Specificity and Sensitivity of Temporalis ES2 Measurements in the Diagnosis of Chronic Primary Headaches

We have evaluated the specificity and sensitivity of temporalis ES2 measurements for the diagnosis of primary headaches. Ninety-four outpatients diagnosed according to IHS criteria were prospectively included: 25 had chronic tension-type headache (code 2.2.), 15 episodic tension-type headache (code 2.1.), 20 migraine without aura (code 1.1.) and 34 chronic daily headaches with daily analgesics/ergotamine abuse (code 8.2.). In chronic tension-type, the sensitivity of the ES2 test was 84% at the 0.1 and the 0.5 Hz, but only 56% at the 2Hz stimulation rates. Its specificity was 100% at 0.1Hz, 90% at 0.5Hz and 95% at 2Hz compared to migraine; positive predictive values were at similar levels. Sensitivity of ES2 at 0.1 Hz was 67% in episodic tension-type headache, but its positive predictive value versus migraine was excellent. Comparing chronic tension-type headache and analgesic abusers, the specificity and positive predictive value of the ES2 test for diagnosing chronic tension-type headache were less satisfactory (60%) while the negative predictive values, however, remained good (83% at 0.1Hz).
The results confirm that the temporalis ES2 test has a higher diagnostic sensitivity in chronic and episodic tension-type headache, but that it has a high negative predictive value for both types of tension-type headache compared to other primary headaches. For diagnostic purposes, the 0.1Hz stimulation rate seems optimal. The 2Hz stimulation rate is the least sensitive, although it may induce total disappearance of ES2 in up to 40% of patients. ES2 is of limited usefulness for separating chronic tension-type headache and chronic drug-abuse headache, possibly because the latter group comprises both tension-type headache and migraine patients.     

Assessment of International Headache Society diagnostic criteria: a reliability study

In 1988 the International Headache Society (IHS) introduced new diagnostic criteria for headaches and craniofacial pain. Since headaches can be diagnosed solely on the basis of information provided by the patient, it is essential that the criteria are reproducible and consistent. Two neurologists evaluated the clinical records of 100 consecutive outpatients and transferred the data on headache and associated phenomena to a form designed to reflect the IHS criteria. Interobserver concordance (kappa statistics) in the application of the diagnostic criteria of primary headaches was: (i) "perfect" to "substantial" for the first IHS digit, being kappa = 1.0 for cluster headache and paroxysmal hemicrania; kappa = 0.88 for migraine; kappa = 0.75 for tension-type headache; (ii) "almost perfect" to "substantial" for the second digit (kappa = 0.94 for cluster headache; kappa = 0.90 for migraine with aura; kappa = 0.81 for episodic tension-type headache; kappa = 0.78 for migraine without aura; kappa = 0.71 for chronic tension-type headache; kappa = 0.66 for cluster headache-like disorder not fulfilling the criteria; (iii) "moderate" for migrainous disorder (kappa = 0.48) and headache of the tension-type (kappa = 0.43) not fulfilling the criteria. These results show that the IHS diagnostic criteria are satisfactorily applicable to high quality medical records abstracted by experienced neurologists.     

Osmophobia in juvenile primary headaches

This study was planned to investigate the prevalence of osmophobia in juvenile headache sufferers and to analyse the diagnostic utility of osmophobia in order to distinguish migraine without aura from episodic tension-type headache. We examined 305 consecutive patients presenting at our Paediatric Headache Centre. A semistructured questionnaire was given to 275 selected patients affected by migraine or tension-type headache. The prevalence of osmophobia during attacks was 18.5%, mainly in migraine patients (25.1%) vs. those with tension-type headache (8.3%). Osmophobia showed more specificity than phonophobia or photophobia in the differential diagnosis between migraine and tension-type headache. In conclusion, this study demonstrates that osmophobia resulted in a symptom with poor sensitivity (27.1%) but high specificity (92%) that could become a supportive diagnostic criterion even in children for the differential diagnosis between migraine without aura and tension-type headache.     

