Cost of disorders of the brain in Europe.
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Brain Diseases↗
Biomedical subjects
Jes Olesen
Publications and source records attributed to Jes Olesen.
Inhibitory effect of BIBN4096BS on cephalic vasodilatation induced by CGRP or transcranial electrical stimulation in the rat.
Calcitonin gene-related peptide (CGRP) is believed to play a pivotal role in the pathogenesis of migraine via activation of CGRP receptors in the trigeminovascular system. The CGRP receptor antagonist, BIBN4096BS, has proven efficacy in the acute treatment of migraine attacks and represents a new therapeutic principle. We used an improved closed cranial window model to measure changes of the middle meningeal artery (MMA) and cortical pial artery/arteriole diameter (PA) and changes in local cortical cerebral blood flow (LCBF(Flux)) in anaesthetised artificially ventilated rats. The ability of BIBN4096BS (i.v.) to prevent the vasodilatatory actions of rat-alphaCGRP, betaCGRP and endogenously released CGRP following transcranial electrical stimulation (TES) was investigated. BIBN4096BS was per se without vasoactive effect on any of the measured variables and significantly inhibited the hypotension induced by both types of CGRP (P < 0.001). The alphaCGRP induced MMA dilatation was reduced from 97.4 +/- 14 to 2.1 +/- 1.3% (P < 0.001) and the betaCGRP induced dilatation was fully blocked by BIBN4096BS. ID(50) was 5.4 +/- 1.6 microg kg(-1) for alphaCGRP and 16.3 +/- 1.6 microg kg(-1) for betaCGRP. Transcranial electrical stimulation induced a 119.1 +/- 6.9% increase in MMA diameter. BIBN4096BS (333 microg kg(-1)) attenuated this increase (19.8 +/- 2.1%) (P < 0.001). Systemic CGRP and TES induced an increase in PA diameter that was not significantly inhibited by BIBN4096BS. The CGRP induced increase in LCBF(Flux) was similar not prevented by the antagonist. We suggest that systemic BIBN4096BS exerts its inhibitory action mainly on large dural blood vessels (MMA).
Animals↗
The relative influence of environment and genes in episodic tension-type headache.
OBJECTIVE: To examine the relative importance of genetic and environmental influence for the development of tension-type headache by analyses of twins. METHODS: The authors screened by questionnaire a population of 5,360 twins born during 1953 to 1960 from the general population for migraine and headache symptoms. The response rate of the questionnaire was 87%. All twin pairs with at least one twin of the pair reporting migraine or headache symptoms were interviewed by telephone by a physician. Correlation of liability and structural equation modeling were applied on tension-type headache. RESULTS: A total of 1,417 subjects had tension-type headache equivalent to a 1-year prevalence of 62%. The male: female ratio was 1:1.24. Chronic tension-type headache was found in 49 twins corresponding to a prevalence of 2% with a male:female ratio of 1:1.21. The prevalence, pain characteristics, frequency, and duration of tension-type headache were similar to what has been found in the general Danish population. The correlation of liability of tension-type headache was low and not significantly different in monozygotic and dizygotic twin pairs: 0.21 (0.03 to 0.39), 0.08 (0 to 0.24). The best fitting model of phenotypic variation consisted of 81% non-shared environmental effects and of 19% additive genetic effects. CONCLUSIONS: Environmental influence is of major importance for episodic tension-type headache and a genetic factor, if it exits, is minor. In chronic tension-type headache the genetic factor may be more important. These data clearly separate episodic tension-type headache from migraine without aura where the phenotypic variation consists of non-shared environmental effects of 39% and of 61% additive genetic effects.
Adult↗
Analysis of the effects of phosphodiesterase type 3 and 4 inhibitors in cerebral arteries.
Inhibitors of phosphodiesterases 3 and 4, the main cyclic AMP (cAMP) degrading enzymes in arteries, may have therapeutic potential in cerebrovascular disorders. We analysed the effects of such phosphodiesterases in guinea pig cerebral arteries with organ bath technique and cyclic nucleotide assays. Guinea pig and human cerebral arteries were used for phosphodiesterase assays. Cilostazol (6-[4-(1-cyclohexyl-1H-tetrazol-5-yl)butoxy]-3,4-dihydro-2(1H)-quinolinone), a phosphodiesterase 3 inhibitor, was compared to conventional phosphodiesterase 3 and 4 inhibitors. Phosphodiesterases 3 and 4 were the major contributors to total cAMP hydrolysis in the arteries examined. The phosphodiesterase 3 inhibitors additionally attenuated cyclic GMP (cGMP) hydrolysis, but relaxant responses were not dependent on an intact endothelium or on the nitric oxide-cGMP pathway. Conversely, the phosphodiesterase 4 inhibitor used was endothelium-dependent and affected by cGMP levels. This suggests that phosphodiesterase 3 inhibitors are still effective under conditions with possible dysfunctional nitric oxide-cGMP pathway, such as in ischemic stroke or cerebral vasospasm.
