Stimulation of nerve cluster during stroke may have beneficial effects

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Two prior trials of the stimulation of the sphenopalatine ganglion (SPG), at the back of the nose, showed beneficial effects in patients with stroke. Leveraging prior pivotal randomised controlled trial results, one of the new studies analyses the same patient group to quantify the full range of benefit at 3 months. Building on a prior investigation assessing the stimulation therapy’s immediate physiologic effects, the other new study determined the range of patients who show improved brain blood flow and motor function during stimulation.

“The stimulation treatment involves inserting a toothpick-sized electrode through a tiny opening in the upper palate of the mouth, positioning it very close to the SPG that sends nerves to blood vessels going to the brain. Stimulating that cluster of nerve cells causes blood vessels to dilate and enhance collateral blood flow to the brain in stroke patients without removing the clot that caused the stroke,” said Dr Jeffrey L Saver, an author of both studies and professor of neurology at The David Geffen School of Medicine at the University of California – Los Angeles.

Researchers performed a new analysis of data from a randomised trial in order to estimate the extent of benefit of SPG stimulation among patients with stroke involving the brain’s cortex, the outer part of the brain that plays an important role in consciousness and is thought to benefit when collateral blood flow around a clot-caused stroke is enhanced.

The study analysed the full range of disability outcomes for 520 patients with confirmed low blood flow in the cortex who were ineligible for treatments to dissolve or remove a clot, usually because they had arrived at the hospital too late or the therapies were not available at that location. As part of the trial, 244 received SPG stimulation, and 276 received a control procedure involving vibrations with no actual electrical stimulation of the area. SPG stimulation was initiated 8-24 hours after stroke symptoms began.

After three months, researchers estimate that out of every 1,000 patients treated with SPG stimulation: 146 more will be less disabled; and 76 more will be functionally independent (able to walk and take care of their own basic needs).

“Even for patients who are not candidates to receive clot-dissolving drugs or to have the clot removed, we may now have other options in the future. This is good news, because while stroke treatment has really come forward in the last 20 years with regards to reopening and restoring blood flow, we’ve lagged behind in figuring out what to do for patients who are ineligible to receive the standard treatments,” said Dr Fausto Ordonez, lead author of the study and a vascular neurology fellow at the University of California – Los Angeles.

In the second study, researchers assessed improvements in SPG stimulation techniques and early physiologic effects in 50 patients with anterior circulation ischemic strokes presenting 8-24 hours after last known well time and with mild deficits who were not eligible for clot-dissolving drugs or clot removal, either because their symptoms were too mild or they arrived at the hospital too long after the onset of stroke symptoms.

Using electrodes and CT scans to guide placement, it takes minutes to correctly implant the stimulation electrodes. Because the SPG also sends nerves to the face and the tear ducts, the proper amount of stimulation for each person could be comfortably determined by monitoring facial tingling or tear production.

Researchers found: during SPG stimulation (tested on the second day of five days of treatment), blood flow to the brain and head increased by an average of 44%; during stimulation, grip strength in the weaker arm increased 26%, and pinch strength increased 42%; after seven days after treatment, recovery in the patients who received SPG stimulation was significantly better (improved total neurologic deficit scores) than matched controls from previous studies of other treatments; and benefits were evident no matter the age, sex, severity of stroke, time before treatment or which side of the body had weakness due to the stroke.

“SPG stimulation substantially increases brain blood flow and improves neurologic function across a broad range of patients when treatment begins up to 24 hours after stroke onset. This helps to explain why it is emerging as a potentially important new therapy for severe ischemic stroke,” said Saver, who is also a member of the American Heart Association Stroke Systems of Care Advisory Group.

Since none of the patients in both studies received clot-busting medications or had their clots mechanically removed, it is unclear whether SPG stimulation could also benefit patients who received those treatments.

“Currently, the guidelines-based stroke treatments aim to remove the clot to restore blood flow. In these studies of SPG stimulation, the clot that’s blocking blood flow is left untreated, and the SPG treatment is used to enhance collateral blood flow around the blockage. Potentially, SPG treatment could also preserve blood flow and brain tissue while a patient is being transferred to a hospital that can complete the clot removal treatment,” Saver said.

