Neurostimulators for the Treatment of Primary Headaches

Massimo Leone; Alberto Proietti Cecchini; Angelo Franzini; Gennaro Bussone

Future Neurology. 2013;8(4):457-467.

Occipital Nerve Stimulation

Peripheral neurostimulation is less invasive than deep brain stimulation. It has been used for several decades for pain control and its analgesic effects may be due to activation of afferent β-amyloid fibers (gate effect) or activation of descending inhibitory pathways.^[37] Animal studies showing that cervical, somatic and trigeminovascular dural afferents converge on nociceptors in the trigeminocervical complex provide a justification for occipital nerve stimulation in headache.^[38] It had also been found that suboccipital steroid injections can produce effective headache prophylaxis.^[39,40] Weiner and Reed were the first to try occipital nerve stimulation for headache.^[41] Experience of peripheral nerve stimulation for painful mononeuropathies and regional pain syndromes suggested that the technique might be useful for 'occipital neuralgia.' They implanted 13 patients with medically intractable 'occipital neuralgia'. After 1.5–6 years of follow-up, 'greater than 50% pain control' had been achieved in 12 patients, and condition resolution in one.

Occipital nerve stimulation is now extensively used for medically intractable chronic cluster headache (Table 2).^[42–52] One reason for this is probably that the technique is intrinsically safer than hypothalamic stimulation.^[8,20] The success rate is generally reported as similar to that for posterior hypothalamic stimulation; however, selection criteria for the two procedures have differed, with patients selected for occipital nerve stimulation generally having less severe chronic cluster headache than those selected for posterior hypothalamic stimulation. Furthermore, follow-up is less extensive in occipital nerve-stimulated patients. Time-to-improvement varied from days to months. None of the occipital nerve stimulation studies in chronic cluster headache were randomized controlled trials.

The first study on occipital nerve stimulation for medically intractable chronic cluster headache was published by Burns et al. in 2007.^[42] They implanted eight patients, the first on the headache side only, the others bilaterally. At a median follow-up of 20 months (range: 6–27 months for bilateral stimulation), two patients reported a substantial improvement in their attacks and five reported a more moderate improvement. Both frequency and severity were reported to have improved, but both required weeks or months to manifest. The first patient experienced side shift. A Belgian study found headache side shift after unilateral implantation in four of the 15 patients implanted.^[43,52] Most other studies have used bilateral implantation.^[42–52] Mean follow-up was 36.8 months. One patient had immediate postoperative infection. Of the 14 remaining patients, 11 experienced at least a 90% improvement and 60% became pain free for prolonged periods.

The most common adverse events with occipital nerve stimulation are lead displacement and infection. The frequency of lead displacement requiring correction varies markedly, with reported frequencies ranging from 0 to 100%.^[52,53] Battery depletion occurs frequently because high current intensities are needed to stimulate the occipital nerve effectively. Stimulation-induced paresthesia and unpleasant sensations owing to traction on the connecting cables are commonly reported by patients.^[52]

Occipital nerve stimulation is also used to treat chronic migraine.^[54–59] Popeney et al. reported on an uncontrolled consecutive series of 25 patients with intractable transformed migraine permanently implanted with C1 through to C3 peripheral nerve stimulators.^[54] After a mean follow-up of 18 months, mean improvement in Migraine Disability Assessment Score (MIDAS) was 88.7% with 15 patients reporting no or little residual disability (MIDAS grade I). Matharu et al. reported impressive improvement in six chronic migraine patients under occipital nerve stimulation: when the stimulator was off, pain reappeared in few minutes, while when on, the pain disappeared within a few minutes.^[55]

Unfortunately, such impressive efficacy has not been confirmed by subsequent studies. Schwedt et al. performed occipital nerve stimulation (eight bilateral and seven unilateral) in 15 patients with various forms of medically refractory chronic headache and assessed them a mean of 19 months (range: 5–42 months) later.^[53] Four of the eight patients with chronic migraine improved markedly, and the two patients with hemicrania continua also benefitted from occipital nerve stimulation. Burns et al. implanted a Bion microstimulator (Boston Scientific Neuromodulation Corporation, CA, USA) in six patients with hemicrania continua: during a minimum follow-up of 6 months (up to 21 months), four patients had pain reductions of 80–90%, but one reported pain worsening.^[56] In the PRISM multicenter, double-blind, randomized controlled trial, drug refractory migraine with aura, migraine without aura, and chronic migraine patients were recruited.^[57] Of the 140 patients randomized, 132 were implanted and 125 completed the 12-week follow-up. There was no significant difference between the treatment arms for reduction in migraine days per month (primary end point). It was suggested that cohort heterogeneity accounted for lack of overall benefit of stimulation, since patients who had overused medication had less favorable outcomes.

