美国头痛学会第45届科学年会集锦
Conference Report
Highlights of the 45th Annual Scientific Meeting of the American Headache Society
June 21-23， 2003， Chicago， Illinois
Stephen D. Silberstein， MD
Medscape Neurology & Neurosurgery 5（2）， 2003. ？ 2003 Medscape
Posted 07/21/2003
Introduction
This material is part of the scientific program of the 45th Annual Scientific Meeting of the American Headache Society， held from June 21-23， 2003， in Chicago， Illinois. This report reviews presentations related to migraine diagnosis， sensitization and headache， menstrual migraine， preventive treatment， organic headache， and pathophysiology.
Migraine Diagnosis
Despite its relatively high prevalence， migraine is an underdiagnosed disorder. Because most patients who seek medical care for headaches present in the primary care setting， a self-administered screening instrument could improve recognition of migraine both among patients and their primary care providers， thereby improving the treatment of migraine.
In a study presented at this years meeting， Lipton， from the Albert Einstein College of Medicine， Bronx， New York， and colleagues[1] established the validity and reliability of a brief， self-administered screening instrument for identifying patients with migraine in the primary care setting. Patients who had visited outpatient primary care for any reason； experienced headaches that interfered with their work， study， or quality of life； or those who presented for a discussion with their physician about their headaches， and who completed a screening questionnaire， were included in the study. Eligible participants were then seen by headache specialists who assigned diagnoses based on International Headache Society （IHS） criteria； specialists were blinded to the initial screening results.
The 9-item screening instrument included 8 items that paralleled the IHS features that defined migraine （pain descriptors， aura， nausea， photophobia， and phonophobia）， and 1 item quantified the patients disability. A total of 433 patients completed the screening and headache specialist evaluations. Of the 9 screening questions， a subset of 3 questions describing disability， nausea， and sensitivity to light performed best for predicting migraine diagnosis， with a sensitivity of 0.81 （95% CI， 0.77 to 0.85）， a specificity of 0.75 （95% CI， 0.64 to 0.84）， and a positive predictive value of 93.3% （95% CI， 89.9 to 95.8）。 The sensitivity and specificity of these 3 questions held up regardless of sex， age， presence of other headache， or previous diagnoses. Because this tool is easy to use， quick to administer， and highly accurate， it could significantly improve the recognition of migraine headaches in the primary care setting.
Sensitization and Headache
Burstein and associates[2] from Harvard Medical School in Boston have shown that most patients develop cutaneous allodynia （CA） （ie， pain resulting from a nonnoxious stimulus to normal skin） during migraine attacks and proposed that the underlying mechanism is sensitization of central trigeminovascular neurons. To prove this， they used repeated quantitative sensory testing to examine patients during an early stage of a migraine attack， administering triptans （5HT1b/1d agonist） before CA was established， and during a late-stage migraine， administering triptans after CA was established. They found that before allodynia was established， triptan therapy completely relieved the headache and prevented later development of allodynia. By contrast， triptan therapy provided little or no relief from the headache and could not suppress allodynia if given after allodynia was established. Late triptan therapy did prevent the worsening of pain upon bending over and throbbing， despite the continuing presence of headache pain and allodynia.
In a recent series of studies，[3-5] these investigators showed that the throbbing pain of migraine is mediated by sensitization of peripheral trigeminovascular neurons， and that CA is mediated by sensitization of central trigeminovascular neurons. During the meeting， Dr. Burstein won the Wolff award for showing that antimigraine drugs， such as triptans， can successfully abort the headache in the absence of CA early on but not after CA is established； that triptans prevent the induction of sensitization in central but not peripheral trigeminovascular neurons； and that triptans cannot abolish previously established peripheral or central sensitization. Based on these findings， Burstein and coworkers have concluded that triptans terminate migraine pain by blocking synaptic transmission between peripheral and central trigeminovascular neurons through presynaptic 5HT1B/1D receptors located in the dorsal horn.
These findings justify reversing the current practice that instructs patients to delay treatment until the attack is fully developed. The new guideline， which calls for early treatment， would increase the therapeutic benefit and reduce the cost of therapy for the million of Americans who are using triptans to treat migraine.
Allodynia and Headache
Allodynia is common in episodic migraine. The development of allodynia worsens the prognosis of migraine patients treated with triptans. Brush allodynia （BA） has not been fully characterized in patients with headache. However， BA is uniquely suited to the evaluation of treatment effects in headache patients because of the ease of testing. Shukla， Richardson， and Young，[6] from Thomas Jefferson University in Philadelphia， Pennsylvania， described dynamic mechanical BA in an inpatient headache population comprising patients with headache admitted to Thomas Jefferson University Hospital.
