Applications of transcranial magnetic stimulation in migraine: evidence from a scoping review.

Transcranial magnetic stimulation (TMS), a non-invasive brain stimulation method, is trying to emerge as a migraine management strategy for both attack treatment and prevention. This scoping review presents 16 among single-pulse (to manage episodic and chronic migraine) and repetitive TMS randomized clinical trials (to manage chronic migraine). The works we reviewed suggest that TMS may be adopted as add-on therapy in those patients who are refractory to pharmacological therapy only with special arrangements for individualized treatment strategies or research. There are still limited clinical research programs and metaanalysis to promote routinely TMS employment, as TMS has been shown either to have no significant effects for any outcome or to be effective for migraine. These diverging conclusions depend on several biasing factors, including the lack of reliable, large, sham-controlled clinical trials, the dyshomogeneity in study designs (including the area of stimulation, the frequency of stimulation, the number of pulses, pulse intensity, and the number of sessions), patient selection criteria (migraine w/o aura, episodic and chronic migraine; TMS contraindication), and the lack of outcomes homogeneity and long-term real-world efficacy data. Therefore, in the future, it will be important to conduct larger randomized trials to confirm TMS usefulness in migraine management (acute attack and prophylactic treatment), identify those patients who may benefit from TMS, maybe independently of pharmacological treatments (i.e., using TMS as an alternative and not only as an add-on treatment). Otherwise, TMS will play a role in treating migraine only with special arrangements for individualized management strategies or research.

Therapeutic implications of cortical spreading depression models in migraine.

Migraine is among the most common and disabling neurological diseases in the world. Cortical spreading depression (CSD) is a wave of near-complete depolarization of neurons and glial cells that slowly propagates along the cortex creating the perception of aura. Evidence suggests that CSD can trigger migraine headache. Experimental models of CSD have been considered highly translational as they recapitulate migraine-related phenomena and have been validated for screening migraine therapeutics. Here we outline the essential components of validated experimental models of CSD and provide a comprehensive review of potential modulators and targets against CSD. We further focus on novel interventions that have been recently shown to suppress CSD susceptibility that may lead to therapeutic targets in migraine.

Lamotrigine in the Prevention of Migraine With Aura: A Narrative Review.

BACKGROUND: Lamotrigine is not recommended in the prevention of migraine in general but some reports suggest that it might be effective for treating specifically migraine with aura (MA). This review aims to summarize the related data from the literature and to better understand this discrepancy. METHODS: All reports from the literature related to the use of lamotrigine in migraine with or without aura published prior to February 2019 found using PUBMED and the 2 keywords "migraine" AND "lamotrigine" were reviewed. Original studies, published in full, systematic reviews, and all case reports were synthetized. We also examined the risk profile, pharmacokinetics, and mode of action of lamotrigine in view of the presumed mechanism of MA. RESULTS: Lamotrigine was tested in different populations of migraineurs, but previous studies had small sample sizes (n < 35) and might not have been powered enough for detecting a potential benefit of lamotrigine in MA. Accumulating data suggest that the drug can reduce both the frequency and severity of aura symptoms in multiple conditions and is well tolerated. CONCLUSION: Lamotrigine appears promising for treating attacks of MA and related clinical manifestations because of its high potential of efficacy, low-risk profile, and cost. Additional studies are needed for testing lamotrigine in patients with MA.

Right-to-Left Shunt and the Clinical Features of Migraine with Aura: Earlier but Not More.