The ONSTIM study was a multicenter, randomized, blinded, controlled-feasibility trial to obtain preliminary safety and efficacy data on occipital nerve stimulation in medically intractable chronic migraine.^[58] Eligible patients received occipital nerve block, and responders were randomized to adjustable stimulation, preset stimulation or medical management. After 3 months, 11 (39%) of those who received adjustable stimulation, 6% of those given preset stimulation, and 0% of those given medical management experienced at least a 50% reduction in headache frequency, or a fall of 3 points on the intensity scale.

In the multicenter double-blind trial by Silberstein et al. 157 chronic migraine patients were implanted with a permanent stimulator system and randomized (2:1) to active occipital nerve stimulation or sham stimulation.^[59] Selection criteria were patients who had tried at least two acute treatments including triptans and ergot and found to be refractory, and at least two different classes of prophylactic medications (e.g., anticonvulsants and β-blockers) and were also found refractory. These criteria are different to those employed to select drug-resistant chronic cluster headache patients for occipital nerve stimulation, and even more different to those required for deep brain stimulation. In fact, in order to be proposed for deep brain neurostimulation, drug-resistant chronic cluster headache patients must be resistant to all known prophylactics, not just two classes of drugs.^[60] After 12 weeks, the active stimulation group was far from attaining the primary end point (at least 50% reduction of headache frequency), and as a consequence sham and active treatments did not differ. Nevertheless, the active stimulation group had a significantly greater reduction in number of headache days and migraine-related disability than the sham group. The following open-label phase lasted for up to 52 weeks, and showed significant and sustained reductions in pain, number of headache days and migraine-related disability.

A study that gathered data from questionnaires before implantation, 1 month after implantation, and on long-term follow-up in 26 (of the 44 implanted) headache patients, also suggested (compare PRISM trial, mentioned above^[57]) that overuse of acute symptomatic treatments was associated with less favorable long-term outcomes in patients receiving occipital nerve stimulation.^[61]

Although none of the occipital nerve stimulation studies in chronic cluster headache were randomized controlled trials, the success rate of occipital nerve stimulation appears to be lower for chronic migraine than for medically intractable chronic cluster headache. Randomized controlled trials on chronic migraine were short-term (maximum 12 weeks) and included patients not shown to be totally drug resistant. By contrast, open studies on chronic cluster headache included patients in poor clinical condition, suffering multiple daily attacks, requiring several daily sumatriptan injections and resistant to all known preventive medications. Furthermore, follow-up in chronic cluster headache patients was often longer than 1 year.^{[42,45,50,52]}

Simultaneous suboccipital and supraorbital stimulation in a series of seven patients with chronic migraine produced an improvement in headache frequency of 90% or more in all patients.^[62] However, no clinically significant response was noted for either stimulation type alone.

The effects of occipital nerve stimulation on intractable SUNCT, short-lasting unilateral neuralgiform headache attacks with autonomic symptoms (SUNA)^[63,64] and primary stabbing headache have been reported.^[63] Results were generally considered to be promising.

With regard to the mechanism of occipital nerve stimulation in headache, reference has already been made to the finding that cervical, somatic, and trigeminovascular afferents converge on nociceptors in the trigeminocervical complex of rats.^[38] It is possible, therefore, that occipital nerve stimulation produces a nonspecific modulatory effect on pain. This hypothesis is supported by a fluorodeoxyglucose-PET study on ten patients with medically refractory chronic cluster headache, which found hypermetabolism in several areas of the pain matrix prior to stimulation, but returned to normal after 3–6 months of stimulation; while the hypermetabolism present in the ipsilateral hypothalamus remained unchanged.^[65]

Although occipital nerve stimulation usually requires weeks or months to become effective, headache attacks usually return shortly after the stimulator has been switched off, becomes displaced or the battery becomes depleted.^[52] These findings indicate that a placebo effect is not at work and that the headache condition has not resolved spontaneously. It has to be said, however, that a placebo effect has not been definitively ruled out.

