Involvement of the ipsilateral-to-the-pain anterior-superior hypothalamic subunit in chronic cluster headache.

BACKGROUND: Despite hypothalamus has long being considered to be involved in the pathophysiology of cluster headache, the inconsistencies of previous neuroimaging studies and a limited understanding of the hypothalamic areas involved, impede a comprehensive interpretation of its involvement in this condition. METHODS: We used an automated algorithm to extract hypothalamic subunit volumes from 105 cluster headache patients (57 chronic and 48 episodic) and 59 healthy individuals; after correcting the measures for the respective intracranial volumes, we performed the relevant comparisons employing logist regression models. Only for subunits that emerged as abnormal, we calculated their correlation with the years of illness and the number of headache attacks per day, and the effects of lithium treatment. As a post-hoc approach, using the 7 T resting-state fMRI dataset from the Human Connectome Project, we investigated whether the observed abnormal subunit, comprising the paraventricular nucleus and preoptic area, shows robust functional connectivity with the mesocorticolimbic system, which is known to be modulated by oxytocin neurons in the paraventricular nucleus and that is is abnormal in chronic cluster headache patients. RESULTS: Patients with chronic (but not episodic) cluster headache, compared to control participants, present an increased volume of the anterior-superior hypothalamic subunit ipsilateral to the pain, which, remarkably, also correlates significantly with the number of daily attacks. The post-hoc approach showed that this hypothalamic area presents robust functional connectivity with the mesocorticolimbic system under physiological conditions. No evidence of the effects of lithium treatment on this abnormal subunit was found. CONCLUSIONS: We identified the ipsilateral-to-the-pain antero-superior subunit, where the paraventricular nucleus and preoptic area are located, as the key hypothalamic region of the pathophysiology of chronic cluster headache. The significant correlation between the volume of this area and the number of daily attacks crucially reinforces this interpretation. The well-known roles of the paraventricular nucleus in coordinating autonomic and neuroendocrine flow in stress adaptation and modulation of trigeminovascular mechanisms offer important insights into the understanding of the pathophysiology of cluster headache.

Long-term occipital nerve stimulation for drug-resistant chronic cluster headache.

Introduction Chronic cluster headache is rare and some of these patients become drug-resistant. Occipital nerve stimulation has been successfully employed in open studies to treat chronic drug-resistant cluster headache. Data from large group of occipital nerve stimulation-treated chronic cluster headache patients with long duration follow-up are advantageous. Patients and methods Efficacy of occipital nerve stimulation has been evaluated in an experimental monocentric open-label study including 35 chronic drug-resistant cluster headache patients (mean age 42 years; 30 men; mean illness duration: 6.7 years). The primary end-point was a reduction in number of daily attacks. Results After a median follow-up of 6.1 years (range 1.6-10.7), 20 (66.7%) patients were responders (≥50% reduction in headache number per day): 12 (40%) responders showed a stable condition characterized by sporadic attacks, five responders had a 60-80% reduction in headache number per day and in the remaining three responders chronic cluster headache was transformed in episodic cluster headache. Ten (33.3%) patients were non-responders; half of these have been responders for a long period (mean 14.6 months; range 2-48 months). Battery depletion (21 patients 70%) and electrode migration (six patients - 20%) were the most frequent adverse events. Conclusions Occipital nerve stimulation efficacy is confirmed in chronic drug-resistant cluster headaches even after an exceptional long-term follow-up. Tolerance can occur years after improvement.

Deep brain stimulation in headache.

BACKGROUND: Deep brain stimulation of the posterior hypothalamic area was first introduced in 2000 to treat drug-refractory chronic cluster headache (CH). FINDINGS: So far, hypothalamic stimulation has been employed in 79 patients suffering from various forms of intractable short-lasting unilateral headache forms, mainly trigeminal autonomic cephalalgias. The majority were (88.6%) chronic CH, including one patient who suffered from symptomatic chronic CH-like attacks; the remaining were short-lasting unilateral neuralgiform headache attacks with conjunctival injection and tearing (SUNCT), one had paroxysmal hemicranias and one symptomatic trigeminal neuralgia. Overall, after a mean follow up of 2.2 years, 69.6% (55) hypothalamic-stimulated patients showed a ≥50% improvement. CONCLUSIONS: These observations need confirmation in randomised, controlled trials. A key role of the posterior hypothalamic area in the pathophysiology of unilateral short-lasting headaches, possibly by regulating the duration rather than triggering the attacks, can be hypothesised. Because of its invasiveness, hypothalamic stimulation can be proposed only after other, less-invasive, neurostimulation procedures have been tried.

