. 2001). Focal malformations of cortical development are the second most frequent cause of refractory epilepsy and can cause temporal and extra-temporal epilepsy. Up to 60% of these patients can be seizure-free after surgery (Fauser et al. 2004), with the outcome dependant on the complete resection of the abnormal cortex (Kim et al. 2009). In the absence of a detectable lesion (MRI-negative patients), surgical resection can also be associated with post-operative seizure. These cases are the best example of the need for additional functional and structural imaging tool to track subtle structural lesions and perform a functional mapping of the epileptogenic networks and the eloquent brain structures, particulary as the latter can be altered by the epileptic disease (Powell et al.

2007). Odds for a seizure-free outcome tend to be lower than in lesional cases but can be as high as 50-60% (Wetjen et al. 2008; Bell et al. 2009). These findings illustrate the importance of brain imaging for detecting focal structural brain abnormalities in the management of patients suffering from epilepsy.

12 1.2.6

Risk of post-operative deficits

Epilepsy surgery is associated with a 2% risk of permanent neurological impairment or mortality, caused by haemorragic, ischemic or infectious complications (Lüders 2008).

The site of surgical resection can be related to more specific deficits: e.g. memory decline (hippocampus) and visual field defect (optic radiation) in temporal lobe surgery, motor deficits in pericentral frontal regions, sensory deficits in parietal resections.

1.3

Conclusion

This chapter highlights the benefits of epilepsy surgery in well selected patients suffering from pharmacoresistant epilepsy. However, a significant proportion of patients is not improved by surgery and predictive factors are needed. Therefore, the development of new non-invasive tools and their combination is critically needed to improve patient selection, guide intracranial electrode placement and improve post-operative outcome while minimizing the risk of deficit. In this context, this work presents recent advances in the mapping of epileptic networks using simultaneous EEG and fMRI recordings and discusses their limitations and clinical relevance.

13

2 Electrical Source Imaging and simultaneous EEG-fMRI

Parts of this chapter have been published as

Vulliemoz S, Michel CM, Daunizeau J, Lemieux L, Duncan JS ; The combination of EEG souce imaging and EEG-correlated functional MRI to map epileptic networks; Epilepsia 2010 Apr 51(4): 491-505.

2.1

Introduction

First developed by Hans Berger in the late 1920’s, electroencephalographic (EEG) recording of human neuroelectrical activity has benefitted from tremendous development fuelled by advances in neurophysiology and digital technology. While routine clinical interpretation remains largely based on the visual interpretation of signal fluctuation of multichannel recordings, spatio-temporal analysis of EEG signals, including Electrical Source Imaging (ESI) have transformed this tool into a modern 3D imaging tool of brain activity. ESI consists in estimating the localisation of the intracerebral electrical generators of the signal recorded on the scalp with a temporal resolution of milliseconds.

This technique has moved on from the research laboratories and is now increasingly implemented in the clinical practice of epilepsy surgery centres to help localising focal epileptic activity and help clinical management of patients with medically refractory seizures.

Another application of EEG to map epileptic networks is the combination of EEG and functional Magnetic Resonance Imaging (EEG-fMRI) that allows whole brain mapping of haemodynamic changes related to specific electrophysiological features selected from the EEG, such as focal or generalised epileptic activity. Following the first proof-of-concept study (Ives et al. 1993), safety and data quality have now been thoroughly assessed and simultaneous EEG-fMRI can be safely performed and arises as a powerful method to explore epileptic networks, but also endogeneous brain rhythms and task-related brain activity.

Formal validation of new localising imaging techniques is a necessary but difficult task, which requires comparison with a gold standard, ideally in large homogeneous patient groups. One possibility is the spatial concordance with radiologically visible lesions that are considered to be the cause of symptomatic epilepsy. However, these can be

14 relatively large and often do not colocalise with the irritative or ictal onset zones. Patients undergoing invasive EEG recording with intracranial electrodes or resective surgery offer opportunities for validation that are unique in clinical and basic brain research. However, it needs to be reminded that validation with intracranial EEG is limited to rather small groups of patients with heterogeneous epileptic syndromes and limited intracranial spatial sampling. Post-operative seizure freedom in patients in whom the estimated epileptic focus was localised in the resection zone represents the most clinical relevant form of validation. In some cases, the resected areas are much larger than the epileptic zone making it difficult to assess the test’s specificity and long-term follow-up is required.

In the following we give an overview of the neurophysiological background, principles, limitations and main clinical validation studies of ESI and EEG-fMRI.

