Familial migraine with and without aura: clinical characteristics and co-occurrence

Migraine with aura (MwA) and migraine without aura (MwoA) are the two common forms of migraine. Many migraine patients suffer from both kinds of attacks. In a questionnaire-based study using the current International Headache Society (IHS) criteria we determined the clinical characteristics and occurrence of MwA + MwoA in 1000 migraine patients belonging to 210 Finnish migraine families. Nine hundred and six patients were able to indicate whether they suffered from MwA (but not MwoA), migraine aura without headache (migraine equivalent) (but not MwA) or MwA and MwoA. Of these patients, 3.2% had experienced MwoA, 11.1% MwA, 40.6% MwA + MwoA, 23.5% MwoA and 20.3% MwA-like symptoms not meeting the IHS criteria. The high prevalence of MwA attacks in the families studied supports the belief that aura has a strong hereditary component. The MwA + MwoA patients had significantly more severe attacks, more typical headache and more prodromal symptoms than the MwA and MwoA subjects. Therefore, it is possible that there is a continuum with pure MwA at the neural and pure MwoA at the headache end of the spectrum, and MwA + MwoA lying in between the two. The MwA + MwoA patients would thus be liable to both types of migraine, making their attacks more characteristic and more severe. This would also explain why the co-occurrence of MwA and MwoA is more common in the clinic compared with population based epidemiological studies. These findings have consequences for future research on liability genes for migraine.     

Sensitivity and specificity of the new international diagnostic criteria for migraine with aura

OBJECTIVES: Since 1998, migraine with aura (MA) has been diagnosed according to the operational diagnostic criteria of the International Headache Society (ICHD-1). Here we present the data underlying the new criteria for MA in the ICHD-2 classification. METHODS: Sensitivity of the new criteria was tested in patients with MA and specificity in patients with reversible non-aura visual disturbances. The diagnoses in both groups of patients were made in a validated semistructured physician-conducted interview. We tested five sets of criteria for sensitivity and specificity comparing with the diagnosis according to the ICHD-1 in 200 patients and the selected set of criteria in 274 additional patients. RESULTS: Four sets of criteria had sensitivity/specificity of 46%/100%, 71%/100%, 62%/95%, and 99%/76%. Sensitivity of the selected set of criteria was 84% (95% CI 79% to 90%) and specificity 97% (95% CI 95% to 99%). According to these criteria at least two of the following should be fulfilled: homonymous visual or unilateral sensory symptoms; at least one aura symptom develops gradually over > or =5 minutes and/or different symptoms occur in succession over > or =5 minutes; each symptom lasts > or =5 and < or =60 minutes. In the additional sample sensitivity of the selected criteria was 90% (95% CI 86% to 94%) and specificity 96% (95% CI 91% to 100%). CONCLUSIONS: The diagnostic criteria for MA selected for ICHD-2 had high sensitivity and specificity. The ICHD-2 criteria are more operational and probably delineate a more homogeneous sample of patients than the ICHD-1. The ICHD-2 for MA is intended equally for research and clinical practice and can be used at different levels of specialisation.     

Restless legs syndrome is not associated with migraine with aura: a clinical study

Based on recent data about the association between restless legs syndrome (RLS) and migraine, we performed an observational study on the occurrence of RLS in patients affected by “pure” migraine with aura (pMA). We recruited 63 patients (33 females and 30 males) affected by MA without other types of primary headache among all patients referred in five Italian headache centers in a 1-year period. The prevalence of RLS in pMA patients (9.5%) is similar to that observed in Italian headache-free subjects (8.3%). No significant differences were found between pMA patients with and without RLS about clinical features of MA attacks and systemic and psychiatric diseases were investigated. Moreover, no association appeared between RLS and familial cases of MA. Differently from migraine without aura, our data do not confirm the existence of an association between RLS and MA, not even when a genetic factor is involved.

     

Circannual periodicity of migraine?

