In collaboration with the Department of Neurology, Leiden University (Netherlands), the University Hospital Schleswig-Holstein and other European university centers, we are conducting a study on the effectiveness of stimulation of the occipital nerves (occipital nerve) in treatment-resistant chronic cluster headache.

the aim of the study

Cluster headaches generally respond well to drug therapy. However, in a group of patients suffering particularly from the chronic form of cluster headache, sufficient effectiveness cannot be achieved or the treatment is not tolerated. There are compelling scientific reasons to believe that occipital nerve stimulation (ONS) is effective in a proportion of these patients. In smaller studies in Germany, the Netherlands, Great Britain and Belgium, the results of the ONS were promising. There were no serious side effects and many patients experienced attacks that were less frequent and less severe. Before this new treatment method is used in more patients, its effectiveness and safety must be confirmed in larger scientific studies. In addition, we would like to find out the best way to stimulate the occipital nerve. To clarify this, we are investigating the effectiveness and safety of different types of stimulation.

What medical devices are used?

In this study, battery-powered electrical stimulation electrodes are placed under the skin of the neck. There is already extensive experience with these electrodes. They have been used for years to treat therapy-resistant, severe pain in the arms and legs. The device used is CE certified. To test the effectiveness of ONS in patients with severe cluster headaches, the pulse generator is inserted under the skin in the abdominal area. The battery and stimulation electrodes are connected by extension cables, which are laid under the skin from the abdominal area to the neck. This procedure is performed in the operating room under general anesthesia.

How is the study carried out?

In order to scientifically prove the effectiveness of ONS, different stimulation parameters must be compared. It is important that neither the patient nor the examiner is informed about the stimulation parameters. The stimulation parameters are randomly determined by a computer. At the end of the study, the patient will be informed of the stimulation parameters used. If medically necessary, the stimulation parameters are determined at an earlier point in time.

If a patient is interested in participating in the study and meets the study criteria after an outpatient preliminary examination, the treating neurologist will discuss the course of the disease with the study coordinator and the neurosurgeon. If it is decided that you can participate, you will be asked to sign a consent form. It will take approximately two months until the operation can be scheduled at the Schleswig-Holstein University Hospital. During this period you will be asked to complete an electronic diary for practice purposes for four weeks, then for eight weeks until surgery. You will be examined before the operation. Allocation to treatment will take place if you meet the inclusion criteria after completing the headache diary for 12 weeks. It is possible that you will not be able to continue taking part in the study after these first three months.

If it has been decided that you can continue to participate in the study, the stimulation program will be drawn in the next step. The exact settings are adjusted during check-ups at set times. Neither you nor the examiner will know which stimulation program is being used during the study. Depending on which program was selected, you may feel a slight tingling sensation at the back of your head. The strength and extent of tingling have no known relationship to the effectiveness of stimulation.

The exact details of the study will be explained to you during your outpatient examination. Further details about the study can be found here

The ethics committee of the Medical Faculty of the Christian Albrechts University in Kiel examined the study project and gave a positive vote.

Which patients can participate?

  • You meet the criteria for chronic cluster headache
  • You have at least 4 attacks per week
  • You meet the criteria for cluster headache that does not respond to treatments
  • You are at least 18 years old
  • You agree not to take any new preventative cluster headache medications or corticosteroids during the study period.

How can you register for an outpatient preliminary examination?

Cluster Headache Competence Center
Pain Clinic Kiel
Heikendorfer Weg 9-27
D-24149 Kiel
Telephone: 0431-20099150
Fax: 0431-20099109
hg@krebsklinik.de
Homepage: https://krebsklinik.de
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Further information about cluster headaches:

https:// painklinik.de/service-fuer-patienten/cluster-kopfschrei/
https://schreinklinik.de/service-fuer-patienten/clusterkopfschrei-wissen/
https://krebsklinik.de/2015/09/30/ kieler-clusterheadache-conference-supply-in-europe-2015/
https://schreinklinik.de/2014/02/21/zentrum-fuer-seltene-kopfschreidiseases/

 

Cluster headaches overview

The main characteristic of trigeminoautonomic headache disorders are severe one-sided pain attacks in the supply area of ​​the ophthalmic nerve, which, in contrast to migraines, are predominantly constant on one side. They are accompanied by distinctive ipsilateral autonomic symptoms. The most common symptoms are conjunctival injection, lacrimation, nasal congestion, and/or rhinorrhea. Clinically, cluster headache, paroxysmal hemicrania and SUNCT syndrome are mainly differentiated based on the duration and frequency of attacks. A special form is hemicrania continua. Here, the eponymous unilateral permanent headache is overlaid by headache attacks, which in turn are accompanied by the typical autonomic symptoms. Trigeminoautonomic headache disorders are generally primary headache disorders. However, unlike migraine, secondary forms are not rare, so a careful anamnesis and further diagnostics including cerebral imaging are required

