Step Three Mandatory Investigations

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The following are considered mandatory investigations at most major epilepsy centres, and each will be discussed separately.

Magnetic Resonance Imaging

High-resolution magnetic resonance imaging (MRI) can be very helpful in detecting epileptogenic structural lesions. According to the American Academy of Neurology guidelines for evaluation of a first unprovoked seizure, brain imaging with computerized tomography (CT) or MRI is recommended and was given a Level B classification [17]. Of course, the EZ might extend beyond the visible region of abnormality. The quality of the MRI has a major impact on its sensitivity, and should be performed using an 'epilepsy protocol'. This protocol uses thin-slice thickness through the temporal lobes in the coronal plane. MRI performed using an epilepsy protocol and reviewed by neuroradiologists with expertise in the field of epilepsy surgery has the highest detection rate of underlying epileptogenic structural abnormalities [18]. Certain sequences should also be performed: three-dimensional T1-weighted images as well as T2 and fluid-attenuated inversion recovery (FLAIR) sequences are essential and standard; gradient echo sequences can detect small cavernomas [19, 20]; and gadolinium should be used when a tumour is suspected.

With increasing magnet strength, improved identification of pathology has been observed. A recent prospective study showed that experienced review of 3-tesla MRI studies resulted in the detection of new lesions in 65% of previously MRI-negative studies [21]. This is significant because multiple studies have shown that patients with a detectable focal lesion on neuroimaging are more likely to be seizure free post-surgically compared with those who have negative imaging [22, 23].

A number of non-conventional MRI sequences and data analysis have also been used in patients with seemingly cryptogenic refractory partial epilepsy, including double inversion recovery, magnetization transfer ratio, T2-mapping, fast FLAIR-based T2 measurement and voxel-based morphometry [24-27]. Most of these techniques do not readily detect focal abnormalities on initial visual analysis and require the use of statistical parametric mapping to demonstrate significant findings. Their clinical utility is currently unknown and their use is largely investigational at this time.

Electroencephalography

Interictal electroencephalography recordings often demonstrate epileptiform discharges in patients with refractory epilepsy. Interictal discharges provide important information for lateralization and localization of the seizure focus, although in a minority of cases they can be falsely localizing. In TLE, the presence of unilateral anterior temporal spikes is a strong predictor of post-operative seizure freedom [28, 29]. In contrast, bitemporal spikes are associated with poorer prognosis, although they do not preclude a successful outcome so long as they occur predominantly on the side to be resected [30]. Resection of a focal epileptogenic brain lesion in infants and children with multi-focal or generalized epileptiform discharges can result in seizure freedom and overall improvement [31]. A similar positive outcome can be seen in patients with tuberous sclerosis [32, 33]. In addition, specific electroencephalogram (EEG) patterns can provide clues about pathology. For example, focal fast rhythmic epileptiform discharges on surface EEG are associated with focal cortical dysplasias [34].

AB had a brain MRI with epilepsy protocol performed, the results of which were normal. A routine EEG showed mild focal slowing in the left temporal region, which suggests the presence of focal cortical dysfunction.

Video-electroencephalography Monitoring

Prolonged video-electroencephalography monitoring, in the majority of surgical candidates, plays an essential role in the pre-surgical evaluation. An optimal session should capture several of the patient's typical seizures. The video recording, along with direct observation by the nurse and/or physician during the seizure, can allow improved characterization of the seizure semiology. Post-ictal deficits, such as the Todd's phenomenon, can also be characterized in the inpatient setting, allowing for improved localization and lateralization.

The typical admission varies from several days to several weeks, largely dependent on how quickly the patient has several seizures for characterization. The number of seizures required depends on the number of distinct seizure types the patient has and how easily these are localized and lateralized upon review. Patients with unilateral interictal spikes and a single seizure type may require two or three seizures, whereas patients with multi-focal discharges and multiple distinct seizure types may require two or three seizures of each type. In order to facilitate rapid, but safe, capture of seizures, the patient's AEDs are weaned off after admission. Provocation techniques such as sleep deprivation, exercise, photic stimulation and hyperventilation can be employed to further increase the likelihood of capturing seizures. Seizure precautions are enforced in the epilepsy monitoring unit, particularly for patients on reduced or discontinued medications.

Ictal EEG often provides valuable lateralizing and localizing information in TLE, although results can be variable with extra-temporal seizures [35]. Characterization of the earliest ictal rhythms associated with the seizure identifies the ictal onset zone. In some patients, the ictal onset is seen following clear behavioural changes, demonstrating that the ictal onset was not captured on scalp EEG. In other patients, the ictal onset is characterized by a bilateral pattern and lateralization is not possible. Patients with prominent motor manifestations may have muscle and/or movement artefacts which confound lateralization. In these poorly localized or lateralized cases, invasive intracranial monitoring may be necessary.

AB undergoes prolonged video-electroencephalography monitoring. After 2 days of monitoring, intermittent spikes with a broad field, covering the left anterior temporal, left mid-temporal, and left parasagittal regions are seen. The highest spike amplitude occurs in the mid-temporal region. He has two typical complex partial seizures, electrographically characterized by rhythmic delta and theta activity over the left temporal and parasagittal regions (Figure 2.1). Based on these findings, AB's seizures clearly lateralize to the left hemisphere. The EZ likely localizes to the left temporal lobe, considering the seizure semiology and amplitude of the interictal discharges. However, the broad field of the interictal discharges, coupled with the ictal pattern which involves the parasagittal region, suggests a more extensive EZ.