Seasonal rhythm of migraine attacks may support a role of the suprachiasmatic nucleus of the hypothalamus in the pathophysiology of migraine. The objective of this study was to provide evidence for seasonal variation in migraine. Eighty-nine female migraineurs volunteered to record every migraine attack in detail for 12 consecutive months. Attacks associated with sleep complaints were defined as insomnia-related. By using Edwards' model for recognition and estimation of cyclic trends, time-series analysis was made. Fifty-eight patients, of which 26 had migraine without aura (MO) and 32 had migraine with aura (MA), completed the study. A total of 1840 attacks were recorded. The mean age ± SD was 36.9 ± 6.0. Patients with a lifetime history of MA showed marked seasonal fluctuation with more attacks in the light season compared to the dark. Time of peak was May 21. Peak/low ratio was 1.30 (95% CI: 1.08–1.55). When insomnia-related attacks ( n  = 312) were removed the seasonal variation became insignificant. There is a seasonal trend with more migraine attacks in the light season compared to the dark season in females with MA, but not MO, living in an arctic area. This is caused by the seasonal variation of insomnia-related attacks in patients with MA.     

Increased risk of migraine with typical aura in probands with familial hemiplegic migraine and their relatives

We investigated the occurrence of migraine without aura (MO) and migraine with typical aura (MA) amongst probands with familial hemiplegic migraine (FHM) and their first degree relatives in order to evaluate the relations between these syndromes. A total of 44 FHM probands and 240 first degree relatives were identified in the Danish population. The pattern of familial aggregation was assessed by population relative risk (PRR) calculations. Amongst FHM probands the PRR of MO was 1.5 (95% CI: 0.8-2.2), whereas the PRR of MA was 7.1 (95% CI: 5.0-9.2). Thus, compared with the general population, FHM probands had no increased risk of MO but a significantly increased risk of MA. A similar pattern was seen amongst their first degree relatives, who had no increased risk of MO, whereas the risk of MA was significantly increased; 7.6 times in FHM-affected first degree relatives and 2.4-times in non-FHM-affected first degree relatives. These results are contrary to a sharing of genetic mechanisms between FHM and MO. Furthermore, they suggest that the genetic abnormality causing FHM may also cause attacks with the symptomatology of MA.     

The extent of right-to-left shunt fails to correlate with severity of clinical picture in migraine with aura

Abstract Several investigations have documented an increased incidence of right-to-left shunt (RLS) in migraine with aura (MA) and have emphasised its role in the physiopathology of aura; so far, however, no data are available concerning a possible correlation between the extent of the RLS and the clinical picture of MA patients. To investigate the possible relationship between the extent of the RLS, revealed by the number of microbubbles (MB) detected during transcranial Doppler with IV injection of ultrasound contrast (TCDc), and the clinical characteristics of MA (age at first onset of migraine, mean annual frequency of attacks and mean duration of the aura phase), 30 consecutive patients with typical aura and migraine headache positive on TCDc evaluation for RLS were enrolled. Permanent RLS was found in 12 patients and latent RLS was found in 18 patients; of these, 6 had a high-grade RLS, 5 medium-grade RLS and 7 low-grade RLS. No correlation has been documented between the number of MBs and the clinical parameters of both patients with latent shunts and those with permanent ones, nor between the clinical parameters of the two groups of patients. These data show that RLS does not seem to affect the clinical manifestation of MA and that the extent of RLS fails to correlate with the severity of the clinical picture of the disorder.     

Neuroexcitatory plasma amino acids are elevated in migraine

To investigate the role of glutamic (Glu) and aspartic acid (Asp) in migraine, we measured the plasma amino acids in migraine patients with and without aura, between and during attacks, and compared the profiles with the plasma amino acid profiles of tension headache patients and healthy controls. Between attacks, migraineurs (notably with aura) had substantially higher plasma Glu and Asp levels than did controls and tension headache patients. In addition, patients with migraine without aura showed low plasma histidine levels. During migraine attacks, Glu (and to a lesser extent Asp) levels were even further increased. The results suggest a defective cellular reuptake mechanism for Glu and Asp in migraineurs, and we hypothesize a similar defect at the neuronal/glial cell level, predisposing the brain of migraineurs to develop spreading depression.     

