Assessment of small intestinal bacterial overgrowth and methane production in patients on chronic proton-pump inhibitor treatment: prevalence and role of rifaximin in its management in primary care.

BACKGROUND: Although proton pump inhibitor (PPI) drugs have considered able to induce small intestinal bacterial overgrowth (SIBO), no data are so far available from primary care (PC). We assessed the prevalence of SIBO and methane (CH4) production consequent to chronic PPI therapy using Lactulose Breath Test (LBT). Secondary aim was to explore the possible role of rifaximin in treating PPI-induced SIBO patients. METHODS: One hundred twenty-five gastroesophageal reflux disease patients, constantly treated with PPI for at least 6 months and undergoing to LBT, were retrospectively assessed. An age-matched control population (control) of 100 patients, which had not used PPI in the last 6 months, was also enrolled. In the PPI group, SIBO positive patients and CH4 producers were treated with rifaximin 1200 mg/daily for 14 days and re-checked with LBT one month after the end of treatment. The area under the curve (AUC) before and after treatment was also calculated for both SIBO positive patients and CH4 producers. RESULTS: In the PPI group, SIBO prevalence was significantly higher vs. controls (38/125 [30.4%] vs. 27/100 [27%], P<0.05). 77/125 (61.6%) PPI patients were found to be CH4 producers vs. 21/100 (21%) controls (P<0.05). Among SIBO patients in the PPI group, 34 (89.4%) were also CH4 producers vs. 17/27 (63%) controls (P<0.05). After treatment, LBT resulted negative in 15/22 SIBO patients (68.1%) (P<0.05) and in 18/34 CH4 producers (52.9%) (P<0.05). At the AUC analysis, an overall reduction of 54.2% for H2 in SIBO patients and of 47.7% for CH4 was assessed after rifaximin treatment (P<0.05). CONCLUSIONS: Our data showed that chronic use of PPI could be able to increase the prevalence of SIBO and to shift the intestinal microbial composition towards a CH4-producing flora. rifaximin could represent a useful therapeutical option for PPI-induced SIBO and for modulating CH4-producing flora.

Migraine during pregnancy and in the puerperium.

Pregnancy can be seen as a positive time for women migraineurs because the elevated estrogen and endogenous opioid levels raise the pain threshold and the stable hormone levels, which no longer fluctuate, eliminate a major trigger factor for the attacks. In a great majority of cases, indeed, migraine symptoms spontaneously improve throughout pregnancy. Generally, migraine without aura (MO) improves better than migraine with aura (MA), which can occur ex novo in pregnancy more frequently than MO. After childbirth, the recurrence rate of migraine attacks increases, especially during the first month; breastfeeding exerts a protective effect against the reappearance of attacks. Migraine and pregnancy share a condition of hypercoagulability; therefore, attention must be paid to the risk of cardiovascular disorders, like venous thromboembolism and ischemic or hemorrhagic strokes. Some of these diseases can be linked to preeclampsia (PE), a serious complication of pregnancy, characterized by hypertension, proteinuria, or other findings of organ failure. This condition is more common in migraineurs compared with non-migraineurs; furthermore, women whose migraines worsen during pregnancy had a 13-fold higher risk of hypertensive disorders than those in which migraine remitted or improved. Pregnancy is generally recognized to exert a beneficial effect on migraine; nonetheless, clinicians should be on the alert for possible cardiovascular complications that appear to be more frequent in this patient population.

Frovatriptan plus dexketoprofen in the treatment of menstrually related migraine: an open study.

At least 50 % of female migraineurs experience migraine associated with the perimenstrual period, even though they may also suffer from attacks at other times of the cycle (menstrually related migraine, MRM). MRM attacks tend to be longer and more intense than those arising in other phases of the menstrual cycle, and are often aggravated by more pronounced vegetative phenomena. In this open preliminary trial, we tested the efficacy of associating frovatriptan and dexketoprofen for the treatment of an acute attack of MRM, diagnosed according to the criteria of the International Headache Society, in 24 patients between 19 and 45 years of age (mean 31.33 ± 7.33). Twenty-one of them completed the study. Pain relief was achieved by 76 % of patients at 2 h and by 86 % at 4 h. A pain-free state was achieved by 48 % at 2 h and by 62 % at 4 h from taking the product. A pain-free state at 24 h was present in 76 % of MRM sufferers, 33 % of whom showed a sustained pain-free state at 24 h. A rescue medication was needed by eight patients. While decidedly encouraging, the data of this study obviously need confirmation with double blind studies involving a greater number of patients.

Treatment strategies for menstrually related migraine.

