Koen Paemeleire

Inositol-trisphosphate-dependent intercellular calcium signaling in and between astrocytes and endothelial cells.

Interactions between astrocytes and endothelial cells are believed to play an important role in the control of blood‐brain barrier permeability and transport. Astrocytes and endothelial cells respond to a variety of stimuli with an increase of intracellular free calcium ([Ca2+]i) that is propagated to adjacent cells as an intercellular Ca2+ wave. We hypothesized that intercellular Ca2+ signaling also occurs between astrocytes and endothelial cells, and we investigated this possibility in co‐cultures of primary astrocytes and an endothelial cell line using caged messengers. Intercellular Ca2+ waves, induced by mechanical stimulation of a single cell, propagated from astrocytes to endothelial cells and vice versa. Intercellular Ca2+ waves could also be induced by flash photolysis of pressure‐injected caged inositol trisphosphate (IP3) and also by applying the flash to remote noninjected cells. Ca2+ waves induced by flash photolysis propagated from endothelial cells to astrocytes but not from astrocytes to endothelial cells even though caged IP3 diffused between the two cell types. Flash photolysis of caged Ca2+ (NP‐EGTA) resulted in an increase of [Ca2+]i but did not initiate an intercellular Ca2+ wave. We conclude that an increase of IP3 in a single cell is sufficient to initiate an intercellular Ca2+ wave that is propagated by the diffusion of IP3 to neighboring cells and that can be communicated between astrocytes and endothelial cells in co‐culture. By contrast, Ca2+ diffusion via gap junctions does not appear to be sufficient to propagate an intercellular Ca2+ wave. We suggest that intercellular Ca2+ waves may play a role in astrocyte‐endothelial interactions at the blood‐brain barrier. GLIA 24:398–407, 1998.

Medication-overuse headache in patients with cluster headache

Objective: Medication-overuse headache (MOH) in cluster headache (CH) patients is incompletely described, perhaps because of the relatively low prevalence of CH. Methods: The authors describe a retrospective series of 17 patients (13 men, 4 women) with CH who developed MOH in association with overuse of a wide range of monotherapies or varying combinations of simple analgesics (n = 9), caffeine (n = 1), opioids (n = 10), ergotamine (n = 3), and triptans (n = 14). The series includes both episodic (n = 7) and chronic (n = 10) CH patients. Results: A specific triptan-overuse headache diagnosis was made in 3 patients, an opioid-overuse headache diagnosis was made in 1 patient, and an ergotamine-overuse headache diagnosis was made in 1 patient. In approximately half of the patients (n = 8), the MOH phenotype was a bilateral, dull, and featureless daily headache. In the other 9 patients, the MOH was characterized by at least one associated feature, most commonly nausea (n = 6), exacerbation with head movement (n = 5), or throbbing character of the pain (n = 5). The common denominator in 15 patients was a personal or family history, or both, of migraine. The 2 other patients gave a family history of unspecified headaches. Medication withdrawal was attempted and successful in 13 patients. Conclusions: Medication-overuse headache is a previously underrecognized and treatable problem associated with cluster headache (CH). CH patients should be carefully monitored, especially those with a personal or family history of migraine.

Astrocyte–endothelial cell calcium signals conveyed by two signalling pathways

Astrocytes and endothelial cells are in close contact with each other at the blood-brain barrier, where important molecular transports take place. Despite these key morphological and functional properties, little is known regarding the dynamic signalling processes that occur between these two cell types. We investigated astrocyte-endothelial cell calcium signalling mechanisms in a coculture model prepared from primary rat cortical astrocytes and ECV304 cells. We used flash photolysis of caged inositol-trisphosphate (IP3) and gentle mechanical stimulation to trigger astrocyte-endothelial cell calcium signals and to investigate the underlying propagation mechanisms. Photolytically releasing IP3 in a single cell triggered increases in cytoplasmic calcium concentration that propagated between astrocytes and endothelial cells in either direction. These propagating calcium signals did not cross cell-free zones and were not affected by fast superfusion or by the purinergic inhibitors apyrase and suramin, indicating that they are communicated through an intracellular pathway in conjunction with gap junctions. Electrophysiological experiments confirmed a low degree of astrocyte-endothelial cell electrical cell-to-cell coupling. Mechanical stimulation of a single cell also triggered astrocyte-endothelial cell calcium signals but, in contrast to the former triggering mode, these signals crossed cell-free zones and were significantly inhibited by apyrase, thus indicating the involvement of an extracellular and purinergic messenger. Astrocyte-endothelial cell calcium signalling also occurred in cocultures prepared with astrocytes and primary rat brain capillary endothelial cells. We conclude that astrocytes and endothelial cells can exchange fast-acting calcium signals (time scale of seconds) that can be communicated through an intracellular/gap junctional pathway and an extracellular purinergic pathway.

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.

Neurostimulation approaches to primary headache disorders

Purpose of reviewConventional management options in medically intractable chronic-headache syndromes, such as chronic migraine, chronic cluster headache and hemicrania continua, are often limited. This review summarizes the current concepts, approaches and outcome data of invasive device-based neurostimulation approaches using occipital-nerve stimulation and deep-brain stimulation. Recent findingsRecently, there has been considerable progress in neurostimulation approaches to medically intractable chronic-headache syndromes. Previous studies have analysed the safety and efficacy of suboccipital neurostimulation in drug-resistant chronic-headache syndromes such as in chronic migraine, chronic cluster headache and hemicrania continua. The studies suggest suboccipital neurostimulation can have an effect even decades after onset of headaches, thus representing a possible therapeutic option in patients that do not respond to any medication. Similarly, to date over 50 patients with cluster headaches underwent hypothalamic deep-brain stimulation. From these, an average of 50–70% did show a significant positive response. SummaryThese findings will help to further elucidate the clinical potential of neurostimulation in chronic headache.