Classic migraine

Systematic prospective records of aura symptoms were obtained from 50 patients, who filled in report forms during the aura phase of two attacks. The pattern of the various aura symptoms was remarkably constant during two attacks. Visual aura was recorded by 94% of the patients, somato-sensory aura symptoms by 40%, motor disturbances by 18% and speech difficulties by 20%. Visual aura was unilateral in 55%, somato-sensory aura symptoms were unilateral in 80% and motor aura was unilateral in 100%. Surprisingly, headache was absent in 20% of the aura attacks. When unilateral headache and unilateral aura symptoms occurred in the same attack, headache was most often contralateral to the somato-sensory and motor aura symptoms. Our observations are in accordance with the hypothesis that the pathophysiological process responsible for the aura symptoms in classic migraine starts at the visual cortex.     

Functional MRI-BOLD of visually triggered headache in patients with migraine.

BACKGROUND: Spreading depression of Leao has been hypothesized as the basis for the visual aura of the migraine attack, supported by cerebral blood flow measurements of spreading hypoperfusion. The early depolarizing or activation phase of experimental spreading depression, however, is associated with a transient but pronounced cerebral blood flow increase that precedes spreading hypoperfusion. OBJECTIVE: To study this early phase of the migraine attack, we investigated visually triggered attacks of headache and visual symptoms using a red-green checkerboard stimulus in patients with migraine. INTERVENTIONS: We studied occipital cortex activation during visual stimulation by measuring occipital cortex perfusion with functional magnetic resonance imaging-blood oxygenation level-dependent contrast in 10 patients with migraine with aura and 2 patients with migraine without aura and 6 healthy subjects. RESULTS: In 6 patients with migraine with aura and 2 patients with migraine without aura, their typical headache with (n = 2) or without visual change was visually triggered at 7.3 minutes (mean time) after visual stimulation began. In 5 of these patients, the onset of headache or visual change, or both, was preceded by suppression of initial activation (mean onset time, 4.3 minutes; P<.001) The suppression slowly propagated into contiguous occipital cortex at a rate ranging from 3 to 6 mm/ min. This neuronal suppression was accompanied by baseline contrast intensity increases that indicated vasodilatation and tissue hyperoxygenation. CONCLUSIONS: We conclude that visually triggered headache and visual change in patients with migraine is accompanied by spreading suppression of initial neuronal activation and increased occipital cortex oxygenation. We postulate that this spreading suppression may be associated with initial activation of a migraine attack, independent of whether there are associated aura symptoms. We further postulate that there may be an association between vasodilation accompanying the initial stage of suppression and the induction of headache.     

Treating migraine with contraceptives

At least 18% of women suffers from migraine. Clinically, there are two main forms of migraine: migraine with aura (MA) and migraine without aura (MO) and more than 50% of MO is strongly correlated to the menstrual cycle. The high prevalence of migraine in females, its correlation with the menstrual cycle and with the use of combined hormonal contraceptives (CHCs) suggest that the estrogen drop is implicated in the pathogenesis of the attacks. Although CHCs may trigger or worsen migraine, their correct use may even prevent or reduce some forms of migraine, like estrogen withdrawal headache. Evidence suggested that stable estrogen levels have a positive effect, minimising or eliminating the estrogenic drop. Several contraceptive strategies may act in this way: extended-cycle CHCs, CHCs with shortened hormone-free interval (HFI), progestogen-only contraceptives, CHCs containing new generation estrogens and estrogen supplementation during the HFI.     

The prevalence of patent foramen ovale in patients with migraine

BACKGROUND AND PURPOSE: Migraine is a common neurologic disorder whose etiology remains unknown. Migraine has been reported as a possible risk factor for ischemic stroke, especially in young women. The relationship between migraine and stroke is stronger in patients suffering from migraine with aura compared to those with common migraine. Coexistence of migraine and patent foramen ovale (PFO) should be also considered. The aim of our study was to evaluate the frequency of PFO in patients with migraine with aura (MA) and compare it with the prevalence of PFO in migraine patients without aura (M) and in a healthy age-matched control group. MATERIAL AND METHODS: We assessed 62 patients (48 females) suffering from migraine with aura, 60 without aura (53 females) and 65 normal controls (51 females). In order to detect PFO the contrast transcranial Doppler was performed during Valsalva maneuver. RESULTS: The presence of PFO was found in 33/62 (53%) patients with MA compared to 15/60 (25%) without aura, and in 16/65 (25%) control subjects. The difference in PFO prevalence between MA patients and M patients and the difference between MA patients and the control group was statistically significant (p<0.05). CONCLUSIONS: Our findings suggest that at least some attacks of migraine with aura may be associated with paradoxical embolism.     

