Assistant Professor of Clinical Neurology, Weill Cornell Medical College
SYNOPSIS: Occipital nerve stimulation is an effective and safe treatment that can help reduce attack frequency and intensity in patients with medically intractable chronic cluster headache.
SOURCE: Wilbrink LA, de Coo IF, Doesborg PG, et al. Safety and efficacy of occipital nerve stimulation for attack prevention in medically intractable chronic cluster headache (ICON): A randomised, double-blind, multicentre, phase 3, electrical dose-controlled trial. Lancet Neurol 2021;20:515-525.
Cluster headache, a type of trigeminal autonomic cephalalgia, is a disabling primary headache disorder that is more prevalent in men and features severe unilateral periorbital pain associated with ipsilateral autonomic symptoms. Patients can endure up to eight attacks per day, and each attack lasts 15 minutes to three hours. Cluster periods can last weeks and up to three months. However, patients with chronic cluster headache either have no pain-free periods or pain-free periods lasting less than three months.
Treatment of cluster headache often entails acute, bridging, and preventive therapies. Patients who do not respond to or cannot tolerate commonly prescribed preventive treatments, such as verapamil and valproic acid (making up about 15% of patients with chronic cluster headache), are described to have medically intractable chronic cluster headache (MICCH). Occipital nerve stimulation (ONS) has been recommended in the treatment of MICCH. ONS features electrodes that are implanted subcutaneously, bi-occipitally, and connected to an implantable pulse generator (IPG) subcutaneously in the abdominal or gluteal region. ONS may inhibit the trigeminocervical complex in the brainstem, where cervical, somatic trigeminal, and dural trigeminovascular afferents synapse.
This study was an international, multicenter, randomized, double-blinded, electric dose-controlled trial assessing ONS in patients with MICCH. Patients included had chronic cluster headache; at least four headache attacks per week; were older than 18 years of age; had magnetic resonance imaging (MRI) of the brain within the past year without relevant findings; and had either non-response, intolerance, or contraindication to verapamil and lithium along with non-response, intolerance, or contraindication to methysergide, topiramate, or gabapentin. The study consisted of a 12-week baseline observation period, a device implantation period (using Medtronic Quad Plus), and a 10-day 10% ONS run-in treatment period, followed by 24 weeks of stepwise increase of ONS intensity to an ultimate goal of either 100% or 30% ONS (masked phase), and another 24-week (weeks 25-48), open-label treatment period in which participants received individually optimized open-label ONS. Investigators did not use a 0% setting because both groups had to experience paresthesia to have a valid control group. The primary outcome was change in weekly mean attack frequency (MAF) in weeks 21-24 compared with baseline. Some of the secondary outcomes included the proportion of patients with more than a 50% reduction in MAF at weeks 24 and 48 compared with baseline, mean attack intensity at weeks 21-24 and weeks 45-48, and adverse events. Data were collected during both the follow-up visits every three months and through using web-based diaries.
From Oct. 12, 2010, until Dec. 3, 2017, 150 patients were enrolled from tertiary headache centers, of which 130 were assigned to treatment and ultimately implanted with ONS (65 patients assigned to 100% ONS and 65 patients assigned to 30% ONS). At weeks 21-24, MAF in the total population was 7.38 (interquartile range [IQR], 2.50 to 18.50), which represented a median decrease of -5.21 (IQR, 11.18 to -0.19; P < 0.0001) compared to baseline. In the 100% and 30% ONS groups, the median decrease in MAF was -4.08 (-11.92 to -0.25) and -6.50 (-10.83 to -0.08), respectively; there was no difference in MAF decrease between weeks 21 and 24 compared to baseline between these two treatment groups (-2.42; 95% confidence interval, -5.17 to 3.33). Interestingly, the median weekly MAF already was reduced in both treatment groups as early as weeks 1-4 after ONS. In the total study population, approximately half the participants had at least a 50% reduction in MAF at weeks 21-24 and weeks 45-48, and a small percentage of patients (nine patients) were completely pain-free at weeks 21-24. A total of 129 adverse events occurred with 100% ONS and 95 adverse events occurred with 30% ONS, of which 17 in the 100% ONS group and eight in the 30% ONS group were labeled as serious (for brief hospitalization for hardware-related issues). Nonetheless, most patients reported they would recommend the therapy to other patients. The most common reported side effects were local pain, impaired wound healing, neck stiffness, and hardware damage.
Both ONS settings of 100% and 30% used in the study showed a significant reduction in attack frequency in patients with MICCH and were safe and well tolerated. This study showed more rapid onset of improvement than shown in similar previous studies, which is important for patients with MICCH who would benefit from rapid relief. Early success of ONS also was shown to be predictive of sustained response at later weeks. An optimal stimulation protocol and trial design to test this new technology should be focused on determining the most effective level of intensity at or below the lowest level that induces paresthesia. It is likely that each patient will have a different level of intensity that results in the effective treatment of headache. ONS may be a more tolerable treatment than some oral medications that have been used historically for cluster headache prevention.