Cluster headache: increased incorporation of (1-14C)arachidonic acid into phosphatidylserine in polymorphonuclear cells

Vasoactive metabolites deriving from arachidonic acid (AA) have been considered as putative mediators in the pathogenesis of various types of headache. In the present study we therefore compare the ability to synthesize AA containing precursor phospholipids in polymorphonuclear cells (PMNs) from healthy controls and cluster headache patients. 3.7% ± 1.4 (mean ± SD) of the (1-¹⁴C)AA incorporated into total PMN glycerophospholipids (GPLs) was recovered in the phosphatidylserine (PS) in a group of cluster headache patients ( n = 12). This was almost twice the value of 1.9% ± 0.8% found in a corresponding group of 24 healthy controls ( p < 0.001). A significant decrease in the incorporation of (1-¹⁴C)AA into phosphatidylcholine (PC) ( p < 0.01) and an increase in the incorporation of (1-¹⁴C)AA into phosphatidyletanolamine (PE) ( p < 0.05) were also found in cluster headache patients when compared to the control group. The increased incorporation of (1-¹⁴C)AA into PS in PMNs from this group of patients is interesting because PS plays an important role in the activation of protein kinase C, an enzyme involved in transmembrane signalling. The clinical implications of the present findings in cluster headache, if any, cannot yet be defined.     

Cluster headache: incorporation of (1-14C)oleic acid into phosphatidylserine in polymorphonuclear cells

As recently demonstrated by our group, polymorphonuclear cells (PMNs) from cluster headache patients have an increased ability to incorporate arachidonic acid (AA) and L-serine into phosphatidylserine (PS). To evaluate whether there is an increased incorporation into PS also from fatty acids not involved in eicosanoid metabolism, PMNs from controls (n = 14) and cluster headache patients (n = 12) were incubated with (1-14C)oleic acid. After 1 h 2.7% +/- 1.1 (mean value +/- SD) of the glycerophospholipid radioactivity was found in PS in controls, whereas 4.2% +/- 1.2 was found in cluster headache patients (p less than 0.005). For phosphatidylcholine (PC) the corresponding figures were 74.2 +/- 5.4 in controls and 66.7 +/- 7.6 in cluster headache patients (p less than 0.01). The results suggest that the de novo biosynthesis of PS is increased and the biosynthesis of PC is decreased in cluster headache. The results may have an effect on the role of PS as an obligate protein kinase C activator.     

Arachidonic acid metabolism in polymorphonuclear cells in headaches

Prostaglandins and leukotrienes have been implicated in the pathogenesis of various types of headache, mainly because some, but not all, cyclo-oxygenase inhibitors are effective in their treatment. We have therefore investigated whether a pathologically changed turnover of arachidonic acid (AA)-containing phospholipids can be seen in headache patients, using isolated polymorphonuclear cells (PMNs) from healthy controls and patients with chronic paroxysmal hemicrania (CPH) and cluster headache. PMNs from healthy controls incorporated 55% of the added (1-14C)AA into total lipids, and 0.5% +/- 0.14% of this radioactivity was found in the phosphatidylserine (PS) fraction. PMNs from a cluster headache and a CPH patient showed 300% and 900% increase in PS labeling from AA, respectively. No other phospholipids showed any difference between controls and patients. The results are discussed in connection with membrane signal transduction via the PS-dependent protein kinase C.     

Increased incorporation of L-(U-14C)serine into phosphatidylserine in polymorphonuclear cells from cluster headache patients

It has recently been demonstrated by our group that polymorphonuclear cells (PMNs) from cluster headache patients incorporate more arachidonic acid (AA) into phosphatidylserine (PS) than PMNs from controls. In the present report, the incorporation of L-(U-14C)serine into PS in PMNs from 14 healthy volunteers and 12 cluster headache patients was studied. PMNs from controls incorporated 1194 +/- 578 (mean +/- SD) cpm of L-(U-14C)serine into PS, 268 +/- 292 cpm into phosphatidylethanolamine, and 57 +/- 71 cpm into sphingomyeline. The corresponding figures in cluster headache patients were 2365 +/- 841 cpm, 291 +/- 207 cpm, and 88 +/- 66 cpm, respectively. Incorporation of L-(U-14C)serine into PS was significantly increased (p less than 0.0004) in PMNs from cluster headache patients, whereas no significant difference was seen in other lipids. The results confirm that patients with cluster headache have an increased incorporation of precursors into PS in isolated PMNs, and they indicate that this is due to an increased de novo synthesis of PS.     