Osmophobia in primary headaches

This study evaluates osmophobia (defined as an unpleasant perception, during a headache attack, of odours that are non–aversive or even pleasurable outside the attacks) in connection with the diagnosis of primary headaches. We recruited 775 patients from our Headache Centre (566 females, 209 males; age 38±12 years), of whom 477 were migraineurs without aura (MO), 92 with aura (MA), 135 had episodic tension–type headache (ETTH), 44 episodic cluster headache (ECH), 2 chronic paroxysmal hemicrania (CPH) and 25 other primary headaches (OPHs: 12 primary stabbing headaches, 2 primary cough headaches, 3 primary exertional headaches, 2 primary headaches associated with sexual activity, 3 hypnic headaches, 2 primary thunderclap headaches and 1 hemicrania continua). Among them, 43% with MO (205/477), 39% with MA (36/92), and 7% with CH (3/44) reported osmophobia during the attacks; none of the 135 ETTH and 25 OPH patients suffered this symptom. We conclude that osmophobia is a very specific marker to discriminate adequately between migraine (MO and MA) and ETTH; moreover, from this limited series it seems to be a good discriminant also for OPHs, and for CH patients not sharing neurovegetative symptoms with migraine. Therefore, osmophobia should be considered a good candidate as a new criterion for the diagnosis of migraine.     

Application of the ICHD-II criteria to the diagnosis of primary chronic headaches via a computerized structured record

BACKGROUND: The authors recently developed a software program designed to analyze clinical data from patients affected by primary headache. The program is based exclusively on the International Classification of Headache Disorders 2nd edition (ICHD-II) criteria. This software examines all the diagnoses of primary headaches on the basis of the variables needed to fulfill these mandatory criteria. METHODS: We tested the software, Primary Headaches Analyser 1.0 INT (PHA), by entering and analyzing clinical data from 200 consecutive patients affected by primary chronic headaches and evaluating the corresponding output diagnoses. RESULTS: The diagnosis of chronic migraine (1.5.1) was obtained in 68 cases (34 %) and that of probable chronic migraine (1.6.5) plus probable medication-overuse headache (8.2.8) in 46 (23%). Chronic tension-type headache (2.3) and probable chronic tension-type headache (2.4.3) plus probable medication-overuse headache (8.2.8) were diagnosed in 24 (12%) and 2 (1%) patients, respectively. Moreover, 4 and 12 patients, respectively, received both the diagnosis of chronic migraine (1.5.1) plus chronic tension-type headache (2.3) and of probable migraine (1.6.1) without aura plus chronic tension-type headache (2.3). In the remaining 44 cases (22%), none of the chronic primary headaches disorders defined by ICHD-II received an output diagnosis from the program. This was due mainly to the fact that the criteria fulfilled were insufficient for the diagnoses of migraine without (1.1) aura plus chronic migraine or, more infrequently, chronic tension-type headache. CONCLUSIONS: Our software program permitted diagnoses of chronic migraine, chronic tension-type or their probable forms (with or without MOH) in 78% of 200 patients with headache 15 or more days per month. In the remaining cases the inability to provide a specific diagnosis may be explained in part by the fact that the criteria for both diagnoses are too stringent and do not accurately reflect variations of the headache pattern in these chronic forms.     

Neuropeptide Y in Juvenile Migraine and Tension-Type Headache

SYNOPSIS
Neuropeptide Y (NPY) is widely distributed throughout sympathetic nerve endings where it is co-stored and co-secreted with noradrenaline. It is considered a marker of noradrenergic function. To determine the role of NPY in the pathogenesis of juvenile headache, we determined its plasma levels in two groups of young migraine patients (with and without aura), in a group of episodic tension-type headache patients and in a group of age and sex-matched healthy subjects. Significantly lower plasma levels of NPY were evident in the migraine patients with aura (P<0.001) and, to lesser extent, in the migraine patients without aura (P<0.02), both assessed in the interictal period, with respect to the control group. Plasma NPY levels tended to significantly increase during attacks in migraine patients with aura (P<0.0009). A less evident, though significant increase was also present during attacks in migraine patients without aura (P<0.02). No significant variations were observed between headache-free periods and attacks in tension-type headache patients. Reduced NPY levels in the interictal period can be considered further evidence of the derangement of the sympathetic function in the course of migraine, particularly that with aura. The increase in NPY levels during migraine attacks could be an expression of sympathetic activation, even though the functional status of this system is less efficient.     