Neuropsychological Testing

A comprehensive cognitive and psychiatric evaluation is an important part of the pre-surgical evaluation. For instance, verbal memory impairment is often seen in the setting of left TLE, and findings on neuropsychological testing can help to lateralize and localize the EZ. The predictive value for lateralization and localization of the epileptogenic focus depends, at least in part, on the criteria utilized and the measures employed. When combined with other modalities such as electroencephalography and MRI, neuropsychological testing has been shown to slightly increase the rate of correct EZ lateralization from 93% to 95% [36].

In addition, neuropsychological testing can be used to predict post-surgical verbal memory function, although findings have been somewhat controversial. Previous findings have suggested that patients with left mesial temporal sclerosis (MTS) are at low risk for

Figure 2.1 Electroencephalogram of Patient AB exhibiting rhythmic sharply contoured delta and theta activity over the left temporal and parasagittal areas.

to to

Figure 2.1 Electroencephalogram of Patient AB exhibiting rhythmic sharply contoured delta and theta activity over the left temporal and parasagittal areas.

developing worsened verbal memory impairment following dominant left anterior temporal lobectomy (ATL) [37]. However, more recent findings suggest that normal baseline verbal memory function prior to ATL, or selective amygdalo-hippocampectomy, might actually increase the risk of post-surgical deterioration in MTS patients [38, 39].

Psychiatric Issues

Overall, the prevalence of psychiatric disorders in patients referred for epilepsy surgery is high [40, 41]. One study analysed psychopathology in patients prior to and following ATL [40]. A DSM-IIIR diagnosis (depression, anxiety and organic/personality disorder being most common) was present in 65% of patients before surgery. New psychiatric problems arose in 31% of patients in the months following surgery; however, in the group as a whole the severity of psychiatric symptoms was lower 6 months post-operatively compared with baseline [40]. Another multicentre study analysed pre- and post-operative results of patients' Beck Psychiatric Symptoms Scales, and found significant improvement in patient depression and anxiety scores post-surgically [42]. This was particularly true for those patients who became seizure free. These findings suggest that ATL is associated with some positive effect on neuropsychological function.

Psychiatric disorders do not preclude a patient from epilepsy surgery, as illustrated by one study of US veterans demonstrating uniform post-surgical results in patients with and without psychiatric illness, although larger studies are needed [43]. Patients with baseline psychopathology can benefit from psychological surveillance, monitoring for any decline or improvement in function post-operatively. Early psychiatric evaluation can also help to identify patients who are at risk for post-ictal psychosis, which can be difficult to manage. Such patients can be placed on anti-psychotic medication prophylactically when admitted for video-electroencephalography.

intracarotid Amytal (wada) Test

The intracarotid amytal or Wada test is used to determine language lateralization and assess memory function prior to surgery [44]. The Wada is performed by placing a catheter in the femoral artery and advancing it to the internal carotid artery (ICA). An anaesthetic agent (most commonly amobarbital) is injected to anaesthetize one cerebral hemisphere and assess function of the contralateral, non-anaesthetized hemisphere. The exact paradigm for testing varies from centre to centre. Many centres utilize clinical criteria (e.g. contralateral hemiplegia) for establishing an adequate injection whereas others will utilize a combination of clinical testing and continuous EEG. Assessment of both language and memory also varies amongst centres. Most paradigms involve presentation of a series of pictures, objects or words during hemispheric anaesthesia followed by recall and recognition testing after a complete return to baseline [45].

The Wada remains the gold standard in determining language and memory laterality. Studies have found that patients with a hemispheric memory deficit ipsilateral to the seizure focus on the Wada have an increased probability of being seizure free post-surgically [46]. However, there are risks associated with the test, including carotid dissection (0.7%), cerebral infarction, arterial spasm with potential transient deficits and transient femoral neuropathy [45, 47]. The Wada is also limited by other factors. Testing procedures are not standardized, making it difficult to compare test results from one epilepsy centre to another. Variation in patient vascular anatomy and cross-filling patterns can lead to misinterpretation of results, thus cerebral angiography is routinely performed prior to injection of anaesthetic [48]. Likewise, insufficient administration of anaesthetic can give falsely lateralizing results. Lastly, the limited supply of amobarbital and the invasive nature of the test make the Wada costly and inefficient.

Alternatives to the Wada Test

Because of these associated risks and limitations, alternative methods to determine language dominance are being investigated, some of which include MEG, functional MRI (fMRl) and repetitive transcranial magnetic stimulation [43, 49-51]. More study and refinement of the latter techniques, however, will be needed before they can supplant the Wada.

AB undergoes a neuropsychological assessment, which reveals normal general cognitive ability (full scale intelligence quotient [IQ] = 104), with mild verbal memory impairment. He also has a Wada test which lateralizes language to the left hemisphere. On testing of left-hemispheric memory (right ICA injection), AB correctly recalls 11 out of 12 objects, and on right-hemispheric testing (left ICA injection), he correctly recalls 12 out of 12 objects. Memory is equally good bilaterally, suggesting AB could have memory impairment following unilateral ATL if hippocampectomy is included. The finding of intact memory function bilaterally also supports the notion of a neocortical focus. Neuropsychological testing reveals mildly impaired verbal (but not visual) memory, which would suggest mild dysfunction of the left temporal region.

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