Single-dose intravenous iron infusion or oral iron for treatment of fatigue after postpartum haemorrhage: a randomized controlled trial.

BACKGROUND AND OBJECTIVES: To evaluate the clinical efficacy of a single-dose intravenous infusion of iron isomaltoside compared with current treatment practice with oral iron measured by physical fatigue in women after postpartum haemorrhage. MATERIALS AND METHODS: Single-centre, open-label, randomized controlled trial. Participants received intravenous iron (n = 97) or oral iron (n = 99), and completed the Multidimensional Fatigue Inventory and Edinburgh Postnatal Depression Scale, and haematological and iron parameters were measured. Primary outcome was the aggregated change in physical fatigue score from baseline to 12 weeks postpartum. RESULTS: The difference in physical fatigue score was -0·97 (95% CI: -1·65; -0·28, P = 0·006) in favour of intravenous iron, but did not meet the predefined difference of 1·8. Across visits, we found statistically significant differences in fatigue and depression scores, as well as in haematological and iron parameters, all in favour of intravenous iron. There were no serious adverse reactions. CONCLUSION: A single dose of intravenous iron was associated with a statistically significant reduction in aggregated physical fatigue within 12 weeks after postpartum haemorrhage compared to standard medical care with oral iron below the prespecified criteria of clinical superiority. As patient-reported outcomes improved significantly and intravenous iron resulted in a fast hematopoietic response without serious adverse reactions, intravenous iron may be a useful alternative after postpartum haemorrhage if oral iron is not absorbed or tolerated.

Single-dose intravenous iron infusion versus red blood cell transfusion for the treatment of severe postpartum anaemia: a randomized controlled pilot study.

BACKGROUND AND OBJECTIVES: There are no randomized trials comparing intravenous iron to RBC transfusion for the treatment of severe postpartum anaemia. The objectives of this study were to evaluate the feasibility of randomizing women with severe postpartum anaemia secondary to postpartum haemorrhage to RBC transfusion or intravenous iron, and to describe patient-reported outcomes, and haematological and iron parameters. MATERIALS AND METHODS: Women with a postpartum haemorrhage exceeding 1000 ml and an Hb between 5·6 and 8·1 g/dl were randomized to 1500 mg of intravenous iron (n = 7) isomaltoside or RBC transfusion (n = 6). Participants completed the Multidimensional Fatigue Inventory and Edinburgh Postnatal Depression Scale, and blood samples were drawn at inclusion, daily during the first week and at weeks 3, 8 and 12. RESULTS: We screened 162 women and included 13 (8%). There was no significant difference between groups in fatigue or depression scores. RBC transfusion was associated with a higher Hb on day 1, inhibition of reticulocytosis during the first week and low iron levels. Intravenous iron was associated with increased reticulocytosis during the first week, repleted iron stores and a higher Hb in weeks 3-12. CONCLUSION: This pilot study shows that intravenous iron could be an attractive alternative to RBC transfusion in severe postpartum anaemia, and that a larger trial is needed and feasible.

Intravenous iron isomaltoside 1000 (Monofer®) reduces postoperative anaemia in preoperatively non-anaemic patients undergoing elective or subacute coronary artery bypass graft, valve replacement or a combination thereof: a randomized double-blind placebo-controlled clinical trial (the PROTECT trial).

BACKGROUND AND OBJECTIVES: This trial explores whether intravenous iron isomaltoside 1000 (Monofer®) results in a better regeneration of haemoglobin levels and prevents anaemia compared to placebo in preoperative non-anaemic patients undergoing cardiac surgery. STUDY DESIGN AND METHODS: The trial is a prospective, double-blind, comparative, placebo-controlled trial of 60 non-anaemic patients undergoing cardiac surgery. The patients were randomized 1:1 to either 1000 mg intravenous iron isomaltoside 1000 administered perioperatively by infusion or placebo. RESULTS: Mean preoperative haemoglobin in the active treatment group was 14·3 g/dl vs. 14·0 g/dl in the placebo group. At discharge 5 days after surgery, haemoglobin levels were reduced to 10·7 and 10·5 g/dl, respectively. One month after surgery, haemoglobin concentration had increased to an average of 12·6 g/dl vs. 11·8 g/dl (p = 0·012) and significantly more patients were non-anaemic in the intravenous iron isomaltoside 1000-treated group compared to the placebo group (38·5% vs. 8·0%; p = 0·019). There were no differences in side-effects between the groups. CONCLUSION: A single perioperative 1000 mg dose of intravenous iron isomaltoside 1000 significantly increased the haemoglobin level and prevented anaemia 4 weeks after surgery, with a short-term safety profile similar to placebo. Future trials on potential clinical benefits of preoperative treatment with intravenous iron in non-anaemic patients are needed.

