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Background: Efficacy and safety data have not previously been compiled for intramuscular interferon beta-1a (IM IFNβ-1a) in patients with multiple sclerosis (MS) ≥ 50 years of age. We investigated the efficacy and safety of IM IFNβ-1a in patients segregated by 50 and 40 years of age in separate meta-analyses., Methods: The MS Clinical Research Group Study, the Controlled High-Risk Subjects AVONEX(®) (IM IFNβ-1a) MS Prevention Study, the IFNβ-1a European Dose-Comparison Study, and a multicenter, open-label antigenicity and safety study of human serum albumin-free IM IFNβ-1a were analyzed., Results: Overall, 906 patients (68 aged ≥ 50 years and 838 aged <50 years, or 323 aged ≥ 40 years and 583 aged <40 years) received IM IFNβ-1a for ≥ 24 months. At baseline, patients ≥ 50 years had significantly higher Expanded Disability Status Scale scores than patients <50 years (3.4 vs. 2.8; P < 0.001), but fewer relapses in the three preceding years (2.6 vs. 3.4; P < 0.001); patients ≥ 40 years and <40 years exhibited similar differences. After 2 years of treatment, there were no significant differences in annualized relapse rate, sustained disability progression, time to sustained disability progression, or number of MRI-identified gadolinium-enhanced lesions between age groups in either analysis. The cumulative probability of relapse was significantly lower in patients ≥ 40 years versus patients <40 years (0.601 vs. 0.702; P < 0.001). Adverse event incidence did not differ significantly between age groups in either analysis., Conclusions: IM IFNβ-1a is effective and well tolerated in patients with MS ≥ 40 and ≥ 50 years as well as younger patients., (© 2011 The Author(s). European Journal of Neurology © 2011 EFNS.)

Objective: The aim of this study was to determine whether frovatriptan would show efficacy in short term prophylactic treatment of episodic cluster headache (ECH) in comparison to placebo., Background: The 5-hydroxytryptamine(1B/d) (5-HT(1B/d) )-agonists naratriptan, eletriptan, and frovatriptan have been shown to reduce the frequency of ECH. So far, no double-blind placebo-controlled trials have investigated the potential prophylactic effects of 5-HT(1B/d) -agonists in ECH., Methods: The trial was conducted as a multi-center, placebo-controlled, randomized, double-blind, prospective phase III parallel-group trial with two independent treatment groups (5 mg frovatriptan vs placebo). It was planned to randomize about 96 patients (48 patients per group) into the trial to obtain 80 evaluable patients (40 patients per group)., Results: The study was prematurely discontinued after 13 months and enrollment of 11, instead of the planned 80 patients, by the sponsor due to infeasibility. Recruitment was slow and each of the patients included conducted major protocol violations. The differences in the primary and secondary endpoints were not significant., Conclusion: This study shows that particular therapeutic aims are impossible to be addressed in a double-blind, randomized, parallel group, study design with specific inclusion and exclusion criteria according to the International Headache Society (IHS) guidelines for controlled trials of drugs in cluster headache. Further studies are required to evaluate the potential efficacy of triptans in the prophylactic treatment of ECH. The outcome of the trial suggests that the recommendations of the Guidelines for controlled Trials of Drugs in Cluster Headache from the IHS should be revised., (© 2010 American Headache Society.)

We report a case-control study with 251 unrelated migraine patients and 192 unrelated healthy controls to evaluate an association between the polymorphisms of the 5-HT transporter (5-HTT) gene rs2066713 and rs1979572 and different migraine phenotypes. We found a genetic association for the A allele of rs1979572 for migraine with aura (MA) especially in women as well as a significant lower prevalence for MA for carrier of the A allele of rs2066713 in women. These findings support previous results suggesting that the 5-HTT gene is involved in the polygenic etiology of MA. These data further suggest that women are more likely to be clinically affected by mutations in the 5-HTT gene than men.

