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Patients suffering from Becker muscular dystrophy (BMD) have dysfunctional dystrophin proteins and are deficient in neuronal nitric oxide synthase (nNOS) in muscles. This causes functional ischemia and contributes to muscle wasting. Similar functional ischemia may be present in brains of patients with BMD, who often have mild cognitive impairment, and nNOS may be important for the regulation of the microvascular circulation in the brain. We hypothesized that treatment with sildenafil, a phosphodiesterase type 5 inhibitor that potentiates nitric oxide responses, would augment both the blood oxygen level-dependent (BOLD) response and cerebral blood flow (CBF) in patients with BMD. Seventeen patients (mean ± SD age 38.5 ± 10.8 years) with BMD were included in this randomized, double-blind, placebo-controlled, crossover trial. Twelve patients completed the entire study. Effects of sildenafil were assessed by 3 T magnetic resonance (MR) scanning, evoked potentials, somatosensory task-induced BOLD functional MR imaging, regional and global perfusion, and angiography before and after 4 weeks of sildenafil, 20 mg (Revatio in gelatine capsules, oral, 3 times daily), or placebo treatment. Sildenafil increased the event-related sensory and visual BOLD response compared with placebo (p

Headache and facial pain are among the most common, disabling and costly disorders in Europe. Correct diagnosis and treatment is important for achieving a high quality of care. As a national organisation whose role is to educate and advocate for the needs of patients with primary headaches, the Danish Headache Society has set up a task force to develop a set of guidelines for the diagnosis, organisation and treatment of the most common types of headaches and for trigeminal neuralgia in Denmark. The guideline was published in Danish in 2010 and has been a great success. The Danish Headache Society decided to translate and publish our guideline in English to stimulate the discussion on optimal organisation and treatment of headache disorders and to encourage other national headache authorities to produce their own guidelines. The recommendations regarding the most common primary headaches and trigeminal neuralgia are largely in accordance with the European guidelines produced by the European Federation of Neurological Societies. The guideline provides a practical tool for use in daily clinical practice for primary care physicians, neurologists with a common interest in headache, as well as other health-care professionals treating headache patients. The guideline first describes how to examine and diagnose the headache patient and how headache treatment is organised in Denmark. This description is followed by individual sections on the characteristics, diagnosis, differential diagnosis and treatment of each of the major headache disorders and trigeminal neuralgia. The guideline includes many tables to facilitate a quick overview. Finally, the particular problems regarding headache in children and headache in relation to female hormones and pregnancy are described.

Introduction: Patients with dystrophinopathies show low levels of neuronal nitric oxide synthase (nNOS), due to reduced or absent dystrophin expression, as nNOS is attached to the dystrophin-associated protein complex. Deficient nNOS function leads to functional ischemia during muscle activity. Dystrophin-like proteins with nNOS attached have also been identified in the brain. This suggests that a mechanism of cerebral functional ischemia with attenuation of normal activation-related vascular response may cause changes in brain function. Methods: The aim of this study was to investigate whether the brain response of patients with Becker muscular dystrophy (BMD) is dysfunctional compared to that of healthy controls. To investigate a potential change in brain activation response in patients with BMD, median nerve somatosensory evoked stimulation, with stimulation durations of 2, 4, and 10 s, was performed while recording electroencephalography and blood oxygen level-dependent (BOLD) functional magnetic resonance imaging. Results: Results in 14 male patients with BMD (36.2 ± 9.9 years) were compared with those of 10 healthy controls (34.4 ± 10.9 years). Compared to controls, the patients with BMD showed sustained cortical electrical activity and a significant smaller BOLD activation in contralateral primary somatosensory cortex and bilaterally in secondary somatosensory cortex. In addition, significant activation differences were found after long duration (10 s) stimuli in thalamus. Conclusion: An altered neurovascular response in patients with BMD may increase our understanding of neurovascular coupling and the pathogenesis related to dystrophinopathy and nNOS.

Activation of the trigeminovascular pain signalling system, including cerebral arteries, meninges, trigeminal ganglion, and brain stem, is involved in migraine. Furthermore, stimulation of cyclic nucleotide (cAMP and cGMP) production as well as inhibition of phosphodiesterases (PDEs) induces headache and migraine. In order to investigate the possible role of PDE in the pain pathway of migraine, expression of the most recently discovered PDE subtypes (9A, 10A and 11A) in cerebral arteries, dura mater, and trigeminal ganglion and nucleus was examined. The presence of mRNA and protein in the middle cerebral artery, basilar artery, meninges, trigeminal ganglion, and spinal trigeminal nucleus of male Sprague-Dawley rats were investigated using real-time PCR, Western blot, and immunohistochemistry. The results were compared to two peripheral arteries: aorta and mesenteric artery, as well as neocortex and cerebellar cortex. Real-time PCR and Western blotting showed that PDE9A, PDE10A and PDE11A are expressed in components of the rat trigeminovascular pain signalling system including middle cerebral artery, basilar artery, meninges, trigeminal ganglion and spinal trigeminal nucleus. Aorta and mesenteric artery as well as cerebral neocortex and cerebellar cortex also showed expression of PDE9A, PDE10A and PDE11A. Immunohistochemistry revealed that PDE9A, PDE10A and PDE11A are localised in the cytosol of nerve cell bodies of the trigeminal ganglion. We here present, for the first time, the expression of PDE9A, PDE10A, and PDE11A in the trigeminovascular system. The functional implications are yet unknown, but their localisation indicates that they may have a role in the pain pathway of migraine as well as trigeminal neuralgia and trigeminal autonomic cephalalgias.