Abstract 1
Background: Sphenopalatine ganglion (SPG) stimulation enhances collateral flow, stabilizes blood-brain barrier, and showed evidence of benefit in patients with confirmed cortical involvement (CCI) when started 8-24h after onset in the ImpACT-24B randomized trial. To characterize SPG stimulation benefit magnitude, we derived number needed to treat (NNT) values based on shifts over all levels of 3 month global disability.
Methods: From the distribution of the 7-level modified Rankin Scale (mRS) at 3m in SPG- and sham-stimulation CCI patients, NNT to benefit (NNTB) and NNT to harm (NNTH) values were derived by automated (algorithmic min-max) and expert generation of joint outcome distribution tables. For dichotomized mRS outcomes, net NNT values were derived directly from absolute risk differences.

Results: Among 520 patients with confirmed cortical infarction ineligible for thrombolysis, 244 were treated with SPG and 276 with sham stimulation. NNT values for dichotomized and shift mRS outcomes are shown in the Table. Of the 6 possible binary cutpoints on the mRS, 4 showed more favorable outcome with SPG stimulation. The dichotomized endpoint with the greatest group difference was ambulatory and capable of bodily self-care (mRS 0-3), 62.3% vs 51.1%, NNTB 8.9. Across all 6 individual possible dichotomizations of the mRS, the NNTB ranged from 8.9 to -166.7. For shifts by 1 or more levels across all 6 transitions of the mRS, the biologically most plausible NNTB was 5.7 (IQR 5.6-6.5), NNTH 34.5 (IQR 30.3-40.0), and net NNTB 6.8 (IQR 6.5-7.7), These values correlated closely with the automatically derived net NNTB of 5.9.
Conclusions: The findings of this pivotal trial indicate that, out of every 1000 CCI patients treated with SPG stimulation, 146 patients will have a less disabled 3-month outcome, including 76 more who will be functionally independent. SPG stimulation can substantially improve the outcome of thrombolysis-ineligible acute ischemic stroke patients.

Fausto E Ordonez, David Liebeskind, Mersedeh Bahr, Ashfaq Shuaib Shuaib, Natan Bornstein, Michael Hill, Carlos Molina, Jeffrey Saver

Abstract 2
Background: Two large RCTs have indicated sphenopalatine ganglion (SPG) stimulation reduces 3m disability in acute ischemic stroke patients with confirmed cortical involvement. The current trial evaluated two refinements in SPG stimulation technique: 1) SPG electrode placement with real-time optical tracking guidance; and 2) stimulation intensity comfortable tolerance level (CTL) selection using non-noxious facial physiologic markers.

Methods: Single, active arm trial at 4 centers, enrolling patients with anterior circulation ischemic stroke <24h, NIHSS 1-6, not receiving recanalization therapies. Stimulation level was based on ipsilateral facial tingling sensation or lacrimation. SPG stimulation effects were assessed by volumetric blood flow in the ipsilateral common carotid artery (ultrasound) and affected hand grasp and pinch strength before and during stimulation, and by NIHSS change by day 7.
Results: Among 50 enrolled patients, age was median 66y (IQR 60-74), 44% female, NIHSS median 5 (IQR 4-5), and median onset-to-screening time 18h (IQR 9-20). Median implantation skin-to-skin time was 4 minutes (IQR 3-7) and all 50 implants were placed correctly. CTL was found based on physiological biomarkers in 96% of patients, including 86% in the optimal, low-medium intensity range. SPG stimulation significantly increased common carotid artery peak systolic and end diastolic blood flow (up 44%, p<0.0001; and up 52%, p<0.0001) and improved pinch strength (up 42%, p<0.0001) and grasp strength (up 26%, p<0.0001). Degree of NIHSS recovery by day 7 was greater than in matched historic controls, median 75% vs 50%, p=0.0003. Forest plot analysis showed benefits were homogenous across the subgroups of: sex, age, time from onset, stroke side, NIHSS, and ASPECTS score.
Conclusion: SPG stimulator placement with real-time optical tracking guidance was fast and accurate, and selection of optimal stimulation intensity levels based on non-noxious facial tingling and lacrimation was feasible in nearly all patients. SPG activation led to cranial blood flow augmentation and improved hand motor function during stimulation, and neurologic deficit reduction at 1 week, consistently across broad patient subsets of age, sex, side, severity, and time to treatment.

Jeffrey L Saver, Nino Kharaishvili, Tamar Janelidze, Maia Beridze, Natia Zarqua, Yoram Solberg, Natan Bornstein

American Heart Association material

Stroke abstract 1

Stroke abstract 2

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