EFNS guideline on the drug treatment of migraine--revised report of an EFNS task force.

BACKGROUND: Migraine is one of the most frequent disabling neurological conditions with a major impact on the patients' quality of life. OBJECTIVES: To give evidence-based or expert recommendations for the different drug treatment procedures in the particular migraine syndromes based on a literature search and the consensus of an expert panel. METHODS: All available medical reference systems were screened for the range of clinical studies on migraine with and without aura and on migraine-like syndromes. The findings in these studies were evaluated according to the recommendations of the European Federation of Neurological Societies (EFNS) resulting in level A, B, or C recommendations and good practice points. RECOMMENDATIONS: For the acute treatment of migraine attacks, oral non-steroidal antiinflammatory drug (NSAID) and triptans are recommended. The administration should follow the concept of stratified treatment. Before intake of NSAID and triptans, oral metoclopramide or domperidone is recommended. In very severe attacks, intravenous acetylsalicylic acid or subcutaneous sumatriptan are drugs of first choice. Status migrainosus can be treated by cortoicosteroids, although this is not universally held to be helpful, or dihydroergotamine. For the prophylaxis of migraine, betablockers (propranolol and metoprolol) flunarizine, valproic acid, and topiramate are drugs of first choice. Drugs of second choice for migraine prophylaxis include amitriptyline, naproxen, petasites, and bisoprolol.

Acute subcortical stroke and early serotonergic modification: a IDAP study.

The intensity dependence of the auditory-evoked potentials (IDAP) is inversely related to serotonergic tone. Depression is frequently observed after stroke, associated with cognitive impairment and increased mortality. Aim of this study was to investigate the serotonergic tone in acute stroke patients by IDAP. Consecutive patients with an acute stroke admitted in our stroke unit were evaluated using clinical and instrumental examinations and compared with healthy controls. The IDAP was calculated as the linear amplitude/stimulus intensity function (ASF) slope, by measuring the peak-to-peak amplitude of Nl-P2 on four blocks of different stimulus intensities. Twenty patients were enrolled; 11 had a right brain infarction; nine had depressive symptoms (DS). The ASF slope of the auditory-evoked potentials was markedly increased in stroke patients compared with controls (P = 0.021). Stroke patients with DS had a significant steeper ASF slope than controls (P = 0.017). There was no statistical difference in ASF slope between stroke patients without DS and controls. Post-stroke depression pathophysiology is still debated. Our study suggests that in acute stroke patients with DS, there is a direct involvement of the serotonergic system, regardless the degree of disability and the site of the lesion.

EFNS guidelines on the treatment of cluster headache and other trigeminal-autonomic cephalalgias.

Cluster headache and the other trigeminal-autonomic cephalalgias [paroxysmal hemicrania, short-lasting unilateral neuralgiform headache attacks with conjunctival injection and tearing (SUNCT) syndrome] are rare but very disabling conditions with a major impact on the patient's quality of life. The objective of this study was to give evidence-based recommendations for the treatment of these headache disorders based on a literature search and consensus amongst a panel of experts. All available medical reference systems were screened for any kind of studies on cluster headache, paroxysmal hemicrania and SUNCT syndrome. The findings in these studies were evaluated according to the recommendations of the European Federation of Neurological Societies resulting in level A, B or C recommendations and good practice points. For the acute treatment of cluster headache attacks, oxygen (100%) with a flow of at least 7 l/min over 15 min and 6 mg subcutaneous sumatriptan are drugs of first choice. Prophylaxis of cluster headache should be performed with verapamil at a daily dose of at least 240 mg (maximum dose depends on efficacy or tolerability). Although no class I or II trials are available, steroids are clearly effective in cluster headache. Therefore, the use of at least 100 mg methylprednisone (or equivalent corticosteroid) given orally or at up to 500 mg i.v. per day over 5 days (then tapering down) is recommended. Methysergide, lithium and topiramate are recommended as alternative treatments. Surgical procedures, although in part promising, require further scientific evaluation. For paroxysmal hemicranias, indomethacin at a daily dose of up to 225 mg is the drug of choice. For treatment of SUNCT syndrome, large series suggest that lamotrigine is the most effective preventive agent, with topiramate and gabapentin also being useful. Intravenous lidocaine may also be helpful as an acute therapy when patients are extremely distressed and disabled by frequent attacks.

