Advances in Clinical Neurophysiology

April 21, 2011


April 2011

Written by Worrell, Gregory A., MD, PhD

In this and future issues of the AAN Clinical Neurophysiology website we will highlight papers of interest to neurophysiology. I welcome all members to consider contributing a review from their own work or others. In this issue two recent articles describing pathological high frequency oscillations, and their potential role as an electrophysiological biomarker of the epileptogenic zone are discussed.

Advances in neuroimaging ushered in the modern era of epilepsy surgery in the late 20th century. Arguably, over the past decade epilepsy surgery has seen little change in efficacy or in the spectrum of patients considered good surgical candidates. Localization of epileptic brain remains the key to successful epilepsy surgery, and researchers are actively pursuing new electrophysiological and imaging biomarkers to improve spatial localization of epileptic brain. The current conceptual approach defines the epileptogenic zone (EZ) as the brain region generating spontaneous seizures, and what must be resected for seizure freedom (1). The brain region generating interictal spikes, called the irritative zone (IZ), provides an interictal map of epileptic brain. The IZ, however, is more widespread than the region generating spontaneous seizures, i.e. the ictal onset zone (IOZ), and the EZ. Unfortunately, the EZ does not have a definitive electrophysiological marker and the relationship between the IZ, IOZ and EZ remain poorly defined. For this reason, chronic intracranial EEG (iEEG) to record habitual seizures remains the gold standard for estimating the EZ and guiding surgery. In practice, the IOZ and the adjacent actively spiking tissue are often removed.

The existence of a reliable interictal marker of the EZ could transform the practice of epilepsy surgery. The reliance on chronic iEEG requiring days of monitoring and associated with significant cost, morbidity, and patient discomfort could be avoided. Perhaps, the most promising candidate for interictal EZ localization are pathological high frequency oscillations (pHFO) (2, 3). There are two recent reports that show localization of epileptic brain and the EZ using interictal pHFO (4, 5). These papers follow a decade of accumulating evidence that pHFO are useful electrophysiological signatures of epileptic brain and seizure generation, see the review (3).

In a study by Wu et. al. (5) an average of 11.8-minutes of intraoperative electrocorticography (ECoG) was used to identify fast ripple pHFO (>250 Hz) and map the EZ. Remarkably, based on these very limited ECoG recordings they found that all patients who had tissue with pHFO resected (19/19) were seizure free. In contrast, none of the patients (5/5) that did not have all fast ripple pHFO tissue resected were seizure free. In a paper by Jacobs et al. (4) from the Montreal group the resection of tissue with interictal pHFO (ripple (100 - 200 Hz) and fast ripple (>250 Hz) pHFO) were found to be correlated with the IOZ and epilepsy surgery outcome. In this study the recordings were manually selected from chronic iEEG recordings and included only a 5-minute record of slow-wave sleep. They found a strong correlation between good surgical outcome and resection of tissue containing pHFO.

These papers do have weaknesses, however, that may limit their immediate impact. In particular, the studies are retrospective reviews using visual analysis of limited EEG data. Of course, these positive results from such limited recordings suggest that the signal (pathological HFO) is robust. The fact that the detection of pHFO was based on subjective visual review is a methodological weakness, but again the positive result may indicate the strength of the result. Multiple groups are currently working on the development of automated detectors for pHFO and their translation to advance epilepsy surgery. In summary, the papers discussed here represent a potentially important direction for improving the localization of epileptic brain and efficacy of epilepsy surgery. Future prospective studies evaluating large intra-operative data streams should follow soon.

  1. J. J. Luders, Y. Comair, Epilepsy Surgery (Lippincott Williams & Wilkins, Philadelphia, 2001).
  2. A. Bragin, J. ,. J. Engel, C. L. Wilson, I. Fried, G. Buzsaki, Hippocampus 9, 137-42 (1999).
  3. J. Engel, A. Bragin, R. Staba, I. Mody, Epilepsia 50, 598-604 (2009).
  4. J. Jacobs, M. Zijlmans, R. Zelmann, C. E. Chatillon, et al., Ann Neurol 67, 209-20 (2010).
  5. J. Y. Wu, R. Sankar, J. T. Lerner, J. H. Matsumoto, et al., Neurology 75, 1686-94 (2010).

