News 25/08/2544

News 25/08/2544

CONFERENCE REPORT - UPDATE ON MIGRAINE HEADACHE: REPORT FROM IHC 2001

Conference Report
Update on Migraine Headache: Report from IHC 2001

IHC 2001: The 10th Congress of the International Headache Society
June 29-July 2, 2001
New York, NY

Introduction

The 10th Congress of the International Headache Society (IHS) was held from June 29 to July 2, 2001 in New York City. Selected presentations regarding migraine with aura, acute treatment, preventive treatment, chronic daily headache, and pathophysiology are reviewed in this report.

Migraine With Aura Including Familial Hemiplegic Migraine and Cluster Headache

Migraine With Aura

There are very few published reports on the clinical features of the headache phase of migraine with aura. The IHS diagnostic criteria for migraine with aura do not mention any headache features. Cologno and colleagues^[1] conducted a prospective study on a consecutive series of 32 patients (22 women and 10 men) with migraine with aura at the Headache Center of the University of Parma Institute of Neurology, Parma, Italy. Six patients who had migraine aura without headache were excluded. In the remaining 26 patients (18 women and 8 men), the duration of the headache phase was less than 24 hours in 23 patients (88.5%). Pain intensity was severe in 13 patients (50.0%). The location of pain was bilateral in 14 patients (53.8%); only 1 patient of 12 had unilateral pain on the side opposite to the aura. These investigators compared the clinical features of the headache phase using IHS criteria for migraine without headache with clinical features of episodic tension-type headache. The headache phase was consistent with the IHS diagnostic criteria for:

Migraine without aura in 7 patients (26.9%)
Migrainous disorder not fulfilling above criteria in 3 patients (11.5%)
Tension-type headache in 6 patients (23.1%)
Tension-type disorder not fulfilling above criteria in 4 patients (15.4%)

The clinical features of the headache phase of migraine with aura vary widely among patients, and in only 50% of cases does the headache phase fulfill the IHS diagnostic criteria for migraine without aura.

Familial Hemiplegic Migraine

Familial hemiplegic migraine is a rare autosomal dominant migraine-with-aura subtype. In this subtype, missense mutations in the CACNA1A gene on chromosome 19, which encode the alpha_1A subunit of the P/Q-type calcium channel, are present in approximately half of the families. The T666M mutation is the most common and has been reported in 13 independent familial hemiplegic migraine families. All families with reported T666M familial hemiplegic migraine have cerebellar ataxia.

In an ongoing genetic screening by Kors from Leiden University Medical Center, The Netherlands, and colleagues from medical centers in the United Kingdom and The Netherlands,^[2] 64 patients with hemiplegic migraine, (33 familial and 31 sporadic cases) underwent CACNA1A mutation analysis. The investigators identified the T666M mutation in 5 unrelated familial hemiplegic migraine families (15% of families) and in 1 apparently sporadic patient with hemiplegic migraine (3% of sporadic cases). Additional cerebellar ataxia was seen in 4of 6 families. In 1 family, not all affected members had hemiparesis during the attacks but rather experienced attacks of confusion, and 1 family displayed progressive cognitive dysfunction.

The T666M mutation is a frequent mutation in the CACNA1A gene as evidenced by 15% of this sample of patients with familial hemiplegic migraine. Notably, a literature review of all mutation analyses of familial hemiplegic migraine families and familial and sporadic cases showed that 19 of 33 families had the T666M CACNA1A mutation. Screening for the T666M mutation should be considered as a first step in patients suspected of having this genetic mutation. The investigators also noted that a considerable heterogeneity was seen among these families, which is likely attributable to other genetic and environmental factors.

Thomsen and associates^[3] from Glostrup University Hospital, Glostrup, Denmark, and Gentofte University Hospital, Hellerup, Denmark, studied the characteristics of aura symptoms and headache in 147 Danish patients with familial hemiplegic migraine. A semistructured telephone interview was conducted in 1881 patients (72% women and 28% men). All patients who had motor symptoms were interviewed and examined by a physician; their relatives were also interviewed (473 individuals).

