Peripheral Neuromodulation for the Management of Headache

The trigeminal autonomic cephalalgias (TACs) are highly disabling primary headache disorders. There are several issues that remain unresolved in the understanding of the pathophysiology of the TACs, although activation of the trigeminal-autonomic reflex and ipsilateral hypothalamic activation both play a central role. The discovery of the central role of the hypothalamus led to its use as a therapeutic target. After the good results obtained with hypothalamic stimulation, other peripheral neuromodulation targets were tried in the management of refractory cluster headache (CH) and other TACs. This review is a summary both of CH pathophysiology and of efficacy of the different neuromodulation techniques. In chronic cluster headache (CCH) patients, hypothalamic deep brain stimulation (DBS) produced a decrease in attack frequency of more than 50% in 60% of patients. Occipital nerve stimulation (ONS) also elicited favorable outcomes with a reduction of more than 50% of attacks in around 70% of patients with medically intractable CCH. Stimulation of the sphenopalatine ganglion (SPG) with a miniaturized implanted stimulator produced a clinically significant improvement in 68% of patients (acute, preventive, or both). Vagus nerve stimulation (VNS) with a portable device used in conjunction with standard of care in CH patients resulted in a reduction in the number of attacks. DBS and ONS have been used successfully in some cases of other TACs, including hemicrania continua (HC) and short-lasting unilateral headache attacks (SUNHA). DBS has good results, but it is a more invasive technique and can generate serious adverse events. ONS has good results, but frequent and not serious adverse events. SPG stimulation (SPGS) is also efficacious in the acute and prophylactic treatment of refractory cluster headache. At this moment, ONS and SPG stimulation techniques are recommended as first line therapy in refractory cluster patients. New recent non-invasive approaches such as the non-invasive vagal nerve stimulator (nVNS) have shown efficacy in a few trials and could be an interesting alternative in the management of CH, but require more testing and positive randomized controlled trials.

Patients with chronic migraines are often refractory to medical treatment. Therefore, they might need other strategies to modulate their pain, according to their level of disability. Neuromodulation can be achieved with several tools: meditation, biofeedback, physical therapy, drugs and electric neurostimulation (ENS). ENS can be applied to the central nervous system (brain and spinal cord), either invasively (cortical or deep brain) or non-invasively [cranial electrotherapy stimulation, transcranial direct current stimulation and transcranial magnetic stimulation]. Among chronic primary headaches, cluster headaches are most often treated either through deep brain stimulation or occipital nerve stimulation because there is a high level of disability related to this condition. ENS, employed through several modalities such as transcutaneous electrical nerve stimulation, interferential currents and pulsed radiofrequency, has been applied to the peripheral nervous system at several sites. We briefly review the indications for the use of peripheral ENS at the site of the occipital nerves for the treatment of chronic migraine.

Occipital nerve stimulation has shown promising results in attack prevention in patients with chronic cluster headache, but evidence from controlled trials is scarce. Conventional (tonic) occipital nerve stimulation elicits paresthesia, hampering blinded comparison to placebo. Using paresthesia-free burst occipital nerve stimulation, we conducted a randomized, placebo-controlled trial. The study is an investigator-initiated, double-blind, randomized, placebo-controlled clinical trial involving participants with chronic cluster headache. It comprised a four-week baseline, a 12-week trial with transcutaneous electrical nerve stimulation, occipital nerve stimulator implantation, a 12-week randomized, double-blind burst occipital nerve stimulation treatment period, and a 12-week open-label tonic occipital nerve stimulation treatment period. The primary outcomes were safety and the proportion of participants reporting a ≥30% reduction in attack frequency in the randomized and open-label trial phases. Participants were enrolled between August 2021 and October 2023. 116 chronic cluster headache patients were assessed for eligibility. Sixty-five were excluded, and 51 entered baseline observation. Before occipital nerve stimulator implantation and randomization, an additional 13 were excluded. Thirty-eight participants underwent occipital nerve stimulator implantation and were randomly assigned to burst occipital nerve stimulation (n = 19) or placebo (n = 19). After the randomized trial phase, the proportion of ≥30% responders was 18.81% (95%CI 0.28%–37.87%) in the burst occipital nerve stimulation group and 50.02% (95%CI 26.87%–73.09%) in the placebo group. The likelihood of reaching the primary endpoint was 31.20% (95%CI 1.29%–61.23%, p = 0.042) higher in the placebo group. After the open-label phase, 42.09% (95%CI 19.91%–64.34%) in the burst occipital nerve stimulation group and 51.11% (95%CI 27.32%–74.88%) in the placebo group had ≥30% frequency reduction. In total, 20 adverse events were registered; eight were treatment-related serious adverse events. The most common adverse event was temporary occipital dysesthesia in eight participants. Occipital nerve stimulation reduced attack frequency but was not superior to placebo. The treatment had an acceptable safety profile and was well-tolerated. The results call for attention to sufficient placebo control when planning further studies. The trial is registered at clinicaltrials.gov (identifier NCT05023460).Study registration date: July 27th 2021.