[i]

Clinical picture

In the episodic form, which dominates at around 85%, the attacks occur periodically in clusters (“cluster” = English for heap). Active cluster periods with an average duration of 2 weeks to 3 months with (usually) daily attacks are followed by symptom-free remission phases that can last for months or years. In chronic cluster headache, cluster attacks occur over more than a year without remission phases lasting at least 4 weeks. The unique feature of cluster headache attacks that last 15 to 180 minutes is the restlessness of those affected. Maintaining bed rest in a flat upper body position always tends to contradict the diagnosis. In many patients, the occurrence of cluster attacks follows certain rhythms. This applies to both cluster periods, which often occur regularly at certain times of the year (spring/autumn), as well as individual attacks. Nocturnal attacks are most common during sleep, either shortly after falling asleep or in the early hours of the morning. Almost half of those affected also describe persistent pain, usually of milder intensity, between attacks [ii] . In individual cases, this can become more severe and require treatment itself.

The diagnostic criteria for cluster headache were revised by the International Headache Society in 2013 (ICHD-3 beta [iii] ). During active cluster periods, attacks in many patients can be reproducibly triggered within 1 hour by ingesting small amounts of alcohol [iv] or by nitro spray. Even though individual cluster attacks cannot be provoked by nicotine consumption, it is striking that non-smokers who suffer from cluster headaches are rare in the episodic form and a rarity in the chronic form [v ] .

Epidemiology

Cluster headache is the most common trigeminal autonomic headache disorder. The lifetime prevalence of 124:100,000 is in a similar range to that of trigeminal neuralgia [vi] , [vii] . Men are affected 4-5 times more often than women. The age at which the disease first occurs is usually between the ages of 20 and 40 [viii] . The episodic form occurs six times more frequently than the chronic form, although transitions in both directions are possible. Overall, heredity factors seem to play a minor role. Less than 10% of those affected know a first-degree relative who is also affected. In a recent meta-analysis, a described association with a change in the hypocretin receptor 2 gene could no longer be confirmed [ix] .

Origin

Results from PET examinations suggested that the attacks were generated in the ipsilateral hypothalamus [x] . Such an overarching influence of the hypothalamus could, among other things, explain the typical circadian rhythm of attacks. The PET examinations led directly to the use of deep brain stimulation to treat treatment-refractory chronic cluster headaches (see below). While the typical accompanying autonomic symptoms are seen as the result of central parasympathetic activation, the actual pain is explained, similarly to migraine, as the result of trigeminovascular activation with a resulting neurogenic inflammation, including in the area of ​​the cavernous sinus. Here, sensory fibers of the ophthalmic nerve, sympathetic nerve fibers, venous vessels that drain the orbit and the internal carotid artery run in a narrow, bony space. Local inflammatory processes can mechanically influence both sensory nerve fibers and blood vessels. The reliable effect of cortisone in cluster headache prevention is attributed to the suppression of this neurogenic inflammation. Triptans and ergotamines act one step earlier and inhibit the release of CGRP, a neuropeptide of the trigeminal vascular system [xi] . However, the rapid initial effect of triptans during an attack, like that of inhalation of oxygen, is likely to be vasoconstriction with pressure relief of the ophthalmic nerve.

Attack therapy

[xii] and sumatriptan 6 mg sc. [xiii] are effective and explicitly approved for the acute treatment of cluster headaches . The latter works so quickly and reliably that a lack of response raises doubts about the diagnosis of cluster headache. Both substances also have a prophylactic effect, although only for a few hours due to their short elimination half-life. The approval limits use to two applications within 24 hours, but not to a certain number of days per month. Daily use is therefore formally permitted. Headaches caused by triptan overuse have also been described in cluster headaches, but they occur rarely and almost always only in patients who also suffer from migraines [xiv] .

Inhalation of 100% oxygen (12/min) [xv] . Oxygen treatment has important advantages compared to triptans. It is very well tolerated, there are no relevant restrictions on use in practice and the treatment can be repeated as often as desired within 24 hours. This is offset by the unwieldiness of portable 2l oxygen bottles, the everyday procurement problems and the lack of prophylactic effect that characterize triptans. Oxygen treatment is therefore not very suitable for breaking nightly series of attacks.

Second-line drugs, both off-label, are sumatriptan 20 mg nasally [xvi] and lidocaine 4% intranasally. Sumatriptan nasal has no advantage over the approved zolmitriptan 5 mg nasal. Lidocaine 4% intranasally is considered an alternative in the presence of contraindications to triptans and ineffectiveness of oxygen. However, the effectiveness is only limited [xvii] .

