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.

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.

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.

Neuromodulation of chronic headaches: position statement from the European Headache Federation.

The medical treatment of patients with chronic primary headache syndromes (chronic migraine, chronic tension-type headache, chronic cluster headache, hemicrania continua) is challenging as serious side effects frequently complicate the course of medical treatment and some patients may be even medically intractable. When a definitive lack of responsiveness to conservative treatments is ascertained and medication overuse headache is excluded, neuromodulation options can be considered in selected cases. Here, the various invasive and non-invasive approaches, such as hypothalamic deep brain stimulation, occipital nerve stimulation, stimulation of sphenopalatine ganglion, cervical spinal cord stimulation, vagus nerve stimulation, transcranial direct current stimulation, repetitive transcranial magnetic stimulation, and transcutaneous electrical nerve stimulation are extensively published although proper RCT-based evidence is limited. The European Headache Federation herewith provides a consensus statement on the clinical use of neuromodulation in headache, based on theoretical background, clinical data, and side effect of each method. This international consensus further gives recommendations for future studies on these new approaches. In spite of a growing field of stimulation devices in headaches treatment, further controlled studies to validate, strengthen and disseminate the use of neurostimulation are clearly warranted. Consequently, until these data are available any neurostimulation device should only be used in patients with medically intractable syndromes from tertiary headache centers either as part of a valid study or have shown to be effective in such controlled studies with an acceptable side effect profile.

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.

Secondary chronic cluster headache treated by posterior hypothalamic deep brain stimulation: first reported case.

INTRODUCTION: Deep brain stimulation (DBS) of the posterior hypothalamus (pHyp) has been reported as an effective treatment for primary, drug-refractory and chronic cluster headache (CCH). We here describe the use of such a procedure for the treatment of secondary CCH due to a neoplasm affecting the soft tissues of the right hemiface. METHODS: A 27-year-old man affected by infiltrating angiomyolipoma of the right hemiface who subsequently developed drug refractory homolateral CCH underwent DBS of the right pHyp region at the Fondazione IRCCS Istituto Nazionale Neurologico Carlo Besta. RESULTS: After surgery, the patient presented a significant reduction in frequency of pain bouts. However, because of a subsequent infection, the entire system was removed. After re-implantation of the system, successful outcome was observed at 2 years follow-up. DISCUSSION: This brief report shows the feasibility of pHyp DBS in secondary drug-refractory CCH syndromes; future reports are needed in order to confirm our positive result.

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.

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.

Occipital nerve stimulation (ONS). Surgical technique and prevention of late electrode migration.

Occipital nerve stimulation (ONS) is an emerging procedure for the treatment of cranio-facial pain syndromes and headaches refractory to conservative treatments. The aim of this report is to describe in detail the surgical intervention and to introduce some useful tricks that help to avoid late displacement and migration of the suboccipital leads. The careful description of the surgical steps may contribute to a standardization of the procedure and make the interpretation of results easier even if obtained in series of patients operated on by different authors.

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.

A neurophysiological study of myoclonus in patients with DYT11 myoclonus-dystonia syndrome.

Mutations in the epsilon-sarcoglycan (SGCE) gene have been associated with DYT11 myoclonus-dystonia syndrome (MDS). The aim of this study was to characterize myoclonus in 9 patients with DYT11-MDS presenting with predominant myoclonus and mild dystonia by means of neurophysiological techniques. Variously severe multifocal myoclonus occurred in all of the patients, and included short (mean 89.1 +/- 13.3 milliseconds) electromyographic bursts without any electroencephalographic correlate, sometimes presenting a pseudo-rhythmic course. Massive jerks could be evoked by sudden stimuli in 5 patients, showing a "startle-like" muscle spreading and latencies consistent with a brainstem origin. Somatosensory evoked potentials and long-loop reflexes were normal, as was silent period and long-term intracortical inhibition evaluated by means of transcranial magnetic stimulation; however, short-term intracortical inhibition revealed subtle impairment, and event-related synchronization (ERS) in the beta band was delayed. Blink reflex recovery was strongly enhanced. Myoclonus in DYT11-MDS seems to be generated at subcortical level, and possibly involves basal ganglia and brainstem circuitries. Cortical impairment may depend from subcortical dysfunction, but it can also have a role in influencing the myoclonic presentation. The wide distribution of the defective SCGE in DYT11-MDS may justify the involvement of different brain areas.

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.