Cephalalgia

Several personal descriptions of migraine with aura from 1870 onwards reported a slow, gradual progression of symptoms. Lashley in 1941 meticulously chartered his own auras and concluded that the symptomatology reflected a cortical process progressing with a speed of 3 mm/min across the primary visual cortex. Leão described cortical spreading depression (CSD) in rabbits in 1944 and noticed its similarity to the migraine aura. Despite these scattered pieces of evidence, the prevailing theory was that the migraine aura was caused by a vasospasm and cortical ischaemia. The advent of a technique for measurements of regional cerebral blood flow (rCBF) in 1974 made it possible to detect spreading oligaemia during migraine aura. Between 1981 and 1990 a series of studies of rCBF during migraine attacks showed reduced brain blood flow posteriorly spreading slowly and contiguously anteriorly and crossing borders of supply of major cerebral arteries. These observations refuted the ischaemic hypothesis. The human studies showed initial hyperaemia followed by prolonged hypoperfusion. The relation between aura and CSD was known to cause short-lasting, and therefore not obvious vasodilation and it was considerably strengthened by the demonstration of a long-lasting oligaemia in rats in the wake of CSD. In the primates CSD is not easily elicited, but it has in recent years been clearly demonstrated in patients with brain trauma and stroke. Finally, mutations for familial hemiplegic migraine have been expressed in mice and lower the threshold for CSD. The seminal papers on rCBF and CSD published in the 1980s caused a dramatic shift in our concepts of migraine aura. They moved attention from ischaemia to CSD and thereby to the brain itself, and paved the way for subsequent discoveries of brainstem mechanisms.

Objectives: This is the first of a pair of studies designed to assess efficacy, safety and tolerability of onabotulinumtoxinA (BOTOX®) as headache prophylaxis in adults with chronic migraine.

Methods: The Phase III REsearch Evaluating Migraine Prophylaxis Therapy 1 (PREEMPT 1) is a phase 3 study, with a 24-week, double-blind, parallel-group, placebo-controlled phase followed by a 32-week, open-label phase. Subjects were randomized (1:1) to injections every 12 weeks of onabotulinumtoxinA (155 U–195 U; n = 341) or placebo (n = 338) (two cycles). The primary endpoint was mean change from baseline in headache episode frequency at week 24.

Results: No significant between-group difference for onabotulinumtoxinA versus placebo was observed for the primary endpoint, headache episodes (−5.2 vs. −5.3; p = 0.344). Large within-group decreases from baseline were observed for all efficacy variables. Significant between-group differences for onabotulinumtoxinA were observed for the secondary endpoints, headache days (p = .006) and migraine days (p = 0.002). OnabotulinumtoxinA was safe and well tolerated, with few treatment-related adverse events. Few subjects discontinued due to adverse events.

Conclusions: There was no between-group difference for the primary endpoint, headache episodes. However, significant reductions from baseline were observed for onabotulinumtoxinA for headache and migraine days, cumulative hours of headache on headache days and frequency of moderate/severe headache days, which in turn reduced the burden of illness in adults with disabling chronic migraine.

Objectives: This is the second of a pair of studies designed to evaluate the efficacy and safety of onabotulinumtoxinA (BOTOX®) for prophylaxis of headaches in adults with chronic migraine.

Methods: PREEMPT 2 was a phase 3 study, with a 24-week, double-blind, placebo-controlled phase, followed by a 32-week, open-label phase. Subjects were randomized (1:1) to injections of onabotulinumtoxinA (155U–195U; n = 347) or placebo (n = 358) every 12 weeks for two cycles. The primary efficacy endpoint was mean change in headache days per 28 days from baseline to weeks 21–24 post-treatment.

Results: OnabotulinumtoxinA was statistically significantly superior to placebo for the primary endpoint, frequency of headache days per 28 days relative to baseline (−9.0 onabotulinumtoxinA/−6.7 placebo, p < .001). OnabotulinumtoxinA was significantly favoured in all secondary endpoint comparisons. OnabotulinumtoxinA was safe and well tolerated, with few treatment-related adverse events. Few patients (3.5% onabotulinumtoxinA/1.4% placebo) discontinued due to adverse events.