BACKGROUND: The causal relationship between patent foramen ovale (PFO) and migraine with aura (MA) is controversial. We aimed at exploring whether attack clinical features relate to the presence of right-to-left shunt (RLS) in MA patients. METHODS: We retrospectively examined a cohort of consecutive patients diagnosed with MA in our headache center and undergoing transcranial doppler (TCD) for RLS detection. We collected from our clinical electronic dossiers, clinical features of MA attacks (type, frequency, duration of aura phenomenon, trigger factors, onset age), family history for MA, thrombophilia genotypes, and the response to preventive treatments. RLS was stratified for severity according to the results of the TCD examination. RESULTS: We found 111 patients. Binary logistic regression analysis showed that among features of MA attacks, only onset age was associated with the presence of RLS (p < 0.0001). Patients with RLS presented the first MA attack at a younger age (p < 0.0001). The greater RLS severity, the younger was onset age (p < 0.00001) and the presence of atrial septal aneurysms (ASA) was associated with a further decrease in onset age (ρ = -539, p < 0.00001). Family history for MA was associated with the presence of RLS (chi-square p = 0.022). Response to preventive treatments was not influenced by the type of treatment (antiplatelet compared with no antiplatelet drugs), comorbidity with migraine without aura, RLS presence, or by their double interactions (Logistic regression, consistently p > 0.05). CONCLUSION: Our findings support the hypothesis that although PFO does not influence MA attack frequency, it is not merely a bystander in MA physiopathology, as RLS, its severity, and the presence of ASA possibly make a difference in the disease history.

Effect of desogestrel 75 µg on headache frequency and intensity in women with migraine: a prospective controlled trial.

Objective: In contrast with combined hormonal contraception, progestin-only contraception is not associated with an increase in venous thromboembolism or stroke. Women with migraine are at increased risk of ischaemic stroke. Several studies have reported a reduction in migraine frequency and intensity with desogestrel 75 µg, a progestin-only pill. At present the quality of data is limited by retrospective study designs, lack of control groups and small sample sizes. We present the first prospective nonrandomised controlled trial. Methods: A total of 150 women with migraine visiting our clinic for contraceptive counselling were screened. The intervention group comprised women who opted for contraception with desogestrel (n = 98); the control group comprised women who continued their usual contraceptive (n = 36). Participants completed daily diaries for 90 days before the intervention and 180 days after the intervention. Results: In the intervention group, we found improvements in migraine frequency (p < .001), migraine intensity (p < .001) and the number of triptans used (p < .001). These improvements were already significant after 90 days of desogestrel use (p < .001). Disability scores also decreased significantly. No improvement was seen in the nonintervention group. Conclusion: These data demonstrate for the first time in a prospective controlled setting that daily use of the progestin desogestrel is associated with a decrease in migraine frequency, migraine intensity and pain medication use in women with migraine, with and without aura, who had previously been experiencing at least three days of migraine per month. Trial registration: The study is registered in the University of Zürich database ( www.research-projects.uzh.ch/unizh.htm ).

Preventive Treatment with Lomerizine Increases Cerebral Blood Flows during the Interictal Phase of Migraine.

BACKGROUND: Changes in regional cerebral blood flow (rCBF) were reported in migraineurs. However, little is known how preventive medications of migraine can influence rCBF. Lomerizine, a calcium channel blocker, has been used for migraine prophylaxis in Japan. We examined rCBF after lomerizine treatment. SUBJECTS AND METHODS: Migraine was diagnosed according to the criteria of the International Classification of Headache Disorders, Third Edition beta. Migraine subtype was classified into migraine with aura (MA) and migraine without aura (MO). Lomerizine (10 mg/day, per oral) was administered for 3 months. Headache Impact Test-6 (HIT-6) and blood pressure (BP) were compared at baseline and end point. Brain single photon emission computed tomography using 99mTc-ethyl cysteinate dimer was performed at the interictal period. Brain SPECT data were analyzed according to revised version of 3-dimensional stereotaxic region of interest template. Clinic-radiological variables were analyzed by paired Student's t test. RESULTS: Ten migraineurs (4 men and 6 women) participated in the present study. Mean age was 54.1 (standard deviation [SD] 10.1) years. Mean duration of migraine was 25.3 (SD 9.8) years. Migraine subtype showed 4 MA and 6 MO patients. Mean score of HIT-6 was 66.3 (SD 11.7). Lomerizine treatment decreased HIT-6 scores significantly (P < .01). BP did not differ significantly after lomerizine treatment. Lomerizine treatment increased rCBF 20% approximately in the frontal, the parietal, the temporal, and the occipital region. CONCLUSIONS: The present study indicated a significant increase in interictal rCBF after lomerizine treatment in migraineurs. The upregulation of rCBF could contribute to the antimigraine mechanism of lomerizine.

