Headaches: Invasive Procedures
Number: 0707
Table Of Contents
PolicyApplicable CPT / HCPCS / ICD-10 Codes
Background
References
Policy
Scope of Policy
This Clinical Policy Bulletin addresses invasive procedures for headaches.
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Experimental and Investigational
Aetna considers the following interventions experimental and investigational for the following headache types because the effectiveness of these approaches has not been established (not an all-inclusive list):
- Cervicogenic headache
- Botulinum toxin (however, botulinum toxin is considered medically necessary for chronic migraine headache when criteria in CPB 0113 - Botulinum Toxin are met)
- C2 ganglion nerve block
- Cryodenervation
- Decompressive neck surgery
- Electrical stimulation
- Ganglionectomy
- Local injections of anesthetics or corticosteroids
- Radiofrequency denervation of cervical facet joints;
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Occipital neuralgia and other types of headache
- Auriculotemporal nerve block
- Cervical rhizotomy
- Cryodenervation
- Decompression or microdecompression of the occipital nerves
- Dorsal column stimulation (see CPB 0194 - Spinal Cord Stimulation)
- Electrical stimulation of the occipital nerve (examples of devices for occipital nerve stimulation are ONSTIM and PRISM)
- Ganglionectomy
- Intradural rhizotomy
- Ligation of the supraorbital and supratrochlear arteries (for the treatment of migraines)
- Neurectomy
- Neurolysis of the great occipital nerve with or without section of the inferior oblique muscle
- Neuroplasty
- Occipital nerve block (also known as occipital infiltration, and including greater occipital nerve block) (Note: Occipital nerve block is allowable only for diagnosing occipital neuralgia)
- Pulsed radiofrequency ablation (see CPB 0735 - Pulsed Radiofrequency)
- Radiofrequency ablation (including the occipital nerve) / radiofrequency denervation / radiofrequency neurotomy
- Resection or partial resection of muscle or tissue from the forehead, peri-orbital, occipital or other facial or scalp areas
- Resection or partial resection of the semispinalis capitus muscle
- Supraorbital nerve block
- Suprascapular nerve block
- Surgical release of the lesser occipital nerve within the trapezius and other procedures to decompress occipital nerves
- Transection/avulsion of the occipital nerve
- Thermal neurolysis (thermal and cryodenervation);
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Cluster headache and other chronic headaches including migraines
Surgery and the following interventions. Surgical interventions include some of the procedures listed below (not an all-inclusive list):
- Ablation or electrical stimulation or topical anesthesia of the sphenopalatine ganglion (sphenopalatine ganglion block//sphenopalatine nerve block)
- Bariatric (obesity) surgery for the treatment of migraines
- Closure of patent foramen ovale
- Decompression of the greater occipital, supra-orbital and supra-trochlear nerves
- Deep brain stimulation
- Gamma knife (stereotactic) radiosurgery
- Greater occipital nerve block (for prophylaxis and treatment of migraine headache)
- Migraine trigger site surgery (nerve excision for the treatment of migraine headache)
- Nerve decompression
- Occipital nerve stimulation
- Peripheral nerve trigger surgery (nerve excision for the treatment of migraine headache)
- Resection of the right and left supra-orbital, supra-trochlear and infra-trochlear nerves
- Resection of musculature, including but not limited to the corrugator supercilii muscle, or any soft tissue from the forehead, peri-orbital, occipital or other facial or scalp areas; manipulation or repositioning of any muscle or other soft tissue within these areas
- Resection of any portion of the trigeminal nerve or its branches
- Sensory nerve decompression
- Sphenopalatine nerve block
- Spinal accessory nerve block
- Stellate ganglion block
- Suboccipital nerve stimulation
- Supraorbital nerve stimulation
- Temporal artery ligation (Note: Temporal artery biopsy is considered medically necessary for diagnosis of suspected temporal arteritis)
- Topical anesthesia of the sphenopalatine ganglion
- Transection of auriculo-temporal nerves
- Transposition of cranial sensory nerves
- Trigeminal nerve block
- Vascular ligation of superficial extracranial arteries
- Ventral tegmental area deep brain stimulation (for the treatment of cluster headaches)
- Vagus nerve stimulation (e.g., gammaCore nVNS) for the prophylaxis and treatment of cluster and migraine headaches;
- Subcutaneous peripheral nerve field stimulation for the treatment of nummular headache;
- Cervical erector spinae plane (ESP) block and rhomboid tendon injections for the treatment of tension/migraine headaches;
- Bilateral temporal branches of facial nerve block, and supratrochlear block for the treatment of headache/neuralgia;
- Superior turbinate resection, with or without total ethmoidectomy for the treatment of rhinogenic contact point headache.
- Cervicogenic headache
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Related Policies
- CPB 0113 - Botulinum Toxin
- CPB 0194 - Spinal Cord Stimulation
- CPB 0292 - Catheter-Directed Cardiac Procedures - for closure of patent foramen ovale for migraine prophylaxis
- CPB 0735 - Pulsed Radiofrequency
- CPB 0863 - Nerve Blocks
Background
A number of procedures or treatments have been proposed for headaches and occipital neuralgia, including injections/blocks, ablative techniques, occipital nerve stimulation, peripherally implanted nerve stimulation or surgical procedures.
Injection therapy delivers local anesthetics, steroids or other agents into the region of the affected nerve(s) thereby reducing pain and inflammation. Examples of injections/blocks used to treat headaches or occipital neuralgia include, but may not be limited to, occipital nerve block, greater occipital nerve block, C2 ganglion nerve block, sphenopalantine nerve block, stellate ganglion block, supraorbital nerve block or supratrochlear nerve block.
Ablative procedures (eg, pulsed radiofrequency ablation, radiofrequency ablation, radiofrequency denervation, radiofrequency neurotomy, cryodenervation, neurolysis, rhizotomy) may be performed in attempt to denervate the occipital nerve (greater or lesser), upper cervical nerve (eg, second cervical nerve, also known as C2), supraorbital, supratrochlear or sphenopalatine ganglion. The proposed goal of denervation is to "shut off" the pain signals that are sent to the brain from the nerves. An additional purported objective is to reduce the likelihood of, or to delay, any recurrence that may occur by selectively destroying pain fibers without causing excessive sensory loss, motor dysfunction or other complications.
Surgical interventions are proposed as a treatment option to relieve impingement of the nerve root(s) and thereby eliminate symptoms caused by compression and injury to the cervical nerves. Examples of surgical interventions include, but may not be limited to, occipital nerve decompression, microdecompression of the occipital nerve, transection/avulsion of the occipital nerve, resection/partial resection of the semispinalis capitus muscle, neuroplasty, sensory nerve decompression, transposition of cranial sensory nerve or ganglionectomy. Another surgical approach is vascular ligation of superficial extracranial arteries (eg, superficial branches of the external carotid artery, main trunk of the superficial temporal artery, frontal branch of the superficial temporal artery, occipital artery or posterior auricular artery) which are theorized as an origin of headache pain in some individuals.
Cervicogenic Headache
Cervicogenic headache (CGH) is a relatively common and still controversial form of headache caused by disease or dysfunction of structures in the cervical spine (e.g., congenital anomalies of the cranio-vertebral junction such as basilar invagination, and atlanto-axial dislocation; injury of the ligaments, muscles, or joints of the neck). It can be triggered by vascular or scar tissue compression of the C2 root and ganglion as well as irritation of other upper cervical nerve roots (e.g., C3, C4). In patients with CGH, attacks or chronic fluctuating periods of neck/head pain may be provoked and/or worsened by sustained neck movements or stimulation of ipsilateral tender points. There are no diagnostic imaging techniques of the cervical spine and associated structures that can determine the exact source of pain. Although it has been advocated by some headache clinicians that the use of nerve blocks is an important confirmatory evidence for diagnosing CGH, the standardization of diagnostic nerve blocks in the diagnosis of CGH remains to be defined. Differential diagnoses of CGH include hemicrania continua, chronic paroxysmal hemicrania, occipital neuralgia, migraine headache and tension headache. Moreover, there is considerable overlap in symptoms and findings between CGH and migraine/tension headaches.A curative treatment for CGH is unlikely to be developed until the etiology of this disorder has been elucidated. Since CGH appears to be refractory to common headache medication, other treatments have been used in the management of CGH. These entail non-invasive therapies such as paracetamol and non-steroidal anti-inflammatory drugs; manual modalities and transcutaneous electrical nerve stimulation; local injections of anesthetic, corticosteroids, or botulinum toxin type A (Botox); as well as invasive surgical therapies such as decompression and radiofrequency lesions of the involved nerve structures (Jansen, 2000; Haldeman and Dagenais, 2001; Martelletti and van Suijlekom, 2004).
In a Cochrane review, Langevin et al (2011) evaluated the literature on the treatment effectiveness of botulinum toxin (BoNT) intra-muscular injections for neck pain, disability, global perceived effect and quality of life in adults with neck pain with or without associated cervicogenic headache, but excluding cervical radiculopathy and whiplash associated disorder. These researchers included randomized and quasi-randomized controlled trials in which BoNT injections were used to treat sub-acute or chronic neck pain. A minimum of 2 review authors independently selected articles, abstracted data, and assessed risk of bias, using the Cochrane Back Review Group criteria. In the absence of clinical heterogeneity, these investigators calculated standardized mean differences (SMD) and relative risks, and performed meta-analyses using a random-effects model. The quality of the evidence and the strength of recommendations were assigned an overall grade for each outcome. They included 9 trials (503 subjects). Only BoNT type A (BoNT-A) was used in these studies. High quality evidence suggested there was little or no difference in pain between BoNT-A and saline injections at 4 weeks (5 trials; 252 subjects; SMD pooled -0.07 (95 % confidence intervals ([CI]: -0.36 to 0.21)) and 6 months for chronic neck pain. Very low quality evidence indicated little or no difference in pain between BoNT-A combined with physiotherapeutic exercise and analgesics and saline injection with physiotherapeutic exercise and analgesics for patients with chronic neck pain at 4 weeks (2 trials; 95 subjects; SMD pooled 0.09 [95 % CI: -0.55 to 0.73]) and 6 months (1 trial; 24 subjects; SMD -0.56 [95 % CI: -1.39 to 0.27]). Very low quality evidence from 1 trial (32 subjects) showed little or no difference between BoNT-A and placebo at 4 weeks (SMD 0.16 [95 % CI: -0.53 to 0.86]) and 6 months (SMD 0.00 [95 % CI: -0.69 to 0.69]) for chronic cervicogenic headache. Very low quality evidence from 1 trial (31 subjects), showed a difference in global perceived effect favouring BoNT-A in chronic neck pain at 4 weeks (SMD -1.12 [95 % CI: -1.89 to -0.36]). The authors concluded that current evidence fails to confirm either a clinically important or a statistically significant benefit of BoNT-A injection for chronic neck pain associated with or without associated cervicogenic headache. Likewise, there was no benefit seen for disability and quality of life at 4 week and 6 months.
In a review on CGH, Pollmann et al (1997) stated that neither pharmacological nor surgical or chiropractic procedures lead to a significant improvement or remission of CGH. These investigators concluded that until controlled studies on large and homogeneous groups of patients are performed, operative intervention can not be recommended for CGH. Edmeads (2001) noted that although expertly administered local anesthetic blocks applied in a rational fashion can be of diagnostic value, their value as treatment for CGH is much less clear. Furthermore, Evers (2004) stated that for the prophylactic treatment of migraine headache, tension headache, and CGH, no sufficient positive evidence for treatment with Botox is obtained from randomized, double-blind, placebo-controlled trials to date.
Stovner et al (2004) reported on the results of a randomized, double-blind, placebo-controlled study of radiofrequency denervation of facet joints C2 through C6 in cervicogenic headache. A total of 12 patients with disabling, long-standing and treatment-resistant unilateral headache were randomly assigned to receive either sham treatment or radiofrequency neurotomy of facet joints C2 through C6 ipsilateral to the pain. Patients were followed for 2 years by self-assessed pain ratings, measurements of sensitivity to pain and neck mobility measurements for two years following treatment. The investigators reported that subjects treated with neurotomy were somewhat improved by 3 months after treatment, but later there were no marked differences between groups. This led the investigator to conclude that radiofrequency denervation of cervical facet joints is probably not beneficial in cervicogenic headache.
Occipital Neuralgia
Occipital neuralgia, occurring more often in women than men, is defined as a paroxysmal jabbing pain in the distribution of the greater or lesser occipital nerves. It is characterized by pain in the cervical and posterior areas of the head that may/may not radiate to the sides of the head as well as into the facial and frontal areas. Occipital neuralgia can arise as a result of compression of the greater or lesser occipital nerves, trauma (e.g., whiplash), localized infections or inflammation, gout, diabetes, blood vessel inflammation and local tumors. It may occur as the nerves exit the trapezii or splenius muscle groups. Compression of these nerves may result in a burning dysasthesias in the occiput with or without radiation behind the ear. Nerve compression can occur from cervical degeneration or post-traumatic compression of the C2 or C3 nerves. The clinical features of the condition are pain and sensory change in the distribution of the relevant nerve, localized nerve trunk tenderness. Clinical signs and symptoms of occipital neuralgia may also be produced by myofascial pain.
Treatments for occipital neuralgia ranges from rest, heat, massage, exercise, antidepressants, nerve blocks, neurectomy, cervical rhizotomy, surgical release of the occipital nerve within the trapezius to neurolysis of the great occipital nerve with or without section of the inferior oblique muscle. However, the effectiveness of many of the invasive procedures has not been firmly established.
Graff-Radford (2001) stated that neurectomy has been employed for occipital neuralgia, but the results are often short-lived. Barolat and Sharan (2000) stated that one of the applications being developed for spinal cord stimulation is occipital neuralgia.
Gille et al (2004) retrospectively evaluated a new surgical treatment consisting of neurolysis of the great occipital nerve and section of the inferior oblique muscle for the treatment of greater occipital neuralgia (n = 10). All the patients had pain exacerbated by flexion of the cervical spine. The average age of the patients was 62 years. The mean follow-up of the series was 37 months. The results of the treatment were assessed according to 3 criteria:- degree of pain on a visual analog scale (VAS) before surgery, at 3 months, and at last follow-up;
- consumption of analgesics before surgery and at follow-up; and
- the degree of patient satisfaction at follow-up.
In 3 cases, anatomic anomalies were found – 1 patient had hypertrophy of the venous plexus around C2; in another, the nerve penetrated the inferior oblique muscle; the third had degenerative C1 to C2 osteoarthritis requiring associated C1 to C2 arthrodesis. The mean VAS score was 80/100 before surgery and 20/100 at last follow-up. Consumption of analgesics decreased in all patients. Seven of the 10 patients were very satisfied or satisfied with the operation. The authors concluded that the new surgical technique provided good results on greater occipital neuralgia if patients are well chosen. The findings by Gille et al (2004) were interesting, but they need to be validated by prospective randomized controlled studies with more patients.
There is a lack of evidence that local injection therapy such as steroids, botulinum toxin and local anesthetics or surgical such as decompression of the C2 nerve root, implantation of spinal cord stimulator, neurolysis of the great occipital nerve and surgical release of the occipital nerve within the trapezius consistently provide sustained pain relief in the majority of patients with CGH and occipital neuralgia. Furthermore, there is also a lack of information regarding which patients might obtain significant benefit from these procedures.
Recently, there has been increased interest in subcutaneous electrical stimulation of the occipital nerve for the treatment of occipital neuralgia. Kapural et al (2005) reported a case series of 6 patients with severe occipital neuralgia who underwent occipital nerve electrical stimulation lead implantation using a modified midline approach. These patients had received conservative and surgical therapies in the past including oral anti-depressants, membrane stabilizers, opioids, occipital nerve blocks, and radiofrequency ablations. Significant decreases in pain VAS scores and drastic improvement in functional capacity were observed during the occipital stimulation trial and during the 3-month follow-up after implantation. The mean VAS score changed from 8.66 +/- 1.0 to 2.5 +/- 1.3 whereas pain disability index improved from 49.8 +/- 15.9 to 14.0 +/- 7.4. These findings need to be validated by randomized controlled studies.
Electrical stimulation of the occipital nerve is also being investigated for the treatment of chronic migraine headaches. However, there is currently a lack of evidence regarding its effectiveness for this indication.
Slavin et al (2006) analyzed records of 14 consecutive patients (9 women and 5 men; mean age of 43.3 years) with intractable occipital neuralgia (ON) treated with peripheral nerve stimulation (PNS). Five patients had unilateral and 9 had bilateral PNS electrodes inserted for trial, which was considered successful if patient reported at least 50 % decrease of pain on the visual analogue scale. Ten patients proceeded with system internalization, and their long-term results were analyzed. At the time of the last follow-up examination (5 to 32 months, mean of 22 months), 7 patients (70 %) with implanted PNS systems continue to experience beneficial effects of stimulation, including adequate pain control, continuous employment, and decrease in oral pain medications intake. Two patients had their systems explanted because of loss of stimulation effect or significant improvement of pain, and 1 patient had part of his hardware removed because of infection. The authors concluded that overall, the beneficial effect from chronic stimulation in their series persisted in more than 50 % of the patients for whom procedure was considered and in 80 % of those who significantly improved during the trial and proceeded with internalization. Thus, chronic PNS may be a safe and relatively effective method for long-term treatment of chronic pain syndrome in patients with medically intractable ON. The results of this small study are promising, but they need to be validated by further investigation.
An interventional procedure consultation from the National Institute for Health and Clinical Excellence (NICE, 2008) concluded: "Current evidence on the safety and efficacy of occipital nerve stimulation for intractable headache is inadequate in both quantity and quality. Therefore this procedure should only be used with special arrangements for clinical governance, consent and audit or research."
Kapural et al (2007) retrospectively described a series of 6 patients with severe occipital neuralgia who received conservative and interventional therapies, including oral anti-depressants, membrane stabilizers, opioids, and traditional occipital nerve blocks without significant relief. This group then underwent occipital nerve blocks using the botulinum toxin type A (BoNT-A) Botox type A (50 U for each block; 100 U if bilateral). Significant decreases in pain VAS scores and improvement in Pain Disability Index (PDI) were observed at 4 weeks follow-up in 5 out of 6 patients following BoNT-A occipital nerve block. The mean VAS score changed from 8 +/- 1.8 (median score of 8.5) to 2 +/- 2.7 (median score of 1), while PDI improved from 51.5 +/- 17.6 (median of 56) to 19.5 +/- 21 (median of 17.5) and the duration of the pain relief increased to an average of 16.3 +/- 3.2 weeks (median of 16) from an average of 1.9 +/- 0.5 weeks (median of 2) compared to diagnostic 0.5 % bupivacaine block. Following block resolution, the average pain scores and PDI returned to similar levels as before BoNT-A block. The authors concluded that BoNT-A occipital nerve blocks provided a much longer duration of analgesia than diagnostic local anesthetics. The functional capacity improvement measured by PDI was profound enough in the majority of the patients to allow patients to resume their regular daily activities for a period of time. This was a retrospective, small study with short-term follow-up; its findings need to be validated by well-designed studies.
In a review on greater occipital nerve blockade, Selekler (2008) stated that studies regarding greater occipital nerve injection in primary headaches began with Michael Anthony and almost all the studies today accept Anthony's studies as reference work. Although more than 20 years had passed, there is insufficient information about this procedure. According to available evidence, steroids are apparently effective in both preventive as well as therapy (for acute attack) in cluster headaches. Effectiveness of occipital nerve blocks for the treatment of migraine headaches is not as dramatic as that observed for cluster headaches. Despite the fact that local anesthetics has a role in relieving acute attacks, single injection is unsuitable as prophylasis. The authors concluded that although there are case reports regarding the effectiveness of occipital nerve blocks in relieving acute pain in cluster headaches and migraine headaches, there is a need for systematized clinical studies.
An American Headache Society Information Paper "Information for Healthcare Professionals: Peripheral Nerve Blocks for Headaches" (Robbins & Blumenfeld, 2012) provides descriptive information about these blocks and includes three literature citations (Ashkenazi & Levin, 2007; Ashkenazi, Blumenfeld, et al, 2010; Blumenfeld, Ashkenazi, et al., 2010). A review article by Ashkenazi & Levin (2007) stated: “Several studies suggested efficacy of GON [greater occipital nerve] block in the treatment of migraine, cluster headache, and chronic daily headache. However, few were controlled and blinded. Despite a favorable clinical experience, little evidence exists for the efficacy of GON block in migraine treatment. Controlled studies are needed to better assess the role of GON block in the treatment of migraine and other headaches. . . . Despite favorable clinical experience, there is currently little convincing evidence for the efficacy of GON block in the acute or preventive treatment of headache. Most data on this topic come from non-controlled studies. Given the potentially high placebo effect that injections to the head have on the degree of pain, these data should be taken with reservation. Well-designed controlled studies are needed to better assess the role of GON block in headache treatment, to determine the patient populations who would benefit the most from this procedure, and to establish the optimal drug combination to use for nerve blockade.”
The AHA Information Paper also cites Expert Consensus Recommendations for the Performance of Peripheral Nerve Blocks for Headaches (Blumenfeld & Ashkenazi, et al., 2010). As the title suggests, this article focuses primarily on recommendations on the proper performance of peripheral nerve blocks for headaches. Regarding the indications for peripheral nerve blocks, the article refers readers to a literature review by Ashkenazi, Blumenfeld, et al. (2010), which is discussed below.
A literature review by Ashkenazi, Blumenfeld, et al. (2010), also cited in the AHA Information Paper, concluded: “Our literature review reveals paucity of controlled data on the efficacy of PNBs and TPIs in headache management. Few studies have addressed this issue, and the majority of those that did had significant limitations, including a small number of patients, a retrospective, non-controlled design, and heterogeneous groups of patients. In addition, the studies that have been done so far differ in the technique used for nerve blockade, the type and doses of local anesthetics used, the injected volume, the location and number of injections, the time intervals between injection sessions, and the way treatment efficacy was assessed. Clearly, there is a need to obtain more data on the efficacy of these treatments in the management of various headache disorders in order to formulate a standardized approach to their use in headache patients.” Specifically regarding the effectiveness of occipital nerve blocks, the review concluded: “The most widely examined procedure in this setting was greater occipital nerve block, with the majority of studies being small and non-controlled.”
An editorial accompanying this systematic review (Blumenfeld & Ashkenazi, Editorial, 2010) stated: “As the review article demonstrates, however, there is a surprising paucity of controlled studies to support the efficacy of these treatments for headache. Moreover, the different studies reveal an inconsistency in the methods used to block the targeted nerves; the type of local anesthetics used, their doses, the volume of injected drug, and even the location of injections have varied considerably among the studies. While some investigators used corticosteroids in addition to local anesthetics to block the nerves, others did not. Clearly, there is a need for more work in this area, and hopefully the articles in this issue will stimulate additional interest and lead to the performance of larger and well-controlled studies.”
Dach et al (2015) noted that several studies have presented evidence that blocking peripheral nerves is effective for the treatment of some headaches and cranial neuralgias, resulting in reduction of the frequency, intensity, and duration of pain. These investigators described the role of nerve block in the treatment of headaches and cranial neuralgias, and the experience of a tertiary headache center regarding this issue. They also reported the anatomical landmarks, techniques, materials used, contra-indications, and side effects of peripheral nerve block, as well as the mechanisms of action of lidocaine and dexamethasone. The authors concluded that the nerve block can be used in primary (migraine, cluster headache, and nummular headache) and secondary headaches (cervicogenic headache and headache attributed to craniotomy), as well in cranial neuralgias (trigeminal neuropathies, glossopharyngeal and occipital neuralgias). In some of them this procedure is necessary for both diagnosis and treatment, while in others it is an adjuvant treatment. The block of the greater occipital nerve with an anesthetic and corticosteroid compound has proved to be effective in the treatment of cluster headache. Regarding the treatment of other headaches and cranial neuralgias, controlled studies are still needed to clarify the real role of peripheral nerve block.