Background: Natalizumab has been recommended for the treatment of relapsing-remitting multiple sclerosis (RRMS) in patients with insufficient response to interferon-beta/glatiramer acetate (DMT) or aggressive MS. The pivotal trials were not conducted to investigate natalizumab monotherapy in this patient population., Method: Retrospective, multicenter study in Germany and Switzerland. Five major MS centers reported all RRMS patients who initiated natalizumab >or=12 months prior to study conduction., Results: Ninety-seven RRMS patients were included [69% female, mean age 36.5 years, mean Expanded Disability Status Scale (EDSS) 3.4; 93.8% were pre-treated with DMT], mean treatment duration with natalizumab was 19.3 +/- 6.1 months. We found a reduction of the annualized relapse rate from 2.3 to 0.2, 80.4% were relapse free with natalizumab. EDSS improved in 12.4% and 89.7% were progression free (change of >or= 1 EDSS point). Eighty-six per cent of patients with highly active disease (>or= 2 relapses in the year and >or= 1 Gadolinium (Gd)+ lesion at study entry, n = 20) remained relapse free. The mean number of Gd enhancing lesions was reduced to 0.1 (0.8 at baseline). Discontinuation rate was 8.2% (4.1% for antibody-positivity)., Conclusion: Natalizumab is effective after insufficient response to other DMT and also in patients with high disease activity.

Retropharyngeal tendinitis is a rare cause of intense neck pain and occipital headache. It is caused by an aseptic inflammatory process in the longus colli tendon, triggered by deposition of calcium hydroxyapatite crystal. Clinically, it can be misdiagnosed as retropharyngeal abscess, traumatic injury, infectious spondylitis, cervical artery dissection, or even meningitis. The diagnosis is made radiographically by a nearly pathognomonic amorphous calcification anterior to C1-C2 and prevertebral soft tissue swelling. We present a new case of this uncommon condition exhibiting some unusual features.

Background: The hypocretin receptor 2 (HCRTR2) G1246A polymorphism has been associated with the risk for cluster headache. Since the hypothalamic hypocretin/orexin system projects throughout the nervous system and affects multiple vegetative functions including generation of rhythmicity, vasomotion, autonomic symptoms as well as modulation of nociception, it may also be linked with migraine., Objective: We thus sought to evaluate whether the HCRTR2 G1246A polymorphism is associated with the risk for migraine., Methods: We prospectively established a cohort of 146 unrelated patients with migraine. The control group consisted of 279 healthy volunteers. We genotyped patients and controls for the HCRTR2 G1246A polymorphism and examined an association with presence or absence of migraine., Results: Genotype and allele frequencies were not significantly different between migraine patients and controls (genotype distribution: chi(2)= 4.13, 2 df, P= .13; allele distribution: chi(2)= 0.9, 1 df, P= .34)., Conclusion: Our study does not support a major contribution of the HCRTR2 G1246A polymorphism to the pathogenesis of migraine in contrast to its effects in cluster headache.

Objective: The aim was to evaluate whether preventive treatment with topiramate in patients with episodic migraine reduces the risk of developing chronic forms of headache., Background: Chronic forms of headache, including chronic migraine or medication overuse headache (MOH), are characterized by 15 or more headache days per month. Acute medication overuse has been shown to be a risk factor for developing chronic headache, but it is not known whether preventive treatment can reduce the risk of developing chronic forms of headache or the development of MOH., Methods: Pooled data from 3 trials in patients with episodic migraine randomized either to treatment with 100 mg topiramate per day (n = 384) or with placebo (n = 372) were analyzed with regard to the number of headache days during a prospective 4-week baseline period and the individual final 4 weeks of each patient's treatment during the planned 26-week double-blind treatment period., Results: The number of headache days per month in the topiramate versus the placebo-treated groups was 7.3 +/- 3.0 versus 7.3 +/- 3.1 during baseline and 4.1 +/- 4.2 versus 5.6 +/- 4.9 during the final 4 weeks, respectively (P < .001). At the end of the study, 8 versus 16 patients fulfilled International Headache Society criteria of chronic headache (odds ratio: 2.11, P= .082). Moreover, a significantly lower number of patients receiving topiramate treatment reported an increase in headache days per month by the end of the study when compared to placebo (66 vs 88 patients, respectively; odds ratio: 1.49, P < .05). Finally, the number of days with usage of acute medication was significantly lower in the topiramate arm compared with placebo (3.3 +/- 3.7 vs 4.3 +/- 3.6, respectively; P < .001)., Conclusion: Preventive treatment with topiramate in patients with episodic migraine may reduce the risk of developing chronic forms of headache.

