A prospective open label 2-8 year extension of the randomised controlled ICON trial on the long-term efficacy and safety of occipital nerve stimulation in medically intractable chronic cluster headache

Abstract

Background: We demonstrated in the randomised controlled ICON study that 48-week treatment of medically intractable chronic cluster headache (MICCH) with occipital nerve stimulation (ONS) is safe and effective. In L-ICON we prospectively evaluate its long-term effectiveness and safety.

Methods: ICON participants were enrolled in L-ICON immediately after completing ICON. Therefore, earlier ICON participants could be followed longer than later ones. L-ICON inclusion was stopped after the last ICON participant was enrolled in L-ICON and followed for ≥2 years by completing six-monthly questionnaires on attack frequency, side effects, subjective improvement and whether they would recommend ONS to others. Primary outcome was the change in mean weekly attack frequency 2 years after completion of the ICON study compared to baseline. Missing values for log-transformed attack-frequency were imputed for up to 5 years of follow-up. Descriptive analyses are presented as (pooled) geometric or arithmetic means and 95% confidence intervals.

Findings: Of 103 eligible participants, 88 (85%) gave informed consent and 73 (83%) were followed for ≥2 year, 61 (69%) ≥ 3 year, 33 (38%) ≥ 5 years and 3 (3%) ≥ 8.5 years. Mean (±SD) follow-up was 4.2 ± 2.2 years for a total of 370 person years (84% of potentially 442 years). The pooled geometric mean (95% CI) weekly attack frequency remained considerably lower after one (4.2; 2.8-6.3), two (5.1; 3.5-7.6) and five years (4.1; 3.0-5.5) compared to baseline (16.2; 14.4-18.3). Of the 49/88 (56%) ICON ≥50% responders, 35/49 (71%) retained this response and 15/39 (38%) ICON non-responders still became a ≥50% responder for at least half the follow-up period. Most participants (69/88; 78% [0.68-0.86]) reported a subjective improvement from baseline at last follow-up and 70/88 (81% [0.70-0.87]) would recommend ONS to others. Hardware-related surgery was required in 44/88 (50%) participants in 112/122 (92%) events (0.35 person-year^-1 [0.28-0.41]). We didn't find predictive factors for effectiveness.

Interpretation: ONS is a safe, well-tolerated and long-term effective treatment for MICCH.

Funding: The Netherlands Organisation for Scientific Research, the Dutch Ministry of Health, the NutsOhra Foundation from the Dutch Health Insurance Companies, and Medtronic.

Keywords: Cluster headache; Medically intractable chronic cluster headache; Neuromodulation; Occipital nerve stimulation.

Fig. 1

Study flowchart. ∗Study termination: Inclusion for the L-ICON study was stopped after the last ICON participant was enrolled in L-ICON and followed for ≥2 years (i.e. ≥3 years after ONS implantation).

Fig. 2

Number of active participants. Because participants in the LICON follow-up study were each enrolled immediately after completion of the ICON study (i.e. 48 weeks after ONS implantation), while the ICON study was still recruiting new patients until December 3rd 2017, the initial LICON participants had a much longer follow-up than those enrolled later. The actual number of active participants is shown relative to the potential maximum number of participants for that period.

Fig. 3

Heat map depicting each individual participants' response to ONS until 8.5 years after ICON study completion. Patients are sorted according to responder status with those on the top achieving the highest number of time points with positive responses. Individual follow-up duration is dependent on enrolment date. Explantation (n = 8), device turned off due to no effect (n = 3) and no effect (n = 2) have been marked as ‘dropout’ (n = 13). End of follow-up due to study ending (n = 57), lost to follow-up (n = 10), personal reasons (n = 4), death due to other disease (n = 4) or attack freedom (n = 3) have been marked as ‘censored’ (n = 75). Data at 24 and 48-week time point are from the ICON trial.

Fig. 4

Evolution of pooled geometric mean score of (a) median weekly attacks and (b) three SF-36 items (mental health sumscore, general health and physical health sumscore) with 95% confidence interval and number of active participants as percentage of possible participants. Because participants in the LICON follow-up study were each enrolled immediately after completion of the ICON study (i.e. 48 weeks after ONS implantation), while the ICON study was still recruiting new patients until December 3rd 2017, the initial LICON participants had a much longer follow-up than those enrolled later. Both the actual number of active participants is shown and the number relative to the potential maximum number of participants for that period.