The phenotype of migraine with unilateral cranial autonomic symptoms documents increased peripheral and central trigeminal sensitization. A case series of 757 patients.

BACKGROUND: Migraine with unilateral cranial autonomic symptoms (UAS) is a putative migraine endophenotype with convincing response to trigeminal-targeted treatments that still needs a thorough characterization. OBJECTIVE: The objective of this article is to carefully investigate the clinical phenotype of migraine with UAS in a large group of patients for more accurate migraine diagnoses, improved clinical management, and better outcome prediction. METHODS: We studied 757 consecutive episodic and chronic migraineurs in a tertiary headache clinic with face-to-face interviews, detailing in depth their lifestyle, sociodemographic and headache characteristics. RESULTS: Migraineurs with UAS (37.4%) differed from the general migraine population with respect to longer attack duration (OR = 2.47, p < 0.02, having >72-hour long attacks), more strictly unilateral (OR = 3.18, p < 0.001) and severe headache (OR = 1.72, p = 0.011), more frequent allodynia (OR = 3.03, p < 0.001) and photophobia (OR = 1.87, p = 0.019). CONCLUSIONS: Migraine patients with UAS are characterized not only by symptoms due to intense peripheral trigeminal activation but also to central sensitization. Our study broadens the knowledge on the clinical and phenotypic characteristics of migraine with UAS, suggests pathophysiological implications, and supports the need for future prospective clinical studies.

Frovatriptan 2.5 mg plus dexketoprofen (25 mg or 37.5 mg) in menstrually related migraine. Subanalysis from a double-blind, randomized trial.

PURPOSE: The purpose of this article is to investigate the efficacy and safety of frovatriptan plus dexketoprofen 25 or 37.5 mg (FroDex25 or FroDex37.5, respectively) compared to that of frovatriptan 2.5 mg (Frova) in menstrually related migraine (MRM). AIM: The aim of this article is to analyze a subgroup of 76 women who treated an MRM attack in this multicenter, randomized, double-blind, parallel-group study. METHODS: The primary end-point was the proportion of patients who were pain free (PF) at two hours. Secondary end-points included pain-relief (PR) at two hours and 48 hours sustained pain free (SPF). RESULTS: PF rates at two hours were 29% under Frova, 48% under FroDex25 and 64% under FroDex37.5 (p < 0.05). PR at two hours was Frova 52%, FroDex25 81% and FroDex37.5 88%, while 48 hours SPF was 18% under Frova, 30% under FroDex25 and 44% under FroDex37.5. CONCLUSION: Combining frovatriptan+dexketoprofen produced higher PF rates at two hours compared to Frova while maintaining efficacy at 48 hours. Tolerability profiles were comparable.

Role of neurostimulation in migraine.

Chronic forms of headache characterized by daily or almost daily headache, affect almost 3 % of general population. They represent the most disabling forms of headache inducing high degree of disability, poor quality of life for patients. During the last decades, several neuromodulatory surgical techniques have been developed for the management of headaches that are unresponsive to medical treatment. Invasive and non invasive central and/or peripheral neurostimulation techniques have been developed by different research groups with encouraging results for different type of headaches. In this report, the acute effect of non invasive vagus nerve stimulation (nVNS) (gammacore) was evaluated to treat migraine attacks in a population of patients affected by high-frequency episodic migraine or chronic migraine. The aim of this study was to verify the efficacy of nVNS to treat migraine attacks in this specific category of patients.

Rationale for use of onabotulinum toxin A (BOTOX) in chronic migraine.

Chronic migraine is a severely disabling headache evolving from episodic migraine as a result of different transforming factors and characterized by atypical pain modulation and peripheral and central sensitization. Discovered by serendipity, onabotulinum toxin A (BoNT-A) represents the only drug specifically approved for CM prophylaxis. According to the dominant opinion, BoNT-A acts peripherally, impairing the exocytosis of neuropeptide and neurotransmitter and the delivery of receptors and ion channels on the cell surface of peripheral trigeminal endings, thereby indirectly reducing central sensitization. However, it is not excluded that BoNT-A has also a central antinociceptive action, probably associated with an enhanced opioidergic and GABA-ergic transmission. This review discusses the rationale for use of BoNT-A in CM including its mechanisms of action and molecular targets and provides suggestions for a more tailored BoNT-A prophylaxis in patients with CM.