Experimental studies have shown that infusion of vasoactive neurotransmitters may trigger headache or migraine-like attacks in man. Pituitary adenylate cyclase activating peptide-38 (PACAP38) is a strong vasodilator found in trigeminal sensory and parasympathetic perivascular nerve fibers. We therefore hypothesized that infusion of PACAP38 would cause headache in healthy subjects and migraine-like attacks in migraine patients. Twelve healthy subjects and 12 migraine patients were examined in two separate studies. All subjects were allocated to receive 10 pmol/kg/min PACAP38 and placebo in a randomized, double-blind crossover study design. Headache was scored on a verbal rating scale (VRS) during hospital (0-2 h) and post-hospital (2-12 h) phases. Mean blood flow velocity in the middle cerebral artery (V(MCA)) by transcranial Doppler (TCD) and diameter of the superficial temporal artery (STA) by high resolution ultrasonography were recorded during hospital phase in migraineurs. PACAP38 infusion caused headache in all healthy subjects and 11 out of 12 migraine patients. Seven migraine patients experienced migraine-like attacks after PACAP38 and none after placebo (P = 0.016). Most of attacks (6 out of 7) occurred during the post-hospital phase [mean time 6 h (range 2-11)]. Two healthy subjects reported migraine-like attacks after PACAP38 during the hospital phase and none during the post-hospital phase. In the hospital phase, the area under the curve (AUC) for headache score was larger during PACAP38 infusion compared to placebo in healthy subjects (P = 0.005) and tended to be larger in migraineurs (P = 0.066). In the post-hospital phase, the AUC for headache was larger after PACAP38 infusion compared to placebo in both healthy subjects (P = 0.005) and migraine patients (P = 0.013). In migraine patients, PACAP38 caused a peak decrease of 16.1% in V(MCA) and a 37.5% increase in STA diameter at 20 min after start of infusion. In conclusion, PACAP38 infusion caused headache and vasodilatation in both healthy subjects and migraine patients. In migraine sufferers, PACAP38 caused delayed migraine-like attacks. The findings stimulate further investigation of the neuronal and vascular mechanisms of PACAP38.

We have previously shown that nitric oxide (NO) and cyclic guanosine monophosphate (GMP) may cause headache and migraine. However, not all findings in previous studies can be explained by an activation of the NO-cGMP pathway. Calcitonin gene-related peptide (CGRP) causes headache and migraine in migraine patients, but CGRP receptor activation causes an increase in cyclic adenosine monophosphate (cAMP). In order to investigate the role of cAMP in vascular headache pathogenesis, we studied the effect of cilostazol, an inhibitor of cAMP degradation, in our human experimental headache model. Twelve healthy volunteers were included in a double-blind, randomized, crossover study. Placebo or cilostazol (200 mg p.o.) was administered on two separate study days. Headache was scored on a verbal rating scale (0-10) and mechanical pain thresholds were measured with von Frey hairs. The median peak headache score 0-16 h postdose was 0 (range 0-2) after placebo and 3.5 (range 0-7) after cilostazol ( P = 0.003). The median headache curve peaked at 6-9 h postdose. The headaches induced were usually bilateral and pulsating. Nausea occurred in two volunteers, photo- and phonophobia were not seen. Two volunteers had a headache that fulfilled International Headache Society criteria for migraine without aura after cilostazol. No change in mechanical pain thresholds in the forehead was seen ( P = 0.25). The headache after cilostazol was equal to or more severe than headache induced by glyceryl trinitrate in previous experiments. The present study thus indicates that increased levels of cAMP may play a role in headache and migraine pathogenesis.

Activation of the trigeminovascular pain signalling system appears involved in migraine pathophysiology. However, the molecular mechanisms are only partially known. Stimulation of cAMP and cGMP production as well as inhibition of their breakdown induce migraine-like headache. Additionally, migraine may be associated with mutations in ion channels. The aim of the present study was to describe the expression of phosphodiesterase 3 (PDE3) and 5 (PDE5) and cyclic nucleotide-gated ion channels (CNG) in cerebral arteries, meninges, and the trigeminal ganglion. mRNA for PDE and CNG was determined in the rat middle cerebral artery, basilar artery, trigeminal ganglion, and dura mater using real-time PCR. PDE and CNG proteins were identified using Western blot. For comparison, rat aorta and mesenteric artery were analysed. PDE3A, PDE3B, and PDE5A mRNA were detected in all tissues examined except for PDE3A mRNA in dura mater and the trigeminal ganglion. PDE5A and PDE3A protein expression was present in both cerebral and peripheral arteries, whereas PDE3B protein was present only in the cerebral arteries. The CNGA4 and B1 subunit mRNAs were detected in cerebral arteries and CNGA2 also in the mesenteric artery. CNGA2 and A3 proteins were found in cerebral arteries and dura and CNGA1, CNGA2 and CNGA3 in the trigeminal ganglion. In conclusion, PDE3A, PDE3B, PDE5A, and five CNG subunits were expressed in several components of the trigeminovascular system of the rat. This suggests that modulation of cAMP and cGMP levels by PDE and activation of CNG may play a role in trigeminovascular pain signalling leading to migraine headache.

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 133xenon 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.

The neuropathology leading to migraine pain has centered on an either a vascular or neuronal origin. Sildenafil, a specific inhibitor of phosphodiesterase 5 (PDE5), was the first compound to induce migraine-like headache in a human headache model without a concomitant artery dilatation.

