-I

M T

-I-IT

12th Migraine Trust International Symposium

1-4 September 1998, Kensington Town Hall, London, UK

Under the auspices of the World Federation of Neurology

CONTENTS

376 LECTURES

378 PLATFORM PRESENTATIONS

394 POSTER PRESENTATIONS

415 AUTHOR INDEX

376 Lectures CEPHALAu;IA18(1998)

PETER WILSON MEMORIAL LECTURE

Migraine art-the migraine experience from within. K I&loll. Department of Psychiatry and
Psychotherapy, Technical University Aachen, Germany

The outcome of a meeting between Peter Wilson MBE, founder of the British Migraine Association, and
Derek Robinson, a marketing executive employed by Boehringer Ingelheim, resulted in the organization of
four national Migraine Art competitions between 1980 and 1987, whereby migraine sufferers were
encouraged to depict their condition by means of paintings, drawings and other forms of illustration. In
collaboration with Derek Robinson, the originator of the Migraine Art concept and curator of the collection,
now consisting of 562 pictures, follow-up enquiries were made to enable artists to explain the sometimes
enigmatic features of their pictures. Techniques of pictorial representational art provide an ideal medium
to express, and communicate, the experiences which occur as signs and symptoms of migraine. Body image
disturbances depicted by the artists include macro- and microsomatognosia and out-of-body experiences
with autoscopy and reduplication phenomena. Other pictures represent visual illusions, such as dysmetrop-
sia, oblique and inverted vision, visual allesthesia, diplopia and polyopia, illusory visual spread, corona
phenomenon, metamorphopsia, illusory splitting and mosaic illusion. Besides many varieties of the typical
zigzagged fortification spectra, Migraine Art pictures illustrate the complete spectrum of hallucinatory
form constants as described by Kluver and other authors in drug-induced visual imagery. Migraine Art,
which provides an almost complete pictorial inventory of some esthetic and visual paroxysmal neuropsycho-
logical symptoms, allows a unique look at the “migraine experience from within’, which will promote the
understanding of the many, and sometimes strange and irritating symptoms experienced by migraine
sufferers.

CUMINGS LECTURE

A decade of nitric oxide research. S Moncada. The Cruciform Project, University College London,
140 Tottenham Court Road, London WlP 9LN, UK

The discovery in 1987 that the biological actions of endothelium-derived relaxing factor are due to the
endogenous release of nitric oxide (NO) revealed the existence of a ubiquitous biochemical pathway. NO
is formed from the amino acid L-arginine by a family of enzymes-the NO synthases-and plays a role
in many physiological functions. Its formation in vascular endothelial cells in response to chemical and
physical stimuli maintains a vasodilator tone that is essential for the regulation of blood flow and pressure.
NO produced by the endothelium and/or platelets also inhibits platelet aggregation and adhesion, inhibits
leukocyte adhesion, and modulates smooth muscle cell proliferation. NO is synthesized in neurones of the
central nervous system, where it acts as a mediator with many physiological functions, including the
formation of memory and the coordination between neuronal activity and blood flow. NO has been
implicated in modulation of pain since the NO synthase inhibitor N”-nitro-L-arginine methyl ester
(L-NAME) reduces hyperalgesia and causes analgesia in animal models of pain. L-NAME has also been
shown to reduce the pain and other symptoms of migraine when given intravenously during an attack. In
contrast, studies have suggested that NO may be involved in the analgesic effects of opiates. In the
peripheral nervous system, NO is now known to be the mediator released by a widespread network of
nerves, previously recognized as nonadrenergic and noncholinergic. These “nitrergic” nerves mediate some
forms of neurogenic vasodilatation and regulate certain gastrointestinal, respiratory and genitourinary
functions. In addition, NO is generated in large quantities during host defence and immunological reactions
where it acts as a cytostatic-cytotoxic agent against invading microorganisms and occasionally host tissues.
The cytostatic/cytotoxic actions of NO result from its inhibitory actions on key enzymes in the respiratory
chain and in the synthesis of DNA in the target cells. NO may also react with oxygen-derived radicals to
produce toxic substances such as peroxynitrite. Thus, NO plays a role in immunological host defence and
is also involved in the pathogenesis of conditions such as septic shock and inflammation. Research is under
way to determine how manipulation of the generation or actions of NO may lead to novel therapies for
the treatment of a variety of diseases.
CEPHALALGIA 18 (1998) L.i?cfures 377

THE MIGRAINE TRUST LECTURE

Measuring migraine disability: implications for clinical trials and clinical practice. RB Lipton. Albert
Einstein College of Medicine, Montefiore Medical Center, 111 East 210th Street, Bronx, New York, NY, USA

The severity of migraine varies considerably among individuals. At one end of the spectrum, migraine
produces high levels of pain and disability with reduced quality of life between attacks. At the other, pain
may be mild or moderate with little or no limitation to functioning. The most disabled half of migraine
sufferers account for over 90% of the economic burden of migraine.
Targeting this most disabled segment of migraine sufferers may provide an efficient strategy for reducing
the burden of illness and maximizing the cost-effectiveness of treatment. Though physicians believe that
the most disabled patients have the greatest need for medical care, communication about migraine-related
disability is often ineffective. We reasoned that a simple, well-validated measure of headache-related
disability might facilitate physician-patient communication, provide a method for screening for headache
sufferers in need of medical care, become a basis for stratification in clinical trials and, ultimately, a tool
for treatment guidelines.
The Migraine Disability Assessment (MIDAS) questionnaire was developed as a brief, self-administered
tool. The score is the sum of missed days and days with significant disability in work outside the home.
In household work and in non-work activities (family, social, and leisure) over a 3-month period. MIDAS
scores were found to be highly reliable in two separate studies conducted in the U.S. and the U.K. They
were also validated against daily disability diaries and against physician judgments (based on case histories)
regarding severity of illness and urgency for care.
In this presentation, I provide an overview of the burden of migraine and describe the development and
validation of the MIDAS questionnaire. Other methods of measuring disability and quality of life of
migraine and the utility of these tools in research and clinical practice are discussed.

MACDONALD CRITCHLEY LECTURE

Migraine, female hormones, and stroke. M-G Bousser, Department of Neurology, Hapita Lariboisiere,
2 rue Ambroise Pare, Paris 75010, France

The close relationships that exist between female hormones and migraine are illustrated by numerous facts:
a higher prevalence in women, frequent onset at puberty, menstrual worsening, efficacy of estradiol in the
prevention of menstrual migraine, improvement during pregnancy, recurrence during postpartum, frequent
worsening with oral contraceptives (OC) and hormone replacement therapy (HRT). Contrasting with the
fact that stroke is viewed as a male condition, more women than men die of a stroke and are incapacitated
or demented because of it. This real epidemy is mostly due to the long female life expectancy and it does
not seem to be significantly modified by HRT, but randomized trials are ongoing. Stroke incidence is also
increasing in young women, mostly because of tobacco smoking, which triples the risk of stroke and
dramatically increases the risk of other factors, such as hypertension, OC, and migraine. Given the high
risk of the association migraine-smoking-OC, young female migraineurs should be advised not to smoke
and, if they use OC, to choose a low estrogen content pill. Migraine is a frequent symptom in some
conditions which are known causes of stroke (APL syndrome, MELAS, CADASIL) suggesting a common
pathogenetic mechanism. Although no firm data exist, it is recommended not to use OC in such patients.
PLATFORM PRESENTATIONS *
CEPHALALGIA 18 (1998) Playbrm presentations 379

1.1
1.3
Self-reported effects of migraine on the families,
Iscomorbidity with major depression specific to
friends, and activities of sufferers. R Smith LA Hasse.
migraine? N Breslau’, LR Schule, KMA Welch3.
University of Cincinnati, Department of Family
Department of Psychiatry, Apartment of Biostatistics,
Medicine, PO Box 670582, Cincinnati, Ohio 45267-0582,
USA 3Department of Neurology; Henry Ford Health System,
1 Ford Place 3A, Detroit, MI, USA
Backgroundand objectives.A nation-wide study of migraine
sufferers in the U.S. was undertaken to determine the We previously reported an association between migraine
impact of migraine on families (R. Smith, “Impact of and major depression, based on retrospective and pro-
Migraine on the Family”, Headache, June 1998). Further spective data from a representative sample of 1,000 young
data from this study are now presented, addressing the adults in southeast Michigan. In this study, we examine
self-reported effects of migraine on the families, friends, whether the association with major depression is specific
and activities of sufferers. Method. Three-hundred-and fifty to migraine, or instead applies also to severe headaches
migraine s&erers (284F, 66M) were identified from a other than migraine. Psychiatric assessment with a struc-
national sample of 4000 U.S. households. Subjects were tured interview (WHO-CIDI) was conducted on a stratified
selected by random-digit dialing and interviewed via random sample of 1,286 persons 18-55 years of age,
telephone using a structured questionnaire. The effects of diagnosed with migraine according to the IHS criteria,
migraine symptoms and history were examined in relation severe headaches other than migraine, or no history of
to the onset of social and/or medical problems, activities either migraine or severe headaches in a telephone survey
cancelled or delayed due to migraine, and the support of of nearly 4,765 persons, using a diagnostic interview
family and friends. Results. Sufferers report an average of validated by a neurologic examination.
6.71 symptoms (1.76 SD; range 2-11). Number of symp-
toms is related to delays of daily activities (Y =0.34; p =
0.0001); activities (r =0.31; p = 0.0001); the onset of social
and/or medical problems (Y = 0.22; p = 0.0001); and support Migraine 23% 42%
from friends (Y = -0.12; p = 0.0268). History of migraine is Severe headache 27% 375s
related to family (Y=-0.11; p=O.O444) and friend (r= Controls 11% 18%
-0.13; p =0.0121) support; delays of daily activities (Y= OR Migraine vs 0.8 (0.4, 1.8) 1.2 (0.8, 1.9)
0.13; p=O.O153) and the onset of social and/or medical Severe headache
problems ( p = 0.12; p = 0.0300). Conclusions. Multiple
migraine symptoms are related to delays of daily activities
and cancellations of social activities along with the onset The table presents the lifetime prevalence of major
of social and/or medical problems and negative support depression in males and females in the three groups. In
from friends. Migraine history is negatively related to both sexes, the prevalence of major depression was higher
support from family and friends and positively related to in those with migraine or severe headache, compared to
delays of daily activities and the onset of social and/or controls: Odds ratios in these comparisons were approxi-
medical problems. The clinical implications of these cor- mately 3.0 in males and 2.5 in females. However, those
relations will be discussed. with migraine did not differ from those with severe
headache, as indicated by the odds ratios (OR) in the table.
In both sexes, the OR is approximately 1.0. The results do
1.2 not support the specificity of the migraine-major depres-
Prevalence of transformed migraine. J Pascuall, sion association. The comorbidity with major depression
J Castilloz, V Guitera’, P Munoz3. ‘Department of applies to severe headaches of various types, including
Neurology, University Hospital, M. Valdecilla, migraine, tension-type headache (TIH) (60% of persons
‘H. C. Camargo, 3P. C. Management, Santander, Spain with severe headaches met IHS criteria for TTH) and other
types of headaches.
Although transformed migraine (TM) is an important
reason for consultation in headache clinics, its actual
prevalence is unknown. The prevalence of TM is studied 1.4
here in a large unselected population. A questionnaire
exploring headache frequency was distributed to 2,252 Impact of headache education program in the
unselected subjects. Those having headache on 10 or more workplace. GD Solomon, CM Kippes, RS Kunkel,
days per month were given a headache diary and exam- Department of General Internal Akdiche, Cleveland
ined by a neurologist, who classified them within TM Clinic, Cleveland, OH, USA
according to the revised Silberstein et al. criteria
(Neurology 1996;47:871). One-thousand-eight-hundred- Objective. To determine the impact of a headache education
and-eighty-three individuals (83.5%) filled in the question- program presented in a workplace setting. Background.
naire. TM was diagnosed in 45 (51% of all chronic daily Headaches are responsible for lost productivity in the
headache patients and 2.2% of all subjects); 40 (89%) were workplace. Health-related quality of life and disability due
women. The mean age at diagnosis was 47 years (range to headache can be assessed using standardized instru-
22-72); 14 (31%) TM patients overused ergotics or anal- ments and may reflect impairments in productivity.
gesics. We conclude that about 2% of the total population Methods. A 45 min, commercially prepared and standard-
suffers from TM. (Supportedby CizjuCantabria and Fundacih ized educational program was delivered to participants at
Valdecilla grunts.) eight companies in the United States. Components of the
380 Platfinm presentations CEPHALALGIA 18 (1998)

program included education on headache types, trigger MIDAS score was 0.84. Cronbach’s alpha, a measure of
factors, prevention and treatment techniques. The program internal consistency, was 0.80. The mean and median
consisted of a slide presentation, participant worksheet, MIDAS scores among migraine cases (mean= 17.5,
and handouts. Prior to the presentation, participants com- median= 14) were considerably higher than those
pleted a baseline questionnaire addressing their headaches among non-migraine controls (mean = 7.9, median =4).
and headache management techniques, the SF-36, and the ConcZusions.This is the first population-based study to
Headache Disability Inventory (HDI). The participants assess the reliability of a disability-related illness severity
completed similar questions 1 month after the presenta- score both for individuals with migraine and non-migraine
tion. Results. A total of 492 participants attended the headaches. The reliability and internal consisten of the
presentations. Paired data, from before and after the pro- MIDAS score for the spectrum of headache su7 erers is
gram, were available for 348 (75%). Compared to baseline, relatively high. Moreover, the MIDAS score highly dis-
1 month after the program a significantly higher percen- criminates individuals with migraine headache from those
tage of participants used non-medication techniques for with other types of headache. Finally, in contrast to the
managing headaches (proper diet, exercise, headache HImQ, MIDAS requires fewer questions, is self-scoring,
diary, breathing/relaxation exercises) ( p < 0.05). One and provides intuitively-meaningful information on lost
month after the program, SF-36 scores significantly days of activity in three domains.
improved (~~0.05) on all domains except physical func-
tioning. The largest improvements were in the domains of 1.6
role-physical and role-emotional. Disability due to head-
ache also decreased after the program ( p < 0.05). Discussion. Migraine symptoms- from children to adults-
This workplace educational intervention had a positive comparlnq different age groups. C Wisher-Bing&,
impact on all measured parameters. Improvement in a Ch Wiiber L, K Zebenholzeri2, M Seriml, A Hafferl’,
worker’s role function (occupation) is important in the Cl-tKienbacher’, A Karwautzl, P Wesself . ‘Department
workplace and should correlate with increased of Neuropsychiatry of Childhood and Adolescence,
productivity. University of Vienna, Vienna, Austria; *Department of
Neurology, University of Vienna, Vienna, Austria

The purpose of this study was to compare the clinical

1.5 features of migraine in children, adolescents and adults.
Reliability of Migraine Disability Assessment (MIDAS) We investigated 257 patients (166F, 91M) aged 3-69 years,
score in a population-based sample of headache divided into four age groups ( I lO, lO-20,20-40 and ~40
sufferem. RB Lipton’, WF Stew&, J Sawye?. ‘Albert years). All patients were referred for recurrent headache
Einstein College NY, USA; ‘Johns Hopkins University, and fulfilled the IHS criteria of migraine without and with
MD, USA; 3Zeneca Pharmaceuticals, Cheshire, UK aura, respectively. Patients with concomitant tension-type
headache and/or analgesics abuse were not included. We
Infroduction.In previous work, we reported that the relia- found that the frequency of the migraine attacks increased
only slightly from 1.1+1.3 to 1.4+1.2 (p=O.oS), whereas
bility of the HImQ, a global illness severity measure for
the duration was five times longer in adults than in
headache that combined information on pain and disabil-
children (7.4+10.0 vs 38.1f31.8, p=O.OOOl).Comparing
ity, was high. While the HImQ was suitable for research,
the headache characteristics revealed an increase of pulsat-
it was not appropriate for use in clinical practice because
ing quality (p = 0.002) and unilaterality (p ~0.0001) and a
the score was difficult to calculate and the global score
decrease of aggravation on physical activity ( p -cO.OOOl)
was difficult to interpret. The MIDAS score, based on with age, whereas intensity was similar in all age groups
responses to five questions, in three domains of activity (p =0.6). The prevalence of nausea did not change.
of daily life, was developed in response to these concerns. Vomiting occurred more often in children and young
Objectim. To examine the reliability and internal consist- adults, and less often in adolescents and older adults, and
ency of the five items comprising the MIDAS score and photo- and phonophobia were more common in adults
the overall MIDAS score in both migraine and non- than in children and adolescents (p eO.0001). Finally, the
migraine headache sufferers selected from a population prevalence of aura symptoms was also significantly higher
sample. Methods. We interviewed a population-based in adults ( p <O.OOOl). In conclusion, the clinical features
sample of 1,062 individuals from Maryland about their of headaches fulfilling the IHS criteria of migraine without
headaches using a clinically validated telephone interview. and with aura, respectively, differ considerably between
The telephone interview has a diagnostic sensitivity for children, adolescents, and adults. These differences should
MS-defined migraine of 91% and a specificity of 9%. be considered in the therapeutic management of migraine
From this survey, we identified samples of migraine cases in different age groups.
and controls with other types of headache who agreed to
complete a mailed version of the MIDAS Questionnaire.
A total of 108 migraine cases and 111 individuals with 2.1
other types of headache completed the MIDAS Effect of menstrual cycle on platelet 5HT levels.
QWStiOnnaire once. Ninety-seven migraine cases and ML Voon’, K Ghose’, B Niven*. Departments of
102 non-migraineurs completed a second MIDAS rPharmacology and 2Mathematics & Statistics, University
Questionnaire an average of 22 days later. Results. The of Otago, Dunedin, New Zealand
test-retest Spearman’s correlation for individual items
ranged from a low of 0.67 to a high of 0.73 for number of Migraine attacks are known to occur more frequently in
missed work days. The test-retest correlation for the total many female patients during the perimenstrual period
CEPHALALGIA 18 (1998) pmentatiims
PlaY;nm 381