Removing interictal fast ripples on electrocorticography linked with seizure freedom in children.

Wu JY, Sankar R, Lerner JT, Matsumoto JH, Vinters HV, Mathern GW.

22-474 MDCC, Division of Pediatric Neurology, Mattel Children's Hospital at UCLA, David Geffen School of Medicine, Los Angeles, CA 90095-1752, USA.

BACKGROUND: Fast ripples (FR, 250-500 Hz) detected with chronic intracranial electrodes are proposed biomarkers of epileptogenesis. This study determined whether resection of FR-containing neocortex recorded during intraoperative electrocorticography (ECoG) was associated with postoperative seizure freedom in pediatric patients with mostly extratemporal lesions.

METHODS: FRs were retrospectively reviewed in 30 consecutive pediatric cases. ECoGs were recorded at 2,000 Hz sampling rate and visually inspected for FR, with reviewer blinded to the resection and outcome.

RESULTS: Average age at surgery was 9.1 ± 6.7 years, ECoG duration was 11.8 ± 8.1 minutes, and postoperative follow-up was 27 ± 4 months. FRs were undetected in 6 ECoGs with remote or extensive lesions. FR episodes (n = 273) were identified in ECoGs from 24 patients, and in 64% FRs were independent of spikes, sharp waves, voltage attenuation, and paroxysmal fast activity. Of these 24 children, FR-containing cortex was removed in 19 and all became seizure-free, including 1 child after a second surgery. The remaining 5 children had incomplete FR resection and all continued with seizures postoperatively. In 2 ECoGs, the location of electrographic seizures matched FR location. FR-containing cortex was found outside of MRI and FDG-PET abnormalities in 6 children.

CONCLUSION: FRs were detected during intraoperative ECoG in 80% of pediatric epilepsy cases, and complete resection of FR cortex correlated with postoperative seizure freedom. These findings support the view that interictal FRs are excellent surrogate markers of epileptogenesis, can be recorded during brief ECoG, and could be used to guide future surgical resections in children. Neurology. 2010 Nov 9;75(19):1686-94. Epub 2010 Oct 6.

High-frequency electroencephalographic oscillations correlate with outcome of epilepsy surgery.

Jacobs J, Zijlmans M, Zelmann R, Chatillon CE, Hall J, Olivier A, Dubeau F, Gotman J.

Montreal Neurological Institute and Hospital, McGill University, Montreal, Quebec, Canada.

OBJECTIVE: High-frequency oscillations (HFOs) in the intracerebral electroencephalogram (EEG) have been linked to the seizure onset zone (SOZ). We investigated whether HFOs can delineate epileptogenic areas even outside the SOZ by correlating the resection of HFO-generating areas with surgical outcome.

METHODS: Twenty patients who underwent a surgical resection for medically intractable epilepsy were studied. All had presurgical intracerebral EEG (500Hz filter and 2,000Hz sampling rate), at least 12-month postsurgical follow-up, and a postsurgical magnetic resonance imaging (MRI). HFOs (ripples, 80-250Hz; fast ripples, >250Hz) were identified visually during 5 to 10 minutes of slow-wave sleep. Rates and extent of HFOs and interictal spikes in resected versus nonresected areas, assessed on postsurgical MRIs, were compared with surgical outcome (Engel's classification). We also evaluated the predictive value of removing the SOZ in terms of surgical outcome.

RESULTS: The mean duration of follow-up was 22.7 months. Eight patients had good (Engel classes 1 and 2) and 12 poor (classes 3 and 4) surgical outcomes. Patients with a good outcome had a significantly larger proportion of HFO-generating areas removed than patients with a poor outcome. No such difference was seen for spike-generating regions or the SOZ.

INTERPRETATION: The correlation between removal of HFO-generating areas and good surgical outcome indicates that HFOs could be used as a marker of epileptogenicity and may be more accurate than spike-generating areas or the SOZ. In patients in whom the majority of HFO-generating tissue remained, a poor surgical outcome occurred.

Ann Neurol. 2010 Feb;67(2):209-20.