BackgroundPhosphodiesterases (PDEs) cleave phosphodiester bonds in cyclic nucleotides and play diverse roles in cell biology. PDE5A is a cytoplasmic phosphodiesterase which specifically degrades cyclic guanosine monophosphate (cGMP), a cell signaling molecule that plays important roles in neuronal signaling and vascular smooth muscle contraction. Inhibition of PDE5A induces headache resembling migraine headaches.AimTo test the hypothesis that Ser102 and Ser104 in PDE5A and/or their phosphoserine derivatives 1) regulate the intracellular localization and/or activity of PDE5A, and 2) modulate the interaction between PDE5A and pharmaceutical reagents in clinical or pre-clinical use for migraine headaches and other types of vascular dysfunction.MethodsWild type PDE5A or PDE5A with substitution mutations (Ser102Ala, Ser104Ala or Ser102Ala/Ser104Ala) were overexpressed in SK-N-AS neuroblastoma cells as C-terminal fusions with green fluorescent protein. Transfected cells were treated with sildenafil, cilostazol, glyceryl trinitrate, calcitonin gene-related peptide (CGRP) or sumatriptan. PDE5A-GFP fusion proteins were localized in fixed cells by immunofluorescence and PDE activity was quantified in cell extracts by standard in vitro assay using [3H] cGMP.ResultsThe intracellular distribution of wild-type, single and double mutant PDE5A was similar and was not altered by exposure to sildenafil, cilostazol, glyceryl trinitrate, calcitonin gene-related peptide (CGRP) or sumatriptan. PDE5 activity was similar for wild type, Ser102Ala and Ser104Ala PDE5A, but activity of the Ser102Ala/Ser104Ala mutant was approximately two-fold higher than wild type. Double mutant Ser102Ala/Ser104Ala migrated as a single band on a native acrylamide gel, while wild-type and single mutant PDE5A migrated as a doublet.InterpretationSer102 and Ser104 may influence the conformational flexibility of PDE5A, which may in turn influence phosphorylation status, allosteric regulation by cGMP or other as yet unknown regulatory mechanisms for PDE5A. PDE5A activation could be important in reversal of migraine-like headache.

Patients with Becker muscular dystrophy (BMD) and Duchenne muscular dystrophy lack neuronal nitric oxide synthase (nNOS). nNOS mediates physiological sympatholysis, thus ensuring adequate blood supply to working muscle. In mice lacking dystrophin, restoration of nNOS effects by a phosphodiesterase 5 (PDE5) inhibitor (sildenafil) improves skeletal and cardiac muscle performance. Sildenafil also improves blood flow in patients with BMD. We therefore hypothesized that sildenafil would improve blood flow, maximal work capacity, and heart function in patients with BMD.A randomized, double-blind, placebo-controlled crossover design with two 4-week periods of treatment, separated by 2-week washout was used. We assessed brachial artery blood flow during maximal handgrip exercise, 6-minute walk test, maximal oxidative capacity, and life quality; cardiac function was evaluated by magnetic resonance imaging (MRI) at rest and during maximal handgrip exercise. Muscle nNOS and PDE5 were tested with Western blotting in 5 patients.Sixteen patients completed all skeletal muscle evaluations, and 13 completed the cardiac MRI investigations. Sildenafil had no effect on any of the outcome parameters. No serious adverse effects were recorded. PDE5 and nNOS were deficient in 5 of 5 biopsies.Despite positive evidence from animal models of dystrophinopathy and physiological findings in patients with BMD, this double-blind, placebo-controlled clinical study showed no effect of sildenafil on blood flow, maximal work capacity, and heart function in adults with BMD. This discrepancy may be explained by a significant downregulation of PDE5 in muscle.

Supersensitivity to induction of headache and arterial dilatation by a donor of nitric oxide (nitroglycerin) has recently been demonstrated in migraine sufferers. The aims of the present study were to examine whether the nitric oxide donor nitroglycerin may induce a typical migraine attack, to exclude placebo-related effects and to describe the relation between middle cerebral artery dilatation and provoked migraine. Nitroglycerin (0.5 μg/kg/min for 20 min) or placebo was infused into 12 migraine patients in a double-blind cross-over trial. Blood velocity in the middle cerebral artery was measured with transcranial Doppler and characteristics of headache and accompanying symptoms were recorded frequently. Headache occurred during the nitroglycerin infusion as previously described but peak headache intensity did first occur 5.5 h after infusion. At this time the induced headaches in 8 of 10 completing patients fulfilled the diagnostic criteria for migraine without aura of the International Headache Society. Furthermore, all patients who normally had unilateral spontaneous migraine attacks also had unilateral headaches after nitroglycerin. Only one subject developed migraine after placebo (p < 0.03). The time pattern of headache and estimated middle cerebral artery dilatation corresponded well. The study therefore demonstrates that activation of the nitric oxide cGMP pathway may cause typical migraine attacks.

Background In preclinical neurological studies, monitoring intracranial pressure (ICP) in animal models especially in rodents is challenging. Further, the lack of methods for long-term ICP monitoring has limited the possibilities to conduct prolonged studies on ICP fluctuations in parallel to disease progression or therapeutic interventions. For these reasons we aimed to set up a simple and valid method for long-term ICP recordings in rats. New method A novel ICP method employing epidural probes was developed and validated by simultaneously ICP recordings in the lateral ventricle and in the epidural space. The two pressures were recorded twice a week for 59 days and the correlation was studied. Results The two pressure recordings correlated exceptionally well and the R2 values on each recording day ranged between 0.99 and 1.00. However, the ventricular probes caused a number of complications including loss of patency and tissue damage probably due to cerebral infection, whereas the epidural probes were safe and reliable throughout the entire study. Comparison with existing methods Epidural probes are much easier to implant than ventricular probes. In addition, these new probes are far less invasive and induce no apparent mechanical tissue damage and highly decrease the infection risk associated with ICP recordings. Conclusion Epidural ICP recorded with this new method is identical to the ventricular ICP for at least 59 days but is far less complicated and safer for the animals. The long-term method described is reliable, valid, inexpensive, and may be used in multiple disease models to study ICP.

Background Understanding of the neuropathology leading to migraine pain has centered on either a vascular or neuronal origin. Sildenafil, a specific inhibitor of phosphodiesterase 5 (PDE5), induces migraine-like headache in a human headache model without concomitant artery dilation. The presence and activity of PDE3 and PDE5 is known in cerebral arteries. However, the presence in the neuronal part of the trigeminovascular pathway, i.e. the trigeminal ganglion and the possible co-localization with calcitonin gene-related peptide (CGRP), is not known. Methods Rat trigeminal ganglia were isolated and immunohistochemistry and in situ hybridization was applied. Evaluations of cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP) hydrolysis were performed using scintillation proximity assays. Results PDE3 and PDE5 were present and active in the trigeminal ganglia. A subset of PDE3- and PDE5-positive neurons contained CGRP. In contrast to cGMP, both sildenafil and cilostazol influenced cAMP hydrolysis. Interpretation Sildenafil may exert its effect on the neuronal part of the migraine pain pathway. In addition to the effects on cGMP signaling, sildenafil may indirectly affect cAMP signaling in the trigeminal ganglion. This result may suggest a common cAMP-related pathway for sildenafil, cilostazol, and CGRP in eliciting migraine pain.