and some patients only suffer from migraine during the functional GI disorders in patients with migraine are
premenstrual phase. Sensitivity of the autonomic nervous lacking. For this reason we aimed to determine the preval-
system is increased during the perimenstrual period ence of upper abdominal symptoms in patients with
(Ghose K, Turner P. Br J Clin Pharmacol 1977;4:500-2). migraine and compared the prevalence of abdominal
Similar changes in platelet 5-hydroxytryptamine (5HT) symptoms in a control population of healthy blood donors.
levels have been demonstrated in normal females Material and mfhods. Abdominal symptoms were assessed
(Lattanzi V, Nardelli GM, Giorgino R. Bollettino-Societa utilizing a validated questionnaire (BDQ, Bowel Disease
Italiana Biologia Sperimentale 1972;48:271-2) and in Questionnaire) in a series of 488 consecutive blood donors
patients with premenstrual migraine (Ashby CR Jr. et al. and 99 patients with migraine with or without aura based
Biol Psychiatry 1988;24:225-33). However, none of these on the International Headache Society criteria. Results.
investigators included any male control group in their Upper abdominal s toms were reported by 38% (95%
experiments. We compared the platelet 5HT levels in 6 confidence interval r”p
CI 0.32-0.44) blood donors compared
to 81% (95% CI 0.67-0.91, p<O.OOl) of migraine patients;
normal drug-free women, aged 20 to 33, with a group of
23% (95% CI 0.18-0.28) of the blood donors reported
6 age-matched male controls. This investigation was frequent dyspepsia (symptoms more than 6 times during
approved by the local ethics committee and informed the last 12 months) compared to 60% (95% CI 0.44-0.74,
written consent was obtained from participating subjects. p<O.OOl) of the migraine atients. Adjusting for age,
Platelet 5HT levels were measured on 4 consecutive weeks gender, and consumption oP nonsteroidal analgesics and
by a slightly modified method described by @‘Andrea G, alcohol, migraine was associated with frequent upper
et al. Thromb Res 1987;48:261-4). There were no significant abdominal symptoms (RR 2.7,95% CI 1.2-6.1). Conclusions.
fluctuations in 5HT levels in males but in women there Upper abdominal symptoms are significantly more fre-
was a progressive rise in levels after midcycle. These were quent in patients with migraine compared to healthy blood
highest and lowest at the premenstrual and postmenstrual donors. This association between migraine and idiopathic
periods, respectively (p = 0.06). These values also differed upper abdominal symptoms may suggest that the same
from men ( p =0.03). Compared to men, mean platelet 5HT pathophysiologic disturbances are linked to the develop-
levels were higher in women (p=O.OOl). Clinical signifi- ment of idiopathic dyspepsia and migraine.
cance of these findings will be discussed.
2.4
2.2 Family history of headache is not a factor in chronic
daily headache resulting from head trauma. J Couch,
Activated protein C resistance in migraine-related
M Swann, University of Oklahoma Health Science
ischemia. S Chaturvedi. Department of Neurology,
Center, 711 SL Young Blvd, Oklahoma, USA
Wayne State University, Detroit MI, USA
The problem of post-traumatic chronic daily headache
Background.Coagulation abnormalities such as anticardio- (PT-CDH) is poorly characterized. We compared PT-CDH
lipin antibodies may be important in the pathogenesis of subjects with CDH subjects who had no apparent cause
migrainous cerebral infarction. Objectives. To determine for their CDH (idiopathic, ICDH) as to history of signific-
the prevalence of activated protein C resistance (APCR) ant headache in parents to determine if such family histo
and the Factor V Leiden (FVL) mutation in a group of is important in the occurrence of PT-CDH. Subjects wi3:
patients with either migrainous cerebral infarction or PT-CDH had <1 headache/month before head injury
migraine equivalents. Methods.Retrospective study of uni- (HI), and had frequent headache onset with HI and sub-
versity-based outpatient neurology clinic. Results. Ten sequently had HA ~20 days/month for at least 6 months
patients were identified with either migrainous cerebral (n = 24). These were age- and sex-matched to 24 subjects
infarction or migraine equivalents. Three patients (30%) with ICDH. Occurrence of significant headache (SHA) in
had an abnormal APCR ratio (defined as less than or equal mother and father was determined by interview of the
to 2.2). One patient was heterozygous for the FVL muta- patient. SHA in the parent was defined as any recurrent
tion. Conclusions. APCR and the FVL mutation may be headache that caused temporary disability or required
important in the production of cerebral or retinal ischemic medication For PT-CDH subjects, parental SHA occurred
symptoms in patients with a migrainous tendency. Larger in 8 mothers, 3 fathers, and in both parents for 2 subjects.
case control studies are necessary to determine the strength For ICDH subjects, parental SHA occurred in 9 mothers,
of this association. 3 fathers, and in both parents for 4 subjects. Statistically
there was no difference between PT-CDH and ICDH in
occurrence of SHA in parents. These data suggest that
2.3 familial occurrence of headache is not a factor in occurrence
of PT-CDH after head injury.
Prevalence of unexplained upper abdominal symptoms
in patients with migraine. T Kurth’, G Holtmann2,
J Neufang-Hiibe?, H Goebel12,HC Diener’. Department 2.5
of Neurology, 2Department of Gastroenterology; Sleep and headache diaries in migraine in children.
University of Essen, Germany ML H&n$iltien, K Aaltonen, K Hoppu. Hospital for
Children and Adolescents, University of Helsinki,
Background. Headache and migraine are frequently Helsinki, Finland
reported by patients with functional gastrointestinal (GI)
disorders (functional dyspepsia and irritable bowel syn- One-hundred-and-thirty-three 4 to 16-year-old children
drome) symptoms. In contrast, data on the prevalence of registered 999 migraine attacks in headache diaries.
382 Platform presentations CEPHALALGIA 18 (1998)

Seventy-four patients recorded 409 attacks using a visual diagnosis and treatment of the primary headaches by non-
analog scale (VAS), 67 patients registered 590 attacks with headache specialists, who tend to stay tuned to their own
a 5-face scale; 8 patients used both scales. The distribution speciality. An awareness ther@re needs fo be created in these
of maximal pain intensity was similar on both scales, and ozmlap specialities.
most of the patients scored it with the highest grades.
Over 68% of the children sometimes had attacks that
3.1
resulted in sleep. Overall, children fell asleep in 33% of
the attacks (n=329). Of these attacks, 209 were finished Increased density of dopamine D3 and D4 receptors on
with sleep within an hour, 55 within 2 h, and 65 after 2 h. lymphocytes in migraine. P Barbanti’, G Fabbrini’,
Children under 8 years fell asleep significantly more often A Ricci2, MP Pascal?, B Caronti’, GL Lenzi’, R Cerbo’.
than older children (ANOVA, p <O.OOOl):62% of the Departments of ‘Neurosciences and of Cardiovascular
attacks resulted in sleep in those under 8 years, 34% in and Respiratory Sciences, University “La Sapienza”,
those aged 8 to 12 years and 24% in those over 12 years. Rome, Italy
The effect of age was slightly greater in males, but sex
alone or combined with age did not have any significant Background. Dopamine is involved in migraine as revealed
effect on the percentage of the attacks in each child that by biological, pharmacological, and genetic evidence.
were terminated with sleep. The pain was relieved without Several drugs used in migraine prophylaxis, such as lisur-
sleep in 431 attacks; medication, intensity, and type of ide, dihydroergocryptine and fhmarizine, act on dopamine
attack were not taken into account. Of the attacks, 165 D2-like receptors. We previously demonstrated that
were resolved within 2 h, 218 within 2 to 4 h, and 48 lasted migraine patients show a higher density of dopamine D5
over 4 h. In 10% of the attacks, the recording failed within receptors on peripheral blood lymphocytes (PBL) than
5 h (50 patients). The registration could not be completed healthy controls. Methods. We studied the expression of
in 14% of the attacks, because they lasted over 5 h (51 dopamine D3 and D4 receptors on PBL membranes (PBLm)
patients). Failure of recording was more common in chil- in 20 untreated patients affected by migraine with (n=6)
dren who used VAS (14%) as compared to children who and without aura (n = 14) (14F, 6M; mean age 28.6, range
used face scale (10%). We suggest that sleep should be 21-38) and in 15 healthy age-matched controls using a
considered as a response in clinical drug trials. Headache radioligand binding assay technique and the dopamine
diaries can be used successfully in young children assisted D2-like receptor agonist [3H]-7-OH-DPAT as a radioligand.
by their parents, and older children can fill them Non-specific binding was defined by incubating PBLm
independently. with dopamine alone and with specific antibodies against
D3 and D4 receptors. Results. [3H]-7-OH-DPAT was spe-
cifically bound to PBLm in a manner consistent with the
2.6 labeling of dopamine D3 and D4 receptors. Migraineurs
showed an increased density (~~0.01) of both D3 and D4
Pitfalls in the management of primary headaches-an receptors on PBLm compared to healthy controls with no
objective headache clinic analysis. K Ravishankar. changes in the receptorial affinity (Kd) between the groups
Headache Clinic, Jaslok Hospital & Research Centre, investigated. Conclusions. Dopamine D3 and D4 receptors
Bombay 400 026, India on PBLm are up-regulated in migraine. This may represent
a peripheral sign of altered dopaminergic function and
Rationale.Though it is well known that primary headaches gives further support to the hypothesis of the involvement
are underdiagnosed and undertreated, objective data on of dopaminergic neurotransmission in migraine.
this subject are lacking. We therefore undertook a prospec-
tive study in order fo identifythe areas whe non-head&~
specialists erred in the management of the different primay 3.2
headaches. Data. Based on a questionnaire and review of Nitric oxide, prostaglandins, and serotonin as co-factors
previous medical records wherever available, data of the migraine attack. G Nattero’, G Mengozzi2.
obtained from 1500 headache clinic patients formed the ‘Department of Clinical Pathophysiology, ‘Department of
basis of this study. Information was obtained regarding Medicine and Experimental Oncology, University of
self-medication, diagnosis made earlier, headache drugs Turin, via Genova 3, Turin, Italy
prescribed and their dosages and the importance given to
patient education and follow-up. Critical assessments were Our previous research showed a chronological correlation
made in each patient regarding the inadequacies in the among 5HT platelet release and PGI, plasma level decrease
management. Our analysis showed that, prior to coming at the onset of cortical spreading oligemia and the sub-
to our clinic 460 patients were self-medicating themselves, sequent phase of migraine crises, with statistically signi-
920 patients had consulted an eye specialist, 70 patients ficant differences in both the spectrofluorometric platelet
with migraine had undergone gastroscopy, 15 patients concentrations and PG12RIA levels between the headache-
with cluster headache had undergone sinus surgery, men- free period and the migraine attack. In this study both
strual migraine was always misdiagnosed, only a limited nitrosyl-hemoglobin complexes, assessed through electron
number of prophylactics were used and there was no paramagnetic resonance (EPR) spectroscopy, and nitrite/
awareness of the IHS classification. While GPs and other nitrate amounts, detected by the Griess calorimetric
specialists were found wanting in both diagnosis and method, were used to evaluate possible roles of nitric
treatment, neurologists too grossly undertreated their oxide (NO) in the pathogenesis of migraine. Increases in
patients. Other interesting observations and suggestions NO levels were found between basal and attack conditions
have been listed. Con&km. This study shows that head- (0.77_+0.34 vs 1.26 f 0.73 arbitrary units and 33.7 +9.9 vs
ache suffering can be substantially reduced by proper 17.3 f 5.8 w/L, for EPR and Griess analysis, respectively;
CEFWALALGIA 18 (1998) Plat$wm presentations 383

n=12). An enhanced NO synthase (NOS) activity (via occur. In the present study we extended the study of
constitutive endothelial NOS and/or neuronal NOS peripheral levels of Mg+ + (in erythrocytes and mono-
up-regulation) could be hypothesized to occur, whereas nuclear cells), in association with a systematic neurophysi-
the involvement of a hyperfunctioning inducible NOS in ological evaluation, to young headache patients, in order
the reperfusion phase, concomitant to increased PGEl to verify whether in juvenile headache neuromuscular
production, as demonstrated also by our findings, could hyperexcitability, studied electromyographically, may be
account for the vasodilation with augmented vessel wall related to the intracellular concentration of Mg+ +. We
permeability and decreased pain threshold in the so-called examined 113 young headache patients: 56 with migraine
trigemino-vascular sterile mflammation of the subsequent without aura (MwA) (mean age 11.6 f 2.5 years), 10 with
phases of the migraine attack. With the mutual interaction migraine with aura (MA) (mean age 13+3.2 years), 13
between NO and rostaglandin pathways, new therapeutic affected by episodic tension-type headache (ETTH) (mean
approaches coul dpbe recognized capable of modulating age 12.2f2.5 years), 4 by chronic tension-type head-
the synthesis and the release of these crucial mediators. ache (CTFH) (mean age 13.5k1.7 years) as well as 30
After the administration of a compound of indomethacin,
patients with two associated headache forms (21 with
prochlorperazine and caffeine, able promptly to relieve
MwA +ETFH, mean age 12.4f2.7 years and 9 with
migraine pain, while EPR-detectable NO levels further
MwA+CTIH, mean age 13.8 +3 years). Data were com-
increased (2.88 f 1.78, p <O.OS with respect to inter&al
condition; p =0.012 by the analysis of variance), nitrite/ pared with those of 20 young age-matched healthy sub-
nitrate concentrations declined to basal values. jects. Clinical diagnosis was made according to the current
MS criteria. The EM graphical test and the biochemic
evaluation of peripheral indices of magnesium status were
3.3 carried out according to Mazzotta et al. (Headache
Cortical spreading depression induces tumor necrosis 1996;11:53-8). Statistical analysis included ANOVA, 11’and
factor a expression in rat brain tissue. Qi-Hui Zhai, multiple regression. In MwA patients, red blood cell Mg+ +
FJ Chen, S Boyer, M Chopp, KMA Welch. Department of levels were significantly lower (1.9 fO.l mmol/L) than
Neurology, Henry Ford Hospital, Detroit, MI, USA those of CTI’H patients (2.2kO.01 mmol/L) and those of
the control group (p<O.OOOl); compared to the values
Cortical spreading depression (CSD), a short-lasting cell found in MA and ETTH patients, a decrease in red blood
membrane depolarization, is the putative mechanism for cells Mg+ + levels was found in MwA patients but the
the aura of migraine. Neurogenic inflammation may be differences between the means of the patient groups were
involved in headache. We report here CSD effects on not statistically significant. No significant differences
expression of tumor necrosis factor a (TNF@ in rat brain. emerged in Mg + + levels determined in mononuclear cells
Sixteen male wistar rats (260-300 g) were anesthetized between all juvenile headache groups and controls. The x2
with halothane. Physiological parameters were monitored. test evidenced a significant prevalence of EMG positive
Multiple CSD episodes were induced by four topical tests in MwA patients (84%) and in patients with an
applications of 2 M KCL at 25 min intervals onto the left association between MwA and ETTH (50%) or MwA and
hemisphere. Cortical direct current potential was continu- CTI’H (66%) with respect to ETTH (15.38%) and CTTH
ously recorded. Another 4 rats were used as saline controls. (0%) ( p < 0.01). Finally, multiple regression showed a signi-
Rats were sacrificed 0.5 (n =3), 2 (n = 5), 4 (n = 4), and 24 ficant association between positive EM graphic tests and
(n =4) h after CSD. Immunohistochemistry was performed the decrease in red blood cell magnesium levels ( p -E 0.008).
to detect TNFol immunoreactivity on frozen cut rat brain The findings of the present research therefore confirm the
tissues at two levels. TNFcl immunopositive cells were possibility of differentiating headache patients also in
counted. Repetitive CSD episodes (2.5 +l.l) provoked childhood and adolescence on the basis of the biochemical
TNFa rotein expression at 0.5 h that declined at 2,4, and
markers of magnesium status and the neurophysiological
24h aKer CSD. Saline did not induce CSD. TNFa was
evidence of neuronal hyperexcitability.
mainly localized within the wall of pial blood vessels and
endothelial cells of parenchymal capillaries at 0.5 com-
pared to 2 and 4 h ( p ~0.01). At 2 h, however, neurons
and astrocytes expressed an increased proportion of TNFa. 3.5
Because TNFa modulates vascular tone, increases endo-
Transformed migraine as a cause of chronic daily
thelial permeability, and mediates inflammation, the
observed changes may have relevance to the mechanism headaches. JS Meyer, S KOMO, GM Margishvili,
of a migraine attack. (Supported by NM grant P50 MA Haque. Department of Neurology, Baylor College
NS32399.) of Medicine and VAMC, Houston, TX, USA

Backgroundand purpose. Chronic daily headaches are daily

3.4 episodes of head pain usually associated with migraine
Intracellular Mg ++ concentration and with or without aura or tension-type headaches alone or
electromyographical ischemic test in juvenile headache. combined (International Headache Society, IHS, classified).
G Mazzotta, P Sarchielli, E Cittadini, F Ruju, A Alberti, They are often associated with rebound headaches and
V Gallai. Interuniversity Centre for the Stud of analgesic abuse. The IHS does not specifically list chronic
Headache and Neurotransmitter Disorder oY CNS daily headaches as a diagnosis. We reported (Headache
(Perugia-Rome-Sassari-Bari). Unit of Perugia, Italy 1996;36:589-94) that migraineurs exhibit excessive cerebral
cortical vasodilation after acetazolamide (Diamox*) which
Headache has often been described in the hyperexcitability usually precipitated typical migraine headaches. We now
syndrome in which calcium and magnesium alterations report cerebral vasodilator responses measured among 11
384 PZatjinmpresentatims CEPHALALGIA 18 (1998)

patients with chronic daily headaches tested with oral ketamine, sumatriptan, and indomethacin, ergotamine,
Diamox@ utilizing CT cerebral blood flow (CBF) measure- NSAIDs.
ments. Methods. Subjects included 11 chronic daily head-
ache patients (aged 55k14.7 years) plus 12 age-matched
migraineurs with and without aura and history of typical 3.7
intermittent migraine headaches (aged 54.7 f 10.0). Local 3D Kinematic analysis of neck movement in whiplash
cerebral vasodilator responses (ALCBF) were tested by headache. G Sandrini, M Bulgheroni, F Antonaci,
26% Xe inhalation before and after Diamox@ 14.3 mg/kg S Ghirmai, S Lanfranchi, G Nappi. University Centre for
body weight. Global cortical, subcortical gray, and white Adaptive Disorders and Headache (UCADH), Section of
matter ALCBFs were calculated. Resulfs. After Diamox@, Pavia I, IRCCS “C. Mondino Foundation”, Pavia, Italy
ALCBF increased in cortical gray matter by 11.8% among
patients with chronic daily headaches and by 16.7% among The conventional clinical and radiological measurements
typical migraineurs, with no significant differences in of neck range of motion (ROM) have largely been provid-
ALCBF between groups. Typical migraine headaches were ing non-univocal results in whiplash headache. The object
provoked by Diamox@ in 9 (82%) patients with chronic of this report is to evaluate the neck movement with a
daily headaches and 11 (92%) migraineurs. Conclusions. non-invasive tool in whiplash headache. Patients and
The above observations substantiate that at least 73% of methods. Thirty-nine patients (M/F=9/30), mean age
chronic daily headache patients have transformed 31-l&- 7.6 years, diagnosed according to the Quebec Task
migraine as judged by provocation of typical migraine Force Classification of Whiplash-Associated Disorders
attacks by Diamox@ with excessive ALCBF increases. (1995) as grade 1 (n = l), grade 2 (n = 31), and grade 3 (n =
Serotonin agonists should be considered in treating chronic 7) entered the study. The illness duration was I 1 year in
daily headaches and avoidance of analgesics. 19 patients and 2 1 year in 20. Eleven patients were tested
at the time of first consultation (TO) and 6 months (T6)
later. 3D-kinemutic analysis of the cervical spine (Elite sysfem).
A multifactorial analysis of neck ROM using passive
3.6 markers, 2 CCD cameras, which allow the real time
Changes in hyperalgesia set-up and subjective recognition of passive markers, 3D co-ordinates recon-
preference for different types of abortive anti-migraine struction with velocity and acceleration computing, has
drugs. M Nicolodi. Interuniversity Centre of been used. The evaluation was carried out on the mean of
Neurochemistry and Clinical Pharmacology of Idiopathic five active consecutive movements at usual velocity as
Headache & Department of Internal Medicine, University follows: flexion-extension, axial rotation, and lateral
of Florence, Florence, Italy bending. Results. The left axial rotation and right lateral
bending ROM differed significantly (~~0.05) in the two
Vascular/visceral hyperalgesia is a common stigma of groups of patients compared with controls. In patients
migraine sufferers. Hyperalgesia depends on the abnormal with whiplash which occurred 11 year a significantly
set-up of CNS, chiefly consisting in neuroplastic changes. reduced ROM was found in right axial rotation and left
Migraine attacks are treated by using NSAIDs or specific lateral bending compared to controls (p<O.O5), while in
all the patients a significantly reduced ROM was found in
anti-migraine drugs such as sumatriptan and ergotamine.
left axial rotation and right lateral bending compared to
Recently, we introduced negative modulators of excitatory
amino acids as treatment of migraine attacks. In 100 controls ( p (0.05). At 6-month follow-up the ROM was
migraine sufferers, we searched for a relationship between significantly improved during left axial rotation and lateral
vascular/visceral hyperalgesia and the preferred analgesic. bending ( p < 0.05) with a slight amelioration during the
Twenty-five patients preferring sumatriptan, 25 indometh- other movements. No statistical correlation was found
acin, 25 ergotamine, 25 NSAIDs were administered the between ROM and type of collision, pain side, or Quebec
Task Force scoring. Conclusion. Alterations in neck move-
following drugs while headache-free: ergotamine, aspirin,
sumatriptan, indomethacin, barbiturates, ketamine. ments were documented by a 3D kinematic analysis in
Between tests, a 5-day latency period was observed. recent whiplash in comparison with whiplash occurring
2 1 year. In the 6 months follow-up a significant improve-
During a second trial the same patients received a 4-day
treatment of the cited drugs. The interval between two ment of the kinematic parameters was observed. (This
different treatments was 2 weeks. As acute treatments, all work was supported by a grant from the Ministry of
Public Health No. 57.2/RF93.28.)
these drugs induced a slight but significant (p >0.05)
decrease of hyperalgesia. Chronic treatment with ketamine
significantly ( p > 0.001) decreased hyperalgesia ( p > O.OOl),
4.1
sumatriptan, indomethacin, and barbiturates behaved sim-
ilarly (p>O.O05); ergotamine induced a minor effect The dose range characteristics of frovatriptan (VML
( p > 0.01); aspirin-induced decrease of hyperalgesia over- 251) a potent cerebroselective 5HTImD agonist in the
lapped the one following acute administration. A direct acute treatment of migraine. A Rapoport, New England
relationship (~~0.05) correlates subjects preferring the Center for Headache, USA; C Keywood. Vanguard
drug under investigation and the higher levels of decrease Medica Ltd, Chancellor Court, Guildford, UK.
of hyperalgesia. We suggest that migraine sufferers prefer
the drug which is more active on hyperalgesia state. In Introduction. Frovatriptan (proposed INN) is a potent,
general population, the drugs more active in modifying cerebroselective 5HTlB11Pagonist being developed for the
vascular/visceral hyperalgesia are, in order of potency: acute treatment of migraine. The dose range characteristics
CEPHALALGIA 18 (1998) PiuY;mn presentations 385

