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.     

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.     

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.     

Cluster headache sine headache: two new cases in one family

We report two cases of cluster headache sine headache occurring in a family of cluster headache sufferers. A 54-year-old female, suffered for 15 years from short-lasting, right-sided attacks of eye reddening, lacrimation, rhinorrea, palpebral oedema and miosis, seven to eight times per day, in periods of 20-30 days. She did not experience headache, either with or without these phenomena. Her son suffers from periorbital, short-lasting, right-sided painful attacks accompanied by eye reddening, lacrimation, rhinorrea and nasal stiffnesss, occurring in periods of 30-35 days. Soon after the end of the current cluster period he still had daily attacks lasting 10-15 min, with the oculo-nasal autonomic phenomena only. The occurrence of cluster headache sine headache and cluster headache in the same family strongly suggests that the first condition is related to the cluster headache syndrome. Cluster headache sine headache should be considered as a subtype of the cluster headache syndrome.     

Serotonin metabolism in cluster headache

Despite some evidence of the involvement of the serotonergic system in cluster headache (CH) pathophysiology, the serotonin (5HT) metabolism has so far been poorly studied. The aim of this study was to investigate plasma and platelet levels of 5HT and 5-hydroxyindoleacetic acid (5HIAA) in CH patients in the active period of the disease. Nineteen CH sufferers and 17 sex- and age-matched healthy controls were studied. CH patients showed significantly higher plasma levels of 5HT and 5HIAA compared to controls (5HT: 5.7±6.1 ng/ml vs 0.2±0.2 ng/ml; p =0.02; 5HIAA: 34.7±46.1 ng/ml vs 0.6±0.7 ng/ml; p =0.004). In platelet 5HT levels were slightly reduced in CH patients in comparison with those of control subjects (662.4±522.3 ng/10⁻⁸ platelets vs 832.1±587.9 ng/10⁻⁸ platelets; n.s.) and 5HIAA levels resulted significantly lower in CH sufferers than in control subjects (3.2±2.6 ng/10⁻⁸ platelets vs 6.7±4.8 ng/10⁻⁸ platelets; p =0.04). Our data suggest that CH is characterized by an increase of plasma serotonergic metabolism that could reflect an involvement of the central serotonergic system in the pathogenesis of CH.     

Cluster headache. Premonitory symptoms

The emergence of symptoms which may precede by days the onset of a series of painful attacks of cluster headache is not often reported in the medical literature. In this report, four patients who described these premonitory symptoms are presented. The importance of premonitory symptoms is emphasized, for they provide a means to institute an early prophylactic therapy and the possibility of clarifying the physiopathology of this primary headache.     

Cluster headache

Cluster headache is a stereotypic, primary headache disorder that is marked by repeated short-lasting attacks of severe, unilateral head pain and associated autonomic symptoms. Cluster headache is probably due to an abnormality in the circadian hypothalamic generator with subsequent trigeminovascular activation. We have reviewed the clinical manifestations, pathophysiology, gender differences, and treatment options in cluster headache.     

Cluster headache and paroxysmal hemicrania: differential diagnosis

The utility of the differences between cluster headache (CH) and paroxysmal hemicrania (PH) is limited by the considerable overlap of their clinical characteristics. We compared 54 patients with CH and eight patients with PH in terms of demographic features, characteristics of headache attacks, associated autonomic features, temporal forms of disorders, and response to verapamil. According to our results, clinical features that distinguished CH and PH patients were: maximal pain localization, ocular in CH patients and extra-ocular in PH group; mean attack duration was longer and mean attack frequency was lower in CH patients in comparison with PH patients. Conjuctival injection was the only autonomic sign seen more frequently in CH patients. There were more CH patients with episodic and more PH patients with unremitting form of the disorder in examined groups. Although statistical analysis pointed out a significant difference between these clinical features, there was no clinical characteristic that exclusively belonged to one of these headache entities. Demographic characteristics (age, gender, social background), the other headache attack features (nocturnal attacks, interattack tenderness), the other autonomic signs, as well as the response to verapamil did not differ significantly between two groups.     

Cluster headache and internal carotid artery dissection: two cases and review of the literature

We describe 2 patients with cluster headache attacks associated with a dissection of the ipsilateral internal carotid artery at the extra-intracranial passage. These cases highlight the need for extensive neuroradiological investigation in cluster headache patients when atypical features are present. We also performed a PubMed search to review the current literature data about this association.     