EFNS guideline on the drug treatment of migraine - report of an EFNS task force.

Migraine is one of the most frequent disabling neurological conditions with a major impact on the patients' quality of life. To give evidence-based or expert recommendations for the different drug treatment procedures of the different migraine syndromes based on a literature search and an consensus in an expert panel. All available medical reference systems were screened for all kinds of clinical studies on migraine with and without aura and on migraine-like syndromes. The findings in these studies were evaluated according to the recommendations of the EFNS resulting in level A,B, or C recommendations and good practice points. For the acute treatment of migraine attacks, oral non-steroidal anti-inflammatory drugs (NSAIDs) and triptans are recommended. The administration should follow the concept of stratified treatment. Before intake of NSAIDs and triptans, oral metoclopramide or domperidon is recommended. In very severe attacks, intravenous acetylsalicylic acid or subcutaneous sumatriptan are drugs of first choice. A status migrainosus can probably be treated by steroids. For the prophylaxis of migraine, betablockers (propranolol and metoprolol), flunarizine, valproic acid, and topiramate are drugs of first choice. Drugs of second choice for migraine prophylaxis are amitriptyline, naproxen, petasites, and bisoprolol.

Cluster headache patients show marked intensity dependence of cortical auditory evoked potentials during and outside the bout.

Central serotonergic neurotransmission was assessed using intensity dependence of cortical auditory evoked potentials (IDAP) in cluster headache (CH) patients during both the active and interictal period. In 15 episodic CH patients and 13 controls previously described methods were used and amplitude-stimulus intensity function (ASF) slopes were computed. In the cluster group mean ASF slope was significantly steeper than in the control group both during the active period (1.53+/-0.90 vs. 0.77+/-0.85, P=0031) and interictally (1.85+/-1.20 vs. 0.77+/-0.85, P=0012). In the cluster group IDAPs of active and interictal period did not differ significantly (P=0378). Duration of the disease or the present bout, distance from the last attack did not correlate with ASF slopes. In conclusion, our results are compatible with decreased level of serotonergic neurotransmission in raphe-cortical pathways. Diminished serotonergic activity in raphe-hypothalamic serotonergic pathways might be hypothesized influencing the activity of hypothalamic neurons and thus play a role in the genesis of cluster headache.

Health-related and condition-specific quality of life in episodic cluster headache.

Health-related quality of life was studied in 35 episodic cluster headache (CH) patients during and after the cluster period, using a generic (SF-36) and a headache-specific (MSQ2.1) instrument. The results were compared with those of age- and sex-matched migraineurs (n = 53) and healthy persons (n = 62). During the cluster period patients had lower scores than controls in all SF-36 and MSQ2.1 domains. The difference was significant for most SF-36 and all MSQ2.1 domains. Although CH patients had lower scores than migraineurs on most scales, the difference was significant only on SF-36 scores measuring bodily pain and social functioning. There was a good correlation between the two instruments. After the termination of the cluster period the quality of life of patients was similar to that of headache-free controls. Generic and headache-specific QoL are severely impaired in CH and this impairment is at least as severe as in migraine.

Reduced gating of middle-latency auditory evoked potentials (P50) in migraine patients: another indication of abnormal sensory processing?

Habituation of cortical evoked responses to repetitive stimuli is reduced in migraine between attacks. To explore another aspect of information processing, we measured auditory sensory gating. The amplitude of the P50 response to the second of two homologous stimuli was significantly less reduced in migraineurs than in healthy volunteers. This lack of auditory sensory gating may be due to a hypofunction of monoaminergic subcortico-cortical pathways, which is also supposed to cause the interictal deficit of cortical habituation to repetitive stimuli.