Measurements of cerebral blood flow (CBF) show large variability among healthy subjects. The aim of the present study was to investigate the relative effect of established factors influencing CBF on the variability of resting CBF. We retrospectively analyzed spontaneous variability in 430 CBF measurements acquired in 152 healthy, young subjects using (133)Xe single-photon emission computed tomography. Cerebral blood flow was correlated positively with both end-tidal expiratory PCO₂ (PETCO₂) and female gender and inversely with hematocrit (Hct). Between- and within-subject CO₂ reactivity was not significantly different. Including PETCO₂, Hct and gender in the model reduced between-subject and within-subject variance by 14% and 13.5%, respectively. Within-subject variability was mainly influenced by PETCO₂ and between-subject variability mostly by Hct, whereas gender appeared to be of little added value when Hct was also accounted for. The present study confirms large between-subject variability in CBF measurements and that gender, Hct, and PETCO₂ explain only a small part of this variability. This implies that a large fraction of CBF variability may be due to unknown factors such as differences in neuron density or metabolism that could be subject for further studies.

Phosphodiesterase 5 (PDE5) is associated with migraine pathophysiology, stroke recovery and vasospasm treatment. The potential vascular interplay of PDE5 inhibitors sildenafil, tadalafil and UK-114,542 was studied by intra- versus extra-luminal administration in rat middle cerebral arteries in vitro and on middle meningeal arteries in vivo. By Western blot PDE5 was detected in both cerebral and meningeal arteries, though with minor variations in band intensity between vascular beds. Rat middle cerebral artery diameter was investigated using pressurised arteriography, applying UK-114,542, sildenafil, and tadalafil intra- or extra-luminally. Effects on the dural middle meningeal artery were studied in the in vivo closed cranial window model. At high concentrations, abluminal sildenafil and UK-114,542, but not tadalafil, induced dilatation of the middle cerebral artery. Luminal application elicited a contraction of 4% (sildenafil, P=0.03) and 10% (tadalafil, P=0.02). In vivo, sildenafil, but not tadalafil, dose-dependently dilated middle meningeal artery concomitant to blood pressure reduction (1-3mg/kg);1mg/kg sildenafil inducing 60 ± 14% (P=0.04) and vehicle (DMSO) 13 ± 6% dilatation. In conclusion, PDE5 inhibitors applied luminally had minor contractile effect, whereas abluminal sildenafil induced middle cerebral artery dilatation above therapeutic levels. In vivo, sildenafil dilated middle meningeal artery concomitant with a reduction in blood pressure. Tadalafil had no dilatory effects. PDE5 inhibitors show differential vascular activity in cerebral arteries from healthy animals; arterial dilatation is seen primarily above therapeutic levels. Such findings support clinical studies showing no vasodilator effects of sildenafil on cerebral arteries in healthy subjects.

Phosphodiesterases (PDEs) are essential regulators of cyclic nucleotide signaling. Little is known of the distribution and function of the cyclic adenosine monophosphate (cAMP) hydrolyzing PDE8A family. Employing immunohistochemistry and Western blots this study maps the distribution of PDE8A in the brain of adult male Sprague-Dawley rats and in the trigeminal ganglion. PDE8A was confined to neuronal perikaryal cytoplasm and to processes extending from those perikarya. The neurons exhibiting PDE8A-immunoreactivity were widely distributed in the forebrain, brain stem, and cerebellum. Strongly immunoreactive neurons were located in the olfactory bulb, the septal area, zona incerta, and reticular nucleus of the thalamus. Less immunoreactivity was seen in the hippocampus and cerebral cortex. Intense staining was detected in both the substantia nigra and the sensory trigeminal nucleus. In cerebellum PDE8A immunoreactivity was located not only in the Purkinje cells, but also in the granular cells as well as the parallel fibres in the molecular layer. PDE8A immunoreactivity was represented in the epithelial lining of the choroids plexus, the dura mater, and the neurons of the trigeminal ganglion. The localization of the cAMP degrading PDE8A may indicate a role for PDE8A in cAMP signaling related to pain transmission, motor function, cognition and olfaction.

(Headache 2010;50:431-441) Objective.— To investigate nitric oxide (NO)-mediated changes in expression of cyclic nucleotide degrading phosphodiesterases 2A (PDE2A), PDE3B, and PDE5A in human endothelial cells. Background.— Nitric oxide induces production of cyclic guanosine monophosphate (cGMP), which along with cyclic adenosine monophosphate (cAMP) is degraded by PDEs. NO donors and selective inhibitors of PDE3 and PDE5 induce migraine-like headache and play a role in endothelial dysfunction during stroke. The current study investigates possible NO modulation of cGMP-related PDEs relevant to headache induction in a cell line containing such PDEs. Methods.— Real time polymerase chain reaction and Western blots were used to show expression of PDE2A, PDE3B, and PDE5A in a stable cell line of human brain microvascular endothelial cells. Effects of NO on PDE expression were analyzed at specific time intervals after continued DETA NONOate administration. Results.— This study shows the expression of PDE2A, PDE3B, and PDE5A mRNA and PDE3B and PDE5A protein in human cerebral endothelial cells. Long-term DETA NONOate administration induced an immediate mRNA up-regulation of PDE5A (1.9-fold, 0.5 hour), an early peak of PDE2A (1.4-fold, 1 and 2 hours) and later up-regulation of both PDE3B (1.6-fold, 4 hours) and PDE2A (1.7-fold, 8 hours and 1.2-fold after 24 hours). Such changes were, however, not translated into significant changes in protein expression indicating few, if any, functional effects. Conclusions.— Long-term NO stimulation modulated PDE3 and PDE5 mRNA expression in endothelial cells. However, PDE3 and PDE5 protein levels were unaffected by NO. The presence of PDE3 or PDE5 in endothelial cells indicates that selective inhibitors may have functional effects in such cells. A complex interaction of cGMP and cAMP in response to NO administration may take place if the mRNA translates into active protein. Whether or not this plays a role in the headache mechanisms remains to be investigated.

