SEARCH

SEARCH BY CITATION

Keywords:

  • Epilepsy;
  • Seizures;
  • Epilepsy surgery;
  • Deep brain stimulation;
  • Neurostimulation

Summary

  1. Top of page
  2. Summary
  3. Methods
  4. Case 1
  5. Case 2
  6. Case 3
  7. Discussion
  8. Disclosure
  9. References
  10. Biography
  11. Supporting Information

Medically refractory epilepsy remains a major medical problem worldwide. Although some patients are eligible for surgical resection of seizure foci, a proportion of patients are ineligible for a variety of reasons. One such reason is that the foci reside in eloquent cortex of the brain and therefore resection would result in significant morbidity. This retrospective study reports our experience with a novel neurostimulation technique for the treatment of these patients. We identified three patients who were ineligible for surgical resection of the intracranially identified seizure focus because it resided in eloquent cortex, who underwent therapeutic trial of focal cortical stimulation delivered through the subdural monitoring grid. All three patients had a significant reduction in seizures, and two went on to permanent implantation, which resulted in long-term reduction in seizure frequency. In conclusion, this small case report provides some evidence of proof of concept of the role of targeted continuous neocortical neurostimulation in the treatment of medically refractory focal epilepsy, and provides support for ongoing investigations into this treatment modality.

A PowerPoint slide summarizing this article is available for download in the Supporting Information section here.

Despite advances in therapy, around 30% of patients with epilepsy remain medically refractory. Those with focal seizures may benefit from surgical resection; however, discrete foci within eloquent cortex represent a special problem, as the expected morbidity with resection often outweighs potential benefits.[1, 2] We report three patients admitted for phase II epilepsy evaluation who had successful trials of electrical stimulation targeting the identified seizure focus and administered through the monitoring grid. Based on short-term efficacy, two patients were implanted with a chronic cortical stimulation system resulting in long-term improvement in seizure frequency.

Methods

  1. Top of page
  2. Summary
  3. Methods
  4. Case 1
  5. Case 2
  6. Case 3
  7. Discussion
  8. Disclosure
  9. References
  10. Biography
  11. Supporting Information

Case ascertainment

We obtained Mayo Clinic Institutional Review Board approval to retrospectively identify patients admitted to our epilepsy monitoring unit who had a therapeutic trial of focal cortical stimulation; all three cases are presented herein.

Therapeutic cortical stimulation trial

All patients had seizures that were refractory to multiple medications and were admitted for intracranial electroencephalography (EEG) monitoring to localize the epileptic focus, which in each case resided in eloquent cortex and thus precluded resection (Fig. 1). Because the risk of invasive monitoring had already been assumed within the standard-of-care phase II evaluation, we had the opportunity to trial therapeutic focal cortical stimulation delivered through the monitoring grid. The Medtronic model 37022 (Minneapolis, MN, U.S.A.) external neurostimulator was utilized, with electrode configurations targeting the seizure focus, stimulation intensities (amplitudes and pulse durations) under the threshold required for motor or sensory activation, and both low (1 Hz) and high (100 Hz) frequencies. Detailed sensory and motor testing confirmed no ill effects at the reported settings for any of the patients.

image

Figure 1. Image of subdural grid overlying the seizure focus that resides in eloquent cortex, in this case the motor strip.

Download figure to PowerPoint

Implantation of chronic cortical stimulator

In each case, significant reduction in seizure activity demonstrated efficacy of this approach for that particular individual, and patients were therefore offered implantation of a chronic cortical stimulating system in a manner analogous to our institution's approach to motor cortex stimulation for pain.[3] A permanently implantable 4 × 4 grid was created by juxtaposition of four Medtronic model 3587A Resume II 4-contact electrodes and positioned over the region where trial stimulation had been effective. Lead extensions were connected and tunneled to a subclavicular pocket where the Medtronic model 37712 Restore Ultra pulse generator was implanted.