Comparison of visual and auditory evoked cortical potentials in migraine patients between attacks.

OBJECTIVE: As both habituation of pattern reversal visual evoked potentials (PR-VEP) (Schoenen J, Wang W, Albert A, Delwaide PJ. Potentiation instead of habituation characterizes visual evoked potentials in migraine patients between attacks. Eur J Neurol 1995;2:115-122) and intensity dependence of auditory evoked cortical potentials (IDAP) (Wang W, Timsit-Berthier M, Schoenen J. Intensity dependence of auditory evoked potentials in migraine: an indication of cortical potentiation and low serotonergic neurotransmission? Neurology 1996;46:1404-1409) were found abnormal in migraine between attacks, we have searched for intraindividual correlations between both tests in 59 migraine patients (22 with aura [MA], 37 without aura [MO]) and in 23 healthy volunteers (HV). METHODS: Amplitude change of the PR-VEP N1-P1 was measured between the 1st and 5th block of 50 sequential averagings during continuous stimulation at 3.1 Hz. IDAP was computed from N1-P2 amplitudes of 100 averagings during stimulations at 40, 50, 60 and 70 dB SL. Amplitude-stimulus intensity function (ASF) slopes and amplitude changes between 40 and 70 dB were calculated. MO and MA differed from HV in PR-VEP amplitude change (P=0.007) and IDAP slope (P = 0.0004). RESULTS: There was no significant correlation between VEP amplitude changes and IDAP slopes, nor between the latter two and attack frequency or disease duration. A negative correlation was found between the amplitude of the first block of averaged responses and potentiation of VEP in all subject groups (P = 0.03) as well as between the amplitude of the auditory evoked potential, at 40 dB, and the percentage of amplitude increase between 40 and 70 dB in MO (P = 0.004) and MA (P = 0.007). ASF slopes and 40 dB amplitudes were significantly correlated only in the MA group (P = 0.002). These results confirm the interictal deficit of habituation in cortical processing of repetitive visual and auditory information in migraine. Since there is no intraindividual correlation between the cortical responses to these sensory modalities they are complementary tools for the study of migraine and may help to identify subgroups of patients with distinct pathophysiological mechanisms. CONCLUSIONS: The strong negative correlation between the initial amplitude of evoked potentials and their amplitude increase during subsequent averaging confirms that the response potentiation in migraine is likely to be due to a reduced preactivation level of sensory cortices.

Prophylactic treatment of migraine with beta-blockers and riboflavin: differential effects on the intensity dependence of auditory evoked cortical potentials.

OBJECTIVE: To investigate the influence of different pharmacological treatments on the intensity dependence of auditory evoked cortical potentials in migraineurs. BACKGROUND: Between attacks, patients with migraine show abnormalities in cortical information processing and decreased brain mitochondrial energy reserve. Both are most probably relevant for migraine pathogenesis, and they could be differentially modified by prophylactic drug therapy. Design.-The intensity dependence of the auditory evoked cortical potentials is, on average, increased in migraine. We have studied this intensity dependence in 26 patients before and after a 4-month period of prophylaxis with beta-blockers (n = 11, all migraine without aura; metoprolol or bisoprolol) or riboflavin (n = 15, migraine without aura: 13, migraine with aura: 2). Recordings were performed at least 3 days before or after an attack. RESULTS: After the treatment with beta-blockers, the intensity dependence of the auditory evoked cortical potentials was significantly decreased (before: 1.66+/-1.02 microV/10 dB; after: 0.79+/-1.06 microV/10 dB, P=.02). The decrease in intensity dependence was correlated significantly with clinical improvement (r = .69, P = .02). There was no change in intensity dependence after riboflavin treatment (before: 1.80+/-0.81 microV/10 dB; after: 1.56+/-0.83 microV/10 dB, P = .39), although the majority of patients showed improvement. CONCLUSIONS: These results confirm that beta-blockers and riboflavin act on two distinct pathophysiological mechanisms. Combining both treatments might enhance their efficacy without increasing central nervous system side effects.

