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Keywords:

  • Cerebral cooling;
  • Epileptiform;
  • Motor threshold

Abstract

  1. Top of page
  2. Abstract
  3. CASE REPORT
  4. DISCUSSION
  5. REFERENCES

Summary:  Purpose: Focal cerebral cooling has been shown to reduce epileptiform activity in animals. There are, however, few reports of this phenomenon in humans.

Methods: Electrocorticography was performed before resection of a right frontal tumor in a patient with partial seizures. Cold saline was applied to the interictal spike focus, and its effect on the epileptiform discharges was observed.

Results: Application of cold saline to the spike focus resulted in a transient, complete cessation of spiking. This effect was reproduced with a second application of cold saline. The motor threshold for electrical stimulation remained unchanged during the application of saline.

Conclusions: In this patient with tumor-related epilepsy, focal cooling of the cortex reproducibly abolished interictal epileptiform discharges without changing the motor threshold to electrical stimulation.

Cooling has been shown to deactivate the central nervous system reversibly (1,2). In addition, several in vivo and in vitro studies have demonstrated a reduction of epileptiform activity in models of epilepsy after gradual cooling (3–6). The mechanism by which this is achieved is not clearly understood, but there is evidence of interference with synaptic transmission and voltage-gated ion channels (7–9). There is some evidence that the antiseizure effect persists beyond acute abortion of seizure activity, with demonstration of a lasting effect on cortical irritability after two periods of cooling (5). There are, however, few accounts of the response of epileptiform activity in humans to cooling (10–12).

In 1969 the successful treatment of five of six patients with medically refractory, focal status epilepticus by using general hypothermia was reported (10). Similar accounts followed (11). More recently, there was a report of rapid termination of intraoperative stimulation-induced seizures and afterdischarges with the application of cold Ringer solution (12). We report the first evidence that focal cortical cooling by application of cold saline can abolish spontaneous epileptiform activity while maintaining intact cortical motor function.

CASE REPORT

  1. Top of page
  2. Abstract
  3. CASE REPORT
  4. DISCUSSION
  5. REFERENCES

History

A 41 year-old man was in good health until 6 years before surgery, when he had a focal motor seizure involving his left arm that progressed to a secondarily generalized tonic–clonic seizure. Magnetic resonance imaging (MRI) revealed a right frontal mass, later determined on biopsy to be a grade II oligoastrocytoma. The patient subsequently underwent resection of the tumor, followed by external beam radiation treatment. He continued to have frequent brief focal motor seizures involving the left arm and leg that proved to be medically intractable. Three months before surgery, a MRI showed no progression of the residual tumor in the right posterior–superior frontal lobe. Nevertheless, because of the intractable seizures, surgery was performed to remove the tumor and to resect adjacent epileptogenic tissue.

Operating room

Electrodes were placed on the cortical surface in four rows of four, as shown in Fig. 1.

image

Figure 1. Right frontal lobe. The electrodes were placed on the right lateral frontal cortex in rows of four, with electrodes 1 (white, solid arrow), 5 (black, solid arrow), 9 (black, dashed arrow), and 13 (white, dashed arrow) along the posterior aspect of the craniotomy. Motor responses to cortical stimulation were marked with white labels.

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Recording from these electrodes revealed a background consisting of a mixture of beta and theta frequency activity with some superimposed slower elements. There were frequent (∼12/min) high-amplitude epileptiform discharges recorded from the precentral gyrus, maximal at electrode 9, with a field extending to electrodes 5 and 13 (Fig. 2).

image

Figure 2. Electrocorticography (ECoG) showing frequent high-amplitude epileptiform discharges, maximal at electrode 9, with a field extending to electrodes 5 and 13.

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Application of cold saline (4°C) to this region for ∼30 s resulted in complete, transient suppression of the epileptiform activity for 6 min (Fig. 3). Of note, the brain temperature was not measured during this time. Before application of the saline, spikes occurred at an average rate of 2.9/30 s, and occurred in all but one of the eight 30-s epochs preceding the application. After application of saline, they were completely absent in the next eight 30-s epochs (p < 0.0014: two-tailed Fisher's Exact test).

image

Figure 3. Application of cold saline resulted in complete suppression of the epileptiform activity for ∼6 min.

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After ∼6 min, the spiking gradually resumed at a reduced rate. Application of saline at room temperature promptly increased the frequency of spiking, presumably because of an associated increase in the surface temperature of the brain. A second application of cold saline reproduced the initial effect.

Shortly after the second application of saline, cortical stimulation was repeated at sites previously associated with a motor response (white labels, Fig. 1). Stimulation was performed with an Ojemann cortical stimulator with a movable, hand-held bipolar probe including two 2-mm spherical electrodes spaced 0.5 cm apart. The stimulus was an alternating square-wave pulse of 1 ms duration at a frequency of 60 Hz, with a current of 6 mA applied for 2 s. The cortex was stimulated every 2 to 10 s. EEG recording was performed during the time of stimulation, but was obscured by artifact for the duration of each stimulus. The threshold for eliciting motor responses was unchanged by the application of cold saline, although the amplitude of the motor response, as seen by intraoperative electromyogram (EMG) and gross movements, seemed slightly attenuated by this maneuver.

DISCUSSION

  1. Top of page
  2. Abstract
  3. CASE REPORT
  4. DISCUSSION
  5. REFERENCES

We report the first observation of reversible termination of spontaneous epileptiform activity in humans with focal application of cold saline. Cooling seemed to be effective without causing complete dysfunction of the involved cortex, as demonstrated by preservation of motor responses. Although the saline was cooled to 4°C, the cortical temperature was probably higher, given the observation that cooling to this temperature typically suppresses cortical function (2). Although the epileptiform activity suppressed by cooling was interictal, these findings suggest that focal cooling may be useful in treating human epilepsy. Animal investigation has suggested that focal cooling devices could be activated to abort evoked seizures (5). An implantable cooling device activated by a seizure-detection or -anticipation algorithm (13,14) might be a future alternative to resective surgery in humans, especially in patients with seizures arising from eloquent cortex. Additionally, cephalic cooling devices (15) may be developed to play a role in the management of medically refractory status epilepticus, likely with less chance of morbidity than with generalized hypothermia.

REFERENCES

  1. Top of page
  2. Abstract
  3. CASE REPORT
  4. DISCUSSION
  5. REFERENCES
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