Case 1

  1. Top of page
  2. Summary
  3. Methods
  4. Case 1
  5. Case 2
  6. Case 3
  7. Discussion
  8. Disclosure
  9. References
  10. Biography
  11. Supporting Information

A 16-year-old female with history of intrauterine right temporoparietal infarction and focal epilepsy since age 3 years presented for evaluation of a 2-year history of recurrent epilepsy partialis continua (EPC) involving left thumb and hand twitching that persisted for weeks at a time. Phase I monitoring failed to show a scalp EEG correlate to the EPC; however, jerk-locked back-averaging revealed a cortical potential preceding the thumb twitch. She proceeded to phase II monitoring where electrocorticography showed rhythmic spiking time-locked to the thumb twitches and emanating from a single contact which was later shown, via stimulation mapping, to overlay motor cortex. When trial cortical stimulation was applied using the contact overlying the seizure focus as the cathode and an adjacent contact as the anode, abrupt cessation of EPC consistently occurred at an amplitude of 7.0 volts (pulse width 120 msec, rate 100 Hz). The latency for return of EPC after cessation of stimulation increased from 5 min after a 1 min stimulation trial to 8 h after a trial of overnight stimulation. After the permanent stimulating grid was implanted (Fig. 2), the EPC abated for 8 weeks; upon its return, the stimulator was activated using the same setting as for trial stimulation and EPC again resolved. The patient was last seen in follow-up 2 years after system implantation, at which point she remained seizure free.

image

Figure 2. CT scout image of patient 1 showing the location of the permanent implantable grid.

Download figure to PowerPoint

Case 2

  1. Top of page
  2. Summary
  3. Methods
  4. Case 1
  5. Case 2
  6. Case 3
  7. Discussion
  8. Disclosure
  9. References
  10. Biography
  11. Supporting Information

A 7-year-old boy had onset at 2 years of age of focal seizures without change in awareness characterized by laughter and right face and arm jerking lasting up to 5 min, occurring on average 15 times daily and occasionally evolving to focal dyscognitive seizures. Phase I monitoring documented seizure origin over the left central region, and phase II monitoring demonstrated seizures arising from an area covered by four contacts, which was found, via stimulation mapping, to reside within a large region of eloquent cortex including both language and hand motor function. During test stimulation covering a 16 contact region of the temporary grid, low-frequency (1 Hz) stimulation resulted in exacerbation of clinical and electrographic seizures, whereas high-frequency (100 Hz, 120 msec, 3.5 volts) stimulation significantly reduced seizure frequency. The patient proceeded to permanent implantation and was dismissed under active stimulation. He was seizure free until 3 months later, at which point multiple daily seizures recurred and it was determined that the stimulator had been inadvertently deactivated. When stimulation resumed, the seizure frequency fell to 1–4 monthly until 16 months after implantation when seizures again increased to preoperative levels. Interrogation of the device revealed it had not been properly charged and was completely depleted. Further education regarding proper device maintenance was given, and it was recommended that the device be fully charged and the patient return for evaluation; however, the patient's family had relocated and he is now followed at another center.

Case 3

  1. Top of page
  2. Summary
  3. Methods
  4. Case 1
  5. Case 2
  6. Case 3
  7. Discussion
  8. Disclosure
  9. References
  10. Biography
  11. Supporting Information

A 9-year-old girl presented for evaluation of 4-year history of left-sided focal as well as generalized tonic–clonic seizures refractory to multiple antiepileptic medications. Phase I monitoring revealed focal seizures with and without evolution to bilateral convulsive seizures correlating with right central discharges. Phase II monitoring revealed nearly continuous epileptiform discharges (EPC) in a focal area correlating with motor cortex on the basis of stimulation mapping; as a result, the patient was not offered surgical resection. Trial stimulation through the temporary grid was performed using the contacts covering the seizure zone as cathodes with surrounding electrodes as anodes. High-frequency stimulation (100 Hz) exacerbated seizure activity, whereas low-frequency (1 Hz, 450 msec, 6.0 volts) stimulation abruptly halted the left-sided EPC both clinically and by EEG criteria. Because of parental concerns regarding possible cognitive side effects, test stimulation was discontinued and EPC resumed. A permanent stimulation system was not implanted, and the patient was dismissed on her usual medications with ongoing EPC.