Treatment of tension-type headache: from old myths to modern concepts.

Tension-type headache (TTH) is the second most common human disease, accounting for intense disability, high costs and numerous workdays lost. Tension-type headache is less simple and easy-to-treat than commonly thought. Antidepressants, despite their poor tolerability, are still the first-choice drugs for preventing TTH. The most widely studied non-pharmacological approach to TTH, cognitive-behavioral techniques, effectively relieve pain only in selected patients. The most frequently used and recommended treatments for acute TTH, NSAIDs and paracetamol have scarce efficacy as documented by their low therapeutic gain over placebo in the 2-h pain-free response. Their effectiveness may be increased by a more proper use and by the adjunction of caffeine, antiemetics, myorelaxants or tranquillizers but the risk of medication-overuse headache must be considered. Hence, the need for more effective and tailored treatments in TTH remains.

Acupuncture in cluster headache: four cases and review of the literature.

Although cluster headache (CH) is the most disabling form of primary headache, little evidences regarding alternative and complementary therapies are available. Only few dated studies and some isolated cases are described. We describe four patients with CH treated with acupuncture as a preventive treatment, combined with verapamil or alone. All patients received acupuncture treatment twice/week for 2 weeks, then once/week for 8 weeks, and then once/alternate weeks for 2 weeks. According to Traditional Chinese Medicine the acupoints selected were: Ex HN-5 Taiyang, GB 14 Yangbai (both only on the affected side), GB 20 Fengchi (on both sides), LI 4 Hegu, LR 2 Xingjiang, SP 6 Sanyinjiao, ST 36 Zusanli (all on both sides). At each point, after the insertion of the needle, the feeling of "De Qi" was evoked; after obtaining this sensation the acupoints were not further stimulated for a period of 20 min, until their extraction. In all patients an interruption of cluster attacks was obtained. To our knowledge, this is the first report concerning acupuncture in CH patients which details the protocol approach, acupoints and duration of the treatment. Our results offer the opportunity to discuss the emerging role of acupuncture in the therapy of CH, assuming a possible influence on opioid system.

Efficacy of frovatriptan and other triptans in the treatment of acute migraine of hypertensive and normotensive subjects: a review of randomized studies.

Migraine might be associated with high blood pressure (BP), which can cause more severe and more difficult to treat forms of headache. To evaluate the efficacy of frovatriptan and other triptans in the acute treatment of migraine, in patients classified according to a history of arterial hypertension, enrolled in three randomized, double-blind, crossover, Italian studies. Migraineurs with or without aura were randomized to frovatriptan 2.5 mg or rizatriptan 10 mg (study 1), frovatriptan 2.5 mg or zolmitriptan 2.5 mg (study 2), frovatriptan 2.5 mg or almotriptan 12.5 mg (study 3). After treating up to three episodes of migraine in 3 months with the first treatment, patients switched to the alternate treatment for the next 3 months. The present analysis assessed triptan efficacy in 60 subjects with a history of treated or untreated essential arterial hypertension (HT) and in 286 normotensive (NT) subjects. During the study, migraine attacks with aura were significantly more prevalent in HT subjects (21 vs. 13 % NT, p < 0.001). The proportion of pain free at 2 h did not significantly differ between HTs and NTs for either frovatriptan (25 vs. 26 %) or the comparators (33 vs. 32 %). Pain relief was achieved in significantly (p < 0.05) fewer episodes in HT subjects for both frovatriptan (41 vs. 52 % NT) and the comparators (48 vs. 58 %). Relapses at 48 h were similarly low in HTs and NTs with frovatriptan (29 vs. 31 %), while they were significantly (p < 0.05) larger in HTs (62 %) than in NTs (44 %) with comparators. No BP or heart rate increment was observed during the study in HT subjects. No difference in tolerability was reported between HTs and NTs. In conclusion, HT individuals tend to be less responsive than NT migraineurs to triptan therapy. However, frovatriptan, in contrast to other triptans, seems to have a sustained antimigraine effect in both HT and NT patients.

Migraine and movement disorders.