Drug prophylaxis

The aim of prophylaxis is to achieve complete freedom from attacks in as short a time as possible. Clinically effective prophylactics can be divided into two groups. The group of short-term prophylactics includes substances with a rapid and reliable onset of action, but which are not suitable or only suitable to a limited extent for long-term therapy. These include prednisolone [xviii] , ergotamine tartrate [xix] and oral triptans such as naratriptan [xx] . However, if there is a chronic cluster headache or cluster periods that usually last more than 4 weeks, substances that are suitable for long-term therapy are required. This group of long-term prophylactics includes verapamil, lithium and topiramate. In practice, a short-term prophylactic is usually initially combined with a long-term prophylactic until the effect of the long-term prophylactic takes effect. The temporary administration of the short-term prophylactic then serves to bridge the time until the slow-dose long-term prophylactic takes effect. Lithium is explicitly approved for cluster headache prophylaxis, and verapamil can be prescribed for approved off-label use following a decision by the Federal Joint Committee.

The number of studies on short-term prophylactics, which have often been used for decades, is limited, but empirically there is no doubt about their effectiveness. The use is usually limited to a period of 7-14 days. With prednisolone, a morning starting dose of 100 mg/day is often chosen and the dose is then gradually reduced. Ergotamine tartrate 2 mg and long-acting triptans such as Naratriptan 2.5 mg are preferably given as a single dose in the evening for predominantly nocturnal attacks (both off-label). If the attacks are spread over the entire day, administration can be given every 12 hours.

Verapamil [xxi] is generally considered the first choice long-term prophylactic due to a favorable effect-side effect ratio. The effective dose range for episodic cluster headaches is 240 to 480 mg in a sustained-release dosage form divided into two daily doses. In the chronic form, significantly higher doses of up to 960 mg are used under ECG monitoring. Lithium [xxii] and topiramate [xxiii] are also effective, but are often significantly less well tolerated. Both substances can be used as monotherapy or in combination with verapamil. When using lithium, the aim is to achieve a morning fasting serum level of 0.6-0.8mmol/l. For topiramate, daily dosages of between 100 and 200 mg are recommended, although in some cases significantly lower dosages are required.

For episodic cluster headaches, drug prophylaxis is stopped when the period subsides; for chronic cluster headaches, the dosage is adjusted according to the activity of the disease.

Neuromodulation

In the past 15 years, a variety of neuromodulation procedures have been presented as innovative treatment options for cluster headaches. Due to their invasiveness, the importance of these procedures did not go beyond that of a last resort for otherwise treatment-resistant chronic cluster headaches. Large numbers of cases, as is usual in drug studies, were illusory from the start.

The oldest procedure, deep brain stimulation in the ipsilateral posterior hypothalamus [xxiv] , was derived directly from the pathophysiological model of attack generation in the hypothalamus (see above). A responder rate of approximately 60% also supported the validity of the model. A fatal postoperative cerebral hemorrhage in a Belgian patient and the simultaneous introduction of subcutaneous occipital nerve stimulation (ONS), which was more attractive for patients because it was less invasive, then sealed the fate of deep brain stimulation [xxv] . At the ONS, the first casuistics and later case series were promising [xxvi] . Current international controlled studies are testing the effectiveness of ONS in preventing cluster headaches (for further information see https:// pain clinic.de).

A neurostimulation procedure currently has a CE mark for the acute treatment of cluster headaches, the Pulsante™ SPG Microstimulator System for stimulation of the sphenopalatine ganglion. In principle, it is a procedure for the acute treatment of cluster headache attacks, which, however, should also lead to a decrease in the number of attacks in some patients [xxvii] . In this stimulation procedure, a small electrode is implanted in the area surrounding the sphenopalatine ganglion. During attacks, a handheld device held against the cheek generates a current flow in the electrode, which leads to the actual modulation of parasympathetic nerve fibers. Approximately 2/3 of patients benefit either from stopping the cluster attacks and/or from reducing the number of attacks. However, there are also complications in the form of facial sensory disturbances in over 80% of patients, some of which can persist for several months or longer.

A newer procedure, transcutaneous vagal stimulation, takes patients' wishes for less invasiveness and thus fewer complications into account. With regular stimulation of the vagus nerve in the neck 3 times a day for 4 minutes in addition to standard drug treatment, a reduction in the number of attacks is said to occur compared to standard drug treatment alone [ xxviii] - without any significant side effects. However, there are no meaningful controlled studies. It remains to be seen how this neurostimulation procedure will prove itself in everyday clinical practice.

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[iii] Headache Classification Committee of the International Headache Society (IHS). The International Classification of Headache Disorders, 3rd edition (beta version). Cephalalgia. 2013 Jul;33(9):629-808.

[iv] Schürks M, Diener HC. Cluster headaches and lifestyle habits. Curr Pain Headache Rep. 2008 Apr;12(2):115-21. Review.