Weekend headache: a retrospective study in migraine without aura and episodic tension-type headache

Our retrospective study was aimed at determining the existence of weekend headache and, if so, whether it has the same clinical features as migraine without aura and episodic tension-type headache, or whether it occurs as a separate form of headache which could find its own place in the International Headache Society classification.
For this study, we reviewed the clinical records of 120 patients with migraine without aura and 120 patients with episodic tension-type headache randomly selected among all those referred to the Headache Center of the University of Parma Institute of Neurology between 1985 and 1996.
A review of these records suggests that weekend headache exists for both types of headache considered. Clinically, it is interesting to note that the male-to-female ratio for the weekend form of tension-type headache was 1:1, as opposed to 1:3 for general episodic tension-type headache. As regards classification, no evidence so far seems to suggest that weekend headache should be considered as an independent entity. Apart from certain features that appear to be peculiar to this form of headache—such as increased pain intensity—it thoroughly fulfills the diagnostic criteria of the primary headaches from which it evolves. Finally, a few clinical features suggest that the weekend may simply be a triggering factor in migraine without aura attacks, while playing a major role in episodic tension-type headache. However, weekend headache is a clinical entity that clearly needs further study.     

Lifetime prevalence and characteristics of recurrent primary headaches in a population-based sample of Swedish twins

OBJECTIVE: To examine the lifetime prevalence and other characteristics of recurrent primary headaches in twins. BACKGROUND: The twin model may provide insights into the role of genetic and environmental influences in headache disorders. However, assumptions as to whether twins are representative of the general population, and whether monozygotic and dizygotic twins are similar have rarely been addressed. METHODS: The study population consisted of a random sample of 17- to 82-year-old twins from the Swedish Twin Registry (n = 1329). Structured interviews on the telephone by lay personnel and the International Headache Society criteria were used for assessment and diagnosis of recurrent primary headaches. Prevalence data of the general population for migraine and tension-type headache was obtained from various published reports. RESULTS: A total of 372 subjects (29%) had ever had recurrent headaches. In total, 241 recurrent headache sufferers fulfilled the criteria for migraine or tension-type headache, and the lifetime prevalence was 7.1% for migraine without aura, 1.4% for migraine always with aura, 1.9% for migraine occasionally with aura, 9.4% for episodic tension-type headache, and 1.3% for chronic tension-type headache. The lifetime prevalence of all migraine and all tension-type headache, including another 84 subjects fulfilling all but one of the criteria for migraine or tension-type headache, was 13.8% and 13.5%, respectively. The corresponding prevalence risk for women was 2.4 (95% confidence interval [CI] 1.7, 3.4) and 1.5 (95% CI 1.1, 2.1), respectively. Zygosity was not a significant predictor for migraine. In tension-type headache, the prevalence risk for dizygotic twins and unlike-sexed twins as compared with monozygotic twins was 1.9 (95% CI: 1.2, 3.1) and 1.8 (95% CI: 1.1, 2.9), respectively. CONCLUSION: There is no twin-singleton or monozygotic-dizygotic difference for the risk of migraine. In tension-type headache, twins seem to have a lower risk than singletons, and this is especially true for monozygotic twins.     

Frequent migraine and migraine status without tension-type headaches: an unusual presentation of rebound headaches

Rebound headaches usually present as daily or almost daily, prolonged, generalized tension-type headaches with superimposed migraine-like attacks. The latter are more frequent, more intense, and longer than any episodic migraine that the patient might have experienced prior to the development of the chronic daily headaches. Rebound presenting as migraine without tension-type pain has been mentioned in a few previous articles on chronic daily headache, but there have been no previous articles stressing that frequent migraine might relate to the analgesics that are being used. These case histories are presented to illustrate that frequent migraine and migraine status without tension-type headaches may be manifestations of rebound and improve when the offending analgesic agents are stopped. If the clinician fails to recognize this unusual presentation of rebound headache, the patient might be placed on unnecessary and often ineffective medications for prophylaxis instead of stopping the offending pain relief medications.     

Serum levels of N-acetyl-aspartate in migraine and tension-type headache

Serum levels of N-acetyl-aspartate (NAA) may be considered a useful marker of neuronal functioning. We aimed to measure serum NAA in cohorts of migraine and tension-type headache patients versus controls, performing correlations with main clinical features. A total of 147 migraine patients (including migraine without aura, with aura and chronic migraine), 65 tension-type headache (including chronic and frequent episodic tension-type headache) and 34 sex- and age-matched controls were selected. Serum was stored at −80 °C. Quantification of NAA was achieved by the standard addition approach and analysis was performed with liquid-chromatography–mass-spectrometry (LC/MS) technique. The NAA levels were significantly decreased in migraine group (0.065 ± 0.019 mol/L), compared with both tension-type headache patients (0.078 ± 0.016 mol/L) and controls (0.085 ± 0.013 mol/L). Control subjects were significantly different from migraine with and without aura and chronic migraine, who differed significantly from episodic and chronic tension-type headache. Migraine with aura patients showed lower NAA levels when compared to all the other headache subtypes, including migraine without aura and chronic migraine. In the migraine group, no significant correlation was found between NAA serum levels, and headache frequency, allodynia and interval from the last and the next attack. The low NAA in the serum may be a sign of neuronal dysfunction predisposing to migraine, probably based on reduced mitochondria function.     