Effects of IV iron isomaltoside-1000 treatment on regional brain iron status in an iron-deficient animal.

BACKGROUND: Iron deficiency has been documented to affect human cognitive function and conditions with brain iron compromise such as the restless legs syndrome (RLS). Intravenous (IV) iron treatment is used to reduce iron deficiency but its effects on brain iron are not known. It is not known if IV iron is effective in correcting regional brain iron deficiencies nor if it poses a risk of producing iron overload in some brain regions. Preclinical study of IV iron in the iron-deficient (ID) murine model is needed to evaluate and develop IV iron treatments for brain iron deficiency. METHODS: Response to tail vein injections of iron (iron isomaltoside-1000, dose equivalent to 1000 mg for 75 kg adult) or vehicle were evaluated for ID mice by microdialysis assessing non-transferrin bound (NTB) iron in the ventral midbrain (VMB) and autopsy at 3 and 10 days post-injection assessing iron content in critical brain regions. RESULTS: The ID mice showed marked circadian variation in NTB extracellular iron. After iron injection, NTB iron was rapidly increased in the VMB and then decreased over 12h to the levels observed for vehicle. Regional brain iron content at 3 and 10 days post-injection in the iron- compared to vehicle-treated group showed significantly more iron for the VMB and nucleus accumbens but not for the other regions (i.e. prefrontal cortex, caudate-putamen, cerebellum, and pons), which also did not show decreased iron content with the ID diet. CONCLUSION: Iron isomaltoside-1000 given IV corrects the regional brain iron deficiency in these ID mice without producing iron overload in any of the brain regions studied. This is the first demonstration of effects of IV iron in the brain and it provides a useful preclinical model for this assessment, particularly relevant for developing iron treatments for conditions with problematic iron deficiency, e.g. RLS.

Habituation of evoked responses is greater in patients with familial hemiplegic migraine than in controls: a contrast with the common forms of migraine.

BACKGROUND: Familial hemiplegic migraine (FHM) is a rare, dominantly inherited subtype of migraine with transient hemiplegia during the aura phase. Mutations in at least three different genes can produce the FHM phenotype. The mutated FHM genes code for ion transport proteins that animal and cellular studies have associated with disturbed ion homeostasis, altered cellular excitability, neurotransmitter release, and decreased threshold for cortical spreading depression. The common forms of migraine are characterized interictally by a habituation deficit of cortical and subcortical evoked responses that has been attributed to neuronal dysexcitability. FHM and the common forms of migraine are thought to belong to a spectrum of migraine phenotypes with similar pathophysiology, and we therefore examined whether an abnormal habituation pattern would also be found in FHM patients. METHODS: In a group of genotyped FHM patients (five FHM-1, four FHM-2), we measured habituation of visual evoked potentials (VEP), auditory evoked potentials including intensity dependence (IDAP), the nociception-specific blink reflex (nsBR) and compared the results to a group of healthy volunteers (HV). RESULTS: FHM patients had a more pronounced habituation during VEP (P=0.025) and nsBR recordings (P=0.023) than HV. There was no difference for IDAP, but the slope tended to be steeper in FHM. CONCLUSION: Contrary to the common forms of migraine, FHM patients are not characterized by a deficient, but rather by an increased habituation in cortical/brain stem evoked activities. These results suggest differences between FHM and the common forms of migraine, as far as central neuronal processing is concerned.

Delayed migraine-like headache in healthy volunteers after a combination of acetazolamide and glyceryl trinitrate.