A large series of clinical and experimental observations on the interactions between migraine and the extrapyramidal system are available. Some previous studies reported high frequency of migraine in some basal ganglia (BG) disorders, such as essential tremor (ET), Tourette's syndrome (TS), Sydenham's chorea and more recently restless legs syndrome (RLS). For example, the frequency of migraine headache in a clinic sample of TS patients was found nearly fourfold more than that reported in the general population. To the best of our knowledge, no controlled studies have been conducted to determine a real association. ET and migraine headache have been considered comorbid diseases on the basis of uncontrolled studies for many years. In a recent Italian study, this comorbid association has been excluded, reporting no significant differences in the frequency of lifetime and current migraine between patients with ET and controls. Among mostly common movement disorders, RLS has been recently considered as possibly comorbid with migraine. Studies in selected patient groups strongly suggest that RLS is more common in migraine patients than in control populations, although no population-based study of the coincidence of migraine and RLS has yet been identified. The exact mechanisms and contributing factors for a positive association between migraine and RLS remain unclear. A number of possible explanations have been offered for the association of RLS and primary headache, but the three most attractive ones are a hypothetical dopaminergic dysfunction and dysfunctional brain iron metabolism, a possible genetic linkage and a sleep disturbance. More recently, the role of BG in pain processing has been confirmed by functional imaging data in the caudate, putamen and pallidum in migraine patients. A critical appraisal of all these clinical and experimental data suggests that the extrapyramidal system is somehow related to migraine. Although the primary involvement of extrapyramidal system in the pathophysiology of migraine cannot as yet be proven, a more general role in the processing of nociceptive information and/or maybe part of the complex behavioral adaptive response that characterizes migraine may be suggested.

Migraine prophylaxis: what is new and what we need?

A wide array of options are now available for migraine prophylaxis. Conventional treatments include beta-blockers, anticonvulsants, antidepressants, calcium antagonists and antiserotoninergic drugs. Emerging medications such as ACE inhibitors, sartans and nutritional supplements are gaining favour for migraine prophylaxis. Botulinum toxin type A is a promising therapeutic tool for chronic migraine. Tonabersat is likely to be a step forward for the treatment of migraine with aura. However, much work is needed to identify predictive clinical features of successful responsiveness and to better define the duration of prophylaxis.

Restless legs syndrome is not associated with migraine with aura: a clinical study.

Based on recent data about the association between restless legs syndrome (RLS) and migraine, we performed an observational study on the occurrence of RLS in patients affected by "pure" migraine with aura (pMA). We recruited 63 patients (33 females and 30 males) affected by MA without other types of primary headache among all patients referred in five Italian headache centers in a 1-year period. The prevalence of RLS in pMA patients (9.5%) is similar to that observed in Italian headache-free subjects (8.3%). No significant differences were found between pMA patients with and without RLS about clinical features of MA attacks and systemic and psychiatric diseases were investigated. Moreover, no association appeared between RLS and familial cases of MA. Differently from migraine without aura, our data do not confirm the existence of an association between RLS and MA, not even when a genetic factor is involved.

Hypertension as a risk factor for migraine chronification.

Progression of episodic migraine to chronic migraine may be related to comorbid medical conditions. In this study, we focused on the role played by arterial hypertension in migraine transformation. Several studies reveal that hypertension is associated with chronic migraine and may induce migraine chronification. Hypertension probably amplifies the effects of migraine on the vascular wall further enhancing the endothelial dysfunction in cerebral vasculature. Consequently, monitoring of blood pressure is recommended in migraineurs showing an otherwise unexplained increase in attack frequency. Studies are needed to verify if prophylactic treatment with drugs improving endothelial function (e.g. calcium channel blockers, beta blockers, calcium inhibitors, ACE inhibitors and sartans) may selectively ameliorate the course of migraine in these patients.

Pharmacotherapy for acute migraines in children and adolescents.