Endothelin receptor A -231 G>A polymorphism: no linkage to primary pediatric headache

OBJECTIVE: To assess whether the biallelic -231 G>A polymorphism of the endothelin type A receptor (EDNRA) gene, previously shown to be a marker of increased risk for developing migraine, has a role in the susceptibility to primary pediatric headache. BACKGROUND: Several studies suggest that endothelin has a role in migraine. A recent association study has shown that the biallelic -231 G>A polymorphism of the EDNRA gene is associated to migraine in an elderly population. METHODS: A total of 126 consecutive unrelated pediatric patients affected by primary headache, classified according to the International Headache Society criteria in migraine (migraine with aura, n = 3; migraine without aura, n = 80), and tension-type headache (episodic tension-type headache, n = 36; chronic tension-type headache, n = 7) patients, were recruited to the study. Sixty-seven healthy blood donors were used as a control group. Genomic DNA was extracted from buccal swabs or blood samples and analyzed by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) for the above-mentioned polymorphism. Allele and genotype frequencies for primary headache patients were analyzed in comparison with the control group. RESULTS: No significant differences were found in the distribution of the EDNRA -231 G>A polymorphic variant when considering both genotype (migraine chi2 = 2.78, P = .25; tension-type headache chi2 = 3.58, P = .17) and allelic frequencies (migraine chi2 = 1.48, P = .22; tension-type headache chi2 = 0.39, P = .56). Furthermore, no significant genotype-related difference was found in relation to clinical features, such as age at onset, frequency, and length of the attacks. CONCLUSIONS: Our study shows that the -231 G>A polymorphism in the EDNRA gene is neither associated with primary juvenile headache nor significantly correlated with main clinical features characteristic of the headache pathology in pediatric settings.     

Outcome of juvenile headache in outpatients attending 23 Italian headache clinics. Italian Collaborative Study Group on Juvenile Headache (Società Italiana Neuropsichiatria Infantile [SINPI])

A multicenter 3-year follow-up study was carried out on young patients with headache referred to tertiary headache centers or pediatric clinics. Three years after the first examination in 1993, 442 (of an original sample of 719) young outpatients with headache (226 females and 216 males) were re-examined. The diagnostic criteria of the International Headache Society (IHS) and those modified for migraine without aura by Winner et al were applied at both the baseline evaluation and the 3-year re-examination. At the follow-up, 290 children still had headache, 101 were in clinical remission, and 51 had dropped out. Using the current diagnostic criteria, only 46.2% of patients having migraine without aura, 50% of those having migraine with aura, and 35.3% of those suffering from migraine disorders which do not fulfill IHS criteria for migraine received the same diagnosis at the time of follow-up. The percentage of patients receiving a diagnosis of migraine without aura rose significantly when new modified criteria were used (60.5%), whereas a drop in the frequency of migraine disorders not fulfilling IHS criteria was observed at follow-up, both in patients with the diagnosis of migraine without aura at the first examination (4.6%) and in patients with migraine not always fulfilling IHS criteria at the first examination (6.2%). Among all patients who received this latter diagnosis at the first examination, it was possible to make a diagnosis of migraine with aura at the follow-up in 8.8% of cases and that of migraine without aura in 26.5%. No significant variations in the frequency of either episodic tension-type headache or chronic tension-type headache were found, with the exception of a slight decrease in the percentage of tension-type headache which did not fulfill IHS criteria, but the difference between the first examination and the follow-up values does not reach the level of statistical significance (5% versus 12%). As far as the evolution of migraine is concerned, 17.4% of patients with migraine were headache-free at the 3-year follow-up. In tension-type headache, the percentage of patients who were headache-free was particularly high in those with the episodic form (32.9%) and in those suffering from tension-type headache not fulfilling IHS criteria (29.1%). The majority of patients who had been diagnosed as having unclassifiable headache at the first examination received a correct diagnosis at the follow-up with the exception of one patient. As observed in adult patients, variations in the headache characteristics were also observed in children and adolescents (that is, migraine with aura can change to migraine without aura, or the latter can transform into episodic tension-type headache or chronic tension-type headache can change into the episodic form). This follow-up study was aimed at reaching a better understanding of headache disturbances in children and adolescents, examining, in particular, variations of headache with time in this stage of life.     