3',5'-Cyclic-AMP Phosphodiesterases↗
Calcitonin gene-related peptide receptor antagonist BIBN 4096 BS for the acute treatment of migraine.
BACKGROUND: Calcitonin gene-related peptide (CGRP) may have a causative role in migraine. We therefore hypothesized that a CGRP-receptor antagonist might be effective in the treatment of migraine attacks. METHODS: In an international, multicenter, double-blind, randomized clinical trial of BIBN 4096 BS, a highly specific and potent nonpeptide CGRP-receptor antagonist, 126 patients with migraine received one of the following: placebo or 0.25, 0.5, 1, 2.5, 5, or 10 mg of BIBN 4096 BS intravenously over a period of 10 minutes. A group-sequential adaptive treatment-assignment design was used to minimize the number of patients exposed. RESULTS: The 2.5-mg dose was selected, with a response rate of 66 percent, as compared with 27 percent for placebo (P=0.001). The BIBN 4096 BS group as a whole had a response rate of 60 percent. Significant superiority over placebo was also observed with respect to most secondary end points: the pain-free rate at 2 hours; the rate of sustained response over a period of 24 hours; the rate of recurrence of headache; improvement in nausea, photophobia, phonophobia, and functional capacity; and the time to meaningful relief. An effect was apparent after 30 minutes and increased over the next few hours. The overall rate of adverse events was 25 percent after the 2.5-mg dose of the drug and 20 percent for the BIBN 4096 BS group as a whole, as compared with 12 percent for placebo. The most frequent side effect was paresthesia. There were no serious adverse events. CONCLUSIONS: The CGRP antagonist BIBN 4096 BS was effective in treating acute attacks of migraine.
Acute Disease↗
A review of European studies on the economic burden of brain diseases.
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Brain Diseases↗
Headache classification update 2004.
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Cluster Headache↗
The phosphodiesterase 3 inhibitor cilostazol dilates large cerebral arteries in humans without affecting regional cerebral blood flow.
Cilostazol, an inhibitor of phosphodiesterase (PDE) type 3, is used clinically in peripheral artery disease. PDE3 inhibitors may be clinically useful in the treatment of delayed cerebral vasospasm after subarachnoid hemorrhage. The authors present the first results on the effect of cilostazol on cerebral hemodynamics in normal participants. In this double-blind, randomized, crossover study, 200 mg cilostazol or placebo was administered orally to 12 healthy participants. Cerebral blood flow was measured using 133Xe inhalation and single photon emission computerized tomography. Mean flow velocity in the middle cerebral arteries (VMCA) was measured with transcranial Doppler, and the superficial temporal and radial arteries diameters were measured with ultrasonography. During the 4-hour observation period, there was no effect on systolic blood pressure (P = 0.28), but diastolic blood pressure decreased slightly compared with placebo (P = 0.04). VMCA decreased 21.5 +/- 5.7% after cilostazol and 5.5 +/- 12.2% after placebo (P = 0.02, vs. placebo), without any change in global or regional cerebral blood flow. The superficial temporal artery diameter increased 17.6 +/- 12.3% (P < 0.001 vs. baseline) and radial artery diameter increased 12.6 +/- 8.6% (P < 0.001 vs. baseline). Adverse events, especially headache, were common. The findings suggest that cilostazol is an interesting candidate for future clinical trials of delayed cerebral vasospasm.
3',5'-Cyclic-AMP Phosphodiesterases↗
A dose-response study of nitric oxide synthase inhibition in different vascular beds in man.