Influence of colors on habituation of visual evoked potentials in patients with migraine with aura and in healthy volunteers.

OBJECTIVE: To investigate whether colored glasses influence the habituation of visual evoked potentials. BACKGROUND: We have previously shown that during pattern-reversal stimulations lasting 2 minutes the amplitude of the visual evoked potential increases in migraine with and without aura between attacks, whereas it decreases in healthy volunteers. Red light was found to increase visually evoked EEG fast activity only in children with migraine with aura. Wearing rose-tinted glasses for 4 months decreased attack frequency in parallel with a reduction of the visually evoked EEG fast activity. METHODS: We compared the change in amplitude of the visual evoked potential using five different tinted glasses in 12 patients with migraine with aura and in 10 healthy volunteers. During continuous stimulation at 3.1 Hz, five blocks of 50 responses were sequentially averaged using red, yellow, green, blue, and grey glasses and without glasses in a random order and analyzed in terms of latencies and N1-P1 amplitudes. Amplitude changes were calculated for each block by comparison with the first block in every condition and analyzed statistically using Zerbe's method. RESULTS: In healthy volunteers, the visual evoked potential amplitude increased with red glasses compared to without glasses (P = .05) or with green glasses (P = .03). In patients with migraine with aura, no significant difference was detected using colored glasses. Our findings in healthy volunteers are in line with earlier reports of increased excitability of the human visual cortex when exposed to red light. The lack of such a pattern in patients with migraine with aura suggests that the visual cortex is interictally hypoexcitable rather than hyperexcitable, which is consistent with studies of transcranial magnetic stimulation.

From neurophysiology to genetics: cortical information processing in migraine underlies familial influences--a novel approach.

Migraine patients show impaired cortical information processing between attacks with deficient habituation of pattern-reversal visual evoked potentials (VEP), and strong intensity dependence of auditory cortical evoked potentials (IDAP). This could be a genetic trait as certain genetic patterns are known for evoked potentials in healthy subjects. VEP-habituation and IDAP were studied in 40 migraine patients, i.e. pairs of 20 parents and their children. We developed a novel approach based on Monte Carlo statistics to selectively assess vertical familial influences. Both groups, parents and children, were characterized by abnormal VEP-habituation and IDAP. However, similarity between related pairs was far more pronounced than similarity between unrelated pairs. Assessed with a novel statistical approach, familial influences proved to be highly significant in determining cortical information processing in migraineurs, thus supporting the important role of genetic factors.

Familial influences on cortical evoked potentials in migraine.

Cortical information processing in migraine patients is impaired between attacks, showing deficient habituation of pattern-reversal visual evoked potentials (VEP), and strong intensity dependence of auditory cortical evoked potentials (IDAP). This could be a genetic trait as certain genetic patterns are known for evoked potentials in healthy subjects. We investigated VEP habituation and IDAP in 20 pairs of migraineurs made up of parents and their children. Using a Monte-Carlo statistical method, we selectively assessed vertical familial influences. VEP habituation and IDAP were abnormal in both parents and children. However, similarity was far more pronounced between related pairs than between unrelated pairs. Familial influences are highly significant in determinants of cortical information processing in migraineurs, hence supporting the important role of genetic factors.

Interictal cortical excitability in migraine: a study using transcranial magnetic stimulation of motor and visual cortices.