Glyceryl trinitrate (GTN) is a pro-drug dissociating nitric oxide throughout the body. It dilates cephalic arteries without increasing cerebral blood flow (CBF). GTN induces headache in healthy volunteers and migraine attacks in migraineurs. Acetazolamide (Az) increases CBF but does not dilate cerebral arteries. The hypothesis tested here was that Az, by dilating cerebral arterioles but not arteries and thereby decreasing pulsatile stretching of the wall of the large arteries and their perivascular sensory nerves, would reduce or prevent the GTN-induced headache We tested this hypothesis in 14 healthy volunteers. In a randomized, double-blind, cross-over study, they were pretreated with Az or placebo followed on both study days by a GTN infusion of 0.5 microg kg(-1) min(-1) for 20 min. Headache was scored on a verbal rating scale and a headache diary was kept for 12 h. Mean blood velocity of the middle cerebral artery was measured (transcranial Doppler). Our hypothesis was disproved, as Az did not decrease GTN-induced headache. Unexpectedly but interestingly, GTN combined with Az induced more delayed headache than GTN alone. Furthermore, a migraine-like headache was observed in three volunteers, who did not develop migraine after GTN alone. The fact that a suitable pharmacological intervention may trigger migraine in individuals with no prior migraine may suggest that the ability to develop migraine without aura is a quantitative genetic trait.

Brain malformation in single median maxillary central incisor.

Clinical and radiographic examinations and MR scan of a 12-year-old girl with SMMCI (single median maxillary central incisor) showed impaired growth and a midline defect involving the central incisor, cranium and the midline structures in the brain, falx cerebri and pituitary gland. She had a severe growth hormone deficiency but no other pituitary hormone deficiencies. She was treated with growth hormone and followed during a four-year period with successful gain in body height and sexual maturation. This study focuses on the developmental association between the involved structures and provides guidelines for early diagnostics.

Screen for CACNA1A and ATP1A2 mutations in sporadic hemiplegic migraine patients.

The aim of this study was to investigate the involvement of the CACNA1A and ATP1A2 gene in a population-based sample of sporadic hemiplegic migraine (SHM). Patients with SHM (n = 105) were identified in a nationwide search in the Danish population. We sequenced all exons and promoter regions of the CACNA1A and ATP1A2 genes in 100 patients with SHM to search for possible SHM mutations. Novel DNA variants were discovered in eight SHM patients, four in exons of the CACNA1A gene and four in exons of the ATP1A2 gene. Six of the variants were considered non-pathogenic. The causal role of the two remaining DNA variants is unknown until functional studies have been made or independent genetic evidence is discovered. Only very few DNA variants were identified in 100 SHM patients, and regardless of whether the identified variants are causal the CACNA1A and ATP1A2 genes are not major genes in SHM.

Familial hemiplegic migraine type 1 shows no hypersensitivity to nitric oxide.

Familial hemiplegic migraine type 1 (FHM-1) is a dominantly inherited subtype of migraine with aura and transient hemiplegia associated with mutations in the CACNA1A gene. FHM-1 shares many phenotypical similarities with common types of migraine, indicating common neurobiological pathways. Experimental studies have established that activation of the nitric oxide-cyclic guanosine monophosphate (NO-cGMP) pathway plays a crucial role in migraine pathophysiology. Therefore, we tested the hypothesis that CACNA1A mutations in patients with FHM-1 are associated with hypersensitivity to NO-cGMP pathway. We included eight FHM-1 patients with R583Q and C1369Y mutations and nine healthy controls, who received intravenous infusions of 0.5 microg kg(-1) min(-1) glyceryl trinitrate (GTN) over 20 min. We recorded: headache intensity on a verbal rating scale; mean flow velocity in the middle cerebral artery (V(meanMCA)) by transcranial Doppler; diameter of the superficial temporal artery (STA) by Dermascan. One patient reported migraine without aura 5 h after start of the GTN infusion. No aura was reported. The AUC(headache) in the immediate phase was more pronounced in patients than in controls (P = 0.01). In the 14 h following GTN infusion, there was no difference in the AUC(headache) between patients and controls (P = 0.17). We found no difference in the AUC(VmeanMCA) (P = 0.12) or AUC(STA) (P = 0.71) between FHM-1 patients and controls. None of the control persons reported migraine-like headache. FHM-1 patients do not show hypersensitivity of the NO-cGMP pathway, as characteristically seen in migraine patients with and without aura. This indicates that the pathophysiological pathways underlying migraine headache in FHM-1 may be different from the common types of migraine.