The study enrolled 78 patients （mean age of 40.4 years； 58 females and 20 males）。 Thirty-two patients （41%） had BA during hospitalization. Patients received 10 brushes with a folded 4 x 4-inch gauze pad at 3 sites bilaterally —— forehead （V1）， jaw （V3）， and forearm —— after which allodynia was measured using a 10-cm visual analogue scale. Headache pain was measured using an 11-point verbal scale.
Patients with BA reported a maximum severity of headache of 6.16 ± 3.0 during the hospitalization， compared with 6.22 ± 2.6 （P = not significant） for patients without BA. The presence of BA did not correlate with age or sex. Of the 78 patients， 61 had chronic migraine （27 with BA）， 4 had cluster headache （4 with BA）， 4 had posttraumatic headache （1 with BA）， 4 had new daily persistent headache， 3 had chronic tension-type headache， 1 had low-pressure headache， and 1 had aura status. No patient in the last 4 groups experienced BA. The forehead was the most common site for allodynia （84%） in this group， and the BA score （5.0） was higher at this location than at the jaw （69%； BA score， 3.6） or the forearm （50%； BA score， 2.3）。 Patients with a history of exclusively or primarily unilateral headaches had allodynia （24/45） more commonly than those with a history of bilateral headaches （8/33； P = .01）。 For the 21 patients with unilateral or mostly unilateral headache at the time of BA testing， the higher BA score was more likely to be ipsilateral （16/21） than contralateral （5/21） to the headache.
Menstrual Migraine
Many women experience migraine associated with hormonal fluctuations， most commonly those associated with menses. True menstrual migraine occurs predominantly around menses. Nonetheless， few prospective trials have examined the efficacy of triptans or nonsteroidal antiinflammatory drugs in this type of migraine.
A multicenter， randomized， double-blind， placebo-controlled， parallel group study[7] prospectively evaluated the efficacy of zolmitriptan in the acute treatment of true menstrual migraine of moderate to severe intensity； most attacks （90%） occurred 2 days before to 5 days after onset of menses. Eligible women received either zolmitriptan， 2.5 -mg tablet （n = 174）， or placebo （n = 160）。 Participants were allowed to treat up to 2 migraine headaches per menstrual period for no more than 3 months. Zolmitriptan resulted in a 2-hour response in 66% of headaches compared with 33% for placebo （P < .001）。 Pain-free rates at 2 hours were 28% for zolmitriptan compared with 9% for placebo （P < .005）。 Headaches recurred in 29% of zolmitriptan-treated attacks （mean time to recurrence， 10 hours） vs 45% of placebo-treated attacks （mean time to recurrence， 7 hours）。
This first randomized， controlled trial to prospectively evaluate the efficacy of a triptan in the acute treatment of true menstrual migraine demonstrated that zolmitriptan treatment delivered significant and sustained efficacy with good tolerability in this migraine subtype.
Preventing Migraine
Migraine is an episodic disorder that causes significant disability， interferes with quality of life， and is associated with substantial healthcare costs. The broad-spectrum antiepileptic drug topiramate has several mechanisms of action that may prevent migraine， including state-dependent inhibition of voltage-gated sodium and calcium channels， inhibition of glutamate-mediated neurotransmission at the alpha-amino-3-hydroxy-5-methylisoxazole-4-propionate （AMPA）/kainate receptor subtype， and enhancement of gamma-aminobutyric acid （GABA） A receptor-mediated chloride flux.
In 2 multicenter， randomized， double-blind， placebo-controlled， 26-week studies （MIGR-001 and MIGR-002）， Mathew， of the Houston Headache Clinic， Houston， Texas， and colleagues[8] evaluated the efficacy and safety of topiramate at daily doses of 50 mg， 100 mg， and 200 mg for preventing migraine headache. During a baseline period of 28 days， participants maintained a headache record. Topiramate was begun at 25 mg daily and titrated by 25 mg/week to a maximum of 200 mg daily. The primary efficacy measure was the reduction of headaches during the mean 28-day migraine period relative to baseline. Secondary measures included the percentage of patients with fewer migraine-days per month relative to baseline， decreased migraine severity and duration， and a 50% reduction in mean monthly frequency of migraine. Almost 1000 patients were randomized； they received placebo （n = 237） or the active drug at daily doses of 50 mg （n = 245）， 100 mg （n = 250）， or 200 mg （n =238）。
Compared with placebo， patients receiving 100- and 200-mg doses experienced significant improvements in each efficacy measure， and mean monthly migraine frequency dropped significantly. In some cases， significant reductions were evident within the first month of treatment. Among the groups treated with topiramate， significantly more patients achieved at least a 50% reduction in mean monthly migraine attacks compared with those receiving placebo. Adverse events leading to discontinuation of topiramate were similar in the 2 studies and included paresthesia， nausea， and fatigue.