Background: Electrophysiological techniques such as laser and contact heat evoked pain-related potentials are very useful for studying trigeminal and somatic pain transmission in humans. These methods are, however, partly invasive, expensive, and therefore not available for broad clinical use. We recently proposed a novel technique of noninvasive transcutaneous electrical stimulation., Objective: To elicit pain-related evoked potentials (PREP) by using a concentric planar electrode and demonstrate their nociceptive specificity., Methods: We registered PREP following stimulation of the forehead and hand in 14 healthy volunteers. Latencies, peak-to-peak amplitudes, and conduction velocities of nociceptive fibers have been estimated. Effects of temporal and spatial summation and of cutaneous anesthesia were evaluated., Results: Stimulation with the concentric planar electrode produced pinprick-like painful sensation. Cutaneous anesthesia led to abolishment of PREP responses. Estimated mean conduction velocity was 11.61 +/- 5.12 m/s, which corresponded well with conduction via A-delta fibers. Spatial as well as temporal summation resulted in a parallel increase of perceived pain intensity and PREP amplitudes., Conclusion: The technique is noninvasive, affordable, and easy to perform and allows quantitative assessment of human nociceptive pathways.

The prevalence of migraine in Germany is up to 14% in the female and up to 8% in the male population and peaks between the age of 35 and 45. Few studies have investigated the productivity loss and resulting costs attributable to migraine in Germany or addressed the question whether these costs can be reduced by optimal treatment. In recent years, 5-HT(1B/D) agonists (so-called triptans), a generation of drugs highly specific for migraine treatment, have been introduced. Seven 5-HT(1B/D) agonists have been approved in Germany with more than 20 dosage forms. We present a model that enables employers to estimate the annual cost of migraine and the annual cost that could be saved by treatment of migraine with rizatriptan compared with the use of non-specific antimigraine medication. A representative German company with 10,000 employees is used for the reference case analysis. This company is predicted to have 580 female and 284 male employees with migraine. These employees are estimated to lose 6992 workdays or 31.8 person years of productive effort annually due to migraine, valued approximately 1,431,719 euros. The value of work loss that could be avoided by treating migraine with rizatriptan is estimated at 619,094 euros annually. These data indicate that costs arising from lost productivity can be reduced by treating migraine headaches with a triptan.

Objective: The study compared efficacy and tolerability of intravenous valproate (iVPA) with intravenous lysine-acetylsalicylic acid (iLAS) in acute migraine attacks. Background.-iLAS has been proven to be a highly effective treatment in acute migraine attacks, but it is not available in many countries and contraindicated in patients with asthma or peptic ulcers. Current data suggest that iVPA may be effective in the treatment of acute migraine attacks., Design/methods: In this randomized, double-blind, parallel-group phase-II study, 40 patients with acute migraine attacks (onset <5 hours, severe or moderate headache on a four-point IHS scale) alternately received iVPA 800 mg or iLAS 1000 mg. Primary outcome criteria were the percentage of patients reporting pain relief after 1 hour and patients who remained sustained pain free for 24 hours following drug administration. Secondary outcome criteria were relief of pain and associated migrainous symptoms (nausea, photophobia, and phonophobia) at 1, 2, 24, and 48 hours following drug administration., Results: There were no significant differences in demographic and clinical features between both treatment groups. Percentage of pain relief after 1 hour in the iVPA and iLAS groups were 25% and 30%, respectively, and of sustained pain free for 24 hours were 20% and 30%, respectively, without significant differences (P = 1 and P= .72, respectively). Both drugs improved associated migrainous symptoms without significant differences at the different time points, but again with a trend in favor of iLAS. No adverse events were observed., Conclusion: Both drugs were effective in acute migraine attacks with a trend in favor of iLAS. As both drugs were well tolerated, further studies with higher doses of iVPA for the treatment of acute migraine attacks are recommended.

