Effect of noninvasive vagus nerve stimulation on acute migraine: an open-label pilot study.

BACKGROUND: We sought to assess a novel, noninvasive, portable vagal nerve stimulator (nVNS) for acute treatment of migraine. METHODS: Participants with migraine with or without aura were eligible for an open-label, single-arm, multiple-attack study. Up to four migraine attacks were treated with two 90-second doses, at 15-minute intervals delivered to the right cervical branch of the vagus nerve within a six-week time period. Subjects were asked to self-treat at moderate or severe pain, or after 20 minutes of mild pain. RESULTS: Of 30 enrolled patients (25 females, five males, median age 39), two treated no attacks, and one treated aura only, leaving a Full Analysis Set of 27 treating 80 attacks with pain. An adverse event was reported in 13 patients, notably: neck twitching (n = 1), raspy voice (n = 1) and redness at the device site (n = 1). No unanticipated, serious or severe adverse events were reported. The pain-free rate at two hours was four of 19 (21%) for the first treated attack with a moderate or severe headache at baseline. For all moderate or severe attacks at baseline, the pain-free rate was 12/54 (22%). CONCLUSIONS: nVNS may be an effective and well-tolerated acute treatment for migraine in certain patients.

Symptoms of cutaneous sensitivity pre-treatment and post-treatment: results from the rizatriptan TAME studies.

The presence of cutaneous allodynia may predict response to triptans. Identical randomized double-blind studies were conducted comparing the efficacy of rizatriptan 10 mg or placebo administered within 1 h of headache onset, while pain was mild. The primary endpoint was freedom from pain at 2 h. Presence of symptoms suggesting cutaneous sensitivity (SCS) at baseline and at 2 h post-treatment was recorded. Before treatment, 29% of rizatriptan patients and 22% of placebo patients reported SCS. At 2 h, the percentage of patients with SCS was significantly decreased with rizatriptan. The presence of SCS pre-treatment was not predictive of response to rizatriptan. Most patients with SCS at 2 h were non-responders. Early treatment with rizatriptan significantly reduced the percentage of patients with SCS at 2 h. The presence of SCS at baseline did not predict pain-free response, but presence of SCS at 2 h correlated with lack of a 2-h pain-free response.

Vagus nerve stimulation relieves chronic refractory migraine and cluster headaches.

Anticonvulsant and antidepressant medications have demonstrated efficacy in migraine treatment. Vagus nerve stimulation (VNS) is an effective treatment for drug-refractory epilepsy and possibly depression and it also has documented analgesic effects. These observations suggested a possible role for VNS in treating severe refractory headaches, and led to a trial of VNS in patients with such headaches. VNS was implanted in four men and two women with disabling chronic cluster and migraine headaches. In one man and one woman with chronic migraines VNS produced dramatic improvement with restoration of ability to work. Two patients with chronic cluster headaches had significant improvement of their headaches. VNS was well tolerated in five patients, while one developed nausea even at the lowest current strength. In conclusion, VNS may be an effective therapy for intractable chronic migraine and cluster headaches and deserves further trials.

Petasites hybridus root (butterbur) is an effective preventive treatment for migraine.

OBJECTIVE: To evaluate the clinical efficacy of a standardized special root extract from the plant Petasites hybridus as a preventive therapy for migraine. METHODS: This is a three-arm, parallel-group, randomized trial comparing Petasites extract 75 mg bid, Petasites extract 50 mg bid, or placebo bid in 245 patients with migraine. Eligible patients met International Headache Society criteria for migraine, were ages 18 to 65, and had at least two to six attacks per month over the preceding 3 months. The main outcome measure was the decrease in migraine attack frequency per month calculated as percentage change from baseline over a 4-month treatment period. RESULTS: Over 4 months of treatment, in the per-protocol analysis, migraine attack frequency was reduced by 48% for Petasites extract 75 mg bid (p = 0.0012 vs placebo), 36% for Petasites extract 50 mg bid (p = 0.127 vs placebo), and 26% for the placebo group. The proportion of patients with a > or =50% reduction in attack frequency after 4 months was 68% for patients in the Petasites extract 75-mg arm and 49% for the placebo arm (p < 0.05). Results were also significant in favor of Petasites 75 mg at 1, 2, and 3 months based on this endpoint. The most frequently reported adverse reactions considered possibly related to treatment were mild gastrointestinal events, predominantly burping. CONCLUSIONS: Petasites extract 75 mg bid is more effective than placebo and is well tolerated as a preventive therapy for migraine. Petasites 50 mg PO bid was not significantly more effective than placebo on the primary study endpoints.