PLASMA TESTOSTERONE LEVELS IN CLUSTER HEADACHE PRELIMINARY RESULTS

SYNOPSIS
Plasma testosterone values were obtained by the RIA method from two groups of cluster headache male patients in separate laboratories. In each group testosterone levels were compared between controls and cluster patients in active and remission periods. Significantly lower values were found in active cluster patients when compared to either cluster-remission or controls. The results are preliminary and suggest a possible association of lowered plasma testosterone levels with active cluster period in cluster headache male patients.     

A Case‐Control Study on Cortical Thickness in Episodic Cluster Headache

Objective.— This study aims at investigating cortical thickness in cluster headache patients as compared with a healthy control group. Background.— The pathobiology of cluster headache is not yet fully understood, although a dysfunction of the hypothalamus has been suggested to be causal. Previous studies in migraine and trigeminal neuropathic pain have demonstrated changes in cortical thickness using cortex segmentation techniques, but no data have been published on cluster headache. Methods.— We investigated 12 men with episodic cluster headache during a phase without acute headache as well as age and sex‐matched healthy controls using high resolution T1‐weighted magnetic resonance imaging acquired at 3T and performed a categorical whole‐brain surface‐based comparison of cortical thickness between groups. Furthermore, a correlation analysis of disease duration and cortical thickness was conducted. Results.— In comparison with control subjects, we found a reduction of cortical thickness in the angular gyrus and the precentral gyrus in cluster headache patients contralaterally to the headache side. These reductions did not correlate with disease duration. The cortical thickness of an area within the primary sensory cortex correlated with disease duration. Conclusions.— This study demonstrates alterations in cortical thickness in cluster headache patients suggesting a potential role of cortical structures in cluster headache pathogenesis. However, it cannot be determined from this study whether the changes are cause or consequence of the disorder. The correlation of cortical thickness with disease duration in the somatosensory cortex may suggest disease‐related plasticity in the somatosensory system.     

Cluster Headache: Pulse Rate Changes Evoked by Hyperoxia and Hypoxia

SYNOPSIS
To test the influence of arterial O₂ saturation (SaO₂) on heart rate in cluster headache, changes in pulse rate induced by hyperoxia and hypoxia were monitored in 11 cluster headache patients (6 during cluster period, and 5 during remission). The results were compared with those obtained in 11 age and sex matched healthy individuals. The subjects were administered 5 min each of 100% O₂ and 12% O₂ in nitrogen in sequence. The aim of the latter procedure was to reduce SaO₂ to approximately 80%. Pulse rate wasrecorded every minute from a finger pulse oximeter during the whole procedure.
Cluster headache patients, in particular during the bout, had a slightly lower basal pulse rate than controls (P>0.5, Student's t-test).This tendency was maintained throughout the test. Hyperoxia and hypoxia resulted in a marked, significant decrease and increase,respectively, in pulse rate from baseline values within each group. However, the difference between groups was not significant at anystage. Cluster headache patients therefore seem to have the same heart rate response to changes in SaO₂ as healthy individuals. Themarked heart rate changes which sometimes accompany cluster headache are unlikely to be caused by SaO₂ changes.     