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Table 1. Summary of results of hypothalamic stimulation studies in drug-resistant chronic cluster headache.
Study (year)	Implanted patients (n)	Mean follow-up (years)	Improved patients (n)^†	Improved (%)	Ref.
Leone et al. (2001, 2006 and 2013)	19	8.7	12	71^‡	[7,9,20]
Schoenen et al. (2005)	4	4	2	50	[8]
Starr et al. (2007)	4	1	2	50	[12]
Owen et al. (2007)	1	0.7	1	100	[13]
Bartsch et al. (2008)	6	1.4	3	50	[16]
Fontaine et al. (2010)	11	1	6	55	[17]
Seijo et al. (2011)	5	2.8	3	60	[19]
Hidding and May (2011)	1	NR	0	0	[18]
D'Andrea et al. (2006)	3	2.5	2	67	[10]
Benabid et al. (2006)	1	1	1	100	[11]
Mateos et al. (2007)	2	1	2	100	[15]
Black et al. (2007)	2	2.6	2	100	[14]
Nikka et al. (2005)^§	2	2	0	0
Total	61	2.4	36	61

^†At least 50% improvement in headache frequency and/or intensity.
^‡Percentage calculated from 17 of out 19 patients: one patient died for reasons other than the neurostimulator and in another patient the electrode was removed owing to infection.
^§[Nikka et al., Pers. Comm.].
NR: Not reported

Table 2. Summary of results of occipital nerve stimulation studies in drug-resistant chronic cluster headache.
Study (year)	Implanted patients (n)	Follow-up (months)	Improved patients (n)^†	Improved (%)	Ref.
Magis et al. (2007 and 2011)	15	36.8	12	80	[43,52]
Burns et al. (2009)	14	17.5	5	36	[44]
Proietti Cecchini et al. (2009)	13	21	8	62	[45]
Lara Lara et al. (2009)	6	6–15	4	67	[46]
de Quintana-Schmidt et al. (2010)	4	6	4	100	[47]
Salom and Lainez (2010)	14	NR	7	50	[48]
Müller et al. (2011)	10	12	9	90	[49]
Fontaine et al. (2011)	13	14.6	10	77	[50]
Strand et al. (2011)	3	12	2	67	[51]
Total	92	17.1	61	66

^†At least 50% improvement in headache frequency or intensity.
NR: Not reported.

Sidebar

Executive Summary

Occipital Nerve Stimulation

Occipital nerve stimulation has achieved good results in drug-resistant chronic cluster headache, but less favorable results are achieved in chronic migraine. Occipital nerve stimulation is widely considered to be the first choice neurostimulation procedure for chronic cluster headache.

Hypothalamic Stimulation

Hypothalamic stimulation is an invasive procedure for drug-resistant chronic cluster headache and other trigeminal autonomic cephalalgias (short-lasting neuralgiform headache attacks with conjunctival injection and tearing, and paroxysmal hemicrania). This technique is tolerable and effective in approximately 60% of treated patients many years after implantation.

Transcranial Magnetic Stimulation

Transcranial magnetic stimulation efficacy has been investigated in migraine, both chronic and episodic, and with and without aura. Results are less favorable than with other neurostimulation procedures.

Transcranial Direct Current Stimulation

Transcranial direct current stimulation seems to have a certain efficacy in reducing migraine intensity rather than frequency.

Cervical Spinal Cord Stimulation

Cervical spinal cord stimulation is a rather invasive procedure that in one study reduced both frequency and intensity of chronic cluster headache.

Sphenopalatine Ganglion Stimulation

Preliminary findings suggest that stimulation can rapidly control ongoing cluster headaches. Surgery-related local adverse events are claimed to be as frequent as with other maxillofacial surgical procedures.

Other Types of Nerve Stimulation

Vagal nerve stimulation to treat drug-resistant chronic migraine and cluster headache may be justifiable when other conditions, such as epilepsy or depression, are also present.

Conclusion

Interest in neurostimulation techniques to treat intractable headache conditions has burgeoned in recent years, but enthusiasm should be tempered as most studies have been open. Although many of these techniques show effectiveness, they should be used with caution: rigorous selection criteria are necessary, and the advantages and disadvantages, including costs, should be extensively evaluated on an individual basis, implying more than usual attention to the patient by the physician.