The aura symptoms included:

Visual, motor, sensory, and aphasic aura in 70% of patients
Visual, sensory in 17%
Sensory, motor, and aphasic aura in 7%
Sensory and motor aura in 4%
Visual and motor aura in 1%
Visual, motor, and aphasic aura in 1%

The median times (minutes) of gradual progression and the median aura durations (minutes) were:

Visual aura -- 10 min (range, 1 to 180)/45 min (range, 1 to 1440)
Sensory aura -- 15 min (range, 1 to 720)/90 min (range, 10 to 2880)
Motor aura -- 15 min (range, 1 to 720)/120 min (range, 10 to 4320)

Median duration for aphasic aura was 60 minutes (range, 5 to 1440), and the most frequently experienced succession of aura symptoms was visual, sensory, motor, and aphasia (63%). Ninety-five percent of patients always experienced a headache during familial hemiplegic migraine attacks. Familial hemiplegic migraine was not seen with motor aura alone and was virtually always associated with other aura symptoms and headache.

Cluster Headache

Prodromal symptoms and aura have been studied extensively in migraine patients, but only a few studies have focused on these symptoms in cluster headache. A group from the Jefferson Headache Center^[4] in Philadelphia, Pennsylvania, recently reported the presence of cluster headache with aura in a small series. Now, Eekers from Atrium Medical Centre, Heerlen, The Netherlands, and coworkers from other Dutch medical centers^[5] assessed prodromal and aura symptoms in cluster headache attacks and periods in a large population of patients with cluster headache. Patients with cluster headache or cluster headache-like syndromes were identified using public announcements and direct mailings to all neurologists (n = 580) and general practitioners (n = 5800) in The Netherlands. This study identified and included 844 men (78%) and 232 women (22%) with IHS-defined cluster headache (male/female ratio 3.6/1).

Six hundred eleven patients (57%) reported 3 classes of prodromal symptoms, preceding the cluster period -- sensory, mood, and autonomic prodromata. Strange, tingling sensations in the area of the eye were reported by 204 patients (33%); 130 (21%) reported these sensations around the nose and 206 (34%) in the area of the neck. Mood prodromata (eg, restlessness and depression) were reported by 409 patients (67%) and autonomic prodromata (eg, nasal congestion, conjunctival injection, and lacrimation) were reported by 385 patients (63%). The period the prodromata preceded the cluster period ranged from 1 day to more than 2 months (median, 7 days). Prodromal symptoms of tingling and a feeling of irritation, which preceded the actual attack by minutes to hours, were reported in 844 patients (78%):

497 (59%) patients reported prodromal symptoms near/around the eye
318 (38%) patients reported prodromal symptoms around
332 (39%) patients experienced prodromal symptoms in the area of the neck

Mood prodromata was reported by 233 (28%) patients, and 188 (22%) reported autonomic phenomena. Two hundred eighty (26%) patients reported aura symptoms; none had migraine with aura in addition to cluster headache. The aura symptoms were categorized as visual (17 patients); sensory (14 patients); aphasia (13 patients); dysarthria (3 patients); or motor (2 patients). This study shows that prodromal symptoms occur more frequently in cluster headache than previously thought and aura does occur in cluster headache and is unrelated to coexistent migraine.

Treatment

Acute

Results of preclinical studies suggest that sumatriptan may not penetrate the brain as well as newer triptans, such as rizatriptan. There is little information, however, about the penetrance of therapeutic doses of these drugs into the central nervous system (CNS) in migraine patients, or the clinical relevance of any differences. Diener from the University of Essen, Essen, Germany, and colleagues^[6] used data from direct head-to-head clinical studies to compare the incidence of CNS adverse events for rizatriptan and sumatriptan. The rates of selected drug-related adverse events are shown in Table 1.

Most adverse events were of short duration and of mild or moderate severity. The investigators concluded that there was no evidence that a "brain-penetrant" triptan (rizatriptan) caused significantly more CNS adverse events than a "less brain-penetrant" triptan (sumatriptan). To the contrary, sumatriptan 100 mg was associated with slightly more CNS adverse events than rizatriptan 10 mg.

