Kamourieh, S

Lagrata, S

Matharu, MS

UCL Discovery

1J Neurol Neurosurg Psychiatry Month 2019 Vol 0 No 0LetterNon-invasive vagus nerve stimulation is beneficial in chronic paroxysmal hemicraniaIntroductIonParoxysmal hemicrania (PH) is a rare primary headache disorder charac-terised by recurrent attacks of severe, strictly unilateral pain, focused around the orbital, supraorbital and temporal regions and associated with autonomic features. Attacks usually occur more than five times a day and last 2–30 min.1 The disorder has an absolute response to indomethacin such that patients are rendered pain-free by therapeutic doses. Between 65% and 88% of patients suffer from the chronic form of PH where the attacks occur for more than 1 year without remission or with remission periods lasting less than 3 months.2 Over 30% of patients report dose-lim-iting side-effects with indomethacin and approximately 20% discontinue the drug due to tolerability problems.3 Although several other drugs have been reported to have efficacy in PH, none offer the same magnitude of response.Evidence to support the role of the vagus nerve in trigeminal pain have been identified in prior studies. Inhi-bition of nociceptive activation of the trigeminocervical neurons have been shown in preclinical animal models, with a dose-dependent effect.4 Non-in-vasive vagus nerve stimulation (nVNS), using the gammaCore device, has been reported to be beneficial in trigeminal autonomic cephalalgias (TACs). A recent audit looking at 15 patients with indo-methacin-responsive headaches, six of whom had PH, concluded that nVNS may be an important adjunct or alterna-tive in those patients with TACs.5MethodGiven these results, we tried nVNS in eight chronic paroxysmal hemicrania (CPH) patients who were intolerant of indomethacin. Patients were diagnosed as CPH based on ICHD-3 beta criteria.1 At initial presentation, some patients reported attacks lasting more than 30 min though most of the attacks lasted less than 30 min; occasional prolonged attacks are a common feature in PH.2 Prior to use, all patients had complete suppression of headaches with indo-methacin but experienced significant side effects. One patient was on a stable dose of pregabalin prior to starting nVNS, the remainder were not on concomitant medication use. Treatment with nVNS was offered as a ‘humanitarian interven-tion’ and ethics board approval for the collection and publication of data was granted by Northwick Park Hospital Research Ethics Committee, Hamp-stead, London, UK (REC Number. 11/LO/1709).Patients administered two consecutive doses three times a day ipsilateral to the pain. The stimulator has a predetermined duration of 2 min and patients can change the stimulation intensity. The patients in this group were asked to increase the stimulation until the point of ‘lip pull’ to ensure optimal stimulation. They were trained on how to use the device and their technique was checked 4 weeks later to ensure it was optimal. Prospec-tive headache diaries were kept at base-line and throughout follow-up. Patients were followed up every 3–6 months when data were collected on headache disability scores (Migraine Disability Assessment Score (MIDAS) and Headache Impact Test (HIT-6) and affective measures (Hospital Anxiety and Depression Scale (HADS)).ElectroCore supplied the devices through a cost sharing programme; the device was supplied free of charge for 3 months and thereafter the device was paid for either by the patient or the healthcare provider.resultsThe results of this case series are shown in table 1. The group consisted of eight patients (five males) with a mean age of 48 years (range: 20–81 years) and median duration of CPH of 8 years (range 3–22 years). Patients had failed to respond to an average of three preventive medi-cations (range: 1–5) and all had dose limiting side effects to indomethacin. Median follow-up of the cohort was 7 months (3–19 months). At 3 months, the mean monthly headache frequency fell by 68.01% (p=0.012) but further dropped