for efficacy and tolerability were examined in two studies. 4.3

Methods. A total of 1442 patients (208M, 1234F) aged 18 to
65 years treated an acute migraine with a single oral dose Successful treatment of severe, disabling migraine
of placebo or frovatriptan 0.5 mg to 40 mg. Primary efficacy headache with a non-prescription combination of
was the proportion of patients whose headache decreased acetaminophen, aspirin, and caffeine: results from three
in severity from moderate or severe to mild or none, 2 h randomized, placebo-controlled studies. J Goldstein. San
post-dose. ResuZts.All doses from 2.5mg to 40mg had Francisco, CA, USA; HD Hoffman, JJ Armellino, JP
similar 2-h response rates (38-48%) that were superior to Battikha. Hillside, NJ, USA; J Couch Jr. Oklahoma City,
placebo (24%) (p-=0.05). Two-hour response rates for OK, USA; H Blumenthal. Tulsa, OK, USA; RB Lipton.
0.5 mg and 1 mg (30% and 26%) were not different to Bronx, NY, USA
placebo. Four-hour response rate for 2.5 mg was 66% and
all doses (51-72%) were superior to placebo (35%) Objective. To evaluate the efficacy of Excedrin Extra
(p <0.02). A dose relationship for adverse events was Strength in the treatment of severe migraine headache.
observed (placebo 31%, frovatriptan 34-71%, 2.5 mg 41%) Background.Three methodologically identical, multicenter
with the incidence increasing noticeably from 10 mg. All studies (n = 1220) showed significant efficacy of acetamin-
doses of frovatriptan were well tolerated. CuncZusion. ophen (AAC) vs placebo in the relief of moderate to severe
Frovatriptan was effective and well tolerated across a migraine headache. Design/mefhods. A subset of particip-
broad dose range. The lowest effective dose was 2.5 mg. ants included in this analysis had severe migraine head-
Higher doses did not have additional efficacy, but had a ache. They were identified from 3 randomized, single-
greater incidence of adverse events. Frovatriptan 2.5 mg dose, double-blind, placebo-controlled studies and met the
represents the optimal combination of efficacy and toler- International Headache Society diagnostic criteria for
ability for acute treatment of migraine. migraine with or without aura. Subjects who were usually
so debilitated as to require bed rest for their attacks or
who experienced vomiting 220% of the time were not
eligible for enrollment. Subjects treated their severe
4.2
migraines with a IL-tabletdose of oral AAC 250 mg, aspirin
EfIicacy, safety, and tolerability of oral eletriptan 250 mg, and caffeine 65 mg per tablet) or placebo. Pam
(40 mg and 80 mg) in the acute treatment of migraine: intensity, disability, nausea, photophobia, and phonopho-
results of a phase III study. TJ Steiner on behalf of the bia were measured hourly from O-6 h postdose. Results.
Eletriptan Steering Committee, Charing Cross and Pam relief (severe migraine headache reduced to mild or
Westminster Medical School none) was significant in AAC subjects compared to placebo
( p < 0.03). At hour 2, 37% of the AAC subjects vs 14% of
The efficacy, safety, and tolerability of oral eletriptan were the placebo subjects had significant pain relief ( p = 0.002).
assessed in a phase III double-blind placebo-controlled At hour 4,63% of AAC subjects vs 35% of placebo subjects
parallel groups trial; 1,151 outpatients with migraine with ( p = 0.002) experienced pain relief. At hour 6,35% of AAC
or without aura (B-IS classification) were asked to treat subjects vs 12% of placebo subjects were pain-free (p=
their next acute attack with headache of moderate to 0.001). Conchsion. Excedrin Extra Strength was effective in
severe intensity, and randomized to placebo (n =238) or treating the pain and associated symptoms of severe
eletriptan 40 mg (n =452) or 80 mg (n =461). The primary disabling migraine. (Supported by: Bristol-Myers Squibb
efficacy measure was headache “response” (intensity Company.)
reduction from severe or moderate to mild or no head-
ache). The intention-to-treat analysis is described. Efficacy
(as headache response) was reported within 2 h of treat-
4.4
ment by 19% of patients on placebo and by 62% ( p < 0.0001)
and 65% (p <O.OOOl)of patients on eletriptan 40 mg and Effect of the combined administration of
80 mg. Headache-free at 2 h were 3% of patients on placebo dextromethorphan propacetamol and magnesium in
and 32% ( p <O.OOOl)and 34% ( p < 0.0001) on eletriptan chronic headache. BM Fusco’, C Saturnine’,
40 mg and 80 mg. Within 1 h headache response was 0 Colantoni’, GM Pitari*, G De Martinol, A Bianchi*.
reported by 9% of patients on placebo and by 33% ‘Department of Pharmacological Sciences, University of
(p ~0.0001) in each eletriptan group. In those in whom it Salermo; *Institute of Pharmacology, University of
was present at baseline, nausea was relieved within 2 h in Catania, Italy
34% on placebo, 57% on 40 mg and 54% on 80 mg; photo-
phobia in 19% on placebo, 53% on 40 mg and 60% on Chronic headache patients represent about 25% of the
80 mg; phonophobia in 22% vs 57% and 59% (all patients reporting to specialized Headache Centers. Their
p <O.OOOl). Headache recurrence within 24 h of treatment headaches have been classified as chronic tension head-
after response within 2 h occurred in 40% on placebo, 30% aches, chronic migraine and chronic headaches ab inifio,
on 40 mg (NS) and 21% (p < 0.01) on 80 mg. The median even if hey did not show significant clinical differences.
times to recurrence were 5 h on placebo and 17 h and 19 h The spinal excitatory circuits involving the NMDA recep-
on eletriptan 40 mg and 80 mg. Eletriptan was generally tors may play a role in their genesis. Dextromethorphan
weU tolerated and most adverse events were mild or is an antagonist of the NMDA receptors, even if the
moderate, and transient. In conclusion, oral eletriptan in effective dose appears too high for human use. Since both
both doses, 40mg and 80 mg, appears safe. This study a high concentration of magnesium and some peripheral
confirms that it is effective and well tolerated in the acute analgesic drugs (particularly paracetamol) interfere with
treatment of migraine. NMDA receptor activation, the effect of a combination of
 386 Platjhn presentations CEPHALALGIA 18 (1998)

oral doses of dextromethorphan (30 mg, 3 times a day), some new medications. The object was to study the efficacy
and slow intravenous infusion of 1 g magnesium pidolate of many medications which have not been used or written
and 1 g pro-pacetamol (a paracetamol precursor) was about, as welI as the efficacy of medicines used often. Four
verified in 10 patients (6 affected by chronicized migraine, hundred and twenty women between the ages of 17 and
4 by chronic headache ab initiu). The therapy was repeated 50 years with any history of menstrual migraines were
for 7 days. The daily headache intensity was evaluated by treated from 6 months to 5 years. There were 30 patients
a verbal scale (no pain, light, moderate, intense) and a in each of the 10 categories of drugs and 30 placebo-
visual analogue scale a week before, during and a month treated controls. Drug groups included NSAIDs, beta
after the treatment. Complete relief from the headache blockers, calcium channel blockers, alpha stimulators, anti-
(lasting at least 20 days) was experienced by 7 patients. depressants, methysergide, lithium, ergots, dihydroer-
The remaining 3 patients reported a discontinuation of the gotamine, sumatriptan, cardiosteroids, danocrine, dopa-
pain for a week, after which the headache reoccurred, but agonists, female and male hormones and combinations.
in light and brief episodes. This study showed that dextro- (Treatment was started 3-4 days before the menstrual
methorphan combined with magnesium and paracetamol cycle and given for a period of 5-8 days. A given medica-
is able to discontinue chronic headaches, possibly by tion or combination was used for 6 cycles before switching
interfering with spinal excitatory circuits. to other medications. Placebo controls were treated with
placebo for 6 months as well.) There is a wide variety of
drugs of varying degrees of efficacy in the difficult-to-treat
4.5 condition of menstrual migraines. There are many new
Light therapy in migraine prophylaxis: an open study. drugs on the horizon. In this study, methysergide, cardios-
L Savi, L Iosca, I Rainero, W Valfre, L Pinessi. teroids, and a combination of ergotamine and dihydroer-
Department of Neurosciences, Headache Center, Torino gotamine were the NSAIDs found to be most effective
University, San Giovanni Hospital, Torino, Italy (63-77%). Ergots, sumatriptan, danocrine, antidepressants,
calcium chemical blockers, and dopa-agonists were moder-
Light therapy was shown to be an effective treatment for ately effective. Beta blockers, clonidine, lithium, and com-
affective disorders, eating disorders and insomnia. The binations of estrogen and testosterone were least effective.
precise mechanism of action of phototherapy is still
unclear. Bright light may elevate brain concentrations of
several neurotransmitters, including serotonin. Several 5.1
studies have shown impaired seroto&n (5HT) metabolism
Neural blockade of intractable migraine and cluster
in migraine. During migraine attack, CAP urinary 5HT headaches. Treatment of central sympathetic
catabolites are increased while platelet 5HT content is
dysfunction. BH Landgrebe. 6609 Blanc0 Road,
reduced. Pharmacological agents CAP that stimulate 5HT
San Antonio 78216, TX, USA
receptors or prevent 5HT m-uptake are currently used in
migraine therapy. The aim of this study was to evaluate
A textbook states that “stellate ganglion blocks (SGB) have
the effects of light therapy in the prophylactic treatment
no effect in migraine (M) since M is due to dilatation of
of migraine attacks. A group of 9 patients (4F, 5M, age
the extracranial vasculature”. Contrary to that statement,
range 31-52 years) was studied. They were all suffering
SGBs substantially relieve or abort M not responsive to
from migraine without aura (MO), according to the
previous pharmacological treatment. After a few SGBs,
International Headache Society (MS) criteria. After a
only prodromal signs or auras occur, but no more M. A
4week run-in period, the patients were subjected to the
few SGBs arrest M in the majority of patients followed
treatment (30 min of bright light, -2500 lux, on 9 alternate
over 20 years. Surgical removal of the stellate ganglion
days). Migraine frequency was evaluated 4 and 8 weeks
(SG) for M gives short-term relief with subsequent recur-
after the therapy by means of direct interview and exam-
rence or worsening of M, since denervation supersensitiv-
ination of headache diaries and compared with the previ-
ity to noradrenaline (NA) and to serotonin develops.
ous situation. A significant reduction in the number of
In cluster headaches (CH), SGBs and sphenopalatine
days with migraine was observed in 7 patients. At present,
ganglion blocks usually result in immediate pain relief.
we are looking for a possible relationship between the
Sympathetic activity is elevated in M and reduced in CH.
response to light-therapy and age, gender, frequency,
The SG is connected to the Locus CoeruZeus(LC), implicated
duration and severity of migraine attacks, mood disorders,
in central sympathetic dysfunction in M. The LC particip-
or anxiety. Our preliminary results show that light therapy
ates in nociception, autonomic, and endocrine functions.
may be an effective treatment in migraine prophylaxis.
Presynaptic alpha-adrenergic agonists injected into the LC
Additional studies are needed to confirm our results.
reduce NA and induce an anesthesia-like state. Stimulation
of the LC, projecting to thalamus, cerebral cortex and
cerebellum, results in simultaneous ipsilateral intracranial
4.6
vasoconstriction and extracranial vasodilatation resem-
Drug treatment of menstrual migraines-a 5-year bling vascular changes in M. Ischemia, not hyperemia,
prospective study. BS Kathpal. Department of provokes headache. Many anti-ischemic and antimigraine
Neurology, Allegheny University, Canonsburg, PA drugs have alpha-adrenergic properties or block beta-
15317, USA adrenergic receptors. Zn addition SGBs attenuate sympath-
etic activity. “Conscious” pain perception takes place in
Drug treatment of menstrual migraines was evaluated the reticular formation and thalamus. EEG abnormalities
over a 5-year period using some well-established and present frequently in M, sometimes with paroxysmal-
cEm-IALALGIA 18(1!398) PZa+rm presentations 387

dysrhythmic patterns, and alterations of visually-evoked had to discontinue treatment because of such effects (con-
potentials point to thalamic and hypothalamic lesions. stipation and somnolence; no sign&ant hypotension
observed). These preliminary results confirm that verapa-
mil is effective and well tolerated in the prophylaxis of
5.2 CH, and suggest the drug as a first-line treatment to
Rapid preventive treatment of episodic cluster prevent CH attacks.
headache. A Pradalier, G Baudesson, A Delage. Hopital
Louis Mourier, Colombes, France
5.4
The onset of efficacy of corticosteroids and other preven- Migraine and ocular pain in glaucoma suspect patients.
tive treatments of episodic chaster headache (ECH) are not M De Marinis’, A de Feo’, S Santarelli2, G De Benedetti2,
clearly understood in the literature. The files of the A Mollicone2, J Pecori Giraldi2, N Accornero’.
Migraine and Headache Center were reviewed in order to Department of Neuroscience, “La Sapienza” University,
determine the most effective preventive treatment of ECH. Rome, Italy; htitute of Ophthalmology, “La Sapienza”
Forty of the 129 files of documented ECH were analysed. University, Rome, Italy
Patients were divided into two groups: the first group (20
cases) received 60 mg/day of prednisolone as a single A relationship between migraine and glaucoma has been
dose for 8 days, then at decreasing doses until D15 when suggested by some authors. This possibility, however, has
treatment stopped. The second group (20 cases) received not been confirmed by others, and may be challenged by
either methysergide or verapamil, selected as a function the fact that objective ocular alterations, such as optic disc
of the contra-indications for each patient. Treatment was abnormalities and visual field defects, are present in glauc-
progressively increased and continued beyond D15. oma and not in migraine patients. We studied the preval-
Results were assessed according to two criteria: course of ence and features of migraine and ocular pain in 220
the number of episodes on Dl, DS and D15 and overall “glaucoma suspect” patients (without ocular disc and
assessment of treatment. The beneficial action of cortico- visual field alterations) and 220 controls. A standardized
steroid therapy was significant on D8 (number of daily questionnaire based on the IHS classification criteria was
episodes 0.8 +0.89 for CS vs 1.65 &-1.03 for other treat- used to assess the features of migraine and ocular pain.
ments), but faded on D15. The beneficial action of the Family history of migraine and glaucoma and duration of
other treatments was only significant after D15. Our study, both diseases were also investigated. A higher prevalence
although retrospective, therefore argues in favor of cortico- of migraine was found in patients (12%), particularly in
steroid therapy as rapid preventive treatment of episodic females (l%), than in controls (6%). Migraine persisted
CH compared to other treatments. in the elderly in patients, whereas it diminished or ceased
over the years in controls. Attacks of atypical “ocular
pain’ not associated with ocular hypertension were found
5.3 to occur only in “glaucoma suspect” patients who suffered
Verapamil efficacy in cluster headache prophylaxis: a from migraine (33%). This “ocular pain” (not severe,
double-blind multicentre study vs placebo. G Bussone’, stabbing, lasting hours) was easily distinguishable from
M Leone’, D D’Amico’, A Attanasio’, F Moschiano2, the migraine pain, and seemed to be time-related to the
F Frediani3. ‘Department of Neurology, Headache history of glaucoma but not to headache or ocular hyper-
Center, Neurological Institute “Carlo Besta”, via Celoria, tension Family history of migraine was more prevalent
n. 11, Milan, Italy; 2Department of Neurology, “L. than family history of glaucoma in these subjects. An
Mandic” Hospital, Merate, Lecco, Italy; 3Headache interaction between “glaucoma suspect” and migraine
Center, “G. Fornaroli” Hospital, Magenta, Milan, Italy may be suggested regardless of the vascular mechanisms
that induce optic disc and visual field abnormalities in
typical glaucoma.
We previously showed that verapamil was effective in the
prophylaxis of cluster headache (CH) in a double-blind
study against lithium. We now report the results of a
5.5
double-blind study of verapamil vs placebo in the preven-
tion of CH. Twenty episodic CH patients completed the Helicobacter pylori chronic gastric infection in
trial. Inclusion criteria were chronic or episodic CH diag- headache patients. L Savi’, A Ponzetto’, A Gasbarrini3,
nosed according to International Headache Society criteria, I Rainero’, L Pines&. lDepartment of Neurosciences,
previous cluster periods lasting at least 1 month, enrolment Headache Center, Torino University, San Giovanni
2-10 days after beginning a cluster period, normal ECG, Hospital, Torino, Italy; apartment of Gastroenterology,
and no hyper- or hypotension, liver or kidney pathology. San Giovanni Hospital, Torino, Italy; 3Angiology, Gemelli
The patients were randomly assigned to either oral verapa- Hospital, Catholic University, Roma, Italy
mil 360 mg (t.i.d., n =13) or placebo (n =7) for 14 days,
after a 5-day run-in without prophylaxis. We found that According to recent studies, Helicubacterpylori (H. ~ZOTZ)
both headache frequency (ANOVA p c 0.001) and analgesic chronic gastric infection may be associated with such
consumption ( p =0X102) were significantly reduced from different vascular disorders as coronary heart disease,
the first treatment week in the verapamil arm and even primary Raynaud phenomenon, and stroke. H. pyhi infec-
more so in the second week, while no amelioration was tion in fact may provoke an immune-mediated release of
observed in the placebo group. Side effects were more vasoactive substances that could be responsible for its
frequently reported in the verapamil group, but no patient involvement in these disorders. Vascular abnormalities,
388 Pla#m presentations CEPHALALGIA 18 (1998)

altered platelet function, increased vasoactive peptides O.O4),and HV (p=O.O3) and between initial amplitude and
plasma levels, and gastrointestinal disorders have fre- auditory evoked potential amplitude change between 40
quently been described in primary headaches. The aim of and 70 dB in MO (p=O.O04) and MA (p=O.O07), but not
this study was to evaluate the prevalence of Ii. pyZori in HV (p=O.14). ASF slope and initial amplitudes did not
chronic gastric infection in patients with primary head- correlate. These results confirm the interictal lack of habitu-
ache. A group of 37 patients (27F, lOM, age range 16-56 ation in cortical processing of visual and auditory informa-
years) were studied. According to International Headache tion in migraine. There is no correlation between the 2
Society (IHS) criteria, 25 patients were suffering from sensory modalities in the same patients. The strong nega-
migraine without aura (MO), 10 from both MO and tive correlation between initial potential amplitudes and
tension-type headache (TTH) and 2 from TTH. H. pylori amplitude potentiation confirms that the latter is probably
gastric infection was diagnosed by means of both due to a reduced cortical preactivation level.
13-carbon urea breath testing and the presence of blood
H. Pyruriantibodies. A control group of 117 blood donors
(89F, 28M, age range 18-58 years) was used for statistical
analysis. H. pylori chronic gastric infection was more 7.2
frequent in young ( ~40 years) MO female patients (43%)
than in controls (14%) (p<O.O5). Our study shows that Riboflavin and betablockers in prophylactic anti-
H. pylori infection is significantly more frequent in young migraine therapy: differential effects on the intensity
females affected by MO. Further studies are needed in dependence of ,cortical auditory evoked potentials.
order to elucidate the relationship between H. pylori infec- PS Sandorl, J Afra2, A Mascia' , J Schoenen’. ‘Neurology
tion and headache. However, our results could point to Department, CHR Citadelle, University of Liege,
the involvement of H. pyluri in the pathogenesis of MO Belgium; ?Neurology Department, Semmelweis
and open the way to new therapeutic strategies. University, Budapest, Hungary