Differential Changes in Receptor-Mediated Transduction in Migraine and Cluster Headache: Studies on Polymorphonuclear Leucocytes

SYNOPSIS
The distinctive clinical features of these conditions are borne out pharmacologically where drugs used with beneficial effects in one condition may exacerbate the other. This led us to investigate whether separate interacting/antagonistic receptor-mediated transduction systems may be affected in these conditions. Previous work in our laboratory indicated that the prostacyclin stimulation of adenylate cyclase in lymphocytes was significantly reduced in cluster headache but unaffected in migraine. Hence in this study, we investigated the polyphosphoinositide system which upon receptor activation gives rise to two second messengers, inositol trisphosphate and diacylglycerol. The chemotactic factor stimulation of inositol phosphate production in polymorphonuclear leucocytes (PMNs) was used as the assay system. The maximum response was obtained at approximately 0.1μM chemotactic factor (EC₅₀=13nM for control subjects). Female migraineurs (9 non-smokers) were compared with a matched group of controls and found to have a significantly reduced PMN response to chemotactic factor stimulation (42% of control at 0.1 μM) while male cluster headache patients (7 smokers) showed a response slightly greater than a matched group of controls (male smokers). Interestingly, cluster headache patients undergoing lithium treatment showed a significantly reduced response (39% of the control response at 0.1 μM chemotactic factor). This indicates that lithium may have its beneficial effect in cluster headache by suppressing an overactive polyphosphoinositide system while being of little benefit in migraine where a substantial depression is already evident. Appropriate targetting of drugs to these transduction systems may offer a useful basis for treatment.     

Abnormal neuromuscular transmission in cluster headache

OBJECTIVE: To identify and investigate any dysfunction of neuromuscular transmission in episodic cluster headache. BACKGROUND: Abnormal neuromuscular transmission has been shown in migraine with aura and in migraine without aura by using single fiber electromyography. Especially for migraine with aura, a genetic cause has been postulated. Episodic cluster headache is a primary headache disorder in which genetic factors may, at times, play a strong role. METHODS: Single fiber electromyography during voluntary contraction of the extensor digitorum communis muscle, nerve conduction studies of upper and lower extremities, and concentric needle electromyography of the extensor digitorum communis were performed on 6 patients with episodic cluster headache and 6 age-matched normal controls. Twenty potential pairs were recorded from each subject. Twenty individual jitter values and a mean jitter value were calculated for each subject. Both mean individual jitter values and numbers of abnormal individual jitter values were compared in patients with cluster headache versus normal controls. RESULTS: Three of 6 patients with episodic cluster headache showed pronounced neuromuscular transmission abnormalities by single fiber electromyography. None of the controls had any neuromuscular transmission abnormality. Another patient with episodic cluster headache had borderline dysfunction of neuromuscular transmission. Transmission was clearly normal in only 2 of 6 patients with cluster headache. CONCLUSION: These results suggest that episodic cluster headache may share the same abnormality of neuromuscular transmission observed in migraine.     

Sensitivity to various stimuli in primary headaches: a questionnaire study

Questions about discomfort or pain produced by various stimuli (e.g., light, sound, exercise, neck movements) are currently used to differentiate between various primary headache disorders. In order to evaluate the usefulness of differences in sensitivity to physical stimuli in headache diagnosis, the answers to a questionnaire about sensitivity to various stimuli were compared in 68 patients with migraine, 45 with tension-type headache, 46 with cluster headache, and 23 patients with cervicogenic headache, and in 71 controls. Even among controls, a high proportion reported that many of these stimuli could elicit some degree of discomfort or pain. Without headache, migraineurs differed from the other patients with headache and controls mainly in their increased sensitivity to light. With headache, patients with tension-type headache were the least sensitive and migraineurs were the most sensitive to all stimuli, except for stimuli stemming from neck movements, to which patients with cervicogenic headache were most sensitive. Migraineurs also reported the highest degree of sensitivity regarding aggravation and provocation of headache. However, the most striking finding was that all patient groups, cluster headache in particular, became significantly more sensitive with headache than without headache to almost all stimulus categories. This may indicate that these headaches share important pathogenetic mechanisms. The fact that no headache had a very specific sensitivity profile may point to weaknesses of present headache classification systems.     