The role of nitric oxide (NO) in migraine has been studied in the experimental glyceryl trinitrate (GTN)-infusion headache model. We hypothesized that GTN-induced headache may activate the trigeminovascular system and be associated with increased levels of sensory neuropeptides, including calcitonin gene-related peptide (CGRP). CGRP, vasoactive intestinal peptide (VIP), neuropeptide Y (NPY) and somatostatin plasma levels were measured before and after placebo/sumatriptan injection and during GTN-induced headache. Following a double-blind randomized cross-over design, 10 healthy volunteers received subcutaneous sumatriptan 6 mg or placebo. This was succeeded by 20 min of GTN (0.12 µg kg−1 min−1) infusion. At baseline no subject reported headache (using verbal rating scale from 0 to 10) and the jugular CGRP-like immunoreactivity (-LI) level was 18.6 ± 2.5 pmol/l. After a 20-min intravenous infusion of GTN 0.12 µg kg−1 min−1, median peak headache intensity was 4 (range 2–6) ( P 0.05). There were no changes in VIP-, NPY- or somatostatin-LI. In conclusion, the NO donor GTN appears not to induce headache via immediate CGRP release.

Compounds which increase cGMP levels are implicated in migraine pathophysiology as well as stroke recovery. Inhibitors of the cGMP degrading enzyme phosphodiesterase type 5 (PDE5) induce headache and migraine in humans, however surprisingly and unlike other migraine inducing drugs without measurable dilatation of cerebral arteries [1] or changes in hemodynamic response or excitability [2]. We aimed to investigate whether sildenafil and tadalafil induced dilatation of rat middle cerebral and meningeal arteries in vitro and in vivo.

Sildenafil (Viagra®), a cyclic guanosine monophosphate-degrading phosphodiesterase 5 inhibitor, induces headache and migraine. Such headache induction may be caused by an increased neuronal excitability, as no concurrent effect on cerebral arteries is found. In 13 healthy females (23±3 years, 70.3±6.6 kg), the effect of sildenafil on a visual (reversing checkerboard) and a hypercapnic (6% CO2 inhalation) response was evaluated using functional magnetic resonance imaging (fMRI, 3 T MR scanner). On separate occasions, visual-evoked potential (VEP) measurements (latency (P100) and maximal amplitude) were performed. The measurements were applied at baseline and at both 1 and 2 h after ingestion of 100mg of sildenafil. Blood pressure, heart rate and side effects, including headache, were obtained. Headache was induced in all but one subject on both study days. Sildenafil did not affect VEP amplitude or latency (P100). The fMRI response to visual stimulation or hypercapnia was unchanged by sildenafil. In conclusion, sildenafil induces mild headache without potentiating a neuronal or local cerebrovascular visual response or a global cerebrovascular hypercapnic response. The implication is that sildenafil-induced headache does not include a general lowering of threshold for a neuronal or cerebrovascular response, and that sildenafil does not modulate the hypercapnic response in healthy subjects.

Dipyridamole inhibits phosphodiesterase 5 (PDE5) and adenosine re-uptake. The most prominent side-effect is headache. We examined the migraine-generating effects of dipyridamole as well as the cerebral blood velocity response in a single-blind study, including 10 patients with migraine without aura and 10 healthy subjects. Dipyridamole 0.142 mg/kg per min was administered intravenously. Headache intensity was scored on a verbal rating scale along with pain characteristics and accompanying symptoms. Blood velocity in the middle cerebral artery ( Vmca), blood pressure and heart rate were recorded repeatedly. Headache was induced in all migraine patients and in eight of 10 healthy subjects ( P = 0.47) with no significant difference in headache intensity ( P = 0.53). However, five patients but only one healthy subject experienced the symptoms of migraine without aura, according to ICHD-2 criteria, within 12 h ( P = 0.14). Four patients reported photophobia after dipyridamole compared with no healthy subjects ( P = 0.087). Vmca decreased ( P < 0.001) during and after dipyridamole infusion with no difference between groups ( P = 0.15) coinciding with initiation, but not cessation of immediate headache. Thus, dipyridamole induces symptoms of migraine and an initial decrease in Vmca in migraine patients, but not significantly more than in healthy subjects. This relatively low frequency of migraine induction, compared with nitric oxide donors and sildenafil, is probably due to the less specific action of dipyridamole on the cGMP signalling pathway as well as a possible bidirectional effect of adenosine on migraine induction.

PACAP38 is an endogenous peptide located in trigeminal perivascular nerve fibers in the brain. It reduces neuronal loss and infarct size in animal stroke models and has been proposed a candidate substance for human clinical studies of stroke. The effect on systemic hemodynamics and regional cerebral blood flow (rCBF) is not well understood. We here present the first study of the effect of PACAP38 on cerebral hemodynamics in humans. PACAP (10 pmol kg(-1) min(-1)) or placebo (0.9% saline) was infused for 20 min into 12 healthy young volunteers in a cross over, double blind study. rCBF was measured with SPECT and (133)Xe inhalation and mean blood flow velocity in the middle cerebral artery was measured with transcranial Doppler ultrasonography. End tidal partial pressure of CO(2) (P(et)CO(2)) and vital parameters were recorded throughout the 2 hour study period. PACAP38 decreased rCBF in all regions of interest (ROIs) by approximately 3-10%, though not uniformly significant. P(et)CO(2) decreased significantly during PACAP38 infusion compared to placebo (P=0.032), peak decrease was 8.9+/-3.8%. After correction for P(et)CO(2), rCBF remained unchanged in most ROIs. Heart rate increased 61.9+/-22.4% (P

Headache is extremely prevalent and experienced by almost everyone. A clinical test for the diagnosis of headache is still lacking, and a detailed clinical description is therefore essential for a precise diagnosis. The second edition of the International Headache Classification is presented, along with a translation into Danish. The major changes from the first edition are a detailed description of several subtypes of migraine, three subdivisions of tension-type headache according to frequency of headache and a major extension of the chapter concerning secondary headaches due to medication overuse. General knowledge of the major subforms of primary and secondary headaches is a very important tool for diagnosis and treatment.