Discussion

  1. Top of page
  2. Summary
  3. Methods
  4. Case 1
  5. Case 2
  6. Case 3
  7. Discussion
  8. Disclosure
  9. References
  10. Biography
  11. Supporting Information

All three patients had focal epilepsy localizing to eloquent cortex that significantly improved during trials of continuous stimulation; long-term improvement occurred in the two implanted with a chronic stimulating system. Although an implantation effect likely contributed to short-term efficacy, the additional improvements under active stimulation conditions were apparent both during the initial test stimulation and at various times after permanent implantation as outlined for the first two patients. All patients tolerated the procedures well. There was no additional morbidity related to the test phase or permanent implantation, and there have been no long-term side effects of stimulation. Our experience mirrors that reported previously in two patients with epileptic foci in motor regions who also experienced reduction in seizure frequency after implantation of a chronic cortical stimulator.[4]

A number of neurostimulation approaches targeting either cortical or subcortical regions and utilizing either continuous or responsive stimulation paradigms have been employed in patients with medically refractory epilepsy. The anterior nucleus of the thalamus has been shown to be an effective target in a number of uncontrolled studies and in the well-controlled Stimulation of the Anterior Nucleus of Thalamus for Treatment of Refractory Epilepsy (SANTE) trial in which the active stimulation group experienced a 40% reduction of seizure frequency compared to baseline (vs. a 15% reduction in the nonstimulated group).[5-8] Other subcortical areas targeted in smaller studies include the centromedian nucleus and the hippocampus, all with varying degrees of success.[9, 10] These approaches rely on effects distant from the seizure focus; however, in cases of discrete nonresectable foci, focal cortical stimulation strategies may be preferred. In the largest controlled trial of cortical stimulation, the Responsive Neurostimulation trial (RNS), stimulation delivered to the seizure focus only after an electrophysiologic signature of seizure activity was detected resulted in a 38% reduction of seizure frequency compared to baseline (vs. a 17% reduction in the nonstimulated group).[11] However, high-resolution recording of epileptogenic regions has suggested that seizures may arise from submillimeter scale epileptiform activity that is not well detected within the spatial and temporal resolutions of conventional sampling techniques.[12] Therefore, by the time a responsive system is able to detect seizure activity at the macroscopic level there has likely already been substantial recruitment of abnormal activities on the microscopic scale. This raises the possibility that continuous cortical stimulation may be more effective by virtue of ongoing modulation of the abnormal microscale oscillations. Certainly, the significant seizure reductions attained during continuous cortical stimulation in our and the previously reported series would suggest a high degree of efficacy of this approach, although the patient numbers are too small to allow for definitive conclusions regarding the relative efficacy of continuous versus responsive stimulation.

Among our patients, it is interesting to note that responses to stimulating frequency were highly individualized, with high-frequency stimulation improving seizures in two patients but worsening them in another; conversely, low-frequency stimulation halted seizure activity in one and exacerbated it in another. As the mechanism of action of stimulation is unknown, any explanations for this discrepancy are purely speculative. It has been proposed that subthreshold high-frequency stimulation can suppress intrinsic firing within cell soma. On the other hand, low-frequency stimulation may elicit long-term depression. Variability in responses may be due to patient or disease-specific factors and may even relate to the specific orientation of the stimulation field with respect to the seizure focus. Regardless, our experience suggests that protocols evaluating the efficacy of neurostimulation should allow for optimization of stimulation parameters to occur on an individual basis.

This small case report provides some evidence of proof of concept of the role of targeted continuous neocortical neurostimulation in the treatment of medically refractory focal epilepsy, and provides support for ongoing investigations into this treatment modality.

Disclosure

  1. Top of page
  2. Summary
  3. Methods
  4. Case 1
  5. Case 2
  6. Case 3
  7. Discussion
  8. Disclosure
  9. References
  10. Biography
  11. Supporting Information

None of the authors have any conflicts of interests to disclosures. We confirm that we have read the Journal's position on issues involved in ethical publication and affirm that this report is consistent with those guidelines.

References

  1. Top of page
  2. Summary
  3. Methods
  4. Case 1
  5. Case 2
  6. Case 3
  7. Discussion
  8. Disclosure
  9. References
  10. Biography
  11. Supporting Information

Biography

  1. Top of page
  2. Summary
  3. Methods
  4. Case 1
  5. Case 2
  6. Case 3
  7. Discussion
  8. Disclosure
  9. References
  10. Biography
  11. Supporting Information
  • Image of creator

    Nicholas Child is a clinical neuromodulation and epilepsy fellow at Mayo Clinic Rochester.

Supporting Information

  1. Top of page
  2. Summary
  3. Methods
  4. Case 1
  5. Case 2
  6. Case 3
  7. Discussion
  8. Disclosure
  9. References
  10. Biography
  11. Supporting Information
FilenameFormatSizeDescription
epi12525-sup-0001-12525.pptxapplication/pptx719K 

Please note: Wiley Blackwell is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.