to 75% (p=0.003) at the final follow-up. A favourable response, defined as a more than 50% reduction in monthly head-ache frequency, was observed in 75% of patients at final follow-up. The median time to reach a 50% improvement was 3 months (range: 3–6 months). There was a reduction in median severity of attacks from verbal rating score (VRS) 8/10 to 6/10 (p=0.050) at 3 months follow-up. At final follow-up, the median severity of attacks dropped from VRS 8/10 to 4/10 (p=0.011). Similarly, there was a reduc-tion in the median duration of attacks from 47.5 min to 21.25 min at 3 months follow-up (p=0.007) and at final follow-up to 23.1 min (p=0.007). Significant reduc-tions were reported in HIT-6 and MIDAS scores. Seven patients showed a reduction in the Hospital Anxiety (HAD-A) scores, while four patients showed a reduction in the Hospital Depression (HAD-D) scores. The average estimated global improve-ment was 64.37% and 71.88% at 3 months and final follow-up, respectively. No adverse events were reported by any patients.dIscussIonOur experience suggests that nVNS has potential use as a preventative therapy for PH in patients unable to tolerate indo-methacin. As detailed above, six of the eight patients had more than 50% reduc-tion in frequency in their monthly head-aches with significant improvements in their disability scores. We identified a 75% favourable response with two patients becoming attack-free.There are limitations to these data, including those inherent to any unblinded series, though despite this our results are encouraging. The strength of the current series includes the use of prospective data. Further research into the use and safety of nVNS in PH is required. However, given the rarity of PH, it is unlikely that an adequately powered, randomised controlled trial will occur in the near future. Our results nonetheless highlight the potential importance of nVNS in this patient group and also the need to ensure patients adhere to treatment for at least 3 months given the latency to median treat-ment efficacy.classIfIcatIon of evIdenceClass IV.salwa Kamourieh,1 susie lagrata,1 Manjit singh Matharu1,21Headache Group, the National Hospital for Neurology and Neurosurgery, London, UK2UCL Institute of Neurology, London, UKcorrespondence to Dr Manjit Singh Matharu, Headache Group, Institute of Neurology and the National Hospital for Neurology and Neurosurgery, Queen Square, London WC1N 3BG, UK;  m. matharu@ uclmail. netcontributors SK: analysis and interpretation of data, drafting and revision of manuscript. SL: data collection, analysis and interpretation of data and revision of manuscript. MSM: study concept, recruitment of subjects, interpretation of data and manuscript revision.Postscriptcopyright. on 18 February 2019 by guest. Protected byhttp://jnnp.bmj.com/J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp-2018-319538 on 1 February 2019. Downloaded from 2 J Neurol Neurosurg Psychiatry Month 2019 Vol 0 No 0Postscripttable 1 Non-invasive vagal nerve stimulation in chronic paroxysmal hemicraniaPatient number 1 2 3 4 5 6 7 8Age 52 52 28 20 43 44 81 63Sex Male Male Male Female Female Male Male FemaleDuration of CPH (years) 3 11 3 6 22 11 8 5Headache characteristics at diagnosisFrequency 8–12/day 6–8/day 5–9/day 4–13/day 10–20/day 5–20/day 4–12/day 5–12/daySeverity (VRS) 10 5–10 7–10 8–10 6–10 4–8 10 8–10Duration (min) 15–30 15–45 15–60 15–120 5–90 5–120 5–20 5–45Median duration (min) 20 20 25 20 10 30 15 15Indometacin dose 225 mg 100 mg 225 mg 75 mg 225 mg 225 mg 100 mg 225 mgSide effects from indometacin Severe lethargy colitisSevere gastrointestinal upsetSevere gastrointestinal upsetSwollen ankles and marked lethargySevere gastrointestinal upset Duodenal ulcerSevere gastrointestinal upsetPreventive treatments failed 3 4 3 3 4 5 3 1Duration of use of VNS (months) 19 10 6 6 7 5 7 3Baseline headaches (1 month pre-VNS)Frequency 5–10/day 2–3/day 5/day 1–2/day 5/day 2/day 4–5/day 2–5/daySeverity (VRS) 10 2–6 7–8 8–10 4–8 5–9 10 9–10Duration (min) 20–30 30–90 