Alternative therapies in headache. Is there a role?

Alternative or complementary modes of treatment often lack scientific proof of efficacy. This is true for many drugs that are used for prophylaxis of headaches as well. Many of these complementary modes are inexpensive, harmless, and possibly effective. Patients can be given a list of options in the following order of clinician preference: aerobic exercise; isometric neck exercise; biofeedback; a combination product containing magnesium, riboflavin, and feverfew; and acupuncture. The patient must decide which of these approaches is appealing, affordable, and realistically doable.

Zolmitriptan provides consistent migraine relief when used in the long-term.

Migraine is a chronic disease that significantly reduces quality of life between, as well as during, attacks. Treatments that provide consistent relief may reduce the burden of the disease. In the open-label phase of a two-part study, patients could choose to treat initial, persistent or recurrent migraine headache of any intensity with 2.5 mg or 5 mg zolmitriptan. This novel study design allowed patients to manage and maximise their migraine relief. Headache response rates and pain-free response rates were assessed within two hours of dosing with zolmitriptan, and response rates were compared across migraines with and without a history of aura, and associated or not with menses. Consistency of response was also assessed in those patients treating at least 20 attacks. Of 49,784 attacks treated, 66% (32,737 attacks) were treated with a single dose of zolmitriptan. Two-hour headache response rates to an initial dose of 2.5 mg or 5 mg zolmitriptan were 85% (median 95%) and 79% (median 88%), respectively, across all attacks. Corresponding pain-free response rates were 69% and 59%. Responses were independent of gender and age and were similar in patients with and without aura and in attacks associated or not associated with menses. Consistent response rates were achieved within individual patients; during months 1 to 3, 64% of patients reported a headache response in > 75% of their migraine attacks. In patients treating at least 20 attacks, 2.5 mg and 5 mg zolmitriptan produced consistently high headache response rates (range 84-91% and 76-84%, respectively) and pain-free response rates (range 70-76% and 58-65%, respectively) across attacks. In the minority of attacks requiring a second dose of zolmitriptan for persistent or recurrent headache, response rates to a second dose were also consistent across attacks. In conclusion, zolmitriptan 2.5 mg and 5 mg show consistent effectiveness in the treatment of multiple migraine attacks in individual patients and are unaffected by gender, age and the presence of aura or the relationship to menses.

Zolmitriptan is effective for the treatment of persistent and recurrent migraine headache.

Zolmitriptan is a 5-HT1B/1D receptor agonist for the acute treatment of migraine. This study examined the efficacy of a second dose of zolmitriptan for the treatment of persistent or recurrent headache. Part 1 was a randomised, placebo-controlled, double-blind evaluation of 2.5 mg and 5 mg zolmitriptan for the treatment of persistent migraine headache, two hours after an initial dose of 2.5 mg zolmitriptan. In part 2 (open-label), patients treated the first two attacks with 2.5 mg zolmitriptan, thereafter patients could treat any initial, persistent or recurrent migraine headache with 2.5 mg or 5 mg zolmitriptan. The unique design of this trial allowed patients to adjust their treatment to attain maximum headache relief and control of their disease. Of 2800 patients treating an initial migraine headache in Part 1, 989 patients took a second dose to treat persistent headache of moderate or severe intensity. Headache response rates were similar across the three treatment groups, but the pain-free response rate was significantly higher with 5 mg zolmitriptan than with placebo (p < 0.001). In Part 2, 2499 patients treated 49,784 migraine attacks (excluding the first two attacks, which had to be treated with 2.5 mg zolmitriptan), of which 66% required only a single dose of zolmitriptan. Patients treated 22% of attacks with a second dose of zolmitriptan for persistent headache. A headache response was achieved in 80% and 73% of persistent headaches treated with 2.5 mg or 5 mg zolmitriptan, respectively. Corresponding pain-free responses following treatment of persistent headaches of any intensity were 64% and 52%. Eight per cent of attacks were treated with a second dose of zolmitriptan for moderate or severe recurrent headache. A headache response was achieved in 90% and 86% of moderate/severe attacks, with a pain-free response in 78% and 70% of attacks of any intensity treated with 2.5 mg and 5 mg, respectively. Zolmitriptan was well tolerated. In conclusion, 2.5 mg and 5 mg zolmitriptan are highly effective in treating both persistent and recurrent migraine headache.