Background: Chronic cluster headache is a severely disabling neurological disorder. Evidence from open-label case series suggest that occipital nerve stimulation may be effective for the treatment of chronic cluster headache. Objective: To evaluate the effectiveness of a microstimulator for chronic cluster headache. Study Design: Prospective, observational feasibility study plus medical record review. Settings: Academic medical center. Methods: Four patients with medically refractory chronic cluster headache underwent implantation of a unilateral bion microstimulator. In-person follow-up was conducted for 12 months after implantation, and a prospective follow-up chart review was carried out to assess long term outcome. Results: Three of the participants returned their headache diaries for evaluation. The mean duration of chronic cluster headache was 14.3 years (range 3 to 29 years). Pain was predominantly or exclusively retroocular/periocular. One participant demonstrated a positive response (> 50% reduction in cluster headache frequency) at 3 months postimplant, while there were 2 responders at 6 months. At least one of the participants continued to show > 60% reduction in headache frequency at 12 months. A chart review showed that at 58-67 months post-implant, all 3 participants reported continued use and benefit from stimulation. No side-shift in attacks was noted in any participant. Adverse events were limited to 2 participants with neck pain and/or cramping with stimulation at high amplitudes; one required revision for a faulty battery. Limitations: Small patient population without control group. Not blinded or randomized. Conclusion: Unilateral occipital nerve stimulation, using a minimally invasive microstimulator, may be effective for the treatment of medically refractory chronic cluster headache. This benefit may occur immediately after implantation, remain sustained up to 5 years after implantation, and occur despite the anterior location of the pain. Prospective, randomized controlled trials of occipital nerve stimulation in chronic cluster headache should proceed. Key words: chronic headache, bion, peripheral nerve stimulation, cluster headache, migraine, occipital

Occipital nerve stimulation (ONS), an established treatment for medically intractable headache syndromes, has lead migration rates quoted up to 24%. In a series of patients with ideal characteristics for this treatment modality, we describe an operative technique for ONS involving the novel use of narrow paddle electrodes: "S8 Lamitrode" (St. Jude Medical [SJM], St. Paul, MN, USA).Five patients (occipital neuralgia [ON] = 4; chronic migraine [CM] = 1) were treated with ONS between 2010 and 2011. All patients had a successful trial of peripheral neurostimulation (Algotec Ltd, Crawley, UK) therapy. Operative technique involved the use of a park-bench position, allowing simultaneous exposure of the occipital and infraclavicular regions. Through a retromastoid/occipital incision just beneath the external occipital protruberance, exposing the extrafascial plane, the S8 Lamitrode is implanted to intersect both greater occipital nerves for bilateral pain or unilateral greater and lesser occipital nerves for unilateral ON or with significant component of the pain relating to the lesser occipital nerve.Over the median follow-up of 12 months, there were no episodes of lead migration or revision. There also was significant improvement in symptoms in all patients.This is the first reported use of S8 Lamitrode electrode for ONS. This narrow electrode is suited for this role leading to minimal trauma during surgical placement, facilitates resolution of problems with lead migration, and optimizes effect with stimulation focused more in direction of the occipital nerves without skin involvement. To date, the SJM Genesis neurostimulation system, with percutaneous electrodes only, is CE mark approved in Europe for peripheral nerve stimulation of the occipital nerves for the management of pain and disability for patients diagnosed with intractable CM. Further developments and studies are required for better devices to suit ONS, thereby avoiding frequently encountered problems and which may clarify the role of paddle leads in ONS.

Peripheral neurostimulation techniques have emerged as promising treatments for patients with medically intractable, highly disabling chronic daily headaches including chronic migraine (CM) and chronic cluster headache (CCH) besides other less common headache syndromes. Encouraging controlled and open label data in medically intractable CM and trigeminal autonomic cephalalgias (TACs) have suggested a meaningful therapeutic role for occipital nerve stimulation (ONS). In view of the frequent occurrence of pain in the first branch of trigeminal nerve, percutaneous supraorbital nerve stimulation alone or in combination with ONS has been used successfully in open label series of CM and CCH patients. In view of its connections with the trigeminovascular system, the stimulation of the sphenopalatine ganglion has been used as a therapeutic target for the treatment of acute cluster headache attacks, with promising results. Preliminary data in patients with epilepsy and migraine have suggested a potential efficacy of vagus nerve stimulation in the treatment of primary headaches. Non-invasive devices targeting peripheral nerves have been developed and initial experience is emerging for the acute and preventive treatments of primary headache disorders. This review analyses the available evidence on the efficacy and safety of the different peripheral neurostimulation techniques.