Passive paradigm single-tone elicited ERPs in tension-type headaches and migraine

The active 'oddball' event-related potential (ERP) P3 is elongated or reduced in migraine and tension-type headaches, indicating a deficit of active attention in these primary headaches. It is then reasonable to study the passive attention function in these headaches through the technology of passive paradigm single-tone elicited ERPs. We invited 32 patients suffering from chronic tension-type headache (CTTH), 17 from frequent episodic tension-type headache (FETH) and 32 from interictal migraine without aura, as well as 28 healthy subjects to undergo passive paradigm single-tone ERPs. There were no statistically significant differences when the mean latencies and amplitudes of N1, P2, N2 or the mean latencies of P3 of the four groups were considered. In contrast, the P3 amplitudes were significantly reduced in the patient groups when compared with healthy controls. However, no further significant difference was found between patient groups when considering P3 amplitude. Our study demonstrated a deficit of passive attention in CTTH, FETH and migraine, but could not separate these headache types in this regard. The reduced P3 in patients might be due to the head pain experienced.     

An Epidemiological Study of Headache Among the Monks of Athos (Greece)

SYNOPSIS
The Monks of Athos in Greece constitute a particular group with unusual sleep schedule and specific diet. In order to study the frequency of headache among them, a special questionnaire was designed. Four hundred forty-nine monks below the age of 50 were approached, 39 of whom suffered from frequent (more than one episode per month, in the last 6 months) headaches (8.68%). The prevalence of migraine was 1.78% (0.66% with aura and 1.11% without) and of tension-type headache 3.34% (1.33% chronic and 2% episodic). Furthermore, 1.87% of monks suffered from mixed headaches (tension-type and migraine attacks as well). Cluster headache was not traced.     

Quality of life of patients with cervicogenic headache: a comparison with control subjects and patients with migraine or tension-type headache

OBJECTIVE: To establish the health-related quality of life of patients with cervicogenic headache and to compare it with a random Dutch sample of control subjects and with patients with migraine without aura or with episodic tension-type headache. METHODS: Thirty-seven patients with cervicogenic headache, 42 patients with episodic tension-type headache, and 39 patients with migraine without aura completed a Medical Outcomes Study 36-Item Short Form questionnaire. RESULTS: Domain scores for "physical functioning" of patients with cervicogenic headache were worse than those of patients with migraine or tension-type headache. Physical functioning scores were lower for patients with tension-type headache than for those with migraine. Migraineurs reported a diminished score for "social functioning" compared to patients with tension-type headache. All Medical Outcomes Study 36-Item Short Form domain scores were significantly lower for patients with cervicogenic headache relative to the control group. CONCLUSIONS: Patients with cervicogenic headache have a quality of life burden that is substantial. Although impairment in the quality of life of patients with cervicogenic headache is comparable to patients with migraine without aura and those with episodic tension-type headache, there are some specific differences.     

Intravenous metamizol (Dipyrone) in acute migraine treatment and in episodic tension-type headache–a placebo-controlled study

Acute headache is a very frequent symptom, responsible for significant demand at primary care units and emergency rooms. In such sets in Brazil, metamizol is easily found but, on the other hand, neither ergotics nor triptans are available. The aim of this study is to compare intravenous metamizol with placebo in the acute treatment of migraine with aura, migraine without aura and episodic tension-type headache. Fifty-four migraine with aura patients, 95 migraine without aura patients and 30 tension-type headache patients were treated with metamizol. Ninety patients (30 migraine with aura, 30 migraine without aura and 30 tension-type headache patients) received placebo. Pain intensity, nausea, aura, photo- and phonophobia were investigated at 30 min and 60 min after the administration of the drug. Significant improvement of pain after 30 min and 60 min post-dosage was achieved from metamizol groups compared with placebo groups. Significant improvement of all other symptoms was achieved after 60 min post-dosage. Side-effects were mild and with small incidence. Metamizol is an effective, safe and low price drug. It may be regarded as a good alternative drug for the treatment of common acute primary headaches.     