Sildenafil (Viagra®), a selective inhibitor of phosphodiesterase 5 (PDE5), induces headache and migraine. Although previously supposed to be a “vascular” headache, no significant cerebral artery dilatation was found in vivo. Thus, we hypothesised that PDE5 may not be present or that sildenafil is less effective on the cGMP hydrolysis in cerebral arteries, and that sildenafil may not be an effective dilator of cerebral arteries under baseline conditions. We evaluated the presence of PDE5 mRNA and protein in human arteries. Furthermore, the effects of two selective PDE5 inhibitors, sildenafil and UK-114,542, and a PDE1 inhibitor UK-90,234 on cGMP hydrolysis were investigated in human and guinea pig cerebral arteries. The vasoactive responses of the compounds were evaluated in guinea pig basilar arteries in vitro, with concomitant measurements of cAMP and cGMP. PDE5 was found in human middle cerebral arteries. Sildenafil and UK-114,542 inhibited cGMP hydrolysis concentration-dependently in both species. In guinea pig arteries, sildenafil induced an endothelium-dependent vasodilatation only at concentrations above 10 nM, which was augmented by sodium nitroprusside and attenuated by reduction of cGMP, but was cGMP independent at high concentrations. UK-114,542 was more and UK-90,234 was less potent than sildenafil. In conclusion, PDE5 is present in human and guinea pig cerebral arteries, and is inhibited by sildenafil at micromolar levels. Sildenafil in vitro is a poor dilator of guinea pig cerebral arteries unless a nitric oxide donor is co-administered, corresponding to the previous findings in vivo.

BIBN4096BS is a CGRP-antagonist effective in the treatment of migraine. Blocking the receptor of a strong vasodilator involves a theoretical risk of causing cerebral vasoconstriction, a probability not previously investigated with BIBN4096BS. Seven healthy volunteers completed this double-blinded placebo-controlled crossover study. The volunteers received randomly 10 min infusions of either placebo, 2.5 mg or 10 mg of BIBN4096BS on 3 separate days. Transcranial Doppler was used to measure the middle cerebral artery blood flow velocity (VMCA); global and regional cerebral blood flow (rCBFMCA) was measured by 133-Xenon inhalation SPECT. The diameter of the temporal and radial artery was measured by highresolution ultrasound. Systemic haemodynamics and partial pressure of CO2 (PetCO2), and adverse events were monitored regularly. BIBN4096BS had no influence on global or regional cerebral blood flow, or on the blood flow velocity in the middle cerebral artery. There was no effect on systemic haemodynamics and adverse events were minor. We conclude that there is no effect of CGRP-receptor blockade on the cerebral or systemic circulation in humans. Circulating CGRP is therefore not likely to exert a vasodilatory activity in the resting state and the use of BIBN4096BS for acute migraine seems to be without risk of cerebral vasoactivity. These data suggest that BIBN4096BS is the first specific antimigraine drug without vasoactive effect.

Adenosine is an endogenous neurotransmitter that is released from the brain during hypoxia and relaxes isolated human cerebral arteries. Many cerebral artery dilators cause migraine attacks. However, the effect of intravenous adenosine on headache and cerebral artery diameter has not previously been investigated in man and reports regarding the effect of intravenous adenosine on cerebral blood flow are conflicting. Twelve healthy participants received adenosine 80, 120 μg kg-1min-1and placebo intravenously for 20 min, in a double-blind, three-way, crossover, randomized design. Headache was rated on a verbal scale (0-10). Regional cerebral blood flow (rCBF) with133Xe inhalation and single-photon emission computed tomography (SPECT) and MCA flow velocity (VMCA) with transcranial Doppler, were measured in direct sequence. Six participants developed headache during 80 μg kg-1min-1and six during 120 μg kg-1min-1compared with none on placebo ( P = 0.006). The headache was very mild and predominantly described as a pressing sensation. When correcting data for adenosine-induced hyperventilation, no significant changes in rCBF ( P = 0.22) or VMCA( P = 0.16) were found between treatments. A significant dilation of the superficial temporal artery (STA) was seen ( P < 0.001). These results show that circulating adenosine has no effect on rCBF or VMCA, while it dilates the STA and causes very mild headache.

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.

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.

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.

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 (Vmca) was recorded by transcranial Doppler ultrasonography and regional cerebral blood flow in the territory of the middle cerebral artery (rCBFmca) 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). Vmca ( P = 0.1) and rCBFmca ( 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.

The aim was to investigate the presence and activity of cGMP hydrolysing phosphodiesterases in guinea pig basilar arteries and the effect of selective and non-selective phosphodiesterase inhibitors on cerebral artery dilatation involving the nitric oxide (NO)-guanosine cyclic 3'5-monophosphate (cGMP) pathway. Immunoreactivity to phosphodiesterases 1A, 1B and 5, but not phosphodiesterase 1C was found in fractions of homogenised cerebral arteries eluted by high-pressure liquid chromatography (HPLC). Both the phosphodiesterase 1 inhibitor 8-methoxymethyl-1-methyl-3-(2methylpropyl)-xanthine (8-MM-IBMX) and the phosphodiesterase 5 inhibitors zaprinast and dipyridamole induced dilatation of cerebral arteries. The dilatory response to 8-MM-IBMX was reduced by 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ) (10 microM) and endothelial removal and restored by sodium nitroprusside (0.1 microM) pretreatment, indicating a close relation to the nitric oxide-cGMP pathway. The responses to zaprinast and dipyridamole, however, were not only moderately affected, but also restored by sodium nitroprusside (0.1 microM) pretreatment. At high concentrations, the dilatory effects of zaprinast and dipyridamole were partly caused by cGMP-independent mechanisms. Targeting the phosphodiesterases present in cerebral arteries, with selective inhibitors or activators of phosphodiesterase, may be a possible new way of treating cerebrovascular disease.