There is growing interest in neuromodulation for primary headache conditions. Invasive modalities such as occipital nerve stimulation, deep brain stimulation and sphenopalatine ganglion stimulation are reserved for the most severe and intractable patients. Non-invasive options such as vagal nerve stimulation (nVNS), supraorbital nerve stimulation (nSONS) and transcranial magnetic nerve stimulation (TMS) have all emerged as potentially useful headache treatments. This review examines the evidence base for non-invasive neuromodulation in trigeminal autonomic cephalalgias and migraine. Although a number of open-label series of non-invasive neuromodulation devices have been published, there is very little controlled evidence for their use in any headache condition. Open-label evidence suggests that nVNS may have a role in the prophylactic treatment of cluster headache and there is limited evidence to suggest it may be useful in the acute treatment of cluster and potentially migraine attacks. There is limited controlled evidence to suggest a role for nSONS in the prophylactic treatment of episodic migraine but there is no evidence to support its use in cluster headache. TMS may be efficacious in the acute treatment of episodic migraine has no controlled evidence to support its use as a preventative in any headache condition. Non-invasive neuromodulation techniques are an attractive treatment option with excellent safety profiles but their use is not yet supported by high-quality randomised controlled trials.

Refractory cluster headache (rCH) is one of the most devastating conditions known to man. Historically, only destructive procedures were available for these desperate patients in which all drug therapies failed. The surgical interventions were aimed at the sensory trigeminal nerve, including the trigeminal sensory root, Gasserian ganglion, and supra- or infraorbital nerves; or the autonomic pathways involved in cluster headache (CH), including the nervus intermedius, nervus petrosus major, and sphenopalatine ganglion. Especially, trigeminal destructive procedures are associated with potential serious long-term consequences such as anesthesia dolorosa, as well as corneal anesthesia and ulceration. The surgical management of rCH is changing drastically with the advent of neuromodulatory techniques, such as occipital nerve stimulation and hypothalamic deep brain stimulation. These techniques were developed based on the physiology of the trigeminocervical complex and on evidence for a hypothalamic generator in CH, respectively. The potential therapeutic effect of each technique should be carefully balanced against known potential long-term consequences, knowing that long-term data on the rate of recurrence of CH after a procedure are generally lacking. No conclusive recommendations can be formulated at present, but we will suggest some guidelines toward implementing surgical interventions for rCH in clinical practice. We will briefly touch upon greater occipital nerve block as a transitional treatment.

Objectives The cluster headache is the most excruciatingly painful primary headache. In some patients, neither preventive treatment nor acute treatment is effective or treatment is poorly tolerated. The sphenopalatine ganglion (SPG) has an important role in the pathophysiology of cluster headache and, for this reason, SPG stimulation has been used to treat cluster headache. Methods We have reviewed the published literature on the role of the SPG in cluster headache and the use of different treatments targeting the SPG. Results Multiple procedures have been used over the SPG to treat pain and trigemino-autonomic symptoms in patients with refractory cluster headache. After obtaining good results in a small number of patients, a miniaturized stimulator was developed. Stimulation of the SPG with this device proved to be efficacious in acute and preventive treatment in a clinical trial involving patients with chronic refractory cluster headache. Implantation of the device is minimally invasive and the most frequent side-effects are mild, such as paraesthesia and pain over the maxillary area. In patients who have used the SPG device for longer than one year, the therapeutic effect remains effective and the side-effects decrease. Conclusions The reported studies have demonstrated that SPG stimulation is a safe and effective treatment for chronic cluster headache. Long-term studies have shown that the effect remains over time and this treatment could be a good choice in patients with chronic refractory headache. We need more data about its potential use in other forms of headache, such as other trigemino-autonomic headaches or migraine.

PO130 / #769 CONVENTIONAL MEDICAL MANAGEMENT VS CERVICAL SPINAL CORD STIMULATION FOR MANAGEMENT OF CHRONIC CLUSTER HEADACHE: A MARKOV DECISION ANALYSIS: E-POSTER VIEWING

Introduction Cluster headache is an extremely debilitating and often difficult-to-treat headache disorder characterized by recurrent attacks of excruciating pain associated with cranial autonomic symptoms. Several invasive neuromodulation procedures have been evaluated in the past, but the combination of these procedures to maximize response has not been studied in groups of patients. Materials and methods In this single-center, retrospective, observational study, we present the long-term clinical evolution of seven patients suffering from refractory chronic cluster headache (CCH), treated with combined sphenopalatine ganglion (SPG) and greater occipital nerve (GON) invasive stimulation, ipsilateral to the side of the pain, between February 2010 and March 2021. The Visual Analogue Scale (VAS) and Headache Impact Test (HIT-6) were used to monitor the response. Results The mean follow-up time was 5.8 years ± 3.4 years (maximum 10.4 years). Six out of the seven patients experienced good-to-excellent initial pain relief and achieved almost complete remission of symptoms afterwards. Mean VAS and HIT-6 score values decreased significantly and steadily during most of the observation period. Electrode migration requiring reintervention occurred in two patients. Conclusion Synergistic invasive SPG-GON stimulation is a relatively safe and promising alternative for effective and long-lasting control of CCH. Further studies involving larger samples are warranted.