Background.Neurophysiological studies in migraine patients

show dysfunction in cortical activity. Steep amplitude
stimuhrs functions were found in the intensity dependence
of cortical auditory evoked potentials (IDAP), which is
ABSTRACT NUMBERING thought to be inversely related to the level of central nervous
CONTINUES WITH 7.1 serotonergic neurotransmission. Prophylactic treatments in
migraine may have different mechanisms of action. We have
studied the IDAP in migraineurs before and after a 4month
prophylaxis with beta-blockers or riboflavin. Methods.IDAP
was assessed by measuring the Nl-P2 component at Cz
during binaural stimulation at 40, 50, 60, and 70dB and
7.1 computing an amplitude-stimulus function (ASF) slope.
Migrameurs were studied at least 3 days before or after an
Combined visual and auditory evoked potentials in attack. Recordings were made before and after prophylactic
migraine patients between attacks. J Afra’, A Proietti- treatment with beta-blockers (metoprolol200 mg/day; biso-
Cecchini3, A Mascia’, J Schoener?. ‘Neurology pro101 10 mg/day, n = 10) and riboflavin (400 mg/day, n =
Department, Semmelweis University, Budapest, 15) for 4 months. ResuEts.Beta-blockers decreased the ASF
Hungary; 2Neurology Department, CHR Citadelle, slope (before: l&6+1.02 uV/lO dB; after: 0.79+1.06 u
University of Liege, Belgium; 3Neurology Department, V/10 dB, paired t-test: p =0.02). By contrast, riboflavin as
Pavia University, “Mondino Foundation”, Italy prophylactic medication did not alter the ASF slope (before:
1.80+0.81 pV/lO dB; after: 1.56kO.83 pV/lO dB, paired t-
Migraine patients show deficient habituation of pattem- test: p =0.39). Conclusion.Prophylactic beta-blockers, which
reversal visual evoked potentials (PR-VEP) (Schoenen et al. are known to change neuronal excitability and to have a
1995) and a strong intensity dependence of cortical audit- potential action on serotonin neurotransmission, seem to
ory evoked potentials (IDAP) (Wang et al. 1997). We dimini& abnormal ASF slopes in migraine patients, whereas
performed the tests described here, examining migraineurs riboflavin, which affects mitochondrial energy metabolism,
with (MA; n = 22) or without aura (MO; n =37) and healthy does not influence pretreatment slopes.
volunteers (HV; n =23). For PR-VEP, 5 blocks of 50
responses were sequentially averaged (continuous stimula-
tion, 3.1 Hz). Nl-Pl latencies and amplitudes were ana-
lyzed. For IDAP we measured Nl-P2 at Cz during
7.3
stimulation at 40, 50, 60, and 70 dB. Amplitude-stimulus
function (ASF) slope and amplitude changes between 40 Hyperoxia of the occipital cortex, red nucleus and
and 70 dB were calculated. MO and MA differed from HV substantia nigra during visual aura of migraine.
in VEP amplitude change ( p = 0.007) and IDAP slope ( p = KMA Welch, Y Cao, S Aurora, G Wiggins, E Vikingstad.
0.0004). VEP potentiation and IDAP slopes did not correl- Department of Neurology, Henry Ford Health Sciences
ate. Attack frequency/disease duration did not correlate CTR, 2799 West Grand Blvd, Detroit, MI, USA
with VEP amplitude change or IDAP slopes. There was a
negative correlation between the amplitude of the first We report the measurement of brain oxygenation during
block and potentiation of VEP in MO ( p =0.03), MA ( p = visual aura indirectly by means of serial T2*-weighted mag-
CEPHALALGIA 18 (1998) Pla tfirmpresentations 389

netic resonance imaging using a 3 Tesla magnet (224 images tendency to overshoot, Which could indicate subclinical
acquired over 13 min). Marked increases in T2*-weighted cerebellar hypermetria.
signal intensity were evident throughout regions of both
occipital cortices and in the red nucleus (RN) and substantia
nigra (SN) bilaterally in a patient first studied 7min after 7.5
onset of left homonomous quadrantanopia. Image intensity
Neurophysiological evaluation of migraine attacks:
increased only in cortical grey matter, spread and receded
effects of 5HTlMD agonists on blink reflex. Preliminary
with the aura, with a time course compatible with experi-
results. M De Tommaso, V Sciruicchio, M Guido,
mental spreading depression (SD). Intensity increases in
G Sasanelli, FM Puca. Clinica Neurologica, Universita di
draining veins confirmed increased occipital cortex oxygena- Bari, Bari, Italy.
tion. We hypothesize that these cortical T2* intensity increases
are best explained by the tissue hyperoxia and hyperemia
In a previous evaluation (de Tommaso et al. 1997), an
that accompany the early phase of SD before flow becomes
early appearance of blink reflex nociceptive component
oligemic. There has been no previous association of migraine (R3) was observed in migraine patients during headache-
with abnormality of RN function. Nigrostriatal dysfunction
free periods. The aim of the study was to evaluate the
has been associated with dysautonomic features of the
effects of 5HTIB11n a g onists on trigeminal function during
migraine attack. Experimental SD activates remote sub-
migraine attacks. We selected 20 patients affected by
cortical structures, either directly by cortical subcortical con-
migraine without aura according to the IHS criteria (1988).
nections or indirectly by subsequent decortication. The
The blink reflex was recorded at perceptive and painful
hyperoxic changes in RN and SN of our patient appeared
thresholds, first within 12 h of the onset of migraine
time-locked with those of the occipital cortex, illustrating the symptoms and the second time at least 2 h after the
link between cortical events and activation of subcortical
consumption of 2.5 mg zolmitriptan (7 patients), 50 mg
structures during a migraine attack. (Supported by NIH sumatriptan (7 patients) or placebo (6 patients), randomly
grant l’50 NS32399.)
assigned. We evaluated patients at least 72 h after the end
of critical symptoms; no patients had taken analgesic drugs
before the recording sessions. We evaluated thresholds,
latency, amplitude and duration of blink reflex Rl, RZ and
7.4 R3 components obtained at the three time points. During
A quantified finger-nose test indicates subclinical the critical phase, the R3 component appeared almost at
cerebellar signs in a subgroup of migraine patients. the painful threshold with higher amplitude than in the
PS Sandor, A Mascia, V De Pasqua, J Schoenen. asymptomatic phase, in which an earlier appearance of R3
Neurology Department, CHR Citadelle, University of almost at the perceptive threshold was detectable, accord-
Liege, Belgium ing to previous findings (de Tommaso et al. 1997). During
migraine attack, placebo and sumatriptan did not signific-
Background. Familial hemiplegic migraine (FHIM) and epis- antly change blink reflex parameters, while zohnitriptan
significantly reduced R3 amplitude at the painful thresh-
odic ataxia type 2 are due to mutations in the chromosome
19p13 gene CACNLlA4 coding for the cll-subunit of a old. Further study could confirm a possible primary tri-
P/Q Ca*+ channel (Ophoff et al. 1996). FHM can be geminal nuclear hyperexcitability in the pathogenesis of
migraine attack and the specific central neuro-inhibitory
associated with cerebellar ataxia. Common types of
role on the trigeminal nerve of zolmitriptan.
migraine have been linked to the same locus (Terwindt
et al. 1997) and in psychomotor testing, dexterity was
found impaired interictally in untreated migraineurs
(Schoenen et al. 1986). Are subclinical cerebellar signs
8.1
detectable in subgroups of migraine patients with dysfunc- Involvement of the dopaminergic system in migraine:
tioning Ca2+ channels? Methods. We quantified the finger- genetic evidence. M Del Zompo, A Cherchi, MA Pahnas,
nose coordination test in 3D space using ELITETM. Subjects M Ponti, A Bocchetta, GL Gessa, Ml? Piccardi.
were instructed to touch a target in the mediosagittal Department of Neurosciences “B-B. Brodie”, University
plane with their index finger, starting from pointing to the of Caligari, Caligari, Italy
side. Eight to ten movements were recorded before and
after increasing initial arm load by 200,400, and 600 g. We Migraine is a common, debilitating disorder which seems
analyzed target-finger distance in 3D and interaural, to be caused by a combination of genetic and environ-
nasooccipital and vertical components for precision within mental factors. Clinical and pharmacological evidence
and between trials. Twenty-three untreated migraineurs suggests that dopamine has a role in the pathogenesis of
between attacks, 14 without aura (MO), 9 with aura (MA), the disorder. The hypothesis of dopamine receptor hyper-
were compared to 6 healthy volunteers (HV). Results. 3D sensitivity in migraineurs is supported by various authors.
deviation and precision within trials showed no difference We performed a genetic study to test the involvement of
between the groups. Compared to HV, the pointing error DA receptor genes DRDl, DRD2, DRD3, DRD4, and DRD5
between the trials was different in MA for the interaural in migraine. We used the Transmission Disequilibrium
direction ( p <0.05) and for vertical direction (p < 0.05). Test (TDT), a family-based association method to examine
These measures did not differ between MO and HV. an isolated population such as Sardinians. We studied 100
Conclusion. For reaching a target in 3D space, migraineurs nuclear families of patients affected by migraine without
are as precise as healthy controls. However, in MA the aura (according to IHS criteria). The presence of symptoms
movement is balanced differently with a compensated caused by altered function of the dopaminergic system,
390 Pla$wm presentations CEPHALALGIA18(1998)

such as nausea and yawning, allowed us to identify a suggest that the wine is likely to have some effect on most
clinical subgroup of “dopaminergic” probands. Observing serotonin receptors in vivo, certainly in the gut and prob-
results of the first 50 triads, no association was detected ably systemically. Each drug appears to have inhibited the
using the TDT test between DRD3, DRD4 and migraine development of 4 out of 6 headaches and probably amelior-
without aura either in the overall sample or in the dopa- ated one further headache each. It is possible, therefore,
mine@ migraineurs. No difference was observed in that the wine is acting on a receptor antagonized by both
DRDZ overall allele distribution, although the allelic distri- these drugs, perhaps 5HT,.
bution at the DRD2 locus differed significantly in the
subgroup of dopaminergic migraineurs (p = 0.004). Allele
1 was the individual allele that appeared to be in disequi- 8.3
librium with migraine without aura (p = 0.02). The genetic Features of migraine in patients with comorbidity
approach could provide molecular support for the hypo- between migraine and panic disorders. A Nuti’,
thesis that the hypersensitivity of the dopaminergic system C Lucetti2, N Pavese2, G Gambaccini2, D Marazziti3,
represents the pathophysiological basis of migraine. We S Pedri3, C Toni3, GB Cassano3, U Bonuccelli2. ‘Viareggio
discuss results regarding the overall sample of 100 triads. Hospital, Viareggio, Italy; Clinical Neurology,
Department of Neuroscience, University of Pisa, Pisa,
Italy; 3CBnical Psychiatry, University of Pisa, Pisa, Italy
8.2
To answer the question of whether a history of panic
The effect of 5HT, receptor antagonists on red wine
disorder (PAD) may modify migraine (M) features, a group
induced headaches. RC Peatfield , K Rhodes2, M Wood3.
of 31 patients with PAD and M was compared with a
‘Princess Margaret Migraine Clinic, Charing Cross
group of 31 migraineurs without psychiatric comorbidity.
Hospital, Fulham Palace Road, London W6; spartment
A Headache Questionnaire (HQ), exploring first-degree
of Pharmacology, Imperial College of Medicine, St
headache loading and symptomatological and longitudinal
Dunstan’s Road, London W6; SmithKline Beecham
characteristics of M, was utilized. The comparison revealed
Pharmaceuticals, Harlow, UK
differences in headache duration (p<O.O05), headache
intensity (p<O.Ol), presence of vomiting (pcO.Ol), and
introduction. Fozard and others have suggested that head-
photo- and phonophobia ( p ~0.01). Patients with
aches induced in susceptible subjects by the trazodone
co-occurrence of M and PAD showed headache attacks
metabolite mCPP are mediated by its agonist effect on
with lower-grade pain, shorter duration, more severe
.5HT,, and/or X receptors, a view supported by the
photophobia and phonophobia and absence of retching.
reasonable correlation of a number of drugs between
Migraine antedated the onset of PAD in patients with
efficacy as migraine prophylactics and affinity at these
comorbidity. These data suggest that the headache attacks
receptors. We have explored the hypothesis that the sensit-
observed in patients with M and PAD are clinically differ-
ivity to red wine reported by about 12% of our migraine
ent from those reported by migraineurs without psychia-
patients is mediated similarly by attempting to antagonize
tric comorbidity. The temporal relationship between PAD
this effect with the nonselective 5HT=,- receptor antag-
and M could indicate that M may be a risk factor for PAD.
onist pizotifen or the selective 5HT, receptor antagonist
ketanserin on a double-blind crossover basis. Methods. Six
volunteer migraine clinic patients, selected from those
8.4
reporting sensitivity to red wine but not other alcoholic
drinks, were pre-loaded on two occasions at least 2 weeks Angina X and migraine: systemic visceral hyperalgesia,
apart with either 3 mg of pizotifen or 20 mg of ketanserin. their common clue. M Nicolodi, F Sicuteri.
After 2 h, they drank 5 ml/kg of Sangiovese di Toscana Interuniversity Centre of Neurochemistry and Clinical
1995 (Cecchiz Sainsbury’s) with two dry biscuits, and Pharmacology of Idiopathic Headache & Department of
reported the development of headache by returning a Internal Medicine, University of Florence, Florence, Italy
questionnaire by post. In a separate experiment, the bind-
ing characteristics of a freeze-dried extract of the same Migraine (M) is characterized by generalized visceral hyp-
wine were measured against a variety of serotonin recep- eralgesia, as documented by using mechanical and osmotic
tors on cultured cells. Results. The wine contained about stimuli. We observed that sumatriptan induced precordial
30 mg/ml of extract; thus 5 ml/kg equates to approxi- catch without electrocardiography changes in some M
mately 150 pg/m.l if distributed in the full body weight as sufferers, while such a sensation was never reported by
water. The wine showed similar characteristics at controls. Thus, it seems that sumatriptan-related precordial
5~1e,1r&zA~~c&7 receptors with pK1 values of about 6-6.3; catch constituted an expression of increased visceral sensit-
thus 50% displacement was seen at each receptor at extract ivity enhanced by a serotonin-dependent central mechan-
concentrations of around 4-5 ug/ml. This seems easily ism. This observation led us to investigate the prevalence
achievable in the in vim study or during social drinking. of angina pectoris without electrocardiography changes or
In the clinical study, no patient developed a headache on coronaro-angiography abnormalities in M sufferers and
both occasions. Two patients did not develop a headache headache-exempts. The study was conducted from 1991
in either test; 2 patients developed mild pain, once after to 1997; it included 402 M sufferers and 374 headache-
ketanserin and once after pizotifen, with no headache on exempt healthy subjects. All the subjects were matched
the other occasion; and 2 patients developed severe pros- regarding sex, age and risk factor for cardiovascular ill-
trating pain on 1 occasion each, again once after ketanserin nesses. Angina pectoris with no sign of electrocardio-
and once after pizotifen. Conclusions. The in vitro studies graphic or coronaro-angiographic involvement occurred
CEPHALALGIA 18 (1998) Ph tform presentations 391

in M sufferers only. Its prevalence was 9.4%. In all cases, were directly contacted in our H Center. Gender differ-
M history arose well before (11.6 years & 7.5 SD) angina. ences and pre-puberty (P) or post-P onset of H represented
This peculiar type of angina, partly overlapping the clinical the principal factors analyzed in relation to the evolution
features of so-called “X angina”, seemingly supports the of H. Chi-squared test was employed. Results. High tend-
occurrence of a generalized lowered visceral pain thresh- ency to remit (34%) or improve (45%) was recorded. A
old in M. It also seems noteworthy that recurrent, severe worse situation was found in 6% and 15% were unchanged.
stable and unstable angina episodes may result in The headaches changed over time, most from M to TTH,
increased visceral hyperalgesia. This condition may con- but the opposite was also true: 17 (26.5%) M sufferers
tribute to “angina crescendo” in that there is a well-known presented episodic TI’H (ETTH), while 3 (8.3%) ETI’H
relationship between sensory and vegetative systems. patients had changed to M. Twenty-nine (90.6%) current
migraineurs were formerly classified as M vs 17 (50%)
TI’H sufferers. M showed a lower tendency to remit in
comparison to TTH (28.1% vs 44.4%). Females presented
8.5 higher rates (78.3%) of duration of H than males (47.5%),
Genetic coagulation abnormalities: shared risk factors regardless of the different subtypes (p<O.Ol). Pre-P or
in migraine with aura and ischemic stroke? D D’Amico, post-P onset of H was not related to the remission or
duration of H. ConcIusion. TTH (not only M) tends to remit
F Moschiano, L Grazzi, M Leone, E Ciusani, C Ariano,
or change over time. The evolution of the clinical character-
A Attanasio, N Erba, F Schieroni, G Bussone.
istics of both types calls into question the “continuum-
Department of Neurology, “L. Mandic” Hospital,
Merate, Lecco, Italy severity theory”. The longer duration of H among females
probably underlines the importance of hormonal factors,
Migraine, particularly migraine with aura (MA), may be a although pre- or post-P onset is not of prognostic impor-
tance. The recognition of prognostic factors for the evolu-
risk factor for ischemic stroke (IS). The reasons for this
tion of H should be the focus of follow-up studies.
association are unknown. Recent data suggest that some
genetic coagulation abnormalities associated with venous
thrombosis may also be involved in IS. We investigated the
presence of resistance to activated protein C (APC) and of
protein S or protein C deficiencies in young adults with 9.1
either MA or IS. We studied 83 MA patients, 31 IS patients Effect of vigabatrin on serum gaba and glutamate
and 124 healthy controls, all aged ~45 years. Chi-square levels in migraine patients and its relationship with
test was used for statistical evaluation. Protein C deficiency
clinical effects and serum dru levels. K Ghose’,
was detected in only one patient in the MA group. APC
D Grattan2, B Niven3, D Berry 4 . Departments of
resistance was found in 12% of MA patients, and in 16% of
‘Pharmacology, 2Anatomy & Structural Biology, and
IS patients, with a 100% correspondence with the genetic 3Mathematics & Statistics, University of Otago, Dunedin,
test (presence of the Arg506Gln factor V mutation). Protein New Zealand; ‘Medical Toxicology Unit, Guy’s & St
S deficiency was 4.8% in MA, and 6.4% in IS. These figures
Thomas’ Hospital Trust, London, UK
are significantly different from those found in our controls
(APC resistance/factor V mutation: MA vs controls p=
Rationale. We reported the prophylactic effect of vigabatrin
0.028, IS vs controls p =0.020: protein S deficiency: MA vs in migraine in a double-blind crossover comparison with
controls p = 0.050, IS vs controls p =0.020). The increased placebo at the XI Migraine Ti_ust International Symposium
frequencies of APC resistance and of protein S deficiency in (Ghose et al. 1996). Each treatment phase lasted 12 weeks,
both disorders suggest that these prothrombotic genetic and there was a 4-week washout period between treatments.
abnormalities may be shared risk factors in MA and IS. They We enrolled 23 patients (17F, 6M), aged 20-64 years. They
might play a role in increasing the risk of cerebrovascular were suffering from either migraine with aura or migraine
disease in young adults with MA. without aura. The dose of trial medication was lOOO-
2OOOmg/day. Analysis of variance indicated a significant
@O-70%) benefit during vigabatrin treatment, but no rela-
tionship with serum drug level was observed. Similar lack
8.6 of correlation was found in patients with epilepsy. Vigabatrin
Juvenile headache outcome: clinical data in favour of by inhibiting GABA tr ansaminase, prolongs the pharmacol*
the “continuum severity theory”. V Guidetti, F Galli, gical effect of GABA. Its clinical benefits may have a relation-
R Cani&no. Department of Child Neurology and ship with serum/platelet GABA activity in epilepsy (Arteaga
Psychiatry, Via dei Sabelli 108, I-00185 Rome, Italy et al. Epilepsia 1992;33:923-31). It is suggested in the litera-
ture that GABA and glutamate may influence the pathogen-
Objecfive. Follow-up studies on headaches (H) with juvenile esis of migraine. We measured the GABA and glutamate
onset have mainly focused on migraine (M) duration or levels in the serum of patients who participated in the above
remission. The possible change of M into other forms and study. Methods. Venous blood was collected during both
the trend toward tension-type H (TIN) have been studied vigabati and placebo treatments. Serum was immediately
less often. The main aim of this study was to analyze the separated and was stored at -80°C for future analysis.
evolution of M and TTH in an &year follow-up, examining Serum GABA and glutamate levels were measured by HPLC
factors related to the outcome of H. Method. In 1996, 100 method. Results. We are currently analysing the relationships
subjects @OF, 4OM, mean age 17.9, SD 2.6, range: 12-26), of serum GABA and glutamate levels with vigabatrin’s
randomly selected among all patients first seen in 1988, clinical effects and serum levels.
392 Plutj;mn presentations CEPHALAIGIA 18 (1998)