1. The effects of progesterone, its A-ring-reduced metabolites, allopregnanolone, tetrahydroxydeoxycorticosterone and the synthetic neuroactive steroid alphaxalone were evaluated in a rat model of plasma extravasation within the meninges following unilateral electrical stimulation (ES) of the trigeminal ganglion (0.6 mA, 5 ms, 5 min) or substance P administration (1 nmol kg-1, i.v.). 2. When administered 55 min prior to electrical stimulation, progesterone (> or = 500 micrograms, s.c.) dose-dependently decreased plasma extravasation within the meninges (ED50: 650 micrograms) but not within conjunctiva and tongue. Promegestone (R5020), a non-metabolized progesterone agonist (1000 micrograms, i.p.) was ineffective. The administration of progestrone (> or = 500 micrograms s.c.) 55 min prior to substance P partially suppressed plasma extravasation within the meninges (ED50: 550 micrograms). 3. The GABAA-antagonist, bicuculline (ED50: 8.2 micrograms kg-1, i.p.) but not the GABAB-antagonist, phaclofen (100 micrograms kg-1, i.p.) attenuated the effects of progesterone after electrical stimulation and substance P administration. 4. The metabolites of progesterone, allopregnanolone (3 alpha-hydroxy-5 alpha- pregnan-20-one (THP); ED50: 0.58 micrograms kg-1, i.p.), tetrahydroxydeoxycorticosterone (3 alpha,21- dihydroxy-5 alpha-pregnan-20-one (THDOC); ED50: 1.2 micrograms kg-1, i.p.) as well as the synthetic steroid alphaxalone (3 alpha-hydroxy-5 alpha-pregnane-11,20-dione; ED50: 1.8 micrograms kg-1, i.p.) suppressed plasma extravasation dose-dependently following ES, whereas the epimer of allopregnanolone, 3 beta-hydroxy-5 alpha-pregnan-20-one (100 micrograms kg-1, i.p.), did not. Extravasation caused by SP administration was partially suppressed by allopregnanolone (> or = 1 microgram kg-1, i.p.) (ED50: 2.1 micrograms kg-1). 5. The effect of progesterone (1000 micrograms, s.c.) and allopregnanolone (100 micrograms kg-1, i.p.) on neurogenic plasma extravasation was reversed by bicuculline (10 micrograms kg-1, i.p.) or by a congener, bicuculline-methiodide (10 micrograms kg-1, i.p.) which does not cross the blood brain barrier. 6. Progesterone (1000 micrograms, s.c.) had no effect on mean arterial blood pressure or heart rate when measured for 60 min after administration. 7. These results indicate that neurosteroid modulation of a GABAA-receptor located outside the blood brain barrier suppresses neurogenic and substance P-induced plasma extravasation within the meninges. The findings are consistent with previously reported data showing that valproic acid and muscimol inhibit meningeal oedema by bicuculline-sensitive mechanisms. Drugs which activate GABAA-receptors and its modulatory sites might be clinically effective in the treatment of migraine and cluster headache.

1. Valproic acid, useful in the treatment of migraine, is an inhibitor of gamma aminobutyric acid (GABA) aminotransferase and activator of glutamic acid decarboxylase. Its mechanism in migraine remains obscure. The effects of valproic acid (2-propylpentanoic acid) were examined on the number of cells expressing c-fos-like immunoreactivity (c-fos-LI), a marker of neuronal activation, within the trigeminal nucleus caudalis (lamina I, IIo, TNC) 2 h after intracisternal injection of the irritant, capsaicin (0.1 ml; 15.25 micrograms ml-1), in urethane-anaesthetized Hartley guinea-pigs. Positive cells were counted in eighteen sections (50 microns) at three representative levels (rostral, middle and caudal) within lamina I, IIo of the TNC in 90 animals. 2. Numerous cells were labelled after capsaicin instillation (244 +/- 25; 1 ml; 15.25 mM) but not after capsaicin vehicle (11 +/- 1). Positive cells were also found within the medial reticular nucleus, the area postrema and the nucleus of the solitary tract. A similar distribution has been demonstrated previously after application of intracisternal irritants such as autologous blood or carrageenin. 3. Valproate (> or = 10 mg kg-1, i.p.) reduced labelled cells by 52% (P < 0.05) in lamina I, IIo but not within the area postrema, the nucleus of the solitary tract or the medial reticular nucleus. A similar finding was obtained previously after administration of sumatriptan, dihydroergotamine or the NK1 receptor antagonist RPR 100,893. 4. Pretreatment with bicuculline (30 micrograms kg-1; i.p.), a GABAA antagonist, but not phaclofen (1 mg kg-1) a GABAB antagonist, reversed the effect of valproate and increased c-fos positive cells within lamina I, IIo. Somewhat paradoxically, bicuculline by itself (30 micrograms kg-1 i.p.) decreased the number of labelled cells suggesting that more than a single GABAergic mechanism can suppress c-fos expression. 5. We conclude that the mechanism of action of valproate is mediated via GABAA receptors. Since valproate decreases both c-fos expression and as previously shown, neurogenic inflammation within the meninges, the GABAA receptor complex might provide an important target for drug development in migraine and related headaches.