Occipital nerve stimulation (ONS) is a treatment with evidence in refractory chronic cluster headache (CCH). However, the variable response rate and cost make it necessary to investigate predictors of response. This is a cross-sectional study conducted through the review of medical records of CCH patients from six hospitals in Madrid. Epidemiological and clinical variables were compared between patients with ONS failure and the rest. ONS failure was defined as the need for device withdrawal or switch off because of lack of response or adverse events. From a series of 88 CCH, 26 (29.6%) underwent ONS surgery, of whom 13/26 (50.0%) failed because lack of response. ONS failure group had an earlier headache onset (mean ± SD) of 27.7 ± 6.9 vs. 36.7 ± 11.8 years, p = 0.026) and a higher smoking rate (100% vs. 42.9%, p = 0.006). Stational fluctuations (58.3% vs. 7.7%, p = 0.007) and nocturnal exacerbations (91.7% vs. 53.9%, p = 0.035) were more frequent in the ONS failure group as well. There was no difference between groups in diagnostic delay, years of evolution prior to surgery, mental illness, comorbidity with other headache disorders or chronic pain conditions or prior response to occipital nerves anesthetic blocks. Some clinical features such as an early debut, smoking and seasonal or circadian fluctuations could be related to failure of ONS in refractory CCH.

Brainstem evoked responses.

ABSTRACTIntroduction: Neuromodulation techniques play an increasing role in the treatment of primary headaches. While initially reserved for refractory cases they are now increasingly taken into consideration in earlier treatment phases and in non-refractory situations. One of the main reasons for this paradigm shift is that most neuromodulation techniques are better tolerated as compared to the majority of pharmacological approaches. However, these techniques have their limitations that should be considered.Areas covered: The review provides an overview of the available techniques and their therapeutic rationale as well as on the evidence for their efficacy and their limitations. The review covers these aspects for non-invasive vagal nerve stimulation, sphenopalatine ganglion stimulation, external trigeminal nerve stimulation, occipital nerve stimulation as well as single-pulse and repetitive-pulse transcranial magnetic stimulation.Expert commentary: Most of the evidence is based on open-label studies. Sham devices used in controlled studies remain problematic as they either do not produce the paresthesias perceived during stimulation or induce some degree of stimulation. Invasive techniques require a surgical intervention with all the potential complications that may arise.In summary, some of the techniques provide an effective expansion of available treatment options but their indication should be thoroughly evaluated before treatment is considered.

Persistent idiopathic facial pain can be extremely difficult and significantly challenging to manage for the patient and the clinician. Pharmacological treatment of these painful conditions is not always successful. It has been suggested that the autonomic reflex plays an important role in the pathophysiology of headaches and facial neuralgia. The key structure in the expression of cranial autonomic symptoms is the sphenopalatine ganglion (SPG), also known as the pterygopalatine ganglion. The role of the SPG in the pathophysiology of headaches and facial pain has become clearer in the past decade. In this case report, we describe a 30-year-old woman with insidious onset of right facial pain. She was suffering from daily pain for more than 9 years prior to her visit at the pain clinic. Her pain was constant with episodic aggravation without a predisposing trigger factor. The patient was evaluated by multiple specialties and tried multimodal therapy, which included antiepileptic medications, with minimal pain relief. A SPG block using short-acting local anesthetic provided significant temporary pain relief. The second and third attempt of SPG block using different local anesthetic medications demonstrated the same responses. After a thorough psychological assessment and ruling out the presence of a correctable cause for the pain, we decided to proceed with SPG electrical neuromodulation. The patient reported significant pain relief during the electrical nerve stimulation trial. The patient underwent a permanent implant of the neurostimulation electrode in the SPG region. The patient was successfully taken off opioid medication and her pain was dramatically responsive during a 6-month follow-up visit. In this article we describe the SPG nerve stimulation and the technical aspect of pterygopalatine fossa electrode placement. The pterygoplatine fossa is an easily accessible location. This case report will be encouraging for physicians treating intractable facial pain by demonstrating a novel therapeutic option. This report shows a minimally invasive approach to the SPG. Key words: Sphenopalatine ganglion, persistent idiopathic facial pain, electrical neuromodulation