Organic Headache
The incidence of subarachnoid hemorrhage is estimated at 8 per 100，000 person-years. The yearly rupture rate of small aneurysms is 0.05% and 0.5% for larger aneurysms （>10 mm diameter）。 Thunderclap headache is recognized as one of the signs of subarachnoid hemorrhage but also has been described in patients presenting with unruptured aneurysms.[9] However， few studies have evaluated patients with headaches subsequently found to have unruptured cerebral aneurysms.
Siow and coworkers，[10] from Thomas Jefferson University， attempted to identify the relationship between unruptured cerebral aneurysm and headache， to describe the headache， and to examine the effects of aneurysm repair on headache characteristics. They measured how often patients with unruptured aneurysms present with headaches， described the salient features of these headaches， and examined the differing presentations and how they relate to the properties of the aneurysms.
The team conducted a retrospective chart review of patients with a diagnosis of unruptured aneurysm presenting to the department of neurosurgery at Thomas Jefferson University over a 1.5-year period. They sent a follow-up questionnaire to all patients meeting the search criteria， asking about their general health and headaches before and after surgery. Of 157 charts， 112 patients met the inclusion criteria. These 112 patients were divided into 3 groups： （1） patients who presented with complaints of headache； （2） patients who had a history of headache but did not present with that complaint； and （3） patients with no history or presenting complaint of headache. Investigators also compared the demographics and health histories of the 3 groups， including smoking， hypertension， heart disease， and stroke. They examined the size of the aneurysm its location and in which side of the brain it was found. Internal carotid artery aneurysm （ICA） was the most common location in all 3 groups. All patients with a history of transient ischemic attack were in group 3. Predictably， patients from groups 1 and 2， who experienced headaches before surgery， were more likely to report postoperative headaches.
In this descriptive study of headache associated with unruptured cerebral aneurysms， differences between groups of patients were found on the basis of the patients presentation. Three patients had thunderclap headache， and none had arterial spasm. This study found no other predictive quality of headaches in patients who were subsequently found to have an unruptured aneurysm.
Multiple Sclerosis-Associated Headaches
Experimentally， the periaqueductal gray matter has been postulated to be the central migraine generator； however， few clinical case studies support this observation. Gee and coworkers，[11] from the University of California Davis Headache Clinic in Sacramento， tried to determine whether the migraines of patients who have multiple sclerosis （MS） are associated with the location of plaque or the number of lesions. The investigators identified the study population through the magnetic resonance imaging [MRI] database of the department of radiology， identifying patients with demyelinating disease who underwent imaging between December 1992 and June 2002. Of 4369 MRI scans， 1533 studies showed possible demyelination. The team then reviewed the medical records of these patients to confirm the diagnosis of MS and to document headache complaints.
In all， 277 patients had definite MS. A questionnaire was mailed to these patients to obtain information about their MS symptoms and headache； 61% of the recipients responded. Researchers examined the MRI films of each patient to document plaque location rather than the actual number of lesions. They used HIS criteria to classify headache types. Overall， 55.6% （154/277） of patients complained of headache； of these， 61.7% （95/154） met criteria for migraine or migrainous headache， 25.3% （39/154） met criteria for tension-type headache， and 13% （20/154） had mixed headache.
Compared with patients without such lesions， those who had MS plaque within the midbrain/periaqueductal gray matter had a 4-fold greater incidence of migraine headaches （OR， 3.91； 95% CI， 2.01 to 7.32； P < .0001）， a 2.5-fold higher incidence of tension-type headaches， and a 2.7-fold higher incidence of migraine plus tension-type headaches. Patients with lesions in 3 or more locations were approximately 2 times more likely to have migraine than patients with lesions in fewer than 3 locations， although this finding did not reach statistical significance.
This study points toward dysfunction within the midbrain/periaqueductal gray matter caused by a demyelinating plaque as a factor that increases the incidence of headache in patients with MS. This finding also implicates this region as a possible site of dysfunction in primary headache sufferers.