9.2 perceptible improvement and lime-to-meaningful

improvement using stopwatches, and provided an overall
Clinical evaluation of a novel, potent, CNS penetrating assessment of the study medication. Results showed ibup-
NK, receptor antagonist in the acute treatment of rofen plus caffeine was significantly ( p < 0.05) more effect-
migraine. HE Connorl, L Bertin’, S Gillies2, DT Beattie’, ive than ibuprofen alone, caffeine alone, and placebo for
P Ward1 and the GR205171 Clinical Study Group, Glaxo peak PID, peak relief, 4 and 6-h SPID, and the subjects’
Wellcome R&D Ltd, ‘Stevenage, Herts or ‘Greenford, overall evaluation. In addition, ibuprofen plus caffeine
Middlesex, UK had significantly ( p < 0.05) earlier time-to-perceptible
improvement and time-to-meaningful improvement than
Background and objectives. Trigeminovascular activation ibuprofen and placebo. All side effects were transient and
appears to be involved in the pathophysiology of migraine, resolved spontaneously. These results indicate that the
and substance P has been proposed as a potential endogen- combination of ibuprofen plti caffeine provides more
ous mediator of this activation, both at the level of the relief than comparable levels of ibuprofen alone in treating
cranial vasculature and centrally within the trigeminal episodic tension-type headache. This work was supported
nucleus caudalis. GR205171 (Gardner et al., Reg Peptides by a grant from Proctor & Gamble.
19%;65:45-53) has been developed as a highly potent,
selective NK, receptor antagonist. It has a high affinity
with human recombinant NK, receptors (pKi= 10.5), 9.4
inhibits neurogenically mediated plasma pritein extra-
vasation in dura of anaesthetized rats (60% inhibition at Rizatriptan RPDTMfor the acute treatment of migraine.
SP Ahrens, WH Visser, K Jiang, SA Reines and the
100 pg/kg i-v.), and inhibits stimulation-evoked expression Rizatriptan RPDTMStudy Group
of c-fos in the trigeminal nucleus caudalis of anaesthetized West Point, PA, USA
guinea-pigs. Pos&on Emission Tomography (PET) studies
were conducted in monkeys to assess central penetration. Rizatriptan (MAXAL~) is a highly selective 5HTlBllD
These data showed that “C-1abelled GR205171 rapidly receptor agonist with rapid absorption and onset of relief
for the acute treatment of migraine. Rizatriptan RPDm is
gains good access to the CNS. This prompted us to conduct
a convenient, novel, freeze-dried formulation of rizatriptan
a randomized, double-blind, placebo-controlled clinical
that rapidly dissolves on the tongue and may be swallowed
trial to assess whether GR205171 would be an effective
without liquids. This allows patients to administer the
acute treatment for migraine. Design. Sixty-three II%-
RPD formulation early during migraine attacks, facilitating
diagnosed migraineurs with or without aura were treated
for a single migraine attack with either a single i.v. dose early headache treatment and giving patients a sense of
control over their disease. Additionally, rizatriptan RPD
of 25 mg GR205171 (n = 31) or placebo (n = 32). The primary
offers significant advantages for migraineurs who prefer
endpoint was headache relief 2 h after the start of the
to take their medication without liquids for fear that
infusion, assessed using a 4point scale. Results and conclu-
liquids would result in, or aggravate, pre-existing nausea.
sion. Analysis did not demonstrate any significant differ-
ence in reduction of headache severity between GR205171 This double-blind, placebo-controlled study examined the
safety and efficacy of rizatriptan RPD 5 mg and 10 mg in
and placebo at any timepoint. These data indicate that
561 migraine patients who treated 1 migraine headache
GR205171 is not effective in the acute treatment of
and up to 2 headache recurrences within 4 h. Headache
migraine. This finding questions the importance of sub-
severity, functional disability, and presence of associated
stance P, acting via peripheral or central NK1 receptors, in
symptoms, were assessed from baseline up to 4 h after
the pathophysiology of migraine headache.
dosing. Adverse events were monitored throuhout the
study- The primary efficacy endpoint was head&he relief
2 h after initial dosing (i.e. reduction from severe/moder-
9.3 ate headache to mild/no headache).
Ibuprofen plus caHeine in the treatment of tension-
type headache. S Diamond’, GE Ruoff, FG Freitag’,
TK Balm3. ‘Diamond Headache Clinic, Chicago, IL, USA;
9.5
westside Family Medical Center, Kalamazoo, MI, USA; Zolmitriptan: one of the more robust supporters of the
?he Proctor & Gamble Company central serotonin theory of migraine. M Nicolodi,
F Sicuteri. Interuniversity Centre of Neurochemistry and
A randomized, double-blind, multicenter, parallel trial Clinical Pharmacology of Idiopathic Headache and
was conducted to assess the efficacy of ibuprofen plus Department of Internal Medicine, University of Florence,
caffeine compared to ibuprofen alone, caffeine alone, and Florence, Italy
placebo in the treatment of episodic tension-type headache.
The study involved 385 subjects with a history of 3-7 We first suggested that the therapeutic action of sumatrip-
tension-type headaches per month, which respond to tan in migraine (M) is due to a central mechanism. Indeed,
treatment with the over-the-counter (OTC) medications, sumatriptan acts in the CNS where serotonergic analgesia
were randomly assigned to use ibuprofen 400 mg plus starts a mechanism, seemingly defective in M. We also
caffeine 200 mg, ibuprofen 400 mg, caffeine 2OOmg, or demonstrated that generalized vascular/visceral hyperal-
placebo to treat a qualifying tension-type headache. gesia is a stigma affecting M sufferers. These findings led
Subjects took a single dose of study medication and us to test possible sumatriptan-induced analgesia in opiate-
evaluated their headache pain and headache relief over abstinent rodents which shared with M sufferers the fea-
the following 6 h. Subjects also determined the onset-to- tures of hyperalgesia and 5HT super-sensitivity. In such
CEPHALALGIA 18 (1998) Pla tfmn presentations 393

experimental conditions, sumatriptan evidenced its ability 9.6

to induce analgesia. Thus, we can conclude that sumatrip-
tan and triptans relieve pain only in those subjects charac- Ganaxolone: New non-triptan shows utility for acute
terized by hyperalgesia, i.e. an abnormal set-up in the migraine. J GoldsteW, K Britch’, S Silberstem3.
CNS, and 5HT receptor super-sensitivity. As a con- ‘San Francisco Headache Clinic, San Francisco, CA, USA;
ToCensys, Inc. Irvine, CA, USA; 3Germantown
sequence, the characteristics which chiefly condition trip-
Neurological Association, Philadelphia, PA, USA
tans-induced analgesia can be listed as follows:
(i) lipophilia, (ii) affinity with peculiar 5HT receptor sub-
Ganaxolone, a synthetic neurosteroid, has shown activity
types, and (iii) increased sensitivity of 5HT receptors. The in inhibiting trigeminal evoked neurogenic inflammation
first 2 conditions are intrinsic to the drug; the third is in rat meninges, an accepted animal model for migraine.
intrinsic to the subject under investigation and makes the Ganaxolone has been evaluated in over 200 acute migraine
drug selective for only some types of pain. Zolmitriptan sufferers. Dose response and plasma levels were assessed
exhibits features matching the 2 main features required in a placebo-controlled, inpatient study, in which 252
for acting in M. Indeed, being highly lipophilic, it clearly premenopausal females, with moderate to severe acute
crosses the blood-brain barrier so as to bind the super- migraines, were treated with 20, 100, 200, and 500 mg
sensitive 5HT CNS receptors. The selectivity of triptans Ganaxolone g-CD-complex or placebo. Compared to pla-
may aid the understanding of some puzzling problems of cebo, more patients treated with the 500 mg dose reported
M characterized by the clear-cut hyperalgesia and 5HT pain relief at 4 h (p=O.O9). Sixty-one percent of patients
super-sensitivity which render triptans effective. whose plasma levels exceeded 80 ng/ml achieved pain
relief at 2 h in the 200 and 500 mg-dose groups. Nearly all
patients that achieved these levels at 2 or 4 h, in both the
200 and 500 mg-dose groups, had pain relief, while only
approximately 25% of those with no measurable plasma
levels in these dose groups reported pain relief. Higher
doses of ganaxolone in tablet preparations and in suspen-
sions have been evaluated in a second study to further
define the formulation preference and dose. Dose-limiting
sedation is the most common side effect. No cardiovascular
toxicity has been seen in animals or patients. Non-triptan
ganaxolone shows promise as a new therapeutic agent for
acute migraine sufferers.
POSTER PRESENTATIONS
CEPHALAIGIA 18 (1998) Posterpresentations 395

P.01 early adolescence, and, from age 20 years, rare attacks

characterized by the onset of a visual scotoma soon fol-
Predictive factors in the prognosis of migraine with lowed by unilateral headache lasting for a few days. At
aura. D Cologno, P Tore& GC Manzoni. Centro Cefalee, age 36, and again at age 38, during stressful periods of his
Istituto Di Neurologia, Universita Di Parma, Parma, Italy life, he suffered two attacks, with sudden onset of amnesia,
an inability to recollect what to do, dates and appoint-
There are few data and studies in the literature on the ments, the use of common objects and repetitive ques-
natural history and evolution over time of migraine with tioning with anxiety. Language and motor functions were
aura (MA). We therefore decided to investigate the clinical normal, but he could not recognize his children visually,
follow-up of 81 MA patients consecutively referred to the though he could recognize their voices. The amnesia lasted
University of Parma Headache Center between 1976 and for 5 h, when it quickly resolved, and a unilateral right-
1985, lo-20 years after their first visit to the center. The sided pounding headache developed, lasting 3 h and
purpose of our review was to determine the existence of responsive to acetaminophen. The second attack was like-
any factors predicting the evolution of MA over time. wise characterized by fixation amnesia upon awakening
Based on the date of their last MA attack, two groups of in the morning, repetitive questioning and failure to recol-
patients were identified: a first group of 22 patients, whom
lect his surroundings, time and common objects, lasting
we considered “symptom free”, i.e., they had not had 4-5 h and followed by unilateral right-sided headache.
attacks for at least 2 years at the end of the follow-up, and Interictal brain MRI and neurological examination were
a second group of 55 patients who were “not symptom- normal. In our patient affected with migraine with and
free”, i.e., they were still having attacks in the last 2 years. without aura, TGA occurred as the aura phase of two
Four patients could not be included in the study because migraine attacks. A relationship of TGA to migraine has
no reliable data were available for them. A comparison of been hypothesized because of its higher prevalence among
MA clinical features at first observation between the two migraineurs. Recent MRI studies in TGA were compatible
patient groups suggested the existence of predictive factors with spreading depression in the mesial temporal lobe.
for a favorable prognosis, such as being male, not suffering Our case report confirms that TGA shares common mech-
from other associated forms of primary headache, and not anisms with migraine.
having natural or artificial light stimulation among the
factors triggering the attacks.

P.02 P.04
Why do patients lie down during headache attacks. A
Diffuse, multifocal, segmental, and reversible
comparison between migraine and tension headache.
vasospasm in thunderclap headache. DW Dodick,
IP Martins’, E Parreira’, T Paiva’. ‘Department of
RD Brown, JW B&ton, J Huston. Department of
Neurology, H. St. Maria, Lisbon, Portugal; 2H. Fernando
Neurology, Mayo Clinic, Rochester, Minnesota, USA
Fonseca, Amadora, Portugal
O~ecf-ive. To highlight the clinical profiles and angiographic
Introducfion. Classical textbook descriptions of migraine
findings of two patients with recurrent thunderclap head-
state that patients tend to lie in bed during attacks. Yet, it
ache without subarachnoid hemorrhage (SAH) and to pre-
is well known &at bending forward aggravates pain and
sent modified diagnostic criteria for this unusual syndrome.
that some individuals avoid lying down because it may
Background. Thunderclap headache may be a benign recur-
worsen migraine (Blau, 1992). We compared migraine and
rent headache disorder or it may represent a serious under-
tension headache patients in these positions during head-
lying process such as SAH or venous sinus thrombosis. The
ache attacks. M&hod and resuIfs. Interviews with 50 consec-
pathophysiology of this disorder in the absence of under-
utive patients, 32 migraineurs and 18 with tension
lying pathology is not well understood and the potential
headache (42F, 7M with an age average of 38.6 years)
angiographic features of this syndrome are not well appreci-
fulfilling the IHS diagnostic criteria, conducted in two
ated. Methods. Two case descriptions with illustrative angi-
centers, show that while the majority of individuals with
ography. Resulfs. Both cases demonstrated the potential for
both diagnoses tend to lie down during headache attacks,
reversible intracranial vasospasm without intracranial
only patients with tension headache will lie flat (x2 = 5.00,
aneurysm or SAH and a benign clinical outcome.
p = 0,02), sin ce 40.7% of migraineurs need to recline on
Conchsions. Primary thunderclap headache has a distinctive
several pillows because lying down aggravates the pain.
clinical and angiographic profile and must be distinguished
The majority of migraineurs (92%) say that lying down by
from central nervous system vasculitis and SAH.
itself will not relieve pain, but in doing so they manage
to get away from noise/light (88%), manage to stay still
(66%) or to sleep (25%), which will help in relieving pain.
P.03 Most patients with tension headache deny any significant
Transient global amnesia occurring as migraine aura. benefit with these measures. Conclusion. Patients with
P Montagna, A CerulIo, P Cortelli. Institute of Clinical migraine headaches go to bed during attacks because this
Neurology, University of Bologna, Via U. Foscolo is an easy way to stay immobile and away from any
740123, Bologna, Italy stimulation, and not because that position helps relieve
migraine attacks, on the contrary, lying flat may aggravate
A 38-year-old physician had had unilateral or bilateral the pain. Tension headache patients may lie flat but do
migraine attacks sometimes associated with vomiting since not improve much in this position.
396 Poster presentations CEPHALALGIA 18 (1998)

P.05 IHS criteria for HARE; 3 of these (6.4% of total) had no

other headache. Preliminary results show that individuals
Chronic headaches and cerebral arteriovenous with refractive errors have significantly more days per
malformations-a prospective study. E Parreira’, month with headaches than the control group (f = -3.51,
IP Martins2, J Campos2. ‘Fernando Fonseca’s Hospital, p =0.0007). However, there were no differences in the
Amadora, Portugal; St. Maria’s Hospital, Lisbon, overall prevalence of headache, or any specific type of
Portugal headache, between groups. Within the study group, sub-
jects with hyperopia have more frequent headaches than
Introducfion. The prevalence and features of headaches patients with other refractive errors (F=2.79, p =0.03) and
associated with cerebral arterio-venous malformations more HARE type headache.
(AVM), usually ‘migraine-like’, are still in question.
Objectives.To determine the characteristics of chronic head-
aches in patients with AVMs. Methods. We conducted a P.07
prospective study in a series of 28 consecutive patients
with AVM referred to us in the last 2 years for neurological Weekend headache and lifestyle. P Torelli, D Cologno,
evaluation. The study was carried out days or a few GC Manzoni. Istituto di Neurologia, Parma Universita di
months after AVM diagnosis and prior to endovascular Parma, Parma, Italy
treatment. A detailed headache history was taken, always
by the same neurologist: location, type, duration and Our study was aimed at determining whether weekend
frequency of attacks; accompanying symptoms and headache (WH) patients share a common pattern in theii
aggravating/relieving factors. The occurrence of chronic work life, family life, and leisure during the week and on
headache was correlated with angiographic features of weekends, and whether or not they modify some of their
AVM. Resulfs. Twenty-eight patients, 18M, 10F were inter- living habits at the weekend. The study comprised a sample
viewed. In all patients the AVM diagnosis was made due of 56 patients referred to the University of Parma Headache
to symptoms other than headache: usually epilepsy and Center between October 1996 and April 1997. The patients
cerebral hemorrhage. Almost half of the patients had were given a specially designed questionnaire which, along-
chronic headaches. Chronic headaches were classified as side their personal data, contained specific questions about
“migraine-like” in 46.2%, “tension-type-like” in 15.4%, the subjects investigated. A review of the data showed that
and the remaining as “uncharacteristic”. They were more maIes are more frequently affected by WH than females and
frequently pulsatile (71.4%), short-lasting (70%), and that WH evolves from a preexisting form of headache. In
strictly unilateral (not shifting side between attacks) (75%). addition, a common pattern emerged, both in the patients’
Whenever headache was unilateral it always corresponded work life-they were privatesector employees with sedent-
to the AVM side. Conclusions. Chronic headaches are ary jobs-and in their perception of it-they considered their
frequent in AVM patients; nevertheless, none of our job as not secure, inadequate to their ski& scarcely reward-
patients consulted a physician because of them and the ing though well-paid, stressfuI, and they continued to feel
diagnosis was made only after other symptoms developed. the strain at home. They considered their family life as
The most distinctive feature of these headaches (although satisfactory, but a review of the data showed plain contradic-
not universal) is that they occur always on the same tions. Weekends were regarded as pleasant, relaxing inter-
location, corresponding to the side of the AVM. ludes during which they tended to modify their living habits.
In particular, a tendency emerged of increased cigarette
P.06 smoking and sexual activity.

Headaches due to refractive errors-a myth? R Gil-

Gouveia, I Pavao-Martins. Department of Neurology, H. P.08
St. Maria, Lisbon, Portugal
Cluster headache without autonomic features: a milder
Headaches and refractive errors are very common condi- form of ical cluster? E Parreira’, A Tome2,
fyp. ‘Hospital Fernando I&seca, Amadora,
IP Martins
tions that occur in the general population-headache
sufferers themselves often attribute their symptoms to a Portugal; ‘Department of Neurology, H. St Maria,
visual problem. The IHS classification of headache includes Lisbon, Portugal
an entity called headache associated with refractive errors
(HARE., code 11.3.2), while stating that its importance is Introduction. Some individuals have episodic unilateral
widely overestimated. Is it? We applied a headache ques- headaches virtually identical to cluster headache except
tionnaire to 105 individuals with documented uncorrected that they lack any autonomic features. It is not known if
refractive errors and a control group with properly cor- they represent the same entity or a distinct one. M&hod.
rected or without refractive errors. The type (using IHS We compared a series of 71 patients with cluster headache,
criteria), frequency, and intensity of headaches in both fulfilling IHS criteria for episodic or chronic cluster, with
groups were compared, as were the type and grade of 8 cases with cluster-like attacks who lacked autonomic
refractive error. The number of hours spent in activities features. Results. Patients with incomplete attacks had
requiring visual strain were also taken into account. The milder and shorter attacks, shorter bouts of pain and less
study group consisted of 53M and 52F (average age 37.6 intense attacks than patients who had all typical cluster
years), of whom 47 (44.8%) complained of usual headaches headache features. besides, in the atypical group there
(2.1% had migraine, 29.8% had tension-type headache, was a more equal distribution between sexes. Apart from
44.7% had other types of headache, and 17% had more that, the two groups were identical concerning age at
than one type of headache). Seven patients fulfilIed the onset, number of attacks per day, behavior (agitation)
CEPHAJALGIAl8(19!38) Poster presentations 397

