Low frequency activation of the sphenopalatine ganglion does not induce migraine-like attacks in migraine patients.

INTRODUCTION: Cephalic autonomic symptoms occur in 27‒73% of migraine patients during attacks. The role of parasympathetic activation in migraine attack initiation remains elusive. Low frequency stimulation of the sphenopalatine ganglion increases parasympathetic outflow. In this study, we hypothesized that low frequency stimulation of the sphenopalatine ganglion would provoke migraine-like attacks in migraine patients. METHODS: In a double-blind randomized sham-controlled crossover study, 12 migraine patients with a sphenopalatine ganglion neurostimulator received low frequency or sham stimulation for 30 min on two separate days. We recorded headache characteristics, cephalic autonomic symptoms, ipsilateral mechanical perception and pain thresholds, mean blood flow velocity in the middle cerebral artery (VMCA) and diameter of the superficial temporal artery during and after stimulation. RESULTS: Five patients (42%) reported a migraine-like attack after low frequency stimulation compared to six patients (50%) after sham (p = 1.000). We found a significant increase in mechanical detection thresholds during low frequency stimulation compared to baseline (p = 0.007). Occurrence of cephalic autonomic symptoms and changes in mechanical perception thresholds, VMCA and diameter of the superficial temporal artery showed no difference between low frequency stimulation compared to sham (p = 0.533). CONCLUSION: Low frequency stimulation of the sphenopalatine ganglion did not induce migraine-like attacks or autonomic symptoms in migraine patients. These data suggest that increased parasympathetic outflow by the sphenopalatine ganglion neurostimulator does not initiate migraine-like attacks.Study protocol: ClinicalTrials.gov registration number NCT02510742.

Cranial parasympathetic activation induces autonomic symptoms but no cluster headache attacks.

Background Low frequency (LF) stimulation of the sphenopalatine ganglion (SPG) may increase parasympathetic outflow and provoke cluster headache (CH) attacks in CH patients implanted with an SPG neurostimulator. Methods In a double-blind randomized sham-controlled crossover study, 20 CH patients received LF or sham stimulation for 30 min on two separate days. We recorded headache characteristics, cephalic autonomic symptoms (CAS), plasma levels of parasympathetic markers such as pituitary adenylate cyclase-activating polypeptide-38 (PACAP38) and vasoactive intestinal peptide (VIP), and mechanical detection and pain thresholds as a marker of sensory modulation. Results In the immediate phase (0-60 min), 16 (80%) patients experienced CAS after LF stimulation, while nine patients (45%) reported CAS after sham ( p = 0.046). We found no difference in induction of cluster-like attacks between LF stimulation (n = 7) and sham stimulation (n = 5) ( p = 0.724). There was no difference in mechanical detection and pain thresholds, and in PACAP and VIP plasma concentrations between LF and sham stimulation ( p ≥ 0.162). Conclusion LF stimulation of the SPG induced autonomic symptoms, but no CH attacks. These data suggest that increased parasympathetic outflow is not sufficient to induce CH attacks in patients. Study protocol ClinicalTrials.gov registration number NCT02510729.

Long-term effectiveness of sphenopalatine ganglion stimulation for cluster headache.

Objectives The sphenopalatine ganglion (SPG) plays a pivotal role in cluster headache (CH) pathophysiology as the major efferent parasympathetic relay. We evaluated the long-term effectiveness of SPG stimulation in medically refractory, chronic CH patients. Methods Thirty-three patients were enrolled in an open-label follow-up study of the original Pathway CH-1 study, and participated through 24 months post-insertion of a microstimulator. Response to therapy was defined as acute effectiveness in ≥ 50% of attacks or a ≥ 50% reduction in attack frequency versus baseline. Results In total, 5956 attacks (180.5 ± 344.8, range 2-1581 per patient) were evaluated. At 24 months, 45% ( n = 15) of patients were acute responders. Among acute responders, a total of 4340 attacks had been treated, and in 78% of these, effective therapy was achieved using only SPG stimulation (relief from moderate or greater pain or freedom from mild pain or greater). A frequency response was observed in 33% ( n = 11) of patients with a mean reduction of attack frequency of 83% versus baseline. In total, 61% (20/33) of all patients were either acute or frequency responders or both. The majority maintained their therapeutic response through the 24-month evaluation. Conclusions In the population of disabled, medically refractory chronic CH patients treated in this study, SPG stimulation is an effective acute therapy in 45% of patients, offering sustained effectiveness over 24 months of observation. In addition, a maintained, clinically relevant reduction of attack frequency was observed in a third of patients. These long-term data provide support for the use of SPG stimulation for disabled patients and should be considered after medical treatments fail, are not tolerated or are inconvenient for the patients.

Sphenopalatine Ganglion (SPG): Stimulation Mechanism, Safety, and Efficacy.