1. The GABA transaminase inhibitor and activator of glutamic acid decarboxylase, valproic acid is being used for the treatment of migraine. Its mechanism of action is unknown. We tested the effects of sodium valproate and GABAA-agonist muscimol on dural plasma protein ([125I]-bovine serum albumin) extravasation evoked by either unilateral trigeminal ganglion stimulation (0.6 mA, 5 ms, 5 Hz, 5 min) or substance P (SP) administration (1 nmol kg-1,i.v.) in anaesthetized Sprague-Dawley rats. 2. Intraperitoneal (i.p.) injection of sodium valproate or muscimol, but not baclofen (< or = 10 mg kg-1, i.p.) dose-dependently reduced dural plasma protein extravasation caused either by electrical trigeminal stimulation (ED50: 6.6 +/- 1.4 mg kg-1, i.p., and 58 +/- 18 micrograms kg-1, i.p. for valproate or muscimol, respectively) or by intravenous substance P administration (ED50: 3.2 +/- 1.4 mg kg-1, i.p. and 385 +/- 190 micrograms kg-1, i.p. for valproate or muscimol, respectively). 3. Valproate (6.6 mg kg-1, i.p.) or muscimol (58 micrograms kg-1, i.p.) had no effect on mean arterial blood pressure or heart rate when measured for 30 min after i.p. administration. 4. The GABAA-antagonist bicuculline (0.01 mg kg-1, i.p.) completely reversed the effect of valproate and muscimol on plasma extravasation following electrical stimulation or substance P administration, whereas the GABAB-receptor antagonist, phaclofen (0.01-1 mg kg-1, i.p.) did not. Bicuculline or phaclofen, given alone, did not alter the plasma extravasation response after either electrical stimulation or SP administration. 5. Valproate decreased plasma extravasation following substance P administration in adult animals, neonatally treated with capsaicin by a bicuculline-reversible mechanism. This suggests that GABAA receptors are not found primarily on those afferent neurones or fibres which are sensitive to capsaicin treatment in neonatal rats.6. We conclude that sodium valproate blocks plasma extravasation in the meninges through GABAA mediated postjunctional receptors probably within the meninges. The dosages required are comparable to those used clinically. Agonists and modulators at the GABAA receptor may become useful for the development of selective therapeutic agents for migraine and cluster headache.

1. The effects of an intravenously administered sumatriptan analogue were examined on c-fos-like immunoreactivity (c-fos-LI), a marker of neuronal activation, evoked within trigeminal nucleus caudalis (TNC) and other brain stem regions 2 h after intracisternal injection of the irritant, capsaicin (0.1 ml, 0.1 mM), in pentobarbitone-anaesthetized Hartley guinea-pigs. 2. C-fos-LI was assessed in eighteen serial sections (50 microns) using a polyclonal antiserum. A weighted average, reflecting total expression within lamina I, IIo of TNC was obtained from three representative levels (i.e., at -0.225 mm, -2.475 mm and -6.975 mm.). 3. Capsaicin caused significant labelling within lamina I, IIo, a region containing axonal terminations of small unmyelinated C-fibres, as well as within the nucleus of the solitary tract, area postrema and medial reticular nucleus. A similar distribution of positive cells was reported previously after intracisternal injection of other chemical irritants such as autologous blood or carrageenin. 4. Pretreatment with a conformationally restricted sumatriptan analogue (with some selectivity for 5-HT1B and 5-HTID receptor subtypes) CP-122,288, reduced the weighted average by approximately 50-60% (P < 0.05) in lamina I, IIo at > or = 100 pmol kg-1, i.v., but did not decrease cell number within area postrema, nucleus of the solitary tract or medial reticular nucleus. A similar pattern was reported previously following sumatriptan, dihydroergotamine or CP-93,129 administration after noxious meningeal stimulation. 5. We conclude that modifications at the amino-ethyl side chain of sumatriptan dramatically enhance the suppression of c-fos expression within TNC, a finding consistent with its remarkable potency against neurogenic plasma protein extravasation within dura mater. CP-122,288 and related analogues may serve as an important prototype for drug development in migraine and related headaches.