Cluster headache due to structural lesions: A systematic review of published cases

BACKGROUNDCluster headache (CH) is a severe incapacitating headache disorder. By definition, its diagnosis must exclude possible underlying structural conditions.AIMTo review available information on CLH caused by structural lesions and to provide better guides in the distinguishing process and to ensure that there is not a potentially treatable structural lesion.METHODSWe conducted a systematic review of 77 published cases of symptomatic CH and cluster-like headache (CLH) in PubMed and Google Scholar databases.RESULTSStructural pathologies associated with CH were vascular (37.7%), tumoral (32.5%) and inflammatory (27.2%). Brain mass-like lesions (tumoural and inflammatory) were the most common diseases (28.6%), among which 77.3% lesions were at the suprasellar (pituitary) region. Cases of secondary CH related to sinusitis rose dramatically, occupying 19.5%. The third most common disease was internal carotid artery dissection, accounting for 14.3%. Atypical clinical features raise an early suspicion of a secondary cause: Late age at onset and eye and retroorbital pains were common conditions requiring careful evaluation and were present in at least one-third of cases. Abnormal neurological examination was the most significant red flag for impaired cranial nerves. CLH patients may be responsive to typical CH treatments; therefore, the treatment response is not specific. CLH can be triggered by contralateral structural pathologies. CLH associated with sinusitis and cerebral venous thrombosis required more attention.CONCLUSIONSince secondary headache could perfectly mimick primary CH, neuroimaging should be conducted in patients in whom primary and secondary headaches are suspected. Cerebral magnetic resonance imaging scans is the diagnostic management of choice, and further examinations include vessel imaging with contrast agents and dedicated scans focusing on specific cerebral areas (sinuses, ocular and sellar regions). Neuroimaging is as necessary at follow-up visits as at the first observation.     

Cluster headache and vertigo

The term "cluster vertigo" was originally used by Gilbert to describe episodes of vertigo in patients with Ménière's syndrome. Since these patients also had co-existing cluster headache, he suggested that both disorders could have had a common pathophysiology. There is no evidence in the literature for an increased incidence of Ménière's syndrome in cluster headache patients, so the argument that cluster headache and Ménière's syndrome may have a common pathogenesis cannot be supported. Subsequent authors have used the term "cluster vertigo" to denote a variant form of cluster headache and have confused the matter further. This was not the intention of the original author. The terminology is misleading and should not be used to describe a sub-type of cluster headache. A case of cluster headache with accompanying vertigo is described as a contrast to the patients described by Gilbert in whom headache and episodes of vertigo occurred independently.     

Cluster headache: On the mechanism behind attack-related sweating

Eighteen cluster headache patients were studied using body heating or exercise tests; all but two of them were also studied with a pilocarpine test (0.1 mg/kg body wt, s.c.). Evaporimeter measurements were made on both sides of the forehead under standard conditions in a thermo room. Heat- and exercise-induced sweating was dearly less pronounced on the symptomatic side than on the non-symptomatic side of the forehead, and was significantly different compared to controls. Pilocarpine on the other hand induced a clearly more pronounced response on the symptomatic side than on the non-symptomatic side, which was also statistically significantly higher than in the control group. These findings suggest a supersensitivity of the sweat glands to pilocarpine on the symptomatic side of the forehead in most cases of cluster headache.     

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.     

Cluster headache: orbital hemodynamic changes during Valsalva maneuver

BACKGROUND: The clinical features of cluster headache (CH) disclose some vascular changes in the symptomatic region, but few instrumental studies have assessed orbital hemodynamics in patients with this disorder. METHODS: Orbital blood flow reactivity elicited by Valsalva maneuver (VM) was studied with ophthalmic artery eco-Doppler in 16 patients (14 men and 2 women; mean age: 41.2) suffering from episodic CH and in 18 healthy controls. Patients were examined twice: first, in a cluster period (between pain attacks), and second, in a remission period. Each time peak-systolic and end-diastolic flow velocities were recorded in both ophthalmic arteries at rest and during all phases of VM. RESULTS: Valsalva phase IV was consistently associated with an increment of blood flow velocities through the ophthalmic arteries. Unlike controls, patients showed an asymmetric vascular reactivity. In the cluster period peak-systolic flow velocity increments were lower on the symptomatic side than on the asymptomatic side (14.1% vs. 34.4%; P < .001), while in remission end-diastolic flow velocity increments were higher in the previously symptomatic orbit (129% vs. 72.9%; P < .05). Vascular reactivity on the asymptomatic side was always similar to that of healthy controls. CONCLUSIONS: In episodic CH, the symptomatic orbit shows an abnormal vascular reactivity. During the cluster period, basal vasodilation and hyperemia could preclude it from admitting a much greater amount of blood at the end of Valsalva. During remission, there might be some latent vascular changes that lead to supersensitive vasodilator responses and/or opening of arteriovenous shunts under certain circumstances such as Valsalva. These phenomena could be relevant in the pathophysiology of CH.     

Cluster headache and the sympathetic nerve

OBJECTIVE: To determine the effect of a sympathetic block at C7 on cluster headache. BACKGROUND: Eleven patients presenting to a pain control unit with cluster headache were included in the study after giving informed consent. METHODS: In all patients, a mixture of 5 mL of 0.5% bupivacaine hydrochloride and 1 cc of methylprednisolone acetate was injected onto the base of the C7 transverse process. RESULTS: The injection was applied during the acute phase of headache in 6 patients and all experienced immediate and complete relief. The other 5 patients received the injection between attacks. Of the 11 patients treated, 8 went into remission by aborting the cluster. In some patients, repeated injections were given before the cluster was aborted. Three patients did not respond to treatment. One patient with chronic paroxysmal hemicrania experienced pain relief of the acute attack after treatment, but the procedure did not abort the subsequent attacks. A surgical sympathectomy removing the stellate ganglion rendered him pain-free for 15 months after which he was lost to follow-up. CONCLUSION: Blocking the sympathetic nerve aborts an acute attack of cluster headache and may play a major role in aborting the cluster. Although only one patient with chronic paroxysmal hemicrania responded to surgical sympathectomy, this procedure may be considered as an alternative if there is poor response to oral medication or a sympathetic block.     