OBJECTIVE: To describe the history of and available data on sphenopalatine ganglion (SPG) neuromodulation in the treatment of headache up to the present. BACKGROUND: The SPG has been a therapeutic target to treat primary headache disorders for over 100 years. Multiple destructive lesions have also been tried with variable rate and duration of success. Neurostimulation of the SPG for cluster headache was first described in 2007. METHODS: This is not a systematic review. The authors review the anatomy and pathophysiology of the SPG and cluster headache and the important clinical trials, relating a history of how SPG neuromodulation reached the current state of approval in the European Union (EU) and pivotal registration study for cluster headache in the US. RESULTS: The EU approved SPG stimulation for cluster headache with a CE Mark in February of 2012. Since then, several EU countries have elected to reimburse implantation for cluster headache, and over 300 patients have been implanted worldwide. CONCLUSIONS: Success rates for implanted SPG neuromodulation in the experimental phase of the European randomized controlled trial, in the open label extension trial, and in the registry of patients implanted outside of the trial remain at about two-thirds of patients implanted being responders, defined as being able to terminate at least 50% of attacks or having at least a 50% decrease in attack frequency or both. A US pivotal registration study is underway to confirm these results and obtain FDA approval for this treatment for cluster headache patients. Further studies in migraine are also underway.

Cluster headache attack remission with sphenopalatine ganglion stimulation: experiences in chronic cluster headache patients through 24 months.

BACKGROUND: Cluster headache (CH) is a debilitating headache disorder with severe consequences for patient quality of life. On-demand neuromodulation targeting the sphenopalatine ganglion (SPG) is effective in treating the acute pain and a subgroup of patients experience a decreased frequency of CH attacks. METHODS: We monitored self-reported attack frequency, headache disability, and medication intake in 33 patients with medically refractory, chronic CH (CCH) in an open label follow-up study of the original Pathway CH-1 study. Patients were followed for at least 24 months (average 750 ± 34 days, range 699-847) after insertion of an SPG microstimulator. Remission periods (attack-free periods exceeding one month, per the ICHD 3 (beta) definition) occurring during the 24-month study period were characterized. Attack frequency, acute effectiveness, medication usage, and questionnaire data were collected at regular clinic visits. The time point "after remission" was defined as the first visit after the end of the remission period. RESULTS: Thirty percent (10/33) of enrolled patients experienced at least one period of complete attack remission. All remission periods followed the start of SPG stimulation, with the first period beginning 134 ± 86 (range 21-272) days after initiation of stimulation. On average, each patient's longest remission period lasted 149 ± 97 (range 62-322) days. The ability to treat acute attacks before and after remission was similar (37 % ± 25 % before, 49 % ± 32 % after; p = 0.2188). Post-remission headache disability (HIT-6) was significantly improved versus baseline (67.7 ± 6.0 before, 55.2 ± 11.4 after; p = 0.0118). Six of the 10 remission patients experienced clinical improvements in their preventive medication use. At 24 months post insertion headache disability improvements remained and patient satisfaction measures were positive in 100 % (10/10). CONCLUSIONS: In this population of 33 refractory CCH patients, in addition to providing the ability to treat acute attacks, neuromodulation of the SPG induced periods of remission from cluster attacks in a subset of these. Some patients experiencing remission were also able to reduce or stop their preventive medication and remissions were accompanied by an improvement in headache disability.

Experimental activation of the sphenopalatine ganglion provokes cluster-like attacks in humans.

BACKGROUND: High frequency (HF) stimulation of the sphenopalatine ganglion (SPG) is an emerging abortive treatment for cluster headache (CH) attacks. HF SPG stimulation is thought to exert its effect by physiologically blocking parasympathetic outflow. We hypothesized that low frequency (LF) SPG stimulation may activate the SPG, causing increased parasympathetic outflow and thereby provoking cluster attacks in CH patients. METHODS: In a double-blind randomized cross-over study, seven CH patients implanted with an SPG neurostimulator were randomly allocated to receive HF or LF stimulation for 3 min on 2 separate days. We recorded headache characteristics and autonomic symptoms during and after stimulation. RESULTS: Six patients completed the study. Three out of six patients (50%) reported ipsilateral cluster-like attacks during or within 30 min of LF SPG stimulation. These cluster-like attacks were all successfully treated with the therapeutic HF SPG stimulation. One out of six reported a cluster-like attack with 3 min HF SPG stimulation, which was also successfully treated with continued HF therapeutic SPG stimulation. DISCUSSION: LF SPG stimulation may induce cluster-like attacks with autonomic features, which can subsequently be treated by HF SPG stimulation. Efferent parasympathetic outflow from the SPG may initiate autonomic symptoms and activate trigeminovascular sensory afferents, which may initiate the onset of pain associated with CH.

Stimulation of the sphenopalatine ganglion (SPG) for cluster headache treatment. Pathway CH-1: a randomized, sham-controlled study.