Conclusions: The results of PREEMPT 2 demonstrate that onabotulinumtoxinA is effective for prophylaxis of headache in adults with chronic migraine. Repeated onabotulinumtoxinA treatments were safe and well tolerated.

Headache is an underestimated burden on general health and social functioning. Accompanying symptoms of headache episodes might influence this impact. In a survey in a headache population in Luxembourg on the social and emotional impact of headaches, accompanying symptoms of headache episodes were evaluated. In 1909 participants with episodic (<15 days per month) headaches (77.1% women), visual symptoms (52.4%) and dizziness (51.1%) were frequent accompanying symptoms of headache episodes. Visual symptoms and dizziness were each independently associated with migraine in both genders and independently associated with greater headache-related disability (scored on the Migraine Disability Scale [MIDAS]), more severe depression, and higher disability as measured by the disease-independent World Health Organization Disability Assessment Schedule (WHODAS). We found that dizziness is a frequent accompanying symptom of headache, particularly in migraine. The presence of dizziness was found to have an exacerbating impact on disability and depression associated with headaches. The effect of dizziness was comparable in magnitude and independent from the presence of visual symptoms.

The objective of the study was to examine migrainous vertigo prospectively by means of a diary. We included 146 patients with at least one migraine attack per month. All patients underwent a semistructured interview, completed questionnaires on depression, anxiety and quality of sleep and kept a diary covering detailed information on headache, vertigo and dizziness over a period of 30 days. A completed diary was returned by 116 patients (79.5%). Based on the diary migrainous vertigo (MV) was diagnosed in 18 patients (15.5%) and non-migrainous vertigo or dizziness (non-MV) in 35 patients (30.2%). MV was present on 65 of 3477 patient days (1.9%) and non-MV on 145 days (4.2%). MV occurred more often on days with headache (P < 0.001). Its median duration was 3 h and it lasted longer on days with headache than on days without headache (P < 0.001). The most prominent specific feature of MV was head motion intolerance. Patients with MV showed anxiety more often (P < 0.001) and tended to have worse quality of sleep and higher depression scores. In conclusion, vertigo and dizziness are frequent symptoms in migraineurs. The 1-month prevalence of MV is 16% and that of non-MV 30% in patients with at least one migraine attack per month. Frequency of MV is higher and duration longer on days with headache. MV is a risk factor for co-morbid anxiety.

Introduction: It is well-known that specific foods trigger migraine attacks in some patients. We aimed to investigate the effect of diet restriction, based on IgG antibodies against food antigens on the course of migraine attacks in this randomised, double blind, cross-over, headache-diary based trial on 30 patients diagnosed with migraine without aura.

Methods: Following a 6-week baseline, IgG antibodies against 266 food antigens were detected by ELISA. Then, the patients were randomised to a 6-week diet either excluding or including specific foods with raised IgG antibodies, individually. Following a 2-week diet-free interval after the first diet period, the same patients were given the opposite 6-week diet (provocation diet following elimination diet or vice versa). Patients and their physicians were blinded to IgG test results and the type of diet (provocation or elimination). Primary parameters were number of headache days and migraine attack count. Of 30 patients, 28 were female and 2 were male, aged 19–52 years (mean, 35 ± 10 years).

Results: The average count of reactions with abnormally high titre was 24 ± 11 against 266 foods. Compared to baseline, there was a statistically significant reduction in the number of headache days (from 10.5 ± 4.4 to 7.5 ± 3.7; P < 0.001) and number of migraine attacks (from 9.0 ± 4.4 to 6.2 ± 3.8; P < 0.001) in the elimination diet period.

Conclusion: This is the first randomised, cross-over study in migraineurs, showing that diet restriction based on IgG antibodies is an effective strategy in reducing the frequency of migraine attacks.