BACKGROUND AND OBJECTIVE: Nitric oxide (NO) is an almost ubiquitous messenger molecule and is implicated in several disorders. NG monomethyl L-arginine ( L-NMMA:546C88) is an inhibitor of all three NO synthases (NOS), the enzymes that catalyse the production of NO. The present study was performed to evaluate the dose-response relation of L-NMMA to improve the design and interpretation of studies in migraine sufferers and other diseases. METHODS: In a double-blind, placebo-controlled, cross-over design, six healthy volunteers were randomised to receive three different doses of L-NMMA (0.3 mg/kg, 1 mg/kg, 3 mg/kg) or placebo (5% dextrose) intravenously (iv) over 5 min on four different days. On a fifth study day, in an open design, the same subjects received L-NMMA in the dose 6 mg/kg iv over 15 min. The effect of L-NMMA on the maximal mean blood velocity (Vmean) in the middle cerebral artery (MCA) (transcranial Doppler), the luminal diameter of the radial artery (high-frequency ultrasound), mean arterial blood pressure (MAP), heart rate and electrocardiogram were repeatedly followed every 5 min until 60 min after start of the infusion, then every 15 min during the following hour, and at 3 h and 4 h. RESULTS: Inhibition of NOS had no effect on Vmean in MCA or on the diameter of the radial artery, but MAP increased and heart rate decreased dose dependently. With a dose of 6-mg/kg L-NMMA infused over a 15-min period, the maximum MAP increase was 20% 20 min after the start of L-NMMA infusion. The maximum decrease of heart rate was 24% 15 min after start of the L-NMMA infusion. CONCLUSION: L-NMMA in a dose that caused marked changes in systemic blood pressure and heart rate had no effect on cerebral and radial arteries in man.
Adult↗
[Interdisciplinary treatment of headache. The Danish Society of Headache].
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Denmark↗
Evidence for a separate type of migraine with aura: sporadic hemiplegic migraine.
OBJECTIVE: To compare clinical characteristics of patients with sporadic hemiplegic migraine (SHM) with those of patients with migraine with typical aura (MA) and patients with familial hemiplegic migraine (FHM). METHODS: The authors used a computer search of Denmark's National Patient Register to screen the population for patients with migraine with aura with motor weakness, and also examined case records from headache clinics and private practicing neurologists and placed advertisements. The authors screened patients and their relatives with a semi-structured validated telephone interview. All recruited patients were then interviewed by a physician and given a neurologic examination. RESULTS: A total of 105 patients with SHM were identified. Seventy-two percent had four typical aura symptoms: visual, sensory, aphasic, and motor. All had at least two symptoms present during SHM attacks. A gradual progression and sequential appearance of aura symptoms was typical; compared with MA, the duration of each aura symptom was usually prolonged and bilateral motor symptoms were more frequent. Of the patients with SHM, 72% fulfilled the criteria for basilar migraine during SHM attacks. The aura was usually followed by headache, as is common in FHM but not MA. CONCLUSIONS: Patients with sporadic hemiplegic migraine had clinical symptoms identical to familial hemiplegic migraine and significantly different from migraine with typical aura. Sporadic hemiplegic migraine is a separate entity, and should be classified with familial hemiplegic migraine.
Adolescent↗
Experimental muscle pain and tenderness following infusion of endogenous substances in humans.
Several human models of myofascial pain exist, but none are similar to clinical pain. The aim of the present study was to develop a clinically relevant model of prolonged human myofascial pain using infusion of the naturally occurring endogenous substances. Initially, bradykinin (Bk), serotonin (5-hydroxytryptamine (5-HT)), histamine (His), prostaglandin E(2) (PGE(2)), adenosine-tri-phosphate (ATP), and their combinations were infused into the trapezius muscle of 36 healthy subjects in a total of 67 sessions to identify substances, which could induce a moderate muscle pain. PGE(2), ATP, and a combination of Bk, 5-HT, His, and PGE(2) produced the intended moderate pain. These substances were further examined in a randomised, blinded, placebo-controlled dose-finding design in 15 healthy subjects in 68 sessions. PGE(2) (3, 6, and 12 nmol/ml) induced mild pain and tenderness not different from placebo. ATP (9000, 18,000, and 36,000 nmol/ml) induced pain of moderate to strong intensity (P=0.04) and the dose of 18,000 nmol/ml furthermore produced moderate local tenderness (P=0.04). Because of unacceptable side effects in subsequent examinations, further studies of ATP in humans were suspended. Infusion of the combination of Bk (92 nmol), 5-HT (156 nmol), His (140 nmol), and PGE(2) (1.95 nmol) produced a moderate pain intensity (P=0.04) and mild tenderness (P=0.04) without inducing unacceptable side effects. Intramuscular infusion of a combination of Bk, 5-HT, His, and PGE(2) induced a prolonged moderate pain and tenderness in healthy humans, and this model may be a valuable tool in future studies of the pathophysiological mechanisms of myofascial pain.