BACKGROUND: The pain and autonomic symptoms of cluster headache (CH) result from activation of the trigeminal parasympathetic reflex, mediated through the sphenopalatine ganglion (SPG). We investigated the safety and efficacy of on-demand SPG stimulation for chronic CH (CCH). METHODS: A multicenter, multiple CH attack study of an implantable on-demand SPG neurostimulator was conducted in patients suffering from refractory CCH. Each CH attack was randomly treated with full, sub-perception, or sham stimulation. Pain relief at 15 minutes following SPG stimulation and device- or procedure-related serious adverse events (SAEs) were evaluated. FINDINGS: Thirty-two patients were enrolled and 28 completed the randomized experimental period. Pain relief was achieved in 67.1% of full stimulation-treated attacks compared to 7.4% of sham-treated and 7.3% of sub-perception-treated attacks ( P < 0.0001). Nineteen of 28 (68%) patients experienced a clinically significant improvement: seven (25%) achieved pain relief in ≥50% of treated attacks, 10 (36%), a ≥50% reduction in attack frequency, and two (7%), both. Five SAEs occurred and most patients (81%) experienced transient, mild/moderate loss of sensation within distinct maxillary nerve regions; 65% of events resolved within three months. INTERPRETATION: On-demand SPG stimulation using the ATI Neurostimulation System is an effective novel therapy for CCH sufferers, with dual beneficial effects, acute pain relief and observed attack prevention, and has an acceptable safety profile compared to similar surgical procedures.

Improved surgical procedure using intraoperative navigation for the implantation of the SPG microstimulator in patients with chronic cluster headache.

INTRODUCTION: The ATI SPG microstimulator is designed to be fixed on the posterior maxilla, with the integrated lead extending into the pterygopalatine fossa to electrically stimulate the sphenopalatine ganglion (SPG) as a treatment for cluster headache. Preoperative surgical planning to ensure the placement of the microstimulator in close proximity (within 5 mm) to the SPG is critical for treatment efficacy. The aim of this study was to improve the surgical procedure by navigating the initial dissection prior to implantation using a passive optical navigation system and to match the post-operative CBCT images with the preoperative treatment plan to verify the accuracy of the intraoperative placement of the microstimulator. METHODS: Custom methods and software were used that result in a 3D rotatable digitally reconstructed fluoroscopic image illustrating the patient-specific placement with the ATI SPG microstimulator. Those software tools were preoperatively integrated with the planning software of the navigation system to be used intraoperatively for navigated placement. Intraoperatively, the SPG microstimulator was implanted by completing the initial dissection with CT navigation, while the final position of the stimulator was verified by 3D CBCT. Those reconstructed images were then immediately matched with the preoperative CT scans with the digitally inserted SPG microstimulator. This method allowed for visual comparison of both CT scans and verified correct positioning of the SPG microstimulator. RESULTS: Twenty-four surgeries were performed using this new method of CT navigated assistance during SPG microstimulator implantation. Those results were compared to results of 21 patients previously implanted without the assistance of CT navigation. Using CT navigation during the initial dissection, an average distance reduction of 1.2 mm between the target point and electrode tip of the SPG microstimulator was achieved. Using the navigation software for navigated implantation and matching the preoperative planned scans with those performed post-operatively, the average distance was 2.17 mm with navigation, compared to 3.37 mm in the 28 surgeries without navigation. CONCLUSION: Results from this new procedure showed a significant reduction (p = 0.009) in the average distance from the SPG microstimulator to the desired target point. Therefore, a distinct improvement could be achieved in positioning of the SPG microstimulator through the use of intraoperative navigation during the initial dissection and by post-operative matching of pre- and post-operatively performed CBCT scans.

A nerve cuff electrode for controlled reshaping of nerve geometry.

The purpose of this study is the development of a nerve electrode that reorganizes nerve geometry slowly and controllably. The Flat Interface Nerve Electrode (FINE) can reshape the nerve into an elongated oval and provide selective stimulation. However, the rate of closure of this electrode is difficult to control. The Slowly Closing - FINE (SC-FINE) is designed with an opening height larger than the size of the nerve to accommodate initial swelling. The electrode closes slowly to reshape the nerve into the desired flat geometry. The SC-FINE is created by combining the reshaping properties of the FINE and the controllable degradation of Poly (DL lactic-co-glycolic) acid (PLGA). Bonding 50/50 or 65/35 PLGA to a stretched FINE increased the opening heights (OH) on average from 0.1 mm to 1.66 +/- 0.45 and 2.05 +/- 0.55 mm respectively. The addition of the PLGA films controls the time course of closure over a period of 16 +/- 1 days and 14 to 16 hours for the 50/50 and 65/35 SC-FINEs respectively in vitro. An in vivo chronic experiment using 50/50 SC-FINEs implanted in 28 rats with an average OH of 1.87 +/- 0.34 mm show that the reshaping periods in vivo and in vitro are similar.