No effect of eletriptan administration during the aura phase of migraine

Migraine aura is a warning sign readily recognized by patients. From the onset of aura it takes 30-60 min before the headache phase starts. Administration of acute medication during aura should provide sufficient time to achieve therapeutic plasma levels, counteracting the headache. To test this hypothesis we evaluated the efficacy of eletriptan 80 mg taken during aura. Patients met International Headache Society diagnostic criteria for migraine with aura, with an attack frequency of at least one per month and with aura occurring in > 50% of recent attacks. Of 123 patients randomized, 87 (71%) were treated with a double-blind, one attack, during the aura phase before headache, dose of either eletriptan 80 mg (n = 43; 74% female; mean age, 40 years), or placebo (n = 44; 82% female; mean age, 40 years). The primary outcome measure was the proportion of patients not developing moderate-to-severe headache within 6 h post-dose. There was no significant difference in the proportion of patients developing moderate-to-severe headache on eletriptan (61%) versus placebo (46%). Eletriptan was well tolerated and did not prolong the aura phase. Typical transient triptan adverse events were observed; most were mild-to-moderate in intensity. This study confirms the findings of two studies showing that triptans are ineffective but safe when given during the migraine aura phrase.     

Interrelations between migraine and tension-type headache in the general population.

In a cross-sectional epidemiological survey of a general population, headache disorders were diagnosed according to a structured interview and a neurological examination using the criteria of the International Headache Society. The prevalences and sex distribution of the primary headache disorders were assessed, and characteristics of and interrelationships between different types of headache were analyzed. Severity and frequency of migraine attacks were not correlated, indicating that the migraine attack is an all-or-none phenomenon triggered with an individually variable threshold. Tension-type headache, in contrast, showed increasing severity with increasing frequency, indicating that it is a graded phenomenon. In the previous year, 6% had migraine without aura (previously called "common migraine") and 4% had migraine with aura (previously called "classic migraine"); 63% had episodic tension-type headache and 3% chronic tension-type headache. In women, migraine without aura was twice as prevalent as migraine with aura; in men, an opposite trend emerged. In migraine without aura, pain was more severe than in migraine with aura. Tension-type headache in migraineurs was not significantly more prevalent than in nonmigraineurs and, except for greater frequency and severity, it did not deviate nosographically from pure tension-type headache. Our results support the contention that migraine and tension-type headache are distinct entities, contradict the so-called continuum-severity model, and indicate that the terms combination headache, mixed headache, and interval headache should be avoided.     

Patent foramen ovale and migraine

Recent epidemiological data suggest a bidirectional link between patent foramen ovale (PFO) and migraine with aura (MA) with a relative risk of 2 for PFO in subjects with MA and for MA in subjects with PFO. There is no evidence for a link between PFO and migraine without aura. This link is not systematic and applies only to subsets of PFO, mostly large ones, and to subsets of patients with MA. Although comorbidity cannot be ruled out, it may be that this link is partly causal and that some large PFOs may favor MA attacks in genetically predisposed subjects, by allowing vasoactive substances, platelet emboli or paradoxical emboli to bypass the lung filter and trigger the cortical spreading depression of the aura. The first double blind randomised trial of PFO closure in refractory MA, "MIST", has failed to show a benefit on the primary efficacy end point: cessation of attacks during the analysis period included between 3 and 6 months after the procedure. There is thus at present no scientific reason to look for PFO or to close PFO in migraine patients.     