Unilateral photophobia or phonophobia in migraine compared with trigeminal autonomic cephalalgias

Our objective was to compare the presence of self-reported unilateral photophobia or phonophobia, or both, during headache attacks comparing patients with trigeminal autonomic cephalalgias (TACs)—including cluster headache, shortlasting unilateral neuralgiform headache attacks with conjunctival injection and tearing (SUNCT) and paroxysmal hemicrania—or hemicrania continua, and other headache types. We conducted a prospective study in patients attending a referral out-patient clinic over 5 months and those admitted for an intramuscular indomethacin test. Two hundred and six patients were included. In episodic migraine patients, two of 54 (4%) reported unilateral photophobia or phonophobia, or both. In chronic migraine patients, six of 48 (13%) complained of unilateral photophobia or phonophobia, or both, whereas none of the 24 patients with medication-overuse headache reported these unilateral symptoms, although these patients all had clinical symptoms suggesting the diagnosis of migraine. Only three of 22 patients (14%) suffering from new daily persistent headache (NDPH) experienced unilateral photophobia or phonophobia. In chronic cluster headache 10 of 21 patients (48%) had unilateral photophobia or phonophobia, or both, and this symptom appeared in four of five patients (80%) with episodic cluster headache. Unilateral photophobia or phonophobia, or both, were reported by six of 11 patients (55%) with hemicrania continua, five of nine (56%) with SUNCT, and four of six (67%) with chronic paroxysmal hemicrania. Unilateral phonophobia or photophobia, or both, are more frequent in TACs and hemicrania continua than in migraine and NDPH. The presence of these unilateral symptoms may be clinically useful in the differential diagnosis of primary headaches.

Calcium signal communication in the central nervous system

Abstract The communication of calcium signals between cells is known to be operative between neurons where these signals integrate intimately with electrical and chemical signal communication at synapses. Recently, it has become clear that glial cells also exchange calcium signals between each other in cultures and in brain slices. This communication pathway has received utmost attention since it is known that astrocytic calcium signals can be induced by neuronal stimulation and can be communicated back to the neurons to modulate synaptic transmission. In addition to this, cells that are generally not considered as brain cells become progressively incorporated in the picture, as astrocytic calcium signals are reported to be communicated to endothelial cells of the vessel wall and can affect smooth muscle cell tone to influence the vessel diameter and thus blood flow. We review the available evidence for calcium signal communication in the central nervous system, taking into account a basic functional unit –the brain cell tripartite‐ consisting of neurons, glial cells and vascular cells and with emphasis on glial‐vascular calcium signaling aspects.

Phenotype of patients responsive to occipital nerve stimulation for refractory head pain

Occipital nerve stimulation (ONS) has been employed off-label for medically refractory head pain. Identification of specific headache diagnoses responding to this modality of treatment is required. Forty-four patients with medically refractory head pain and treated with ONS were invited to participate in a retrospective study including a clinical interview and, if necessary, an indomethacin test to establish the headache phenotype according to the International Classification of Headache Disorders, 2nd edn (ICHD-II). We gathered data from questionnaires before implantation, at 1 month after implantation, and at long-term follow-up. Twenty-six patients consented and were phenotyped. At 1 month follow-up and at long-term follow-up a significant decrease in all pain parameters was noted, as well as in analgesic use. Quality of sleep and quality of life improved. Patient satisfaction was generally high as 80% of patients had ≥ 50% pain relief at long-term follow-up. The overall complication rate was low, but revisions were frequent. After phenotyping, two main groups emerged: eight patients had ‘Migraine without aura’ (ICHD-II 1.1) and eight patients ‘Constant pain caused by compression, irritation or distortion of cranial nerves or upper cervical roots by structural lesions’ (ICHD-II 13.12). Overuse of symptomatic acute headache treatments was associated with less favourable long-term outcome in migraine patients. We conclude that careful clinical phenotyping may help in defining subgroups of patients with medically refractory headache that are more likely to respond to ONS. The data suggest medication overuse should be managed appropriately when considering ONS in migraine. A controlled prospective study for ONS in ICHD-II 13.12 is warranted.

31P-MRS demonstrates a reduction in high-energy phosphates in the occipital lobe of migraine without aura patients

Background: Differences in brain energy metabolism have been found between migraine patients and controls in previous phosphorus magnetic resonance spectroscopy (31P-MRS) studies, most of them emphasizing migraine with aura (MwA). The aim of this study was to verify potential changes in resting-state brain energy metabolism in patients with migraine without aura (MwoA) compared to control subjects by 31P-MRS at 3 tesla. Methods: Quantification was performed using the phantom replacement technique. MRS measurements were performed interictally and in the medial occipital lobe of 19 MwoA patients and 26 age-matched controls. Results: A significantly decreased phosphocreatine concentration ([PCr]) was found as in previous studies. While adenosine triphosphate concentration ([ATP]) was considered to be constant in previously published work, this study found a significant decrease in the measured [ATP] in MwoA patients. The inorganic phosphate ([Pi]) and magnesium ([Mg2+]) concentrations were not significantly different between MwoA patients and controls. Conclusions: The altered metabolic concentrations indicate that the energy metabolism in MwoA patients is impaired, certainly in a subgroup of patients. The actual decrease in [ATP] adds further strength to the theory of the presence of a mitochondrial component in the pathophysiology of migraine.

Self-medication of regular headache: a community pharmacy-based survey.

Background:  This observational community pharmacy‐based study aimed to investigate headache characteristics and medication use of persons with regular headache presenting for self‐medication.