M. Sanchez del Rìo

Neurophysiological tests and neuroimaging procedures in non-acute headache: guidelines and recommendations

The use of instrumental examinations in headache patients varies widely. In order to evaluate their usefulness, the most common instrumental procedures were evaluated, on the basis of evidence from the literature, by an EFNS Task Force (TF) on neurophysiological tests and imaging procedures in non‐acute headache patients. The conclusions of the TF regarding each technique are expressed in the following guidelines for clinical use.

Dose, Efficacy and Tolerability of Long-Term Indomethacin Treatment of Chronic Paroxysmal Hemicrania and Hemicrania Continua

Indomethacin has consistently been proven to provide complete and sustained relief of symptoms in hemicrania continua (HC) and chronic paroxysmal hemicrania (CPH), but is not devoid of side-effects. The goal of this retrospective study is to assess the dose and side-effects of prolonged indomethacin treatment of HC and CPH. Twenty-six patients with either HC or CPH were followed during an average of 3.8 years after onset of treatment with indomethacin. Relief of symptoms occurred within 3 days of treatment, with 84 ± 32 mg/day of indomethacin. With time, 42% of patients experienced a decrease of up to 60% in the dose of indomethacin required to maintain a pain-free state. Six (23%) patients showed adverse events, mostly gastrointestinal and relieved with ranitidine. No major side-effects were observed. These results indicate that prolonged indomethacin treatment of HC or CPH has a good safety and tolerability profile with a reduction of up to 60% in the initial dose.

Neurophysiological tests and neuroimaging procedures in non‐acute headache (2nd edition)

Background and purpose:  A large number of instrumental investigations are used in patients with non‐acute headache in both research and clinical fields. Although the literature has shown that most of these tools contributed greatly to increasing understanding of the pathogenesis of primary headache, they are of little or no value in the clinical setting.

Placebo adverse events in headache trials: headache as an adverse event of placebo

We analysed the adverse events of placebo in acute and preventive randomized, double-blind, placebo-controlled studies for migraine treatment. Fifty-seven trials (oral triptans, non-steroidal anti-inflammatory drugs, nasal ergot alkaloids and preventive agents) were included. From 10 to 30% of subjects reported adverse events after placebo. Most common were features associated with a migraine attack, such as nausea, phono- and photophobia. Other frequent complaints resembled those of the active drug (e.g. chest pressure in triptan trials). A third group of adverse events appeared to be coincidental (e.g. sleep disturbance). Adverse events following placebo are probably related to the drug under study and the symptomatology of migraine; some have no obvious explanation.

5-Hydroxytryptamine1B/1D and 5-hydroxytryptamine1F receptors inhibit capsaicin-induced c-fos immunoreactivity within mouse trigeminal nucleus caudalis

In order to investigate the c-fos response within the trigeminal nucleus caudalis (Sp5C) after noxious meningeal stimulation, capsaicin (0.25, 0.5, 1 and 5 nmol) was administered intracisternally in urethane (1 g/kg) and α-chloralose (20 mg/kg) anaesthetized male mice. Capsaicin induced a robust and dose-dependent c-fos-like immunoreactivity (c-fos LI) within Sp5C. C-fos LI was observed within laminae I and II of the entire brain stem from the area postrema to C2 level, being maximum at the decussatio pyramidum level. The area postrema, solitary tract, medullary and lateral reticular nuclei were also labelled. The 5-hydroxytryptamine1B/1D/1F receptor agonist sumatriptan (0.01, 0.1, 1 and 10 mg/kg), administered intraperitoneally 15 min before capsaicin stimulation (1 nmol), decreased the c-fos response within Sp5C, but not within solitary tract. The novel specific 5-hydroxytryptamine1F agonist LY 344864 (0.1 and 1 mg/kg, i.p.) significantly decreased the c-fos LI within the Sp5C as well. These findings suggest that intracisternally administered capsaicin activates the trigeminovascular system and that the pain neuro-transmission can be modulated by 5-hydroxytryptamine1B/1D/1F receptors in mice. Thus, the availability of this model in mice, taken together with the possibility of altering the expression of specific genes in this species, may help to investigate further the importance of distinct proteins in the neurotransmission of cephalic pain.

Evaluation and proposal for optimization of neurophysiological tests in migraine: part 2--neuroimaging and the nitroglycerin test.

Neuroimaging methods have been widely used in headache and migraine research. They have provided invaluable information on brain perfusion, metabolism and structure during and outside of migraine attacks, contributing to an improved understanding of the pathophysiology of the disorder. Human models of migraine attacks are indispensable tools in pathophysiological and therapeutic research. This review of neuroimaging methods and the attack-provoking nitroglycerin test is part an initiative by a task force within the EUROHEAD project (EU Strep LSHM-CT-2004-5044837-Workpackage 9) with the objective of critically evaluating neurophysiological tests used in migraine. The first part, presented in a companion paper, is devoted to electrophysiological methods, this second part to neuroimaging methods such as functional magnetic resonance imaging, positron emission tomography and voxel-based morphometry, as well as the nitroglycerin test. For each of these methods, we summarize the results, analyse the methodological limitations and propose recommendations for improved methodology and standardization of research protocols.

Secondary hypnic headache or symptomatic nocturnal hypertension? Two case reports

According to current criteria, hypnic headache (HH) syndrome is a rare condition diagnosed in subjects complaining of exclusively sleep-related dull headache attacks. At least two of the following features must be present: recurrence > 15 times per month; persistence of pain 15min after waking; age at onset > 50 years; absence of autonomic symptoms and no more than one of the following features: nausea, photophobia or phonophobia. The pain should not be attributable to any other condition (1). Its pathophysiology is still poorly understood, but it has been considered a chronobiological disorder (2). Although HH is regarded as an idiopathic headache syndrome, secondary cases have been described (3–8). These disorders may be an incidental finding or may be related to HH to some extent, as their suppression has significantly changed the clinical course. To the best of our knowledge, there have been six case reports of secondary HH because of: obstructive sleep apnoea (3); posterior fossa meningioma (4); ischaemic stroke in the pontine reticular formation (5); nocturnal arterial hypertension (6); pituitary macroadenoma (7); and transient HH syndrome after withdrawal of long-term lithium treatment (8). Here we describe two patients with a HH syndrome according to International Headache Society (IHS) criteria in whom nocturnal arterial hypertension was detected and its correction resulted in headache resolution.