Combined hormonal contraceptives and migraine: An update on the evidence.

Combined hormonal contraceptives are contraindicated in women who have migraine with aura, in whom these drugs can increase the risk of ischemic stroke. However, this contraindication is based on data from the 1960s and 1970s, when oral contraceptives contained much higher doses of estrogen. Stroke risk is not significantly increased with today's preparations, many of which contain less than 30 µg of ethinyl estradiol. Further, in continuous regimens, ultra-low-dose formulations--those that contain less than 20 µg of ethinyl estradiol--may help prevent menstrual migraine and reduce the frequency of aura.

Migraine and percutaneous patent foramen ovale closure: a systematic review and meta-analysis.

BACKGROUND: The association between patent foramen ovale (PFO) and migraine with aura (MA) is well established. However, the benefits of PFO closure are less certain in patients with migraine without aura (MwoA). METHODS: We systematically searched Pubmed for pertinent clinical studies published from January 2000 to July 2015. The primary end-point was the elimination or significant improvement of migraine symptoms after PFO closure. RESULTS: Upon screening an initial list of 315 publications, we identified eight studies that included 546 patients. Overall, our analysis indicated a significant improvement of migraine in 81% of MA cases compared to only 63% of MwoA cases. The summary odds ratio was 2.5 (95% confidence interval 1.09-5.73), and the benefits of PFO closure were significantly greater for patients with MA compared to patients with MwoA (P = 0.03). CONCLUSIONS: The presence of aura provides a reference standard for the clinical selection of patients with migraine for PFO closure intervention.

Acupuncture for the prevention of episodic migraine.