An UpToDate review stated: "For patients with suspected occipital neuralgia who have moderate to severe pain or debilitating symptoms, we suggest a local occipital nerve block (Grade 1B). This method can be both diagnostic and therapeutic. Pain relief is typically prompt and may last several weeks or even months. The procedure is generally safe and can be repeated when pain recurs. Other causes for the neuralgiform pain should be explored if occipital nerve block fails."
Ducic et al (2009) presented the largest reported series of surgical neurolysis of the greater occipital nerve in the management of occipital neuralgia. A retrospective chart review was conducted to identify 206 consecutive patients undergoing neurolysis of the greater or, less commonly, excision of the greater and/or lesser occipital nerves. Pre-operative and post-operative VAS and migraine headache indices were measured. Success was defined as a reduction in pain of 50 % or greater. Of 206 patients, 190 underwent greater occipital nerve neurolysis (171 bilateral); 12 patients underwent greater and lesser occipital nerve excision, whereas 4 underwent lesser occipital nerve excision alone. The authors found that 80.5 % of patients experienced at least 50 % pain relief and 43.4 % of patients experienced complete relief of headache. Mean pre-operative pain score was 7.9 +/- 1.4. Mean post-operative pain was 1.9 +/- 1.8. Minimum duration of follow-up was 12 months. There were 2 minor complications. The authors concluded that neurolysis of the greater occipital nerve appears to provide safe, durable pain relief in the majority of selected patients with chronic headaches caused by occipital neuralgia. The drawbacks of this study were the retrospective, uncontrolled, and non-blinded nature of the study. Well-designed studies are especially important for studying interventions for pain, due to placebo effects, the waxing and waning nature of the condition, and the potential effects of other concurrent treatments on the person's pain.
In a prospective, randomized cross-over study, Serra and Marchioretto (2012) investigated the safety and effectiveness of occipital nerve stimulation (ONS) for chronic migraine (CM) and medication overuse headache (MOH) patients and evaluated changes in disability, quality of life, and drug intake in implanted patients. Eligible patients who responded to a stimulation trial underwent device implantation and were randomized to "Stimulation On" and "Stimulation Off" arms. Patients crossed-over after 1 month, or when their headaches worsened. Stimulation was then switched On for all patients. Disability as measured by the Migraine Disability Assessment (MIDAS), quality of life (SF-36), and drug intake (patient's diary) were assessed over a 1-year follow-up. A total of 34 patients (76 % women, 34 % men, mean age of 46 +/- 11 years) were enrolled; 30 were randomized and 29 completed the study. Headache intensity and frequency were significantly lower in the On arm than in the Off arm (p < 0.05) and decreased from the baseline to each follow-up visit in all patients with Stimulation On (median MIDAS A and B scores: baseline = 70 and 8; 1-year follow-up = 14 and 5, p < 0.001). Quality of life significantly improved (p < 0.05) during the study. Triptans and non-steroidal anti-inflammatory drug use fell dramatically from the baseline (20 and 25.5 doses/month) to each follow-up visit (3 and 2 doses/month at 1 year, p < 0.001). A total of 5 adverse events occurred: 2 infections and 3 lead migrations. The authors concluded that according to the results obtained, ONS appears to be a safe and effective treatment for carefully selected CM and MOH patients. The drawbacks of this study were single-center study, relatively small number of patients, and absence of a control group. The authors stated that further analyses on larger populations in multi-center trials may strengthen these promising findings.
Vadivelu et al (2012) reviewed retrospectively their experience with ONS in patients with a primary diagnosis of Chiari malformation and a history of chronic occipital pain intractable to medical and surgical therapies. They presented a retrospective analysis of 22 patients with Chiari malformation and persistent occipital headaches who underwent occipital neurostimulator trials and, after successful trials, permanent stimulator placement. A trial was considered successful with greater than 50 % pain relief as assessed with a standard VAS score. Patients with a successful trial underwent permanent placement approximately 1 to 2 weeks later. Patients were assessed post-operatively for pain relief via the VAS. Sixty-eight percent of patients (15 of 22) had a successful stimulator trial and proceeded to permanent implantation. Of those implanted, 87 % (13 of 15) reported continued pain relief at a mean follow-up of 18.9 months (range of 6 to 51 months). Device-related complications requiring additional surgeries occurred in 40 % of patients. The authors concluded that ONS may provide significant long-term pain relief in selected Chiari I malformation patients with persistent occipital pain. Moreover, they stated that larger and longer-term studies are needed to further define appropriate patient selection criteria and to refine the surgical technique to minimize device-related complications.
Acar et al (2008) noted that surgical removal of the second (C2) or third (C3) cervical sensory dorsal root ganglion is an option to treat occipital neuralgia (ON). These investigators evaluated the short-term and the long-term effectiveness of these procedures for management of cervical and occipital neuropathic pain. A total of 20 patients (mean age of 48.7 years) were identified who had undergone C2 and/or C3 ganglionectomies for intractable occipital pain and a retrospective chart review undertaken. Patients were interviewed regarding pain relief, pain relief duration, functional status, medication usage and procedure satisfaction, pre-operatively, immediately post-operative, and at follow-up (mean of 42.5 months). C2, C3 and consecutive ganglionectomies at both levels were performed on 4, 5, and 11 patients, respectively. All patients reported pre-operative pain relief following cervical nerve blocks. Average VAS scores were 9.4 pre-operatively and 2.6 immediately after procedure. Ninety-five percent of patients reported short-term pain relief (less than 3 months). In 13 patients (65 %), pain returned after an average of 12 months (C2 ganglionectomy) and 8.4 months (C3 ganglionectomy). Long-term results were excellent, moderate, and poor in 20, 40 and 40 % of patients, respectively. Cervical ganglionectomy offers relief to a majority of patients, immediately after procedure, but the effect is short-lived. Nerve blocks are helpful in predicting short-term success, but a positive block result does not necessarily predict long-term benefit and therefore can not justify surgery by itself. However, since 60 % of patients report excellent-moderate results, cervical ganglionectomy continues to have a role in the treatment of intractable ON. The findings of this small study need to be validated by well-designed studies.
Pisapia and colleagues (2012) examined the effectiveness of C2 nerve root decompression and C2 dorsal root ganglionectomy for intractable ON and C2 ganglionectomy after pain recurrence following initial decompression. A retrospective review was performed of the medical records of patients undergoing surgery for ON. Pain relief at the time of the most recent follow-up was rated as excellent (headache relieved), good (headache improved), or poor (headache unchanged or worse). Telephone contact supplemented chart review, and patients rated their pre-operative and post-operative pain on a 10-point numeric scale. Patient satisfaction and disability were also examined. Of 43 patients, 29 (67 %) were available for follow-up after C2 nerve root decompression (n = 11), C2 dorsal root ganglionectomy (n = 10), or decompression followed by ganglionectomy (n = 8). Overall, 19 of 29 patients (66 %) experienced a good or excellent outcome at most recent follow-up. Among the 19 patients who completed the telephone questionnaire (mean follow-up of 5.6 years), patients undergoing decompression, ganglionectomy, or decompression followed by ganglionectomy experienced similar outcomes, with mean pain reduction ratings of 5 +/- 4.0, 4.5 +/- 4.1, and 5.7 +/- 3.5. Of 19 telephone responders, 13 (68 %) rated overall operative results as very good or satisfactory. The authors concluded that in the third largest series of surgical intervention for ON, most patients experienced favorable post-operative pain relief. For patients with pain recurrence after C2 decompression, salvage C2 ganglionectomy is a viable surgical option and should be offered with the potential for complete pain relief and improved quality of life. Only 10 patients with C2 dorsal root ganglionectomy were available for follow-up. The moderate rate of follow-up (67 %) may have skewed these results.
Also, UpToDate reviews on “Occipital neuralgia” (Garza, 2012) and “Cervicogenic headache” (Biondi and Bajwa, 2012) do not mention the use of cryo-denervation and ganglionectomy.
The supraorbital nerve is located on the front of the face over the eyebrow. It supplies sensory innervation to the upper eyelid, forehead, and scalp, extending almost to the lambdoidal suture. A nerve block is a procedure in which an anesthetic agent is injected directly near a nerve to block pain. It is a form of regional anesthesia.
In a randomized controlled trial (RCT), Liu and co-workers (2017) evaluated the effectiveness and tolerability of transcutaneous ONS (tONS) in patients with migraine, and examined if different tONS frequencies influenced treatment effectiveness. Patients were randomized to 1 of 5 therapeutic groups prior to treatment for 1 month. Groups A to C received tONS at different frequencies (2-Hz, 100-Hz, and 2/100-Hz), group D underwent sham tONS intervention, and group E received topiramate orally. The primary outcomes were the 50 % responder rate and headache characteristics. A total of 110 patients completed the study. The 50 % responder rate was significantly greater in the groups undergoing active tONS and topiramate, compared with sham-treated group. A significant reduction in headache intensity was noted in each test group compared with the sham group; the groups undergoing tONS at different frequencies did not differ significantly. From baseline to the 1-month treatment period, tONS group with 100-Hz and topiramate group exhibited significant decreases in headache duration. The authors concluded that tONS therapy is a new promising approach for migraine prevention. It has infrequent and mild adverse events (AEs) and may be effective among patients who prefer non-pharmacological treatment.
Neurolysis
Choi and Jeon (2016) stated that occipital neuralgia is defined by the International Headache Society as paroxysmal shooting or stabbing pain in the dermatomes of the greater or lesser occipital nerve. Various treatment methods exist, from medical treatment to open surgical procedures. Local injection with corticosteroid can improve symptoms, though generally only temporarily. More invasive procedures can be considered for cases that do not respond adequately to medical therapies or repeated injections. Radiofrequency lesioning of the greater occipital nerve can relieve symptoms, but there is a tendency for the pain to recur during follow-up. There also remains a substantial group of intractable patients that do not benefit from local injections and conventional procedures. Moreover, treatment of occipital neuralgia is sometimes challenging. More invasive procedures, such as C2 gangliotomy, C2 ganglionectomy, C2 to C3 rhizotomy, C2 to C3 root decompression, neurectomy, and neurolysis with or without sectioning of the inferior oblique muscle, are now rarely performed for medically refractory patients. Recently, a few reports have described positive results following peripheral nerve stimulation of the greater or lesser occipital nerve. Although this procedure is less invasive, the significance of the results is hampered by the small sample size and the lack of long-term data. Clinicians should always remember that destructive procedures carry grave risks: once an anatomic structure is destroyed, it cannot be easily recovered, if at all, and with any destructive procedure there is always the risk of the development of painful neuroma or causalgia, conditions that may be even harder to control than the original complaint.
This review cited 3 retrospective studies (n = 206, n = 10, and n = 18, respectively) on the use of nerve neurolysis for the treatment of occipital neuralgia. Moreover, it stated that neurolysis of the occipital nerve (with or without sectioning of the inferior oblique muscle), C2 gangliotomy, C2 ganglionectomy, C2 to C3 rhizotomy, C2 to C3 root decompression, and neurectomy were historically introduced for medically refractory patients. However, the results were variable … Of these approaches, both occipital neurolysis and occipital nerve stimulation (ONS) have been used commonly in the clinical field, recently. In selective cases, these methods have shown good outcomes, but a well-designed randomization study with a long-term observation is not yet available.
Intradural Rhizotomy
Kapoor and associates (2003) described CT fluoroscopy-guided percutaneous C2 to C3 nerve block for the confirmation of diagnosis of ON and for demonstrating to patients the sensory effects of intradural cervical dorsal rhizotomy (CDR) before the definitive surgical procedure. A total of 17 patients with ON underwent 32 CT fluoroscopy-guided C2 or C2 and C3 nerve root blocks. Of the 17 patients, 9 had ON following prior neck or skull base surgeries. On the basis of the positive results of the nerve blocks in terms of temporary pain relief, all 17 patients underwent unilateral (n = 16) or bilateral (n = 1) intradural C1 (n = 9), C2 (n = 17), C3 (n = 17), or C4 (n = 7) dorsal rhizotomies. All patients were followed-up for a mean of 20 months (range of 5 to 37) for assessment of pain relief; 16 patients were assessed for degree of satisfaction with and functional state after surgery. All patients had temporary relief of symptoms after percutaneous CT-guided block (positive result) and felt that occipital numbness was an acceptable alternative to pain. Immediately after surgery, all patients had complete relief from pain. At follow-up, 11 patients (64.7 %) had complete relief of symptoms, 2 (11.8 %) had partial relief, and 4 (23.5 %) had no relief; 7 of 8 (87.5 %) patients without prior surgery had complete relief of symptoms and 1 (12.5 %) patient had partial relief, as opposed to complete relief in 4 of 9 (44.4 %), partial relief in 1 of 9 (11.2 %), and no relief in 4 of 9 (44.4 %) patients with a history of prior surgery. Because of the small number of patients, this difference was not statistically significant (p = 0.110); 11 of 16 (68.8 %) patients stated that the surgery was worthwhile; 8 of 16 (50 %) patients felt they were more active and functional after surgery, whereas 25 % felt they were either unchanged or less functional than before surgery. None of the patients without a history of prior surgery reported a decreased sense of functional activity following rhizotomy. The authors concluded that CT fluoroscopy-guided percutaneous cervical nerve block was useful for the confirmation of ON, for demonstrating to patients the sensory effects of nerve sectioning, and possibly as a guide for selection of patients for intradural CDR. Moreover, they noted that although not statistically significant, there was a trend toward better response to rhizotomy in patients without prior head or neck surgery.
Gande and colleagues (2016) noted that the long-term effectiveness of CDR in the management of ON has not been well described. In a retrospective chart-review study, these researchers reviewed their 14-year experience with CDR to evaluate pain relief and functional outcomes in patients with medically refractory ON. A total of 75 ON patients who underwent CDR from 1998 to 2012 were included in this analysis; 55 patients were included because they met the International Headache Society's (IHS) diagnostic criteria for ON, responded to CT-guided nerve blocks at the C2 dorsal nerve root, and had at least 1 follow-up visit. Telephone interviews were additionally used to obtain data on patient satisfaction; 42 patients (76 %) were women, and the average age at surgery was 46 years (range of 16 to 80). Average follow-up was 67 months (range of 5 to 150). Etiologies of ON included the following: idiopathic (44 %), post-traumatic (27 %), post-surgical (22 %), post-cerebrovascular accident (4 %), post-herpetic (2 %), and post-viral (2 %). At last follow-up, 35 patients (64 %) reported full pain relief, 11 (20 %) partial relief, and 7 (16 %) no pain relief. The extent of pain relief after CDR was not significantly associated with ON etiology (p = 0.43). Of 37 patients whose satisfaction-related data were obtained, 25 (68 %) reported willingness to undergo repeat surgery for similar pain relief, while 11 (30 %) reported no such willingness; a single patient (2 %) did not answer this question; 21 individuals (57 %) reported that their activity level/functional state improved after surgery, 5 (13 %) reported a decline, and 11 (30 %) reported no difference. The most common acute post-operative complications were infections in 9 % (n = 5) and CSF leaks in 5 % (n = 3); chronic complications included neck pain/stiffness in 16 % (n = 9) and upper-extremity symptoms in 5 % (n = 3) such as trapezius weakness, shoulder pain, and arm paresthesias. The authors concluded that CDR provided an effective means for pain relief in patients with medically refractory ON. In the appropriately selected patient, it may lead to optimal outcomes with a relatively low risk of complications. Moreover, the authors noted a number of drawbacks, including the retrospective nature of the study, the lack of comparison groups, not using a validated tool to quantify pain, and lack of follow-up in 1/3 of subjects to confirm pain relief. They stated that a larger prospective study with regular follow-up and comparison with other treatment modalities is needed to confirm the effectiveness of CDR.
Choi and Jeon (2016) stated that more invasive procedures, such as C2 gangliotomy, C2 ganglionectomy, C2 to C3 rhizotomy, C2 to C3 root decompression, neurectomy, and neurolysis with or without sectioning of the inferior oblique muscle, are now rarely performed for medically refractory patients.
Furthermore, an UpToDate review on “Occipital neuralgia” (Garza, 2017) does not mention intradural rhizotomy as a therapeutic option.
Cluster Headache
Cluster headaches are characterized by repeated attacks of severe headache usually occurring several times a day. Patients with chronic cluster headache have unremitting illness that requires daily preventive medical treatment for years. Burns et al (2007) examined the effectiveness of occipital nerve stimulation (ONS) in the treatment of patients with refractory chronic cluster headache (n = 8). Electrodes were implanted in the suboccipital region for ONS. Other than the first patient, who was initially stimulated unilaterally before being stimulated bilaterally, all patients were stimulated bilaterally during treatment. At a median follow-up of 20 months (range of 6 to 27 months for bilateral stimulation), 6 of 8 patients reported responses that were sufficiently meaningful for them to recommend the treatment to similarly affected patients with chronic cluster headache. Two patients noticed a substantial improvement (90 % and 95 %) in their attacks; 3 patients noticed a moderate improvement (40 %, 60 %, and 20 to 80 %, respectively) and 1 reported mild improvement (25 %). Improvements occurred in both frequency and severity of attacks. These changes took place over weeks or months, although attacks returned in days when the device malfunctioned (e.g., with battery depletion). Adverse effects were lead migrations in 1 patient and battery depletion requiring replacement in 4. The authors concluded that ONS in cluster headache seems to offer a safe, effective treatment option that could begin a new era of neurostimulation therapy for primary headache syndromes.
In a pilot study, Magis et al (2007) evaluated the effectiveness of ONS in the treatment of patients with drug-resistant chronic cluster headache (drCCH). A total of 8 patients with drCCH had a sub-occipital neurostimulator implanted on the side of the headache and were asked to record details of frequency, intensity, and symptomatic treatment for their attacks in a diary before and after continuous ONS. To detect changes in cephalic and extra-cephalic pain processing, these researchers measured electrical and pressure pain thresholds and the nociceptive blink reflex. Two patients were pain-free after a follow-up of 16 and 22 months; 1 of them still had occasional autonomic attacks. Three patients had around a 90 % reduction in attack frequency. Two patients, 1 of whom had had the implant for only 3 months, had improvement of around 40 %. Mean follow-up was 15.1 months (standard deviation of 9.5, range of 3 to 22 months). Intensity of attacks tends to decrease earlier than frequency during ONS and, on average, is improved by 50 % in remaining attacks. All but 1 patient were able to substantially reduce their preventive drug treatment. Interruption of ONS by switching off the stimulator or because of an empty battery was followed within days by recurrence and increase of attacks in all improved patients. Occipital nerve stimulation did not significantly modify pain thresholds. The amplitude of the nociceptive blink reflex increased with longer durations of ONS. There were no serious adverse events. The authors concluded that ONS could be an efficient treatment for drCCH and could be safer than deep hypothalamic stimulation. The delay of 2 months or more between implantation and significant clinical improvement suggests that the procedure acts via slow neuromodulatory processes at the level of upper brain stem or diencephalic centers.
In a retrospective analysis, Schwedt et al (2007) examined the safety and effectiveness of ONS for medically intractable headache. Pre- and post-implantation data regarding headache frequency, severity, disability, depression and post-stimulator complications were collected. A total of 15 patients (12 females and 3 males) with age ranging from 21 to 52 years (mean of 39 years) were included in this study. Eight patients had chronic migraine, 3 chronic cluster, 2 hemicrania continua and 2 had post-traumatic headache. Eight patients underwent bilateral and 7 had unilateral lead placement. They were measured after 5 to 42 months (mean of 19 months). All 6 mean headache measures improved significantly from baseline (p < 0.03). Headache frequency per 90 days improved by 25 days from a baseline of 89 days; headache severity (0 to 10) improved 2.4 points from a baseline of 7.1 points; MIDAS disability improved 70 points from a baseline of 179 points; HIT-6 scores improved 11 points from a baseline of 71 points; BDI-II improved 8 points from a baseline of 20 points; and the mean subjective percent change in pain was 52 %. Most patients (60 %) required lead revision within 1 year. One patient required generator revision. The authors concluded that ONS may be effective in some patients with intractable headache. Surgical revisions may be commonly required. They noted that safety and effectiveness results from prospective, randomized, sham-controlled studies in patients with medically refractory headache are needed to validate these preliminary findings.
Jasper and Hayek (2008) noted that there is limited evidence that ONS is a useful tool in the treatment of chronic severe headaches. In a review on ONS for headache, Goadsby et al (2008) stated that far from proven and with much work to be done, neurostimulation therapy by means of ONS is an exciting potential development for patients and doctors. Furthermore, Trentman and Zimmerman (2008) stated that ONS may be an effective minimally invasive treatment modality for refractory headache disorders; however, further studies are needed.
Burns et al (2009) described the clinical outcome of ONS for 14 patients with intractable CCH. A total of 14 patients with medically intractable CCH were implanted with bilateral electrodes in the suboccipital region for ONS and a retrospective assessment of their clinical outcome wereobtained. At a median follow-up of 17.5 months (range of 4 to 35 months), 10 of 14 patients reported improvement and 9 of these recommended ONS. Three patients noticed a marked improvement of 90 % or better (90 %, 90 %, and 95 %, respectively), 3 a moderate improvement of 40 % or better (40 %, 50 %, and 60 %, respectively), and 4 a mild improvement of 20 to 30% (20 %, 20 %, 25 %, and 30 %, respectively). Improvement occurred within days to weeks for those who responded most and patients consistently reported their attacks returned within hours to days when the device was off. One patient found that ONS helped abort acute attacks. Adverse events of concern were lead migrations and battery depletion. The authors concluded that intractable CCH is a devastating, disabling condition that has traditionally been treated with cranially invasive or neurally destructive procedures. Occipital nerve stimulation offers a safe, effective option for some patients with CCH. However, they stated that more work is needed to evaluate and understand this novel therapy.
Narouze (2010) stated that cluster headache is a strictly unilateral head pain that is associated with cranial autonomic symptoms and usually follows circadian and circannual patterns. Chronic cluster headache, which accounts for about 10 % to 15 % of patients with cluster headache, lacks the circadian pattern and is often resistant to pharmacological management. The sphenopalatine ganglion (SPG), located in the pterygopalatine fossa, is involved in the pathophysiology of cluster headache and has been a target for blocks and other surgical approaches. Percutaneous radiofrequency ablation of the SPG was shown to have encouraging results in those patients with intractable cluster headaches.
Ansarinia et al (2010) examined the effects of electrical stimulation of SPG for acute treatment of cluster headaches. A total fo 6 patients with refractory CCH were treated with short-term (up to 1 hour) electrical stimulation of the SPG during an acute cluster headaches. Headaches were spontaneously present at the time of stimulation or were triggered with agents known to trigger clusters headache in each patient. A standard percutaneous infra-zygomatic approach was used to place a needle at the ipsilateral SPG in the pterygopalatine fossa under fluoroscopic guidance. Electrical stimulation was performed using a temporary stimulating electrode. Stimulation was performed at various settings during maximal headache intensity. Five patients had cluster headaches during the initial evaluation. Three returned 3 months later for a second evaluation. There were 18 acute and distinct cluster headache attacks with clinically maximal VAS intensity of 8 (out of 10) and above. Electrical stimulation of SPG resulted in complete resolution of the headache in 11 attacks, partial resolution (greater than 50 % VAS reduction) in 3, and minimal to no relief in 4 attacks. Associated autonomic features of cluster headache were resolved in each responder. Pain relief was noted within several minutes of stimulation. The authors concluded that SPG stimulation can be effective in relieving acute severe cluster headache pain and associated autonomic features. They stated that chronic long-term outcome studies are needed to determine the utility of SPG stimulation for management and prevention of cluster headaches.
