Sphenopalatine Ganglion Stimulation to Augment Cerebral Blood Flow
Authors: Bornstein Natan M. , Saver Jeffrey L. , Diener Hans-Christoph , Gorelick Philip B. , Shuaib Ashfaq , Solberg Yoram , Devlin Thomas , Leung Thomas , Molina Carlos A. , Skoloudik David , Fiksa Jan , Krieger Derk , Andersen Grethe , Berrouschot Joerg , Hobohm Carsten , Schneider Dietmar , Griewing Bernd , Endres Matthias , Hausler Karl-Georg , Kimmig Hubert , Ringleb Peter , Weimar Christian , Schilling Matthias , Kohrmann Martin , Hetzel Andreas , Kaps Manfred , Cheung Raymond , Sobolewski Piotr , Nyke Walenty , Czlonkowska Anna , Stepien Adam , Waldemar Brola , Słowik Agnieszka , Zbigniewem Stelmasiakiem , Lubiński Ignacy , Portela Pedro , Segure Tomas , Marti-Fabregas Joan , Alonso Maria , Nunez Antonio , Miguel Miguel Blanco , Campello Anna , Arenillas Joaquin , Marshall Nash , Chiu David , Shownkeen Harish , Rymer Marilyn , Sen Souvik , Roubec Martin , Kuliha Martin , Lakomý Ctirad , Tyl David , Kemlink David , Doležal Ondřej , Rekova Petra , Krejčí Veronika , Christensen Anders , Belhage Bo , Maschmann Christian , Kruse Larsen Christian , Pott Frank , Christensen Hanne , Marstrand Jakob , Nielsen Jens Kjellberg , Meden Per , Prytz Svend , Rosenbaum Sverre , Hedemann Sorensen Jens Christian , Stenhoj Meier Kaare , Schmift Ettrup Kare , Dupont Hougaard Kristina , Von Wietzel Paul , Stoll Anett , Schwetlick Hans , Pradel Hendirk , Hemprich Alexander , Schulz Andreas , Frerich Bernhard , Hobohm Carsten , Weise Christopher , Michalski Dominik , Schaller Felix , Schiefke Franziska , Helmrich Jens , Pelz Johann , Schnieder Martin , Schneider Martin , Matzen Peter , Langos Rudiger , Müller-Duerwald Stephan , Lukhaup Sven , Bauer Ute , Kloppig Wolfgang , Hiermann Erich , Mucha Gregor , Soda Hassan , Weinhardt Renate , Mucha Teresa , Ziegler Volker , Abbushi Alexander , Hotter Benjamin , Winter Benjamin , Anthofer Birgit , Noack Cornelia , Laubisch Dinah , Heldge Schneider Gerd , Jan Jungehulsing Gerhard , Mueller Heiko , Dreier Jens , Fiebach Jochen , Flechsenhar Julia , Villringer Kersten , Ebinger Martin , Rozanski Michael , Vajkoczy Peter , Klingebiel Randolf , Steinicke Robert , Pittl Sandra , Hoffmann Sarah , Maul Stephan , Krause Thomas , Liman Thomas , Plath Thomas , Nowe Tim , Schmidt Wolf , Fritzsch Carsten , Haas Christopher , Will Hans-Gerd , Haußmann-Betz Katja , Bayat Mohsen , Pordzik Tomazs , Hug Andreas , Staff Christian Jürgen , Lichy Christoph , Eggers Georg , Kloss Manja , Bendszus Martin , Herrmann Oliver , Seeberger Robin , Schwarting Soenke , Rhode Stefan , Rizos Timolaos , Hacke Werner , Frank Benedikt , Bozkurt Bessi , Holle Dagny , Mueller Daniel , Koch Dirk , Shanib Hind , Sudendey Joachim , Brenck Johannes , Busch Kolja , Gartzen Kristina , Gasser Thomas , Hagenacker Tim , Buerke Boris , Prigge Gudrun , Minnerup Jens , Albers Johannes , Wermker Kai , Schwindt Wolfram , Kallmünzer Ringlestein, Bernd , Hauer Eva , Breuer Lorenz , Schellinger Peter , Kollmar Rainer , Sauer Roland , Schwab Stefan , Struffert Tobias , Funfack Anette , Stechmann Anne , Schlaeger Axel , Laeppchen Claus , Schuchardt Florian , Klingler Jan-Helge , Reis Janine , Lambeck Johann , Friedrich Mirko , Laible Mona , Wellermeyer Philip , Beck Sandra , Rutsch Sebastian , Niesen Wolf-Dirk , Tanislav Christian , Schaaf Heidrun , Kerkmann Heiko , Schirotzek Ingo , Allendörfer Jens , Wolff Stephanie , Yuk-Lun Lau Alexander , Yin Yan Chan Anne , Siu Deyond , Wong Edward HC , Chu Wong George Kwok , Leung Howan , Wong Lawrence K.S. , Zhu Xian Lun , Yan Soo Yannie Oi , Ting Tse Alan Choi , Kit Leung Gilberto Ka , Leung Kar Ming , Ngai Hung Kwan , Wai Mei Kwan May , Man Yu Tse Mona , Tse Philip , Hon Chan Ping , Lee Raymand , Shek Kwan Chang Richard , Yin Yu Pang Shirley , Fong Kwong Hon Sonny , Cheng Tat Sun , Lui Wai Man , Wo Mak Windsor Wai , Sobota Anna , Wiater Baeta , Loch Barbara , Wolak Genowefa , Łabudzka Irena , Dabal Jan , Grzesik Marcin , Sledzinska Monika , Hatalska-Żerebiec Renata , Szczuchniak Wiktor , Gójska Anna , Nałęcz Dariusz , Gasecki Dariusz , Kozera Grzegorz , Dylewicz Łukasz , Niekra Marcin , Kwarciany Mariusz , Chomik Piotr , Skowron Piotr , Kobayashi Adam , Chabik Grzegorz , Makowicz Grzegorz , Bembenek Jan , Jędrzejewska Julia , Karlinski Michal , Czepiel Wojciech , Brodacki Bogdan , Staszewski Jacek , Kosek Jarosław , Jadczak Marcin , Durka-Kęsy Marta , Kaluzny Krzysztof , Ziomek Małgorzata , Fudala Małgorzata , Sosnowski Zbigniew , Ferens Antoni , Szczygieł Elżbieta , Banaszkiewicz Krzysztof , Ziomek Maciej , Wnuk Marcin , Szczepańska-Szerej Anna , Jach Ewa , Maslanko Grazyna Elzbieta , Wojczal Joanna , Luchowski Piotr , Kowalczyk Andrzej , Jakubiak Jerzy , Kopcewicz Joanna , Gajda Maciej , Wichlinska-Lubinska Malgorzata , Rodriguez David , Santamarin Estevo , Pagola Jorge , Lorente Guerrero Juan , Ribo Marc , Rubiera Marta , Maisterra Olga , Pinero Soccoro , Catalina Iglesias Valera , Plans Gerard , Quesada Helena , Aparicio Caballero Marco Alberto , Portela Pedro Cardona , De Diego Antonio Belinchon , Garay David Sopelana , García Rodriguez Máximo Rafael , Martin Oscar Ayo , Braña Silvia Crusat , Garcia Jorge , Hernandez Fernando Munoz , Catala Ignasi , Marti-Vilalta Josep Lluis , Delgado Mederos Rachel , de Quintana Schmid Cristian , Martinez-Ramirez Sergi , Valcarcel Gonzalez Jaime , Masjuan Vallejo Jaime , Diamantopoulus Jorge , Del Alamo Marta , Poveda Pedro Domingo , Pastor Andres Garcia , Carballal Calros Fernandez , Diaz Fernando , Garcia Leal Roberto , Juretschke Ruiz , Echabe Eduardo Arán , Sanchez Jose Castillo , Yanez Manuel Rodriguez , Garcia Ramon Serramito , Muino Rogelio Leira , Rivas Susana Arias , Lopez Gonzalez Demian Manzano , Cuadrado Elisa , Giralt Eva , Villalba Gloria , Roquer Jaime , Angel Ois , Jimenez Maria , Cedeño René Robles , Salinas Ruy , Lejarreta Saioa , Silva Yolanda , Fraile Adela , Calleja Ana , Cepeda Landínez Guillermo Arturo , Tellez Nieves , Garcia Bermejo Pablo , Santos Pérez Jaime , Herranz Rosa Fernandez , Hunt Peter , Browning Donald , Violette Michael , Hoddeson Robert , Rose James , Zhang Jonathan , Mazumdar Avi , Echiverri Henri , Chow James , Lovick Darren , Coleman Martin , Akhtar Naveed , Sugg Rebecca , Zanation Adam , Germanwala Anand , Senior Brent , Huang David , Aucutt-Walter Natalie , Kasner Scott , LeRoux Peter , von Kummer Rüdiger , Palesch Yuko 
Published: May 2019

