4.2 Spontaneous brain activity in epilepsy patients
4.2.2 The clinical investigation of epilepsy
The three corner stones of epilepsy diagnosis are 1. clinical history and examination, 2. Again clinical history, and 3. structural MRI and EEG. In focal epilepsies, another line of work up
relates to the identification of the most likely seizure origin. While seizure semiology alone often is helpful to narrow down the potential focus, when treatment with anticonvulsive medication is unsatisfactory, further diagnostic tests are required in view of potential surgical intervention.
4.2.2.1 Neurophysiology
4.2.2.1.1 Electroencephalography
EEG is a neurophysiologic technique that measures bioelectric neural currents arising in the pyramidal neurons of the cerebral cortex. These currents produce excitatory postsynaptic potentials (EPSP) and inhibitory postsynaptic potentials (IPSP) along the dendritic tree of the pyramidal neurons. Current flow within the pyramidal neurons is called the primary current.
The intracellular currents produce compensatory extracellular currents called secondary currents, also known as volume currents. These propagate throughout the body in a manner determined by the conductivity of each tissue. EEG records potential differences arising from secondary currents when electrodes are attached to the scalp or implanted into the brain (Barkley and Baumgartner, 2003).
EEG is important for the investigation of epilepsy. It is used to support the clinical diagnosis by the identification of localized – or general – paroxysmal discharges or patterns. The inter-ictal EEG does not provide a reliable index of the severity, control or prognosis of epilepsy. A reduction in the amount of epileptiform activity shows only a weak association with reduced seizure frequency. But a correlation between the number of interictal discharges and
cognitive function has been proposed (Binnie, 2003).
4.2.2.1.2 Magnetencephalography
Over the recent years, magnetoencephalography (MEG) has emerged as another clinical neurophysiological tool providing unique data not obtainable by other neuroimaging
techniques – reflected by the number of new devices being set up. While it is mainly being used in the area of cognitive research (event-related potential studies), MEG can also be used clinically. Unlike in EEG, where usually ongoing brain activity is monitored and reported, MEG serves to model the sources of interictal epileptic discharges (Barkley and Baumgartner, 2003).
4.2.2.2 Imaging
While neurophysiological investigations can reveal pathological function of the brain, structural imaging will highlight morphological abnormalities. One aim of the different functional imaging techniques is to bridge the gap between the former approaches by identifying pathological function in the spatial structural domain.
4.2.2.2.1 Structural Magnetic Resonance Imaging
Visualisation of lesions that give rise to focal epilepsy and identification of patients who are suitable for surgical treatment are important goals in the imaging of epilepsy. In patients with newly diagnosed epilepsy, MRI is clearly superior to X-ray computed tomography (CT) and may identify an epileptogenic lesion in 12–14%, but up to 80% of the patients with recurrent seizures have structural abnormalities evident on MRI. The most common abnormalities identified are hippocampal sclerosis (HS), malformations of cortical development (MCD), vascular malformations, tumours, and acquired cortical damage (Salmenpera and Duncan, 2005).
4.2.2.2.2 Magnetic resonance spectroscopy
Over the last decade single voxel Magnetic Resonance Spectroscopy (MRS) and MRS imaging have advanced as non-invasive tools for the investigation of cerebral metabolism (McLean and Cross, 2009). Depending on the imaging coil used, metabolites such as N-Acetyl-Aspartate, cholin, myoinositol, creatinine, glutamate (proton MRS), phospho-esters,
phosphor-creatinine, adenosine-triphosphate and others (phosphor MRS) can be quantified regionally and point to (lateralized) pathological brain tissue (Kuzniecky, 1999). Currently, MRS is still compromised by its limited spatial sampling and long acquisition times and so far has struggled to find entry into routine epilepsy-specific use (Kuzniecky, 2004).
4.2.2.2.3 Positron Emission Tomography
Maps can be derived from 18F-deoxyglucose (FDG) and 15O-water (H215O) Positron Emission Tomography reflecting cerebral glucose metabolism and cerebral blood flow respectively.
Studies with FDG-PET have defined the major cerebral metabolic associations and consequences of epilepsy but the data are unspecific with regard to aetiology, and abnormalities are often more widespread than the pathological lesions. The place of the investigation is in the presurgical work up of patients with refractory focal epilepsy and normal or non-definitive MRI scans. In these instances, or if data are discordant the goal is to generate a hypothesis that may then be tested with intracranial EEG recordings (Salmenpera and Duncan, 2005).
PET studies of specific ligands may be used to demonstrate the binding of specific ligands—
for example, 11C-flumazenil (FMZ) to the central benzodiazepine-GABAA receptor complex,
11C-diprenorphine and 11C-carfentanil to opiate receptors, and 11C-deprenyl to MAO-B. The technique is costly and scarce, but gives quantitative data with superior spatial resolution to SPECT (see below) (Hammers, 2004).
GABAA–benzodiazepine receptors: flumazenil 11C-flumazenil (FMZ) is a useful marker of the GABAA– central benzodiazepine receptor (cBZR) complex.
FMZ PET detects abnormalities in the medial temporal lobe of TLE patients with normal MRI.
Potentially surgically useful reductions in hippocampal or extrahippocampal FMZ binding have been found in 47% of MRI negative TLE patients.
Studies of extratemporal epilepsy patients including those with normal MRI have indicated that surgically useful abnormalities of 11C-FMZ binding can be found in half of the cases (Duncan and Koepp, 2000).
In summary, PET offers a tool for investigating neurochemical abnormalities associated with epilepsies. The method is an important research tool and can be useful in selected clinical situations, especially when there is not good concordance between MRI, EEG, and other data (Theodore, 2002). Further ligands, particularly tracers for excitatory amino acid receptors, subtypes of the opioid receptors and the GABAB receptor, will improve the characterisation of different epileptic syndromes (Salmenpera and Duncan, 2005).
4.2.2.2.4 Single Photon Emission Computed Tomography
Single photon emission computed tomography (SPECT) is a nuclear medicine imaging method that allows measurements of regional cerebral blood flow changes in the areas affected by epileptic activity. A comparison of the ictal (tracer injection as early as possible during a seizure) with the interictal perfusion pattern is considered to indicate brain tissue involved in seizure generation - or propagation (Van Paesschen et al., 2007).
4.2.2.2.5 Functional Magnetic Resonance Imaging
Functional magnetic resonance imaging (fMRI) is a non-invasive neuroimaging technique commonly applied clinically in psychology, cognitive and basic neuroscience research. In specialized centers, it is being used routinely as a tool for clinical decision-making in epilepsy.
It has proven useful to determine language location and laterality in patients eliminating the need for invasive tests (Powell and Duncan, 2005). fMRI can been used pre-surgically to guide resection margins, preserving eloquent cortex (e.g. motor mapping). Other fMRI paradigms assessing memory, visual and somatosensory systems show great promise.
Simultaneous recording of electroencephalogram (EEG) and fMRI has also provided insights into the networks underlying seizure generation and is increasingly being used in epilepsy centres (Beers and Federico, 2012) - as becomes evident throughout this thesis.