Respiratory Sinus Arrhythmia in Cluster Headache Syndrome

SYNOPSIS
Respiratory sinus arrhythmia is regarded as indicative of cardiac vagal integrity. A ratio of the longest R-R interval to the shortest R-R interval during deep breathing test (E:I ratio) was calculated in controls (n=49), cluster headache (n=33) and CPH (n=4) patients, E:I ratio decreased with age but was not dependent upon sex or upon smoking habits. Furthermore, there were no significant differences as regards E:I ratio between cluster headache patients in and outside a bout, or between patients with right-sided and left-sided headache. However, the E:I ratio was found to be significantly lower in the cluster headache group as such, when compared with controls, but the number of patients disclosing pathological or borderline results was small, 2 and 2, respectively. This may indicate that a putative vagal dysfunction in cluster headache is usually less marked than in patients with e.g. diabetic autonomic neuropathy. Significant attack-related change in the E:I ratio were detected in all individual patients though these changes were not of a uniform nature from individual to individual. E:I ratios were rather high in 3 out of 4 CPH patients examined. However, the number of patients in this group is too small to allow definite statements about the difference between CPH end cluster headache with regard to E:I ratios. There was no significant difference between E:I ratios outside and during a mild, short, mechanically precipitated attack in a single CPH patient.     

Sympathetic skin response in migraineurs and patients with medication overuse headache

BACKGROUND: Autonomic dysfunction has been reported in patients with migraine, and it may play a role in promoting attacks. OBJECTIVE: To investigate changes in the autonomic function of migraineurs and patients with medication overuse headache via sympathetic skin response, and to determine whether psychiatric comorbidity is related to any changes recorded. METHODS: A consecutive series of patients with migraine (n = 45) and medication overuse headache (n = 53) were studied. Patients with other chronic diseases requiring medication were excluded. Sympathetic skin response latencies and amplitudes from the patients with headache (N = 98) and 40 healthy controls were compared statistically. RESULTS: Sympathetic skin response latencies in patients with medication overuse headache and in migraineurs were significantly longer than in controls. To analyze the effect of psychiatric comorbidity, patients with medication overuse headache and migraineurs were each divided into 2 groups: those with psychiatric comorbidity and those without comorbidity. When the sympathetic skin response results of these 4 groups were compared with controls, the only statistically significant difference was between the sympathetic skin response latencies of controls and the latencies of patients with psychiatric comorbidity. We could not find any difference between the results from patients without psychiatric comorbidity and those of controls. CONCLUSION: Psychiatric disease may affect the results of autonomic function testing in migraineurs and patients with medication overuse headache. Consideration should be given to excluding patients with psychiatric comorbidity from studies investigating autonomic dysfunction in patients with headache.     

Concentration and uptake of 5-hydroxytryptamine in platelets from cluster headache and migraine patients

Concentrations of 5-hydroxytryptamine (5-HT) in platelets were determined in 33 cluster headache patients (17 males) and in 34 migraine patients (16 males) outside attacks. The 5-HT uptake into platelets was measured and the kinetic constants V_max and K_m determined in 26 cluster patients (14 males) and in 30 migraine patients (13 males). Significantly lower 5-HT concentrations in whole blood were found in cluster headache and migraine patients than in 50 healthy controls (19 males). The V_max and K_m values of the 5-HT uptake were significantly lower in cluster headache and migraine patients compared with 22 healthy controls (9 males). The 5-HT concentrations and the kinetics of the 5-HT uptake did not differ between cluster headache and migraine. In healthy controls a significant positive correlation was found between the 5-HT uptake rate at 0.25 μM and K_m but not in cluster headache and migraine patients. The 5-HT concentrations in whole blood correlated positively with V_max and K_m, respectively, in cluster headache and with K_m in healthy controls but not with V_max nor with K_m in migraine. There was no obvious relation between the kinetics of platelet monoamine oxidase (MAO) and the 5-HT uptake except for an increased incidence of low V_max of MAO and low K_m of the 5-HT uptake in cluster headache. The kinetics of the 5-HT uptake was apparently not related to the state of migraine. The results indicate a possible constitutional trait in cluster headache and migraine expressed as low 5-HT concentrations in whole blood and low V_max and K_m of the 5-HT uptake into platelets.     

