Summary: Sphenopalatine ganglion stimulation increased cerebral blood flow, stabilized the blood-brain barrier and reduced infarct size in preclinical models of ischemic stroke. The stimulation also showed benefit in randomized human trials and improved functional outcomes.
Research led by a UCLA scientist found that a new nerve stimulation therapy to increase blood flow could help patients with the most common type of stroke up to 24 hours after onset.
A study of 1,000 patients found evidence that the technique, called active nerve cell cluster stimulation, reduced the patients’ degree of disability three months after they suffered an acute cortical ischemic stroke, which affects the surface of the brain.
Dr. Jeffrey Saver, director of the UCLA Comprehensive Stroke Center, was the co-principal investigator of the study, which was conducted at 73 medical centers in 18 countries.
“We believe this represents the advent of an entirely new treatment for patients with acute ischemic stroke,” said Saver, who also is senior associate vice chair for clinical research in neurology at the David Geffen School of Medicine at UCLA. The study is published today in The Lancet.
Unlike the two currently approved therapies for acute stroke, which open blocked arteries by dissolving or removing a clot, the new approach applies electrical stimulation to nerve cells behind the nose, increasing blood flow in the brain by dilating undamaged arteries and bypassing the blockage to treat the threatened region of the brain.
In previous studies to understand the mechanism by which the treatment would work, scientists found that the nerve cell cluster stimulation not only increases blood flow, but also preserves the blood-brain barrier, which prevents brain swelling. It also improved neurons’ ability to compensate for injury and form new connections.
In a study subset of 520 people who had major deficits and confirmed injury to the cerebral cortex, 40% of those who did not have the stimulation had favorable outcomes, versus 50% of those who did have the stimulation. Although those results fell just short of statistical significance, when the data is combined with similar findings from an earlier trial, the cumulative statistics indicate that the therapy is effective when administered eight to 24 hours after the onset of a cortical acute ischemic stroke.
The treatment uses a small neurostimulator electrode that is temporarily implanted through the roof of the mouth. (The implant requires only local anesthesia.) During the study, the electrode actively stimulated the nerve cell cluster four hours a day for five consecutive days.
The first treatment for ischemic stroke, the clot-dissolving drug alteplase, was approved by the Food and Drug Administration in 1996. When administered soon after onset, the drug, which is also called tPA, can sometimes clear a blocked artery, restore blood flow and avert stroke damage. However, its effectiveness diminishes if treatment is delayed beyond three hours, it does not work for all patients, and some people have conditions that preclude its use.
More recently, the FDA has approved clot-retrieval devices that are threaded through arteries to capture and remove blockages. Used alone or in conjunction with tPA, those devices have extended treatment time to 24 hours after the onset of stroke in some patients, although earlier treatment is more effective. But the devices require expertise that may be absent outside of major medical centers.
“Stroke continues to be a major cause of death and disability in the United States and around the world, making it imperative that we develop new, effective treatments to complement existing therapies, including in the extended treatment window,” Saver said.
The trial found that the new stimulation treatment can be safe and effective for people who are not eligible for clot-dissolving medication, Saver said. Future studies will determine the effectiveness of the new therapy when it is used with clot-dissolving medications and clot-retrieving devices.
Saver and Dr. Natan Bornstein of Tel Aviv University and the Shaare Zedek Medical Center in Israel, were the study’s co-first authors.
Funding: The research was funded by device manufacturer BrainsGate Ltd. Saver, Bornstein and other authors were paid by BrainsGate for serving on a steering committee that provided guidance on the study’s design and approach.
About this neuroscience research article
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An injectable implant to stimulate the sphenopalatine ganglion for treatment of acute ischaemic stroke up to 24 h from onset (ImpACT-24B): an international, randomised, double-blind, sham-controlled, pivotal trial
Background Sphenopalatine ganglion stimulation increased cerebral collateral blood flow, stabilised the blood–brain barrier, and reduced infarct size, in preclinical models of acute ischaemic stroke, and showed potential benefit in a pilot randomised trial in humans. The pivotal ImpACT-24B trial aimed to determine whether sphenopalatine ganglion stimulation 8–24 h after acute ischaemic stroke improved functional outcome.
Methods ImpACT-24B is a randomised, double-blind, sham-controlled, pivotal trial done at 73 centres in 18 countries. It included patients (men aged 40–80 years and women aged 40–85 years) with anterior-circulation acute ischaemic stroke, not undergoing reperfusion therapy. Enrolled patients were randomly assigned via web-based randomisation to receive active sphenopalatine ganglion stimulation (intervention group) or sham stimulation (sham-control group) 8–24 h after stroke onset. Patients, clinical care providers, and all outcome assessors were masked to treatment allocation. The primary efficacy endpoint was the difference between active and sham groups in the proportion of patients whose 3-month level of disability improved above expectations. This endpoint was evaluated in the modified intention-to-treat (mITT) population (defined as all patients who received one active or sham treatment session) and the population with confirmed cortical involvement (CCI) and was analysed using the Hochberg multi-step procedure (significance in both populations if p<0·05 in both, and in one population if p<0·025 in that one). Safety endpoints at 3 months were all serious adverse events (SAEs), SAEs related to implant placement or removal, SAEs related to stimulation, neurological deterioration, and mortality. All patients who underwent an attempted sphenopalatine ganglion stimulator or sham stimulator placement procedure were included in the safety analysis. This trial is registered with ClinicalTrials.gov, number NCT00826059.
Findings Between June 10, 2011, and March 7, 2018, 1078 patients were enrolled and randomly assigned to either the intervention or the sham-control group. 1000 patients received at least one session of sphenopalatine ganglion stimulation or sham stimulation and entered the mITT population (481 [48%] received sphenopalatine ganglion stimulation, 519 [52%] were sham controls), among whom 520 (52%) patients had CCI on imaging. The proportion of patients in the mITT population whose 3-month disability level was better than expected was 49% (234/481) in the intervention group versus 45% (236/519) in the sham-control group (odds ratio 1·14, 95% CI 0·89–1·46; p=0·31). In the CCI population, the proportion was 50% (121/244) in the intervention group versus 40% (110/276) in the sham-control group (1·48, 1·05–2·10; p=0·0258). There was an inverse U-shaped dose–response relationship between attained sphenopalatine ganglion stimulation intensity and the primary outcome in the CCI population: the proportion with favourable outcome increased from 40% to 70% at low–midrange intensity and decreased back to 40% at high intensity stimulation (p=0·0034). There were no differences in mortality or SAEs between the intervention group (n=536) and the sham-control group (n=519) in the safety population.
Interpretation Sphenopalatine ganglion stimulation is safe for patients with acute ischaemic stroke 8–24 h after onset, who are ineligible for thrombolytic therapy. Although not reaching significance, the trial’s results support that, among patients with imaging evidence of cortical involvement at presentation, sphenopalatine ganglion stimulation is likely to improve functional outcome.