2.2

Neurophysiological background

2.2.1

Origin of the EEG signal

Scalp EEG electrodes record fluctuations in electrical potential caused by the summed excitatory and inhibitory post-synaptic potentials generated by populations of cortical pyramidal neurons with effective orientation perpendicular to the cortical surface (Niedermeyer&Lopes da Silva 2005). The solid angle theory applied to EEG generators explains why short lasting axonal action potentials of about 1 ms duration do not result in a combined macroscopic electric signal, despite frequent firing and high amplitude (Gloor 1985). Synchronous cortical activity over at least 6-10 cm² of gyral surface is necessary for pathological events to be clearly detectable with scalp electrodes (Tao et al. 2005). The infolding and multi-laminar structure of the cortex can make the relationship between generators and electrodes complex (Megevand et al. 2008) and some neuronal activity gives rise to a “closed” electric field (e.g. stellate cells) invisible to scalp electrodes (Nunez&Silberstein 2000).

2.2.2

Origin of the fMRI signal

Functional MRI (fMRI) studies measure local changes in brain oxygenation by detecting differences in magnetic susceptibility between oxy- and deoxyhaemoglobin (Blood Level Oxygen Dependant, BOLD signal changes). The interpretation of fMRI studies relies on

15 the assumption that an increase of regional “neuronal activity” results in an increase in metabolic demand, an excessive increase in perfusion and a decreased concentration of deoxygenated haemoglobin in local venous blood (increase of BOLD signal) (Buzsaki et al. 2007; Logothetis 2008).

Animal studies have shown that BOLD signal changes do not correlate with the firing rate of action potentials (single- or multi-unit activity) in local neurons. It correlates much better with the local field potential, which represents the sum of perisynaptic electrical activity, as measured by extracellular intracranial electrodes. Neuronal activity and the BOLD signal vary over very different time scales (milliseconds vs seconds). The coupling between both variables can be modelled by Haemodynamic Response Function (HRF) (Glover 1999). Following a single short lasting stimulus (and consequently a short lasting evoked neuronal activity), there is an initial dip of the BOLD signal, then an increase to reach the peak about 5 seconds after the stimulus and finally an undershoot with a return to baseline after about 20 seconds. Spatially, fMRI studies typically use voxels with a volume of the order of 50 mm³ and are well suited to the anatomical scale of the haemodynamic changes (Logothetis 2008).

The interpretation of sustained negative BOLD changes observed in animal studies (Shmuel et al. 2006; Maier et al. 2008) as well as neurophysiological (Shmuel et al.

2002) and epilepsy studies in humans (Kobayashi et al. 2006a; Salek-Haddadi et al.

2006) is difficult and context dependent. A decrease in metabolic demand may be associated with a selective increase in neuronal activity (or synchrony), as in the case of the alpha rhythm (Laufs et al. 2006b) or generalised spike and wave epileptic discharges (Aghakhani et al. 2004; Hamandi et al. 2006), suggesting that reduced inhibition might have caused a reduction of metabolism despite an increased activity in selected neuronal populations. In localisation-related epilepsies, it is not clear whether the observed transient negative BOLD changes reflect surround inhibition, impaired neurovascular coupling, distant downstream/upstream metabolic decrease, propagated epileptic activity or, less probably, a vascular theft mechanism (Kobayashi et al. 2006a;

Salek-Haddadi et al. 2006).

16 2.3

Electrical Source Imaging (ESI)

2.3.1

Methodological principles

ESI can estimate the localisation of the electric source(s) within the brain volume which generate Interictal Epileptiform Discharges (IED, Spikes) recording with scalp electrodes. The relationship between a specific distribution of postulated electric sources in the brain and the resulting scalp voltage map is determined by the forward model:

the construction of a mathematical model of the head’s electromagnetic and geometrical properties to calculate the volume conduction; These head models can be categorised either as spherical or realistic models, the latter giving a more accurate description of individual head and brain morphology but are more computationally demanding. For a given scalp voltage field, there is an infinite number of possible source configurations, giving rise to the fundamental non-unicity of the inverse electromagnetic problem (Helmholtz 1853). As a consequence, solving the inverse problem requires assumptions about the sources and the volume conductor, in order to reduce the space of solutions (number and spatial configuration of possible solutions). Common assumptions for neural sources are equivalent dipoles and distributed solutions. Dipolar solution estimate the localisation and orientation of one or a few equivalent dipole(s) generating a given scalp voltage map as recorded by EEG electrodes. Distributed linear solutions estimate the activity of each point (source) in a solution space (usually the grey matter) and are better suited for extended sources but require further assumption to solve the inverse problem, among which is the restriction of the solutions to the grey matter and the smoothness of the solution. Dipolar and distributed linear solutions applied to spike localisation have been compared, with simulated EEG data (Grova et al. 2006) or clinical recordings (Ebersole 1999). The result of the comparison depends on the nature of the dataset and the spatial extent of neuronal generators.

