Occipital Nerve Stimulation in Medically Intractable Chronic Cluster Headache
Occipital Nerve Stimulation in Medically Intractable Chronic Cluster Headache
Cluster headache (CH) is a primary headache disorder characterized by recurrent short-lasting
 attacks (15 to 180 minutes) of excruciating unilateral periorbital pain accompanied by
 ipsilateral cranial autonomic signs. The 1-year prevalence of CH is about 0.1 %, the male:
 female ratio is 3:1. The majority of patients have cluster periods of weeks to months with
 frequent attacks which are alternated with symptom-free periods of months to several years;
 the episodic from of CH. In about 10% of patients the CH is chronic (CCH) in which either no
 remission occurs within 1 year or the remissions last less than 1 month. At least 10 % of CCH
 patients are refractory to medical treatment or cannot tolerate the treatments.

 Recent pilot studies suggest that occipital nerve stimulation (ONS) in medically intractable
 CCH (MICCH) might offer an effective alternative to medical treatment. There are no
 randomised clinical trials and a placebo effect cannot be excluded. Long term tolerability is
 known from other indications.

 Here the investigators propose a prospective, randomised, double blind, parallel group
 multi-centre international clinical study to compare the reduction in attack frequency from
 baseline of occipital nerve stimulation (ONS) in patients with MICCH between two different
 stimulation conditions: high (100%) and low (30%) stimulation.

 Following implantation there will first be a run-in phase of 10 days of 10% stimulation
 intensity, followed by a stepwise monthly increase up to either 30% or 100%. Patients will be
 assessed monthly by a blinded assessor. The primary outcome measure is the mean number of
 attacks over the last 4 weeks of the double blind 6 month treatment period in the 100% versus
 the 30% treatment group. Hereafter, in an open extension phase of 6 months, all patients will
 receive 100% stimulation or the stimulation considered optimal by the patient.

 Secondary outcome measures include the rate of responders (≥ 50% reduction in attack
 frequency during the last 4 weeks of each treatment period), patient's satisfaction,
 medication use, quality of life, mean pain intensity, economic evaluation and whether
 patients would recommend the treatment to another patient. The investigators will also
 investigate whether predictive factors can be identified for efficacy.
Trigeminal autonomic cephalalgias (TACs) are characterized by frequent, short-lasting attacks
 of unilateral extremely severe headaches accompanied by ipsilateral facial autonomic features
 and are the most severe of the primary headache disorders. TACs include cluster headache
 (CH), paroxysmal hemicrania (PH) and short-lasting unilateral neuralgiform headache with
 conjunctival injection and tearing (SUNCT). CH is the most common form of TAC. The 1-year
 prevalence is about 1 in 1000, with the vast majority of patients having episodic CH (ECH):
 periods of weeks to months with frequent attacks which are alternated with symptom-free
 periods of several months to years. About 10% have chronic CH (CCH): attack free periods of
 less than one month in every 12 months, unless treatment is given. The chronic form can be
 primary unremitting from onset, or can be secondary, transform from the episodic form. CCH
 may spontaneously become episodic.

 Effective acute treatments for CH attacks are injectable or intranasal triptans and oxygen
 inhalation. Steroids (only for a short period), verapamil, lithium carbonate and methysergide
 are the most effective preventive therapies. At least 10% of patients with CCH is or may
 become refractory to or cannot tolerate medical therapy. For patients with medically
 intractable CCH (MICCH) there is no common treatment. Different experimental treatments, such
 as deep brain stimulation (DBS), radiofrequency lesions, glycerol injections, gamma knife,
 and surgery or root section of the trigeminal nerve are either substantially ineffective, or
 have significant short-comings with serious complications such as death or neurological
 deficits such as anaesthesia dolorosa or lack of efficacy.

 CH has considerable impact on socio-economic and personal functions due to direct costs of
 healthcare services and indirect costs of lost work days and decreased work efficacy. Higher
 pain scores and a higher percentage of patients with poor health due to pain and social
 functioning are found among CH patients compared with patients suffering from migraine. The
 impact on social functions, quality of life and use of healthcare of patients with MICCH is
 most likely even larger, although precise figures are not available. In the study of Burns et
 al. patients, suffering from MICCH, had on average over four attacks per day. Attacks of CH
 have been described by patients as being worse than child birth. Recently treatment of
 headache was listed as one of the top priorities of US National the Institute of Medicine's
 agenda for comparative-effectiveness research.

 Functional imaging studies in CH identified activations in the region of the posterior
 hypothalamus, which led to the use of neurostimulation therapy in MICCH. Hypothalamic DBS was
 shown to be effective in some patients with MICCH but unfortunately this treatment is
 associated with a high risk of (even lethal) consequences.