Platelet aggregation profiles in cluster headache

BACKGROUND: Platelets are activated in patients with cluster headache, during both the remission period and the active cycles. OBJECTIVE: To delineate more clearly the origin of platelet activation in cluster headache. Methods.-Platelet aggregation induced by collagen (0.5 micro g/mL and 2 micro g/mL), adenosine diphosphate (10-5 M and 10-6 M), and platelet-activating factor (10-6 M and 10-7 M) was determined by the Born's method in 26 patients with cluster headache and 24 sex- and age-matched controls. RESULTS: The platelets of patients with cluster headache aggregated significantly less to collagen at a concentration of 0.5 micro g/mL compared to those of controls (P =.04). The extent of platelet aggregation obtained with a higher dose of collagen (2 micro g/mL) was in the same range in both groups. Platelet aggregation obtained via adenosine diphosphate at a concentration of 10-6 M was significantly reduced in patients with cluster headache in comparison to controls (P =.002), but no differences were found at a concentration of 10-5 M. In contrast, the platelets of patients with cluster headache aggregated significantly more to platelet-activating factor at both the concentrations of 10-6 M (P =.001) and 10-7 M (P =.00001) compared to those of controls. CONCLUSIONS: This study suggests that platelet aggregation is impaired in patients with cluster headache during the active phase of the disease. We found hypoaggregation in response to low doses of collagen and adenosine diphosphate, and hyperaggregation when platelets were stimulated with platelet-activating factor. Any interpretation of these results can only be speculative. It may be that impairment of platelet aggregation with collagen and adenosine diphosphate may indicate a derangement of nitric oxide function, while the hypersensitivity to platelet-activating factor may be due to fluctuations in its plasma levels.     

Acetazolamide Testing of Cerebral Vasodilator Capacity Provokes "Vascular" But Not Tension Headaches

Cerebrovascular capacitance was tested by measuring local cerebral blood flow (LCBF) by xenon-contrasted CT scanning before and after the oral administration of 14.3 mg/kg of acetazolamide among 45 subjects including 15 age-matched controls without history of headache, 20 migraineurs with and without aura, 3 patients with cluster headache, and 7 patients with tension-type headache. Percentage increases of LCBF were measured in 10 regions located throughout both hemispheres. Laterality indices for asymmetric LCBF increases were calculated. Local cerebral blood flow in cortical gray matter increased 5.9% in controls, 9.9% in patients with tension headaches, but 18.6% in both migraine and cluster headache patients; significantly greater LCBF increases than among controls or among patients with tension headaches (P<0.05). Increases in LCBF were significantly asymmetric among migraine and cluster patients and provoked typical unilateral vascular headaches which responded to sumatriptan. Maximal asymmetric LCBF increases also corresponded to the reported side of the induced headaches confirming their vascular pathogenesis. Patients with tension headaches and controls without history of headache did not develop head pain after acetazolamide.     

Cluster headache and "dynamite headache": Blood flow velocities in the middle cerebral artery

Nitroglycerin (NG) induces in cluster headache patients and controls an increase in systemic diastolic blood pressure and/or heart rate and a decrease in blood flow velocity in the middle cerebral artery (VMCA). Termination of NG induced cluster headache-like attack was correlated to an increase of VMCA compared to the VMCA before NG administration (p less than 0.01). This increase was not found in patients without attack or in controls. The NG induced "dynamite headache" in the controls subsided when blood pressure and heart rate were normalized, but the decrease of VMCA still prevailed. Orbital phlebograms have shown pathologic changes in cluster headache and in Tolosa-Hunt syndrome but not in controls. Ocular sympathetic nerves are involved in cluster headache but seldom in Tolosa-Hunt syndrome. It is suggested that the start of a cluster headache attack is due to an increase and the termination of the attack to a decrease of blood flow to the sympathoplegic phlebopathic cavernous sinus.     