Cluster headache management with methylphenidate (Ritalin)

The authors report rapid cluster headache relief in a 43-year-old man with a 5-year history of refractory cluster headache. The patient described complete headache relief within 10 minutes of taking 10 mg of methylphenidate (Ritalin) when used to abort the onset of his headaches. Subsequently, a scheduled Ritalin dose taken each morning was sufficient to prevent his nightly headaches. In addition, 1 week of prophylactic methylphenidate therapy halted the series of cluster headaches. This is the first reported case of relief of cluster headaches with methylphenidate.     

Cluster headache: clinical presentation, lifestyle features, and medical treatment

BACKGROUND: Cluster headache (CH) is a rare but severe headache form with a distinct clinical presentation. Misdiagnoses and mismanagement among these patients are high. OBJECTIVE: To characterize clinical features and medical treatment in patients with CH. METHODS: We established a cohort of 246 clinic-based and non-clinic-based CH patients. The diagnosis of CH was verified according to International Headache Society (IHS) criteria. We used standardized questionnaires to assess associated factors as well as success or failure of treatments. RESULTS: The majority (75.6%) was not treated before at our clinic-77.6% were males; 74.8% had episodic CH, 16.7% had chronic CH, in the remaining patients, the periodicity was undetermined because they were newly diagnosed. Cranial autonomic features were present in 98.8%, nausea and vomiting in 27.8%, and photophobia or phonophobia in 61.2% of CH patients. Most (67.9%) reported restlessness during attacks and 23% a typical migrainous aura preceding the attacks. The rate of current smoking was high (65.9%). Half of the patients reported that alcohol (red wine in 70%) triggered CH attacks. Eighty-seven percent reported the use of drugs of first choice (triptans 77.6%, oxygen 71.1%) with sumatriptan subcutaneous injection being the most effective drug for acute therapy (81.2%). The most frequently used preventive medications were verapamil (70.3%) and glucocorticoids (57.7%) with equally high effectiveness. CONCLUSIONS: Apart from the IHS criteria additional features like nausea/vomiting and migrainous aura may guide the diagnosis of CH. A large number of CH patients do not receive adequate treatments.     

Cluster headache syndrome associated with middle cerebral artery arteriovenous malformation

Cluster headache (CH) is an idiopathic cephalagic syndrome, although several pathological processes have been described in association with this syndrome. We report two cases of cluster headache in hospitalized patients with middle cerebral artery dependent arteriovenous malformation (AVM). After surgical removal of the AVM the headache completely resolved, suggesting that complementary studies and treatment of the underlying actinology may be indicated for secondary forms of cluster headache.     

Cluster headache is not associated with signs of a systemic inflammation

OBJECTIVE: To investigate whether there is clinical or biochemical evidence for a transient systemic inflammation during active periods of cluster headache. METHODS: Twenty-seven male and female consecutively selected patients with episodic cluster headache filled in questionnaires aiming at detecting any concurrent systemic vasculitic or rheumatoid disease. They were physically examined by both a neurologist and a rheumatologist independent of each other. Blood and urine samples were taken one to three times during an active cluster period and once in remission. The following analyses were performed: hemoglobin, erythrocyte sedimentation rate, C-reactive protein, complete blood counts including differential counts, creatinine, albumin, creatine kinase, electrophoreses of serum (with haptoglobin, orosomucoid, IgG, IgM), von Willebrand's factor, antinuclear antibodies, rheumatoid factor, cytoplasmic antineutrophil cytoplasmic autoantibodies, perinuclear antineutrophil cytoplasmic autoantibodies, and routine urinary tests. An age- and sex-matched control group of 99 consecutive patients attending the Outpatient Department of Neurology for symptoms/diseases other than severe headache completed the same questionnaire as the patient group. RESULTS: Only one patient with cluster headache showed clinical signs (livedo reticularis) that could have been due to an ongoing systemic vasculitis. Most symptoms were equally or even more prevalent in the control group than among the patients with cluster headache. However, cold feet were about twice as prevalent among female patients with cluster headache than in the control group. This was considered due to their smoking habits. Laboratory tests showed no statistically significant differences between the active cluster periods and remission. There were some slightly abnormal values in single laboratory tests, some of which were probably due to concurrent upper respiratory infections. The findings of laboratory tests for one patient could have been due to nephritis. All patients were negative for cytoplasmic antineutrophil cytoplasmic autoantibodies and perinuclear antineutrophil cytoplasmic autoantibodies. CONCLUSIONS: These results were taken as evidence that no systemic inflammation is present during the active cluster headache period. However, whether a local retro-orbital inflammation underlies the pathophysiology of cluster headache remains obscure.