To improve understanding of secondary treatment failure in migraine patients, we evaluated ‘headache return’ as a novel endpoint to assess returning headaches according to their severity, expanding on current standard assessments of overall recurrence or relapse rates, in a six-month observational study of triptan-treated migraineurs. A total of 359 patients (91% female; mean age, 42.5 years) recorded data for 2168 headaches in electronic diaries. Two-thirds of headaches responded to triptan treatment (improved-to-mild or no pain two hours post-dose); 34% of headaches had a pain-free response. By 48 hours post-dose, 19% of all responding headaches returned; 24% of headaches achieving a pain-free response returned, predominantly to mild pain. More severe baseline headache, short duration since diagnosis of migraine, and female gender were associated with increased likelihood of headache return. Treatment satisfaction declined with increasing severity of headache return, demonstrating the value of assessing headache return by severity to fully evaluate its impact.

Aims: The aims of this survey were: (i) to examine the pharmacoepidemiology of triptans in a headache centre; (ii) to compare the characteristics of patients who continued to take triptans with those of patients who had discontinued them.

Methods: We enrolled all migraine patients according to ICHD-II criteria, ensuring they were over 18 years of age, consecutively examined during a follow-up visit at the Headache Centre of the University Hospital of Modena from October 2008 to March 2009. Only patients who had used or were using a triptan were included. A specific questionnaire about the use and tolerability of triptans was created for the study and administered to every patient.

Results: On the whole, 343 patients (migraine without aura: 72%; chronic migraine: 26%; migraine with aura: 2%; mean age 40.4 ± 10 years) had used or were using triptans. Most patients (72%) continued to use triptans, above all for their efficacy. The minority (28%) discontinuing them were younger and suffered from less severe migraine; 59% of them had discontinued triptans because of adverse effects. Indeed, 92% of these patients versus 57% of patients who were currently using triptans reported adverse effects (p < .0001, Fisher’s exact test). The number of patients reporting adverse effects significantly decreased with age (r = −0.230, p < .005, simple linear regression analysis). The triptan discontinued by the highest percentage of patients (84%) was subcutaneous 6 mg sumatriptan. Significantly more patients reported adverse effects with subcutaneous 6 mg (89%) and tablet 100 mg sumatriptan (67%) than with any other triptan.

Conclusions: The increase of the tolerability of triptans with age could partly explain why younger patients suffering from less severe migraine tend to discontinue triptans more than older patients suffering from more severe migraine. In the latter, the efficacy and better tolerability (but not necessarily safety) of triptans could foster the overuse of these medications.

Objective: The objective of the study was to compare the cerebral distribution of white matter lesions (WMLs) between migraine patients with different aura symptoms.

Methods: Migraine with aura (MA) patients were consecutively enrolled as part of the Shunt-Associated Migraine (SAM) study. According to clinical symptoms, aura was classified as motor, aphasic, sensory, visual or vertebrobasilar. Standard and FLAIR (fluid attenuated inversion recovery) T₂-weighted MRI sequences were inspected for WMLs by three independent raters blinded to clinical data. WMLs were assessed in the periventricular areas (PV-WMLs) with the Fazekas scale and in the deep white matter (D-WMLs) with the Schelten's scale. Interobserver agreement was good to excellent (k = 0.64 to 0.96, p < .0001).

Results: One hundred and eighty-five patients (77% women) were included. Aura symptoms were classified as visual in 172 (99%) patients, sensory in 76 (42%), aphasic in 54 (30%), motor in 39 (21%) and vertebrobasilar in 17 (9%) patients. One hundred and four patients (57%) exhibited more than one type of aura. D-WMLs were mainly detected in the frontal lobes (86%). There was no association between type of aura and the presence of WMLs in any cerebral location.

Conclusion: Aura symptoms do not influence the cerebral distribution of WMLs associated with migraine disease.

Repetitive low-frequency electrical stimulation (LFS) induces pain inhibition in healthy volunteers and in animals, but it is unknown whether it has an analgesic effect in patients with headache. The aim of this study was to investigate if LFS could induce prolonged pain inhibition, called long-term depression (LTD), in patients with chronic tension-type headache (CTTH). Twenty CTTH patients and 20 healthy volunteers were exposed to 20 min LFS (1 Hz) to the forehead. LTD was measured as a decrease in pain response to electrical stimulation in a 1-h post-LFS period following LFS. The LFS induced a significant and stable inhibition of pain (LTD) both in patients with CTTH (post-LFS average decrease in pain rating: 19.6 ± 3.9%, all P < 0.005, Holm–Sidak) and in healthy controls (30.1 ± 5.0%, all P < 0.001, Holm–Sidak). During the LFS period, the pain ratings decreased consistently in both groups. In conclusion, a significant and stable pain inhibition (LTD) can be induced in CTTH patients by LFS.