[v] Ferrari A, Zappaterra M, Righi F, Ciccarese M, Tiraferri I, Pini LA, Guerzoni S, Cainazzo MM. Impact of continuing or quitting smoking on episodic cluster headache: a pilot survey. J Headache Pain. 2013 Jun 6;14:48.

[vi] Fischera M, Marziniak M, Gralow I, Evers S. The incidence and prevalence of cluster headache: a meta-analysis of population-based studies. Cephalalgia. 2008 Jun;28(6):614-8.

[vii] Manzoni GC, Torelli P. Epidemiology of typical and atypical craniofacial neuralgias. Neurol Sci. 2005 May;26 Suppl 2:s65-7. Review.

[viii] Ekbom K, Svensson DA, Träff H, Waldenlind E. Age at onset and sex ratio in cluster headache: observations over three decades. Cephalalgia. 2002 Mar;22(2):94-100.

[ix] Weller CM, Wilbrink LA, Houwing-Duistermaat JJ, Koelewijn SC, Vijfhuizen LS, Haan J, Ferrari MD, Terwindt GM, van den Maagdenberg AM, de Vries B. Cluster headache and the hypocretin receptor 2 reconsidered: a genetic association study and meta-analysis. Cephalalgia. 2015 Aug;35(9):741-7.

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[xi] Edvinsson L, Goadsby PJ. Neuropeptides in migraine and cluster headache. Cephalalgia. 1994 Oct;14(5):320-7. Review.

[xii] Hedlund C, Rapoport AM, Dodick DW, Goadsby PJ. Zolmitriptan nasal spray in the acute treatment of cluster headache: a meta-analysis of two studies. Headache.2009 Oct;49(9):1315-23.

[xiii] Göbel H, Lindner V, Heinze A, Ribbat M, Deuschl G. Acute therapy for cluster headache with sumatriptan: findings of a one-year long-term study. Neurology.1998 Sep;51(3):908-11.

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[xv] Cohen AS, Burns B, Goadsby PJ. High-flow oxygen for treatment of cluster headache: a randomized trial. JAMA. 2009 Dec 9;302(22):2451-7.

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[xvii] Robbins L. Intranasal lidocaine for cluster headache. Headache. 1995 Feb;35(2):83-4.

[xviii] Jammes JL. The treatment of cluster headaches with prednisone. Dis Nerv Syst. 1975 Jul;36(7):375-6.

[xix] Mathew NT. Dosage and administration of ergotamine tartrate and dihydroergotamine. Headache. 1997;37 Suppl 1:S26-32. Review.

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[xxi] Leone M, D'Amico D, Frediani F, Moschiano F, Grazzi L, Attanasio A, Bussone G.Verapamil in the prophylaxis of episodic cluster headache: a double-blind study versus placebo. Neurology. 2000 Mar 28;54(6):1382-5.

[xxii] Manzoni GC, Bono G, Lanfranchi M, Micieli G, Terzano MG, Nappi G. Lithium carbonate in cluster headache: assessment of its short- and long-term therapeutic efficacy. Cephalalgia. 1983 Jun;3(2):109-14.

[xxiii] Láinez MJ, Pascual J, Pascual AM, Santonja JM, Ponz A, Salvador A. Topiramate in the prophylactic treatment of cluster headache. Headache. 2003 Jul-Aug;43(7):784-9.

[xxiv] Leone M, Proietti Cecchini A, Franzini A, Broggi G, Cortelli P, Montagna P, May A, Juergens T, Cordella R, Carella F, Bussone G. Lessons from 8 years' experience of hypothalamic stimulation in cluster headache. Cephalalgia. 2008 Jul;28(7):787-97

[xxv] Schoenen J, Di Clemente L, Vandenheede M, Fumal A, De Pasqua V, Mouchamps M, Remacle JM, de Noordhout AM. Hypothalamic stimulation in chronic cluster headache: a pilot study of efficacy and mode of action. Brain. 2005 Apr;128(Pt 4):940-7.

[xxvi] Mueller O, Diener HC, Dammann P, Rabe K, Hagel V, Sure U, Gaul C. Occipital nerve stimulation for intractable chronic cluster headache or migraine: a critical analysis of direct treatment costs and complications. Cephalalgia. 2013 Dec;33(16):1283-91

[xxvii] Schoenen J, Jensen RH, Lantéri-Minet M, Láinez MJ, Gaul C, Goodman AM, Caparso A, May A. Stimulation of the sphenopalatine ganglion (SPG) for cluster headache treatment. Pathway CH-1: a randomized, sham-controlled study. Cephalalgia. 2013 Jul;33(10):816-30.

[xxviii] Gaul C, Diener HC, Silver N, Magis D, Reuter U, Andersson A, Liebler EJ, Straube A; PREVA Study Group. Non-invasive vagus nerve stimulation for PREVention and Acute treatment of chronic cluster headache (PREVA): A randomized controlled study. Cephalalgia. 2015 Sep 21.