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Epilepsy diagnostics
Epilepsy diagnostics
Despite the enrichment of epilepsy pharmacotherapy through a multitude of newly permitted and often better tolerated substances, medication treatment has not achieved complete seizure freedom for all epilepsy patients. This applies in under 10% of epilepsy patients with primary generalised epilepsies, but is as high as 30 per cent in those with focal epilepsies.
These patients are exposed to a whole host of risks: traumatic brain injuries directly related to seizures (e.g. contusions due to fall), or indirectly by seizures caused by injuries (e.g. burns when cooking), by the occurrence of generalised status epilepticus which still carries a higher risk of fatality, and by sudden unexpected death of epilepsy patients (SUDEP), a syndrome with a prevalence of up to 1:100 patients per year and most likely caused by effects of epileptic discharges on the vegetative nervous system.
Even patients with predominantly bland epileptic seizures often find themselves heavily handicapped in their social environment by their condition, for instance in terms of mobility (driving license), choice of and ability to exercise a profession, and limitations on the kind of sport and on social contacts. In case of suspected focal epilepsy, patients have the option of undergoing a diagnostic process to localise the epileptogenic zone with a view to performing epilepsy surgery.
Preconditions for performing presurgery epilepsy assessment
The basic precondition for presurgery assessment is the classification of the epilepsy syndrome as symptomatic or cryptogenic epilepsy with focal seizures. First indications are provided by the patient's own description of the semiology of the seizure and by witnesses of the seizure (e.g. a seizure preceded by an aura, or predominantly one-sided signs such as increased muscle tonus during the further course of the seizure), EEG (e.g. with focal dysrhythmia or focal spikes or sharp waves), and MR-imaging evidence of a cerebral lesion.
Normally, presurgical epilepsy assessment is only considered once treatment has been tried with different medications. Important in evaluating the responsiveness to medication is that the administered preparations are suitable for the treatment of focal epilepsies and that the optimal dose is not only administered to the so-called therapeutically effective serum level, but adjusted up or down according to the individual tolerance threshold.
Previously, presurgical assessment was only carried out once drug resistance had been firmly established. After the failure of first- and second-line preparations in monotherapy and of two-way combination therapy the likelihood that any further changes to medication will achieve a seizure free status is however less than 5%. Given that epilepsy surgery can often improve considerably the chance of seizure freedom, presurgical assessment of whether the patient would make a good candidate for operative treatment should be given consideration by this time.
Presurgical Epilepsy Assessment
Two principle questions will be addressed in the presurgical epilepsy assessment:
1. Is it possible to identify one single focus from which epileptic seizures spread? What are the chances of seizure freedom following surgical removal of the focus?
2. Does the topography of the focus permit complete surgical removal without subjecting the patient to risk of considerable neurological or neuropsychological deficits?
Diagnostic Methods
Careful consideration of the medical history of a patient can deliver the first hypothesis about the localisation of a focus. Causal risk factors such as head injury or encephalides, infantile febrile convulsions or family history of epileptic seizures, age of onset of first signs of epilepsy, and additional cognitive impairments reported by the patient are documented.
A more precise idea of the location of seizure origin can often be achieved already by detailed assessment of the seizure semiology based on the self reports of patients and on reports of those who have witnessed the seizures. Seizures always preceded by an aura are a reliable indicator of which eloquent symptomatogenic brain areas are the first to be involved in the seizure events. Other semiological aspects can provide information about the lateralisation or localisation of the focal zone (see below). The duration of the seizure, its occurrence during the course of the day and possible continued postictal impairments of the patient can provide valuable information about the brain areas involved in the seizure events.
The electroencephalography is still the only method that delivers functional proof of the epileptic nature of the episodes in question. Evidence of brain potentials (spikes/sharp waves) typical for epilepsy can be achieved in up to 90% of patients by using repeated interictal routine EEGs, including sleep registrations, provided that suitable configurations of electrodes and electrode montages are implemented. The interpretation of such evidence should not neglect the fact that while there is a high specificity of epilepsy-typical potentials in adults these potentials may reflect a normal, benign variant in children that is not necessarily associated with epilepsy.