BACKGROUND: Acupuncture is often used for migraine prevention but its effectiveness is still controversial. We present an update of our Cochrane review from 2009. OBJECTIVES: To investigate whether acupuncture is a) more effective than no prophylactic treatment/routine care only; b) more effective than sham (placebo) acupuncture; and c) as effective as prophylactic treatment with drugs in reducing headache frequency in adults with episodic migraine. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL: 2016, issue 1); MEDLINE (via Ovid, 2008 to January 2016); Ovid EMBASE (2008 to January 2016); and Ovid AMED (1985 to January 2016). We checked PubMed for recent publications to April 2016. We searched the World Health Organization (WHO) Clinical Trials Registry Platform to February 2016 for ongoing and unpublished trials. SELECTION CRITERIA: We included randomized trials at least eight weeks in duration that compared an acupuncture intervention with a no-acupuncture control (no prophylactic treatment or routine care only), a sham-acupuncture intervention, or prophylactic drug in participants with episodic migraine. DATA COLLECTION AND ANALYSIS: Two reviewers checked eligibility; extracted information on participants, interventions, methods and results, and assessed risk of bias and quality of the acupuncture intervention. The primary outcome was migraine frequency (preferably migraine days, attacks or headache days if migraine days not measured/reported) after treatment and at follow-up. The secondary outcome was response (at least 50% frequency reduction). Safety outcomes were number of participants dropping out due to adverse effects and number of participants reporting at least one adverse effect. We calculated pooled effect size estimates using a fixed-effect model. We assessed the evidence using GRADE and created 'Summary of findings' tables. MAIN RESULTS: Twenty-two trials including 4985 participants in total (median 71, range 30 to 1715) met our updated selection criteria. We excluded five previously included trials from this update because they included people who had had migraine for less than 12 months, and included five new trials. Five trials had a no-acupuncture control group (either treatment of attacks only or non-regulated routine care), 15 a sham-acupuncture control group, and five a comparator group receiving prophylactic drug treatment. In comparisons with no-acupuncture control groups and groups receiving prophylactic drug treatment, there was risk of performance and detection bias as blinding was not possible. Overall the quality of the evidence was moderate. Comparison with no acupunctureAcupuncture was associated with a moderate reduction of headache frequency over no acupuncture after treatment (four trials, 2199 participants; standardised mean difference (SMD) -0.56; 95% CI -0.65 to -0.48); findings were statistically heterogeneous (I² = 57%; moderate quality evidence). After treatment headache frequency at least halved in 41% of participants receiving acupuncture and 17% receiving no acupuncture (pooled risk ratio (RR) 2.40; 95% CI 2.08 to 2.76; 4 studies, 2519 participants) with a corresponding number needed to treat for an additional beneficial outcome (NNTB) of 4 (95% CI 3 to 6); there was no indication of statistical heterogeneity (I² = 7%; moderate quality evidence). The only trial with post-treatment follow-up found a small but significant benefit 12 months after randomisation (RR 2.16; 95% CI 1.35 to 3.45; NNT 7; 95% 4 to 25; 377 participants, low quality evidence). Comparison with sham acupunctureBoth after treatment (12 trials, 1646 participants) and at follow-up (10 trials, 1534 participants), acupuncture was associated with a small but statistically significant frequency reduction over sham (moderate quality evidence). The SMD was -0.18 (95% CI -0.28 to -0.08; I² = 47%) after treatment and -0.19 (95% CI -0.30 to -0.09; I² = 59%) at follow-up. After treatment headache frequency at least halved in 50% of participants receiving true acupuncture and 41% receiving sham acupuncture (pooled RR 1.23, 95% CI 1.11 to 1.36; I² = 48%; 14 trials, 1825 participants) and at follow-up in 53% and 42%, respectively (pooled RR 1.25, 95% CI 1.13 to 1.39; I² = 61%; 11 trials, 1683 participants; moderate quality evidence). The corresponding NNTBs are 11 (95% CI 7.00 to 20.00) and 10 (95% CI 6.00 to 18.00), respectively. The number of participants dropping out due to adverse effects (odds ratio (OR) 2.84; 95% CI 0.43 to 18.71; 7 trials, 931 participants; low quality evidence) and the number of participants reporting adverse effects (OR 1.15; 95% CI 0.85 to 1.56; 4 trials, 1414 participants; moderate quality evidence) did not differ significantly between acupuncture and sham groups. Comparison with prophylactic drug treatmentAcupuncture reduced migraine frequency significantly more than drug prophylaxis after treatment ( SMD -0.25; 95% CI -0.39 to -0.10; 3 trials, 739 participants), but the significance was not maintained at follow-up (SMD -0.13; 95% CI -0.28 to 0.01; 3 trials, 744 participants; moderate quality evidence). After three months headache frequency at least halved in 57% of participants receiving acupuncture and 46% receiving prophylactic drugs (pooled RR 1.24; 95% CI 1.08 to 1.44) and after six months in 59% and 54%, respectively (pooled RR 1.11; 95% CI 0.97 to 1.26; moderate quality evidence). Findings were consistent among trials with I² being 0% in all analyses. Trial participants receiving acupuncture were less likely to drop out due to adverse effects (OR 0.27; 95% CI 0.08 to 0.86; 4 trials, 451 participants) and to report adverse effects (OR 0.25; 95% CI 0.10 to 0.62; 5 trials 931 participants) than participants receiving prophylactic drugs (moderate quality evidence). AUTHORS' CONCLUSIONS: The available evidence suggests that adding acupuncture to symptomatic treatment of attacks reduces the frequency of headaches. Contrary to the previous findings, the updated evidence also suggests that there is an effect over sham, but this effect is small. The available trials also suggest that acupuncture may be at least similarly effective as treatment with prophylactic drugs. Acupuncture can be considered a treatment option for patients willing to undergo this treatment. As for other migraine treatments, long-term studies, more than one year in duration, are lacking.

Safety and efficacy of melatonin in pediatric migraine prophylaxis.