Approximately 50% of migrainous women suffer from menstrually related migraine (MRM), a type of migraine in which the attacks occur at the same time as or near the menstrual flow. Attacks of MRM tend to be longer, more intense and disabling and sometimes less responsive to treatment than non-menstrual migraines. Similar to the management of non-menstrual migraine, the use of triptans and NSAIDs is the gold standard for MRM treatment. In this paper, the most important studies in the literature that report the effectiveness of triptans, of certain associated drugs and other analgesic agents are summarized. Preventive strategies that can be used if a prophylactic treatment is needed is also analyzed, with particular attention paid to the use of perimenstrual prophylaxis with triptans and/or NSAIDs. Moreover, considering the peculiar interaction between menstrual migraine and female sex hormones, brief mention is made to possible hormonal manipulations.

Premenstrual syndrome and migraine.

Premenstrual syndrome (PMS) includes a wide variety of physical, psychological, and cognitive symptoms that occur recurrently and cyclically during the luteal phase of the menstrual cycle and disappear soon after the onset of menstruation. Headache, often of migrainous type, is one of physical symptoms often reported in the diagnostic criteria for PMS. Menstrual migraine (MM) is a particular subtype of migraine occurring within the 2 days before and the 3 days after the onset of menses. According to this definition, therefore, some attacks of MM certainly occur in conjunction with the period of maximum exacerbation of PMS symptoms. The relationship between MM and PMS has been investigated through diary-based studies which have confirmed the possible correlation between these two conditions. In this paper we provide indications for the treatment of MM, making particular reference to those therapies that may be useful in the treatment of PMS symptoms. Even if triptans are the gold standard for the acute treatment, if symptomatic treatment is not sufficient one can resort to a short-term perimenstrual prophylaxis. Non-steroidal anti-inflammatory drugs have been demonstrated effective in MM prophylaxis. Among natural products there is some evidence of efficacy for magnesium, phytoestrogens, and ginkgolide B. Finally, also a combined oral contraceptive containing drospirenone, taken continuously for 168 days, has shown promising results.

Oral contraceptives in migraine therapy.

Even if sometimes combined oral contraceptives (COCs) can initiate or aggravate headaches, in particular migraine, the headaches generally tend to improve after the first months of COC use. If migraine persists, in many patients the attacks are more likely to occur during the pill-free week, and an oral contraceptive-induced menstrual migraine (OCMM) occurs. In case of OCMM, some hormonal manipulations are available, by eliminating or reducing the hormone-free interval (HFI), in order to prevent this estrogen-withdrawal headache. It is possible to use a continuous COCs regimen, to shorten the HFI to less than the traditional 7 days, to use a low-dose estrogen supplementation after the 21 days of COCs or to prescribe a progestogen-only pill (POP). Interestingly, the use of a POP is a safe option also for women suffering from migraine with aura (in which COCs are absolutely contraindicated) and a recent trial suggests that its use can reduce the frequency of migraine attacks and the duration of aura symptoms too.

Joint Metabonomic and Instrumental Analysis for the Classification of Migraine Patients with 677-MTHFR Mutations.

Migraine is a neurological disorder that correlates with an increased risk of cerebrovascular lesions. Genetic mutations of the MTHFR gene are correlated to migraine and to the increased risk of artery pathologies. Also, migraine patients show altered hematochemical parameters, linked to an impaired platelet aggregation mechanism. Hence, the vascular assessment of migraineurs is of primary importance.Transcranial Doppler sonography (TCD) is used to measure cerebral blood flow velocity (CBFV) and vasomotor reactivity (by an index measured during breath-holding - BHI). Aim of this study was the metabolic profiling of migraine subjects with T/T677-MTHFR and C/T677-MTHFR mutations and its correlation with CBFV and BHI.Metabonomic multidimensional techniques were used to describe and cluster subjects. Fifty women suffering from migraine (age: 18-64; 21 with aura) underwent TCD examination, hematochemical blood analysis, Born test, and genetic tests for MTHFR mutation. Fourteen (7 with aura) had T/T677, 18 (8 with aura) had C/T677, and 18 (6 with aura) had no mutation. The total number of variables was 24.Unsupervised and supervised techniques_showed the correlation between CBFV and BHI with mutation. Discriminant analysis allowed for classifying the subjects with 95.9% sensitivity and 89.0% specificity. Aura was not correlated to mutation or variations of instrumental data.Our study showed that metabonomics could be effectively applied in clinical problems to show the overall correlation structure of complex systems in pathology. Specifically, our results confirmed the importance of TCD in the metabolic profiling and follow-up of migraine patients.

Non-pharmacological management of migraine during pregnancy.