We aimed to determine the prevalence of primary headache among schoolchildren in the city of Agri, located in eastern Turkey, where geographical, climatic and socio-economic conditions differ greatly from those of other regions of Turkey. A cross-sectional school-based (ages ranging from 11 to 18) study was conducted from January to April 2006. Diagnosis was based on the second edition of the International Classification of Headache Disorders. This population was evaluated by a two-stage clustered sampling procedure. In the first phase, 1385 children were asked whether they had had a headache within the past year. For the second-step interview, 540 children (38.9%) with a complaint of headache were selected. Five children who had complained of headaches in the first interview did not agree to participate in the second stage. Of the remaining 535, 473 were identified as having primary headache and 62 as having secondary headache. Overall, one-year prevalence of headache subtypes was 14.3% for migraine, 3.5% for probable migraine, 8.6% for pure tension-type headache, 4.6% for migraine plus tension-type headache, and 3.0% for probable migraine plus tension-type headache. The prevalence of migraine was higher in our study than in previous studies.

We present a 58-year-old man with neurological manifestations indicating increased intracranial pressure in association with hyperthyroidism. Hyperthyroidism due to a hyperfunctioning solitary thyroid nodule was the underlying cause, since all the symptoms disappeared after the treatment of hyperthyroidism. Our aim is to emphasize that hyperthyroidism should be suspected in a patient with progressive symptoms of increased intracranial pressure.

Cutaneous allodynia (CA), pain in response to innocuous cutaneous stimuli, is recognized as a sign of central sensitization during migraine episodes. It is either restricted within the pain area on the ipsilateral head, or extends within and outside the head. Moreover, CA can be elicited in response to thermal (heat or cold) and/or mechanical stimuli. This raises the question as to whether cephalic and extracephalic CAs share the same properties. We assessed cephalic and extracephalic CAs in migraine episodic patients using a questionnaire completed at home during migraine attacks. A total of 67 episodic migraine patients (58 women, nine men; 40 ± 13 years old) addressed all questions in the questionnaire. Forty-nine patients (73%) cited one or more allodynic symptoms during or immediately after the migraine attack. Almost all 49 patients reported cephalic CA, whereas 24 (49%) also reported extracephalic CA. Occurrence and extension of CA correlated (P = 0.005) with headache intensity. Modalities of cephalic and extracephalic CA were different (χ² = 12.03; P = 0.002), extracephalic CA being mostly thermal (75%) whereas cephalic CA was mostly mechanical (92%). This suggests that cephalic and extracephalic CAs involve different mechanisms.

We report a case of secondary hypnic headache in a patient with a haemangioblastoma of the cerebellum. The number of secondary cases is steadily increasing in the medical literature and magnetic resonance imaging of the brain should be considered mandatory after arriving at a presumptive diagnosis.

We describe a 23-year-old male patient who presented with spontaneous intermittent and increasing attacks of severe, left-sided thunderclap headache combined with rapidly progressive muscle weakness and dysphasia, including gradual loss of consciousness. Subsequent CT, MRI and DSA showed progressive brain ischaemia and oedema within the left cerebral hemisphere with strict ipsilateral segmental arterial vasoconstriction. Despite extensive medical care, including steroids, the patient deteriorated rapidly. However, the clinical course changed dramatically within 15 h after the start of an intravenous infusion of prostacyclin at a dose of 0.9 ng/kg/min, with an almost complete recovery of consciousness and speech. In addition the pathophysiological alterations seen on magnetic resonance (imaging and digital) subtraction angiography including diffusion-weighted imaging and apparent diffusion coefficient maps shortly before prostacyclin treatment were clearly reduced when the patient was examined 3–4 days later and he continued to recover thereafter. Although not fully compatible, our case had several clinical characteristics and radiological findings reminiscent of those of the ‘segmental reversible vasoconstriction syndrome’, sometimes called the Call–Fleming syndrome.