The course and prognosis of Crohn disease has previously been described in a regional group of patients in Copenhagen County. The aim of the present study was to reveal the quality of life. as judged by the patients, and compared to age- and sex-matched healthy controls.Out of 100 consecutive out-patients with Crohn disease, 94 patients accepted to participate together with 94 age- and sex-matched healthy controls. A modified McMaster Inflammatory Bowel Disease Questionnaire (IBDQ23) was used, excluding bowel-related questions. Medical students conducted interviews without knowing who were Crohn disease patients and who were controls. The bowel-related questions and Crohn's Disease Activity Index (CDAI) were assessed by gastroenterologists at inclusion in the study. Responses were indicated on a seven-point scale (7 best/1 worst). Mean numeric score was calculated as well as a delta score, i.e. the difference in score between a patient and the matched control.In 21 of 23 questions the median delta score was zero, indicating no difference between patient and control. The median total delta score was 0.4 in favour of healthy controls (P0.001), and significantly higher in patients in relapse, 0.9, than in patients in remission, 0.3 (P0.01). The median total numeric score was 5.7 for patients and 6.1 for controls.Although patients with Crohn disease scored significantly lower on the quality of life scale than matched healthy controls, the differences were smaller than could be expected, taking the chronic disease into consideration. Disease activity correlated with the quality of life score.

Dipyridamole is used for secondary prophylaxis in ischemic stroke and as a vasodilator agent in myocardial scintigraphy. An important side effect to administering dipyridamole is headache. The aim of the current study was to investigate the effects of dipyridamole on cerebral blood flow, large artery diameter, and headache induction. Twelve healthy subjects were included in this single-blind placebo-controlled study in which placebo (0.9% NaCl) and dipyridamole 0.142 mg/kg·min were administered intravenously over 4 minutes 1 hour apart. Blood flow velocity in the middle cerebral artery (Vmca) was recorded by transcranial Doppler and regional cerebral blood flow in the middle cerebral artery (rCBFmca) was measured using single photon emission computed tomography and 133Xenon-inhalation. Blood pressure, heart rate, and pCO2 were measured repeatedly. Headache response was scored every 10 minutes on a verbal scale from 0 to 10 (10 = worst). Dipyridamole caused a decrease in pCO2 ( P < 0.001). pCO2 corrected rCBFmca was 41.7 ± 6.9 mL/100 g ·min after placebo versus 41.2 ± 6.9 after dipyridamole ( P ≥ 0.05). pCO2 corrected Vmca decreased 8.4% ± 11.7 ( P < 0.001) after dipyridamole, indicating a mean 5.6% ± 6.7 ( P = 0.005) relative increase of the arterial diameter. After dipyridamole the median peak headache score was 2 (range 0 to 7) compared with 0 (range 0 to 3) after placebo ( P = 0.02). Dilatation of the middle cerebral artery outlasted the headache response. In conclusion, dipyridamole causes a modest pCO2 independent dilatation of the MCA, which is time-linked to the onset, but not to the cessation, of headache.