In a prospective, cross-over, double-blind, multi-center study, Fontaine et al (2010) evaluated the safety and effectiveness of unilateral hypothalamic deep brain stimulation (DBS) in 11 patients with severe refractory CCH. The randomized phase compared active and sham stimulation during 1-month periods, and was followed by a 1-year open phase. The severity of CCH was assessed by the weekly attacks frequency (primary outcome), pain intensity, sumatriptan injections, emotional impact (HAD) and quality of life (SF12). Tolerance was assessed by active surveillance of behavior, homeostatic and hormonal functions. During the randomized phase, no significant change in primary and secondary outcome measures was observed between active and sham stimulation. At the end of the open phase, 6/11 responded to the chronic stimulation (weekly frequency of attacks decrease [50 %]), including 3 pain-free patients. There were 3 serious adverse events, including subcutaneous infection, transient loss of consciousness and micturition syncopes. No significant change in hormonal functions or electrolytic balance was observed. Randomized phase findings of this study did not support the effectiveness of DBS in refractory CCH, but open phase findings suggested long-term effectiveness in more than 50 % patients, confirming previous data, without high morbidity. Discrepancy between these findings justifies additional controlled studies.
Akram and colleagues (2016) presented outcomes in a cohort of medically intractable CCH patients treated with ventral tegmental area (VTA) DBS. In an uncontrolled, open-label, prospective study, a total of 21 patients (17 men; mean age of 52 years) with medically refractory CCH were selected for ipsilateral VTA-DBS by a specialist multi-disciplinary team including a headache neurologist and functional neurosurgeon. Patients had also failed or were denied access to ONS within the UK National Health Service. The primary end-point was improvement in the headache frequency; secondary outcomes included other headache scores (severity, duration, headache load), medication use, disability and affective scores, quality of life (QOL) measures, and adverse events (AEs). Median follow-up was 18 months (range of 4 to 60). At the final follow-up point, there was 60 % improvement in headache frequency (p = 0.007) and 30 % improvement in headache severity (p = 0.001). The headache load (a composite score encompassing frequency, severity, and duration of attacks) improved by 68 % (p = 0.002). Total monthly triptan intake of the group dropped by 57 % post-treatment. Significant improvement was observed in a number of QOL, disability, and mood scales. Side effects included diplopia, which resolved in 2 patients following stimulation adjustment, and persisted in 1 patient with a history of ipsilateral trochlear nerve palsy. There were no other serious AEs. The authors concluded that the findings of this study suggested that VTA-DBS may be a safe and effective therapy for refractory CCH patients who failed conventional treatments. This study provided Class IV evidence that VTA-DBS decreases headache frequency, severity, and headache load in patients with medically intractable CCH. This was an open-label study; thus, a placebo effect cannot be excluded. Well-designed studies are needed to validate these findings.
Other Headaches
Asensio-Samper and colleagues (2008) presented the case of a patient with headache because of post-traumatic supra-orbital neuralgia, refractory to medical treatment, with good analgesic control following peripheral nerve stimulation. The authors stated that peripheral nerve stimulation may be considered a safe, reversible treatment for patients with headache secondary to supra-orbital neuralgia who respond poorly to pharmacological treatment, thus avoiding irreversible alternatives such as surgery. Moreover, in a review on neurostimulation in chronic cluster headache, Magis and Schoenen (2008) noted that recent case reports mentioned effectiveness of supra-orbital and vagus nerve stimulation. Whether these methods have a place in the management of patients with intractable chronic cluster headache remains to be determined.
Mathew (2009) stated that comparator studies that assess treatment effects in a clinical setting have improved the understanding of the efficacy and tolerability of prophylactic treatments for chronic migraine. It is premature to recommend device-based treatments, such as ONS, vagal nerve stimulation, and patent foramen ovale closure for chronic migraine, because clinical trials are still in the preliminary stages.
Franzini et al (2009) stated that ONS is an emerging procedure for the treatment of cranio-facial pain syndromes and headaches refractory to conservative treatments. Paemeleire and Bartsch (2010) stated that ONS was originally described in the treatment of occipital neuralgia. However, the spectrum of possible indications has expanded in recent years to include primary headache disorders, such as migraine and cluster headaches. Retrospective and some prospective studies have yielded encouraging results, and evidence from controlled clinical trials is emerging. Moreover, these researchers noted that ONS is far from a standardized technique at the moment. They reviewed the recent literature on the topic, both with respect to the procedure and its possible complications. An important way to move forward in the scientific evaluation of occipital nerve stimulation to treat refractory headache is the clinical phenotyping of patients to identify patients groups with the highest likelihood to respond to this modality of treatment. This requires multi-disciplinary assessment of patients. The development of occipital nerve stimulation as a new treatment for refractory headache offers an exciting prospect to treat the most disabled headache patients. Data from ongoing controlled trials will shed new light on some of the unresolved questions.
In a retrospective, descriptive study, Poggi et al (2008) evaluated the effectiveness of surgical decompression of multiple migraine trigger sites in a clinical practice setting, and compared the results to those previously published. A total of 18 patients who had undergone various combinations of surgical decompression of the supraorbital, supratrochlear, and greater occipital nerves and zygomaticotemporal neurectomy were included in this analysis. All patients had been diagnosed with migraine headaches according to neurological evaluation and had undergone identification of trigger sites by botulinum toxin type A injections. Following surgical decompression, the number of migraines per month and the pain intensity of migraine headaches decreased significantly. Three patients (17 %) had complete relief of their migraines, and 9 of 18 (50 %) had at least a 75 % reduction in the frequency, duration, or intensity of migraines; and 39 % of patients have discontinued all migraine medications. Mean follow-up was 16 months (range of 6 to 41 months) after surgery. All subjects stated they would repeat the surgical procedure. The authors conclded that the findings of this study supported the theory that peripheral nerve compression triggers a migraine cascade. They verified a reduction in duration, intensity, and frequency of migraine headaches by surgical decompression of the supraorbital, supratrochlear, zygomaticotemporal, and greater occipital nerves. They stated that a significant amount of patient screening is needed for proper patient selection and trigger site identification for surgical success. These findings need to be validated by well-designed studies.
Kung et al (2011) stated that migraine headache can be a debilitating condition that confers a substantial burden to the affected individual and to society. Despite significant advancements in the medical management of this challenging disorder, clinical data have revealed a proportion of patients who do not adequately respond to pharmacologic intervention and remain symptomatic. Recent insights into the pathogenesis of migraine headache argue against a central vasogenic cause and substantiate a peripheral mechanism involving compressed craniofacial nerves that contribute to the generation of migraine headache. Botulinum toxin injection is a relatively new treatment approach with demonstrated efficacy and supports a peripheral mechanism. Patients who fail optimal medical management and experience amelioration of headache pain after injection at specific anatomical locations can be considered for subsequent surgery to decompress the entrapped peripheral nerves. Migraine surgery is an exciting prospect for appropriately selected patients suffering from migraine headache and will continue to be a burgeoning field that is replete with investigative opportunities. The authors stated that future research will elucidate the anatomical relationships of migraine trigger points and possibly identify additional sites that have the capacities to generate migraines ... Research is currently being conducted to examine the long-term benefits of migraine surgery.
Magis and Schoenen (2011) reviewed the latest clinical trial results in anti-migraine treatment. The oral calcitonine gene-related peptide antagonist telcagepant is effective in acute treatment. Compared to triptans, its effectiveness is almost comparable but its tolerance is superior. The same is true for the 5HT-1F agonist lasmiditan. Triptans, as other drugs, are more efficient if taken early but NSAIDs and analgesics remain useful for acute treatment, according to several meta-analyses. Single-pulse transcranial magnetic stimulation during the aura rendered more patients pain-free (39 %) than sham stimulation (22 %) in 1 study. Topiramate could be effective for migrainous vertigo, but it did not prevent transformation to chronic migraine in patients with high attack frequency. Onabotulinumtoxin A was effective for chronic migraine and well tolerated, but the therapeutic gain over placebo was modest; the clinical profile of responders remains to be determined before widespread use. Occipital nerve stimulation was effective in intractable chronic migraine with 39 % of responders compared to 6 % after sham stimulation. This and other neuromodulation techniques, such as sphenopalatine ganglion stimulation, are promising treatments for medically refractory patients; but large controlled trials are needed. One study suggested that outcome of patent foramen ovale closure in migraine might depend on anatomic and functional characteristics.
In a prospective, observational study, Bond et al (2011) examined if weight loss after bariatric surgery is associated with improvements in migraine headaches. A total of 24 patients who had migraine according to the ID-Migraine screener were assessed before and 6 months after bariatric surgery. At both time points, patients had their weight measured and reported on frequency of headache days, average headache pain severity, and headache-related disability over the past 90 days via the Migraine Disability Assessment questionnaire. Changes in headache measures and the relation of weight loss to these changes were assessed using paired-sample t tests and logistic regression, respectively. Patients were mostly female (88 %), middle-aged (mean age of 39.3), and severely obese (mean body mass index of 46.6) at baseline. Mean (+/- SD) number of headache days was reduced from 11.1 +/- 10.3 pre-operatively to 6.7 +/- 8.2 post-operatively (p < 0.05), after a mean percent excess weight loss (% EWL) of 49.4 %. The odds of experiencing a greater than or equal to 50 % reduction in headache days was related to greater % EWL, independent of surgery type (p < 0.05). Reductions in severity were also observed (p < 0.05) and the number of patients reporting moderate-to-severe disability decreased from 12 (50.0 %) before surgery to 3 (12.5 %) after surgery (p < 0.01). The authors concluded that severely obese migraineurs experience marked alleviation of headaches following significant weight reduction via bariatric surgery. They stated that future studies are needed to determine whether more modest, behaviorally produced weight losses can result in similar migraine improvements. Limitations of this study included its observational nature, small number of patients, and the lack of a control group. It would also be interesting to determine if there is a dose-response relationship (i.e., whether greater weight loss results in greater improvement).
Gaul et al (2011) noted that cluster headache is the most common type of trigemino-autonomic headache, affecting approximately 120,000 persons in Germany alone. The attacks of pain are in the peri-orbital area on one side, last 90 minutes on average, and are accompanied by trigemino-autonomic manifestations and restlessness. Most patients have episodic cluster headache; about 15 % have chronic cluster headache, with greater impairment of their quality of life. The attacks often possess a circadian and seasonal rhythm. Oxygen inhalation and triptans are effective acute treatment for cluster attacks. First-line drugs for attack prophylaxis include verapamil and cortisone; alternatively, lithium and topiramate can be given. Short-term relief can be obtained by the subcutaneous infiltration of local anesthetics and steroids along the course of the greater occipital nerve, although most of the evidence in favor of this is not derived from randomized clinical trials. Patients whose pain is inadequately relieved by drug treatment can be offered newer, invasive treatments, such as deep brain stimulation in the hypothalamus (DBS) and bilateral ONS. The authors concluded that pharmacotherapy for the treatment of acute attacks and for attack prophylaxis is effective in most patients. For the minority who do not gain adequate relief, newer invasive techniques are available in some referral centers. Definitive conclusions as to their value can not yet be drawn from the available data.
The Work Loss Data Institute’s clinical guideline on “Neck and upper back (acute & chronic)” (2011) listed greater occipital nerve block (diagnostic and therapeutic) as one of the interventions/procedures that are under study and are not specifically recommended.
The Institute for Clinical Systems Improvement's clinical practice guideline on "Diagnosis and treatment of headache" (2011) does not mention the use of decompression of the occipital/greater occipital, supra-orbital and supra-trochlear nerves. Furthermore, an UpToDate review on "Overview of chronic daily headache" (Garza and Schwedt, 2012) does not mention the use of decompression of the occipital, supra-orbital and supra-trochlear nerves as a therapeutic option.
Saper et al (2011) presented preliminary safety and efficacy data on ONS in patients with medically intractable CM. Eligible subjects received an occipital nerve block, and responders were randomized to adjustable stimulation (AS), pre-set stimulation (PS) or medical management (MM) groups. Seventy-five of 110 subjects were assigned to a treatment group; complete diary data were available for 66. A responder was defined as a subject who achieved a 50 % or greater reduction in number of headache days per month or a 3-point or greater reduction in average overall pain intensity compared with baseline. Three-month responder rates were 39 % for AS, 6 % for PS and 0 % for MM. No unanticipated adverse device events occurred. Lead migration occurred in 12 of 51 (24 %) subjects. The authors concluded that results of this feasibility study offer promise and should prompt further controlled studies of ONS in CM.
In an editorial that accompanied the afore-mentioned study, Schwedt (2011) stated that the findings by Saper et al suggested that ONS is a promising treatment for CM and that further clinical trials are needed. Schwedt noted several drawbacks of the study –- patients were taking migraine prophylactic medications; the effects of these medications on study results can not be determined,
- high complication rates – 24 % of subjects had lead migration and 14 % had infection,
- short-term follow-up – this study only reported 3 months of follow-up; the need for battery replacement has to be considered when discussing stimulator therapy, and
- only 39 % of subjects had benefits that met a priori criteria for response.
Schwedt stated that if ONS is to be considered a viable therapy, benefits must be persistent over a prolonged duration of time with acceptable complication rated and battery life.
Strand et al (2011) evaluated the effectiveness of a microstimulator for chronic cluster headache. 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. Three of the participants returned their headache diaries for evaluation. The mean duration of chronic cluster headache was 14.3 years (range of 3 to 29 years). Pain was predominantly or exclusively retro-ocular/peri-ocular. One participant showed a positive response (greater than 50 % reduction in cluster headache frequency) at 3 months post-implant, while there were 2 responders at 6 months. At least 1 of the participants continued to show greater than 60 % reduction in headache frequency at 12 months. A chart review showed that at 58 to 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. The authors concluded that 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. They stated that prospective, randomized controlled trials of occipital nerve stimulation (ONS) in chronic cluster headache should proceed.
Lambru and Matharu (2012) stated that advances in the management of headache disorders have meant that a substantial proportion of patients can be effectively treated with medical treatments. However, a significant minority of these patients are intractable to conventional medical treatments. Occipital nerve stimulation is emerging as a promising treatment for patients with medically intractable, highly disabling chronic headache disorders, including migraine, cluster headache and other less common headache syndromes. Open-label studies have suggested that this treatment modality is effective and recent controlled trial data are also encouraging. The procedure is performed using several technical variations that have been reviewed along with the complications, which are usually minor and tolerable. The mechanism of action is poorly understood, though recent data suggest that ONS could restore the balance within the impaired central pain system through slow neuromodulatory processes in the pain neuromatrix. While the available data are very encouraging, the ultimate confirmation of the utility of a new therapeutic modality should come from controlled trials before widespread use can be advocated; more controlled data are still needed to properly assess the role of ONS in the management of medically intractable headache disorders. The authors concluded that future studies also need to address the variables that are predictors of response, including clinical phenotypes, surgical techniques and stimulation parameters.
Presently, the Food and Drug Administration (FDA) has not approved any device for ONS. Clinical trials are currently underway for 2 ONS devices – ONSTIM® (Medtronic Neuro) and PRISM® (Boston Scientific Corporation) – to ascertain the safety and effectiveness of ONS for migraine headaches.
The Taiwan Headache Society’s treatment guidelines for “Acute and preventive treatment of cluster headache” (Chen et al, 2011) evaluated both the acute and the preventive treatments for cluster headache now being used in Taiwan, based on the principles of evidence- based medicine. These investigators assessed the quality of clinical trials and levels of evidence, and referred to other treatment guidelines proposed by other countries. Throughout several panel discussions, these researchers merged opinions from the subcommittee members and proposed a consensus on the major roles, recommended levels, clinical efficacy, adverse events and cautions of clinical practice regarding acute and preventive treatments of cluster headache. The majority of Taiwanese patients have episodic cluster headaches, because chronic clusters are very rare. Cluster headache is characterized by severe and excruciating pain which develops within a short time and is associated with ipsilateral autonomic symptoms. Therefore, emergency treatment for a cluster headache attack is extremely important. Within the group of acute medications currently available in Taiwan, the subcommittee determined that high-flow oxygen inhalation has the best evidence of effectiveness, followed by intra-nasal triptans. Both are recommended as first-line medical treatments for acute attacks. Oral triptans were determined to be second-line medications. For transitional prophylaxis, oral corticosteroids are recommended as the first-line medication, and ergotamine as the second-line choice. As for maintenance prophylaxis, verapamil has the best evidence and is recommended as the first-line medication. Lithium, melatonin, valproic acid, topiramate and gabapentin are suggested as the second-line preventive medications. Surgical interventions, including ONS, DBS, radiofrequency block of the sphenopalatine ganglion, percutaneous radiofrequency rhizotomy and trigeminal nerve section, are invasive and their long-term effectiveness and adverse events are still not clear in Taiwanese patients; therefore, they are not recommended currently by the subcommittee. The transitional and maintenance prophylactic medications can be used together to attain treatment effectiveness. Once the maintenance prophylaxis achieves effectiveness, the transitional prophylactic medications can be tapered gradually. The authors suggested corticosteroids be used within 2 weeks, if possible. The duration of maintenance treatment depends on the individual patient's clinical condition, and the medications can be tapered off when the cluster period is over.
Also, the National Clinical Guideline Centre’s guideline on “Headaches: Diagnosis and management of headaches in young people and adults” (NICE, 2012) as well as the Institute for Clinical Systems Improvement’s clinical e guideline on “Diagnosis and treatment of headache” (Beithon et al, 2013) did not mention surgery as a therapeutic option.
Furthermore, an UpToDate review on “Chronic migraine” (Garza and Schwedt, 2014) states that “Occipital nerve stimulation – There are inconsistent data from small randomized trials regarding the benefit of occipital nerve stimulation for the treatment of chronic migraine. In the largest trial, there was no significant difference at 12 weeks for the primary endpoint, the percentage of patients that had a ≥ 50 percent reduction in mean daily pain score in the active compared with the control group. However, there were statistically significant if modest improvements with active stimulation for a number of secondary endpoints, including the percentage of patients with a ≥ 30 percent reduction in mean daily pain score, and reduction in the mean number of headache days and migraine-related disability. The findings from these reports are limited by concerns about blinding in the control (sham treatment) groups, given that active treatment causes paresthesia, and relatively high rates of complications, including lead migration in 14 to 24 percent of subjects. Further trials are needed to determine if occipital nerve stimulation is a useful therapy for chronic migraine”. This review also does not mention the use of surgical interventions as therapeutic options.
Lip and Lip (2014) identified the extent of patent foramen ovale prevalence in migraineurs and examined if closure of a patent foramen ovale would improve migraine headache. An electronic literature search was performed to select studies between January 1980 and February 2013 that were relevant to the prevalence of patent foramen ovale and migraine, and the effects of intervention(s) on migraine attacks. Of the initial 368 articles presented by the initial search, 20 satisfied the inclusion criteria assessing patent foramen ovale prevalence in migraineurs and 21 presented data on patent foramen ovale closure. In case series and cohort studies, patent foramen ovale prevalence in migraineurs ranged from 14.6 % to 66.5 %. Case-control studies reported a prevalence ranging from 16.0 % to 25.7 % in controls, compared with 26.8 % to 96.0 % for migraine with aura. The extent of improvement or resolution of migraine headache attack symptoms varied. In case series, intervention ameliorated migraine headache attack in 13.6 % to 92.3 % of cases. One single randomized trial did not show any benefit from patent foramen ovale closure. The overall data did not exclude the possibility of a placebo effect for resolving migraine following patent foramen ovale closure. The authors concluded that this systematic review demonstrated firstly that migraine headache attack is associated with a higher prevalence of patent foramen ovale than among the general population. Moreover, observational data suggested that some improvement of migraine would be observed if the patent foramen ovale were to be closed. They stated that a proper assessment of any interventions for patent foramen ovale closure would require further large randomized trials to be conducted given uncertainties from existing trial data.
Ashkenazi et al (2010) stated that interventional procedures such as peripheral nerve blocks (PNBs) and trigger point injections (TPIs) have long been used in the treatment of various headache disorders. There are, however, little data on their efficacy for the treatment of specific headache syndromes. Moreover, there is no widely accepted agreement among headache specialists as to the optimal technique of injection, type, and doses of the local anesthetics used, and injection regimens. The role of corticosteroids in this setting is also debated. These researchers performed a PubMed search of the literature to find studies on PNBs and TPIs for headache treatment. They classified the abstracted studies based on the procedure performed and the treated condition. They found few controlled studies on the efficacy of PNBs for headaches, and virtually none on the use of TPIs for this indication. The most widely examined procedure in this setting was greater occipital nerve block, with the majority of studies being small and non-controlled. The techniques, as well as the type and doses of local anesthetics used for nerve blockade, varied greatly among studies. The specific conditions treated also varied, and included both primary (e.g., migraine, cluster headache) and secondary (e.g., cervicogenic, post-traumatic) headache disorders. Trigeminal (e.g., supra-orbital) nerve blocks were used in few studies. Results were generally positive, but should be taken with reservation given the methodological limitations of the available studies. The procedures were generally well-tolerated. The authors concluded that there is a need to perform more rigorous clinical trials to clarify the role of PNBs and TPIs in the management of various headache disorders, and to aim at standardizing the techniques used for the various procedures in this setting.
The Institute for Clinical Systems Improvement’s clinical guideline on “Diagnosis and treatment of headache” (ICSI, 2013) did not mention trigeminal nerve block as a therapeutic option.
Giblin et al (2014) described a case of cervicogenic headache with associated autonomic features and pain in a trigeminal distribution, all of which responded to third occipital nerve radiofrequency ablation. This study discussed the case of a 38-year old woman with history of migraines and motor vehicle accident. Right third occipital nerve diagnostic blocks and radiofrequency lesioning were carried out. Outcome measures included pain reduction; physical findings, including periorbital and mandibular facial swelling, tearing, conjunctival injection, and allodynia; and use of opioid and non-opioid pain medicines. The patient had complete relief of her pain and autonomic symptoms, and was able to stop all pain medications following a dedicated third occipital nerve lesioning. The authors concluded that this case illustrated the diagnostic and therapeutic complexity of cervicogenic headache and the overlap with other headache types, including trigeminal autonomic cephalgias and migraine. It represented a unique proof of principle in that not only trigeminal nerve pain but also presumed neurogenic inflammation can be relieved by blockade of cervical nociceptive inputs. They stated that further investigation into shared mechanisms of headache pathogenesis is warranted.
Ambrosini and Schoenen (2016) reviewed minimally invasive interventions targeting pericranial nerves that could be effective in patients with primary headaches who were refractory to conventional treatments. The interventions entailed nerve blocks/infiltrations to the percutaneous implantation of neuro-stimulators as well as surgical decompression procedures. These researchers analyzed the published data (PubMed) on their effectiveness and tolerability. The authors concluded that there is clear evidence for a preventative effect of suboccipital injections of local anesthetics and/or steroids in cluster headache, while evidence for such an effect is weak in migraine. Percutaneous ONS provided significant long-term relief in more than 50 % of drug-resistant CCH patients, but no sham-controlled trial has tested this. The evidence that ONS has lasting beneficial effects in CM is at best equivocal. Suboccipital infiltrations are quasi-devoid of side effects, while ONS is endowed with numerous, though reversible, AEs. These investigators stated that claims that surgical decompression of multiple pericranial nerves is effective in migraine are not substantiated by large, rigorous, randomized and sham-controlled trials.
Cho and colleagues (2017) noted that although CM is a common disorder that severely impacts patient functioning and QOL, it is usually under-diagnosed, and treatment responses often remain poor even after diagnosis. In addition, effective therapeutic options are limited due to the rarity of RCTs involving patients with CM. These investigators discussed updated pharmacological, non-pharmacological, and neuro-stimulation therapeutic options for CM. Pharmacological treatments include both acute and preventive measures. While acute treatment options are similar between CM and episodic migraine (EM), preventive treatment with topiramate and botulinum toxin A exhibited efficacy in more than 2 RCTs. In addition, several studies have revealed that behavioral interventions such as cognitive behavioral therapy, biofeedback, and relaxation techniques are associated with significant improvements in symptoms. Thus, these therapeutic options are recommended for patients with CM, especially for refractory cases. Neuro-stimulation procedures, such as ONS, supraorbital transcutaneous stimulation (e.g., Cefaly), non-invasive vagal nerve stimulation (VNS; e.g., gammaCore), and transcranial direct current stimulation, have shown promising results in the treatment of CM. However, current studies on neuro-stimulation suffer from small sample size, no replication, or negative results.