OBJECTIVE: Preventive therapy in migraine must be started with frequent or disabling headaches in children, while, no drugs have been approved for migraine preventive therapy of them up to now. The aim of the present research was to investigate safety and efficacy of melatonin in pediatric migraine prophylaxis. METHODS: In a quasi- experimental study, monthly frequency, severity and duration of headache, migraine disability and clinical side effects in sixty migraineur referred children to Pediatric Neurology Clinic of Shahid Sadoughi Medical Sciences University, Yazd, Iran from January to June 2013 whom were treated with single dose of 0.3 mg/kg melatonin for three months, were evaluated. RESULTS: Thirty two (53.3%) girls and 28(46.7%) boys with mean age of 10.31 ± 2.39 years were evaluated, 38 of whom (63.3%) had migraine without aura. Clinical adverse events were seen in 23.3% (N=14) of children including sleepiness in seven, vomiting in four, mild hypotension in two and constipation in one child. Excessive daytime sleepiness as a serious side effect was seen in three children which caused the drug use to be stopped. Monthly frequency, severity and duration of headache reduced from 15.63 ± 7.64 to 7.07 ± 4.42 attacks, from 6.20 ± 1.67 to 3.55 ± 2.11 scores, and from 2.26 ± 1.34 to 1.11 ± 0.55 hours, respectively. Pediatric Migraine Disability Assessment score decreased from 31.72 ± 8.82 to 17.78 ± 10.64. (All p < 0.05). CONCLUSION: Melatonin might be considered as an effective and without life-threatening side effects drug in prophylaxis of migraine in children.

The premonitory phase of migraine and migraine management.

OBJECTIVE: The objective was to determine, through a literature review, whether treatment during the premonitory phase of migraine is a potentially useful migraine management strategy. METHODS: A general literature review was done with regard to the nature of migraine premonitory symptoms, their frequency, their reliability in predicting migraine attacks, and the effectiveness of medication treatment when given during the premonitory phase. RESULTS: Many different symptoms have been reported as premonitory symptoms that occur before migraine attacks. Up to 87% of patients with migraine may experience premonitory symptoms, although some studies have provided estimates as low as 33%. In selected patients, premonitory symptoms may be relatively reliable predictors of a migraine attack to follow. Both naratriptan (open-label study) and domperidone (double-blind, randomized, placebo-controlled study) have been reported to be effective when given during the premonitory phase. CONCLUSIONS: More research is needed, but there is some evidence that medication treatment during the premonitory phase has the potential to be helpful in selected patients with migraine.

Headache direction and aura predict migraine responsiveness to rimabotulinumtoxin B.

OBJECTIVE: To report a retrospective analysis of patients with migraine headaches treated with rimabotulinumtoxin B as preventive treatment, investigating an association between clinical responsiveness with migraine directionality and migrainous aura. BACKGROUND: The Phase III Research Evaluating Migraine Prophylaxis Therapy studies demonstrated onabotulinumtoxin A is effective in the preventive management of chronic migraine headaches. Jakubowski et al reported greater response to onabotulinumtoxin A in migraine patients reporting inward-directed head pain (imploding or ocular) compared with outward-directed head pain (exploding), suggesting subpopulations of patients may be better candidates for its use. No correlation was found between those reporting migrainous aura and onabotulinumtoxin A responsiveness. METHODS: One hundred twenty-eight migraine patients were identified who had received rimabotulinumtoxin B injections over an average of 22 months, or 7 injection cycles. Migraine directionality was reported as inward directed (imploding, n = 72), eye centered (ocular, n = 28), outward directed (exploding, n = 16), and mixed (n = 12). RESULTS: One hundred two out of one hundred twenty-eight patients (80%) improved; of these, 58 (57%) demonstrated a >75% reduction in monthly headache frequency (">75%-responders"), 76% of which noted sustained benefits >12 months with repeated injections every 10-12 weeks. Those reporting ocular- and imploding-directed headaches were significantly more likely to be >75%-responders, compared with exploding- and mixed-directed headaches (P < .0025). Patients with ocular-directed headaches were most likely to be sustained >75%-responders. Patients reporting migrainous aura were more likely to be >75%-responders (P = .0007). Those reporting exploding- and mixed-directed headaches were more likely to be nonresponders (P < .0001). CONCLUSIONS: Reported migraine directionality and presence of migrainous aura predict migraine headache responsiveness to rimabotulinumtoxin B injections.

The effect of patent foramen ovale closure on visual aura without headache or typical aura with migraine headache.