Adult↗
Migraine can be induced by sildenafil without changes in middle cerebral artery diameter.
Migraine is considered a neurovascular disease involving dilatation of cerebral arteries. Nitric oxide (NO) donors induce dilatation of cerebral and extracranial arteries and migraine, but NO has several mechanisms of action in addition to its cyclic guanosine monophosphate (cGMP)-mediated vasodilatation. We examined whether sildenafil (Viagra), a selective inhibitor of cGMP-hydrolysing phosphodiesterase 5 (PDE5), which acts exclusively by increasing cGMP, can induce migraine and dilatation of cerebral arteries. We included 12 patients with migraine without aura in this double-blind, placebo-controlled crossover study, in which placebo or sildenafil 100 mg was administered orally on two separate days. Blood flow velocity in the middle cerebral artery (V(mca)) was recorded by transcranial Doppler ultrasonography and regional cerebral blood flow in the territory of the middle cerebral artery (rCBF(mca)) was measured using SPECT (single photon emission computed tomography) and xenon 133 inhalation. Radial and temporal artery diameters were studied using high-frequency ultrasonography. Headache response, tenderness of pericranial muscles, blood pressure and heart rate were measured repeatedly. We found that migraine attack was induced by sildenafil in 10 of 12 migraine patients and by placebo in two of 12 patients (P = 0.01). V(mca) (P = 0.1) and rCBF(mca) (P = 0.93) remained unchanged after sildenafil. Temporal (P = 0.47) and radial (P = 0.87) artery diameter and pericranial tenderness (P = 0.16) were unaffected by sildenafil. Systolic and diastolic blood pressures were unchanged but heart rate increased from a mean of 62 +/- 2 to 74 +/- 3 beats/min (P = 0.01) after sildenafil. Our results demonstrate that migraine may be induced via a cGMP-dependent mechanism, and we show for the first time that this occurs without initial dilatation of the middle cerebral artery. We propose that triggering mechanisms may reside within the perivascular sensory nerve terminals or the brainstem. However, other sites of action may also be possible and future studies are needed to elucidate this. In the clinical use of sildenafil, patients who have migraine should be informed about the risk of migraine attacks.
3',5'-Cyclic-GMP Phosphodiesterases↗
Migraine without aura and migraine with aura are distinct disorders. A population-based twin survey.
OBJECTIVE: To investigate the co-occurrence of migraine without aura (MWOA) and migraine with aura (MWA) in a population-based twin survey. BACKGROUND: Migraine without aura and MWA are multifactorial disorders. If MWOA and MWA share common genes, co-occurrence should be observed more frequently than expected, ie, the product of the prevalence in the general population. MATERIAL AND METHODS: The study population included all living Danish monozygotic (MZ) and same-gender dizygotic (DZ) twin pairs born between 1953 and 1960: 5360 twins (2026 MZ, 3334 DZ). The sample included 2840 men and 2520 women. All received a posted questionnaire, and those with possible migraine were interviewed via telephone by trained physicians (V.U. or M.G.). Twins who did not respond to the questionnaire and who had a co-twin with possible migraine were contacted by telephone. The questionnaire response rate was 87% (4660 of 5360), and the telephone interview was participated in by 90% (2035 of 2272). The physician interviewers were unaware of questionnaire answers, zygosity, and the clinical diagnosis of the co-twin. The criteria of the International Headache Society were used to establish a diagnosis of migraine. RESULTS: Lifetime prevalence in the twin sample: 7% of men and 19% of women had MWOA, while 7% of men and 8% of women had MWA. Lifetime prevalence of MWA in twin pairs with MWOA: MZ men, 2% (1 of 47); MZ women, 6% (5 of 90); DZ men, 9% (7 of 75); and DZ women, 10% (19 of 182). Lifetime prevalence of MWOA in twin pairs with MWA: MZ men, 3% (1 of 33); MZ women, 5% (3 of 58); DZ men, 9% (4 of 44); and DZ women, 13% (10 of 76). The observed and the expected numbers of twins with co-occurrence of MWOA and MWA based on the prevalence in the general population were not significantly different in either men or women (men, P=.1 and women, P=.5). CONCLUSION: The results strongly suggest that MWOA and MWA are distinct disorders, and identification of common genes for MWOA and MWA, thus, should not be expected to result from future genetic research.
