Cluster headache: present and future therapy.

Cluster headache is characterized by severe, unilateral headache attacks of orbital, supraorbital or temporal pain lasting 15-180 min accompanied by ipsilateral lacrimation, rhinorrhea and other cranial autonomic manifestations. Cluster headache attacks need fast-acting abortive agents because the pain peaks very quickly; sumatriptan injection is the gold standard acute treatment. First-line preventative drugs include verapamil and carbolithium. Other drugs demonstrated effective in open trials include topiramate, valproic acid, gabapentin and others. Steroids are very effective; local injection in the occipital area is also effective but its prolonged use needs caution. Monoclonal antibodies against calcitonin gene-related peptide are under investigation as prophylactic agents in both episodic and chronic cluster headache. A number of neurostimulation procedures including occipital nerve stimulation, vagus nerve stimulation, sphenopalatine ganglion stimulation and the more invasive hypothalamic stimulation are employed in chronic intractable cluster headache.

Central and Peripheral Neural Targets for Neurostimulation of Chronic Headaches.

PURPOSE OF REVIEW: Chronic headache sufferers are estimated to be around 3% of the population. These patients have a high disease burden. When prophylactic treatments have low efficacy and tolerability, patients are in need of alternative therapeutic strategies and options. RECENT FINDINGS: In the last decade, a number of neuromodulation procedures have been introduced as treatment of chronic intractable headache patients when pharmacological treatments fail or are not well tolerated. Neurostimulation of peripheral and central nervous system has been carried out, and now, various non-invasive and invasive stimulation devices are available. Non-invasive neurostimulation options include vagus nerve stimulation, supraorbital stimulation and single-pulse transcranial magnetic stimulation; invasive procedures include occipital nerve stimulation, sphenopalatine ganglion stimulation and hypothalamic deep brain stimulation. In many cases, results supporting their use derive from open-label series and small controlled trial studies. Lack of adequate placebo hampers adequate randomized controlled trials. In this paper, we give an overview on the main neurostimulation procedures in terms of results and putative mechanism of cation.

Success, failure, and putative mechanisms in hypothalamic stimulation for drug-resistant chronic cluster headache.

Drug-resistant chronic cluster headache (CH) is an unremitting illness with excruciatingly severe headaches that occur several times daily. Starting in 2000, a total of 19 patients with long-lasting chronic CH, with multiple daily attacks unresponsive to all known prophylactics, received stimulation of the posterior inferior hypothalamic area ipsilateral to the pain as treatment. We report long-term follow-up (median 8.7 years, range 6-12 years) in 17 patients. Long-lasting improvement occurred in 70% (12 of 17): 6 are persistently almost pain-free; another 6 no longer experience daily attacks but rather episodic CH interspersed with long-lasting remissions. In 5 of 6 almost pain-free patients, the stimulators have been off for a median of 3 years (range 3-4 years). Five patients did not improve: 4 had bilateral CH, and 3 developed tolerance after experiencing relief for 1-2 years. Adverse events are electrode displacement (n=2), infection (electrode n=3; generator n=1), electrode malpositioning (n=1), transient nonsymptomatic third ventricle hemorrhage (n=1), persistent slight muscle weakness on one side (n=1), and seizure (n=1). This exceptionally long follow-up shows that hypothalamic stimulation for intractable chronic CH produces long-lasting improvement in many patients. Previous experience was limited to a median of 16 months. Important new findings are as follows: stimulation is well tolerated for many years after implantation; after several years during which stimulation was necessary for relief, a persistent almost pain-free condition can be maintained when stimulation is off, suggesting that hypothalamic stimulation can change disease course; tolerance can occur after marked long-lasting improvement; and bilateral chronic CH seems to predict poor response to hypothalamic stimulation.

Neuromodulation in drug-resistant primary headaches: what have we learned?

In the last years neurostimulation procedures have been introduced to treat primary neurovascular headaches, namely cluster headache and migraine. Hypothalamic stimulation is now accepted as therapeutic procedure to treat drug-resistant chronic cluster headache when patients suffer from daily multiple attacks. The inadequacy of the definition of the term "chronic" according to the International Headache Society criteria for both cluster headache and migraine when it is used to select patients for neurostimulation procedures is now evident. On the same side, there is no agreement about the use of the term "drug-resistant" again when it is used to select patients for neurostimulation procedures. We have proposed that only patients suffering from daily neurovascular headaches in the last 1-2 years, with complete drug-resistance should be proposed for invasive procedures.

Drug-resistant primary headache patients undergoing surgical therapies: how should we assess outcomes?

The introduction of neurostimulation procedures for chronic drug-resistant primary headaches has offered new hope to patients, but has also introduced new problems. The methods to be used in assessing clinical outcomes and monitoring treatment efficacy need careful attention. The International Headache Society guidelines recommend that treatment efficacy should be monitored by getting patients to report the number of attacks per day, in a headache diary. The headache diary is a fundamental instrument for objectively assessing subjective pain in terms of headache frequency, intensity and duration and analgesic consumption. The huge discrepancy sometimes reported between patient satisfaction and headache improvement suggests that patient satisfaction should not be a primary efficacy endpoint, and more importantly should not be put forward as an argument in establishing the efficacy of highly experimental neurostimulation procedures.

Cluster headache: pharmacological treatment and neurostimulation.

Cluster headache is a primary headache syndrome that is characterized by excruciatingly severe, strictly unilateral attacks of orbital, supraorbital or temporal pain, which last 15-180 min and are accompanied by ipsilateral autonomic manifestations (e.g. lacrimation and rhinorrhea). The attacks typically occur with circadian rhythmicity, being experienced at fixed hours of the day or night. In episodic cluster headache, attacks usually occur daily in 6-12-week bouts (cluster periods) followed by remission periods. In chronic cluster headache there is no notable remission. Cluster headache attacks reach full intensity very quickly and abortive agents need to be administered without delay. The pathophysiology of cluster headache is imperfectly understood and treatment has so far been mainly empirical. However, neuroimaging studies have prompted the successful use of hypothalamic stimulation to treat the condition. More recently, the less invasive technique of occipital nerve stimulation has shown promise in drug-refractory chronic cluster headache. This Review discusses both acute and preventive treatments for cluster headache and includes suggestions of how to use the available medications. The rationale, study results and selection criteria for neurostimulation procedures are also summarized, as are the disadvantages of these procedures.