We performed transcranial magnetic stimulations of the motor and visual cortices in healthy controls (n = 27) and in patients suffering from migraine without (n = 33) or with (n = 25) aura between attacks. By using a 13-cm circular coil placed over the vertex and recordings of the first dorsal interosseus muscle, we measured thresholds (at rest and during contraction), amplitudes of motor evoked potentials and cortical silent periods. Paired stimulations with short (1-20 msec) interstimulus intervals were performed to assess intracortical inhibition. The visual cortex was stimulated with the same coil placed over the occipital scalp (7 cm above the inion) and the prevalence and threshold of phosphene production was determined. In patients with migraine with aura, motor thresholds during isometric contraction were significantly higher, whereas the prevalence of stimulation-induced phosphene production was lower compared with healthy controls. These changes were not correlated with attack frequency or disease duration. No differences were found between subject groups in thresholds at rest, motor evoked potential amplitudes, cortical silent periods, or response curves after paired stimuli. These results are in favor of cortical hypoexcitability rather than hyperexcitability in patients with migraine with aura between attacks.

Dopamine and migraine: a review of pharmacological, biochemical, neurophysiological, and therapeutic data.

The dopamine theory of migraine pathogenesis, first proposed by F. Sicuteri in 1977, has attracted renewed interest after an increased frequency of the dopamine D2 receptor (DRD2) gene allele NcoI C was found in patients with migraine with aura. Therefore we reviewed the relevant literature. The most compelling argument favoring an interictal hypersensitivity of dopamine receptors in migraineurs stems from pharmacologic studies of the gastric and autonomic effects of dopaminergic agents such as apomorphine, but none of these studies was blinded and placebo-controlled. Various DRD2 antagonists abort migraine attacks after parenteral administration, while there is circumstantial evidence that dopamine agonists may be useful for prophylaxis. Most drugs used in these trials, however, lack selectivity for dopamine receptors. Both in pharmacological and therapeutic studies most patients had migraine without aura. We conclude that data suggesting a primary role for the dopaminergic system in migraine pathogenesis are unconvincing. Based on well established interactions between central amines, a reduced release of serotonin between attacks could lower dopamine release which would lead to receptor hypersensitivity.

Craniometric measures in cluster headache patients.

Blockade of venous drainage in the cavernous sinus, which may play a pivotal role in the pathophysiology of cluster headache (CH), could be triggered by local inflammation. It could also be favored by a constitutional narrowness of the cavernous sinus region. Before exploring the latter with magnetic resonance imaging (MRI), we determined whether external morphometric skull measures are different among CH patients (n = 25), healthy volunteers (n = 21), and migraine patients (n = 20). All subjects were males of comparable age distribution. Six measures were taken: inion-nasion perimeter, inion-nasion distance over the vertex; distance between the upper ends of tragus; diameter at the level of the temporal fossa; diameter at mid inion-nasion perimeter at ear level; and inion-nasion diameter. CH patients had significantly smaller values than healthy subjects and/or migraine patients in all but one measure (ANOVA and Duncan's post-hoc analysis). This may suggest that they have a narrower anterior/middle cranial fossa, and possibly a narrower cavernous sinus loggia, which needs to be confirmed by a quantitative MRI study.

Neurophysiological approach to primary headache pathophysiology.

Electroencephalography (EEG), evoked potentials (EP), and electromyography (EMG) techniques are useful tools in the clinical assessment of headache and in understanding the pathophysiological mechanisms of these pathologies. EEG and EP studies in migraine revealed functional abnormalities in cortical electrical activity and in sensory processing. EMG studies resulted in pain syndromes involving nerves or myofascial structures such as tension-type headache and cluster headache. Moreover, it was possible to test the effect of old and new drugs with the help of these neurophysiological techniques. An updated review is reported of the literature.

Visual evoked potentials during long periods of pattern-reversal stimulation in migraine.