Emerging therapies for chronic migraine.

Not all chronic migraines are medication-overuse headaches and so the challenge is how to treat them. Currently available pharmacological therapies may be ineffective or they are abandoned because of intolerable side effects. There is still much room for novel therapeutic approaches in those with drug refractory migraine (RM). Occipital nerve stimulation (ONS) and botulinum toxin type A have finally gained a level of evidence based on the results of RCTs and pooled analysis, which by and large have shown at least a modest but valuable therapeutic effect. For a long time, these two approaches were only supported by clinical experience and open-label studies. Considering the disabling nature of migraine disorder, the large prevalence and serious impact on health-related quality of life and health care costs, any degree of response to treatment is acceptable and welcomed by the patient. An important issues for future studies would be better patient selection when finding candidates for each procedure.

From neuroimaging to patients' bench: what we have learnt from trigemino-autonomic pain syndromes.

Trigeminal autonomic cephalalgias (TACs) are primary headaches including cluster headache, paroxysmal hemicrania, and short-lasting unilateral neuralgiform headache attacks with conjunctival injection and tearing (SUNCT). A number of neuroimaging studies have been conducted in last decade showing involvement of brain areas included in the pain matrix. Apart from pain matrix involvement, other neuroimaging findings data deserve special attention. The hypothalamic activation reported in the course of TAC attacks coupled with the efficacy of hypothalamic neurostimulation to treat drug-resistant TAC forms clearly indicate the posterior hypothalamus as a crucial area in TAC pathophysiology. In animal models this brain area has been shown to modulate craniofacial pain; moreover, hypothalamic activation occurs in other pain conditions, suggesting that posterior hypothalamus has a more complex role in TAC pathophysiology rather than simply being considered as a trigger. In contrast, hypothalamic activation may serve as a crucial area in terminating rather than triggering attacks. It also could lead to a central condition facilitating initiation of TAC attacks.

Long-term experience of neuromodulation in TACs.

Improvement in the biomedical and biotechnological research fields have allowed refinement of the neuromodulation approach in the treatment of a subgroup of medical disorders otherwise refractory to pharmacological treatment, such as chronic primary headaches. Chronic pain conditions imply central sensitisations and functional reorganisation that cannot be quickly or easily reversed. It appears evident that conventional treatment can sometimes be unsuccessful or only partially successful, and that relapse is common. Cluster headache (CH) is the most frequent trigeminal autonomic cephalalgia (TAC) and the most representative of this spectrum of disorders characterised by the association of headache and loco-regional signs and symptoms of facial parasympathetic activation. The striking features of circadian rhythmicity of attacks and circannual periodicity of cluster period, together with the neuroendocrine abnormalities, are suggestive of a neurochronobiological disorder with a central-diencephalic pathogenetic involvement, confirmed by direct evidence in functional neuroimaging studies of ipsilateral posterior hypothalamic activation during cluster attack. In 2000 these findings prompted a functional neurosurgery approach, with the first case of deep brain hypothalamic stimulation (DBS) in a severely disabled chronic CH patient. Since then, 18 implants in our centre and many others in different countries have been performed. Although the outcomes are encouraging, the invasive nature of the technique and the occurrence of rare but major adverse events have suggested a safer peripheral approach with occipital nerve stimulation (ONS).

Therapeutic neurostimulation in chronic headaches: problems of patient selection.

Chronic daily headache that does not respond or no longer responds to prophylaxis is commonly encountered at specialist headache centres. Animal and brain imaging studies indicate that peripheral neurostimulation affects brain areas involved in pain modulation, providing a rationale for its use in these conditions. We examine problems related to the selection of chronic daily headache patients for peripheral neurostimulation. These conditions are often associated with analgesic (including opioid) overuse, and psychiatric or other comorbidities, and the terms used to describe them (chronic migraine, transformed migraine, chronic daily headache and chronic tension-type headache) are insufficiently informative about these patients when proposed for neurostimulation. Longitudinal studies indicate that pre-existing subclinical depressive and anxious states play a key role in chronicisation and that the probability of responding to treatment is inversely related to headache frequency. These considerations suggest the need for extensive characterisation of patients proposed for neurostimulation. We propose that patients being considered for neurostimulation should be followed for at least a year, and that their headache over this time should consistently be frequent (all or most days) and drug refractory. We also propose that only completely drug-resistant (as opposed to partially drug-resistant) patients be considered for neurostimulation unless there are other indications.