during the attacks, percentage of response to oxygen or determined for the MT, and (ii) an SI of 1.5 x MT. Results.
ergotamine, pain localization and follow-up time. We Although the mean MT was higher in MwA compared
conclude that cluster attacks without autonomic features with C (63.1 f4.4 vs 58.1+8.9), the difference was not
may represent milder forms of otherwise typical cluster significant. At an SI of 1.5 x MT, the mean CSSP did not
headache. Prospective studies with larger number of dither between the groups (MwA 141.7k31.9 vs C
patients are necessary to confirm these findings. 162.4 k36.6). At the SI of the MT, however, the CSSP was
shorter in MwA patients than in controls (62.9 f27.3 vs
106.3+ 19.6, p =O.OOl). There was an inverse correlation
P.09 between the duration of CSSP and an increased frequency
of headache (p=O.O2). Conclusions. The shortened CSSP
Interictal cortical excitability in migraine: a study using that we measured in MWA patients compared to normal
transcranial magnetic stimulation of motor and visual controls with low intensity magnetic stimulation suggests
cortices. J Aura, A Mascia, P Gerard, A Maertens de reduced central inhibition resulting in increased excitabil-
Noordhout, J schoenen. Neurology Department, CHR ity of cortical neurons in migraine subjects. The association
Citadelle, University of Liege, Belgium of CSSP reduction with increased frequency of migraine
suggests further that brain excitability is the basis of
We performed transcranial magnetic stimulations (TMS) susceptibility to migraine attacks. (Supported by:
of the motor and visual cortices in healthy controls (HV; International Headache Society Fellowship Award.)
n =27) and in patients suffering from migraine without
(MO; II=33) or with (MA; n = 25) aura between attacks.
P.ll
Using a 13-an circular coil placed over the vertex and
recordings of the first dorsal interosseus muscle, we meas- Neurophysiological periodicity in migraine and chronic
ured thresholds (at rest and during contraction), ampli- daily headache (CDH). M Siniatchkin, A Vein. Russian
tudes of motor evoked potentials (MEP), and cortical silent Headache Center, Moscow Medical Academy, Russia
periods. Paired stimulations with short (l-20ms) inter-
stimulus intervals were carried out to assess intracortical Objective. Periodic changes of neurophysiological para-
inhibition. The visual cortex was stimulated with the same meters in migraine have been previously described (Gerber
coil placed over the occipital scalp (7 cm above the inion), and Kropp, 1994). Increased amplitude and reduced
and the prevalence and threshold of phosphene production habituation of contingent negative variation (CNV) were
were determined. In MA patients, motor thresholds during observed only a few days before an attack. The aims of
isometric contraction were significantly higher (p=O.O5), this study were to replicate described results and to
investigate neurophysiological periodicity in CDH
whereas the prevalence of stimulation-induced phosphene
patients. Methods. Fifteen females suffering from migraine
production was lower compared to HV (p=O.O3). These
without aura and 15 females diagnosed as having CDH
changes were not correlated with attack frequency or evolved from migraine were studied. The physiological
disease duration. No differences were found between recordings were performed l-4 days before and 2 days
subject groups in thresholds at rest, MEP amplitudes, after a migraine attack. The CNV was obtained from Cz
cortical silent periods, or response curves after paired using the reaction time paradigm. Fast Fourier transforma-
stimuli. These results support the theory of cortical hypo- tion of 20 EEG epochs was carried out in order to evaluate
rather than hyperexcitability in migraine with aura patients the power of EEG bands. Results. After an attack, migraine
between attacks. patients did not differ from CDH patients according to
CNV amplitudes, except regarding PINV, which was more
pronounced in CDH sufferers. Moreover, CDH patients
P.10 demonstrated reduced habituation of early CNV and
Cortical stimulation silent period is shortened in increased power in beta and theta bands. Before an attack,
migraine with aura. S Aurora, F Al-Sayed, L Norris, mi aine patignts were characterized by increased ampli-
tuCYe and reduced habituation of early and total CNV, and
KMA Welch. Department of Neurology, Henry Ford
by enhanced power in beta and theta bands, compared to
Health Sciences Center, 2799 West Grand Blvd, Detroit,
recordings made after an attack. CDH patients demon-
MI, USA
strated few periodic changes of analyzed parameters.
Discussion. We were able to replicate the results of neuro-
Objectives.Central neuronal hyperexcitability may be the physiological periodicity in migraine. However, in CDH,
physiological disturbance that predisposes subjects to this periodicity seems to be impaired and the patients are
migraine attacks. To test this hypothesis, we studied the characterized by permanent abnormalities in spontaneous
cortical stimulation silent period (CSSP) elicited by and event-related brain activities. These abnormalities
transcranial magnetic stimulation (TMS), which is, in part, could explain the more frequently occurring migraine
a measure of central inhibition of motor pathways in attacks and non-migraineous headaches in CDH.
migraine with aura (MwA) patients and normal controls
(C). Methods. In nine MwA patients (mean age 35.9 f7)
and 9 C (mean age 37.6 f7), we carried out transcranial P.12
stimulation using a 95mm circular coil and Caldwell MES CNV in offspring of migraine patients. P Kropp,
10 stimulator to determine resting motor threshold (MT) M Siniatchkin, U Stephani, WD Gerber. Institute of
for bilateral FDI (first dorsal interossei) muscles. All sub- Medical Psychology, University of Kiel, Germany
jects performed isometric voluntary contraction of FDI
maintained at 2OY%of maximal effort, during which we Objective and mefhod. Recently, genetic studies of migraine
measured bilateral CSSP at (i) the stimulus intensity (SI) have aroused special interest. However, it is still difficult
398 Poster presentations CEPHALALGIA 18 (1998)

to determine which functional abnormalities observed in P.14

migraine could be genetically determined and which not.
Increased amplitude and reduced habituation of event- Wavelength of photophobia in headache-free
related potentials are important pathophysiological fea- migraineurs. AD Main’, A Dowson2. ‘European Institute
tures of the migrainous brain. We recorded contingent of Health & Medical Sciences; 2Royal and East Surrey
negative variation (CNV) from C,, C3 and Ca using a Research Unit, Guildford, UK
reaction time paradigm in 20 migraine families (20 parents
suffering from migraine, age: 40.2 f4.2 years, M:F =3:22, Migraine and headache sufferers suffer from photophobia
20 healthy parents with no history of migraine, age: during and between attacks. The aim of this study was to
42.3 f 7.3 years, M:F =22:3, and their 20 healthy offspring, ascertain whether the photophobia that sufferers experi-
age: 11+3.1 years, M:F=9:11) in order to investigate the ence between attacks was related to a particular part of
possibility of inheritance of CNV abnormalities. Results. the visible light spectrum. The discomfort threshold for
Parents suffering from migraine and their healthy offspring white light and visible light of low, medium and high
were characterized by significantly increased amplitude of wavelength was tested in three groups of subjects: a group
an early component of CNV and its reduced habituation of 21 migraineurs (mean age 35.5 years) whose attacks
compared to healthy parents. No changes between groups conformed to the International Headache Society (MS)
were observed in other CNV components or in reaction diagnostic criteria for migraine, a group of 19 headache
time. Differences in CNV parameters were ordered as sufferers (mean age 32.4 years) whose attacks fell outside
follows: magnitude of cortical negativity: healthy of the IHS criteria for migraine, and a group of 21 control
parents (migraine parents < offspring; extent of reduction subjects (mean age 36.3 years) who had less than one
of habituation of early CNV: healthy parents<migraine headache per month. The results indicate significant
parents (offspring. Discussion. High amplitude and differences between groups. The migraine group had a
reduced habituation of event-related potentials seem not lower discomfort threshold when compared to the head-
to be sufficient and necessary pathophysiological features ache group at the lower wavelength (p=O.O006) and
for development of migraine, but represent a possible higher wavelength ( p =0.0171). The migraine group had
predisposition. These abnormalities could be good candid- a lower discomfort threshold when compared to the con-
ates for functional-genetic studies of headache. trol group with white light ( p =0.0268), lower wavelength
(p=O.O002), medium wavelength (p=O.O074), and high
wavelength ( p = 0.0163). The results did not show signific-
ant differences between the headache and control groups.
The control group showed a decrease in discomfort thresh-
P.13
old levels over the course of a day with white light only.
Trigeminal SEP examinations in cluster headache The results suggest that the photophobia experienced by
patients. CS Ertsey, ZS Aranyi, I Jelencsik. Department migraine sufferers between attacks is more pronounced at
of Neurology, Semmelweiss Medical University, Balassa the lower end of the visible light spectrum. Levels vary
U.G., Hungary randomly according to the time of day.

The pathophysiology of cluster headache is still not fully

understood. Recently, data for the activation of the trigemi-
P.15
novascular system have been published. In order to investi-
gate further the involvement of the trigeminal nerve in Perfusion-weighted imaging in a patient with migraine
cluster headache, we examined 31 attack-free patients with aura. MJA Lainez’, MJ Monzon’, J Parra’, C Peiro’,
(27M, mean age: 45.9 + 12.4 years), 29 episodic during the J Sancho’, V Martine2. Departments of Neurology and
active period, and 2 chronic. An age- and sex-matched %Ieuroradiology, H. General Universitario, Valencia,
group of 15 healthy subjects served as controls. Trigeminal Spain
somatosensory evoked potentials (SEPs) were evoked by
surface electrical stimulation on each side of the corners Objecfives. Functional magnetic resonance imaging (fRM1)
of the mouth. Recordings were made by surface electrodes has proved to be a useful non-invasive tool to study
placed at contralateral C5-C6 electrode positions with hemodynamic changes during spontaneous attacks of
reference at Fz. P19 latency, and its interside differences migraine with aura. We report the case of a woman
were used as the main indicators. N13-P19 interpeak diagnosed with migraine with aura and the results of
latency and morphological interside differences were also fRMI during the migmineous aura and interictally. Case
studied. Slight, although not significant, alterations of P19 report. The patient was a woman of 36, diagnosed with
latency and waveform occurred on the headache side as cutaneous neurofibromatosis. She had hemicranial left
compared to the other side in the same subject. N13-P19 headaches that began in the occipital area and radiated
interpeak latency was lower on the headache side, with into the eye. The headache was preceded by visual disturb-
marginal significance ( p =0.0951, Wilcoxon signed rank ance and scotoma. She was admitted because of persistent
test). The P19 latency and N13-P19 interpeak latency headache and neurological deficit. An MRI study of the
values did not differ significantly from those of the control brain showed a left suboccipital neurofibroma. The
group. It is concluded that, in the present setting, the diffusion-weighted MRI was normal. A decrease in relative
activation of the trigeminovascular system in cluster head- cerebral blood flow and in cerebral blood volume and an
ache does not seem to be reflected in trigeminal sensory increase in tissue mean transit time were observed in the
function. More refined techniques and recording of early gray matter of the occipital cortex contralateral to the
responses may give further information. affected visual hemifield during spontaneous migrainous
CEF’HALALGIA 18 (1998) Poster presentations 399

aura. The perfusion RMI study was normal after the decreases in healthy volunteers &IV). Good & Mortimer
headache. Discussion and concZusions.We consider the neur- (1991) differentiated between MO and MA in children by
ofibroma to be responsible for the status migrainosus by measuring visual evoked fast activity (VEFA) to white,
activation of the trigeminovascular system through the red and blue stimuli; red light induced higher amplitudes
stimulation of the trigeminal nucleus caudalis and the only in MA. Four months’ use of rose-tinted glasses
cervical spinal cord at the C-l level. Using fRM1, we decreased attack frequency in parallel with a reduction of
confirmed the appearance of cerebral vasoconstriction at VEFA in children. We compared amplitude changes of
the occipital pole during the aura phase with a perfusion- PR-VEP using tinted glasses of 5 different colors in 12 MA
weighted RMI technique. patients and in 10 HV. During continuous stimulation at
3.1 Hz, 5 blocks of 50 responses were sequentially averaged
using red, yellow, green, blue, and grey glasses as well as
P.16 without glasses and analyzed in terms of latencies and
Nl-P2 amplitudes. Amplitude changes were calculated for
Histamine-dependent nociception and antinociception
each block by comparison with the first block and analyzed
in chronic migraine. M Nicolodi’, PL Del Bianco’,
using Zerbe’s method. In HV, amplitude increased using
AR Volpe2, F Sicuteri’. ‘Interuniversity Centre of
red glasses compared to no glasses ( p =0.05) or green
Neurochemistry and Clinical Pharmacology of Idiopathic
glasses ( p = 0.03). In MA patients, no significant difference
Headache and Department of Internal Medicine,
was detected using colored glasses. Our finding in HV is
University of Florence, Florence, Italy; Tentre of
in line with earlier reports of increased excitability of the
Receptor Biochemistry, National Council of Researches,
human visual cortex to red light (Takayashi & Tsukahara
Rome, Italy
1976). The lack of this pattern in MA patients suggests
that the visual cortex is interictally hypo- rather than
Headache-marked, sudden (24.7 seck3.9 SD latency)
hyperexcitable, which is in line ,with our studies of
worsening following histamine is a well-known phenom-
transcranial magnetic stimulation (Afra et al. 1998).
enon occurring chiefly in chronic migraine (M). We demon-
strated that histamine itself can be used in treatment of
chronic M. This apparent paradox seemingly depends on P.18
the double-faced action of histamine. Indeed, in 19 patients,
Vector analysis of visual evoked potentials in migraine
we show that histamine acts on the kallikrein-kinins
with visual aura. A Padron, P Coutin. Unidad de
system. Such action causes both an activation of the kinins
Neurologia, Hospital Universitario de Los Andes,
system and an increase (p>O.OOOl) of kininase I and II.
* f Merida, Venezuela
ICnumse I releases L-arginine, a substratum for nitric oxide
(NO) synthesis. Indeed, histamine induces an increase
Several reports have described VEP asymmetries in
( p > 0.0001) in NO. Bradykinin excites B2 receptors, medi-
patients with migraine, while others have reported the
ating the painful sensation, while NO acts on vasodilat-
usefulness of vector analysis of VEP in posterior visual
ation. We also showed that nicotinic acid, a potent
pathway lesions. Vector analysis of both pattern-reversal
vasodilative agent, induces no pain and no change in the
(PR) and LED goggle VEP was done in patients with the
kallikrein-kinins system. Therefore, we can conclude that
diagnosis of migraine with visual aura, and 25 healthy
histamine-induced pain is due to the increased release of
control subjects. There were no latency or amplitude
bradykinin. Histamine-induced analgesia is observed as a
abnormalities in any individual patient. However, in many
delayed result either of short-lasting therapy with histam-
patients, the vector angle deviated away from its normal
ine (described elsewhere) or of acute administration.
mid-line orientation, showing a significant statistical
Indeed, in 30% (n =16 out of 50) of chronic M sufferers,
difference between patients and controls (p <O.OOOl).
we observed that low doses of histamine given acutely
Eleven out of 44 measurements (25%) were outside normal
(3 ~g/kg/i.v./bolus) induce an immediate worsening of
limits for PR-VEPs, while 36 out of 46 measurements
headache followed by total headache disappearance which
(78.26%) were outside normal limits for goggle VEPs. In
lasts 11.9 days k3.9 SD. A central mechanism dependent
all cases, the observed deviations were towards the same
on activation of H2 and H3 receptors is seemingly involved
side for each eye, suggesting a retrochiasmatic defect
in histamine-dependent analgesia.
reflected in asymmetries of VEP topography in patients
with migraine with aura, similar to those observed in
patients with well-defined occipital lesions. It is concluded
P.17
that vector analysis of VEPs is a useful physiopathologic
VEP amplitude is not increased by red light in marker for the assessment of occipital dysfunction in
migraine with aura:,indication of interictal cortical patients having migraine with aura.

Semmelweis University, Budapest, Hungary; ‘Neurology,

P.19
Ophthalmolo& and ‘Med Stat Department, CHR Excitatory amino acid transmission in the
Citadelle, University of Liege, Belgium trigeminocervical complex: a role in migraine?
RJ Storer, PJ Goadsby. Institute of Neurology,
We have previously shown that during pattern-reversal Queen Square, London, UK
stimulations lasting 2 min, the amplitude of the visual
evoked potential (PR-VEP) increases interictally in Interest in the fundamental mechanisms underlying head-
migraine with (MA) and without aura (MO), while it ache, particularly the pathophysiology of migraine and
400 Poster presentations CEPHALALGIA 18 (1998)

cluster headache, has led to the study of the physiology antagonist). In contrast to its effect on the SSS-evoked
and pharmacology of the trigeminovascular system and response, alniditan suppressed the response to receptive
its central ramifications. Cats were anesthetized field stimulation by only 27f 13% (n =6). Receptive field
(ac-chloralose60 mg/ kg, intraperitoneally), paralyzed (gal- responses were often recorded at a time when the SSS-
lamine 6 mg/kg intravenously), and ventilated after pre- evoked response was suppressed. Therefore, alniditan
paration for physiological monitoring. The animals were modulates the trigeminovascular system by an action at
placed in a stereotaxic frame. A midline craniotomy and central 5HTle11Preceptors. In view of the differential effect
C, laminectomy were performed to allow access to the on craniovascular vs cutaneous trigeminal input to the
superior sagittal sinus and C2 dorsal horn, respectively. same cell, it appears that alniditan has an action at presyn-
The sinus was stimulated electrically after isolation from aptic receptors in the TNC.
the underlying cortex, and units linked to stimulation
recorded with a tungsten-in-glass microelectrode placed
in the most caudal part of the trigeminal nucleus, termed P.21
the trigeminocervical complex. Signals from the neurons Cortical spreading depression (CSD) in the cat
were amplified, filtered and passed to a microcomputer visualized with magnetic resonance imaging (MRI).
where post-stimulus histograms were constructed on-line MI Smith’, Ml? James’, KHYJBockhorse, LD Hall’, GC
to analyze the responses to stimulation. Units responded Houston2, CLH Huang, N Papadakis2, JM Smith2,
to sag&al sinus stimulation with a typical latency of EJ Williams2, D Xin$, AA Parsonsl, TA Carpente?.
8-10 ms and all units studied had a probability of firing ‘Neurosciences Research, SmithKline Beecham
of 0.6 or greater. Intravenous injection of the non- Pharmaceuticals, Harlow, Essex, UK; 2Herchel Smith
competitive NMDA receptor antagonist MK-801(4 mg/ kg, Laboratory, Cambridge University School for Clinical
intravenously) resulted in a substantial and prolonged Medicine, Cambridge, UK
blockade of firing of units in the trigeminocervical com-
plex. Similarly, administration of the non-NMDA excitat- The role of CSD in migraine initiation and maintenance is
ory amino acid blocker, GYKI-52444, led to a dose- controversial, not least because it is well known in experi-
dependent inhibition of trigeminovascular evoked mental models but difficult to detect clinically. We
responses in the trigeminovascular complex. These data developed MRI protocols weighted for diffusion @WI)
demonstrate the participation of both NMDA and non- and T,* (T,*WI) to visualize CSDs and their sequelae in
NMDA mediated mechanisms in transmission within the the complex brain of the cat. Female cats (3.2 kg), main-
trigeminovascular complex, and, for the first time, provide tained under a-chloralose anaesthesia, were mechanically
a clear pre-clinical implication of glutamate+ mechan- ventilated and monitored within a normal physiological
isms within primary headache systems, such as migraine range. CSDs were initiated with KC1 ( -30 mg) on the
and cluster headache. cortical surface and monitored using an Ag/AgCl elec-
trode. DWI (at 2T, b factors - lOO/-850), alternated with
T,*WI (15~set intervals, m-plane resolution 0.39 mm), were
P.20 targeted horizontally through the suprasylvian (SG) and
Alniditan modulates the trigeminovascular system by marginal gyri. Within l-2 minutes post-KCl, a complex,
hemispheric CSD wave was initiated (coincident with
an action at 5HTlwlD rece ors. PM Boersl”,
C Donaldson3, AS ZagamiG , GA Lambert’. ‘Institute of reduced dc potential) with apparent diffusion coefficient
reduced by - 18% spreading at 3.4f0.59 mm/min
Neurological Sciences, Prince Henry and Prince of Wales
(mean f SD). In the following 25-60 min, further fragment-
Hospitals; ‘Department of Medicine, St George Hospital;
ary waves (l-5) were observed spreading less widely and
3University of New South Wales; Sydney, Australia
quickly (2.1 f0.57 mm/min), often confined to the SG.
The trigeminovascular system plays an important role in T,*WI indicated acute activation (first wave > subsequent).
CSD waves were not detected with DWI pre-KC1 or
the pathophysiology of migraine. Drugs which are agonists
contralaterally. These studies may provide an enabling
at 5HT1B,1Dreceptors, such as sumatriptan, zolmitriptan methodology to observe cortical changes during migraine.
and alniditan, are effective antimigraine drugs. We have
conducted this series of experiments to assess the ability
of alniditan to modulate sensory input from the superior
P.22
sagittal sinus (SSS) at the level of the trigeminal nucleus
caudalis (TNC). Experiments were conducted on 11 adult Basal nitric oxide (NO) plasma levels in migraine.
cats anaesthetized with halothane (during sur ery) and D D’Amico’, A Ferraris’, A Catania2, A Carlin2,
a-chloralose (60 mg/kg i-p. followed by 20 mg Bkg i.v. at M Leone’, L Grazzil, A Attanasio’, G Bussone’.
regular intervals). Animals were paralyzed with gallamine ‘Headache Center, Neurological Institute “Carlo Besta”,
(20 mg i.v.). The SSS was stimulated electrically and single Via Celoria n. 11, Milan, Italy; ‘Third Division of
unit recordings made in the region of the TNC with a Medicine, “Maggiore” Hospital, Milan, Italy
7-barrel tungsten-in-glass microelectrode. Responses from
22 cell somata were recorded in the TNC. Several properties of nitric oxide (NO) suggest that it may
Microiontophoretic application of tiditan (usually play a role in the mechanisms giving rise to migraine as it is
I 20nA) suppressed the SSS-evoked response by 2 30% in involved in vasodilation, neurogemc inflammation and elab-
20/22 neurones (mean su pression 64f4%). The effect of oration of painful stimuli. Our working hypothesis was that
alniditan was sign&an tpy reduced in the presence of NO plasma levels in migraineum are different from those
iontophoretically-applied GR127935 (a selective 5HT1B,1D found in healthy subjects. We studied 84 migraine patients,
CEPHALAIAXA 18 (19!38) 401