Puledda and Goadsby (2017) reviewed current neuro-modulation treatments available for migraine therapy, both in the acute and preventive setting. The published literature was reviewed for studies reporting the effects of different neuro-modulation strategies in migraine with and without aura. The use of non-invasive: single pulse transcranial magnetic stimulation (SpringTMS), non-invasive VNS, supraorbital nerve stimulation, and transcranial direct current stimulation, as well as invasive methods such as ONS and sphenopalatine ganglion stimulation, were evaluated. Available evidence showed that non-invasive techniques represent promising treatment strategies, whereas an invasive approach should only be used where patients are refractory to other preventives, including non-invasive methods. The authors concluded that neuro-modulation is emerging as an exciting approach to migraine therapy, especially in the context of failure of commonly used medicines or for patients who do not tolerate common side effects. They stated that more studies with appropriate blinding strategies are needed to confirm the results of these new therapeutic approaches.
Leone and Cecchini (2017) noted that in the past 10 years, a number of neuro-modulatory procedures have been introduced as treatment of chronic intractable headache patients when pharmacological treatments fail or are not well-tolerated. Neuro-stimulation of peripheral and central nervous system has been carried out, and now, various non-invasive and invasive stimulation devices are available. Non-invasive neuro-stimulation options include VNS, supraorbital stimulation and single-pulse transcranial magnetic stimulation; invasive procedures include ONS, sphenopalatine ganglion stimulation and hypothalamic DBS. In many cases, results supporting their use were derived from open-label series and small controlled trial studies. The authors stated that a lack of adequate placebo hampered adequate RCTs.
Occipital Nerve Block for Chronic Migraine Headaches
Szperka and colleagues (2016) described current patterns of use of nerve blocks and trigger point injections for treatment of pediatric headache. A survey was created in REDCap, and sent via email to the 82 members of the Pediatric and Adolescent Section of the American Headache Society in June 2015. The survey queried about current practice and use of nerve blocks, as well as respondents' opinions regarding gaps in the evidence for use of nerve blocks in this patient population. Forty-one complete, 5 incomplete, and 3 duplicate responses were submitted (response rate complete 50 %). About 78 % of the respondents identified their primary specialty as Child Neurology, and 51 % were certified in headache medicine; 26 (63 %) respondents perform nerve blocks themselves, and 7 (17 %) refer patients to another provider for nerve blocks. Chronic migraine with status migrainosus was the most common indication for nerve blocks (82 %), though occipital neuralgia (79 %), status migrainosus (73 %), chronic migraine without flare (70 %), post-traumatic headache (70 %), and new daily persistent headache (67 %) were also common indications. The most commonly selected clinically meaningful response for status migrainosus was greater than or equal to 50 % reduction in severity, while for chronic migraine this was a greater than or equal to 50 % decrease in frequency at 4 weeks. Respondents inject the following locations: 100 % inject the greater occipital nerve, 69 % lesser occipital nerve, 50 % supraorbital, 46 % trigger point injections, 42 % auriculo-temporal, and 34 % supra-trochlear. All respondents used local anesthetic, while 12 (46 %) also use corticosteroid (8 bupivacaine only, 4 each lidocaine + bupivacaine, lidocaine + corticosteroid, bupivacaine + corticosteroid, lidocaine + bupivacaine + corticosteroid, and 2 lidocaine only). The authors concluded that despite limited evidence, nerve blocks are commonly used by pediatric headache specialists. There is considerable variability among clinicians as to injection site(s) and medication selection, indicating a substantial gap in the literature to guide practice, and supporting the need for further research in this area.
Kocer (2016) reported the effects of greater occipital nerve (GON) blocks on refractory CM headache. A total of 9 patients who were receiving the conventionally accepted preventive therapies underwent treatment with repeated GON block to control CM resistant to other treatments. GON blocking with lidocaine and normal saline mixture was administered by the same physician at hospital once-monthly (for 3 times in total). Patients were assessed before the injection and every month thereafter for pain frequency and severity, number of times analgesics were used and any apparent adverse effects (AEs) during a 6-month follow-up; 8 of 9 patients reported a marked decrease in frequency and severity of migraine attacks in comparison to their baseline symptoms; 1 reported no significant change (not more than 50 %) from baseline and did not accept the second injection; GON block resulted in considerable reduction in pain frequency and severity and need to use analgesics up to 3 months after the injection in the present cases. The patients did not report any AEs. The authors noticed a remarkable success with refractory CM patients. They believed that this intervention can result in rapid relief of pain with the effects lasting for perhaps several weeks or even months. Moreover, they stated that further controlled clinical trials are needed to evaluate the effect of GON block in the treatment of refractory migraine cases.
In an uncontrolled, open-label, prospective study, Miller and associates (2016) evaluated the long-term efficacy, functional outcome and safety of occipital nerve stimulation (ONS) in patients with intractable chronic migraine patients (n= 53). Patients were implanted in a single-center between 2007 and 2013; they had a mean age of 47.75 years (range of 26 to 70), and had suffered chronic migraine for around 12 years and had failed a mean of 9 (range of 4 to 19) preventative treatments prior to implant; 18 patients had other chronic headache phenotypes in addition to chronic migraine. After a median follow-up of 42.00 months (range of 6 to 97) monthly moderate-to-severe headache days (i.e., days on which pain was more than 4 on the verbal rating score and lasted at least 4 hours) reduced by 8.51 days (p < 0.001) in the whole cohort, 5.80 days (p < 0.01) in those with chronic migraine alone and 12.16 days (p < 0.001) in those with multiple phenotypes including chronic migraine. Response rate of the whole group (defined as a greater than 30 % reduction in monthly moderate-to-severe headache days) was observed in 45.3 % of the whole cohort, 34.3 % of those with chronic migraine alone and 66.7 % in those with multiple headache types. Mean subjective patient estimate of improvement was 31.7 %. Significant reductions were also seen in outcome measures such as pain intensity (1.34 points, p < 0.001), all monthly headache days (5.66 days, p < 0.001) and pain duration (4.54 hours, p < 0.001). Responders showed substantial reductions in headache-related disability, affect scores and quality of life (QOL) measures. Adverse event (AE) rates were favorable with no episodes of lead migration and only 1 minor infection reported. The authors concluded that ONS may be a safe and efficacious treatment for highly intractable chronic migraine patients even after relatively prolonged follow up of a median of over 3 years. Moreover, they stated that there are still concerns over the risk to benefit ratio and cost-effectiveness of ONS despite positive open-label data and a well-designed double-blind controlled trial with long-term follow-up is needed to clarify the position of neuromodulation in chronic migraine.
Cuadrado and colleagues (2017) stated that currently there is no evidence to guide the acute treatment of migraine aura. These researchers described the effect of greater occipital nerve (GON) anesthetic block as a symptomatic treatment for long-lasting (prolonged or persistent) migraine aura. Patients who presented with migraine aura lasting more than 2 hours were consecutively recruited during 1 year at the Headache Unit and the Emergency Department of a tertiary hospital. All patients underwent a bilateral GON block with bupivacaine 0.5 %. Patients were followed-up for 24 hours. A total of 22 auras were treated in 18 patients. Auras consisted of visual (n = 13), visual and sensory (n = 4) or sensory symptoms alone (n = 5); 11 episodes met diagnostic criteria for persistent aura (greater than 1 week) without infarction. The response was complete without early recurrence in 11 cases (50 %), complete with recurrence in less than 24 hours in 2 cases (9.1 %), and partial with greater than or equal to 50 % improvement in 6 cases (27.3 %). Complete responses without recurrence were more common in cases with prolonged auras lasting less than 1 week than in those with persistent auras (72.7 % versus 27.3 %; p = 0.033). The authors concluded that GON block could be an effective symptomatic treatment for prolonged or persistent migraine aura. Moreover, they stated that RCTs are still required to confirm these results.
In a prospective, long-term, open-label, uncontrolled observational study, Rodrigo and co-workers (2017) evaluated the long-term efficacy and tolerability of ONS for medically intractable chronic migraine. Patients who met the International Headache Society criteria for chronic migraine, all of them having been previously treated with other therapeutic alternatives, and who met all inclusion and exclusion criteria for neuro-stimulation, received the implantation of an ONS system after a positive psychological evaluation and a positive response to a preliminary occipital nerve blockage. The implantation was performed in 2 phases:- a 10 day trial with implanted occipital leads connected to an external stimulator and
- if more than 50 % pain relief was obtained, permanent pulse generator implantation and connection to the previously implanted leads.
After the surgery, the patients were thoroughly evaluated annually using different scales: pain visual analog scale (VAS), number of migraine attacks per month, sleep quality, functionality in social and labor activities, reduction in pain medication, patient satisfaction, tolerability, and reasons for termination. The average follow-up time was 9.4 ± 6.1 years, and 31 patients completed a 7-year follow-up period. A total of 37 patients were enrolled and classified according to the location and quality of their pain, accompanying symptoms, work status, and psychological effects. Substantial pain reduction was obtained in most patients, and the VAS decreased by 4.9 ± 2.0 points. These results remained stable over the follow-up period; 5 of the 35 permanently implanted patients with migraine attacks at baseline were free from these attacks at their last visits, whereas the pain severity decreased 3.8 ± 2.5 (according to the VAS) in the remaining patients; 7 of the 35 permanent implanted devices were definitively removed: 2 devices because of treatment inefficacy, and 5 devices because the patients were asymptomatic and considered to be cured from their pain, even with the stimulation off. Systemic side effects were not observed. The authors noted that they had considered that the trigemino-cervical autonomous and cervical connection may explain why ONS might relieve chronic migraine pain, but this is just a theoretical explanation which should be demonstrated in future studies. They stated that the results achieved in this study suggested that ONS may provide long-term benefits for patients with medically intractable chronic migraine. These outcomes were slightly better than previous reports and were maintained over the 7-year follow-up. These researchers believed that an accurate selection of patients, realization of diagnostic occipital nerve blocks, psychological evaluations, rigorous surgical technique, and appropriate parameter programming helped them achieve these outcomes. Moreover, they stated that controlled and larger studies are needed to confirm these results. Drawbacks of this study included its uncontrolled and open-label design; and not all patients completed the 7-year follow-up period.
In a placebo-controlled study, Gul and colleagues (2017) evaluate the efficacy of greater occipital nerve (GON) blockade in patients with CM by using a control group. These researchers included 44 CM patients and randomly divided the patients into 2 groups: group A (bupivacaine) and group B (placebo). GON blockade was administered 4 times (once-weekly) with bupivacaine or saline. After 4 weeks of treatment, patients were followed-up for 3 months, and findings were recorded once-monthly for comparing each month's values with the pre-treatment values. The primary end-point was the difference in the frequency of headache (headache days/month); VAS pain scores were also recorded. A total of 44 patients had completed the study; no severe adverse effects had occurred. Group A showed a significant decrease in the frequency of headache and VAS scores at the first, second, and third months of follow-up. Similarly, group B showed a significant decrease in the frequency of headache and VAS scores at the first month of follow-up, but second and third months of follow-up showed no significant difference. The authors concluded that these findings suggested that GON blockade with bupivacaine was superior to placebo, had long-lasting effect than placebo, and was found to be effective for the treatment of CM. These researchers stated that GON blockade is a promising treatment for headaches, but its indications, selection criteria, and best techniques are unclear. They stated that more studies are needed to better define the safety and cost-effectiveness of GON blockade in CM.
Viana and Afridi (2018) reviewed the published literature on migraine with prolonged aura (PA), specifically with regards to the phenotype and treatment options. A recent study found that about 17 % of migraine auras are prolonged and that 26 % of patients with migraine with aura have experienced at least 1 PA. The characteristics of PA are similar to most typical auras with the exception of a higher number of aura symptoms (in particular sensory and/or dysphasic). There are no well-established treatments at present which target the aura component of migraine. Other than case reports, there have been open-label studies of lamotrigine and GONs. The only randomized, blinded, controlled trial to-date has been of nasal ketamine showing some reduction in aura severity but not duration. A small open-labelled pilot study of amiloride was also promising. The authors concluded that larger randomized, controlled trials are needed to establish whether any of the existing or novel compounds mentioned is significantly safe and effective.
UpToDate reviews on “Acute treatment of migraine in adults” (Bajwa and Smith, 2018a) and “Preventive treatment of migraine in adults” (Bajwa and Smith, 2018b) do not mention occipital nerve block as a therapeutic option.
Furthermore, an UpToDate review on “Chronic migraine” (Garza and Schwedt, 2018) stated that “Occipital nerve stimulation – There are inconsistent data from small randomized trials regarding the benefit of occipital nerve stimulation for the treatment of chronic migraine. In the largest trial, there was no significant difference at 12 weeks for the primary endpoint, the percentage of patients that had a ≥ 50 % reduction in mean daily pain score in the active compared with the control group. However, there were statistically significant if modest improvements with active stimulation for a number of secondary endpoints, including the percentage of patients with a ≥ 30 % reduction in mean daily pain score, and reduction in the mean number of headache days and migraine-related disability. The findings from these reports are limited by concerns about blinding in the control (sham treatment) groups, given that active treatment causes paresthesia, and relatively high rates of complications, including lead migration in 14 to 24 % of subjects. Further trials are needed to determine if occipital nerve stimulation is a useful therapy for chronic migraine”.
Shauly et al (2019) stated that few therapeutic options exist for CM, with peripheral nerve blocks having long been used to reduce the frequency and severity of migraines. Although the therapeutic effects have been observed in clinical practice, the efficacy has never been fully studied. In the past 10 years, however, several RCTs have been conducted to examine the efficacy of GON block in the treatment of CM. These researchers carried out a systematic review of the literature in the citation databases PubMed, Embase, Medline, and the Cochrane Library. The initial search of databases yielded 259 citations, of which 33 were selected as candidates for full-text review. Of these, 9 studies were selected for inclusion in this meta-analysis. Studies were analyzed that reported mean number of headache days per month in both intervention and control groups. A total of 417 patients were studied, with a pooled MD of -3.6 headache days (95 % CI: -1.39 to -5.81 days). This demonstrated that GON block intervention significantly reduced the frequency of migraine headaches compared with controls (p < 0.00001). Pooled MD in pain scores of -2.2 (95 % CI: -1.56 to -2.84) also demonstrated a significant decrease in headache severity compared with controls (p < 0.0121). The authors concluded that GON blocking should be recommended for use in migraine patients, especially those that may require future surgical intervention. The block may act as an important stepping stone for patients experiencing migraine headache because of its usefulness for potentially assessing surgical candidates for nerve decompression. Level of Evidence = II.
The authors stated that this review/meta-analysis had several drawbacks. First, patients in the control group in 3 of these studies were also given bupivacaine or lidocaine, whereas the intervention included corticosteroids. The end-points of these studies were very similar to the rest of the included studies, but variations between the control and intervention groups may skew the results of this meta-analysis. Second, inherent in all meta-analyses, is the quality of included studies. Quality was assessed using the Jadad scale, which is commonly used to evaluate RCTs. The main advantages of the scale are that it is easy to use, contains many of the elements shown to correlate with bias, and has been demonstrated as being extremely reliable through extensive use across the literature. However, limitations exist primarily because of the scale’s simplicity – with randomization and blinding being only 2 of dozens of variables that may lead to study bias. Those studies included in this meta-analysis demonstrated high Jadad scores, but the method of randomization or blinding was not consistent between RCTs. This systematic review and meta-analysis may also reflect the limitations of the currently available literature on GON blockade. Most of the included studies exhibited a relatively small sample size, with the largest sample size being only 72 patients, including both intervention and control groups, which may have skewed study results. It is a well-known phenomenon that, in RCTs, treatment effects may be over-estimated in a smaller trial, although all end-points were found to favor treatment with 95 % CI. Furthermore, follow-up duration averaged only approximately 4 weeks, which may not have been enough time to fully evaluate the long-term effects of local anesthetics. Thus, a clinical trial with a much larger sample population and longer period of observation should follow.
Blake and Burstein (2019) stated that unremitting head and neck pain (UHNP) is a commonly encountered phenomenon in headache medicine and may be observed in the setting of many well-defined headache types. The prevalence of UHNP is unclear, and establishing the presence of UHNP may require careful questioning at repeated patient visits. The cause of UHNP in some patients may be compression of the lesser and greater occipital nerves by the posterior cervical muscles and their fascial attachments at the occipital ridge with subsequent local perineural inflammation. The resulting pain is typically in the sub-occipital and occipital location, and, via anatomic connections between extra-cranial and intra-cranial nerves, may radiate frontally to trigeminal-innervated areas of the head. Migraine-like features of photophobia and nausea may occur with frontal radiation. Occipital allodynia is common, as is spasm of the cervical muscles. Patients with UHNP may comprise a subgroup of CM, as well as of chronic tension-type headache, new daily persistent headache and cervicogenic headache. Centrally acting membrane-stabilizing agents, which are often ineffective for CM, are similarly generally ineffective for UHNP. Extracranially-directed treatments such as occipital nerve blocks, cervical trigger point injections, botulinum toxin (BTX) and monoclonal antibodies directed at calcitonin gene related peptide, which act primarily in the periphery, may provide more substantial relief for UHNP; additionally, decompression of the occipital nerves from muscular and fascial compression is effective for some patients, and may result in enduring pain relief. The authors concluded that further study is needed to determine the prevalence of UHNP, and to understand the role of occipital nerve compression in UHNP and of occipital nerve decompression surgery in chronic head and neck pain.
Occipital Nerve Stimulation for the Treatment of Occipital Neuralgia
Brewer and colleagues (2013) noted that occipital nerve stimulation (ONS) may provide relief for refractory headache disorders. However, scant data exist regarding long-term ONS outcomes. These investigators examined the long-term outcome in ONS patients with medically intractable primary headache disorders. The methods used were retrospective review of the medical records of all (non-industry study) patients who were trialed and implanted with occipital nerve stimulator systems at the authors’ institution, followed by a phone interview. Up to 3 attempts were made to contact each patient, and those who were contacted were given the opportunity to participate in a brief phone interview regarding their ONS experience. Data for analysis were gleaned from both the phone interview and the patient's medical records. A total of 29 patients underwent a trial of ONS during the 8.5-year study period; 3 patients did not go on to permanent implant, 12 could not be contacted, and 14 participated in the phone interview. Based upon the phone interview (if the patient was contacted) or chart review, ONS was deemed successful in 5 (42 %) of the 12 migraine, 4 (80 %) of 5 cluster headache, and 5 (62.5 %) of 8 miscellaneous headache patients, and therapy was documented as long as 102 months. In 1 of the 26 patients, success of ONS could not be determined. Among patients deemed to have successful outcomes, headache frequency decreased by 18 %, severity by 27 %, and migraine disability score by 50 %; 58 % of patients required at least 1 lead revision. The authors concluded that these results, although limited by their retrospective nature, that ONS can be effective long term despite technical challenges. The number of patients within each headache subtype was insufficient to draw conclusions regarding the differential effect of ONS. Moreover, they stated that randomized controlled long-term studies in specific, intractable, primary headache disorders are needed. (It is unclear how many of the 8 patients with miscellaneous headache had occipital neuralgia [ON]; and how many of the 14 who responded to the phone survey had ON; and occipital neuralgia is not listed as one of the keywords in the abstract).
Palmisani and associates (2013) performed a retrospective review of patients treated with ONS at 2 large tertiary referral centers to optimize future treatment pathways. Patient's medical records were retrospectively reviewed, and each patient was contacted by a trained headache expert to confirm clinical diagnosis and system efficacy. Results were compared to reported outcomes in current literature on ONS for primary headaches. A total of 25 patients underwent a trial of ONS between January 2007 and December 2012, and 23 patients went on to have permanent implantation of ONS. All 23 patients reached 1-year follow-up, and 14 of them (61 %) exceeded 2 years of follow-up; 17 of the 23 had refractory CM (rCM), and 3 refractory ON; 11 of the 19 rCM patients had been referred with an incorrect headache diagnosis; 9 of the rCM patients (53 %) reported 50 % or more reduction in headache pain intensity and or frequency at long term follow-up (11 to 77 months). All 3 ON patients reported more than 50 % reduction in pain intensity and/or frequency at 28 to 31 months; 10 (43 %) subjects underwent surgical revision after an average of 11 ± 7 months from permanent implantation - in 90 % of cases due to lead problems; 7 patients attended a specifically designed, multi-disciplinary, 2-week pre-implant program and showed improved scores across all measured psychological and functional parameters independent of response to subsequent ONS. The authors concluded that this retrospective review:- confirmed the long-term ONS success rate in refractory chronic headaches, consistent with previously published studies;
- suggested that some headaches types may respond better to ONS than others (ON versus CM);
- called into question the role of trial stimulation in ONS;
- confirmed the high rate of complications related to the equipment not originally designed for ONS; and
- emphasized the need for specialist multi-disciplinary care in these patients.
These researchers stated that their findings were consistent with published studies that suggested ONS has a place in the management of patients with refractory chronic migraine and with refractory occipital neuralgia; however, much work needs to be done to refine patient selection and optimize the treatment. This study has high-lighted important specific areas to focus on in the future clinical and research use of ONS. They noted that there is a need to refine patient selection for ONS and ensure optimal medical, psychological and surgical management at all stages – a multi-disciplinary team comprising of headache, psychology, and neuromodulation specialists is essential for this. Such teams should be used in future randomized controlled trials with long-term follow-up to further determine the place for ONS in refractory chronic headache management and improve patient outcomes.
The authors stated that their analysis had several drawbacks. Its design was flawed by the well-known limitations of retrospective case-series studies. Lead/anchor technology and surgical technique have evolved so some of the problems the authors had highlighted are already being addressed. Different measures were collected over the years, and the choice of using patients’ subjective report of headache’s intensity / frequency reduction to define long-term success was not highly robust. Any prospective trial should now endorse the outcome measures defined by Task Force of the International Headache Society Clinical Trials Sub-Committee. Finally, these researchers couldn’t collect enough information to report and comment on medication-overuse headache.
Sweet et al (2015) stated that ONS constitutes a promising therapy for medically refractory ON because it is reversible with minimal side effects and has shown continued efficacy with long-term follow-up. These researchers conducted a systematic literature review and provided treatment recommendations for the use of ONS for the treatment of patients with medically refractory ON. A systematic literature search was conducted using the PubMed database and the Cochrane Library to locate articles published between 1966 and April 2014 using MeSH headings and keywords relevant to ONS as a means to treat ON. A second literature search was conducted using the PubMed database and the Cochrane Library to locate articles published between 1966 and June 2014 using MeSH headings and keywords relevant to interventions that predict response to ONS in ON. The strength of evidence of each article that underwent full text review and the resulting strength of recommendation were graded according to the guidelines development methodology of the American Association of Neurological Surgeons/Congress of Neurological Surgeons Joint Guidelines Committee. A total of 9 studies met the criteria for inclusion in this guideline. All articles provided Class III Level evidence. The authors concluded that based on the data derived from this systematic literature review, the following Level III recommendation can be made: the use of ONS is a therapeutic option for patients with medically refractory ON. (Level III recommendation: Evidence from case series, comparative studies with historical controls, case reports, and expert opinion, as well as significantly flawed randomized controlled trials).
Liu et al (2017) presented a case of successful relief of bilateral ON using unilateral ONS and discussed the possible underlying mechanisms. These researchers presented the case of a 59-year old woman with severe bilateral ON treated with unilateral ONS. They also reviewed previous studies of ONS for ON, discussing the possible mechanisms of ONS in the relief of ON. The patient reported complete pain relief after consistent unilateral ONS during the follow-up period. The underlying mechanisms may be linked to the relationship between pain and several brain regions, including the pons, midbrain, and periaqueductal gray. The authors concluded that ONS is a safe and effective option for treating ON. Moreover, these researchers stated that future studies are needed to clarify the mechanisms by which unilateral occipital stimulation provided relief for bilateral neuralgia in this case.