INTRODUCTION: Migraine is increasingly recognized as an extremely burdensome and disabling disorder in both children and adolescents. A proper treatment plan is needed to improve the quality of life of both children and families as well as to minimize the risk of disease progression. AREAS COVERED: This review focuses on the current pharmacotherapy for acute migraine in pediatric populations, taking into account specific considerations for those drugs tested in randomized, placebo-controlled trials (RCTs). EXPERT OPINION: A large number of RCTs have documented the efficacy, tolerability, and safety of different compounds. Triptans appears more effective than placebo but results are variable and inconsistent. Almotriptan and rizatriptan are effective as oral formulations, as well as sumatriptan and zolmitriptan as both oral and nasal spray formulations. Adding non-steroidal anti-inflammatory drugs (NSAIDs) reinforces triptan's effectiveness. Furthermore, small RCTs have documented both the efficacy of ibuprofen and the ineffectiveness of acetaminophen. Naproxen, ketoprofen, diclofenac, and indomethacin - NSAIDs effective in acute migraines in adults - should be tested also in pediatric subjects. Furthermore, the authors suggest that dopamine receptor antagonists should be considered in cases of severe migraines. Lastly, better designed RCTs are needed to fine-tune current therapeutic resources.

Trigeminal sensory pathway function in patients with SUNCT.

OBJECTIVE: Short-lasting unilateral neuralgiform headache with conjunctival injection and tearing (SUNCT) is a rare primary headache whose origins are unclear. To seek information on its pathophysiology, we studied the trigeminal Abeta and Adelta pathways by recording trigeminal reflexes and laser evoked potentials (LEPs) in patients with SUNCT. METHODS: Trigeminal reflexes and LEPs were recorded in 11 consecutive patients. Ten patients had neuroimaging evidence documenting idiopathic SUNCT and one had a posterior fossa tumour that compressed the trigeminal nerve thus causing symptomatic SUNCT. RESULTS: Whereas the patients with idiopathic SUNCT had normal trigeminal reflex and LEP responses, the patient with symptomatic SUNCT had abnormal responses. CONCLUSIONS: Our neurophysiological findings show that idiopathic SUNCT spares the trigeminal sensory pathways whereas symptomatic SUNCT does not. SIGNIFICANCE: Neurophysiological testing can easily differentiate the idiopathic and symptomatic forms of SUNCT. It also suggests that the two forms are pathophysiologically distinct entities.

Generation of monoclonal antibodies reacting with human epithelial ovarian cancer.

Fusion of the murine myeloma line P3-X63-Ag8-U1 with spleen cells from a mouse immunized with a membrane preparations (CM) of a mucinous ovarian cystoadenocarcinoma yielded two monoclonal antibodies, MOv1 and MOv2, which reacted by solid-phase radioimmunoassay with immunizing tumor CM but were unreactive with normal kidney CM as well as with plasma proteins and peripheral blood cells from the immunizing carcinoma patient. MOv1 and MOv2 were further tested by solid-phase radioimunoassay on a panel of different CM from fresh surgical specimens of ovarian and nonovarian carcinomas, benign ovarian tumors, normal ovary and kidney tissues, and on various tumor cell lines. In addition, the antibodies were characterized by immunofluorescence on live cells from cell lines and surgical specimens, and on frozen sections of benign and malignant ovarian tumors, of nonovarian tumors, and of normal tissues. The results obtained indicate that MOv1 and MOv2 recognize two different epitopes on molecules present on malignant and benign ovarian mucinous tumors and colonic glands. In addition, the antigen recognized by MOv2 was also detected in carcinmas of lung, colon, stomach, and breast; in gastrointestinal glands; and in the glandular lumina of normal lactating breast.

Reduced density of dopamine D2-like receptors on peripheral blood lymphocytes in Alzheimer's disease.

Clinical and pathological evidence points to an involvement of dopamine in Alzheimer's disease (AD). The present study was designed to assay dopamine D1-like and D2-like receptors on peripheral blood lymphocytes (PBL) in 20 patients with AD and in 25 healthy controls by radioligand binding assay techniques with [3H][R]-(+)-(-)chloro-2,3,4,5 tetrahydro-5-phenyl-1H-3-benzazepin-al-hemimaleate (SCH 23390) and [3H]7-hydroxy-N,N-di-n-propyl-2-aminotetraline (7OH-DPAT) as radioligands. The density of dopamine D1-like receptors and the affinity of [3H]SCH 23390 and [3H]7OH-DPAT binding to PBL were similar in both groups investigated. AD patients revealed a lower density of dopamine D2-like receptors on PBL than controls (P=0. 0016). The pharmacological profile of [3H]SCH 23390 and [3H]7OH-DPAT binding to PBL was consistent with the labeling of dopamine D5 and D3 receptor subtypes, respectively. The reduced density of dopamine D2-like receptors on PBL is consistent with the observation of changes in the expression of D2-like receptors in dopaminergic brain areas in AD. Our findings support the hypothesis of an involvement of dopamine in AD, even in those patients with no evidence of Parkinsonism, behavioral abnormalities or psychosis.