52 with migraine without aura and 32 with migraine with to neoplastic involvement of bone is the most prevalent
aura, according to the IHS criteria. Mean age was 34.1 years, pain syndrome in cancer patients (CP). Endogenous opioid
range 18-59 years. There were 22M and 62F; 112 healthy peptides have been widely studied in headache because
subjects were used as controls. All patients were in a pain- of their probable role in pain modulation. This study was
free period and were not using prophylactic drugs. Blood undertaken to evaluate plasma met-enkephalin (ME)
samples were collected after a nitrate-free diet for the previ- behavior in patients with CTTH and chronic pain related
ous 48 h. NO levels were measured as plasma nitrites using to bone metastases due to lung cancer. Six patients with
the Griess technique. Statistical analysis was performed by C’ITH and 9 patients with CP were studied. ME was
Mann-Whitney Rank Sum test. Mean NO plasma levels were determined by radioimmunoassay with specific antibody
higher in migraine patients than in controls (44.281+29.688 and expressed in pmol/ml f SEM. Plasma ME levels in
and 35.565f23.645~ol/ml, respectively; mean+SD; p= the C’ITI-I group (0.36 kO.01) were not different from those
0.005). Both migraine without and migraine with aura in the CP group (0.31 kO.03). These results suggest a
patients had significantly increased levels. Scatter plot ana-
similar opioid pattern in both types of chronic pain inde-
lysis revealed 2 groups, character%& by NO levels <or >
pendent of their etiology.
to 60 pal/ml. Dividing migraine patients according to
headache frequency (attacks/month O-l/month or >2), an
association between higher NO plasma levels and higher
frequency was found (x2 test, p -cO.OOl).In conclusion, the
increase in basal NO plasma levels in migraine suggests a
constitutional functional alteration in those systems in which P.25
this molecule is the final messenger in migraineurs. Serum interleukin-lg and tumor necrosis factor-a in
idiopathic cervicogenic headache. P Martelletti’,
P.23 G Stirparo2, M Giacovazzo’. ‘Department of Clinical
Medicine, University “La Sapienza”, Rome, Italy;
Differential distribution of 5HTIB- and SHT,,-receptors 21nstitute of Biomedical Technologies CNR, Rome, Italy
on human trigeminal sensory neurons: an
immunohistochemical study. D Shaw, JD Pickardl,
There is now solid evidence to consider cervicogenic
D Smith, RG Hill, J Longmore. Merck Sharp & Dohme,
headache (CH), an uncommon and controversial headache
Neuroscience Research Centre, Harlow, Essex, UK, CM20
disorder, as a multifactorial pain syndrome arising from
2QR; ‘Department of Neurosurgery, Addenbrooke’s
Hospital, Hills Road, Cambridge, UK, CB2 2QQ neck structures (Pollman W, et al. Cephalalgia
1997;17:801-6). No evidence of inflammation has been
The antimigraine activity of 5HT,,,,,-receptor agonists demonstrated in CH, although diagnostic use of epidural
has been attributed, at least in part, to inhibition of the corticosteroid revealed short-term clinical effectiveness
release of pro-vasodilator neuropeptides from trigeminal (Martelletti P, et al. Eur Rev Med Pharmacol Sci
sensory fibers. We conducted immunohistochemical stud- 1998;1:1-11). Our laboratory has reported impaired func-
ies using selective 5HTls- and SHT,u-receptor antibodies tion of proinflammatory cytokine interleukin-1B (IL-l p),
to determine the identity of this prejunctional inhibitory but not of Tumor Necrosis Factor-a (TNF-a) in patients
receptor on trigeminal fibers within the meninges and the suffering from another form of unilateral headache, such
brainstem in man. Both 5HTu& and 5HT1n-ir were as cluster headache (Martelletti P, et al. Cephalalgia
detected on cell bodies of the trigeminal ganglion, whereas 1993;13:343-5). Here we reported a marked increase of
only 5HT1P-ir (but not 5HT,,-ir) was detected on trigeminal both cytokines IL-lp and TNF-a in 11 idiopathic CH
sensory fiirs. In the dura mater 5HT,,-receptor, ir was in-patients (8F, 3M; mean age 39.5 k8.4) studied before
detected on perivascular nerve sensory fibers and in the (TO) and during attacks provoked by neck movements
brainstem, 5HTu,-ir was confined to discrete areas associ- (Tl) when compared with 9 sex- and age-matched healthy
ated with the trigeminal sensory system. In the trigeminal subjects (C) (IL-@: CH TO vs C p < 0.002, CH Tl vs C
nucleus caudalis, 5HT1P-receptor ir fibers were shown to p <O.OOl, CH TO vs CH Tl p < 0.05; TNF-CZ;CH TO vs C
co-express substance P or CGRP. 5HT,B-receptor ir was ~~0.03, CH Tl vs C p<O.Ol, CH TOvs CH Tl n.s.). These
widespread in other areas of the brainstem not associated data have been obtained by measuring in serum samples
with the trigeminal sensory system. In conclusion, in man, taken from jugular venous blood the cytokine panel levels
some of the substance p-containing and CGRP-containing by specifically directed enzyme linked immunoassays. The
trigeminal sensory neurons selectively also express 51-IT1P-
enhanced production of both IL-1B and TNF-a in CH, as
receptors. These receptors may be important in regulating
shown in the present experiment, could firstly represent a
the release of neuropeptides from these fibers.
specific signal from the immune system with a subsequent
activation of the well-known links existing between the
P.24 immunopeptides and neuropeptides, such as SP or CGRP
Plasma met-enkephalin and chronic pain. (Martelletti P, et al. Cephalalgia 1993;13:343-5). The IL-la
M Figuerolals, M Barontin?, JA Leston2. ‘Cedie, Conicet, and TNF-cc increase that we measured during the CH
HTAL de Ntios; 2Department of Neurology, HTAL de mechanically-induced attacks could be stress-related, but
Clinicas, Buenos Aires, Argentina this would not account for the high values detected during
the interictal phase of CH. Although the role of these pro-
Chronic tension type headache (CTI’H) is the most fre- inflammatory cytokines in CH is to be determined, both
quent type of chronic head pain. Nociceptive pain related IL-l p and TNF-or may promote hyperalgesia in CH.
402 Poster presentations CEPHALALGIA 18 (1998)

P.26 migraine. The first, (Raskin NH, et al. Headache

1987;27:416-20), reported the development of migraine-
Nitric oxide synthase and cyclooxygenase activation in
like headache in previously unaffected patients following
cultured lymphocytes and monocytes of mi aine
the implantation of a stimulating electrode into the ventro-
patients. P MartelIetti’, A Zicari2, G Stirparo Y, M Lipari2,
C RinaIdi2, M Giacovazzo’. ‘Department of Clinical lateral PAG. The second, (Weiller C, et al. Nat Med
Medicine, University “La Sapienza”, Rome, Italy; 1995;1:658-60), revealed increased neuronal activity (using
2Department of Experimental Medicine and Pathology, positron emission tomography) in the contralateral PAG
University “La Sapierua”, Rome, Italy; 31nstitute of before and following the successful treatment of the head-
Biomedical Technologies CNR, Rome, Italy ache. This study was designed to determine the regions
of the PAG involved in processing pain of intracranial
The molecular events that modulate the network existing
origin. In alpha-chloralose anaesthetized animals, the
between nitric oxide synthase (NGS) and cyclooxygenase
(COX) represent the most important goal in the research superior sagittal sinus (SSS) was electrically stimulated
fields concerning the brain activities and functions (0.3 Hz, 150 V, 250 l.& for 1 (monkey) or 2 (cat) h. Sections
(Salvemini D, et al. Proc Natl Acad Sci USA 1993;90:7240-4). of the midbrain (40 fun) were cut and subsequently pro-
Both systems are involved in the control of the physiological cessed for Fos (fos-x antibody kindly provided by Dr
process as well as in the pathogenesis of several intlammat- G. Evan). Increased Fos expression due to SSS stimulation
ory diseases, i.e. for migraine without aura (MWA) was seen in the whole PAG. This activation was mostly
(MartelIetti P, et al. J Mol Med 1997;75:448-53). We recently observed in the lateral and ventral areas of the caudal
demonstrated that during NO-donor (NOD) MWA attack, PAG. Both the lateral and ventral segments of the PAG
elevated amounts of nitrite (No,-) are present in serum, are known to receive input from the superficial laminae
peripheral blood mononuclear cells (PBMCs), supematants, of the trigeminal nucleus caudalis (TNC) and upper cer-
and extracts (Martelletti P, et al. Int J Clin Lab Res 199828). vical spinal cord and the nucleus of the solitary tract and
Since NOS and COX are mutually controlled systems, we its caudal extension lamina X of the cervical spinal cord
investigated their activation in purified populations of (Bandler R, Shipley MT. Trends Neurosci, 1994;17:379-89).
1ymPhocytes WY) and monocytes (MO) obtained from
15MWA patients in basal conditions compared to those
from 10 controls (C). Ly and MO populations were cultured
in vitro for 24 h at 37°C in the atmosphere of 5% CO,. At the
P.28
end of the incubation, supernatants were collected and the Involvement of vessels in trigeminal pain: shedding
present amount of PGE, was determined by RIA assay, light on the trigeminovascular system. A May’,
whereas the level of NO products was measured as NO,- A Bahra’ , P J Goadsby’, C BucheP , RSJ Frackowi&.
accumulation, using the Griess reagent. Cyclic 3’,5’- ‘Department of Clinical Neurology and wellcome
guanosine monophosphate (cGMP) efflux was also assayed Department Cognitive Neurology; Institute of
in Ly and MO supematants using an EIA kit. We demon- Neurology, Queen Square, London, UK
strated that NO,- release was significantly lower in MWA
Ly (5.25 f0.49 @t/lo6 cells/24 h) than in C (11 f 0.46 @I/ Rationale. The issue of vascular vs neurogenic mechanisms
106 cells/24 h; p (0.05). A parallel trend in Ly has been
in primary headaches, such as migraine and cluster head-
observed for cGMP (1480+100 fmol/l@ cells/24 h vs
ache (CH), is still unresolved. The pathophysiological
2101 f82 final/106 cells/24 h; p < 0.01). By contrast, PGE2
concept of vascular he&zchs is based on the idea that
are released by MWA Ly to a greater extent (2.4 f 0.08 ng/
changes in vessel diameter or gross changes in cerebral
106cells/24 h) than C (1.7f0.03 ng/lo6 cells/24 h; p<O.O5).
Interestingly, MO showed fulI activation of the studied blood flow trigger the pain. This idea could, in part,
systems. In fact, all these parameters were higher in MWA explain the mechanism of action of vasoconstrictor drugs.
MO than in C (NO,-: 91.25f8.2 @l/106 cells/24h vs Methods. We studied 17 patients (aged 25-62, mean 46
55 + 6.3 w/106 cells/24 h; p < 0.001. cGMI? 5662 f 562 fmol/ years) with cluster headache diagnosed according to IHS
106cells/24 hvs2843+210 fmo1106celIs/24h;p<0.001.PGE+ criteria (9 patients in the active period, 8 patients out of
4.137kO.03 rig/l@@ cells/24 h vs 2.531 f 0.02 ng/lo6 cells/ the bout) using PET. CH was provoked by inhalation of
24 h; p ~0.001). These in r&o studies in MWA which is not nitroglycerin. Each patient had 12-13 consecutive scans.
NOD dependent suggest that: (i) the mechanisms leading Only patients in the active period experienced pain as
to NOS and COX activation are different in Ly and MO well as the autonomic symptoms associated with cluster
systems; (ii) the purified MO represent the most appropriate headache. The patients outside the bout experienced no
experimental model in the study of NOS/COX activity, cluster headache attack. Results. In addition to the activa-
rather than PBMCs or Ly; (iii) the cGMP increased extrusion tions in structures associated with cluster headache, such
substantiates the NOS activation. Our data call for a derange- as the cingulate, insula cortex, frontal lobe, thalamus, and
ment of NO-ergic system as a marker of MWA terrain. the ipsilateral posterior hypothalamic grey area, significant
increases in activation were found in the basilar and
P.27 carotid arteries. Dilatation of these vessels was confirmed
Fosexpression in the periaqueductal gray following using magnetic resonance angiography. Conclusions. As
stimulation of the superior sagittal sinus (SSS) in both activation of vessels has been identified in experimental
the cat and the monkey. KL Hoskin, D Bulmer, pain, our data suggest that the observed dilatation of
M Lasalandra, A Jonkman, PJ Goadsby. Department of intracranial vessels in trigeminal pain is not, as has been
Clinical Neurology, Institute of Neurology, Queen implied, inherent to a specific headache syndrome. Clinical
Square, London, England and animal data rather suggest that the observed vasodilat-
Two crucial clinical studies have suggested a role for the ation is the effect of a trigemino-parasympathetic reflex,
periaqueductal gray (PAG) in the pathogenesis of and is not strictly linked to the clinical syndrome. We take
CEF’HALAICIA 18 (1!298) Poster presentations 403

the view that the known physiology and pathophysiology attacks/each patient). The same procedure was repeated
of the systems involved dictate that primary headaches, administering the drugs 4 h after the onset of different
such as CH and migraine should be collectively regarded attacks. The intensity of the attacks was measured using
as neurovas~clar headaches to place emphasis on the inter- a verbal scale. The efficacy of the drugs followed this
action between nerves and vessels, which is the underlying order: sumatriptan < ergotamine < indomethacin. A signi-
characteristic of these syndromes. ficant decrease in drug effectiveness was observed with
later administration. The efficacy of the oral dose was
reduced to about 70% of the one observed during early
P.29 administration, whereas the efficacy of the intrarectal and
VAS headache diary to evaluate chronic headache. the subcutaneous/intramuscular doses was reduced by
about 30%. The results of the present study indicate that
K Dobashi, F Sakai, H Igarashi, Y Unno. Department of
gastro-intestinal absorption plays a role in the decrease in
Medicine, Kitasato University, Kitasato, Japan
efficacy of anti-migraine drugs taken later in the attacks,
even ii other mech&nisms a&also involved.
Purpose. We developed a new visual analogue scale (VAS)
headache diary to obtain detailed information about
patient headaches and related features. Method. We studied
133 patients (28M, 105F, mean age 41 years) diagnosed on P.31
their initial visit as having migraine, tension-type head- Low headache recurrence with naratriptan-clinical
ache, combined headache or chronic daily headache. All parameters related to recurrence. F Sheftell’, C Watson’,
the patients kept diaries in which their headaches were DG Pait’, S O’Quinr?, P Winte3. ‘New England Center
recorded. Patients logged headache severity over time for Headache, Stamford, CT, USA; Glaxo Wellcome Inc,
using a visual analogue scale from l-10. They also RTP, NC, USA; Glaxo Wellcome Plc, Greenford, UK
recorded the nature of the headaches and associated
symptoms the use of medicine, and any triggering factors. Objective. To identify clinical parameters that affect the
Results. Comparison between the initial diagnosis made incidence of headache recurrence (HR) and time to HR
from a patient’s history taken at a clinic and later diagnosis with naratriptan. Background. The incidence of HR within
using our headache diary disclosed that patients usually 24 h of successful treatment with naratriptan 2.5 mg tablets
had more than one headache. If the patient had recorded (17-28%) is lower than reported for other specific 5HT1
in the diary characteristics, time course, and impact of agonists (30~40%). Understanding clinical parameters that
treatment for headache, it was possible to differentiate affect HR may further enhance the low incidence of HR
visually between migraine and tension-type headache, for naratriptan. Mefhods. HR (significant worsening of
which was not a straightforward task at the time of the headache after achieving relief) and time to HR were
initial visit. Thirty-five patients had coexisting migraine examined across 4 placebo-controlled naratriptan clinical
and tension-type headache. Conclusion. Our headache trials in migraine patients. Three clinical parameters (pre-
diary provides prospective information about the patients dose pain severity, no pain 4 h postdose and duration of
and is an effective means of educating patients about the headache prior to treatment) were evaluated as to their
disease and its treatment. impact on HR. Results. Predose pain severity had no effect
on-the incidence of HR. However, the time to recurrence
was longer in patients with moderate pain predose.
P.30 Patients with no pain 4 h postdose had a lower incidence
Timing-related efficacy of the anti-migraine drugs: of HR and a longer time to HR. The duration of the
F&ct of administrations during different phases of the headache predose was longer for patients experiencing
attack. BM Fusco’, C Saturnine’, 0 Colantoni’, HR than for those who did not experience HR. Conclusions.
S Salomonti, A Bianchi*. ‘Department of Pharmaceutical The overall incidence of headache recurrence is low after
Sciences; *Institute of Pharmacology, University of naratriptan 2.5mg. The low incidence of recurrence for
Catania, Italy naratriptan may be enhanced in those patients who obtain

Early administration of anti-migraine drugs seems to be

much more effective than administration later in the attack.
As the oral route is most frequently used, alteration of Incidence of HR
Predose pain severity
gastro-intestinal absorption at the peak of the attack could
moderate or severe 23%
be a possible cause. In this study, we have evaluated the moderate 22%
efficacy of sumatriptan, ergotamine and indomethacin severe 23%
administered in different ways and at different times No pain 4 h postdose 17%
during the attack. Forty-five subjects affected by attacks of Time to HR (median)
migraine without aura (lasting at least 12 h) were divided Predose pain severity
into 3 groups of 15. The first group was treated with moderate or severe 11.8 h
sumatriptan during the first hour after onset of the attacks moderate 14.5 h
severe 9.3 h
(for each patient, 5 attacks were treated with oral doses, 5
No pain 4 h postdose 17.8 h
with suppositories, and 5 with subcutaneous injections).
Duration of headache predose (median)
The second and third groups received ergotamine and NoHR 97.5 min
indomethacin, respectively, via the same modalities (oral HR 3145.0 min
doses, suppositories, and intramuscular injections x 5
 Poster prewntatims CEF’HALALGIA 18 (19%)