Migrainous women note a significant improvement in their headaches during pregnancy. However, persistent or residual attacks need to be treated, keeping in mind that many drugs have potential dangerous effects on embryo and foetus. It is evident, therefore, that hygiene and behaviour measures capable of ensuring the best possible well-being (regular meals and balanced diet, restriction of alcohol and smoking, regular sleeping pattern, moderate physical exercise and relaxation) are advisable during pregnancy. Among non-pharmacological migraine prophylaxis only relaxation techniques, in particular biofeedback, and acupuncture have accumulated sufficient evidence in support of their efficacy and safety. Some vitamins and dietary supplements have been proposed: the prophylactic properties of magnesium, riboflavin and coenzyme Q10 are probably low, but their lack of severe adverse effects makes them good treatment options.

Spectral changes of near-infrared spectroscopy signals in migraineurs with aura reveal an impaired carbon dioxide-regulatory mechanism.

Subjects suffering from migraine with aura (MwA) present an altered cerebral autoregulation during migraine attacks. It is still unclear whether MwA sufferers present a normal autoregulation during attack-free periods. In this study, we characterized cerebral autoregulation in the frequency domain by analyzing the spontaneous oscillations superimposed on the cerebral hemodynamic signals, as detected by near-infrared spectroscopy (NIRS). Ten healthy women (age: 38.4 +/- 9.5 years) and ten women suffering from MwA (age: 35.2 +/- 10.5 years) underwent NIRS recording in resting conditions and during breath-holding (BH). Being the NIRS signals during BH nonstationary, we used the Choi-Williams time-frequency distribution to perform spectral analysis. We considered 256 s of signals and quantified the variation in the power of the very-low frequencies (VLF: 20-40 mHz) and of the low frequencies (LF: 40-140 mHz) as response to BH. Results showed that BH increases the power in the LF band both in healthy and MwA subjects. Considering the signal of the deoxygenated hemoglobin, the average power increase in the LF band was equal to 20% +/- 15.4% for the healthy group and significantly lower, 4.8% +/- 8.3%, in the MwA group (Student's t test, P < 0.02). No significant difference was observed in the VLF band or in the oxygenated hemoglobin signal power variations of the LF and VLF bands. The resulting data reveal a possible impairment in the carbon dioxide-regulatory mechanism in MwA subjects.

Oral contraceptives in migraine.

Combined oral contraceptives are a safe and highly effective method of birth control, but they can also raise problems of clinical tolerability and/or safety in migraine patients. It is now commonly accepted that, in migraine with aura, the use of combined oral contraceptives is always contraindicated, and that their intake must also be suspended by patients suffering from migraine without aura if aura symptoms appear. The newest combined oral contraceptive formulations are generally well tolerated in migraine without aura, and the majority of migraine without aura sufferers do not show any problems with their use; nevertheless, the last International Classification of Headache Disorders identifies at least two entities evidently related to the use of combined oral contraceptives: exogenous hormone-induced headache and estrogen-withdrawal headache. As regards the safety, even if both migraine and combined oral contraceptive intake are associated with an increased risk of ischemic stroke, migraine without aura per se is not a contraindication for combined oral contraceptive use. Other risk factors (tobacco use, hypertension, hyperlipidemia, obesity and diabetes) must be carefully considered when prescribing combined oral contraceptives in migraine without aura patients, in particular in women aged over 35 years. Furthermore, the exclusion of a hereditary thrombophilia and of alterations of coagulative parameters should precede any decision of combined oral contraceptive prescription in migraine patients.

Migraine and stroke: the role of oral contraceptives.

The use of oral contraceptives (OCs) confers an increased risk for ischaemic stroke (IS). This risk slightly decreases, but remains significant, if low-dose formulations are used, particularly if other risk factors, such as hypertension or smoking, are associated. Some inherited prothrombotic conditions (e.g., Factor V Leiden, G20210A prothrombin or methylenetetrahydrofolate reductase C677T polymorphism) could also greatly increase the IS risk if present in OC users. Migraine, particularly with aura, is an independent risk factor for IS, and the patient's IS risk is probably affected by other individual risk factors (e.g., age, genetic predisposition to thrombosis, presence of patent foramen ovale or enhanced platelet aggregation) which seem to be over-represented in migraine patients. IS risk among migraineurs is further increased when OCs are currently used and can become very high if associated with smoking. Consequently, in 2004 the WHO stated in its 'Medical Eligibility Criteria for Contraceptive Use' that women suffering from migraine with aura at any age should never use OCs. Moreover, since the exposure to the effects of OCs may greatly increase the IS risk in some migraine subpopulations with specific personal characteristic, testing for these risk factors may allow for more accurate stratification of the population at risk before long-term use of OCs is prescribed.

The diagnostic iter of patent foramen ovale in migraine patients: an update.

