Cluster headache not responsive to sumatriptan: A retrospective study.

INTRODUCTION: Subcutaneous sumatriptan, a 5HT1B/1D agonist, is the most effective drug in cluster headache acute treatment. About 25% of the patients do not respond to subcutaneous sumatriptan; the reasons for this are unknown. In this study, we compare clinical characteristics of cluster headache patients responding and non-responding to subcutaneous sumatriptan. METHODS: We retrospectively investigated the clinical records of 277 cluster headache patients. Patients reporting repeated satisfactory response to subcutaneous sumatriptan within 15 minutes were considered responders. RESULTS: Of 206 cluster headache patients who had used subcutaneous sumatriptan (mean age 45.6, 16% females, 48% chronic), 91% were responders, and 9% non-responders. Compared to responders, non-responders had longer and more frequent attacks: 60 (median; IQR 38-90) vs. 100 (60-120) minutes (p = 0.028), 4 (2.5-5) vs. 3 (2-4) attacks/day (p = 0.024). No other difference was found. CONCLUSIONS: In cluster headache attacks with long duration and high frequency, pain mechanisms not involving 5HT1B/1D receptors may play a more relevant role.

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.

Personality disorders in cluster headache: a study using the Millon Clinical Multiaxial Inventory-III.

A great deal of studies suggests that cluster headache (CH) patients are usually comorbid to anxiety-mood spectrum disorders and psychopathological symptoms; however, the personality profiles reported in the literature strictly depend on type of assessment used. Psychiatric comorbidities have been extensively studied in migraine and they are recognized to represent a major risk factor associated with poorer outcome, playing a role in the headache chronification process at once as cause and consequence of it. By contrast the incidence and role of psychopathological aspects in CH is still not clarified, insufficiently explored as the striking severity of such a physical pain apparently leaves no room to psychological explanations. The aim of the present study is to describe psychopathological aspects of CH patients by means of the Millon Clinical Multiaxial Inventory-III (MCMI-III), a psychological assessment tool compatible to Diagnostic and Statistical Manual of Mental Disorders (DSM-IV) that correlates personality disorders (PDs) and clinical syndromes. We included all consecutive inward patients with CH between January 2014 and December 2016. Patients were evaluated using the MCMI-III a validated inventory assessing 14 PDs Scales (coordinate with DSM-IV Axis II disorders) and ten Clinical Syndrome Scales (coordinate with DSM-IV Axis I disorders). Twenty-six CH patients (24 chronic CH) were tested. Personality disorders were present in 92% of the patients. The most frequent PDs were: obsessive-compulsive (30.8%), histrionic (26.9%), narcissistic (11.5%), paranoid (11.5%) and avoidant (11.5%). According to the MCMI-III, patients with CH showed a high prevalence of personality disorders (Axis II-DSM-IV). PDs in CH patients can play an important role in determining CH course toward chronification. These preliminary results suggest that behavioral treatments can find room to support more conventional drug and neurostimulation therapies in these patients. In addition, the very high prevalence of PDs in our patients suggests that CH could in some cases be considered among the spectrum of somatoform and pain syndromes in patients with PDs.

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.

Cluster headache: what has changed since 1999?

The peripheral and central origin of pain in cluster headache (CH) and trigeminal autonomic cephalgias (TACs) has been matter of debate. In the last decade, a number of information came from both animal and human studies. This paper briefly highlights main data from these studies. Taken together, there is now sufficient body of evidence indicating that CH and TACs can be regarded as a unique headache spectrum-syndrome, due to involvement of specific brain areas.

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.

Hypothalamic deep brain stimulation in the treatment of chronic cluster headache.