Figure 1.1 summarizes the usual analysis steps required for ESI.

17 Figure 1.1: Principle of Electrical Source Imaging

A) EEG recording and analysis: (A1): Distribution of the electrodes on the scalp (in this case 256 electrodes). (A2): The exact position of the electrodes on the head can be determined with the use of a photogrammetry system (Electrical Geodesic Inc). (A3):

EEG recording and visual identification of interictal spikes. (A4): Averaging of similar epileptiform potentials leading to a potential map for each timepoint during the epileptiform discharge.

B) Head model: (B1): structural MRI. (B2): brain segmentation into different tissue classes. (B3): The grey matter is identified. (B4): The solution space is defined based on the gray matter definition. White matter, ventricles and large cavities within the brain are excluded from the solution space.

C) Inverse solution: For each timepoint within the spike wave complex, a mathematic algorithm (inverse solution calculation) is used to estimate the location of the epileptic source within the solution space (B4) based on the voltage map of that timepoint (A4).

From Lantz G, Grouiller F, Spinelli L, Seeck M, Vulliemoz S; Localisation of focal epileptic activity in children using high density EEG source imaging, Epileptologie, 2011 June, 84-90

18 2.3.2

Clinical ESI studies in focal epilepsy and validation studies

The comparison of ESI and invasive EEG recordings has been carried out with simultaneous scalp ESI and invasive recordings in patients with temporal lobe epilepsy.

ESI was able to differentiate between medial and lateral temporal spikes (Dinesh Nayak et al. 2004; Zumsteg et al. 2006) and to identify patterns of propagation within the temporal lobe. Concordance between intracranial EEG and dipolar sources has been found in over 90% of technically feasible cases in temporal and frontal lobe epilepsy (Gavaret et al. 2004; Gavaret et al. 2006). In another study of patients with both temporal and extra-temporal epilepsies recorded with dense-array EEG (128 electrodes), a distributed linear ESI model was concordant at a lobar level in 94% of 32 patients including 100% of patients with temporal lobe epilepsy (Michel et al. 2004).

Good concordance between ESI and the resection area was obtained in 79% of post-operative seizure-free cases. Finally ESI can be accurate despite large brain lesions (Brodbeck et al. 2009). The limitation of these studies is that they were un-blinded, retrospective and that the additional localisation information compared to other imaging modalities was not analysed. Finally, a large study investigated the sensitivity and specificity of ESI in a large group of 152 operated patients with temporal and extratemporal epilepsy. In the same group of patiehts, the results were compared with those of other conventional technique of localisation of the epileptic focus, namely MRI, PET and SPECT. ESI had a sensitivity of 84% and a specificity of 89% that were comparable to MRI when the analysis was based on high density EEG recordings and individual anatomy of the brain. For low density recordings or template head models, results were much less accurate.

2.4

EEG-fMRI

2.4.1

Methodological principles

Simultaneous EEG-fMRI recordings require that the artefacts caused by the interaction between both recording systems are kept to a minimum and are later corrected.

Moreover, it is necessary to follow a strict acquisition protocol in order to guarantee patient safety. Non ferro-magnetic MR compatible electrodes, cables and amplifiers are needed to record the EEG inside the MRI scanner. High amplitude and high frequency gradient artefacts on the EEG are caused by the switch of the scanner’s gradients and

19 pulse-related artefacts are caused by small amplitude head movement time-locked to the cardiac cycle. These two artefacts can be successively corrected by the substraction of average artefact templates, allowing the interpretation of EEG (Aarts et al. 1984; Allen et al. 1998; Allen et al. 2000). For fMRI data in epileptic patients, the conventional analysis strategy is to identify epileptic spikes on the corrected EEG and enter their timing into a statistical model (General Linear Model), together with centre-specific choices of confounds (e.g. motion, cardiac cycle) to model other sources of variance of the BOLD signal. The statistical estimation of this model identifies the voxels in which the BOLD signal time course is significantly correlated with the occurrence of the spikes.

2.4.2

Clinical EEG-fMRI studies in focal epilepsy and validation

So far, most EEG-fMRI studies in focal epilepsy have been exploratory whole-brain studies aiming at demonstrating BOLD changes throughout the brain linked to any pathological discharges on scalp EEG. The yield of BOLD responses is predominantly affected by EEG criteria (spike frequency). EEG-fMRI studies on patients with malformations of cortical development found changes extending beyond the radiological

So far, most EEG-fMRI studies in focal epilepsy have been exploratory whole-brain studies aiming at demonstrating BOLD changes throughout the brain linked to any pathological discharges on scalp EEG. The yield of BOLD responses is predominantly affected by EEG criteria (spike frequency). EEG-fMRI studies on patients with malformations of cortical development found changes extending beyond the radiological