OBJECTIVES: The aim of this study was to assess the prevalence of right-to-left (R to L) shunt in patients with visual aura and evaluate the effect of shunt closure on resolution of aura. BACKGROUND: Right-to-left shunting is associated with migraine headache (MH) with aura. Some patients present with visual aura without headaches. It is unclear whether visual aura without headache is a form of migraine or a transient neurologic dysfunction. METHODS: Of patients referred to the University of California, Los Angeles for suspected patent foramen ovale (PFO), 225 had visual aura with or without MH. Patients were assessed for a shunt and evaluated for MH and/or visual aura. They were divided into 3 groups: 1) visual aura associated with MH; 2) visual aura unrelated in time to MH; and 3) visual aura without MH. The frequency of R to L shunt was compared with a control group of 200 patients. Eighty patients underwent PFO closure. Residual shunts, MH, and visual aura were reassessed after 3 and 12 months. RESULTS: The prevalence of R to L shunt in Groups A, B, and C was 96%, 72%, and 67%, respectively, versus 18% in the control group (p < 0.0001). The frequency of shunting was similar in Group B versus Group C, but much higher in all 3 groups compared with control subjects. Twelve months after PFO closure, symptoms of aura were resolved in 52%, 75%, and 80% of patients in Groups A, B, and C, respectively (p = NS). CONCLUSIONS: The similar distribution of R to L shunting in all 3 patient groups and the correlation between PFO closure and improvement of aura suggests a similar pathophysiology between the presence of PFO and the visual aura phenomenon, whether or not headache is present in the symptom complex.

[Gap junctional intercellular communication: a new mechanism in pathophysiology of migraine with aura. Therapeutic applications]. / La communication intercellulaire par l'intermédiaire des jonctions gap: un nouveau mécanisme dans la physiopathologie de la migraine avec aura. Applications thérapeutiques.

Migraine is a common, recurrent and disabling primary headache disorder, which affects up to 20% of the population. About a third of patients with migraine have attacks with aura, a focal neurological disturbance that manifests itself as visual, sensitive or motor symptoms. Cortical spreading depression, a wave of electrical activity that moves across the cerebral cortex through neuronal-glial cell gap junctions, would be involved in the triggering of migraine aura. Moreover, cortical spreading depression activates perivascular trigeminal afferents in the neocortex, that through central and peripheral reflex, cause inflammatory reaction in the meninges to generate the headache. Tonabersat, a novel benzopyran compound, was selected for clinical trial on the basis of its inhibitory activity on cortical spreading depression and neurogenic inflammation in animal models of migraine. Moreover, tonabersat inhibited trigeminal ganglion neuronal-glial cell gap junctions, suggesting that this compound could prevent peripheral sensitization within the ganglion. In clinical trial, tonabersat showed a preventive effect on attacks of migraine with aura but had no efficacy on non-aura attacks and in the acute treatment of migraine. In conclusion, neuronal-glial cell gap junctional intercellular communication seems to be involved in the pathophysiology of migraine with aura and is emerging as a new promising therapeutic target for prophylactic treatment of patients with chronic attacks.

Suppressive effect of chronic peroral topiramate on potassium-induced cortical spreading depression in rats.

OBJECTIVE: To evaluate the chronic effect of topiramate (TPM) on cortical spreading depression (CSD), which is thought to be related to migraine aura. METHODS: Male rats (n = 30) were randomized to once-daily peroral treatment with TPM (50, 100, 200 or 600 mg/kg) or vehicle for 6 weeks. We evaluated the characteristics of CSD induced by topical application of KCl under isoflurane anesthesia and the changes in plasma level of TPM in each group. The effect of single administration of TPM on CSD was also evaluated. RESULTS: After the final administration of TPM, when the plasma level of TPM was high, KCl-induced CSD frequency and CSD propagation velocity were dose-dependently reduced and the interval between CSD episodes was elongated, compared with the vehicle control. However, before the final administration of TPM, when the plasma level was very low, the KCl-induced CSD profile was the same as that in the vehicle control. Single administration of TPM did not alter the CSD profile. Local cerebral blood flow was not significantly altered by chronic administration of TPM. CONCLUSION: TPM suppressed the frequency and propagation of CSD along the cerebral cortex, and might be a candidate for relief of migraine.