Polymorphism at codon 129 or codon 219 of PRNP and clinical heterogeneity in a previously unreported family with Gerstmann-Sträussler-Scheinker disease (PrP-P102L mutation).

We present a new, large, Italian family affected by Gerstmann-Sträussler-Scheinker syndrome (GSS) associated with the Pro to Leu point mutation at codon 102 of the prion protein gene (PRNP). The affected members of this family show a remarkable phenotypic variability of the disease: three of them had a clinical picture characterized by dementia and a brief illness duration (less than 1 year), while the other five members presented an ataxic, slowly evolving syndrome (a clinical duration of 3 to 4 years) with no evidence of cognitive impairment. Despite these remarkable clinical differences among affected members, we found no correlation between the clinical presentation and the codon 129 or codon 219 genotypes. These data suggest that factors as yet unidentified may influence the clinical expression of the disease.

Increased density of dopamine D5 receptor in peripheral blood lymphocytes of migraineurs: a marker for migraine?

The expression of dopamine D5 receptor was investigated in peripheral blood lymphocytes of 11 migraine patients and of ten healthy control subjects using a radioligand binding technique with [3H]SCH 23390 as a ligand. [3H]SCH 23390 is a benzazepine derivative with potent antagonist properties at the dopamine D1-like receptors. [3H]SCH 23390 was specifically bound to peripheral blood lymphocytes of migraineurs and control subjects in a manner consistent with the labelling of a dopamine D5 receptor. In migraineurs a statistically significant higher density of lymphocyte dopamine D5 receptor compared with controls was noticeable, whereas the affinity of the radioligand was unchanged. The increased density of dopamine D5 receptor in peripheral blood lymphocytes may reflect the dopaminergic hypersensitivity displayed by migraineurs and may represent a relatively simple and reliable peripheral marker of altered dopaminergic function.

Dopamine hypersensitivity in migraine: role of the apomorphine test.

We investigated the effects of apomorphine administration at two different doses (2-10 micrograms/kg, s.c.) in 35 migraineurs in headache-free period and in 20 age-matched healthy control subjects, with and without pretreatment with domperidone. Neither patients or controls complained of headache at either dose, whereas at the dose of 10 micrograms/kg migraineurs showed a statistically significant higher incidence of dopaminergic symptoms (nausea, vomiting, drowsiness, yawning, dizziness, sweating) than controls. Furthermore, symptoms due to postsynaptic dopamine receptors activation (i.e., nausea and vomiting) only appeared in migraineurs. No symptom, however, resembled those characterizing a spontaneous migraine attack. In conclusion, migraineurs show a lower threshold for dopamine receptor activation than normal subjects.

Improvement of tumor cell detection using a pool of monoclonal antibodies.

It has been proven that monoclonal antibodies which are not strictly tumor specific may be useful in clinical oncology for diagnosis and in in vitro therapy. These applications, however, are hampered by the heterogeneous expression on tumor cells of the epitopes defined by the majority of monoclonal antibodies produced so far. The use of combined monoclonals could complement their antitumor specificity and solve the problem. In this perspective we selected nine monoclonal antibodies directed against different antigens of primary and metastatic breast cancer cells. The reactivity of the pool of these nine monoclonals versus a single antibody (MBr1) was determined by immunofluorescence on tumor cell lines, on frozen sections of various carcinomas, and on live cells obtained from malignant effusions. The results obtained with the pool, compared to those using MBr1 alone, showed a remarkable increase in the number of immunopositive breast and other carcinomas and the number of immunopositive cells within each positive tumor. In fact, the percentage of immunoreactive breast carcinomas increased from 79% to 100%, and the percentage of immunoreactive carcinomas of other sites from 61% to 89%. In addition, the number of positive breast carcinomas showing 100% immunoreactive cells increased from 5% with MBr1 to 71% when the pool was used.