Familial hemiplegic migraine type 2 does not share hypersensitivity to nitric oxide with common types of migraine.

Familial hemiplegic migraine type 2 (FHM-2) and common types of migraine show phenotypic similarities which may indicate a common neurobiological background. The nitric oxide-cyclic guanosine monophosphate (NO-cGMP) pathway plays a crucial role in migraine pathophysiology. Therefore, we tested the hypothesis that ATP1A2 mutations in patients with FHM-2 are associated with hypersensitivity to NO-cGMP pathway. Eight FHM-2 patients with R202Q, R763C, V138A and L764P mutations and nine healthy controls received intravenous infusions of 0.5 mug kg(-1) min(-1) glyceryl trinitrate (GTN) over 20 min. We recorded the following variables: headache intensity on a verbal rating scale; mean flow velocity in the middle cerebral artery (V(meanMCA)) by transcranial Doppler; diameter of the superficial temporal artery (STA) by ultrasound. The primary end-points were differences in incidence of migraine headache and area under the curve (AUC) for headache score during an immediate phase (0-120 min) and a delayed phase (2-14 h) after start of infusion. We found no difference in the incidence of reported migraine between FHM-2 patients, 25% (two out of eight), and controls, 0% (0 out of nine) (95% confidence interval -0.06, 0.56) (P = 0.21). The AUC(headache) in the immediate (P = 0.37) and delayed (P = 0.09) phase was not different between patients and controls. The GTN infusion resulted in a biphasic response in patients. During the immediate phase, the median peak headache occurred at 30 min and tended to be higher in patients, 1 (0, 3.8), than in controls, 0 (0, 1) (P = 0.056). During the delayed phase, the median peak headache occurred 4 h after the start of the infusion and was significantly higher in patients, 2.5 (0, 3), than in controls, 0 (0, 0) (P = 0.046). We found no difference in the AUC(VmeanMCA) (P = 0.77) or AUC(STA) (P = 0.53) between FHM-2 patients and controls. GTN infusion failed to induce more migraine in FHM-2 patients than in controls. The pathophysiological pathways underlying migraine headache in FHM-2 may be different from the common types of migraine.

The genetic spectrum of a population-based sample of familial hemiplegic migraine.

Familial hemiplegic migraine (FHM) is a rare subtype of migraine with aura and transient hemiplegia. FHM mutations are known in three genes, the CACNA1A (FHM1) gene, the ATP1A2 (FHM2) and the SCN1A (FHM3) gene and seem to have an autosomal-dominant mode of inheritance. The aim of this study was to search for FHM mutations in FHM families identified through a screen of the Danish population of 5.2 million people. FHM patients were diagnosed according to the International Classification of Headache Disorders and all FHM patients had a physical and neurological examination by a physician. A total of 147 FHM patients from 44 different families were identified; 43 FHM families participated in this study. Linkage analysis of these families shows clear linkage to the FHM locus (FHM1) on chromosome 19, supportive linkage to the FHM2 locus whereas no linkage was found to the FHM3 locus. Furthermore, we sequenced all exons and promoter regions of the CACNA1A and ATP1A2 genes and screened for the Q1489K mutation in the SCN1A gene. CACNA1A gene mutations were identified in three of the FHM families, two known FHM mutations, R583Q and T666M and one novel C1369Y mutation. Three FHM families were identified with novel mutations in the ATP1A2 gene; a family with a V138A mutation, a family with a R202Q mutation and a family with a R763C mutation. None of the Danish FHM families have the Q1489K mutation in the SCN1A gene. Our study shows that only 14% (6/42) of FHM families in the general Danish population have exonic FHM mutations in the CACNA1A or ATP1A2 gene. The families we identified with FHM mutations in the CACNA1A and ATP1A2 genes were extended, multiple affected families whereas the remaining FHM families were smaller. The existence of many small families in the Danish FHM cohort may reflect less bias in FHM family ascertainment and/or more locus heterogeneity than described previously.

The Visual Aura Rating Scale (VARS) for migraine aura diagnosis.