Headache and hemodialysis: a prospective study

OBJECTIVE: To determine the prevalence and clinical characteristics of headache in patients undergoing hemodialysis and to compare the prevalence of headache prior to and following the beginning of a hemodialysis program. BACKGROUND: About 70% of patients receiving hemodialysis complain of headache. Despite this, headaches have not been well studied in this group of patients. METHODS: We evaluated a series of patients with chronic renal failure who attended 3 hemodialysis services in a Brazilian town from January of 1998 to December of 1999. Patients with headache were prospectively followed and classified according to the International Headache Society criteria. The headaches were also categorized according to their temporal profile relative to hemodialysis. RESULTS: Headache was reported by 87 (70.7%) of the 123 patients studied. Prior to beginning dialysis, 48% had migraine, 19% had episodic tension-type headache, and 8% had both. Headache related to arterial hypertension was the second most frequent headache diagnosis in these patients (25.4%). Fifty patients (57.5%) experienced headache during the session of hemodialysis. Thirty-four were classified as dialysis headache, 7 were classified as migraine, 7 as episodic tension-type headache, and 2 were unclassified. Twenty-four patients (27.6%) reported dramatic improvement of their headaches after the beginning of the dialysis program. CONCLUSIONS: Headache is common in patients undergoing hemodialysis. Classification of such headaches according to the International Headache society criteria may be difficult.     

Brain-derived neurotrophic factor in primary headaches

Brain derived neurotrophic factor (BDNF) is associated with pain modulation and central sensitization. Recently, a role of BDNF in migraine and cluster headache pathophysiology has been suspected due to its known interaction with calcitonin gene-related peptide. Bi-center prospective study was done enrolling four diagnostic groups: episodic migraine with and without aura, episodic cluster headache, frequent episodic tension-type headache, and healthy individuals. In migraineurs, venous blood samples were collected twice: outside and during migraine attacks prior to pain medication. In cluster headache patients serum samples were collected in and outside cluster bout. Analysis of BDNF was performed using enzyme-linked immunosorbent assay technique. Migraine patients revealed significantly higher BDNF serum levels during migraine attacks (n = 25) compared with headache-free intervals (n = 53, P < 0.01), patients with tension-type headache (n = 6, P < 0.05), and healthy controls (n = 22, P < 0.001). There was no significant difference between patients with migraine with aura compared with those without aura, neither during migraine attacks nor during headache-free periods. Cluster headache patients showed significantly higher BDNF concentrations inside (n = 42) and outside cluster bouts (n = 24) compared with healthy controls (P < 0.01, P < 0.05). BDNF is increased during migraine attacks, and in cluster headache, further supporting the involvement of BDNF in the pathophysiology of these primary headaches.     

Nitric oxide in primary headaches

Nitric oxide (NO) has been proposed to be a key molecule in migraine. Experimental evidence suggests its intervention in vasodilatation and activation of the trigeminovascular system as well as its involvement in the supraspinal pathways implicated in head and pain processing. Other findings suggest the implication of NO in coupling neuronal and vascular changes during spreading depression. A potential role for NO has also been proposed in the pathophysiological mechanisms underlying cluster headache and chronic tension-type headache. The most relevant evidence for an increased response to exogenous NO in all primary headaches emerges from the experimental model of nitroglycerin-induced headache. Moreover, the effectiveness of non-selective NO synthase inhibitor L-N-monomethylarginine (L-NMMA) further supports the involvement of NO in migraine and chronic tension-type headache. The endogenous increase in NO production has been shown only in studies carried out during spontaneous migraine attacks which demonstrated increased levels of nitrites and cGMP in peripheral blood and internal jugular blood; the latter was followed by an increased production of algogenic and vasodilatatory prostanoids. These data suggest the potential activation of cyclooxygenase (COX) due to NO. Additional evidence suggests the increased activity of L-arginine/NO pathway in the platelet model in migraine patients. This increase was also evident between attacks, more accentuated during attacks and expressed to a greater extent during late luteal phase in menstrual migraine. Higher NO production in platelet was also demonstrated in patients affected by chronic daily headache and they are accompanied by significant lower serotonin content and higher levels of intracellular calcium. Whether these changes may be expressed in the central nervous system is a matter of discussion. These data taken together suggest a crucial role played by NO in neurovascular headaches and chronic headaches. Further research concerning NO in all primary headaches will be aimed at verifying changes of reliable markers of NO metabolism and NO effects, to better understand the complex COX/NO synthase (NOS) interactions, to investigate the effectiveness of selective NOS inhibitors in discriminating neural versus vascular involvement of NO. Received: 15 October 2000 / Accepted in revised form: 30 January 2001