Adult↗
The phosphodiesterase 5 inhibitor sildenafil has no effect on cerebral blood flow or blood velocity, but nevertheless induces headache in healthy subjects.
Cyclic nucleotides are important hemodynamic regulators in many tissues. Glyceryl trinitrate markedly dilates large cerebral arteries and increases cGMP. Here, the authors study the effect of sildenafil, a selective inhibitor of cGMP-hydrolyzing phosphodiesterase 5 on cerebral hemodynamics and headache induction. Ten healthy subjects were included in a double-blind, placebo-controlled crossover study where placebo or sildenafil 100 mg (highest therapeutic dose) were administered on two separate days. Blood velocity in the middle cerebral artery (Vmca) was recorded by transcranial Doppler, and regional cerebral blood flow in the perfusion area of the middle cerebral artery (rCBFmca) was measured using single photon emission computed tomography and xenon inhalation. Radial and temporal artery diameters were studied using high-frequency ultrasound. Blood pressure and heart rate were recorded repeatedly. Headache responses and tenderness of pericranial muscles were scored verbally. Sildenafil caused no significant changes in rCBFmca, Vmca, or in temporal or radial artery diameter, but heart rate increased and diastolic blood pressure decreased significantly compared to placebo. Despite the lack of cerebral arterial dilatation, sildenafil caused significantly more headache than placebo. The present results show that sildenafil 100 mg does not dilate cerebral or extracerebral arteries but nevertheless causes headache, which may be attributed to nonvascular mechanisms.
3',5'-Cyclic-GMP Phosphodiesterases↗
Muscle palpation with controlled finger pressure: new equipment for the study of tender myofascial tissues.
While manual palpation is the most important method for evaluation of tender myofascial tissues, it lacks reliability. Therefore, we have developed an instrument, called a 'palpometer', which allows the measurement of pressure exerted during palpation. The palpometer consists of a thin pressure-sensitive plastic device attached to the palpating finger, and of a scale recording the pressure applied to the device. Known forces were applied to the pressure sensitive device under various experimental conditions and the corresponding values were read on the palpometer scale. Then 14 observers, blinded to the palpometer scale, palpated the temporal muscle on the same subject twice, with an interval of 1 week. A highly significant correlation was found between palpometer recordings and forces applied to the pressure-sensitive device (P < 0.0001). Exerted force at a given palpometer value varied 3.1% within and 7.2% between 2 observers. During palpation of the temporal muscle pressure intensities within the 14 observers did not differ significantly from week to week (P = 0.68). Between the 14 observers pressure intensities varied considerably with a range of 73.5-196 arbitrary units. Thus, a reliable instrument for measuring pressure intensities during palpation of myofascial tissue has been developed. The large variation in palpation pressures between observers indicates that palpation of tender myofascial tissue may be considerably improved by use of the palpometer. This instrument will be indispensable in research studies employing palpation and in the training of physicians to diagnose myofascial pain disorders.
Adult↗
Muscle tenderness and pressure pain thresholds in headache. A population study.
Tenderness and pain thresholds in pericranial muscles were studied in a random sample of 735 adults aged 25-64 years. This study was a part of a multifaceted, epidemiological study of different headache disorders. Manual palpation and pressure pain threshold were performed by observers blinded to the persons' history of headache. The aim of the study was to evaluate the possible role of pericranial myofascial nociception in headache pathogenesis. Tenderness in migraineurs did not differ from non-migraineurs. Subjects with episodic tension-type headache and females with chronic tension-type headache were more tender than the rest of the population, and males without any experience of headache were less tender than the rest of the male population. A strong positive correlation between tenderness and frequency of tension-type headache was found (males: P < 10(-4); females: P < 10(-5)), while no relation between tenderness and migraine frequency was seen (P = 0.43). In subjects having actual headache at the day of examination tenderness was 32% increased compared to a matched group with identical usual frequency of headache, but without headache during the examination. A significant relation of tenderness to the recency of last episode of headache was detected in both sexes after control for usual frequency and actual headache (males: P < 10(-3); females: P < 10(-4)). Pressure pain thresholds were largely normal indicating normal pain processing and contradicting the idea that tension-type headache mainly is due to generally increased pain sensitivity. This study supports the pathogenetic importance of muscular factors in tension-type headache, while muscular factors are of no primary importance in migraine.
Adult↗