Pathophysiology
There is mounting evidence that neurogenic inflammation is important in the pathophysiology of migraine. Such inflammation activates trigeminal sensory neurons and promotes the development of central sensitization within the trigeminal nucleus caudalis （TNC）。 Several preclinical studies have shown that N-methyl-D-aspartate， AMPA， and group III metabotropic glutamate receptors are involved in the excitation of the TNC.[12，13]
Luo and colleagues，[14] from the Jefferson Headache Center in Philadelphia， used an in vivo microdialysis method to monitor the changes in extracellular neurotransmitters （including glutamate， glutamine， 5-HT， and norepinephrine） in the TNC induced by the application of an inflammatory soup （a mixture of histamine， 5-HT， bradykinin， and prostaglandin E2 in phosphate buffer） on the intracranial dura. Investigators found that extracellular levels of glutamate in the TNC fell during the first half hour after the soup was applied to the dura. After that， glutamate rose continuously and reached a level of about 3 times baseline values 3 hours after the sensitization. Serotonin levels rose immediately， then fell. The investigators suggested that the initial rise in serotonin may have inhibited the early release of glutamate. Electrophysiologic recordings of neurons in the TNC during sensory stimulation before and after sensitization confirm these data. Thus， shortly after inflammation， neuronal excitability in the TNC declines but subsequently the response to sensory stimuli increases， and the receptive field expands. They observed no significant changes in levels of glutamine or GABA.
The investigators concluded that the excitatory glutamate neurotransmitter participates in the TNC sensitization-effects response to inflammatory stimulation of the intracranial dura， which provides mechanistic insight and raises therapeutic possibilities for primary headaches， such as migraine. In addition， the initial increase in serotonin probably inhibited early glutamate release.
References
Lipton RB， Kolodner K， Dodick D， et al. A self-administered screener for migraine in primary care： The ID Migraine Validation Study. Headache. 2003；43 （Abstract）。
Yarnitsky D， Goor-Aryeh I， Bajwa Z， et al. Possible parasympathetic contributions to peripheral and central sensitization during migraine. Headache. 2003；43 （Abstract）。
Burstein R， Collins B， Bajwa Z， et al. Triptan therapy can abort migraine attacks if given before the establishment or in the absence of cutaneous allodynia and central sensitization： clinical and preclinical evidence. Headache. 2002；42：390 （Abstract）。
Burstein R， Collins B， Jakubowski M. Defeating migraine pain with triptans： a race against the developing allodynia. AAN. 2003； Abstract S15.001.
Burstein R. Deconstructing migraine headache into peripheral and central sensitization. Pain. 2001；89：107-110. Abstract
Shukla P， Richardson E， Young WB. Brush allodynia in an inpatient headache unit. Headache. 2003； 43 （Abstract）。
Tuchman M， Abu-Shakra S， Silberstein SD， et al. Oral zolmitriptan exhibits high efficacy and low recurrence rates in the acute treatment of true menstrual migraine： results of a randomized controlled trial. Headache. 2003；43 （Abstract）。
Mathew N， Brandes J， Jacobs D， et al. Topiramate in the prevention of migraine headache： Results from two randomized， double-blind， placebo-controlled studies. Headache. 2003；43 （Abstract）。
Linn FH， Wijdicks EF. Causes and management of thunderclap headache： a comprehensive review. Neurology. 2002；8：279-289.
Siow HC， Silberstein SD， Hopkins M， Peres MF. Unruptured cerebral aneurysms and headache. Headache. 2003；43 （Abstract）。
Gee JR， Chang JT， Dublin AB， Vijayan N. Role of brainstem lesion in the genesis of headache： an imaging study of multiple sclerosis. Headache 2003； 43 （Abstract）。
Mitsikostas DD， Sanchez del Rio M. Receptor systems mediating c-fos expression within trigeminal nucleus caudalis in animal models of migraine. Brain Res Brain Res Rev. 2001；35：20-35. Abstract
Classey JD， Knight YE， Goadsby PJ. The NMDA receptor antagonist MK-801 reduces Fos-like immunoreactivity within the trigeminocervical complex following superior sagittal sinus stimulation in the cat. Brain Res. 2001；907：117-124. Abstract
Luo J， Piovesan E， Oshinsky ML. Neurochemistry of sensitization in the trigeminal nucleus caudalis. Headache. 2003；43 （Abstract）。
