Electrical Stimulation of Collateral Flow Promising in Acute Stroke

May 27, 2019

A novel potential approach to treating acute ischemic stroke — by the electrical stimulation of an area at the back of the nose — has shown promising results in initial studies.

The approach involves inserting a small electrode the size of a toothpick into the soft palate to stimulate the sphenopalatine ganglion, the source of parasympathetic innervation to the anterior cerebral circulation, with the aim of increasing collateral circulation and maintaining blood flow to vulnerable ischemic tissue in acute ischemic stroke.  

"We saw dramatic evidence of benefit with lower doses of electrical stimulation in patients with cortical strokes," said study author Jeffrey Saver, MD, Ronald Reagan UCLA Medical Center, Los Angeles, California.  

"The intervention also appears effective when started up to 24 hours after stroke onset, thus potentially offering a treatment option for patients who have missed the thrombolysis window and may not be suitable for thrombectomy," coauthor, Natan Bornstein, MD, Shaarei Zedek Medical Center, Jerusalem, Israel, added. 

Saver presented results of a 1000-patient study of sphenopalatine ganglion stimulation (ImpACT-24B) at the 5th European Stroke Organisation Conference (ESOC) 2019. The study was concurrently published online May 24 in The Lancet.

Saver explained that good collateral blood flow is associated with slower infarct expansion, and improved prognosis and outcome in patients with acute ischemic stroke. Animal studies have shown that sphenopalatine ganglion stimulation up to 24 hours after the onset of stroke preserved the penumbra, reduced cerebral infarct volume, increased neuronal survival, and preserved the blood–brain barrier leading to reduced cerebral edema and improved neurologic outcome.

In addition, a preliminary study in 253 patients (ImpACT-24A) involving sphenopalatine ganglion stimulation showed potential benefit in improving functional outcome compared with a sham control.

The current larger ImpACT-24B trial builds on these results.

For the study, 1000 patients with anterior-circulation acute ischemic stroke, not undergoing reperfusion therapy, were randomized to receive active sphenopalatine ganglion stimulation or sham stimulation (control) starting 8 to 24 hours after stroke onset (median 19 hours). The stimulation was administered in daily 4-hour sessions, beginning immediately after the placement procedure and continuing for 5 consecutive days.

The trial had two primary endpoints — improvement in 3-month disability level beyond expectation in the whole population and in those patients with cortical strokes (52% of those enrolled).

An improvement beyond expectation was defined as a modified Rankin Scale score (mRS) one point or more lower than expected based on a prespecified prognostic model incorporating the baseline NIHSS score, age, and stroke brain side.

This occurred in 49% of the intervention group vs 45% of the sham-control group in the whole population, a nonsignificant difference (odds ratio [OR], 1.14; P = .31).

However, a better effect was seen in patients with cortical strokes. In this population, 50% improved more than expected in the intervention group vs 40% in the sham-control group (OR, 1.48; P = .0258).

Because there were two primary endpoints the P value for significance was .025.

"The P value for the cortical stroke patients of .0258 is as close as you can come to having a positive trial without it being formally positive," Saver commented.

Similar results were seen for all secondary clinical efficacy endpoints, suggesting that this is a real effect, he added.

He explained why the intervention could benefit patients with cortical stroke in particular. "This is collateral enhancing therapy — it is dilating the blood vessels around the blocked vessel. There are more collaterals in the superficial lining of the brain that go the cortical region than go to the deeper regions, so we would expect patients with cortical strokes to respond better."

Dose Response Supportive 

The study was also able to investigate a dose response, as different doses of stimulation were delivered to individual patients.

Saver noted: "Each patient received a different dose depending on their personal tolerance. We went up to the level that caused facial discomfort to each patient's maximum tolerance levels then backed off a little bit."  

"We saw a very clear inverse U-shaped dose–response curve, with patients who received low to medium doses of stimulation having better outcomes, whereas patients with high stimulation did only as well as control," he said.  

He pointed out that the proportion of patients with a favorable outcome increased from 40% to 70% at low–midrange intensity and decreased back to 40% at high intensity stimulation, Saver reported. 

"If we just look at the patients with cortical stroke who received the optimal dose — in the low to medium range — a favorable outcome at 3 months was achieved in 69% vs 40% of control patients with a highly statistically significant P value [.0001]," he added.

"Dose–response relationships are regarded as a special class of supporting evidence," Saver noted. "It is very hard for a dose–response relationship like this to arise from the play of chance, so this provides strong support that this is a genuine biological treatment effect."

In addition, the dose–response relationship seen in this trial "matched perfectly" with that seen in the previous pilot study, and fits with what is seen in animal models, he said. 

Saver reported that a pooled analysis of patients with cortical stroke from the ImpACT-24A and ImpACT-24B studies showed "a very robust effect" of the intervention, with 49.7% showing greater improvement than expected vs 38.3% of controls (P = .004).

"This is a clinically relevant benefit, with 10 or more patients with cortical stroke out of every 100 having a favorable outcome," he said.

In The Lancet article, the authors add: "This effect magnitude is nearly that of intravenous alteplase as a reperfusion therapy in less than 3-hour therapies and exceeds that of intravenous alteplase in 3- to 4.5-hour therapies, both well established, guideline-based treatments. The clinical benefit was even higher when the optimal, low–midrange intensity stimulation of the sphenopalatine ganglion was delivered in this trial. This optimal dose range is attainable in most patients as it falls within the low–medium range of comfortable tolerance levels." 

The authors describe the procedure for placing the neurostimulator electrode as "simple and fast."

"The procedure can be done by neurologists," Saver added, "and does not require expensive infrastructure, advanced imaging, or special surgical skills, so [it] could be used in a wide range of frontline hospitals."

Commenting on the study for Medscape Medical News, Götz Thomalla, MD, University of Hamburg Medical Center, Germany, co-chair of the ESOC session at which the study was presented, said: "It is certainly an interesting new idea and we are always looking for new approaches beyond just opening the vessels. However, the main study just missed significance and there are many further questions as to how to optimally use this stimulation, so further data are needed." 

The study was funded by BrainsGate Ltd (Caesarea, Israel), which makes the image-guided navigation system for electrode placement used in the study. Saver and Bornstein received payments from BrainsGate for service on the study steering committee. Some other authors are employees of BrainsGate or own stock options in the company. 

5th European Stroke Organisation Conference (ESOC) 2019. Presented May 24, 2019.

The Lancet. Published online May 24, 2019.  Abstract

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