Cluster headache (CH) is a short-lasting unilateral headache associated with ipsilateral craniofacial autonomic manifestations. A positron emission tomography (PET) study has shown that the posterior hypothalamus is activated during CH attacks, suggesting that hypothalamic hyperactivity plays a key role in CH pathophysiology. On this basis, stimulation of the ipsilateral posterior hypothalamus was hypothesized to counteract such hyperactivity to prevent intractable CH. Ten years after its introduction, hypothalamic stimulation has been proved to successfully prevent attacks in more than 60% of 58 hypothalamic implanted drug-resistant chronic CH patients. The implantation procedure has generally been proved to be safe, although it carries a small risk of brain haemorrhage. Long-term stimulation is safe, and nonsymptomatic impairment of orthostatic adaptation is the only noteworthy change. Microrecording studies will make it possible to better identify the target site. Neuroimaging investigations have shown that hypothalamic stimulation activates ipsilateral trigeminal complex, but with no immediate perceived sensation within the trigeminal distribution. Other studies on the pain threshold in chronically stimulated patients showed increased threshold for cold pain in the distribution of the first trigeminal branch ipsilateral to stimulation. These studies suggest that activation of the hypothalamus and of the trigeminal system are both necessary, but not sufficient to generate CH attacks. In addition to the hypothalamus, other unknown brain areas are likely to play a role in the pathophysiology of this illness. Hypothalamus implantation is associated with a small risk of intracerebral haemorrhage and must be performed by an expert neurosurgical team, in selected patients.

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.

Vagus nerve stimulation in drug-resistant daily chronic migraine with depression: preliminary data.

Drug refractory chronic daily headache (CDH) is a highly disabling condition. CDH is usually regarded as the negative evolution of chronic migraine (CM) and is characterized by high prevalence of psychiatric disorders, especially mood disorders. Vagal nerve stimulation (VNS) is an established treatment option for selected patients with medically refractory epilepsy and depression. Neurobiological similarities suggest that VNS could be useful in the treatment of drug-refractory CM associated with depression. The aim of the study was to evaluate the efficacy of VNS in patients suffering from drug-refractory CM and depressive disorder. We selected four female patients, mean age 53 (range 43-65 years), suffering from daily headache and drug-refractory CM. Neurological examination and neuroradiological investigations were unremarkable. Exclusion criteria were psychosis, heart and lung diseases. The preliminary results in our small case series support a beneficial effect of chronic VNS on both drug-refractory CM and depression, and suggest this novel treatment as a valid alternative for this otherwise intractable and highly disabling condition.

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.

Application of revised criteria for chronic migraine and medication overuse headache in a tertiary Headache Centre.

Various diagnostic criteria have been proposed for chronic daily headaches. We tested the recently proposed revised criteria of the International Headache Society in a sample of patients with chronic daily headaches, most of whom were overusing acute medications, to assess their applicability in clinical practice compared to alternative classification systems.

Effects of nimesulide on nitric oxide-induced hyperalgesia in humans--a neurophysiological study.

Nonsteroidal anti-inflammatory drugs (NSAIDs) are known to induce analgesia mainly via the inhibition of cyclo-oxygenase. Several reports suggest that chronic pain is mediated by central sensitization, an N-methyl-D-aspartate (NMDA)-mediated phenomenon influenced by cyclo-oxygenase activity and nitric oxide (NO). In this double-blind study, we evaluated the effects of a preferential inhibitor of the inducible isoform of cyclo-oxygenase-2, nimesulide, on the spinal nociceptive flexion reflex (RIII reflex) before and after administration of an NO donor in healthy volunteers. Nimesulide caused a reduction of the RIII reflex area, which persisted after NO donor administration. Conversely, in the placebo group the RIII reflex area significantly increased following the administration of the NO donor. These data suggest a central effect for nimesulide, possibly related to a reduction of nociceptive activity at spinal level.

Changes in nociceptive flexion reflex threshold across the menstrual cycle in healthy women.

OBJECTIVE: We assessed the influence of changes in steroid hormones across the menstrual cycle on the spinal nociceptive reflex. METHOD: We studied in 14 healthy women during the follicular and luteal phase the nociceptive flexion reflex (RIII reflex), an objective neurophysiological method that allows exploring possible abnormal functioning of the pain-control system. The basal body temperature (BBT) was used to evaluate the different phases of the ovarian cycle. The menstrual distress questionnaire (MDQ) was also applied for monitoring somatic and psychological symptoms during the cycle. RESULTS: During the luteal phase, the threshold of the RIII reflex (Tr) and the psychophysical threshold for pain (Tp) were both significantly reduced compared with the follicular phase. Moreover, the reflex threshold in the luteal phase was negatively correlated to the total MDQ score of the recording day. CONCLUSIONS: A higher sensitivity to pain stimuli was observed during the luteal phase of the menstrual cycle, which probably results from a reduction in the inhibitory descending control on spinal nociceptive flexion reflex. Complex neuromodulatory interactions of ovarian steroids with other systems of neurotransmission (especially serotonergic) may account for these observations.