Role of magnesium in the pathogenesis and treatment of migraines.

The importance of magnesium in the pathogenesis of migraine headaches is clearly established by a large number of clinical and experimental studies. However, the precise role of various effects of low magnesium levels in the development of migraines remains to be discovered. Magnesium concentration has an effect on serotonin receptors, nitric oxide synthesis and release, NMDA receptors, and a variety of other migraine related receptors and neurotransmitters. The available evidence suggests that up to 50% of patients during an acute migraine attack have lowered levels of ionized magnesium. Infusion of magnesium results in a rapid and sustained relief of an acute migraine in such patients. Two double-blind studies suggest that chronic oral magnesium supplementation may also reduce the frequency of migraine headaches. Because of an excellent safety profile and low cost and despite the lack of definitive studies, we feel that a trial of oral magnesium supplementation can be recommended to a majority of migraine sufferers. Refractory patients can sometimes benefit from intravenous infusions of magnesium sulfate.

Intravenous magnesium sulfate rapidly alleviates headaches of various types.

BACKGROUND: Circumstantial evidence points to the possible role of magnesium deficiency in the pathogenesis of headaches and has raised questions about the clinical utility of magnesium as a therapeutic regimen in some headaches. METHODS: We evaluated the efficacy of intravenous infusion of 1 gram of magnesium sulfate (MgSO4) for the treatment of patients with headaches and attempted to correlate clinical responses to the basal serum ionized magnesium (IMg2+) level. We also determined if patients with certain headache types exhibit low serum IMg2+ as opposed to total serum magnesium. Using a case-control comparison at an outpatient headache clinic, a consecutive sample of patients presenting with a moderate or severe headache of any type were included in the study. Of the 40 patients in the study (mean age 38.2 +/- 9.4 years; range 14 to 55; 11 men [39.2 +/- 7.3 years] and 29 women [37.8 +/- 10.2 years]), 16 patients had migraines without aura, 9 patients had cluster headaches, 4 patients had chronic tension-type headaches, and 11 had chronic migrainous headaches. Total serum magnesium was measured with atomic absorption spectroscopy and a Kodak Ektachem DT-60. Sensitive ion selective electrodes were utilized to measure serum IMg2+ and ionized calcium (ICa2+); ICa2+/IMg2+ ratios were calculated. RESULTS: Complete elimination of pain was observed in 80% of the patients within 15 minutes of infusion of MgSO4. No recurrence or worsening of pain was observed within 24 hours in 56% of the patients. Patients treated with MgSO4 observed complete elimination of migraine-associated symptoms such as photophobia and phonophobia as well as nausea. Correlation was noted between immediate and 24-hour responses with the serum IMg2+ levels. Immediate pain relief was observed in 32 (80%) of 40 patients (P < 0.001). In 18. of the 32 patients, pain relief persisted for at least 24 hours (P < 0.005). Of these 18 patients, 16 (89%) had a low serum IMg2+ level. Total magnesium levels in contrast in all subjects were within normal range (0.70-0.99 mmol/L). No side effects were observed, except for a brief flushed feeling. Of the 8 patients with no relief, only 37.5% had a low IMg2+ level. Patients demonstrating no return of headache or associated symptoms within 24 hours of intravenous MgSO4 exhibited the lowest initial basal levels of IMg2+. Non-responders exhibited significantly elevated total magnesium levels compared to responders. Although most subcategories of headache types investigated (ie, migraine, cluster, chronic migrainous) exhibited low serum IMg2+ during headache and prior to intravenous MgSO4, the patients with cluster headaches exhibited the lowest basal levels of IMg2+ (P < 0.01). All headache subjects except for the chronic tension group exhibited rather high serum ICa2+/IMg2+ ratios (P < 0.01, compared to controls). CONCLUSIONS: Intravenous infusion of 1 gram of MgSO4 results in rapid relief of headache pain in patients with low serum IMg2+ levels. Measurement of serum IMg2+ levels may have a practical application in many types of headache patients. Low serum and brain tissue ionized magnesium levels may precipitate headache symptoms in susceptible patients.