Mekhail and co-workers (2017) noted that a recent multi-center study presented 52-week safety and efficacy results from an open-label extension of a randomized, sham-controlled trial for patients with chronic migraine (CM) undergoing ONS. These researchers presented the data from a single-center of 20 patients enrolled at the Cleveland Clinic's Pain Management Department. Patients were implanted with a neurostimulation system, randomized to an active or control group for 12 weeks, and received open-label treatment for an additional 40 weeks. Outcomes collected included number of headache days, pain intensity, Migraine Disability Assessment (MIDAS), Zung Pain and Distress (PAD), direct patient reports of headache pain relief, quality of life (QOL), satisfaction, and adverse events (AEs). Headache days per month were reduced by 8.51 (± 9.81) days (p < 0.0001). The proportion of patients who achieved a 30 % and 50 % reduction in headache days and/or pain intensity was 60 % and 35 %, respectively. MIDAS and Zung PAD were reduced for all patients; 15 (75 %) of the 20 patients at the site reported at least 1 AE. A total of 20 AEs were reported from the site. The authors concluded that these findings supported the 12-month efficacy of 20 CM patients receiving peripheral nerve stimulation of the occipital nerves in this single-center trial. This was a small (n = 20), single-center study on the use of occipital nerve stimulation for the treatment of chronic migraine; not ON. Moreover, these investigators stated that despite advancements on surgical techniques, AES with ONS remain prominent, thus warranting further research into both technology and implantation technique.
Furthermore, an UpToDate review on “Occipital neuralgia” (Garza, 2019) states that “Occipital nerve stimulation has been employed in selected cases of severe occipital neuralgia unresponsive to less invasive measures, but this method should be reserved for use in a pain center with expertise in neuromodulation”.
Migraine Surgery
The American Headache Society guidelines (Loder et al, 2013) recommended against surgical deactivation of migraine trigger points. It stated that “The value of this form of “migraine surgery” is still a research question. Observational studies and a small controlled trial suggest possible benefit. However, large multicenter, randomized controlled trials with long-term follow-up are needed to provide accurate estimates of the effectiveness and harms of surgery. Long-term side effects are unknown but potentially a concern”.
Sphenopalatine Nerve Block / Sphenopalatine Ganglion Stimulation
Candido et al (2013) noted that the sphenopalatine ganglion (SPG) is located with some degree of variability near the tail or posterior aspect of the middle nasal turbinate. The SPG has been implicated as a strategic target in the treatment of various headache and facial pain conditions, some of which are featured in this manuscript. Interventions for blocking the SPG range from minimally to highly invasive procedures often associated with great cost and unfavorable risk profiles. The purpose of this pilot study was to present a novel, FDA-cleared medication delivery device, the Tx360® nasal applicator, incorporating a trans-nasal needleless topical approach for SPG blocks. This study featured the technical aspects of this new device and presented some limited clinical experience observed in a small series of head and face pain cases. After Institutional Review Board (IRB) approval, the technical aspects of this technique were examined on 3 patients presenting with various head and face pain conditions including trigeminal neuralgia (TN), chronic migraine headache (CM), and post-herpetic neuralgia (PHN). The subsequent response to treatment and quality of life was quantified using the following tools: the 11-point Numeric Rating Scale (NRS), Modified Brief Pain Inventory - short form (MBPI-sf), Patient Global Impression of Change (PGIC), and patient satisfaction surveys. The Tx360® nasal applicator was used to deliver 0.5 ml of ropivacaine 0.5 % and 2 mg of dexamethasone for SPG block. Post-procedural assessments were repeated at 15 and 30 minutes, and on days 1, 7, 14, and 21 with a final assessment at 28 days post-treatment. All patients were followed for 1 year. Individual patients received up to 10 SPG blocks, as clinically indicated, after the initial 28 days. Three women, aged 43, 18, and 15, presented with a variety of headache and face pain disorders including TN, CM, and PHN. All patients reported significant pain relief within the first 15 minutes post-treatment. A high degree of pain relief was sustained throughout the 28 day follow-up period for 2 of the 3 study participants. All 3 patients reported a high degree of satisfaction with this procedure. One patient developed minimal bleeding from the nose immediately post-treatment, which resolved spontaneously in less than 5 minutes. Longer term follow-up (up to 1 year) demonstrated that additional SPG blocks over time provided a higher degree and longer lasting pain relief. The authors concluded that SPG block with the Tx360® is a rapid, safe, easy, and reliable technique to accurately deliver topical trans-nasal analgesics to the area of mucosa associated with the SPG. This intervention can be delivered in as little as 10 seconds with the novice provider developing proficiency very quickly. They stated that further investigation is certainly needed related to technique efficacy, especially studies comparing efficacy of Tx360 and standard cotton swab techniques; especially controlled, double-blind studies with a higher number of patients.
In a double-blind, parallel-arm, placebo-controlled, randomized pilot study, Cady et al (2015a) examined if repetitive SPG blocks with 0.5 % bupivacaine delivered through the Tx360 are superior in reducing pain associated with chronic migraine (CM) compared with saline. This study used a novel intervention for acute treatment in CM. Up to 41 subjects could be enrolled at 2 headache specialty clinics in the US. Eligible subjects were between 18 and 80 years of age and had a history of CM defined by the second edition of the International Classification of Headache Disorders appendix definition. They were allowed a stable dose of migraine preventive medications that was maintained throughout the study. Following a 28-day baseline period, subjects were randomized by computer-generated lists of 2:1 to receive 0.5 % bupivacaine or saline, respectively. The primary end-point was to compare numeric rating scale scores at pre-treatment baseline versus 15 minutes, 30 minutes, and 24 hours post-procedure for all 12 treatments. SPG blockade was accomplished with the Tx360, which allows a small flexible soft plastic tube that is advanced below the middle turbinate just past the pterygopalatine fossa into the intra-nasal space. A 0.3 cc of anesthetic or saline was injected into the mucosa covering the SPG. The procedure was performed similarly in each nostril. The active phase of the study consisted of a series of 12 SPG blocks with 0.3 cc of 0.5 % bupivacaine or saline provided 2 times per week for 6 weeks. Subjects were re-evaluated at 1 and 6 months post-final procedure. The final dataset included 38 subjects, 26 in the bupivacaine group and 12 in the saline group. A repeated measures analysis of variance showed that subjects receiving treatment with bupivacaine experienced a significant reduction in the numeric rating scale scores compared with those receiving saline at baseline (M = 3.78 versus M = 3.18, p = 0.10), 15 minutes (M = 3.51 versus M = 2.53, p < 0.001), 30 minutes (M = 3.45 versus M = 2.41, p < 0.001), and 24 hours after treatment (M = 4.20 versus M = 2.85, p < 0.001), respectively. Headache Impact Test-6 scores were statistically significantly decreased in subjects receiving treatments with bupivacaine from before treatment to the final treatment (Mdiff = -4.52, p = 0.005), whereas no significant change was seen in the saline group (Mdiff = -1.50, p = 0.13). The authors concluded that SPG blockade with bupivacaine delivered repetitively for 6 weeks with the Tx360 device demonstrated promise as an acute treatment of headache in some subjects with CM. Statistically significant headache relief was noted at 15 and 30 minutes and sustained at 24 hours for SPG blockade with bupivacaine versus saline. The Tx360 device was simple to use and not associated with any significant or lasting adverse events. They stated that further research on SPG blockade is needed.
Cady et al (2015b) performed a double-blind, parallel-arm, placebo-controlled, randomized pilot study using a novel intervention for acute treatment in CM. A total of 41 subjects were enrolled at 2 headache specialty clinics in the USA. Eligible subjects were between 18 and 80 years of age and had a history of CM defined by International Classification of Headache Disorders-II definition. Subjects were allowed a stable dose of migraine preventive medications that was maintained throughout the study. Following a 28-day baseline period, subjects were randomized by computer-generated lists 2:1 to receive 0.3 cc of 0.5 % bupivacaine or saline, respectively, delivered with the Tx360 twice a week for 6 weeks. Secondary end-points reported in this manuscript include post-treatment measures including number of headache days and quality of life measures. The final data set included 38 subjects: 26 in the bupivacaine group and 12 in the saline group. The primary end-point for the study, difference in numeric pain rating scale scores, was met and reported in a previous article. The supplemental secondary end-points reported in this manuscript did not reach statistical significance. When looking collectively at these end-points, trends were noticed and worthy of reporting. Subjects receiving bupivacaine reported a decrease in the number of headache days 1 month post-treatment (Mdiff = -5.71), whereas those receiving saline only saw a slight improvement (Mdiff = -1.93). Headache Impact Test 6 scores were decreased in the bupivacaine group at 1 month (Mdiff = -5.13) and 6 months (Mdiff = -4.78) post-treatment, but only a modest reduction was seen for those receiving saline at 1 and 6 months, respectively (Mdiff = -2.08, Mdiff = -1.58). Furthermore, subjects receiving bupivacaine reported a reduction in acute medication usage and improved quality of life measures (average pain in the previous 24 hours, mood, normal work, and general activity) up to 6 months post-treatment . The changes in these measures for the saline group were minimal. The authors concluded that data from this exploratory pilot study suggested that there may be long-term clinical benefits with the use of repetitive SPG blockades with bupivacaine delivered with the simple to use Tx360 device. These include a sustained reduction of headache days and improvement in several important quality of life assessments. The SPG blockades were not associated with any significant or lasting adverse events. They stated that further research on SPG blockade is needed.
Fontaine and colleagues (2018) stated that CH is a primary headache and considered as one of the worst pains known to man. The SPG plays a pivotal role in cranial autonomic symptoms associated with pain. Lesioning procedures involving the SPG and experimental acute SPG stimulation have shown some degree of efficacy with regard to CH. A neuromodulation device, chronically implanted in the pterygopalatine fossa, has been specifically designed for acute on-demand SPG stimulation. In a placebo-controlled pilot study in 28 patients suffering from refractory chronic CH, alleviation of pain was achieved in 67.1 % of full stimulation-treated attacks compared to 7 % of sham stimulation-treated attacks (p < 0.0001). Long-term results (24 months; 33 patients) confirmed the efficacy of SPG stimulation as an abortive treatment for CH attacks. Moreover, 35 % of the patients observed a greater than 50 % reduction in attack frequency, suggesting that repeated use of SPG stimulation might act as a CH-preventive treatment. Globally, 61 % of the patients were acute responders, frequency responders, or both, and 39 % did not respond to SPG stimulation. The safety of SPG microstimulator implantation procedure was evaluated in a cohort of 99 patients; facial sensory disturbances were observed in 67 % of the patients (46 % of them being transient), transient allodynia in 3 %, and infection in 5 %. The authors concluded that SPG stimulation appeared to be a promising innovative, efficient, and safe therapeutic solution for patients suffering from severe CH. It has shown its efficacy in aborting CH attacks compared to placebo stimulation, suggesting that it is particularly adapted for CH patients who are not sufficiently improved by abortive treatments such as sumatriptan and oxygen. Moreover, these researchers stated that further studies comparing SPG stimulation with standard abortive and/or preventive CH treatments are needed to define more precisely its place within the management of severe chronic and/or episodic CH.
The authors stated that this study had several drawbacks. Although SPG stimulation appeared as a promising, safe, and efficient technique to treat CH attacks, data assessing its safety and efficacy remain limited, and the quality of evidence concerning this therapy, according to the GRADE assessment system is low. All the currently available data come from a single study and a registry, including a limited number of patients (respectively, 43 and 56 patients), and both of these studies were promoted and supported by the company commercializing the implantable device. In the pilot study, 15 out of the 28 reported patients have had less than 10 CH attacks during the randomized phase, meaning that the conclusions were based mostly on the analysis of the remaining 13 patients. This study compared active stimulation with sham stimulation and demonstrated that SPG stimulation therapeutic effect was not due to a placebo effect. However, no study compared SPG stimulation with the current standard abortive treatment, namely sumatriptan injection and/or oxygen inhalation, in terms of efficacy, delay between treatment administration and pain relief, amplitude of pain relief, respective constraints and safety, and costs. Further studies will have to address these points. Similarly, although a preventive effect has been suggested by the association of repeated SPG stimulation and decrease of attack frequency, no study compared SPG stimulation with CH prophylactic treatment or other surgical alternatives for refractory chronic CH, namely ONS and DBS. These data will be needed to determine the exact place of SPG stimulation in the management of CH. Moreover, all the previous data have been collected in refractory CH, and no published data are available regarding the interest of SPG stimulation in episodic CH.
Spinal Accessory Nerve Block
The spinal accessory nerve (ninth cranial nerve) is also known as the accessory nerve. It has 2 roots, which leave the cranium together, along with the vagus nerve, via the jugular foramen. The fibers of the spinal root pass inferiorly and posteriorly to provide motor innervation to the superior portion of the sternocleidomastoid muscle. The spinal accessory nerve exits the posterior border of the sternocleiodomastoid muscle in the upper third of the muscle. The nerve, in combination with the cervical plexus, provides innervation to the trapezius muscle. Spinal accessory nerve block is useful in the diagnosis and treatment of spasm of the sternocleidomastoid or trapezius muscle. There is no reliable data on use of the spinal accessory nerve block for headache.
UpToDate reviews on “Cervicogenic headache” (Bajwa and Watson, 2018), “Chronic migraine” (Garza and Schwedt, 2018) and “Occipital neuralgia” (Garza, 2018) do not mention spinal accessory nerve (cranial nerve IX) block as a therapeutic option.
Trigeminal Nerve Block
Ashkenazi et al (2010) stated that interventional procedures such as peripheral nerve blocks (PNBs) and trigger point injections (TPIs) have long been used in the treatment of various headache disorders. There are, however, little data on their efficacy for the treatment of specific headache syndromes. Moreover, there is no widely accepted agreement among headache specialists as to the optimal technique of injection, type, and doses of the local anesthetics used, and injection regimens. The role of corticosteroids in this setting is also debated. These researchers performed a PubMed search of the literature to find studies on PNBs and TPIs for headache treatment. They classified the abstracted studies based on the procedure performed and the treated condition. They found few controlled studies on the efficacy of PNBs for headaches, and virtually none on the use of TPIs for this indication. The most widely examined procedure in this setting was greater occipital nerve block, with the majority of studies being small and non-controlled. The techniques, as well as the type and doses of local anesthetics used for nerve blockade, varied greatly among studies. The specific conditions treated also varied, and included both primary (e.g., migraine, cluster headache) and secondary (e.g., cervicogenic, post-traumatic) headache disorders. Trigeminal (e.g., supra-orbital) nerve blocks were used in few studies. Results were generally positive, but should be taken with reservation given the methodological limitations of the available studies. The procedures were generally well-tolerated. The authors concluded that there is a need to perform more rigorous clinical trials to clarify the role of PNBs and TPIs in the management of various headache disorders, and to aim at standardizing the techniques used for the various procedures in this setting.
The Institute for Clinical Systems Improvement’s clinical guideline on “Diagnosis and treatment of headache” (Beithon et al, 2013) did not mention trigeminal nerve block as a therapeutic option.
Giblin et al (2014) described a case of cervicogenic headache with associated autonomic features and pain in a trigeminal distribution, all of which responded to third occipital nerve radiofrequency ablation. This study discussed the case of a 38-year old woman with history of migraines and motor vehicle accident. Right third occipital nerve diagnostic blocks and radiofrequency lesioning were carried out. Outcome measures included pain reduction; physical findings, including periorbital and mandibular facial swelling, tearing, conjunctival injection, and allodynia; and use of opioid and non-opioid pain medicines. The patient had complete relief of her pain and autonomic symptoms, and was able to stop all pain medications following a dedicated third occipital nerve lesioning. The authors concluded that this case illustrated the diagnostic and therapeutic complexity of cervicogenic headache and the overlap with other headache types, including trigeminal autonomic cephalgias and migraine. It represented a unique proof of principle in that not only trigeminal nerve pain but also presumed neurogenic inflammation can be relieved by blockade of cervical nociceptive inputs. They stated that further investigation into shared mechanisms of headache pathogenesis is warranted.
Furthermore, UpToDate reviews on Cervicogenic headache” (Bajwa and Watson, 2018), “Chronic migraine” (Garza and Schwedt, 2018) and “Occipital neuralgia” (Garza, 2018) do not mention trigeminal nerve block as a therapeutic option.
Subcutaneous Peripheral Nerve Field Stimulation for the Treatment of Nummular Headache
Bunger and colleagues (2018) noted that subcutaneous peripheral nerve field stimulation (sPNFS) is an established procedure for the treatment of chronic localized neuropathic pain of peripheral origin. Nummular headache (also known as coin-shaped cephalagia) is defined as a mild-to-moderate, pressure-like pain that is felt exclusively in a rounded or elliptical area typically 2 to 6 cm in diameter. While the pathogenesis of nummular headache remains unclear, its treatment primarily focuses on conservative methods with limited prospects of success. The role of sPNFS in the treatment of nummular headache has not been investigated as yet. These researchers examined if sPNFS can be a therapeutic option in the management of nummular headache. They reported that of sPNFS showed a positive effect in the treatment of nummular headache. The authors concluded that sPNFS stimulated free subcutaneous nerves and transmitted a pleasant form of paresthesia in the area of pain. If regular conservative therapy has already been exhausted, then sPNFS might be an effective new option in the treatment of nummular headache. These investigators stated that sPNFS is a minimally invasive and low-risk procedure. However, the high treatment cost and restrictions regarding fitness to undergo MRI are points of criticism. Moreover, they stated that further studies are needed to define its potential and role in the treatment of nummular headache.
Greater Occipital Nerve Block for Prophylaxis and Treatment of Migraine Headache
Inan and associates (2016) stated that peripheral nerve blocks have been used in primary headache treatment since a long time. These researchers examined the efficiency of GON block in migraine prophylaxis. Data from migraine without aura patients who had GON block were collected and divided into 2 groups: Group PGON (n = 25), which included patients who were under medical prophylaxis and had GON block, and Group GON (n = 53), which included patients who had only GON blocks. Migraine was diagnosed using IHS classification. Data of 78 patients were analyzed. Headache attack frequency, headache duration, and severity were compared between and within groups in a 3-month follow-up period. These investigators found the decrease in headache parameters after GON block in both groups was significantly similar. Headache attack frequency decreased from 15.73 ± 7.21 (pre-treatment) to 4.52 ± 3.61 (third month) in Group GON and from 13.76 ± 8.07 to 3.28 ± 2.15 in Group PGON (p < 0.05). Headache duration decreased from 18.51 ± 9.43 to 8.02 ± 5.58 at third month in Group GON and from 15.20 ± 9.16 to 7.20 ± 4.16 in Group PGON (p < 0.05). Headache severity decreased from 8.26 ± 1.32 to 5.16 ± 2.64 in Group GON and from 8.08 ± 0.90 to 5.96 ± 1.20 in Group PGON (p < 0.05). There was no statistically significant difference between the groups in third month after treatment (p > 0.05). The authors concluded that "this study showed significant decreases in headache parameters in both groups. As GON blocks were performed in patients unresponsive to medical prophylaxis, a decrease in the headache parameters in Group PGON similar to that in Group GON could be attributed to GON blocks. Thus, these results suggested that repeated GON blocks either with prophylactic agents or alone can be considered an effective management tool in migraine treatment.
Allen and colleagues (2018) noted that GON blocks are frequently used to treat migraine headaches, although a paucity of supporting clinical evidence exists. In a retrospective, cohort study, these researchers examined the efficacy of GON block in acute treatment of migraine headache, with a focus on pain relief. This trial was undertaken between January 2009 and August 2014 and included patients who underwent at least 1 GON block and attended at least 1 follow-up appointment. Change in the 11-point numeric pain rating scale (NPRS) was used to assess the response to GON block. Response was defined as "minimal" (less than 30 % NPRS point reduction), "moderate" (31 to 50 % NPRS point reduction), or "significant" (greater than 50 % NPRS point reduction). A total of 562 patients met inclusion criteria; 423 were women (75 %). Mean age was 58.6 ± 16.7 years. Of these 562, 459 patients (82 %) rated their response to GON block as moderate or significant. No statistically significant relationship existed between previous treatment regimens and response to GON block. GON block was equally effective across the different age and sex groups. The authors concluded that greater occipital block appeared to be an effective option for acute management of migraine headache, with promising reductions in pain scores. Moreover, these researchers stated that large placebo-controlled clinical trials are needed to confirm these findings, along with those from several smaller observational studies and randomized trials. They stated that further data would help to solidify the use of GON block in the treatment of migraine headache and potentially assist with its inclusion within future treatment guidelines.
Furthermore, UpToDate reviews on “Preventive treatment of migraine in adults” (Bajwa and Smith, 2019, 2019a) and “Acute treatment of migraine in adults” (Bajwa and Smith, 2019b) do not mention greater occipital nerve block as a management tool.
Migraine Trigger Site Surgery / Peripheral Nerve Trigger Surgery for the Treatment of Migraine Headache
Kurlander and colleagues (2014) evaluated the efficacy of surgical deactivation of temporal-triggered migraine headaches. These researchers also examined the effect of surgical de-activation of temporal-triggered migraine headaches on migraine triggers and associated symptoms besides the pain. They analyzed the charts of 246 patients receiving surgery for temporal-triggered migraine headaches by a single surgeon over a 10-year period, who were followed for at least 1 year. Median regression adjusted for age, sex, and follow-up time was used to determine post-operative reduction in temporal-specific migraine headache index, which is the product of frequency, severity, and duration. The association between individual symptom or trigger resolution and index value reduction was studied by logistic regression. Details of the surgical treatment were discussed; 85 % of patients reported a successful surgery (greater than or equal to 50 % improvement of headache index) at least 12 months after surgery (mean follow-up of 3 years); 55 % reported complete elimination of temporal migraine headache. Symptoms resolving with successful site II surgery included nausea, photophobia, phonophobia, difficulty concentrating, vomiting, blurry vision, and eyelid ptosis (p < 0.05). Triggers resolving included let-down after stress, air travel, missed meals, bright lights, loud noises, fatigue, weather change, and certain smells (p < 0.05). The authors concluded that surgical de-activation of temporal-triggered migraine headaches was effective regardless of age, sex, or follow-up time. Successful site II surgery was associated with changes in specific symptoms and triggers. This information could assist in trigger avoidance and contribute to constellations used for temporal-triggered migraine headaches trigger-site identification. Level of evidence = IV.
Gfrerer and associates (2014) stated that in an effort to replicate and expand migraine trigger-site deactivation surgery as a therapeutic option, these researchers and others have developed non-endoscopic algorithms. The exclusion of endoscopic techniques may be useful for surgeons with little experience or limited access to the endoscope and in patients with challenging anatomy. A total of 43 consecutive trigger deactivation procedures in 35 patients were performed. Pre-operative and 12-month post-operative migraine questionnaires and patient charts were reviewed. Response to surgery in terms of migraine symptom relief and AEs were evaluated. The overall positive response rate was 90.7 %. Total elimination of migraine headaches was reported in 51.3 % of those with a positive response, greater than 80 % resolution of symptoms was reported in 20.5 %, and 28.2 % had resolution between 50 and 80 %. No significant effect was reported following 9.3 % of procedures. There were no major AEs. The authors concluded that non-endoscopic trigger deactivation was a safe and effective treatment in select migraine headache patients. The authors concluded that although surgical techniques and understanding of the mechanisms of relief are evolving, results continue to be promising. This series confirmed that excellent results can be attained without the endoscope. These investigators continued to study these patients prospectively to improve patient selection and refine the protocol. Level of evidence = IV.