Triptans are effective, well-tolerated, rapid-acting drugs for the treatment of migraine attacks; however, headache recurrence is a common problem with triptans. Gobel and colleagues^[7] from the Kiel Pain Clinic, Kiel, Germany examined whether naratriptan 2.5 mg plus naproxen 500 mg can reduce the rate of headache recurrence vs naratriptan alone. The half-life of the nonsteroidal anti-inflammatory drug naproxen is 12 to 24 hours, which is significantly higher than that of naratriptan (6 hours).

Fifty patients (37 women and 13 men) with IHS-criteria migraine with or without aura treated their next 2 migraine attacks in an open crossover design, with either naratriptan 2.5 mg monotherapy or combination naratriptan 2.5 mg plus naproxen 500 mg. A significant headache reduction (ie, severe/moderate headache to mild/none) was documented after 2 hours in 40% of migraine attacks treated with naratriptan; after 4 hours this increased to 58% (29/50 attacks). A greater reduction in headache was seen with combination naratriptan 2.5 mg plus naproxen 500 mg -- a significant headache reduction was seen in 54% of attacks (27/50 attacks) after 2 hours and in 70% of attacks (35/50 attacks) after 4 hours. Nine patients (31%) had headache recurrence within 24 hours in the naratriptan monotherapy group compared with 4 patients (11.4%) in the naratriptan plus naproxen group. The time to headache recurrence was shorter in the monotherapy group (14.2 hours) than in the combination therapy group (18.4 hours).

The investigators concluded that the combination of a triptan with a long-acting nonsteroidal anti-inflammatory drug appears to augment the overall benefit patients may get from a triptan. They found combination therapy to be especially useful in patients who have long migraine attacks and thus high headache recurrence rates.

Preventive Treatment

Topiramate. Young and colleagues^[8] from Thomas Jefferson University, Philadelphia, Pennsylvania, used a retrospective chart review to determine the efficacy and tolerability of topiramate for episodic and chronic migraine prophylaxis. Seventy-four patients who had been taking topiramate for at least 6 weeks were identified from an electronic medical records system (68 women and 6 men; 50 with chronic migraine and 24 with episodic migraine). Twenty percent of these patients were on monotherapy and 80% were on polytherapy. The mean daily dose of topiramate for all patients was 208 mg and the mean duration of treatment prior to analysis was 133 days.

Mean headache frequency decreased as follows:

All patients -- from 20.6/28 days to 13.6/28 days (P < .001)
Episodic migraine patients -- from 9.9/28 days to 5.1/28 days (P < .02)
Chronic migraine patients -- from 25.7/28 days to 17.7/28 days (P < .01).

Headache frequency declined by at least 50% in:

44.6% of all patients
58.3% of episodic migraine patients
38% of chronic migraine patients

Among participants, 74% reported using less abortive medication; 58% of patients with episodic migraine experienced shorter migraine duration. Six patients discontinued topiramate therapy because of adverse events (2) or lack of efficacy (4). The most common adverse events were paresthesias (25%), cognitive difficulties (15%), dizziness (4%), and nausea (4%). These results show that topiramate is effective in reducing headache frequency, severity, and duration for patients with episodic migraine and chronic migraine. The investigators also noted that psychiatric comorbidity did not affect treatment outcome.

Levetiracetam. Levetiracetam is a new anticonvulsant with an unknown mechanism of action. Krusz^[9] from Anodyne PainCare, Dallas, Texas, treated 30 patients who had chronic refractory headache with levetiracetam in an open-label study. All had responded poorly to previously prescribed anticonvulsants. Each patient had tried at least 2 drugs; 18 patients had tried up to 4 different agents. Twenty-five patients were receiving at least 1 drug when levetiracetam was added (initially 250 mg in the evening, with the dose increased weekly). Krausz used a 1-month run-in period up to 1000 mg twice daily and made further dosage adjustments during active therapy.

After 3 months of active therapy, 14 patients reported a greater than 50% reduction in their migraine frequency and severity. In some patients, dosage was adjusted to 4500 mg/day (in 2-3 doses). Twelve patients were able to discontinue or taper most of their prior preventive medications; 4 patients had a 25% to 50% decrease in their headache patterns; and 4 are in the run-in phase. Eight patients had no response or discontinued the medication because of adverse events (n = 3). The preliminary results from this ongoing study suggest that levetiracetam may add a new migraine prophylaxis strategy to existing available neuronal stabilizing agents.