Patent foramen ovale (PFO) is a frequent finding in migraine patients. The standard technique for PFO diagnosis is actually trans-oesophageal echocardiography (TEE). It requires the injection of a contrast agent unable to pass the pulmonary filter; hence, it is possible to detect a right-to-left shunt by observing the presence of the contrast medium in the cardiac left compartment. The transcranial Doppler (TCD) device accurately measures the blood flow velocities in different cerebral arteries. It can record microembolic signals (MES) backscattered by microbubbles travelling in the cerebral circulation, and distinguish cardiac shunts from pulmonary shunts. The number of MES is correlated to the entity of the shunt. The near-infrared spectroscopy (NIRS) technique tracks the changes in the concentration of oxygenated and reduced haemoglobin in the brain tissue. PFO is revealed by an alteration of the normal vasoreactivity pattern of the subject during functional stimuli. Magnetic resonance imaging (MRI) provides, at the same time, detailed anatomical information and functional measurements. MRI dynamic perfusion sequences can be used to reliably detect PFO either by visual assessment or by signal-time curves in the pulmonary artery and in the left atrium. A good correlation between TEE and MRI grading scores has been demonstrated, even though the interindividual variability of performing the Valsalva manoeuvre could greatly reduce the sensitivity of the method. Further prospective studies are needed to confirm the PFO MRI grading and to assess the sensitivity and specificity of the method.

Patent foramen ovale detected by near-infrared spectroscopy in patients suffering from migraine with aura.

There is an increased prevalence of patent foramen ovale (PFO) in women with migraine with aura (MwA) compared to controls, but the role of PFO in triggering aura is still debated. The aim of this study was to test a group of women suffering from MwA with near-infrared spectroscopy (NIRS), to assess the NIRS capability of discriminating between subjects with and without PFO. Eighty-eight MwA patients (mean age 37.4+/-10.7 years, range 16-62 years) underwent NIRS measurement of the cerebral variations of the oxygenated (O2Hb) and reduced haemoglobin (HHb) during breath-holding. The prevalence of O2Hb vs. HHb was used to assess the presence of PFO. As a gold standard, the presence of PFO was assessed by transcranial Doppler sonography (TCD). At the TCD analysis 48 patients (55%) showed PFOs, 32 of which were permanent. NIRS correctly detected 36 subjects out of 40 without PFO, and 38 subjects out of 48 having PFO: sensitivity was 79%; specificity was 90%. All the false negatives were permanent shunts. MwA patients with PFO showed a delayed increase in the O2Hb concentration and a reduced oxygenation with respect to subjects without PFO. NIRS is effective in identifying the presence of PFO in a MwA population, but TCD achieves better diagnostic performances. The NIRS provides additional information about the cerebral vasoreactivity and highlights substantial differences between patients with latent and permanent shunts that warrant further studies.

Menstrual migraine: clinical and therapeutical aspects.

Estrogens fluctuations, particularly their premenstrual fall, are currently regarded as the main triggers of menstrual migraine (MM). MM presents in two clinical forms: pure MM, where attacks are confined to the perimenstrual period (PMP), and menstrually related migraine, where attacks always occur during, but are not confined to, the PMP. MM episodes are usually longer, more intense, more disabling and more refractory than nonmenstrual attacks. Acute management of MM should initially be abortive and primarily sought with triptans. If this fails, short-term perimenstrual prophylaxis with NSAIDs, coxibs, triptans or ergotamine derivatives can be considered. Hormone manipulations, mainly application of percutaneous estradiol gel in PMP or administration of oral contraceptives in extended cycles, constitute an alternative approach for nonresponders.

Acupuncture in the prophylactic treatment of migraine without aura: a comparison with flunarizine.

OBJECTIVES: In a randomized controlled trial extending over 6 months, we evaluated the effectiveness of acupuncture versus flunarizine in the prophylactic treatment of migraine without aura. METHODS: One hundred sixty women with migraines were randomly assigned to acupuncture treatment (group A, n = 80) or to an oral therapy with flunarizine (group F, n = 80). In group A, acupuncture was carried out in weekly sessions for the first 2 months and then once a month for the next 4 months. The same acupoints were used at each treatment: LR3 Taichong, SP6 Sanyinjiao, ST36 Zusanli, CV12 Zhongwan, LI4 Hegu, PC6 Neiguan, GB20 Fengchi, GB14 Yangbai, EX-HN5 Taiyang, GV20 Baihui. In group F, 10 mg flunarizine were given daily for the first 2 months and then for 20 days per month for the next 4 months. RESULTS: The frequency of attacks and use of symptomatic drugs significantly decreased during treatment in both groups. The number of attacks after 2 and 4 months of therapy was significantly lower in group A than in group F, and analgesic consumption was significantly lower in group A at 2 months of treatment. At 6 months no such differences existed between the two treatment groups. Pain intensity was significantly reduced only by acupuncture treatment. Side effects were significantly less frequent in group A. CONCLUSIONS: Acupuncture proved to be adequate for migraine prophylaxis. Relative to flunarizine, acupuncture treatment exhibited greater effectiveness in the first months of therapy and superior tolerability.