Background and Purpose—
Many patients with acute ischemic stroke are not eligible for thrombolysis or mechanical reperfusion therapies due to contraindications, inaccessible vascular occlusions, late presentation, or large infarct core. Sphenopalatine ganglion (SPG) stimulation to enhance collateral flow and stabilize the blood-brain barrier offers an alternative, potentially more widely deliverable, therapy.

Methods—
In a randomized, sham-controlled, double-masked trial at 41 centers in 7 countries, patients with anterior circulation ischemic stroke not treated with reperfusion therapies within 24 hours of onset were randomly allocated to active SPG stimulation or sham control. The primary efficacy outcome was improvement beyond expectations on the modified Rankin Scale of global disability at 90 days (sliding dichotomy), assessed in the modified intention-to-treat population. The initial planned sample size was 660 patients, but the trial was stopped early when technical improvements in device placement occurred, so that analysis of accumulated experience could be conducted to inform a successor trial.

Results—

Among 303 enrolled patients, 253 received at least one active SPG or sham stimulation, constituting the modified intention-to-treat population (153 SPG stimulation and 100 sham control). Age was median 73 years (interquartile range, 64–79), 52.6% were female, deficit severity on the National Institutes of Health Stroke Scale was median 11 (interquartile range, 9–15), and time from last known well median 18.6 hours (interquartile range, 14.5–22.5). For the primary outcome, improved 3-month disability beyond expectations, rates in the SPG versus sham treatment groups were 49.7% versus 40.0%; odds ratio, 1.48 (95% CI, 0.89–2.47);
P
=0.13. A significant treatment interaction with stroke location (cortical versus noncortical) was noted,
P
=0.04. In the 87 patients with confirmed cortical involvement, rates of improvement beyond expectations were 50.0% versus 27.0%; odds ratio, 2.70 (95% CI, 1.08–6.73);
P
=0.03. Similar response patterns were observed for all prespecified secondary efficacy outcomes. No differences in mortality or serious adverse event safety end points were observed.

Conclusions—
SPG stimulation within 24 hours of onset is safe in acute ischemic stroke. SPG stimulation was not shown to statistically significantly improve 3-month disability above expectations, though favorable outcomes were nominally higher with SPG stimulation. Beneficial effects may distinctively be conferred in patients with confirmed cortical involvement. The results of this study need to be confirmed in a larger pivotal study.

Clinical Trial Registration—

URL:
https://www.clinicaltrials.gov
. Unique identifier: NCT03767192.