To supplement the traditional ICHD-2 diagnosis for migraine with aura (MA) we developed a diagnostic scale for migraine aura that quantifies the importance of the cardinal characteristics of MA. Since more than 99% of MA patients have visual aura, we developed for simplicity a Visual Aura Rating Scale (VARS). In total 427 patients with MA (ICHD-2) or nonaura visual disturbances were diagnosed in a validated semistructured interview by a trained physician. The patients were separated into a derivation sample and a validation sample. By regression analysis we identified the visual aura characteristics associated with MA in the derivation sample. Based on the identified characteristics we developed VARS and derived a predictive VARS score which was tested in the validation sample. The VARS score is the weighted sum of the presence of five visual symptom characteristics: duration 5-60 min (3 points), develops gradually > or = 5 min (2 points), scotoma (2 points), zig-zag lines (2 points), and unilateral (1 point). The maximum score is 10 points. A VARS score of 5 or more diagnosed MA with a sensitivity of 96% (95% CI 92-99%) and a specificity of 98%(95% CI 95-100%) in the derivation sample, and a sensitivity of 91% (95% CI 86-95%) and a specificity of 96% (95% CI 91-100%) in the validation sample. VARS adds evidence based weights to a number of clearly specified characteristics; it is easy to learn, apply and teach and may therefore be a valuable addition to traditional ICHD-2 diagnosis.

Peroperative depth of anaesthesia may influence postoperative opioid requirements.

BACKGROUND: Studies on monitoring the depth of anaesthesia have shown that with the use of these monitors the peroperative consumption of anaesthetics can be reduced. Studies have also indicated that the peroperative depth of anaesthesia may affect the postoperative course. The purpose of this study was to evaluate a possible relation between the depths of anaesthesia and the postoperative pain score and consumption of morphine. METHODS: We used middle latency auditory evoked potentials (MLAEPs) for monitoring the depth of anaesthesia. The study was prospective, observer blinded and included 50 women scheduled for elective abdominal hysterectomy. Anaesthesia was induced using propofol and remifentanil. Before leaving the recovery room the patients were provided with a programmed patient-controlled pump (PCA), which was only activated on demand. Auditory evoked potentials were registered from just before induction of anaesthesia and during the whole procedure, but the anaesthetist did not have access to the monitor. RESULTS: Fifty patients were included and seven were excluded. The remaining 43 patients were divided into two groups: Group High (n=12) with an AAI>28 for >5% of the registration time and Group Low (n=31) with an AAI>28 for <5% of the registration time. Group High had significantly higher morphine requirements in the recovery and activated the PCA-pump more frequently during the first 24 postoperative hours. CONCLUSION: The results indicate that the peroperative depth of anaesthesia may have effects on the postoperative analgesic requirements.

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.

Sporadic hemiplegic migraine.

Sporadic hemiplegic migraine (SHM) is defined as migraine attacks associated with some degree of motor weakness/hemiparesis during the aura phase and where no first degree relative (parent, sibling or child) has identical attacks. The present review deals with recent scientific studies according to which: The SHM prevalence is estimated to be 0.005%; SHM patients have clinical symptoms identical to patients with familial hemiplegic migraine (FHM) and significantly different from patients with migraine with typical aura (typical MA); SHM affected had no increased risk of migraine without aura (MO), but a highly increased risk of typical MA compared to the general population; SHM patients only rarely have mutations in the FHM gene CACNA1A; SHM attacks in some cases can be treated with Verapamil. The reviewed data underlie the change in the International Classification of Headache Disorders 2nd edition where SHM became separated from migraine with typical aura or migraine with prolonged aura. All cases with motor weakness should be classified as either FHM or SHM.

The effect of propranolol on glyceryltrinitrate-induced headache and arterial response.