Functional MRI-BOLD of brainstem structures during visually triggered migraine

BACKGROUND: Previously, hyperoxia and blood volume increase were reported in the red nucleus and substantia nigra during spontaneous migraine with aura. OBJECTIVE: To further understand the pathophysiologic role of these centers, activation of brainstem structures was investigated in patients with visually triggered migraine. METHODS: Twenty-six patients with migraine (23 with aura and 3 without aura), and 10 normal control subjects were studied with blood oxygen level-dependent (BOLD) fMRI during repeated checkerboard visual stimulation. Three axial image sections, which covered the occipital cortex and brainstem, were acquired 224 times with a temporal resolution of 3.5 seconds. RESULTS: Repetitive visual stimulation triggered symptoms in 12 patients; four who had migraine with aura developed both visual symptoms and headaches, and six who had migraine with aura and two who had migraine without aura had headaches only. Four patients who had migraine with aura experienced the onset of their usual aura or onset of their typical headache either during the experiment or immediately after. In the remaining 10 patients with migraine, and all control subjects, visual stimulation failed to trigger symptoms at any time. In 75% of the patients who developed symptoms during stimulation, baseline T2*-weighted MR signal intensities increased in the red nucleus and substantia nigra before occipital cortex signal elevation or the onset of visually triggered symptoms. CONCLUSION: Activation (hyperoxia and blood volume increase) of the red nucleus and substantia nigra in association with visually triggered symptoms of migraine suggest that these brainstem structures are a part of a neuronal network activated during an attack.     

Transcranial Doppler in spontaneous attacks of migraine.

BACKGROUND AND PURPOSE: Our aim in this study was to compare headache-free and spontaneous migraine measurements of blood flow velocity and the pulsatility index in the anterior cerebral artery, middle cerebral artery, and posterior cerebral artery. METHODS: Thirty-one patients (nine having experienced migraine with aura and 22 migraine without aura) were studied in headache-free periods and during spontaneous migraine attacks with transcranial Doppler ultrasonography. RESULTS: During attacks of migraine with aura, blood flow velocities (particularly the diastolic velocity [p = 0.05]) were reduced while the pulsatility index increased (p = 0.05), whereas a generalized increase in diastolic velocity (p less than 0.02) and a decrease in the pulsatility index (p = 0.05) were observed during attacks of migraine without aura. Significant variations of blood pressure and heart rate were never found. CONCLUSIONS: These findings are consistent with constriction of resistance vessels in migraine with aura and dilatation of the vessels in migraine without aura. This disparity could be due to a difference between the two migraine types or could be related to the fact that in this study the time interval between headache onset and transcranial Doppler was shorter in the migraine-with-aura group. The latter explanation would apply if, in fact, both types of migraine evolve from hypoperfusion to hyperperfusion during their time course, although perhaps with a difference in intensity.     

Clinical characteristics of menstrually related and non-menstrual migraine

Migraine attacks increase during the perimenstrual period in approximately half of female migraineurs. There are differences in the pathogenesis and clinical features of menstrually related and non-menstrual migraine attacks. The objective of this study was to compare the characteristics of migraine in patients with menstrually related and non-menstrual migraine, and to investigate the differences between premenstrual, menstrual, and late-menstrual migraine attacks. Three-hundred and thirty-two women with migraine without aura were evaluated using questionnaires and diaries to determine the characteristics of headache, preceding and accompanying symptoms, and the relation of migraine attacks and menstruation. One-hundred and sixty-three women had menstrually related migraine without aura (49.1%). Duration of disease and duration of headache were longer (p = 0.002 and p < 0.001, respectively), and nausea, vomiting, phonophobia, and aggravation of headache with physical activity were more frequent in patients with menstrually related migraine (p = 0.005, p = 0.006, p < 0.001 and p = 0.006, respectively). Premonitory symptoms and allodynia were observed more frequently in the menstrually related migraine group (p = 0.012 and p = 0.004, respectively). Perimenstrual migraine attacks occurred premenstrually (days ?2 and ?1) in 46 patients (25.3%), menstrually (days 1 to 3) in 90 patients (49.4%), and late menstrually (days 4 to 7) in 19 patients (10.4%). Our results showed that the duration of headache was longer and accompanying symptoms were more frequent and diverse in patients with menstrually related migraine without aura, suggesting that these findings may reflect the increase in excitability or susceptibility of the brain in these patients.     