Mathew (2014) noted that migraine headache trigger site deactivation surgery is a term that encompasses 4 different surgical procedures that are performed based on headache onset location for the preventative treatment of migraine headaches. Multiple studies have demonstrated some efficacy of these procedures, but closer evaluation of the methodology of these studies revealed major flaws in study design. The author provided an overview of the procedures and pre-surgical screening tools, as well as a critical evaluation of 2 of the major studies that have been published. In addition, the author provided his opinion on future study designs that may help to better determine the potential efficacy of these experimental procedures and potential headache subtypes (contact point headache, supra-orbital neuralgia, and occipital neuralgia) that may respond to peripheral decompression surgery.
McGeeney (2015) stated that in the past 10 years surgical treatments for migraine involving proposed trigger sites have been described and popularized by plastic surgeons in particular. Various related techniques aimed to free up "trigger sites" by removal of small facial muscles or "decompressing" small facial nerves. The basis for migraine trigger site surgery is without merit. There was 1 positive placebo-controlled study with many drawbacks. Natural history and placebo mechanisms explain the outcomes from migraine surgery. The American Headache Society (AHS) recommends that the migraine surgery not be performed outside of a clinical trial. The author concluded that migraine trigger site surgery should not be performed.
Kurlander and co-workers (2016) examined the efficacy of surgical deactivation of frontal migraine headaches. In addition, these investigators evaluated the effect of surgical deactivation of frontal migraine headaches on migraine triggers and associated symptoms besides the pain. Charts of 270 patients undergoing surgery performed by a single surgeon for frontal migraine headaches, who were followed for at least 1 year, were analyzed. Median regression adjusted for age, sex, and follow-up time was used to determine post-operative reduction in frontal-specific Migraine Headache Index, which is the product of duration, frequency, and severity. Reduction in migraine-days, which is the product of duration and frequency, was also measured. The association between individual symptom or trigger resolution and frontal-specific Migraine Headache Index reduction was studied by logistic regression. Details of the surgical treatment were discussed and complication rates are reported; 86 % of patients reported a successful operation (greater than or equal to 50 %improvement of frontal-specific Migraine Headache Index) at least 12 months after surgery (mean follow-up of 3 years); 84 % of patients had a successful operation as measured by migraine-days; 57 % of patients reported complete elimination of frontal migraine headaches. Symptoms resolving with successful site I surgery beyond the headaches include visual aura and blurred or double vision (p < 0.05). Triggers resolving with successful site I surgery included fatigue, weather change, and missed meals (p < 0.05). The authors concluded that surgical deactivation of frontal migraine headaches provided long-lasting migraine relief. Successful site I surgery was associated with changes in specific symptoms and triggers. This information could assist in trigger avoidance and contribute to constellations used for frontal migraine headache trigger-site identification. Level of evidence = IV.
Ascha and colleagues (2017) reported the surgical technique and efficacy of deactivation of occipital-triggered migraine headaches. In addition, these researchers reported the effect of surgical deactivation of occipital-triggered migraine headaches on migraine triggers and associated symptoms other than pain. A total of 195 patients undergoing surgery for occipital-triggered migraine headaches performed by a single surgeon, and followed for at least 1 year, were analyzed. Median regression adjusted for age, sex, and follow-up time was used to determine post-operative reduction in occipital-specific Migraine Headache Index, which was the product of migraine duration, frequency, and severity. Reduction in migraine-days was also measured. The association between symptom or trigger resolution and occipital-specific Migraine Headache Index reduction was studied by logistic regression. Details of surgical treatment were discussed and complication rates reported; 82 % of patients (n = 160) reported successful surgery at least 12 months post-operatively (mean follow-up of 3.67 years); 86 % (n = 168) had successful surgery as measured by migraine-days; 52 % reported complete occipital-triggered migraine headaches elimination. Symptoms resolving with successful surgery beyond headache include being bothered by light and noise, feeling light-headed, difficulty concentrating, vomiting, blurred/double vision, diarrhea, visual aura, numbness and tingling, speech difficulty, and limb weakness (p < 0.05). Triggers resolving with successful surgery included missed meals; bright sunshine; loud noise; fatigue; certain smells; stress; certain foods; coughing, straining, and bending over; let-down after stress; and weather change (p < 0.05). The authors concluded that surgical deactivation of occipital-triggered migraine headaches provided long-lasting migraine relief; successful site IV surgery was associated with changes in specific symptoms and triggers. This could assist in trigger avoidance and aid occipital-triggered migraine headache trigger-site identification. Level of evidence = IV.
In a systematic review and meta-analysis on “Surgical management of migraine headaches”, Nagori and associates (2019) analyzed the available evidence on the role of surgery in improving outcomes in patients with migraine headaches. These researchers performed an electronic search of PubMed, Scopus, CENTRAL (Cochrane Central Register of Controlled Trials), and Google Scholar databases was performed for English-language articles reporting results of peripheral nerve surgery for migraine headaches. The search strategy revealed a total of 1,528 records, of which 23 studies were included in the review. A total of 1,151 headache patients were treated in the included studies. The trigger site of migraine addressed varied across studies. Meta-analysis of data of 616 patients revealed that migraine surgery significantly reduced migraine headache frequency (random: mean, 9.52; 95 % CI: 7.14 to 11.9; p < 0.00001; I = 94 %). Similarly, when data of 797 patients were analyzed, there was statistically significant reduction in migraine headache intensity in patients undergoing migraine headache surgery (random: mean, 3.97; 95 % CI: 3.31 to 4.62; p < 0.00001; I = 94 %). On pooling of data of all 23 studies, 8.3 % to 76.4 % of patients reported complete elimination of headache after surgery, whereas 3.9 % to 33.3 % had no relief. The authors concluded that peripheral nerve decompression surgery was highly effective in reducing migraine headache frequency and migraine headache intensity. However, not all patients benefited from the surgical procedure, with a small subset showing no improvement. These investigators stated that further clinical and anatomical studies are needed to define the exact mechanism of nerve compression in migraine patients and as to why a subset of patients did not respond to surgical treatment.
Long and colleagues (2019) reported the surgical technique and efficacy of migraine treatment using the less commonly studied auriculotemporal nerve (site V). These researchers examined symptom relief and differences in migraine headache parameters (i.e., intensity, duration, and migraine-free days) after site V surgery. Patients undergoing site V surgery for auriculotemporal nerve-triggered migraine headaches were analyzed. Charts were reviewed retrospectively for age, sex, dates of surgery and follow-up, pre-operative migraine data, types of surgery, and laterality. Post-operatively, patients completed a migraine headache questionnaire by means of office visit, phone, e-mail, or video conference. A total of 43 patients were included in the study (36 women; median age of 50 years; interquartile range [IQR], 40 to 57 years). The majority of patients underwent bilateral surgery (n = 36) and reported site-specific relief (n = 34). The average follow-up was 17.2 months. The number of migraine-free days (per month) increased from 12.6 days before surgery to 25.1 days after surgery (median increase of 12.6 days; p < 0.005). Median migraine intensity scores decreased from 8.3 to 3.2 after surgery (median decrease of 5.1; p < 0.005) on 10-point severity scale. Migraine duration decreased from 1.2 hours/day to 0.5 hour/day after surgery (median decrease of 0.7 hour/day, p < 0.005). The median difference in migraine duration was the only value found not to be statistically significant, defined as p < 0.005. On both univariate and multivariate analyses, patient-reported site relief was significantly associated with decreased migraine intensity. The authors concluded that surgery for auriculotemporal nerve-triggered migraine headaches improved migraine headache parameters. This study was the first to examine surgical efficacy of this less commonly studied trigger site. Level of evidence = IV. This was a relatively small study (n = 43); these preliminary findings need to be validated by well-designed studies.
Bertozzi and associates (2018) noted that the auriculo-temporal and zygomatico-temporal nerves are the 2 primary trigger points in the temporal area of migraine headache. Different surgical approaches are described in literature, either open or endoscopic ones. These investigators described the currently adopted strategies to treat temporal trigger points in migraine headache. Furthermore, they reported their personal experience in the field. Regardless of the type of approach, outcomes observed were similar and ranged from 89 % to 67 % elimination / greater than 50 % reduction rates. All procedures were minimally invasive and only minor complications were reported, with an incidence ranging from 1 % to 5 %. The authors concluded that just like upper limb compressive neuropathies, migraine headache is believed to be caused by chronic compression of peripheral nerves (i.e., the terminal branches of trigeminal nerve) caused by surrounding structures (e.g., muscles, vessels, and fascial bands) the removal of which eventually resulted in improvement or elimination of migraine attacks. They stated that particular attention should be paid to the close nerve/artery relationship often described in anatomical studies and clinical reports. Moreover, these researchers stated that further studies are needed to precisely delineate pathophysiology of migraine headaches and to identify all potential compression points at trigger zones.
Vincent and co-workers (2019) noted that the headache phase of migraine could in selected cases potentially be treated by surgical decompression of one or more "trigger sites" located at frontal, temporal, nasal, and occipital sites. In a systematic review meta-analysis, these investigators examined the available evidence for the surgical treatment of migraine headache and ascertained the effect size of this treatment in a specific patient population. This study was conducted following the PRISMA guidelines. An online database search was performed. Inclusion was based on studies published between 2000 and March 2018, containing a diagnosis of migraine in compliance with the classification of the IHS. The treatment must consist of 1 or more surgical procedures involving the extra-cranial nerves and/or arteries with outcome data available at minimum 6 months. A total of 847 records were identified after duplicates were removed, 44 full text articles were assessed and 14 records were selected for inclusion. A total number of 627 patients were included in the analysis. A proportion of 0.38 of patients (random effects model, 95 % CI: 0.30 to 0.46]) experienced elimination of migraine headaches at 6 to 12 months follow-up. Using data from 3 RCTS, the calculated OR for 90 to 100 % elimination of migraine headaches was 21.46 (random effects model, 95 % CI: 5.64 to 81.58) for patients receiving migraine surgery compared to sham or no surgery. The authors concluded that migraine surgery led to elimination of migraine headaches in 38 % of the migraine patients included in this review. Moreover, these researchers stated that more elaborate randomized trials are needed with transparent reporting of patient selection, medication use, and surgical procedures and implementing detailed and longer follow-up times; standardization of surgical approaches is of key importance for a further assessment of the real effect of this treatment.
The authors stated that the evidence from the included studies should be viewed with caution due to limitations in methodology and risk of multiple forms of bias, including, but not limited to, selection and observer bias. An important limitation of the included surgical articles was a lack of transparent patient selection methods with the obvious risks of selection bias and lack of detailed patient characteristics before/after surgery. There is often absence of clearly defined and widely-used outcome measures and accurate description of pharmacological treatment during the full study period. Furthermore, the lack of clear definitions for the sham groups and their (however logical due to ethical considerations) small group size with uneven allocation of patients to treatment and control groups led to a considerable expectancy effect in the sham groups. They stated that there is a pressing need for evaluation of these methods. This study provided a report of the current standings in literature, and urged the start of new well-designed and documented RCTs in the future.
Furthermore, an UpToDate review on “Preventive treatment of migraine in adults” (Bajwa and Smith, 2019a) states that “Results from a single-center, blinded, randomized controlled trial suggest that surgical removal of muscle or nerve tissue from headache "trigger sites" may be an effective treatment for select patients with frequent migraine headache. However, the trial results have been received with skepticism by some headache experts due to methodologic flaws including poor case definition. In addition, the proposed mechanism of benefit (trigger site deactivation) does not fit with current pathophysiologic models of migraine. The trial screened 317 patients with frequent moderate to severe migraine headache (with or without aura) and found 76 who were eligible for inclusion, which required both identification of the predominant "trigger site" where "migraine pain started and settled consistently" and a positive response to botulinum toxin injection at the trigger site. Eligible patients, who had approximately 10 migraine headaches per month at baseline, were randomly assigned to treatment with either actual surgery (n = 49) or sham surgery (n = 26) at their trigger site. Actual surgery involved removal of glabellar muscles from patients with frontal trigger sites, removal of a segment of the zygomaticotemporal branch of the trigeminal nerve from those with temporal trigger sites, and resection of a segment of the semispinalis capitis muscle (under general anesthesia) from those with occipital trigger sites. The sham surgery group had exposure but not resection of the muscles and nerves through a similar incision. At 12 months, actual surgery was statistically superior to sham surgery on a variety of outcome measures, including complete elimination of migraine headaches (57 versus 4 %), and a reduction of greater than or equal to 50 % in the migraine headache index, calculated by multiplying the headache frequency, intensity, and duration (84 versus 58 %). Confidence intervals were not reported. Improvement with surgery was independent of trigger site. The surgery was well-tolerated. Given the methodologic flaws in the study design, independent confirmation of benefit in more rigorous trials is needed. In addition, only a minority of patients with frequent migraine (those with identifiable trigger sites and a positive response to botulinum toxin injection) would appear to be candidates”.
Cryoablation for the Treatment of Occipital Neuralgia
In a retrospective study, Kim and colleagues (2015) examined the safety and efficacy of cryoablation (CA) for treatment of occipital neuralgia (ON). All patients received local anesthetic injections for ON. Patients with greater than or equal to 50 % relief and less than 2 week duration of relief were treated with CA. A total of 38 patients with an average age of 49.6 years were included. Of the 38 patients, 20 were treated for unilateral greater ON, 10 for unilateral greater and lesser ON, and 8 for bilateral greater ON. There were 10 men and 28 women, with an average age of 45.2 years and 51.1 years, respectively. The average relief for all local anesthetic injections was 71.2 %, 58.3 % for patients who reported 50 to74 % relief (Group 1) and 82.75 % for patients who reported greater than 75 % relief (Group 2). The average improvement of pain relief with CA was 57.9 % with an average duration of 6.1 months overall. Group 1 reported an average of 45.2 % relief for an average of 4.1 months with CA. In comparison, Group 2 reported an average of 70.5 % relief for 8.1 months. The percentage of relief (p = 0.007) and duration of relief (p = 0.0006) was significantly improved in those reporting at least 75 % relief of pain with local anesthetic injections (Group 2 versus Group 1). Although no significance in improvement from CA was found in men, significance was observed in women with at least 75 % benefit with local anesthetic injections in terms of duration (p = 0.03) and percentage (p = 0.001) of pain relief with CA. The average pain score prior to CA was 8 (0 to 10, VAS), this improved to 4.2, improvement of 3.8 following CA at 6 months (p = 0.03). Of the 38 patients, 3 (7.8 %) adverse effects were observed; 2 patients reported post-procedure neuritis and 1 was monitored for procedure-related hematoma. The authors concluded that CA was safe, and should be considered in patients with ON. Moreover, these researchers stated that study limitations included the retrospective nature of the study; and only the percentage of relief, pain score, and duration of relief were collected. They stated that questionnaires and validated tools in the quantification of pain and function, though dependent of subjective personal interpretations and variations, would have provided more robust data. Furthermore, although the same technique was employed for all the patients, 3 different practitioners carried out the procedures over the 5-year period.
Stogicza and associates (2019) describe a safe ultrasound (US)-guided cryo-neuroablation technique of the proximal greater occipital nerve (GON). These investigators provided a description of the procedure based on experience in the authors' clinic. With the patient in the prone position, the US probe was placed parallel to the inferior oblique capitis muscle (IOCM). The GON was observed on top of the IOCM; a midline 2-mm incision allowed access to the bilateral GONs with a single skin entry. Using an in-plane approach, the cryo-probe was advanced to the nerve in a medial-to-lateral direction, with constant US visualization, staying away from the spinal cord and vertebral artery, which increased safety. The authors concluded that based on anecdotal evidence from the authors' clinic, cryo-neuroablation of the proximal GON could be performed safely at the level of the IOCM. Moreover, these researchers stated that drawbacks of this study included the procedure described was based on anecdotal evidence from a small number of patients; however, the procedure is promising and formal study is needed.
Temporal Artery Ligation for the Treatment of Migraine
Fan et al (2006) introduced a new procedure for the treatment of intractable cases of migraine. These researchers eliminated the excessive vascular and nervous effect by ligation of superficial temporal artery and middle meningeal artery and severance of greater superficial petrosal nerve. A total of 10 patients with cases of severe migraine underwent the surgery. A follow-up of 2 to 18 years showed no recurrences. Among the patients, 3 were living and well for more than 10 years. The authors concluded that with an extra-dural approach, the procedure was relatively safe and simple. It represented a good alternative for the treatment of intractable cases of migraine. This was a small study (n = 10); and its findings were confounded by the combined use of ligation of superficial temporal artery and middle meningeal artery and severance of greater superficial petrosal nerve.
Latimer et al (2011) noted that newly discovered historical case files revealed Dr. Harvey Cushing's previously unpublished early attempts at surgical cure of migraine. Following IRB approval, and through the courtesy of the Alan Mason Chesney Archives, the authors reviewed the microfilm surgical records for the Johns Hopkins Hospital from 1896 to 1912. Patients undergoing surgical intervention by Dr. Harvey Cushing for the treatment of migraine were selected for further review. All 4 patients in the series were women and aged from 29 to 41 years. They were admitted and observed in the hospital until a migraine occurred. Surgeries were performed while the women were in the midst of an attack. Cushing used surgical strategies including decompression, temporal artery ligation, and removal of the spine of the second vertebra. In each case, the patients' headaches eventually returned following surgery. Cushing relied on a combination of contemporary theories on migraine including humeral science, vasospastic theory, organic cause, and increased intra-cranial pressure. His unpublished efforts foreshadowed future surgical efforts at curing migraines.
Furthermore, an UpToDate review on “Preventive treatment of migraine in adults” (Smith, 2020) does not mention temporal artery ligation as a therapeutic option.
Transection of Auriculo-Temporal Nerves for the Treatment of Migraine
Peled (2016) stated that the targets for the surgical treatment of temporal headaches are the zygomatico-temporal branch of the trigeminal nerve and the auriculo-temporal nerve. The former is often accessed by means of an endoscopic brow approach or potentially by laterally extending a trans-palpebral incision. An established surgical approach, the Gillies incision, was modified to access the zygomatico-temporal nerve, as it was felt to combine the advantages of the traditional techniques. A total of 19 patients underwent zygomatico-temporal nerve decompression and neuroplasty or neurectomy and muscle implantation using this surgical approach. A 3.5-cm incision was made behind the anterior, temporal hairline and the zygomatico-temporal branch of the trigeminal nerve was approached directly, remaining superficial to the deep temporal fascia. Each patient was examined pre-operatively and post-operatively with regard to the frequency, duration, and severity of their symptoms to calculate a Migraine Headache Index (MHI) score. All evaluations were performed at least 1 year post-operatively. The mean pre-operative MHI score was 131.7 and the mean post-operative score was 52 (p < 0.0001). There were no surgical complications. There appeared to be no differences between those patients who had decompression and neuroplasty versus those who underwent neurectomy and implantation, as both groups experienced significant reductions in MHI scores following the procedure. The anterior temporal approach to the zygomatico-temporal nerve was both safe and effective. The advantages of this approach included a hidden scar, the ability to directly manipulate the nerve for transection or preservation, and access to the auriculo-temporal nerve through the same incision.
Furthermore, an UpToDate review on “Preventive treatment of migraine in adults” (Smith, 2020) does not mention transection of auriculo-temporal nerves as therapeutic option.Bilateral Temporal Branches of Facial Nerve Block / Supratrochlear Block for the Treatment of Headache/Neuralgia
There is a lack of evidence to support the use of bilateral temporal branches of facial nerve block for the treatment of headache/neuralgia.
Pareja et al (2017) noted that the supratrochlear nerve supplies the medial aspect of the forehead. Due to the intricate relationship between supraorbital and supratrochlear nerves, neuralgic pain in this region has been traditionally attributed to supraorbital neuralgia. No cases of supratrochlear neuralgia have been reported so far. These researchers described clinical features unique to supratrochlear neuralgia. From 2009 through 2016, they prospectively recruited patients with pain confined to the territory of the supratrochlear nerve. A total of 15 patients (13 women, 2 men; mean age of 51.4 years, standard deviation [SD] 14.9) presented with pain in the lower paramedian forehead, extending to the eyebrow in 2 patients and to the internal angle of the orbit in another. Pain was unilateral in 11 patients (6 on the right, 5 on the left), and bilateral in 4; 6 patients had continuous pain and 9 described intermittent pain. Palpation of the supratrochlear nerve at the medial 3rd of the supraorbital rim resulted in hypersensitivity in all cases. All but 1 patient exhibited sensory disturbances within the painful area; 14 patients underwent anesthetic blockades of the supratrochlear nerve, with immediate relief in all cases and long-term remission in 3; 6 of them had received unsuccessful anesthetic blocks of the supraorbital nerve; 5 patients were treated successfully with oral drugs and 1 patient was treated with radiofrequency. The authors concluded that supratrochlear neuralgia is an uncommon disorder causing pain in the medial region of the forehead. It may be differentiated from supraorbital neuralgia and other similar headaches and neuralgias based on the topography of the pain and the response to anesthetic blockade.
Currently, there is insufficient evidence to support the use of supratrochlear block for the treatment of headache/neuralgia.
Cervical Erector Spinae Plane (ESP) Block / Rhomboid Tendon Injections for the Treatment of Tension/Migraine Headaches
Hernandez et al (2020) stated that intractable headaches can be debilitating, often leading to significant distress, prolonged medical treatment, and unanticipated hospital admissions. There have been significant advances in the treatment of primary intractable headaches such as migraines, tension headaches, and cluster headaches beyond medical management. Treatments may now include interventional strategies such as trigger-point injections, peripheral nerve stimulators, or peripheral nerve and ganglion blocks. There are few studies, however, describing the use of interventional techniques for the management of intractable secondary headaches, including those attributed to injury or infection. A new regional anesthetic technique, the erector spinae plane (ESP) block, was initially used for neuropathic thoracic pain. ESP block has since been reported to provide acute and chronic pain relief of the shoulder, spine, abdomen, pelvis, thorax, and lower extremity. Additionally, there has been 1 case report to describe the use of the ESP block in the treatment of refractory tension headache. These investigators reported 4 cases of effective analgesia for intractable secondary headache resistant to medical management with high thoracic ESP blocks. In each case, the ESP block provided instant pain relief. The authors suggested that the findings of this case-series study indicated that the ESP block may be a useful intervention in patients with severe secondary headache or posterior cervical pain where conventional therapies have limited success, although more studies are needed.
Also, UpToDate reviews on “Tension-type headache in adults: Acute treatment” (Taylor, 2021a), and “Tension-type headache in adults: Preventive treatment” (Taylor, 2021b) do not mention cervical erector spinae plane (ESP) block and rhomboid tendon injections as a management / therapeutic options.
Furthermore, UpToDate reviews on “Acute treatment of migraine in adults” (Smith, 2021a), and “Preventive treatment of migraine in adults” (Smith, 2021b) do not mention cervical erector spinae plane (ESP) block and rhomboid tendon injections as a management / therapeutic options.
Ligation of the Supraorbital and Supratrochlear Arteries for the Treatment of Migraines
An UpToDate review on “Chronic migraine” (Garza and Schwedt, 2021) does not mention ligation of the supraorbital or supratrochlear artery as a management / therapeutic option.
Superior Turbinate Resection for the Treatment of Rhinogenic Contact Point Headache
Abu-Samra et al (2011) noted that the nasal contact point may act as a trigger point or peripheral enhancer in patients with chronic daily headaches. A total of 42 patients had unsatisfactory response to medical treatment for chronic daily headache with radiologic evidence of nasal contact point. Of them, 12 (28.5 %) patients were positive for the local anesthetic test. Those patients were operated upon to separate this contact by either septoplasties or submucous resections with or without partial turbinectomies. The mean headache frequency was reduced from 22 to 7 days/month. The mean headache severity was reduced from 5.6 to 2.4; 8 (19 %) patients became completely free from headache and its medications, 6 (75 %) of them were positive for local anesthetic test. The patients were satisfied with post-operative monotherapy, or headache severity and frequency could be tolerated without medications in 26 (62 %) patients. There was no improvement in 7 (16.6 %) patients and only 1 patient (2 %) became worse. The overall satisfaction was 83 % and 81 % for positive and negative anesthetic tests, respectively. The average monthly medication cost was reduced from $85 to $32. The authors concluded that nasal contact point surgery could improve the outcome for drug therapeutic effect in unresponsive chronic daily headache patients to such medications with reduction of its dose and cost. They noted that nasal contact point may act as a trigger or as a precipitating factor for chronic daily headache. Moreover, these researchers stated that the main drawback of this trial was no control group could be initiated for comparing the results, as all patients were chosen from those with medical refractoriness to their headache.