45–60 15–120 5–80 60–120 15–20 30–45Follow-up at 3 monthsFrequency 2–3 week 1/day 2/week 5/month 1/day 1–2/day 0 2–5/daySeverity (VRS) 5–6 2–3 4–5 5–9 1–2 1–2 0 9–10Duration (min) 15–20 30–60 20–30 5–20 5–30 30–60 0 30–45Follow-up at 6 monthsFrequency 1/week 1/day 2/week 5/month 0 N/A 0 N/ASeverity (VRS) 6–7 2–4 4–5 5–9 0 N/A 0 N/ADuration (min) 15–20 30–60 20–30 5–20 0 N/A 0 N/ALast follow-upFrequency 1/week 1/day 2/week 5/month 0 1-2/day 0 2–5/daySeverity (VRS) 6–7 2–4 4–5 5–9 0 1–2 0 9–10Duration (min) 20 30–60 20–30 5–20 0 30–60 0 30–45HIT-6Baseline 70 59 69 74 50 48 40 743 months 60 55 59 31 46 48 36 766 months 65 54 59 30 36 N/A 36 N/ALast follow-up 66 54 59 30 36 48 36 N/AMIDASBaseline 21 5 190 71 81 0 0 1053 months 4 5 167 68 0 0 0 1206 months 18 5 78 67 0 N/A 0 N/ALast follow-up 14 5 78 67 0 0 0 N/AHADS-ABaseline 2 9 12 17 20 2 1 183 months 6 6 4 18 19 0 0 176 months 5 6 0 19 19 N/A 0 N/ALast follow-up 3 6 0 19 19 0 0 N/AHADS-D Baseline 3 6 14 14 16 2 1 153 months 1 5 7 14 9 0 0 166 months 3 5 0 15 9 N/A 0 N/ALast follow-up 6 5 15 15 9 0 0 N/APatients estimate of improvement 70% 70% 90% 80% 100% 65% 100% 0%CPH, chronic paroxysmal hemicrania; HADS-A/D, Hospital Anxiety and Depression Scale—Anxiety/Depression; HIT-6, Headache Impact Test-6; MIDAS, Migraine Disability Assessment; N/A, no data available; VNS, vagus nerve stimulation; VRS, verbal rating scale (0–10; 0 pain free, 10 very severe pain).copyright. on 18 February 2019 by guest. Protected byhttp://jnnp.bmj.com/J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp-2018-319538 on 1 February 2019. Downloaded from 3J Neurol Neurosurg Psychiatry Month 2019 Vol 0 No 0Postscriptcompeting interests SK and SL reports no disclosures. MSM serves on the advisory board for Allergan, St Jude Medical and Medtronic and has received payment for the development of educational presentations from electroCore, Allergan, Medtronic and St Jude Medical.Patient consent for publication Obtained.ethics approval Northwick Park Hospital research ethics Committee, Hampstead, London, UK.Provenance and peer review Not commissioned; externally peer reviewed.data sharing statement raw data may be made available on written request to the corresponding author.open access this is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See: http:// creativecommons. org/ licenses/ by- nc/ 4. 0/.© Author(s) (or their employer(s)) 2019. re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.to cite Kamourieh S, Lagrata S, Matharu MS. J Neurol Neurosurg Psychiatry epub ahead of print: [please include Day Month Year]. doi:10.1136/jnnp-2018-319538received 15 September 2018revised 16 November 2018Accepted 5 December 2018J Neurol Neurosurg Psychiatry 2019;0:1–3.doi:10.1136/jnnp-2018-319538RefeRences 1 Headache Classification Subcommittee of the International Headache Society. The international classification of headache disorders. 3rd edn, 2013: 629–808. 2 Cittadini e, Matharu MS, Goadsby PJ. Paroxysmal hemicrania: a prospective clinical study of 31 cases. Brain 2008;131:1142–55. 3 Dodick DW. Indomethacin-responsive headache syndromes. Curr Pain Headache Rep 2004;8:19–26. 4 Akerman S, Simon B, romero-reyes M. Vagus nerve stimulation suppresses acute noxious activation of trigeminocervical neurons in animal models of primary headache. Neurobiol Dis 2017;102:96–104. 5 tso Ar, Marin J, Goadsby PJ. Noninvasive vagus nerve stimulation for treatment of indomethacin-sensitive headaches. JAMA Neurol 2017;74:1266–7.copyright. on 18 February 2019 by guest. Protected byhttp://jnnp.bmj.com/J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp-2018-319538 on 1 February 2019. Downloaded from 

Non-invasive vagus nerve stimulation is beneficial in chronic paroxysmal hemicrania

http://discovery.ucl.ac.uk/10068341/1/Matharu_Non-invasive%20vagus%20nerve%20stimulation%20is%20beneficial%20in%20chronic%20paroxysmal%20hemicrania_VoR.pdf

Non-invasive vagus nerve stimulation is beneficial in chronic paroxysmal hemicrania

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