Coenzyme Q10. The precise cause of migraine is unknown, however, magnetic resonance spectroscopy and DNA analyses suggest that in some individuals, migraine is a direct result of mitochondrial impairment. Coenzyme Q10, a naturally occurring substance, is essential to the electron transport chain. Coenzyme Q10 could be a successful migraine prophylactic if, as some evidence suggests, migraine is caused by mitochondrial dysfunction.

Rozen and associates^[10] from Thomas Jefferson University Hospital assessed the efficacy of high-dose coenzyme Q10 as prophylaxis against migraine headaches. Patients (N = 32; 26 women, 6 men) with a history of episodic migraine with or without aura were treated with coenzyme Q10 150 mg/day. During the 1-month baseline period and 3-month therapy phase, 31 of 32 patients completed the study; 61.3% of patients had more than a 50% reduction in number of days with migraine and 93.5% had at least a 25% reduction in number of days with migraine. The average number of days with migraine during the baseline period was 7.34, which was reduced significantly to 2.95 days after 3 months of therapy. Mean reduction in migraine frequency was 13.1% after 1 month of treatment and 55.3% by the end of 3 months of therapy. Coenzyme Q10 appears to be effective in the prevention of migraine, with no side effects reported. Efficacy is seen within 4 weeks of initiation, but 5-12 weeks are usually needed to produce a greater than 50% reduction in days with migraine.

Chronic Daily Headache

Scher from NINDS/NIH, Bethesda, Maryland, and colleagues^[11] examined whether the consumption of dietary caffeine or over-the-counter (OTC) analgesics containing caffeine is associated with the onset of chronic daily headache. Patients with chronic daily headache (180+ headache days/year) and controls (2-104 headache days/year) were identified from a community sample of adults via telephone interview.

Results showed that dietary and OTC-analgesic caffeine consumption was higher in whites and in those with lower educational levels. Dietary consumption was also higher in those who snored, had a psychiatric diagnosis, or migraine. Patients younger than 40 years consumed more dietary caffeine and were more likely to report first-choice use of caffeine-containing OTC analgesics than were younger controls (Table 2). No differences were found for the older cases and controls.

Adjusted odds ratios (OR) for either high dietary caffeine (top quartile) or caffeine-containing OTC analgesic use for the younger group were:

Pre-chronic daily headache -- OR = 3.73 (P = .000, attributable fraction = 29%)
Post-chronic daily headache -- OR = 2.42 (P = .003, attributable fraction = 26%).

These associations applied to individuals with migraine and those with tension-type headaches. Odds ratios increased slightly when caffeine-containing medications were included. The study showed that caffeine consumption was associated with the onset of chronic daily headache only in those younger than age 40. The lack of an association in those over age 40 "may reflect age-related differences in biological vulnerability or the age at which caffeine habits are established." Because only one third of subjects used analgesics on a daily basis the investigators speculated that other factors must be important.

Pathophysiology

Bolay and colleagues^[12] from Massachusetts General Hospital, Boston, proposed that cortical spreading depression (CSD) and the migraine aura contribute to trigeminal activation, which generates headache in susceptible individuals. They tested whether CSD causes peripheral and central trigeminovascular activation by examining whether CSD:

Enhances dural arterial blood flow.
Augments neurogenically mediated plasma protein extravasation in the ipsilateral dura mater.
Induces central nervous system activation

CDS was induced electrically or by pinprick under barbiturate anesthesia in ventilated rats with spreading depression.

There was little change in blood flow within the middle meningeal artery before and during CSD propagation. Middle meningeal artery flow began to increase after 5 minutes, and the flow achieved a its maximum rate after approximately 20 minutes and slowly returned to baseline (1 hour). Plasma protein leakage (horseradish peroxidase) was prominent around the dural vasculature on the CDS side, which was blocked by chronic nasociliary (trigeminal) nerve transection. Within the ipsilateral trigeminal nucleus caudalis (TNC), numbers of c-fos-positive neurons were significantly higher, but were reduced by chronic trigeminal nerve transection or by sumatriptan.