Patel et al (2013) noted that patients present to physicians across multiple disciplines with the complaint of sinus headache. This lay term is widely accepted in the media, yet has been repeatedly questioned in the medical literature, and experts in the fields of otolaryngology, neurology, and allergy have agreed that it is an over-used and often incorrect diagnosis in the majority of patients. There have been review articles and consensus panels established regarding this issue; however, thus far no guidelines based purely on a review of the level of evidence provided by the literature. These investigators carried out a systematic review of the literature and the Clinical Practice Guideline Manual, Conference on Guideline Standardization (COGS), and the Appraisal of Guidelines and Research Evaluation (AGREE) instrument recommendations were followed. Study inclusion criteria included adult population greater than 18 years of age, self-diagnosed or physician-diagnosed "sinus headache", clearly defined diagnostic criteria in diagnostic studies, and clearly defined primary clinical endpoint in therapeutic studies. They identified and examined the literature on diagnosing and treating patients with a primary complaint of sinus headache. The literature was reviewed for both quality of research design as well as benefit and harm of the proposed interventions. The authors concluded that if a thorough neurologic and otolaryngologic evaluation was performed, the majority of patients presenting with sinus headache in the absence of significant acute inflammatory findings will be diagnosed with migraine. In this situation, the appropriate treatment for the majority of patients presenting with sinus headache is migraine-directed therapy. In a highly select group of patients, directed nasal surgery addressing endonasal contact points may be an option.
Peric et al (2016) noted that even in the absence of inflammatory disease, facial pain often results from pressure of 2 opposing nasal mucosa surfaces. These researchers examined the effectiveness of surgical treatment of contact point headache (CPH). This trial enrolled patients with unilateral facial pain and without nasal/paranasal sinus disease. These investigators confirmed the presence of mucosal contact by nasal endoscopy and by computed tomography (CT). A total of 42 participants with the 3 most common anatomical variations underwent complete evaluation: 17 with concha bullosa (CB), 11 with septal deviation (SD), and 14 with septal spur (SS). All participants were treated by topical corticosteroid, adreno-mimetic, and antihistamine. Subjects without improvement were treated surgically. These researchers examined the severity of pain using a VAS before surgical treatment and 1, 6, 12, and 24 months after. The patients with SS had more severe facial pain in comparison with patients with CB (p = 0.049) and SD (p = 0.000). Subjects with CB had higher degree of facial pain than the ones with SD (p = 0.001). After an unsuccessful medical treatment and surgical removal of mucosal contacts, the decrease of headache severity was more intense in patients with CB and SS (p = 0.000) than in the patients with SD (p = 0.01). The authors concluded that these findings suggested that topical medications had no effects; and that surgical removal of mucosal contacts could be effective in the treatment of CPH. The results of surgical treatment were better in cases of facial pain caused by SS and CB, than in those caused by SD.
La Mantia et al (2018) stated that RCPH is a headache syndrome secondary to mucosal contact points in the sino-nasal cavities, in the absence of inflammatory signs, hyperplastic mucosa, purulent discharge, sino-nasal polyps, or masses. It may result from pressure on the nasal mucosa due to anatomic variations among which the septal deviation, septal spur, and concha bullosa, are the most commonly observed. In recent years, RCPH has remained a subject of controversy regarding both its pathogenesis and treatment. These investigators examined the effect of surgical and medical treatment of pain relief in patients with RCPH, evaluating the intensity, duration, and frequency of headaches, and the impact of different treatments on QOL. A total of 94 patients with headache, no symptoms or signs of acute and chronic sino-nasal inflammation and who presented with intra-nasal mucosal contact points positive to the lidocaine test were randomized into 2 equal groups and given medical or surgical treatment. These investigators employed VAS, number of hours, and days with pain to characterize the headache and MIDAS to evaluate the migraine disability score before and 3 to 6 months after treatment. After treatment the severity, duration, and frequency of the headache decreased significantly (p < 0.001, p < 0.001, and p = 0.031, respectively) as well as the MIDAS in the surgical group compared with medical group. The authors concluded that the findings of this study suggested that surgical removal of mucosal contact points was more effective than local medical treatment in improving the therapeutic outcomes in patients with contact point headache. Moreover, these researchers noted that the short-term follow-up in this study could have led to a positive bias response secondary to cognitive dissonance; thus, a longer follow-up is needed to lessen the effects of cognitive dissonance and quantify post-operative benefit. They stated that the literature regarding RCPH surgical interventions is rather contradictory. Moreover, they stated that these data demonstrated both much better results from surgical therapy for contact point headache in comparison with local medical treatment modalities and emphasized the importance to push for a more scientific basis for the study of headache surgery to improve the therapeutic results both short-term and long-term periods.
Smith et al (2019) stated that although some causes of rhinogenic headache, such as acute sinusitis, have clear diagnostic criteria, others, such as "sinus headache" and mucosal contact points, are more nebulous. Misdiagnosis of these entities and primary headaches may result in unnecessary medical or surgical treatment. In a systematic review, these investigators examined the current understanding of diagnosis and treatment of rhinogenic headaches, including sinus and mucosal contact point headaches, in children. PubMed, SCOPUS, and the Cochrane databases were searched for studies on sinus headache and mucosal contact point headaches in children. Studies were evaluated for level of evidence, and risk of bias was examined by Methodological Index for Non-Randomized Studies (MINORS) scoring. Diagnostic criteria, management strategies, and other clinical data were analyzed. A total of 8 studies met the inclusion criteria; level of evidence was predominantly IV; 40 % of pediatric patients with migraine had been previously misdiagnosed with sinus headache. Of 327 pediatric patients in 2 studies, between 55 % and 73 % had at least 1 cranial autonomic symptom associated with their migraine. For children with mucosal contact point headaches, surgical management in select patients improved headache intensity or severity in 17 (89 %) cases. The authors concluded that the majority of pediatric patients with sinus headache harbored a primary headache disorder, with migraine being most common. Physicians should suspect primary headache disorders in pediatric patients with chronic headaches and a normal examination. Although some case series were supportive of surgical management for mucosal CPHs in children, the level of evidence supporting these recommendations is insufficient. These researchers stated that high-quality clinical trials are needed for continuing to improve outcomes in patients with these clinical entities.
Barinsky et al (2020) examined the current understanding of rhinogenic headache in the pediatric population. These investigators reported that 1 study showed that 40 % of pediatric patients with migraine had previously received an incorrect diagnosis of sinus headache; 2 studies found that over 50 % of pediatric patients with migraines have associated cranial autonomic symptoms, possibly elucidating the reasons for misdiagnosis. Some case reports showed successful treatment of rhinogenic CPH (RCPH) with the surgical resection of mucosal contact points, although this diagnosis continues to be debated. Many pediatric patients diagnosed with a sinus-related headache actually meet criteria for primary headache disorders. Primary headache disorders should be considered in pediatric patients with headache and associated rhinologic symptoms. The authors concluded that some literature suggested that mucosal CPHs could be surgically treated in children; however, the level of evidence was inadequate, and additional robust trials are needed.
In a meta-analysis, Maniaci et al (2021) examined endoscopic surgery's role in the treatment of RCPH. These researchers carried out a comprehensive review of the last 20 years' English language regarding RCPH and endoscopic surgery. They included the analysis papers reporting post-operative outcomes through the VAS or the Migraine Disability Assessment scale. These investigators provided 18 articles for a total of 978 RCPH patients. While 777 (81.1 %) subjects underwent functional nasal surgery for RCPH, 201 patients (20.9 %) were medically treated. A significant decrease from the VAS score of 7.3 ± 1.5 to 2.7 ± 1.8 was recorded (p < 0.0001). At quantitative analysis on 660 patients (11 papers), surgical treatment demonstrated significantly better post-operative scores than medical (p < 0.0001). The authors concluded that at comparison, surgical treatment in patients with RCPH exhibited significantly better values at short-term, medium-term, and long-term follow up. Endoscopic surgery should be proposed as the choice method in approaching the symptomatic patient. Moreover, these researchers stated that to identify the optimal treatment features of RCPH and in particular among the subgroups those most likely to surgical or medical treatment, future studies should describe in a precise and detailed manner the initial symptomatologic characteristics of the medical or surgical intervention. With these premises, it will be possible to directly compare the specific treatment outcomes in the short-medium and the long-term already in the study design.
The authors stated that this meta-analysis, subdividing patients according to average follow-up, confirmed that surgical therapy could lead to optimal results both in the short-medium and long-term, with no statistical differences between subgroups (p = 0.28). However, almost all studies included not differing RCPH modalities of interventions and the specific anatomical structures responsible, not allowing to distinguish the corresponding results at follow-up through the sub-analysis. Even in the studies in which long-term follow-up and promising outcomes were reported in both medical and mostly surgical treatment, it was not possible to identify the anatomical structures with the most favorable response to medical or surgical treatment or both. The systematic literature review found that the comparison between the MIDAS score in patients undergoing surgery led to substantial improvements in the post-operative group. In particular, patients presented an overall Grade 3 to 4 switched from 73 % to 5 % while a full resolution was registered in 19 % of cases (p < 0.001 in all grades). Several studies analyzed did not have a prospective study protocol nor adequate randomization. In addition, the initial diagnostic classification was not performed routinely in all the studies to obtain a diagnostic confirmation of the rhinogenic headache and achieve an evaluable parameter at the post-treatment follow-up.
Li et al (2022) stated that most research on mucosal contact headache has focused on mucosal contact between the nasal septum and middle or inferior turbinate; however, rarely have any studies examined how headache is related to the only 1 contact point between superior turbinate and nasal septum. These researchers examined how headache is related to the only 1 contact point between superior turbinate and nasal septum. A total of 80 patients with headache were selected. The mucosal contact between superior turbinate and nasal septum was removed to study the relationship between the contact point and headache, with a follow-up of 12 months. Headache symptoms in 56 cases disappeared entirely. Significant relief was observed in 20 patients, and unsatisfactory results in only 4 patients, with the success rate being 95 %. The authors concluded that some patients with headaches who had intra-nasal mucosal contact areas benefitted from the surgery. Satisfactory results were achieved by endo-nasal surgery in 95 % of the patients in whom intra-nasal contact points were believed to be the cause of their headaches who had a mucosal contact point between the superior turbinate and the septum. These preliminary findings need to be validated by well-designed studies.
Vagus Nerve Stimulation
In an open-label, single-arm, pilot study, Goadsby et al (2014) evaluated a novel, non-invasive, portable vagal nerve stimulator (nVNS) for acute treatment of migraine. Participants with migraine (with or without aura) were eligible for this study. Up to 4 migraine attacks were treated with two 90-second doses, at 15-minute intervals delivered to the right cervical branch of the vagus nerve within a 6-week time period. Subjects were asked to self-treat at moderate or severe pain, or after 20 minutes of mild pain. Of 30 enrolled patients (25 females, 5 males, median age of 39 years), 2 treated no attacks, and 1 treated aura only, leaving a full analysis set of 27 treating 80 attacks with pain. An adverse event was reported in 13 patients, notably: neck twitching (n = 1), raspy voice (n = 1) and redness at the device site (n = 1). No un-anticipated, serious or severe adverse events were reported. The pain-free rate at 2 hours was 4 of 19 (21 %) for the first treated attack with a moderate or severe headache at baseline. For all moderate or severe attacks at baseline, the pain-free rate was 12/54 (22 %). The authors concluded that nVNS may be an effective and well-tolerated acute treatment for migraine in certain patients. These preliminary findings need to be validated by well-designed studies.
Nesbitt et al (2015) reported their initial experience with a novel device, designed to provide portable, non-invasive, transcutaneous stimulation of the vagus nerve, both acutely and preventively, as a treatment for cluster headache. Patients with cluster headache (11 chronic, 8 episodic), from 2 centers, including 7 who were refractory to drug treatment, had sufficient data available for analysis in this open-label observational cohort study. The device, known as the gammaCore, was used acutely to treat individual attacks as well as to provide prevention. Patient-estimated efficacy data were collected by systematic inquiry during follow-up appointments up to a period of 52 weeks of continuous use. A total of 15 patients reported an overall improvement in their condition, with 4 reporting no change, providing a mean overall estimated improvement of 48 %. Of all attacks treated, 47 % were aborted within an average of 11 ± 1 minutes of commencing stimulation; 10 patients reduced their acute use of high-flow oxygen by 55 % with 9 reducing use of triptan by 48 %. Prophylactic use of the device resulted in a substantial reduction in estimated mean attack frequency from 4.5/24 hours to 2.6/24 hours (p < 0.0005) post-treatment. The authors concluded that these data suggested that non-invasive vagus nerve stimulation may be practical and effective as an acute and preventive treatment in chronic cluster headaches. They stated that further evaluation of this treatment using randomized sham-controlled trials is thus warranted. This study provided Class IV evidence that for patients with cluster headache, transcutaneous stimulation of the vagus nerve aborts acute attacks and reduces the frequency of attacks.
In a prospective, open-label, observational study, Knife et al (2015) examined the use of cervical non-invasive vagus nerve stimulation (nVNS) for the acute treatment and prevention of migraine attacks in treatment-refractory episodic and chronic migraine (EM and CM) and examined the impact of nVNS on migraine-associated sleep disturbance, disability, and depressive symptoms. A total of 20 patients with treatment-refractory migraine were enrolled in this 3-month trial. Patients administered nVNS prophylactically twice-daily at pre-specified times and acutely as adjunctive therapy for migraine attacks. Pain intensity (visual analogue scale [VAS]); number of headache days per month and number of migraine attacks per month; number of acutely treated attacks and time to achieve pain relief; sleep quality (Pittsburgh Sleep Quality Index [PSQI]); migraine disability assessment (MIDAS); depressive symptoms (Beck Depression Inventory [BDI]); and adverse events (AEs) were evaluated. Of the 20 enrolled patients, 10 patients each had been diagnosed with EM and CM. Prophylaxis with nVNS was associated with significant overall reductions in patient-perceived pain intensity (mean VAS scores at baseline versus 3 months: 7.75 ± 0.64 versus 4.05 ± 0.76; 95 % confidence interval [CI]: 3.3 to 4.1; p < 0.0001), mean number of headache days per month (baseline versus 3 months: 14.7 ± 4.1 versus 8.9 ± 3.66; 95 % CI: 3.3 to 8.3; p < 0.0001), and mean number of migraine attacks per month (baseline versus 3 months: 7.3 ± 3.85 versus 4.45 ± 2.48; 95 % CI: 0.8 to 4.9; p < 0.01). For acutely treated migraine attacks, a reduction in mean time (mins) to achieve pain relief (baseline versus 3 months: 84.5 ± 39.1 versus 52.75 ± 16.42; 95 % CI: 12.6 to 51.0; p < 0.002) was noted. Significant improvements, more evident in patients with EM, were noted in MIDAS and BDI scores along with a trend toward improvement in PSQI daytime dysfunction sub-score (p = 0.07). No severe or serious AEs occurred. The authors concluded that in this study, treatment with nVNS was safe and provided clinically meaningful decreases in the frequency, intensity, and duration of migraine attacks in patients with treatment-refractory migraine; and improvements in migraine-associated disability, depression, and sleep quality were also noted. Moreover, these researchers stated that the role of nVNS in migraine therapy is being further examined in ongoing large-scale, randomized, sham-controlled trials with long-term follow-up.
The authors stated that the drawbacks of this study included its open-label design, lack of control arm and prospective run-in period, self-recollected reporting of acute pain relief and pain freedom findings, and its small patient population (n = 20; 10 in each of the EM and CM groups). The lack of a control arm did not allow for examination of the placebo effect, which has been noted consistently in studies of migraine interventions. The method used for reporting acute pain relief and pain freedom was based on patients’ general impressions and did not involve the use of a validated pain scale.
In a prospective, double-blind, sham-controlled, multi-center, pilot study, Silberstein et al (2016) examined the feasibility, safety, and tolerability of nVNS for the prevention of CM attacks. This trial enrolled adults with CM (greater than or equal to 15 headache days/month) entered the baseline phase (1 month) and were subsequently randomized to nVNS or sham treatment (2 months) before receiving open-label nVNS treatment (6 months). The primary endpoints were safety and tolerability. Efficacy endpoints in the intent-to-treat (ITT) population included change in the number of headache days per 28 days and acute medication use. A total of 59 participants (mean age of 39.2 years; mean headache frequency, 21.5 day/month) were enrolled. During the randomized phase, tolerability was similar for nVNS (n = 30) and sham treatment (n = 29). Most adverse events (AEs) were mild/moderate and transient. Mean changes in the number of headache days were -1.4 (nVNS) and -0.2 (sham) (Δ = 1.2; p = 0.56); 27 subjects completed the open-label phase. For the 15 completers initially assigned to nVNS, the mean change from baseline in headache days after 8 months of treatment was -7.9 (95 % CI: 11.9 to -3.8; p < 0.01). The authors concluded that therapy with nVNS was well-tolerated with no safety issues; persistent prophylactic use may reduce the number of headache days in CM. Moreover, these researchers stated that larger, sham-controlled studies are needed; and a study with a 9-month open-label period is currently planned. This study provided Class II evidence that for patients with CM, nVNS was safe, well-tolerated, and did not significantly change the number of headache days. This pilot study lacked the precision to exclude important safety issues or benefits of nVNS.
The authors stated that the drawbacks of this study included the small sample size (n = 30 I the nVNS group), blinding challenges, and high discontinuation rate. Blinding in device studies is challenging, especially in comparison with drug studies. The sham device was identical to the nVNS device but did not deliver an active signal. A sham device should mimic the functionality and sensation of active treatment without producing treatment effects or device-related AEs. Missing data and high discontinuation rates occurring disproportionately across treatment groups could affect study outcomes. In this study, discontinuation rates were higher in controls than in the nVNS group; however, no discontinuations stemmed from device-related AEs.
In a randomized, double-blind, sham-controlled study, Silberstein and colleagues (2016) evaluated nVNS as an acute CH treatment. A total of 150 subjects were enrolled and randomized (1:1) to receive nVNS or sham treatment for less than or equal to 1 month during a double-blind phase; completers could enter a 3-month nVNS open-label phase. The primary end-point was response rate, defined as the proportion of subjects who achieved pain relief (pain intensity of 0 or 1) at 15 minutes after treatment initiation for the first CH attack without rescue medication use through 60 minutes; secondary end-points included the sustained response rate (15 to 60 minutes). Sub-analyses of episodic cluster headache (eCH) and chronic cluster headache (cCH) cohorts were pre-specified. The intent-to-treat population comprised 133 subjects: 60 nVNS-treated (eCH, n = 38; cCH, n = 22) and 73 sham-treated (eCH, n = 47; cCH, n = 26). A response was achieved in 26.7 % of nVNS-treated subjects and 15.1 % of sham-treated subjects (p = 0.1). Response rates were significantly higher with nVNS than with sham for the eCH cohort (nVNS, 34.2 %; sham, 10.6 %; p = 0.008) but not the cCH cohort (nVNS, 13.6 %; sham, 23.1 %; p = 0.48). Sustained response rates were significantly higher with nVNS for the eCH cohort (p = 0.008) and total population (p = 0.04). Adverse device effects (ADEs) were reported by 35/150 (nVNS, 11; sham, 24) subjects in the double-blind phase and 18/128 subjects in the open-label phase. No serious ADEs occurred. The authors concluded that in one of the largest randomized sham-controlled studies for acute CH treatment, the response rate was not significantly different (versus sham) for the total population; nVNS provided significant, clinically meaningful, rapid, and sustained benefits for eCH but not for cCH, which affected results in the total population. They stated that this safe and well-tolerated treatment represents a novel and promising option for eCH.
The authors noted that the drawbacks of this study included the analysis of the cCH cohort as part of the primary end-point, the need for careful interpretation of sub-analyses results, challenges with blinding inherent in medical device studies, and the time to first measurement of response used to define the primary efficacy end-point. Primary end-point results were significant for the eCH cohort but were diminished overall by the cCH cohort results. When sub-analyses results were interpreted, the lack of statistical powering and the potential for type 1 and type 2 errors (in the eCH and cCH cohorts, respectively) should be considered. The difference in AE descriptions provided by subjects treated with the nVNS (e.g., drooping/pulling of the lip/face) and sham (e.g., burning, soreness, stinging) devices may help to explain results of the blinding analyses, which were similar to those observed in previous sham‐controlled trials. The burning sensation and other pain‐related AEs reported by the sham‐treated group in ACT1 may have led to a placebo effect based on impressions that the subjects were receiving active treatment. Sham device-associated pain may have also produced a diffuse noxious inhibitory control (DNIC) effect, a phenomenon in which the application of a noxious electrical stimulus to remote body regions inhibits dorsal horn activity and attenuates the original pain. Potential placebo and DNIC effects in the sham group may have reduced the magnitude of the therapeutic benefit associated with nVNS treatment. Another drawback was that the time-point used to define the ACT1 primary end-point was 15 minutes after treatment initiation, which has been used in other CH studies, rather than after treatment completion. In ACT1, this 15‐minute interval comprised an 8‐minute nVNS stimulation period followed by only a 7‐minute period that appeared to be sufficient for significant treatment effects to become evident in the eCH cohort but not in the cCH cohort or total population. The 15‐minute assessment time-point may have also contributed to the non-significant difference in average pain intensities between the nVNS and sham groups; other potential contributing factors include the combined statistical influence of the responders and non-responders as well as the assessment after all attacks (rather than after the first attack). Thus, methodological implications in ACT1 regarding distinct effects among the eCH and cCH cohorts, the painful sham stimulation, and the use of a longer time-point to first measurement of response such as 30 minutes, as used in CH studies of other therapies, should be considered for future RCTs.
In a prospective, open-label, randomized study, Gaul and associates (2016) compared adjunctive prophylactic nVNS (n = 48) with standard of care (SoC) alone (control; n = 49) for the acute treatment of cCH. A 2-week baseline phase was followed by a 4-week randomized phase (SoC plus nVNS versus control) and a 4-week extension phase (SoC plus nVNS). The primary end-point was the reduction in the mean number of CH attacks per week. Response rate, abortive medication use and safety/tolerability were also assessed. During the randomized phase, individuals in the intent-to-treat population treated with SoC plus nVNS (n = 45) had a significantly greater reduction in the number of attacks per week versus controls (n = 48) (-5.9 versus -2.1, respectively) for a mean therapeutic gain of 3.9 fewer attacks per week (95 % CI: 0.5 to 7.2; p = 0.02). Higher (greater than or equal to 50 %) response rates were also observed with SoC plus nVNS (40 % (18/45)) versus controls (8.3 % (4/48); p < 0.001). No serious treatment-related adverse events occurred. The authors concluded that adjunctive prophylactic nVNS is a well-tolerated novel treatment for chronic CH, offering clinical benefits beyond those with SoC.