WCN 2013 No: 2405 Topic: 7 Neuromuscular disorders Low and high frequency repetitive nerve stimulation in the diagnosis of myasthenia gravis N. Kvirkvelia, N.Mikava, R. Nikolaishvili, M. Jibladze, T. Akhvlediani, R. Shakarishvili. Department of Neurology and Neurosurgery, Ivane Javakhishvili Tbilisi State University, Tbilisi, Georgia; Sarajishvili Institute of Clinical Neurology and Neurosurgery, Tbilisi, Georgia; Neurology Department, Khechinashvili University Clinic, Georgia; Ivane Javakhishvili Tbilisi State University, Tbilisi, Georgia Background: Diagnosis of myasthenia gravis (MG) typically is made based on patient's history and clinical findings. However, the diagnosis must be verified by the electrophysiological investigation of neuro-muscular transmission. The repetitive nerve stimulation (RNS) is an electrodiagnostic technique used to assess the efficacy of neuromuscular transmission. Objective: The objective of this study was to evaluate combined muscle action potential (CMAP) changes in response to high and low frequency rates of RNS in patients with MG. Patients and methods: The correlation of muscle strength and CMAP changes were investigated in 104 myasthenic patients. The muscle strength was graded on a scale from 0 to 5. Two stimulating parameters were used throughout the experiments — the low frequency stimulation (LFS) and high frequency stimulation (HFS). Results: It was found that in 15% of muscles with clinically detectable weakness the CMAP amplitudewas decreased, by 21% in area, and by8% in duration of the negative phase. The positive correlation was observed between the negative phase of CMAP and the muscle strength and negative correlation was observed between the negative phase duration and the muscle strength. Conclusion:We used RNS in a large cohort of patients as an additional tool for the confirmation of the MG diagnosis. We registered higher decrement in larger muscle groups which are more commonly affected clinically. However, smaller muscles, such as the abductor digiti quinti muscle are often preferable to investigate, because they create less discomfort for the patient and have fewer artifacts. doi:10.1016/j.jns.2013.07.1636 Abstract WCN 2013 No: 2277 Topic: 7 Neuromuscular disorders Altered somatosensory neurovascular coupling in patients with becker muscular dystrophy WCN 2013 No: 2277 Topic: 7 Neuromuscular disorders Altered somatosensory neurovascular coupling in patients with becker muscular dystrophy U. Lindberg, C. Kruuse, S. Joergensen, J. Vissing, N. Witting, E. Rostrup, H.B. Larsson. Functional Imaging Unit, Diagnostic Department, Glostrup Hospital, University of Copenhagen, Denmark; Lundbeck Foundation Center for Neurovascular Signalling, Glostrup, Denmark; Neurology, Herlev Hospital, University of Copenhagen, Herlev, Denmark; Department Neurology, Rigshospitalet, University of Copenhagen, Kbh O, Denmark Background: In patients suffering from Becker muscular dystrophy (BMD) variable degrees of cognitive impairment have been reported in addition to the well-known muscular and cardiac symptoms. BMD is caused by mutations in the dystrophin gene, changing the cellular dystrophin complex and subsequent muscular blood flow. Few studies have addressed the mechanisms of cognitive impairment. Lack of dystrophin, however, causes secondary loss of vasoactive molecules such as nitric oxide, which is as an important player in brain vascular control. We hypothesised that dystrophin can be involved in neurovascular coupling and cerebral reactivity measured by functional MRI and EEG. Objective: To study the baseline electrophysiological and fMRI BOLDresponse to external somatosensory stimulation in BMD patients compared to age and sex-matched healthy controls. Patients and methods: 17 men (mean age 38.5, range 25–63) with BMD and 8 healthy sex matched controls were included. Functional MRI (fMRI, BOLD) (3T, Phillips) and EEG with evoked potentials were performed during a somatosensoric stimulation paradigm on the dominant median nerve. Results: BMD patients showed a significantly (p b 0.02) decreased electrophysiological adaptation together with a decreased (p b 0.01) BOLD-response in the primary somatosensory cortex when compared to healthy controls. Conclusion: The preliminary results suggest that patients with BMD have a fundamentally altered cerebral neurovascular coupling, which could impact cognitive function in BMD patients. doi:10.1016/j.jns.2013.07.1637 Abstract — WCN 2013 No: 2379 Topic: 7 — Neuromuscular disorders Two cases of POEMS syndrome: Initially misdiagnosed as CIDP WCN 2013 No: 2379 Topic: 7 — Neuromuscular disorders Two cases of POEMS syndrome: Initially misdiagnosed as CIDP O. Watanabe, K. Arimura, T. Nakamura, Y. Arimura, Y. Inamori, Y. Takata, K. Michizono, E. Matsuura, H. Takashima. Neurology and Geriatrics, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima, Japan POEMS syndrome (also known as Crow-Fukase syndrome) is a serious systemic disease characterized by polyneuropathy, anasarca, skin lesions and associated with osteoclastic bone lesions and with M-proteinemia. The diagnosis of POEMS syndrome is made robust by finding increased serum vascular endothelial growth factor (VEGF) in addition to the combination of the mentioned characteristic manifestations. The diagnosis of advanced POEMS syndrome is not difficult when the combinations of characteristic manifestations are fulfilled. However, in the initial stages, only half of POEMS patients start with neuropathy. Neuropathy in POEMS syndrome is characterized by a subacute, progressive sensorimotor type of polyneuropathy with mixed features of demyelination and axonal degeneration. However, nerve conduction study (NCS) results of POEMS syndrome occasionally fulfill the electrophysiological criteria for chronic inflammatory demyelinating polyradiculoneuropathy (CIDP), thus leading to the caveat of an often initial misdiagnosis of CIDP. We herein present two female patients with POEMS syndrome. Case 1: A 67-year-old woman was admitted to one university hospital with a 1.5-year history of progressive weakness and paraesthesia. Her weakness and paraesthesia initially affected his lower limbs, progressing within 2 months to her upper limbs. Case 2: A 24-year-old woman was admitted to another university hospital with a 2-month history of progressive paraesthesia and muscle weakness affecting her lower limbs. Both cases were electrophysiologically diagnosed as CIDP, then treated with intravenous Abstracts / Journal of the Neurological Sciences 333 (2013) e422–e480 e459

BackgroundPhosphodiesterase 5 (PDE5) is associated with migrainepathophysiology, stroke recovery and vasospasm treat-ment [1,2]. We have shown previously that vasodilata-tion was not a prerequisite for migraine induction;sildenafil elicited migraine-like attacks in migrainepatients without measurable changes in intra- or extra-cerebral artery diameter. Further, sildenafil was found tonot affect neurovascular response or excitability [3].However, dural artery responses were not accounted forin the human studies and minor vascular changes offunctional importance may not have been detected.The potential vascular interplay of PDE5 inhibitors sil-denafil, tadalafil and UK-114,542 were studied by intra-versus extra-luminal administration in rat middle cere-bral arteries (MCA) in vitro and on middle meningealarteries (MMA) in vivo.AimTo examine a possible vascular site of action, if any, ofeach of sildenafil and tadalafil by investigating 1) theeffects of PDE5 inhibitors in vitro dilatation of the mid-dle cerebral artery (MCA) with controlled luminal orextra-luminal application of the drugs and 2) the in vivoeffects of intravenous PDE5 inhibitors on the middlemeningeal artery (MMA) dilatation in a closed cranialwindow model in rats.MethodsRat MCA diameter was investigated using pressurisedarteriography, applying UK-114,542, sildenafil, andtadalafil intra- or extra-luminally. Effects on MMA werestudied in the in vivo closed cranial window model.ResultsAt high concentrations, abluminal sildenafil and UK-114,542, but not tadalafil, induced dilatation. Luminalapplication elicited a contraction of 4 % (sildenafil, p =0.03) and 10 % (tadalafil, p = 0.02).In vivo, sildenafil,but not tadalafil, dose-dependently dilated MMA conco-mitant to blood pressure reduction (1-3 mg/kg);1 mg/kgsildenafil inducing 60 ± 14 % (p = 0.04) and vehicle(DMSO) 13 ± 6 % dilatation.ConclusionPDE5 inhibitors applied luminally had contractile effecton MCA. Abluminal sildenafil induced MCA dilatationabove therapeutic levels. In vivo, sildenafil dilated MMA.Tadalafil had no dilatory effects. PDE5 inhibitors showdifferential vascular activity in arteries, although clini-cally the potential for headache induction appears simi-lar. Such findings support clinical studies showing novasodilatory effects of sildenafil on cerebral arteries inhealthy subjects.