The investigators concluded that CDS "caused relatively long lasting hyperemia within dura mater, neurogenically mediated ipsilateral edema within meninges, and ipsilateral neuronal activation within the TNC." The work by Bolay and colleagues establishes CSD as a stimulus for trigeminovascular activation and thus an initiating or sensitizing factor for headache in migraineurs.

Table 1. Drug-Related Adverse Events

Adverse Event % of Patients With Adverse Event(s)

Rizatriptan 10 mg vs Sumatriptan 100 mg vs Sumatriptan 50 mg vs Placebo P Value

Any CNS drug-related adverse event 17% 23% -- 9% .030

21% -- 19% 10% NS

Dizziness 6% 7% -- 3% NS

8% -- 8% 3% NS

Drowsiness 7% 6% -- 3% NS

7% -- 6% 3% NS

Adverse Event	% of Patients With Adverse Event(s)
Rizatriptan 10 mg	vs Sumatriptan 100 mg	vs Sumatriptan 50 mg	vs Placebo	P Value
Any CNS drug-related adverse event	17%	23%	--	9%	.030
21%	--	19%	10%	NS
Dizziness	6%	7%	--	3%	NS
8%	--	8%	3%	NS
Drowsiness	7%	6%	--	3%	NS
7%	--	6%	3%	NS

Table 2. Consumption of Caffeine in Younger Subjects (< 40 Years)

Consumption of dietary caffeine (P < .000)

Pre-chronic daily headache -- 651mg/week higher than younger controls

Post-chronic daily headache -- 602mg per week higher than younger controls

Consumption of first-choice use of caffeine-containing OTC analgesics

Pre-chronic daily headache -- 15% in younger subjects vs 4% in controls (P = .001)

Post-chronic daily headache -- 18% in younger subjects vs 8% in controls (P = .012)

References

Cologno D, Torelli P, Manzoni GC. A prospective study of the headache phase in 26 migraine with aura patients. Cephalalgia. 2001;21:294-295. Abstract P1-A9.
Kors EE, Terwindt GM, Giffin NJ, et al. Expanding the phenotypic spectrum of the CACNA1A gene T666M Mutation. Cephalalgia. 2001;21:347. Abstract P1-G10.
Thomsen LL, Eriksen MK, Olesen J, Russell MB. Clinical characteristics of Danish families with familial hemiplegic migraine. Cephalalgia. 2001;21:301. Abstract P1-A24.
Silberstein SD, Niknam R, Rozen TD, Young WB. Cluster headache with aura. Neurology. 2000;54:219-221.
Eekers PJ, Vliet JA, Haan J, Koehler PJ, Ferrari MD. Prodromal symptoms and aura in cluster headache patients: a nation-wide study in 1844 Dutch patients. Cephalalgia. 2001;21:265-266. Abstract OR-10.
Diener HC, Silberstein SD, McCarroll KA, Allen C, Lines CR. Do 'CNS-penetrant' triptans cause more adverse events? Cephalalgia. 2001;21:424-425. Abstract P2-K44.
Gobel H, Heinze A, Heinze-Kuhn K, Zumbroich V. Naratriptan plus naproxen: increase of efficacy and reduction of headache recurrence in acute migraine. Cephalalgia. 2001;21:417. Abstract P2-K27.
Young WB, Shechter AL, Hopkins MM. Topiramate: a case series study in migraine prophylaxis. Cephalalgia. 2001;21:370-371. Abstract P2-I7.
Krusz JC. Levetiracetam as prophylaxis for resistant headaches. Cephalalgia. 2001;21:373. Abstract P2-I12.
Rozen TD, Oshinsky ML, Gebeline CA, et al. Open-label trial of high-dose Coenzyme Q10 as a migraine preventive. Cephalalgia. 2001;21:380-381. Abstract P2-I30.
Scher AI, Lipton RB, Stewart WF. Is caffeine a risk factor for chronic daily headache? Results from the frequent headache Epidemiology study (FRHE). Cephalalgia. 2001;21:473. Abstract P3-P19.
Bolay H, Reuter U, Dunn A, Chiarugi A, Boas D, Moskowitz M. Meningeal and central trigeminovascular activation following cortical spreading depression. Cephalalgia. 2001;21:526. Abstract LB-2.