Prophylactic drug trials in migraine are long-lasting and expensive and require long-term toxicology information. A human migraine model would therefore be helpful in testing new drugs. Immediate headache and delayed migraine after glyceryltrinitrate (GTN) has been well characterized. We have recently shown that sodium valproate has prophylactic effect in the GTN model. Here we report our experience with propranolol in this model. Nineteen subjects with migraine without aura and 16 sex- and aged-matched healthy subjects were included in a two-centre randomized double-blind cross-over study. Fourteen migraine subjects and 14 healthy subjects completed the study and results from comparison of the 28 subjects are reported. Randomly propranolol 160 mg or placebo were each given daily for 14 days to both migraine and healthy subjects. A 20-min intravenous infusion of GTN 0.25 microg/kg per min was administered on a study day at the end of both pretreatment periods. Headache was registered for 12 h after GTN infusions. Its intensity was scored on a numerical verbal rating scale from 0 to 10. Fulfilment of International Headache Society (HIS) criteria was recorded for 24 h. Radial and superficial temporal artery diameters and blood velocity of both middle cerebral arteries were measured. All migraine subjects developed headache after GTN. No reduction of overall peak headache was found after propranolol (median 5, range 0-7) compared with placebo (median 5, range 0-10) (P = 0.441). Eight of the 14 completing migraine subject developed IHS 1.1 migraine after GTN, two subjects on both days, three subjects only after placebo, and three subjects only after propranolol. No reduction of GTN-induced migraine was found after propranolol compared with placebo (5 vs. 5, P = 1.000). All healthy subjects developed headache after GTN. No reduction of overall peak headache was found after propranolol (median 2, range 1-5) compared with placebo (median 1, range 1-7) (P = 0.315). Two subjects fulfilled IHS criteria 1.1 for migraine without aura after propranolol but not after placebo. The fulfilment was short lasting and did not require rescue medication. Headache after GTN was more pronounced in migraine subjects than in healthy subjects both with (P = 0.003) and without pretreatment with propranolol (P = 0.017). We found that 2 weeks of propranolol constricted the radial artery in healthy subjects but not in migraine subjects. GTN-induced vasodilatation abolished this difference. Mean maximum blood flow velocity in the middle cerebral artery was higher in healthy subjects than in migraine patients (P = 0.003-0.033) and unaffected by propranolol. We observed no effect of propranolol on GTN-induced headache and migraine. This could indicate that GTN induces migraine at a deeper level of the pathophysiological cascade of migraine than the prophylactic effect of propranolol. Propranolol does not constrict cerebral arteries, which therefore cannot be part of its mechanism of action in migraine.

New international classification of migraine with aura (ICHD-2) applied to 362 migraine patients.

The International Classification of Headache Disorders 2nd edition (ICHD-2) subdivides migraine with aura (MA) differently from the ICHD-1 and includes new diagnostic criteria. The aim of the present study was to evaluate how the new classification works in practice and in comparison with the ICHD-1. The patients were recruited from a screen of the Danish National Patient Registry and from Danish neurologists. We included 362 patients diagnosed with MA according to the ICHD-1 in a validated semistructured physician-conducted interview. According to the ICHD-2, 89% (322 of 362) had MA and 11% (40 of 362) had probable MA. The MA patients had one or more ICHD-2 subtype of MA: 54% (173 of 322) had typical aura with migraine headache (MA-MH), 40% (129 of 322) had typical aura with non-migraine headache (MA-NMH), 37% (120 of 322) had aura without headache (MA-WOH), and 7% (26 of 322) had basilar-type migraine (MA-B). Of patients with MA-MH 34% (59 of 173) had co-occurrence of MA-WOH, 9% (16 of 173) had co-occurrence of MA-B and 5% (8 of 173) had co-occurrence of both MA-WOH and MA-B. Of patients with MA-NMH 27% (35 of 129) had co-occurrence of MA-WOH. Only 6% (18 of 322) of the MA patients had exclusively MA-WOH and <1% (2 of 322) had exclusively MA-B. Patients with MA-MH had an earlier age at onset (P = 0.044), an increased lifetime number of MA attacks (P = 0.054) and a higher co-occurrence of migraine without aura (P = 0.002) than patients with MA-NMH. Patients with MA-B tended to have an earlier age at onset and more severe attacks and patients with MA-WOH had a higher age at onset and less severe attacks than patients with MA-MH. The variations between ICHD-2 subtypes of MA indicate that patients with similar subtype of MA share phenotype and very likely have similar underlying aetiology.

Plasma levels of cAMP, cGMP and CGRP in sildenafil-induced headache.