The authors stated that study limitations included the lack of a placebo/sham device, an open-label study design, the short treatment duration and the use of patient-reported outcomes. No placebo arm was incorporated into the study because a suitable placebo/sham device had not yet been designed. Instead of a placebo/sham arm, SoC was deemed the most appropriate control treatment that was reflective of a real-world clinical scenario. The open-label study design and short treatment duration may have contributed to a placebo effect in both treatment groups. The 16.7 % response rate in the control group during the extension phase may partially reflect a placebo response to nVNS. The initial response experienced in the control group during the randomized phase may have also impacted the capacity for a meaningful response to nVNS during the extension phase. Furthermore, fewer individuals in the control arm (50 %) than in the nVNS arm (64.4 %) were highly adherent (greater than or equal to 80 %) to prophylactic nVNS, which may have further confounded response rates and reductions in abortive medication use in this group. Only patients with chronic, treatment-refractory CH were included because of their stable CH attack frequency and intensity. A 2.5-month study duration was deemed sufficient to observe a treatment effect. Treatment response in favor of nVNS was consistent across intent-to-treat (ITT), modified ITT (mITT) and per-protocol populations (per-protocol population was defined as participants in the mITT population who had greater than or equal to 12 days of observation in the randomized phase and no major protocol violation). Because no CH-specific QoL instruments exist, the EQ-5D-3L and Headache Impact Test-6 (HIT-6) measures were considered most appropriate, and nVNS prophylaxis resulted in meaningful improvements for both measures. The apparent lack of effect of acute nVNS therapy on CH duration or severity was consistent with findings in the chronic CH population that were reported in a recent study of acute nVNS therapy for CH. The nVNS adherence rates in this study (50 to 64 %) were consistent with those reported for prophylactic non-invasive neuromodulation in migraine and were considered meaningful given that twice-daily nVNS requires more effort and participation than a conventional oral medication regimen.
Morris et al (2016) stated that cluster headache (CH) is a debilitating condition that is generally associated with substantial health care costs. Few therapies are approved for abortive or prophylactic treatment. Results from the prospective, randomized, open-label PREVA study suggested that adjunctive treatment with a novel non-invasive vagus nerve stimulation (nVNS) device led to decreased attack frequency and abortive medication use in patients with chronic CH (cCH). These researchers examined if nVNS is cost-effective compared with the current standard of care (SoC) for cCH. They developed a pharmacoeconomic model from the German statutory health insurance perspective to estimate the 1-year cost-effectiveness of nVNS + SoC (versus SoC alone) using data from PREVA. Short-term treatment response data were taken from the clinical trial; longer-term response was modelled under scenarios of response maintenance, constant rate of response loss, and diminishing rate of response loss. Health-related quality of life (HR-QOL) was estimated by modelling EQ-5D data from PREVA; benefits were defined as quality-adjusted life-years (QALY). Abortive medication use data from PREVA, along with costs for the nVNS device and abortive therapies (i.e., intra-nasal zolmitriptan, subcutaneous sumatriptan, and inhaled oxygen), were used to assess health care costs in the German setting. The analysis resulted in mean expected yearly costs of €7,096.69 for nVNS + SoC and €7,511.35 for SoC alone and mean QALY of 0.607 for nVNS + SoC and 0.522 for SoC alone, suggesting that nVNS generated greater health benefits for lower overall cost. Abortive medication costs were 23 % lower with nVNS + SoC than with SoC alone. In the alternative scenarios (i.e., constant rate of response loss and diminishing rate of response loss), nVNS + SoC was more effective and cost-saving than SoC alone. The authors concluded that in all scenarios modelled from a German perspective, nVNS was cost-effective compared with current SoC, which suggested that adjunctive nVNS therapy provided economic benefits in the treatment of cCH. Notably, the current analysis included only costs associated with abortive treatments. Treatment with nVNS will likely promote further economic benefit when other potential sources of cost savings (e.g., reduced frequency of clinic visits) are considered.
The authors stated that this analysis was subject to certain limitations. The PREVA study provided data from an 8-week period, which were extrapolated to assess cost-effectiveness over 1 year. Although there have been few cost-effectiveness evaluations of neuro-modulatory techniques for the treatment of primary headache disorders, such studies have generally included time horizons of at least 3 years. Considering the timeframe of PREVA, a 1-year time horizon was chosen for this analysis to preserve robustness and to avoid introducing unnecessary uncertainty. As in patients with epilepsy, evidence suggests that patients with headache may have improved response to VNS with longer-term treatment. Although increases in response rate with long-term VNS have yet to be explored in CH, the current analysis could be viewed as conservative because the duration of PREVA may not have allowed demonstration of the full benefit of nVNS. As with any probabilistic analysis, some degree of uncertainty is inherent in the current investigation. To address this, a sensitivity analysis and a range of alternative scenarios were included, and results from all of these suggested that nVNS + SoC was more effective and cost-saving than SoC alone. Results were relatively insensitive to assumptions about late responders in the nVNS + SoC arm. In the sensitivity analysis, where the 4 late-responding patients were classified as non-responders, nVNS + SoC was dominant over SoC alone in all modelled scenarios. The current analysis could not be directly extrapolated across all of Europe because it evaluated cost-effectiveness from a German health insurance perspective. To examine the generalizability of these findings, these investigators performed the same analysis from a U.K. perspective and found similar results. For the base case, the probabilistic analysis resulted in mean expected costs of £5,409.83 for nVNS + SoC and £5,393.31 for SoC alone and mean QALY of 0.538 for nVNS + SoC and 0.438 for SoC alone. The incremental cost-effectiveness ratio of nVNS + SoC was £166.12, and 47 % of the probabilistic simulations resulted in cost savings for nVNS + SoC over SoC alone. The degree to which these results can be generalized to other countries may vary depending on specific drug prices and the availability of generic medications in those markets.
On April 14, 2017, the FDA approved the gammaCore nVNS for the acute treatment of pain associated with eCH in adult patients.
Yuan and Silberstein (2017) stated that neuromodulation is an emerging area in headache management. Through neurostimulation, multiple brain areas can be modulated to alleviate pain, hence reducing the pharmacological need. These investigators discussed the recent development of the VNS for headache management. Early case series from epilepsy and depression cohorts using invasive VNS showed a serendipitous reduction in headache frequency and/or severity. Non-invasive VNS, which stimulates the carotid vagus nerve with the use of a personal handheld device, also demonstrated efficacy for acute migraine or CH attacks. Long-term use of nVNS appeared to exert a prophylactic effect for both chronic migraine and cCH. In animal studies, nVNS modulated multiple pain pathways and even lessen cortical spreading depression. Progression in nVNS clinical efficacy over time suggests an underlying disease-modifying neuromodulation. The authors concluded that nVNS appears to be as effective as the invasive counterpart for many indications. They noted that with an enormous potential therapeutic gain and a high safety profile, further development and application of nVNS is promising.
Mwamburi and colleagues (2017a) noted that CH is a debilitating disease characterized by excruciatingly painful attacks that affects 0.15 % to 0.4 % of the US population. Episodic cluster headache manifests as circadian and circannual seasonal bouts of attacks, each lasting 15 to 180 minutes, with periods of remission. In cCH, the attacks occur throughout the year with no periods of remission. While existing treatments are effective for some patients, many patients continue to suffer. There are only 2 FDA-approved medications for eCH in the United States, while others, such as high-flow oxygen, are used off-label. Episodic CH is associated with co-morbidities and affects work, productivity, and daily functioning. The economic burden of eCH is considerable, costing more than twice that of non-headache patients. These researchers stated that gammaCore adjunct to SoC was found to have superior efficacy in treatment of acute eCH compared with sham-gammaCore used with SoC in ACT1 and ACT2 trials. However, the economic impact has not been characterized for this indication. These investigators conducted a cost-effectiveness analysis of gammaCore adjunct to SoC compared with SoC alone for the treatment of acute pain associated with eCH attacks. The model structure was based on treatment of acute attacks with 3 outcomes: failures, non-responders, and responders. The time horizon of the model is 1 year using a payer perspective with uncertainty incorporated. Parameter inputs were derived from primary data from the RCTs for gammaCore. The mean annual costs associated with the gammaCore-plus-SoC arm was $9,510, and mean costs for the SoC-alone arm was $10,040. The mean quality-adjusted life years for gammaCore-plus-SoC arm were 0.83, and for the SoC-alone arm, they were 0.74. The gammaCore-plus-SoC arm was dominant over SoC alone. All 1-way and multi-way sensitivity analyses were cost-effective using a threshold of $20,000. The authors concluded that gammaCore dominance, representing savings, was driven by superior efficacy, improvement in QOL, and reduction in costs associated with successful and consistent abortion of episodic attacks. They stated that these findings serve as additional economic evidence to support coverage for gammaCore. Moreover, they stated that additional real-world data are needed to characterize the long-term impact of gammaCore on co-morbidities, utilization, QOL, daily functioning, productivity, and social engagement of these patients, and for other indications.
Mwamburi and colleagues (2017b) stated that the FDA has cleared gammaCore (nVNS) for the treatment of eCH. With the exception of subcutaneous sumatriptan, all other treatments are used off-label and have many limitations. The FDA approval process for devices differs from that of drugs. These researchers performed a review of the literature to evaluate new evidence on various aspects of gammaCore treatment and impact. The ACute Treatment of Cluster Headache Studies (ACT1 and ACT2), both double-blind sham-controlled randomized trials, did not meet the primary end-points of the trials; but each demonstrated significant superiority of gammaCore among patients with eCH. In ACT1, gammaCore resulted in a higher response rate (RR) (RR, 3.2; 95 % CI: 1.6 to 8.2; p = 0.014), higher pain-free rate for greater than 50 % of attacks (RR, 2.3; 95 % CI: 1.1 to 5.2; p = 0.045), and shorter duration of attacks (MD, -30 minutes; p < 0.01) compared with the sham group. In ACT2, gammaCore resulted in higher odds of achieving pain-free attacks in 15 minutes (OR, 9.8; 95 % CI: 2.2 to 44.1; p = 0.01), lower pain intensity in 15 minutes (MD, -1.1; p < 0.01), and higher rate of achieving responder status at 15 minutes for greater than or equal to 50 % of treated attacks (RR, 2.8; 95 % CI: 1.0 to 8.1; p = 0.058) compared with the sham group. The PREVention and Acute Treatment of Chronic Cluster Headache (PREVA) study also demonstrated that gammaCore plus SoC was superior to SoC alone in patients with cCH. Medical costs, pharmacy refills, and pharmacy costs were higher in patients coded for CH in claims data compared with controls with non-headache codes. These researchers stated that gammaCore is easy to use, practical, and safe; delivery cannot be wasted; and patients prefer using gammaCore compared with SoC. The treatment improved symptoms and reduces the need for CH rescue medications. They stated that current US reimbursement policies, which predated nVNS and are based on expensive, surgically implanted, and permanent implanted vagus nerve stimulation (iVNS), need to be modified to distinguish nVNS from iVNS. The authors concluded that there is sufficient evidence to support the need to modify current reimbursement policies to include coverage for gammaCore (nVNS) for eCH. Moreover, they stated that 1 drawback was that the information available from publications that contribute to a review was as reported. This review, however, added new information to the body of evidence, particularly in comparison with previous reviews. While authors of previous reviews had identified gammaCore as a beneficial intervention for patients with CH, they also pointed to a gap and a need for clinical trials to provide further evidence on its safety and effectiveness. They stated that the recommended future path is to collect real-world data that are specific to patients suffering from eCH and CH with regard to use or non-use of gammaCore via a registry to monitor usage and performance measurement. Additionally, stakeholders should periodically review data from claims databases to evaluate long-term outcomes related to symptoms, utilization, cost, and reimbursement burden and the impact on co-morbidities and all-cause healthcare utilization, to better understand the value associated with gammaCore use beyond symptom relief. Also needed are continued research efforts, using RCTs, to characterize the benefits of gammaCore in other indications, including migraine, specific inflammatory illnesses, cardiac diseases, and psychiatric disorders.
Simon and Blake (2017) noted that stimulation of the cervical vagus nerve with iVNS has been used clinically for more than 20 years to treat patients with epilepsy. More recently, gammaCore, a nVNS, was developed, which has been purported to also stimulate the vagus nerve without the cost and morbidity associated with an iVNS system. gammaCore has been used to acutely treat various types of primary headaches, including migraine and CH, and for the prevention of episodic, chronic, and menstrual migraines and CH. The gammaCore device was cleared by the FDA for the acute treatment of pain in eCH patients. These investigators summarized the clinical work that has been published in the use of gammaCore for treating primary headache disorders, presented an overview of studies demonstrating that nVNS does indeed stimulate similar vagus nerve fibers as the implantable VNS system, and then presented several animal headache-related studies that address the mechanism of action (MOA) of nVNS. The authors concluded that preliminary clinical studies in various primary headache disorders are encouraging. Human studies and modeling have demonstrated that nVNS activates vagus nerve fibers similar to those implicated in the clinical benefits of iVNS. They stated that continuing human and animal research is needed to further elucidate the MOA and to help define optimal signal parameters and treatment paradigms for headache and other disorders.
Gaul and associates (2017) stated that although the PREVA trial did not examine the effects of nVNS in patients with eCH, the rapid beneficial effects on attack frequency observed within 2 weeks of treatment initiation in this cCH analysis, combined with the established safety profile of nVNS, suggested that a trial in eCH would be clinically reasonable.
In a randomized, double-blind, sham-controlled, multi-center trial, Tassorelli et al (2018) examined the safety, efficacy, and tolerability of nVNS (gammaCore) for the acute treatment of migraine. A total of 248 participants with EM with/without aura were randomized to receive nVNS or sham within 20 mins from pain onset. Subjects were to repeat treatment if pain had not improved in 15 mins. nVNS (n = 120) was superior to sham (n = 123) for pain freedom at 30 mins (12.7 % versus 4.2 %; p = 0.012) and 60 mins (21.0 % versus 10.0 %; p = 0.023) but not at 120 mins (30.4 % versus 19.7 %; p = 0.067; primary endpoint; logistic regression) after the 1st treated attack. A post-hoc repeated-measures test provided further insight into the therapeutic benefit of nVNS through 30, 60, and 120 mins (odds ratio [OR] 2.3; 95 % CI: 1.2 to 4.4; p = 0.012). nVNS demonstrated benefits across other endpoints including pain relief at 120 mins and was safe and well-tolerated. The authors concluded that this randomized sham-controlled trial supported the abortive efficacy of nVNS as early as 30 mins and up to 60 mins after an attack. Findings also suggested effective pain relief, tolerability, and practicality of nVNS for the acute treatment of episodic migraine. Moreover, these researchers stated that PRESTO and a forthcoming randomized sham-controlled study of nVNS for the prevention of episodic migraine (ClinicalTrials.gov identifier: NCT02378844) may also help the migraine community by informing future recommendations regarding neuromodulation trials.
The authors stated that the drawbacks of this study included the selection of an appropriate sham device, which is a consistent challenge in neuromodulation studies. The sham device in this study had an active signal that was strong enough to be perceived but was not intended to stimulate the vagus nerve, as recommended in published literature. The apparent strength of the sham signal helped to maintain blinding but could have conceivably elevated the effects of sham treatment across all endpoints, limiting the ability of clinically meaningful active therapeutic gains to achieve statistical superiority. These researchers hypothesized that the higher-than-expected sham results could represent either a psychobiological placebo effect, or a physiologically active response potentially related to an unanticipated low level of vagal or other activity generated by an active sham signal being applied to the neck.
In a randomized, double-blind, sham-controlled study, Goadsby et al (2018) compared non-invasive vagus nerve stimulation (nVNS) with a sham device for acute treatment in patients with episodic or chronic CH (eCH, cCH). After completing a 1-week run-in period, subjects were randomly assigned (1:1) to receive nVNS or sham therapy during a 2-week double-blind period. The primary efficacy endpoint was the proportion of all treated attacks that achieved pain-free status within 15 mins after treatment initiation, without rescue treatment. The Full Analysis Set comprised 48 nVNS-treated (14 eCH, 34 cCH) and 44 sham-treated (13 eCH, 31 cCH) subjects. For the primary endpoint, nVNS (14 %) and sham (12 %) treatments were not significantly different for the total cohort. In the eCH subgroup, nVNS (48 %) was superior to sham (6 %; p < 0.01). No significant differences between nVNS (5 %) and sham (13 %) were observed in the cCH subgroup. Th authors concluded that combing both eCH and cCH patients, nVNS was no different to sham. For the treatment of CH attacks, nVNS was superior to sham therapy in eCH but not in cCH. These results confirmed and extended previous findings regarding the safety, efficacy, and tolerability of nVNS for the acute treatment of eCH.
The authors stated that the potential for unblinding is an inherent concern in the study of any medical device. The issue was addressed in this trail with a sham device that delivered a perceptible tingling sensation without stimulating the vagus nerve. Similar proportions of subjects in each group correctly guessed their treatment assignment, which suggested adequate blinding. Nevertheless, this study had several drawbacks, including its short duration, which did not allow for evaluation of continued/change in response with long-term nVNS therapy. Some evidence suggested that patients who initially respond to nVNS as acute therapy for CH had a stable response with continued treatment. In epilepsy, long-term nVNS therapy has been associated with improved efficacy, which suggested possible disease-modifying effects. Such effects have yet to be substantiated in CH. Another drawback was the imbalance between CH subtypes, with the eCH subgroup comprising less than 30 % of subjects. This imbalance was probably due, in part, to the nature of the study sites (i.e., tertiary care centers) and the recruitment of subjects throughout the year rather than specifically when attack bouts were most common among patients with eCH, such as during seasonal transition periods. The stipulation that subjects’ preventive treatment regimens continue unchanged during the run-in and double-blind periods may have impeded enrollment of individuals with eCH, who may have opted to begin bridging therapies immediately rather than participate in the study. During the open-label period, subjects could alter their CH treatment regimens by adding prophylactic therapies, or changing doses of existing treatments, or both. This stipulation confounded the results, making it impossible to discern whether changes in efficacy outcomes were attributable to nVNS therapy or to other changes in treatment during this period. Furthermore, there was the possible bias of multiple attack treatment that these researchers mitigated using the analytic technique, and with the secondary endpoints of treated attacks on a per subject basis. Moreover, a substantial number of attacks were treated in both arms, making multiple successful attack treatment by individuals an unlikely source of the positive outcome.
Marin et al (2018) noted that evidence supports the use of nVNS (gammaCore) as a promising therapeutic option for patients with CH. These researchers carried out an audit of real-world data from patients with CH (the majority of whom were treatment refractory) to examine early U.K. clinical experience with nVNS used acutely, preventively, or both. They retrospectively analyzed data from 30 patients with CH (29 chronic, 1 episodic) who submitted individual funding requests for nVNS to the National Health Service. All patients had responded to adjunctive nVNS therapy during an evaluation period (typical duration, 3 to 6 months). Data collected from patient interviews, treatment diaries, and physician notes were summarized with descriptive statistics. Paired t-tests were used to examine statistical significance. The mean (SD) CH attack frequency decreased from 26.6 (17.1) attacks/week. before initiation of nVNS therapy to 9.5 (11.0) attacks/week (p < 0.01) afterward. Mean (SD) attack duration decreased from 51.9 (36.7) mins to 29.4 (28.5) mins (p < 0.01); and mean (SD) attack severity (rated on a 10-point scale) decreased from 7.8 (2.3) to 6.0 (2.6) (p < 0.01). Use of abortive treatments also decreased. Favorable changes in the use of preventive medication were also observed. No serious device-related adverse events (AEs) were reported. The authors concluded that significant decreases in attack frequency, severity, and duration were observed in these patients with CH who did not respond to or were intolerant of multiple preventive; and/or acute treatments. These real-world findings complemented evidence from clinical trials demonstrating the safety and effectiveness of nVNS in CH.
The authors stated that drawbacks of this study included its small sample size (n = 30) and inherent inclusion bias. By definition, this was a responder study, and patient responses were not likely representative of the CH population as a whole.
de Coo et l (2019) noted that 2 randomized, double-blind, sham-controlled trials (ACT1, ACT2) examined nVNS as acute treatment for CH. These investigators analyzed pooled ACT1/ACT2 data to increase statistical power and gain insight into the differential efficacy of nVNS in episodic and chronic cluster headache. Data extracted from ACT1 and ACT2 were pooled using a fixed-effects model. Main outcome measures were the primary endpoints of each study. This was the proportion of participants whose first treated attack improved from moderate (2), severe (3), or very severe (4) pain intensity to mild (1) or nil (0) for ACT1 and the proportion of treated attacks whose pain intensity improved from 2 to 4 to 0 for ACT2. The pooled population included 225 participants (episodic: n = 112; chronic: n = 113) from ACT1 (n = 133) and ACT2 (n = 92) in the nVNS (n = 108) and sham (n = 117) groups. Interaction was shown between treatment group and cluster headache subtype (p < 0.05); nVNS was superior to sham in episodic but not chronic cluster headache (both endpoints p < 0.01). Only 4 patients discontinued the studies due to adverse events (AEs). The authors concluded that nVNS was a well-tolerated and effective acute treatment for episodic cluster headache. Moreover, these researchers stated that additional studies are needed to further elucidate the mechanism of action and possibly related reasons for failure in the acute treatment of cCH, including potential studies of the effects of nVNS on parasympathetic output from the trigeminal autonomic reflex for patients with episodic and cCH. This could lead to better understanding of the pathogenesis of CH.
The authors stated that there are a number of possible explanations for why patients with cCH had a poorer response to acute treatment. Inter-paroxysmal pain is considerably more common in chronic than in episodic CH, complicating achievement of pain-free status in the chronic subgroup. The presence of inter-paroxysmal pain was not measured in ACT1 or ACT2, representing a limitation of this pooled analysis. In addition, these investigators stated that long-term safety can be judged only after monitoring repeated use of nVNS over longer periods.
Silberstein et al (2020) conducted a narrative review of recent scientific and clinical research into nVNS for headache, including findings from mechanistic studies and their possible relationships to the clinical effects of nVNS. Findings from animal and human studies have provided possible mechanistic explanations for nVNS efficacy in headache involving four core areas: Autonomic nervous system functions; cortical spreading depression inhibition; neurotransmitter regulation; and nociceptive modulation. These researchers discussed how overlap and interplay among these areas may underlie the use of nVNS in the context of clinical evidence supporting its safety and efficacy as acute and preventive therapy for both cluster headache and migraine. Possible future nVNS applications were also discussed. The authors concluded that significant progress over the past several years has yielded valuable mechanistic and clinical evidence that, combined with the excellent safety and tolerability profile of nVNS, suggested that it should be considered a 1st-line treatment for both acute and preventive treatment of cluster headache, an effective option for acute treatment of migraine, and a highly relevant, practical option for migraine prevention. These researchers noted that all the clinical studies of nVNS reviewed here allowed adjunctive use of preventive medications, acute treatments, or both, but no studies have been conducted to quantify the specific adjunctive benefits of nVNS when combined with individual pharmacologic products. Moreover, they stated that in the absence of head-to-head studies, specific conclusions regarding the comparative efficacy of different treatments cannot be drawn. This article was funded by electroCore, Inc.
Ventral Tegmental Area Deep Brain Stimulation
In an uncontrolled, open-label, prospective clinical trial, Akram and colleagues (2016) presented outcomes in a cohort of medically intractable CCH patients treated with ventral tegmental area deep brain stimulation (VTA-DBS). A total of 21 patients (17 males; mean age of 52 years) with medically refractory CCH were selected for ipsilateral VTA-DBS by a multi-disciplinary team including a headache neurologist and functional neurosurgeon. Patients had also failed or were denied access to ONS within the UK National Health Service. The primary end-point was improvement in the headache frequency. Secondary outcomes included other headache scores (severity, duration, headache load), medication use, disability and affective scores, QOL measures, and AEs. Median follow-up was 18 months (range of 4 to 60). At the final follow-up point, there was 60 % improvement in headache frequency (p = 0.007) and 30 % improvement in headache severity (p = 0.001). The headache load (a composite score encompassing frequency, severity, and duration of attacks) improved by 68 % (p = 0.002). Total monthly triptan intake of the group dropped by 57 % post-treatment. Significant improvement was observed in a number of QOL, disability, and mood scales. Side effects included diplopia, which resolved in 2 patients following stimulation adjustment, and persisted in 1 patient with a history of ipsilateral trochlear nerve palsy. There were no other serious AEs. The authors concluded that the findings of this study supported that VTA-DBS may be a safe and effective therapy for refractory CCH patients who failed conventional treatments. This small, uncontrolled study provided Class IV evidence that VTA-DBS lowered headache frequency, severity, and headache load in patients with medically intractable CCH. These preliminary findings need to be validated by well-designed studies.
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