Intravenous magnesium sulphate relieves migraine attacks in patients with low serum ionized magnesium levels: a pilot study.

1. We tested the hypothesis that patients with an acute attack of migraine headache and low serum levels (< 0.54 mmol/l) of ionized magnesium are more likely to respond to an intravenous infusion of magnesium sulphate (MgSO4) than patients with higher serum ionized magnesium levels. 2. Serum ionized magnesium levels were drawn immediately before infusion of 1 g of MgSO4 in 40 consecutive patients with an acute migraine headache. 3. Pain reduction of 50% or more as measured on a headache intensity verbal scale of 1 to 10, occurred within 15 min of infusion in 35 patients. In 21 patients, at least this degree of improvement or complete relief persisted for 24h or more. Pain relief lasted at least 24h in 18 of 21 patients (86%) with serum ionized magnesium levels below 0.54 mmol/l, and in 3 of 19 patients (16%) with ionized magnesium levels at or above 0.54 mmol/l (P < 0.001). Mean ionized magnesium levels in patients with relief lasting for at least 24h were significantly lower than in patients with no relief or brief relief (P < 0.01). 4. Measurement of serum ionized magnesium levels may be useful in identifying patients with migraine headaches who may respond to an intravenous infusion of MgSO4.

Intravenous magnesium sulfate relieves cluster headaches in patients with low serum ionized magnesium levels.

Patients with cluster headaches have been reported to have low serum ionized magnesium levels. We examined the possibility that patients with cluster headaches and low ionized magnesium levels may respond to an intravenous infusion of magnesium sulfate. Thirty-eight infusions of magnesium sulfate were given to 22 patients with cluster headaches. The mean ionized magnesium level prior to 23 infusions which provided relief for at least 2 days and enabled the patient to skip two or more attacks, was 0.521 +/- 0.016 mmol/L; this value was 0.561 +/- 0.016 prior to 15 infusions which were ineffective. These latter 15 infusions were preceded by higher total magnesium levels. The ionized magnesium level prior to the 23 effective infusions was below 0.54 mmol/L in 19 patients. Five of the 15 ineffective infusions were accompanied by basal ionized magnesium levels below 0.54 mmol/L. In 76% of the infusions, there was a correlation between a response and an ionized magnesium level below 0.54 mmol/L. Nine patients (41%) obtained clinically meaningful improvement. Spontaneous remissions and a placebo effect might have accounted for some of the improvement. However, this should have applied equally to all patients, regardless of the ionized magnesium level. Measurements of ionized magnesium may prove useful in elucidating the pathogenesis of cluster headache and in identifying patients who may benefit from treatment with magnesium.

Chronic daily headache--one disease or two? Diagnostic role of serum ionized magnesium.

The entity of chronic daily headache (CDH) is well documented, but is not included in the current classification. We divided patients with CDH into groups with and without migrainous features. This division resulted in clearly distinguishable syndromes of daily migrainous headaches (DMH) and daily tension-type headaches (DTH). Family history of headaches was more common in patients with DMH. Patients in both groups had a high incidence of caffeine or drug overuse. The clinical division into DMH and DTH was supported by our finding of a higher incidence of disturbed magnesium (Mg) metabolism in patients with DMH. Of 26 patients with DMH, 8 (30.8%) had low serum ionized, but not total, Mg levels, and 16 (61.5%) had high ionized calcium/magnesium ratios. The corresponding numbers for the 22 patients with DTH were 1 (4.5%) and 8 (36.4%). These new laboratory measurements offer possible biological markers for the diagnosis of different headache syndromes.