 Structures in the occipital region of the head are mainly innervated by the greater occipital
 nerve that is a branch of the C2 spinal root. Convergence of cervical, somatic trigeminal and
 dural trigeminovascular afferents on second order nociceptors in the brain stem is well
 documented. Stimulation of the greater occipital nerve increased metabolic activity in
 cervical regions of the spinal cord and in the trigeminal nucleus caudalis in the cat. In
 humans an occipital nerve blockade decreased the ipsi- and contralateral R2 response,
 confirming the anatomic and functional convergence of afferent cervical and trigeminal
 pathways. These studies suggest that modulation of these pathways may influence headache.

 Suboccipital injection of corticosteroid with local anaesthetics was shown to be effective in
 a placebo-controlled trial. In this study 4 patients suffering from CCH were included. In all
 patients the attacks recurred eventually. The authors suggest that suboccipital steroid
 injections ought to be tried as a single shot treatment before invasive treatments are
 considered such as DBS, but in later studies this turned out to be of no predictive value of
 the response to neuromodulation therapies.

 Along the same line, stimulation of the greater occipital nerve (ONS) has been tried with
 some success in intractable headaches including CCH. Burns et al. described 14 patients
 suffering from MICCH and were treated with ONS in an open retrospective study. Ten patients
 improved; three improved by 90% or more, 3 by 40%-90% and 4 by 20-30%. In a prospective open
 ONS study on MICCH patients Magis et al. showed a reduction in attack frequency of 79.9%. No
 serious complications were described in both studies.
Inclusion Criteria:

 * Diagnosis of patients with CH shall be in accordance with The International
 Classification of Headache Disorders, 2nd Edition:

 A. At least 5 attacks fulfilling criteria B-D B. Severe or very severe unilateral orbital,
 supraorbital and/or temporal pain lasting 15-180 minutes if untreated

 C. Headache is accompanied by at least 1 of the following:

 1. ipsilateral conjunctival injection and/or lacrimation

 2. ipsilateral nasal congestion and/or rhinorrhoea

 3. ipsilateral eyelid oedema

 4. ipsilateral forehead and facial sweating

 5. ipsilateral miosis and/or ptosis

 6. a sense of restlessness or agitation D. Attacks have a frequency from 1 every other
 day to 8 per day E. Not attributed to another disorder

 -  Chronic cluster headache A. Attacks fulfilling criteria A-E for Cluster headache
 B. Attacks recur over >1 year without remission periods or with remission periods
 lasting <1 month

 -  ICHD-II criteria for CCH (see above)

 -  Minimum mean attack frequency of 4 attacks per week

 -  Minimum age of 18 years old

 -  Signed study specific informed consent form

 -  Agreeing to refrain from starting new prophylactic CH medication, including
 steroids, or any other therapy aimed at CH and agrees to maintain existing
 prophylactic CH medication from 4 weeks before entering the baseline period
 throughout the duration of the double blind phase of the study. It is allowed to
 change the dose of prophylactic medication during the study based on the opinion
 of the treating medical specialist.

 -  Availability during follow-up period

 -  An MRI to exclude structural lesions potentially causing CCH.

 -  Medically intractable (see below)

 Definition medically intractable :

 Failed adequate trials of regulatory approved and conventional treatments according to
 local national guidelines

 Adequate trial:

 Appropriate dose and duration of treatment according to local guidelines Appropriate length
 of time Consideration of medication overuse

 Failed:

 No therapeutic or unsatisfactory effect, intolerable side effects, contraindications to use

 Must have tried agents of at least three classes of the following, of which 1 and 2 are
 obligatory, and 1 should come from 3-5: (recommendation of Goadsby et al. applied to Dutch
 national guidelines)

 1. Verapamil

 2. Lithium

 3. Methysergide

 4. Topiramate

 5. Gabapentin

 Exclusion Criteria:

 -  Other significant neurological or disabling diseases which in the opinion of the
 clinician may interfere with the study

 -  Pregnancy or the wish to become pregnant during the study period

 -  Cardiac pacemaker and other neuromodulatory devices

 -  Psychiatric or cognitive disorders and/or behavioural problems which in the opinion of
 the clinician may interfere with the study

 -  Taking CH prophylactic medication for conditions other than CH which in the opinion of
 the clinician may interfere with the study

 -  Serious drug habituation and/or overuse of acute headache medication for other
 headaches than CH

 -  Inability to complete the (electronic) diary in a sensible and accurate manner

 -  Structural intracranial or cervical vascular lesions that may potentially cause CH

 -  Previous destructive surgery involving the C2 or C3 roots (vertebrae) or deep brain
 stimulation

 -  Enrollment in other clinical studies that may confound the results of this study

 -  Requiring anticoagulation therapy or antithrombotic or thrombocyte
 aggregation-inhibitor for a concomitant condition that cannot be stopped
 peri-operatively. The local peri-operative protocol of each individual participating
 centre will be followed