The localising value of interictal discharges is limited by the fact that the particular placement of the electrodes often measures no more than spread of discharges. For example, even when sphenoid electrodes are used sharp waves that are generated in the hippocampus or in the amygdala are not measurable. These waves can only be registered when they spread temporobasally and temporolaterally. Bilateral spreading of sharp waves frequently occurs in temporal lobe epilepsies. Errors are easily made in localising epileptogenic zones in temporo-occipital or parieto-occipital regions because of the particularly rapid propagation of interictal spikes/sharp waves across frontal or temporal lobes.
Simultaneous video-EEG-seizure monitoring, which has now been digitalised, lies at the heart of presurgery epilepsy assessment in identifying the origin of the seizure. A more precise semiological analysis is carried out based on video registration. For example, version, cloni, dystonic or tonic posturing indicate a symptomatogenic zone in the contralateral hemisphere, while motor automatisms or eyelid blinking suggest the ipsilateral hemisphere; receptive or expressive language disorders during or after a seizure point to the involvement of the language dominant hemisphere. A number of these seizure aspects (e.g. mnemonic disorders, aphasia, increased tonus) can only be determined with the appropriate tests performed during the seizure.
In most cases the ictal EEG recording can provide electrophysiological evidence that the episodes requiring therapy are in fact epileptogenic. The ictal surface-EEG can however fail to deliver sufficient information about the zone of seizure origin for a number of reasons: rapid spread of activity across extended areas of the cortex, discharge predominantly in deeper brain structures, and muscle and movement artefacts. In this case or when the results of the ictal surface-EEG and the results based on other information are discordant it may be necessary to perform invasive EEG registrations with electrodes positioned in the subdural space or in the brain. Multi-contact depth electrodes, subdural strip electrodes and subdural grid electrodes are commonly used for this; the latter are suitable for determining the epileptic focus and for identifying eloquent brain areas that have to be preserved during an operation.
In addition to this, the temporal correlation of EEG and video data allows an estimation of the proximity of the electrodes to the epileptogenic zone and a better interpretation of the semiological data over the course of this seizure by comparing the onset of EEG-changes with the semiology.
Imaging procedures
MR imaging: The improved performance of MR imaging and continued progress in MR sequences that are fundamental to epileptological examinations has made MR imaging an increasingly sensitive instrument with which to confirm potential epileptogenic lesions. MR imaging data does not of course enable the epileptogenity of the lesion to be verified. Cortical dysplasias, which represent the greatest challenge to the quality of imaging, have particularly benefited from the recent progression in MR imaging sensitivity; it is however still difficult to judge in which regions there are aberrant alterations to the laminate structure of the cerebral cortex that can not be distinguished from normal cortex but nevertheless possess a considerable epileptogenic potential.
Magnetic Resonance-Spectroscopy:
Spectroscopic investigations can reveal reductions in N-Acetylaspartate ipsilateral to the epileptogenic zone. The sensitivity and specificity of this finding is currently under further investigation in a series of studies. Newer high magnetic field devices have also been used to visualise neurotransmitters such as GABA and this will probably increase the validity of this methodology further.
PET:
The FDG-PET also has a high localising sensitivity on account of it being able to reveal the presence of hypometabolic areas in the vicinity of epileptogenic zones. The progress made in MR imaging performance does however mean that the indication for FDG-PET has shifted as is the case with the other multimodal imaging techniques to patients with inconsistent data. But additional tracers such as flumazenil and alpha-methyltyrosine could still result in PET assuming a more important role in the future in cases that present difficulties for presurgical epilepsy assessment.