Clinical features of episodic migraine and transformed migraine: a comparative study

Transformed migraine (TM) is one of the most frequent types of chronic daily headache. Eighty patients: 40 with episodic migraine (EM) and 40 with TM with ages ranging from 18 to 60 years old were studied. Females were the majority. At first examination, the mean age was similar in both groups. The initial age of migraine attacks was significantly smaller in the TM group. Time history of episodic attacks was similar in both groups. In the EM group, the headache was predominantly located on only one side of the head; whereas in the TM group, on more than one side. There was variation in the character of pain and intensity in the TM group. Nocturnal awakening with headache, aura and family history did not show significant association with EM or TM. The TM was distinguished from the EM in relation to the frequency, location and pain intensity of the headache. Patients with early migraine headache onset may exhibit a further risk of developing TM.     

The prevalence and characteristics of migraine in a population-based cohort: the GEM study.

OBJECTIVE: To describe the distribution of migraine and its subtypes in the general population. BACKGROUND: Previous population-based studies are limited by small samples or a narrow age range, do not provide prevalence estimates of migraine with and without aura, or underestimate prevalence by not accounting for patients missed as a result of using imperfect screening instruments. METHODS: The participants in the Genetic Epidemiology of Migraine Study were comprised of 6,491 adults, age 20 to 65 years, selected randomly from two county population registries in the Netherlands to participate in a general health survey (52.7% response). Migraineurs were identified as follows: All participants were screened on headache history. Those meeting screen-positive criteria were given a detailed questionnaire on headache. A total of 1,292 randomly selected screen-positives (83% of screen-positives) and 197 randomly selected screen-negatives (5% of screen-negatives) were administered a semistructured clinical interview by telephone. Final diagnosis met 1988 International Headache Society criteria. Prevalence of migraine was estimated for sex and 5-year age strata. RESULTS: The lifetime prevalence of migraine in women was 33% and the 1-year prevalence of migraine in women was 25%. In men, the lifetime prevalence was 13.3% and the 1-year prevalence was 7.5%. Among patients with migraine in the past year, 63.9% had migraine without aura, 17.9% had migraine with aura, and 13.1% had migraine both with and without aura. The prevalence of migraine was significantly higher in women and not associated with socioeconomic status. Migraineurs suffered a median of 12 migraine attacks per year; 25% had at least two attacks per month. CONCLUSIONS: The prevalence of migraine is higher then previously reported. The coexistence of migraine with and without aura occurs frequently and has implications for future studies on the genetics of migraine.     

Patent foramen ovale, a possible cause of symptomatic migraine: a study of 74 patients with acute ischemic stroke

Recent studies reported an increased prevalence of patent foramen ovale (PFO) in patients with migraine with aura (MA+). To investigate the possible relationship between MA+ and paradoxical embolism, we studied the prevalence of both conditions. Investigation of PFO was undertaken in 74 consecutive patients presenting with an acute stroke of undetermined origin. The patients were questioned about MA+ or migraine without aura (MA-) according to the criteria of the International Headache Society. Follow-up was performed to investigate the evolution of MA+ and MA- according to different treatments of stroke. PFO was found in 44 of 74 patients, 16 of whom had MA+ (36%), compared to 4 (13%) MA+ patients without PFO (p = 0.03). Of 25 patients in whom the PFO was considered to play a causal role in the stroke, 13 (52%) had MA+, whereas only 3 (16%) of 19 patients in whom PFO was considered unrelated had MA+ (p = 0.014). Thirty-nine of the patients with MA+ and MA- were studied over a mean follow-up of 13 months. Seven of 15 patients with MA+ and PFO, treated either with surgical closure or anticoagulants, noticed complete disappearance of MA+ attacks. The prevalence of MA+ is high among stroke patients with PFO. In patients with a high presumption of paradoxical embolism, the proportion of MA+ is increased, and this suggests a possible role of this association in the occurrence of the cerebrovascular event. Forty-seven percent of patients with PFO and MA+ reported complete suppression of their aura attacks after surgical closure or anticoagulant treatment. This finding suggests that at least in some patients, MA+ attacks may be due to paradoxical embolism.