Neuroendocrine dysfunction in cluster headache

Current views on cluster headache pathogenesis indicate a primary central nervous system dysfunction, in particular a hypothalamic involvement. To confirm the hypothalamic involvement in cluster headache we evaluated the hypothalamic-pituitary axis responsiveness with the thyrotrophin releasing hormone (TRH) test. A dose of 200 micrograms of TRH was administered i.v. to nine healthy controls, 32 patients with cluster headache during cluster period and 16 in remission period. Delta maximum thyrotrophin (TSH) was significantly lower in patients with cluster headache during cluster period (p less than 0.05 versus healthy controls and cluster headache patients in remission). No difference was observed between healthy controls and cluster headache patients in remission. A monoaminergic dysfunction at the hypothalamic level is hypothesized.     

Cluster Headache and Intercalated Seizures in a Young Man: Therapeutic Effectiveness of Flunarizine

A young man suffering from both cluster headache and epilepsy is reported. Since the age of 37 he had recurrent generalized tonic-clonic seizures; one year later cluster headache attacks began. Neurological examination, standard laboratory tests and CT-scan were normal. The EEG showed medium-voltage sharp waves, not blocking upon eye opening, over the right parieto-temporal region. Flunarizine was added to his phenytoin therapy; it controlled both paroxysmal disorders. After six months, flunarizine was discontinued and during a one year follow-up the patient remained symptom-free. This calcium channel blocker can be regarded as an ideal drug in patients suffering from both cluster headache and epilepsy; it controls this headache syndrome and is a useful add-on to standard anti-convulsant therapy.     

Changes in Neutrophil Met-Enkephalin Containing Peptides in Episodic Cluster Headache

We have previously demonstrated an increase in plasma met-enkephalin levels during the pain attacks in episodic cluster headache. The present study was undertaken in order to clarify the source of the plasma met-enkephalin increase. Recent evidence has shown that peripheral blood polymorphonuclear cells contain peptides derived from the proenkephalin A system, which can be released by specific stimuli. We studied neutrophil met-enkephalin containing peptides (NMECP) in 27 episodic cluster headache patients: 24 in a cluster period (6 of them during a pain attack), and 3 in the remission period. Neutrophil met-enkephalin containing peptide levels (after sequential enzymatic digestion with trypsin and carboxypeptidase B) were determined by radioimmunoassay with specific antiserum. Neutrophil peptide concentration (pmol/mg prot) was lower (p less than 0.01) in patients during the pain attack (14.4 +/- 0.36) than after their pain had subsided (36.7 +/- 0.31) and lower than in the remission period patients (35.8 +/- 0.4). We conclude that neutrophil met-enkephalin containing peptides decrease during pain in episodic cluster headache, and that they may be involved in the concomitant plasma met-enkephalin increase.     

Abnormal 5-HT1D receptor function in cluster headache: a neuroendocrine study with sumatriptan

The purpose of this study was to assess the sensitivity of 5-HT(1D) receptors in patients with episodic cluster headache using sumatriptan as a pharmacological probe. The drug, a selective 5-HT(1B/1D) agonist, stimulates the secretion of growth hormone and inhibits the release of prolactin, adrenocorticotropic hormone (ACTH) and cortisol. These effects may be used to explore the function of serotonergic systems in vivo. We administered subcutaneous sumatriptan and placebo to 20 patients with cluster headache (10 in the active phase and 10 in the remission period) and to 12 controls. The sumatriptan-induced increase of growth hormone concentrations was significantly (P < 0.05) blunted in patients with active cluster headache. Prolactin and ACTH responses to the drug were significantly (P < 0.05) reduced in patients with cluster headache, both in the active and in the remission period. Our results suggest that cerebral serotonergic functions mediated by 5-HT(1D) receptors are altered in patients with episodic cluster headache.