Sildenafil, a selective inhibitor of the cyclic guanosine monophosphate (cGMP) degrading phosphodiestrase 5 (PDE5), induced migraine without aura in 10 of 12 migraine patients and in healthy subjects it induced significantly more headache than placebo. The aim of the present study was to determine whether the pain-inducing effects of sildenafil would be reflected in plasma levels of important signalling molecules in migraine: cGMP, cyclic adenosine monophosphate (cAMP) and calcitonin gene-related peptide (CGRP). Ten healthy subjects (four women, six men) and 12 patients (12 women) suffering from migraine without aura were included in two separate double-blind, placebo-controlled, cross-over studies in which placebo or sildenafil 100 mg was administered orally. Plasma levels of CGRP, cAMP and cGMP were determined in blood from the antecubital vein. Despite the ability of sildenafil to induce headache and migraine, no significant differences in plasma levels of CGRP, cGMP and cAMP were detected after sildenafil compared with placebo. In conclusion, plasma levels of CGRP, cGMP and cAMP remain normal during sildenafil-induced headache or migraine. However, since previous studies indicate an important role of these signalling molecules, the present study questions whether cAMP and cGMP in peripheral blood can be used for monitoring pathophysiological events in headache and migraine mechanisms.

Clinical characteristics of 362 patients with familial migraine with aura.

The objectives of the present study were to describe the clinical characteristics of patients with severe familial non-hemiplegic migraine with aura (NHMA) and to compare these data to those from cases in previous population-based Danish studies using the same methodology. NHMA families were recruited from the Danish patient registry and from Danish neurology practices. A total of 362 NHMA patients were diagnosed according to the 1988 International Headache Society criteria using a validated semistructured physician-conducted interview. Visual aura occurred in almost every NHMA attack. In aura without headache visual aura occurred primarily in isolation. Aura without headache was most common in older, male patients. Several clinical characteristics of familial NHMA differed from migraine with aura in the general population: firstly, the age at onset was lower, secondly, the age at cessation was higher, thirdly, aura symptoms were more severe and finally, the co-occurrence of migraine without aura was higher in familial NHMA. There seems to be a correlation between more severe symptoms and familial aggregation. These results have both clinical and scientific implications.

The prophylactic effect of valproate on glyceryltrinitrate induced migraine.

In this study the human glyceryltrinitrate (GTN) model of migraine was for the first time used to test the effect of a prophylactic drug. We chose to test valproate due to its well documented effect as a migraine prophylactic drug. Efficacy of this compound would support the usefulness of the model in prophylactic antimigraine drug development. Twelve patients with migraine without aura were included in a randomized double blind crossover study. Valproate 1000 mg or placebo was given daily, each for a minimum of 13 days. On the last treatment day of each arm a 20 min intravenous infusion of GTN (0.25 microg/kg/min) was given. Headache was registered for 12 h after the infusion and headache intensity was scored on a scale from 0 to 10. Fulfillment of IHS criteria was recorded for 24 h. The middle cerebral arteries were evaluated by transcranial Doppler and the diameter of the superficial temporal and radial arteries were measured with high frequency ultrasound. GTN evoked migraine fulfilling IHS criteria 1.1 in 6 patients after placebo and in 2 patients after valproate (P = 0.125). Including additionally 3 patients on placebo and 1 patient on valproate who felt they had suffered a migraine attack, but who had as associated symptoms only photophobia or phonophobia, a significant reduction in the number of patients with induced migraine after valproate was seen (P = 0.031). Median peak headache intensity was 1 (range 0-9) after valproate compared to 4.5 (range 0-8) after placebo (P = 0.120). Pretreatment with valproate as compared to placebo reduced the velocity in both middle cerebral arteries after GTN (left P = 0.021, right P = 0.031). No effect of valproate was seen in the diameter of the superficial temporal artery (P = 0.781) or the radial artery (P = 0.367) before or after GTN. The study indicates that a prophylactic effect of valproate may be demonstrated using the GTN human migraine model. Although, all headache parameters were reduced after valproate compared to placebo, only one parameter was statistically significantly reduced probably because of the small number of patients. The size of the effect was similar to that of valproate in clinical trials. The GTN model may therefore be a valid tool for testing new prophylactic antimigraine drugs.