SPECT:
SPECT-scans are used to show changes in the blood perfusion and to assess benzodiazepine receptor density. Proof of ictal hyperperfusion in patients in whom MR imaging has failed to reveal a lesion or who do not show a pattern of seizure in the surface EEG is particularly valuable as a means to strengthening the hypothesis that there is an epileptogenic zone or to at least provide helpful information for the implantation of intracranial electrodes. By subtracting the interictal hypoperfusion in the vicinity of the focus and by superimposing these SPECT images onto the MR images the sensitivity of the thus ascertained location can be enhanced.
The iomazenile SPECT is used to show changes in the benzodiazepine receptor density. The increase in GABAergic activity in the inhibitory surround zone of the focus results in a down-regulation of GABA receptors that also carry benzodiazepine receptors; the reduced binding with iomazenile is proven as a measure of this.
Neuropsychologie:
Patients with focal epilepsy are not only impaired in neuropsychological performance during a seizure. Subtle investigative methods also reveal interictal performance deficits. These are caused by a number of factors: the primary lesion, interictal discharges and subclinical seizure patterns that are projected into the neighbourhood of the epileptogenic zone, thus interfering with information processing, and, finally, the inhibitory surround of the focus that also manifests itself in the PET investigation as hypometabolism. The preoperative epilepsy diagnosis has led to the development of test batteries that can provide information about location. For example, a reduction in the ability to learn words may indicate a temporal neocortical function deficit in the language dominant side, while an impaired ability to actively retrieve learned words is indicative of a hippocampal function deficit on the same side.
Besides its contribution to focus localisation, neuropsychology is becoming increasingly important in the prognosis of additional potential deficits that occur as a consequence of the operative removal of the focus. Such deficits could for instance affect memory performance if a well-functioning hippocampus is removed. If on the other hand memory performance is clearly and already attenuated before the operation as a result of pervasive neuronal degeneration surgical intervention can be expected to result in considerable further loss.
Wada-Test:
Verbal memory deficits as well as dysphasias can be sustained following operations to the language dominant side of the brain. Knowledge of the lateralisation of the Broca and Wernike area is therefore fundamental to surgical planning. This is done by injecting a briefly active barbituate (NA-Amytal) into the right or left internal carotid artery that transiently puts the function of the corresponding half of the brain to sleep so that the laterality of language dominance can be assessed.
If the suspected area of seizure origin lies in proximity to language centres electrophysiological mapping of the language region by means of subdural implanted grid electrodes is normally indispensable. This mapping allows the boundaries of the area to be determined with a spatial resolution of ca. 1 cm and to provide the surgeon with precise information about the possible extent of the planned resection.
The WADA internal carotid artery test may be inadequate for assessment of verbal memory after removal of the hippocampus because the additional impairment to the language areas has cast doubt on the value of testing this way. In individual cases a highly selective WADA test of the chorioideal anterior or posterior arteries may be required that only inactivates the function of temporomesial structures and enables assessment of the remaining learning and memory abilities.
Given that the WADA-test and similarly grid implantation are invasive procedures that are not entirely without risk the main emphasis of further development in methodology lies in the field of functional imaging and in fMRI in particular. The MR imaging evidence of cortical activation during language and memory tasks helps in some cases to make the use of invasive procedures unnecessary.
In summary, presurgical epilepsy assessment has a range of procedures at its disposal with which to gather information about the location of epileptogenic zones in focal epilepsies and to correspondingly plan the surgical intervention. The aim of this is to keep the size of the resected tissue as small as possible and to reduce as much as possible the potential risk of neuropsychological deficits resulting from the intervention. Of those pharmaco-resistant patients who are operated on, up to 80% become entirely seizure free, depending on the aetiology of the epilepsy and the location of the epileptogenic zone, and the remaining patients often achieve a considerable reduction in the frequency of seizures and/or seizure intensity. The extensive expertise required in screening suitable candidates for surgery and in applying the broad spectrum of diagnostic methods can only be achieved in larger centres.