We have previously shown that during repetitive pattern-reversal stimulation, lasting 2 min, the amplitude of the visual evoked potential (PR-VEP) increases in migraineurs when tested interictally whereas it decreases in healthy control subjects. According to Sappey-Marinier et al. (J Cereb Blood Flow Metab 1992; 12: 584-92) habituation of the PR-VEP in normal subjects is maxima after 12 min, at a time when there is a decrease of stimulation-enhanced lactate levels in the occipital cortex. We have therefore compared PR-VEP during long periods of repetitive stimulation in healthy control subjects (n = 25) and in patients suffering from migraine without (n = 25) and with aura (n = 15) between attacks. During uninterrupted stimulation at 3.1 Hz VEPs were sequentially averaged in blocks of 100 responses for a total duration of 15 min and analysed in terms of latencies and peak-to-peak amplitudes of N1-P1 and P1-N2 peaks. Amplitude changes from the baseline were calculated for each block, by comparison with the first block, and analysed statistically using Zerbe's method. The N1-P1 and P1-N2 amplitudes in the first block tended to be lower in migraineurs than in healthy control subjects. During the 15 min of stimulation, amplitudes of both components progressively decreased in control subjects, but remained stable in both groups of patients. The difference between patients and control subjects proved to be significant (P < 0.05). The neurophysiological data were not correlated with clinical features such as attack frequency or duration of illness. These results are yet another demonstration in migraine of an interictal habituation deficit in cortical information processing, which might favour lactate accumulation in sensory cortices during sustained activation.

Intensity dependence of the cortical auditory evoked potentials as a surrogate marker of central nervous system serotonin transmission in man: demonstration of a central effect for the 5HT1B/1D agonist zolmitriptan (311C90, Zomig).

As shown in animal studies, 5HT1B/D agonists can inhibit activity in the trigeminal nucleus caudalis, which may be advantageous for their antimigraine effect. To demonstrate a possible central nervous system (CNS) action of these compounds in man we studied their effect on the intensity dependence of the cortical auditory evoked potentials (IDAPs), thought to be inversely related to central serotonergic transmission. An amplitude/stimulus intensity function (ASF) slope was computed in healthy volunteers and migraine patients between attacks before and 2 h after oral 311C90 (zolmitriptan "Zomig") 10 mg (n=14), 311C90 5 mg (n=7), sumatriptan 100 mg (n=14), dexfenfluramine 15 mg (n=4), lorazepam 1.25 mg (n=4) and placebo (n=14). 311C90 10 mg and, to a lesser degree, 5 mg significantly increased the mean ASF slope (p=0.007 and 0.05 vs placebo). There was a significant positive correlation between plasma levels of 311C90 and ASF slope changes. Sumatriptan and lorazepam had little effect, but dexfenfluramine produced a significant ASF slope decrease. 311C90 is able to modify a CNS activity that is modulated by serotonin, i.e. the IDAP. This effect is probably the consequence of its superior lipophilicity compared to sumatriptan and of activation of prejunctional 5HT1B/D autoreceptors, which lowers central serotonin release and thus the preactivation level of sensory cortices.

SPECT and TCD studies in cluster headache patients.

We investigated regional cerebral blood flow (rCBF) with Tc99m-HMPAO single photon emission computed tomography (SPECT) and blood flow velocity in the middle cerebral artery (MCA) with transcranial Doppler (TCD) ultrasound. Nineteen cluster headache patients participated in the study, 9 of them underwent both examinations, whereas in 6 patients only SPECT and in 4 patients only TCD was performed. Patients were examined during spontaneous and/or provoked attacks and when symptom-free in a cluster period. Six patients showed moderate frontal hyperperfusion, 2 had frontal hypoperfusion whereas no change from headache-free rCBF occurred in 7 patients. Statistical analysis of MCA velocities in 13 patients showed a significant decrease in the mean flow velocity compared with the headache-free values on the symptomatic side. Our findings suggest that the alteration of cerebral circulation during cluster attacks might be of secondary nature.

[Headache in ischemic cerebrovascular diseases]. / Fejfájás ischaemiás cerebrovasculáris megbetegedésekben.

Most of the previous publications investigating the clinical features of ischemic cerebrovascular diseases stated headache as a main symptom. According to our experiences however headache seemed to be a rare symptom accompanying ischemic attacks. The clinical history of 204 cerebrovascular patients treated at the Department of Neurology of Semmelweis Medical University was analysed prospectively and retrospectively with special regard to the frequency of headache appearing as a clinical symptom. Our investigations did not prove causal relationship between ischemic disease and headache.