Clinical studies with the NOVA ISE for IMg2+.

The Nova ISE for IMg2+ was utilized to examine IMg2+ in plasma and serum of patients with a variety of pathophysiologic and disease syndromes (e.g., long-term renal transplants [LTRT], during and before cardiac surgery, migraine headaches, head trauma, pregnancy, chronic fatigue syndrome [CFS], non-insulin dependent diabetes mellitus [NIDDM], asthma and after excessive dietary intake of Mg). The results indicate that LTRT treated with cyclosporin A, migraine, head trauma, pregnancy, NIDDM, diseased pregnant, and asthmatic patients all on the average, exhibit significant depression in IMg2+ but not total Mg (TMg). Patients with CFS failed to exhibit changes in serum IMg2+ or TMg levels. Increased dietary load of Mg, for only 6 days, resulted in significant elevations of serum IMg2+ but not TMg. Correlations between the clinical course of several of these syndromes and the fall in IMg2+ were found. The Ca2+/Mg2+ ratio appears to be an important guide for signs of peripheral vasoconstriction and or spasm and possibly enhanced atherogenesis. Overall, the data point to important uses for ISE's for IMg2+ in the diagnosis and treatment of disease states.

Trigeminal neuralgia (tic douloureux).

Trigeminal neuralgia is not common, but is a debilitating pain syndrome. After the diagnosis is established, a stepwise approach to treatment is recommended. Carbamazepine is the drug of choice. When carbamazepine fails to relieve pain, baclofen and then phenytoin are used. A number of second-line drugs, such as clonazepam, divalproex sodium, chlorphenesine carbamate, and pimozide can also be tried. A large number of patients will respond to one or another drug or to a combination of two drugs. When medical treatment fails, several surgical procedures have been found to be effective. Percutaneous radiofrequency gangliolysis is the most widely used procedure with a high success rate. All surgical procedures must be performed by an experienced physician in order to achieve the lowest possible rate of serious complications.

Deficiency in serum ionized magnesium but not total magnesium in patients with migraines. Possible role of ICa2+/IMg2+ ratio.

It has been suggested that magnesium (Mg) may play a role in the pathogenesis of headaches. Serum and intracellular measurements of Mg in headache patients have produced inconsistent results. The recent development of an ion-selective electrode for Mg2+ allowed precise measurement of serum ionized magnesium (IMg2+) in patients with various headache syndromes. Low serum IMg2+ and a high ICa2+/IMg2+ ratio were found in 42% of patients having an attack of migraine, but only in 23% of patients with a severe continuous headache. Total serum Mg was normal in both groups of patients. However, in patients with low serum IMg2+ total serum Mg was lower than in patients with normal serum IMg2+. These results are compatible with the serotonin and vascular concepts of migraine pathogenesis. Low IMg2+ and a high ICa2+/IMg2+ would result in cerebral vasospasm and reduced blood flow in the brain. The activity of serotonin receptors can also be affected by changes in IMg2+ levels. The finding of a difference in IMg2+ levels in two different headache types suggests a possible novel classification of headaches and that migraine patients with a low serum IMg2+ or a high ICa2+/IMg2+ ratio may benefit from Mg supplementation.

Cerebral infarction and subdural hematoma. Advantage of nuclear magnetic resonance imaging in cerebral ischemia.

Visual hallucinations were the initial complaints in a patient with a posterior cerebral artery occlusions who fell and sustained bilateral subdural hematomas. In addition to poor vision, the patient experienced formed visual hallucinations of the epileptic type in the hemianopic field. The hemianopia was dense with macular sparing. CAT scans, which were done pre- and postoperatively, showed no abnormalities in the temporal and occipital lobes to explain the "epileptic visual hallucinations" and macular sparing. The NMR scan showed low-density changes in those areas. At the time that the NMR scan was done, most of the patient's deficits, including the hemianopia and hallucinations, had resolved.