complete pain relief postdose, those with less severe bia). Design/mefhods. Thirty-one patients were surveyed
attacks and those who treat a migraine attack earlier. regarding the degree of success achieved with Alniditan
Whether this is true with other triptans remains to be to relieve migraine pain and associated symptoms as
investigated. These data may help us to understand mech- outlined above. Values from O-4 (0 = least effective relief)
anistic issues related to incidence of and time to recurrence. were used. Results. Results were analyzed and recorded
in percentage form. The ability of Alniditan to relieve pain
and associated symptoms during an acute migraine attack
P.32 was considered EXCELLENT by 66% (n =21), VERY
GOOD by 10% (n =3), GOOD by 3% (n =3), FAIR by 0%
Hclicobacter pylori eradication ameliorates migraine:
(n = 0), and POOR by 20% (n =6) of the patients. Twenty-
a prolonged follow-up stud . A Gasbarrini’, G Fiorel,
five percent of patients receiving a 1.4 mg dose of Alniditan
M Giacovazzo’, M Gabrielli7. Internal Medicine “‘La
reported headache relief 15 min after Alniditan injection,
Sapienza” University, Catholic University, Rome, Italy
and only 16% of patients receiving 1.4mg of Alniditan
reported headache recurrence within 24h of treatment.
H. pylori infection, the most common cause of gastritis,
Conclusion. Alniditan was found to be an effective drug in
has been associated with some functional vascular patho-
logies. The aim of this study was to assess the prevalence reducing pain and associated symptoms of the migraine
syndrome (nausea, vomiting, photophobia and phonopho-
of H. pylori infection in migraine and whether its eradica-
bia) in 76% of the study participants. Supported by: Janssen
tion is able to reduce disease attacks. Two-hundred-and-
Pharmaceuticals.
twenty-five patients (16OF, 65M; mean age 36 +13 years)
affected by primary migraine were evaluated. H. pylori
was diagnosed by ‘3c-urea breath test. Arnoxicillin (1 g
bid), claritluomycin (250 mg tid) and a proton pump P.34
inhibitor (bid) were given to infected patients at the time Itt vitro metabolism of eletriptan in human liver
of diagnosis for 7 days. Feeling of discomfort, duration, microsomes. R Hyland, BC Jones, P McCleverty,
and frequency of migraine attacks per week were assessed RJ Mitchell, P Morgan. Department of Drug Metabolism,
1,3,6 and 12 months after eradication. Forty-eight percent Pfizer Central Research, Sandwich, Kent, UK
of patients (105/225) were infected by H. pylori. After
therapy, 84% of patients experienced eradication. Attacks Eletriptan (UK-116,044, (R)-3-(l-methyl-2-pyrrolidinyl-
of migraine completely disappeared in 23% of eradicated methyl)-5-[2-( phenylsulphonyl)ethyl]-lH-indole) is a new
patients. Feelings of discomfort, duration, and frequency selective agonist at the “5HT&ike” receptor (Gupta P,
of migraine attacks per week were significantly reduced et al. Cephalalgia 1996;16:386). The compound has been
in 75% of the remaining eradicated patients during the shown to be clinicalIy effective in the acute treatment of
entire follow-up period. The presence of aura did not migraine and is associated with a low incidence of side
influence the clinical response of migraine to H. pylori effects (Jackson NC. Cephalalgia 1996;16:368). Excretion
eradication. None of the treated but uneradicated patients studies in humans using [‘“cl radiolabelled eletriptan have
showed a reduction in the manifestations of migraine. A shown that less than 20% of a dose is accounted for by
significant reduction in the weekly consumption of anti- unchanged eletriptan in total excreta, indicating that the
inflammatory drugs was observed in eradicated patients elimination of eletriptan in humans is primarily metabolic.
when compared to uninfected or to treated but uneradi- The involvement of cytochrome P450 in the metabolism
cated patients. H. pylori eradication significantly amelior- of eletriptan has been established in human liver micre
ates migraine through a significant decrease in intensity, somes where metabolism of eletriptan was supported by
frequency, and duration of disease attacks during pro- NADPH in microsomal preparations, whilst no turnover
longed follow-up. The reduction of the vasoactive sub- was observed in the absence of NADPH. Several metabol-
stances produced by the immune system in response to ites of eletriptan have now been identified in human
infection may be the pathogenetic mechanism underlying liver microsomal extracts and the CYP enzyme(s) respons-
this observation. ible have been investigated. A major metabolite in
human liver microsomes was the product of pyrrolidine
N-demethylation (UK-135,800), and this metabolite is also
P.33 known to be an active circulating metabolite in human
A patient satisfaction-based evaluation of efficacy of plasma. Enzyme kinetic studies in human liver microsomes
alniditan in the acute treatment of migraine. indicated the involvement of a single enzyme in the
J Goldstein. San Francisco Headache Clinic, 900 Hyde generation of this metabolite. The formation of UK-135,800
Street, Suite 230, San Francisco, CA, USA was inhibited in a concentration dependent fashion by the
CYP3A4inhibitor ketoconazole, whilst selective inhibitors
Objecfive. To assess overall patient satisfaction with of other P450 enzymes had little effect. The rate of metabol-
Alniditan (a 5HT 1 D receptor agonist chemically similar ism across a bank of human liver microsomes correlated
to sumatriptan) in the treatment of acute migraine attacks. strongly with CYP3A4 activity (I= 0.91), but not with the
Backgrounds. Subjects were recruited from clinical trials activity of other P450 enzymes. In microsomes from cells
ALN-INT-16, ALN-INT-17, and ALN-USA-18, following expressing a range of individual P45Os, only CYP3A4
the close of ALN-USA-18. The patients were surveyed to produced significant amounts of UK-135,800. These studies
evaluate their satisfaction with the drug based on its ability illustrate the importance of cytochrome P450, in particular
to relieve pain and associated symptoms of the migraine the CYP3A4 enzyme, in the metabolism of eletriptan
syndrome (nausea, vomiting, photophobia and phonopho- in man.
CEPHALALGIA 18 (1998) Poster presentations 405

P.35 double-blind, placebo-controlled crossover study in

young (18-36 years) and elderly (65-93 years), male and
Rizatriptan shows craniovasculu selectivity for human female volunteers. Plasma concentrations of eletriptan
isolated middle meningeal over coronary arteries-a were determined in samples collected up to 24 h post-
comparison with sumatriptan. 2 Razza ue’, D Shawl, dose, by high performance liquid chromatography using
AP Davenpore, JJ Maguirg, JD Pickard4 , L Maskel12, RG ultraviolet detection. There were no statistically significant
Hill’, J Longmorel. ’Department of Pharmacology, Merck gender differences in the pharmacokinetics of eletriptan in
Sharp and Dohme, Terlings Park, Eastwick Road, systemic exposure to eletriptan (as measured by C- and
Harlow, Essex, UK; weurosurgery Unit, Addenbrookes, AUC), time to maximum plasma concentrations (T_) or
Cambridge, UK. elimination rate (kl). However, a comparison between the
elderly and young showed that elimination rate (lo) was
Background and objectives. 5HT,B,1i-,-receptor agonists are reduced with an increase in the associated half-life from
effective in treating migraine and can cause vasoconstric- 4.3 h in the young to 5.7 h in the elderly (p c 0.0001). This
tion of both cranial and peripheral blood vessels. The resulted in a slightly higher systemic exposure to eletriptan
extent of constriction is graded across different vascular (with an increase in AUC by 18%; n.s.), but no apparent
beds, and thus in this study a comparison of the vasocon- change in C-. These changes were probably due to the
strictor effects of rizatriptan and sumatriptan was made reduction in hepatic clearance often associated with age.
in human middle meningeal (M&IA) and coronary arteries With respect to change from baseline, eletriptan 8Omg
(CA), accompanied by measurement of levels of expression differed by +lO mmHg and +6 mrnHg for SBP and DBP,
of SI!YIT,~-
and SHT,,+eceptors in the two tissues. Methods. respectively, compared to placebo. These resolved in 6 h
Cumulative contractile concentration-effect curves were and were not considered clinically relevant. Eletriptan was
constructed to 5HT, rizatriptan and sumatriptan in ring generally well-tolerated and there were no serious adverse
segments of human isolated MMA and CA (endothelium events in any subject group. In conclusion, this study
denuded). Data analysis was by ANOVA and non-linear found that there was no clinically significant effect of
regression analysis, with n=6-7 arteries per gender or age on the tolerability, pharmacokinetics, or
group. 5HT,B,,,-receptor expression was determined pharmacodynamics of oral eletriptan.
using specific antibodies and standard immunohistochemi-
cal techniques. Results. The ECm values obtained for MMA
were 0.032, 0.090, and 0.071 @i for 5HT, rizatriptan, and P.37
sumatriptan, respectively. All agonists were lo-fold I-Point acupuncture as treatment in acute headache.
weaker in producing contraction in CA. Rizatriptan caused R Pothmam?, G Bollig’, I Vormbaum’, T Vogtmann’,
a significantly greater contraction of human isolated MMA B Kroner-Herwig, J Mau’, S SchneiderZ, C Juhra2.
than sumatriptan, whereas in contrast, rizatriptan was less Department of Children’s Neurology/Headache Project
effective than sumatriptan in causing constriction of CA Ev. Krankenhaus, Oberhausen’, Institute of Statistics,
(see Table 1). 5HT,,-receptor expression was significantly Heir&h-Heine-University, Dusseldorf; Institute of
higher in MMA compared to CA. 5HT,,-receptor immuno- Clinical Psychology, Georg-August-University,
reactivity was not detected in either vessel type. Conclusion. Giittingen3; Germany
Jn isolated blood vessels, rizatriptan displayed greater
craniovascular selectivity over coronary artery selectivity Headache is the number-one illness in Germany. Acute
than sumatriptan, and its vasoconstrictor effects were headache treatment-usually by means of drugs by the
mediated through 5HT,B-receptors which predominate in patient himself-is effective in about 50% of cases. The
MMA over the coronary artery. aim of our study was to investigate whether a short
T&e 1. L values for 5HT, rizatriptan and sumatriptan temporal muscle acupuncture stimulation is good clinical
in MMA and CA. (Data repmsented as means with asymptotic practise for pain-reduction compared to nonspecific needle
errors in brackets. The values were expressed as the maximum stimulation. Method. All patients with acute migraine or
contraction relative to 45 mM KCl) tension-type headache were given an i.v.-line with sodium-
chloride. They were randomized into three groups: one-
5HT Rizatri@an Sumatriptan third were injected bitemporally (Ex. 2 =Taiyang). After a
short periostal prick of 2 set the needle was withdrawn
to a position half of the depth for 15 min. One-third were
zhdy 1) 160.6
78.2 (8.8)
(7.2) 132.6
24.8 (6.2)
(1.0) 105.3
58.1 (4.2)
(0.7) needled at nonspecific placebo-points (10 cm lateral of C7).
CA (study 2) 102.0 (1.5) 22.2 (1.8) 43.7 (1.8)
The needles were positioned in the subcutis for 15 min.
One-third were needled nonspecifically plus 500 mg ASS
intravenously. The results were rated four times within
1 h of treatment using a Xl-point visual analog scale (VAS).
P.36
In addition, we carried out a surface-EMG and pressure-
The safety, tolerability, pharmacokinetics, and algometry of the head and neck. Results. In the pilot study
pharmacodynamics of oral eletriptan in young acupuncture at Taiyang (Ex 2) was performed 18 times in
and elderly, male and female subjects. KA Milton’, 16 patients. Only 3 patients had residual pain after 10 min;
E Tan’, MJ Boy&, S Warrington2. ‘Pfizer Central 15 patients were completely headache-free after 16 min. A
Research, Sandwich, Kent, UK; 2Hammersmith Medicines randomized prospective study with 342 patients is ongo-
Research, Central Middlesex Hospital, London, UK ing. Cunchsion. The first results are very encouraging. A
simple triggerpoint linked acupuncture seems to fulfill the
The safety, tolerability, pharmacokinetics, and pharmaco- expectations for a non-medical as well as clinical additive
dynamics of oral eletriptan 80 mg were investigated in a acute headache management.
406 Poster presentations CEPHALALGIA 18 (1998)

P.38 differences among treatments were observed in mean PR,

QRS, and QTc interval measurements or in QTc dispersion.
Efficacy and tolerability of oral almotriptan in the No subject after receiving almotriptan had prolonged QTc
treatment of migraine. M Robert, X Cabarrocas, interval values. C,, ranged from 49.51 f 13.05 ng/ml
FJ Fernandez, JM Zayas, P Ferrer for and on behalf of the (12.5 mg) up to 213.5 +60.9 ng/ml (50 mg). AUC ranged
Almotriptan Multiple Attacks Study Group. Research from 266.1 k39.1 ng.h/ml (12.5 mg) up to 1123
Center, Almirall Prodesfarma, S.A. Barcelona, Spain ng.h/ml+ 191.4 ng.h/ml (50 mg). L values were
2.5 +0.7 h in all cases. No significant differences in pharm-
Objective. To assess the efficacy and tolerability of 6.25 and acokinetic parameters were seen between males and
12.5 mg oral almotriptan, a selective 5HTI agonist females. As no clinically relevant findings were observed,
developed for the acute treatment of migraine, in a ran- the correlation between plasma concentrations of almotrip-
domized, double-blind, parallel-group and placebo- tan and cardiovascular effects was not carried out.
controlled study. Methods. Nine-hundred-and-eight Almotriptan was well tolerated at any dose. No serious
migraineurs diagnosed according to the International adverse events were recorded during the study.
Headache Society criteria treated up to three migraine Conclusions. Results show no findings in terms of electro-
attacks with a single oral dose of almotriptan 6.25 or cardiographic effects, PR, QRS, QTc interval measure-
12.5 mg or placebo. The primary measure of efficacy per ments, or in QTc dispersion when comparing the active
attack was the percentage of patients who experienced doses versus placebo. The pharmacokinetics of almotriptan
headache relief (moderate or severe pain reduced to mild was linear at the dose range studied.
or no pain) 2 h post-dose. Comparisons of treatment
groups were carried out by means of a Fisher’s exact test.
Other efficacy (headache relief and pain-free at different
time points, use of rescue medication, headache recurrence
P.40
and migraine-related symptoms) and safety variables were
also assessed. Resulfs. In the first attack, the only one in Efficacy and tolerability of ‘Zomig’ in adolescent
which patients could not be influenced by a previous migraine. AJ Dowson’, PE Fletcheti, DS Millson3.
result, headache relief 2 h post-dose was reported in 65% ‘Neurolo p Headache Service, Rings College Hospital,
of patients receiving almotriptan 12.5 mg compared with London; Zeneca Pharmaceuticals, Wilmington,
55% and 32% of patients receiving almotriptan 6.25 mg Delaware, USA; 3Zeneca Pharmaceuticals, Macclesfield,
and placebo, respectively (p < 0.05 almotriptan 12.5 mg Cheshire, UK
and 6.25 mg versus placebo, and 12.5 mg versus 6.25 mg).
Almotriptan was well tolerated. During the first attack, Adolescent migraine, although less common than migraine
16% of patients suffered at least one adverse event after in the adult population, is a significant, often unrecognized
placebo, compared with 13% and 18% after almotriptan health problem, leading to poor school attendance/per-
6.25 mg and 12.5 mg, respectively (p=N.S.). ConcIusions. formance, and under-employment. A pharmacokinetic
Oral almotriptan at doses of 6.25 and 12.5 mg is an effective study of 5 mg zolmitriptan in adolescents and adults found
and well-tolerated drug for the acute treatment of no clinically significant differences between the two age
migraine. Moreover, 12.5 mg seems to have the optimum groups, although a shorter t+ in adolescents suggested
ratio of efficacy to tolerability. faster elimination (t+ 3.01 h vs 3.75 h). Adolescents had a
higher exposure to the active zolmitriptan metabolite
183C91 but dose adjustment is not warranted based on
pharmacokinetics alone. As part of a large open-label
P.39 phase of an international study, 38 adolescent patients
Electrocardiographic effects and pharmacokinetics of (2OF, 18M; age range 12-17 years) were recruited by 25
oral almotriptan in healthy subjects. M Robert’, centers and offered free and unlimited access to zolmitrip-
SJ Warrington*, JM Zayas’, X Cabarrocas’, tan (‘Zomig’) tablets to manage their migraine attacks. A
FJ Fernandezl, P FerrerI. ‘Research Center, Almirall total of 350 attacks of any intensity were treated over a
Prodesfarma, S.A. Barcelona, Spain; *Hammersmith 9-month period. The first two attacks were treated with
Medicines Research Ltd, London, UK. zolmitriptan 2.5 mg; thereafter, patients could choose to
treat migraine headache with doses of 2.5 or 5 mg. Two-
Objectim. To assess the electrocardiographic effects, accord- hour headache response (subsequent to the first two
ing to CPMP guidelines, and the pharmacokinetics of oral attacks) was consistent across moderate/severe attacks
almotriptan, a selective 5HT1 agonist developed for the treated with either 2.5 or 5 mg zolmitriptan, 88% (n = 106)
acute treatment of migraine, in a double-blind, randomized and 69% (II = 72), respectively. This is similar to the consist-
and cross-over study. Mefhods. Twenty-four healthy volun- ent results seen in the adult population in this study. Of
teers were selected and randomly assigned to receive all attacks treated with 5 mg zolmitriptan more were of
single oral doses of 12.5, 25, 50 mg of almotriptan and severe intensity compared to those treated with 2.5 mg
placebo separated by 7-day wash-out periods. Physical (37% vs 23%). No serious AEs were reported in this
examinations, laboratory tests, and vital signs were per- adolescent population and the overall incidence of AEs
formed, adverse events, standard 12-lead ECG, 50 mm/s was similar to those reported by adults in this study.
12-lead ECGs and 12-h Holter were recorded and blood Zolmitriptan was effective and well tolerated in the adoles-
samples for drug plasma level measurements were taken cent patient population. Pharmacokinetic, clinical efficacy,
throughout the study. Results. No clinically relevant find- and tolerability data support that dose adjustment in
ings were found in any types of ECG performed. No adolescents is not warranted. However, additional clinical
CEF’HALALGIA 18 (1998) Pm ter presentatims 407

studies are required to fully evaluate the efficacy and on patients treated with L-758,298 60 mg (n = 39) or its
tolerability of zolmitriptan in adolescents. corresponding placebo (n =21). The primary efficacy
endpoint was headache pain relief at 2 h. Results. At 2 h
postdose, 13 of 39 patients (33%) on L-758,298 60 mg and
P.41 11 of 21 (52%) on placebo reported pain relief. There was
no statistical difference in the percentage of patients
Effectiveness of muscle relaxant for chronic tension- reporting pain relief between groups. Adverse experiences
type headache. Y Unno, F Sakai, E Saito, E Kawashima. were generally mild and transient, the most common
Department of Medicine, Kitasato University, Kitasato, ( 2 5%) being antecubital ecchymosis, dizziness, and drow-
Japan siness; none was serious. Conclusions. L-758,298, although
generally well tolerated, was not efficacious as an abortive
Purpose. Effectiveness of muscle relaxant for chronic ten- migraine treatment. The results indicate that NK1 antagon-
sion-type headache (C‘TTH) was evaluated clinically and ism is not an effective mechanism for acute migraine, but
by measuring objective parameters; pericranial muscle do not preclude a potential role as prophylactic therapy.
hardness and temporalis muscle exteroceptive suppression
(ES2). M&hods. Forty-one patients (lull, 29F, mean age 47
years) were studied. Hardness of trapezius muscles and
P.43
posterior neck muscles was evaluated by manual palpation Treatment of hemicrania epileptica with stellate
and using a newly developed muscle hardness meter ganglion blocks: a case of the interrelationship of
(Brain, 1995). The duration of ES2 was tested in accord migraine and epilepsy. BH Landgrebe. 6609 Blanc0
with the method described by Schoenen et al. Patients Road, San Antonio 78216, TX, USA
took either centrally acting muscle relaxant (eperizone
hydrochloride) or minor tranquilizer without muscle Hemicrania epileptica as a seizure equivalent with EEG
relaxing effect (tofisopam) for 4 weeks. Results. Pericranial activity is rare. It is frequently associated with complex
muscles were harder in patients with CITH (trapezius partial epilepsy. Brain trauma can elicit seizures and severe
muscle 82 kPa/cm, posterior neck muscles 92 kPa/cm) migraine. Stellate ganglion blocks (SGB) relieve severe
than in normals (82 kPa/cm, 92 kPa/cm). ES2 was shorter hemicrania, reduce frequency and severity of seizures as
in CTTH (20.4 msec) than in normals (40.2 msec). After 4 well as psychomotor equivalents like aggressivity and
weeks treatment, headache was improved in 48.8% of dysphoria. After an occipital head injury one patient
patients. There was no significant difference between the developed elementary visual hallucinations, severe
migraine, and generalized seizures. Several SGBs aborted
muscle relaxant treated group and the minor tranquilizer
not only the migraine but hallucinations and seizures. The
treated group for improvement of headache, muscle hard-
beneficial effect of SGBs is long-lasting, even in cases
ness or ES2. Muscle relaxant was effective for patients
refractory to conventional antiepileptic drugs. Due to
presenting moderate to severe hardness of trapezius
denervation hypersensitivity, surgical removal of the stel-
muscles (97.0~ 126.0 kPa/an). Discussion. We could not late ganglia failed to “cure cryptogenic epilepsy” (Penfield,
demonstrate significant effectiveness of centrally acting Jasper). Seizures can precipitate migraine. Cerebral isch-
muscle relaxant for CTI’H. There may be a subgroup of emia in migraine might trigger epilepsy, particularly invol-
CTI’H with increased muscle hardness for whom muscle ving the temporal lobe. Migraine and seizures intensively
relaxant is effective. activate the sympathetic NS. Increased GABA levels in
migraine, reflecting cerebral ischemia, might facilitate the
release of noradrenaline (NA) through a presynaptic effect
P.42 on NAergic nerve endings. Increased sympathetic function
A placebo-controlled, in-clinic study to explore the significantly increases pinocytic activity and thus blood
brain barrier permeability and during hypoxia negatively
preliminary safety and efficacy of intravenous L-758,298
modulates cerebral blood flow. Increased permeability to
(a prodrug of the NK, receptor antagonist L-754,030) in
albumin, pronounced in thalamus and hypothalamus, may
the acute treatment of migraine. B Norman,
produce brain edema and ultimately tissue damage.
D Panebianco, GA Block for the L-758,298 003 Study
Hemicrania epileptica might be generated in the thalamus.
Group, West Point, PA, USA.
Drugs which stimulate the sympathetic system, like the
alpha2-antagonist idazoxan, promote seizures. SGB
Rationale. Substance P, acting via NK, receptors, may be reduces sympathetic hyperactivity. Beta-adrenoceptors
involved in the pathogenesis of migraine. L-758,298 is an (propranolol) and al ha-adrenoceptor agonists (clonidine)
IV prodrug of L-754,030, a potent selective and brain inhibit the release o P NA. They significantly reduce sym-
penetrant NKI receptor antagonist. This study assessed pathetic activity, increase seizure threshold, and are effect-
the preliminary safety and efficacy of L-758,298 for the ive in treatment and prophylaxis of migraine.
acute treatment of migraine. Des@. This double-blind
study was conducted in 72 male and female migraineurs.
Upon experiencing a moderate or severe migraine, patients P.44
reported to the clinic for an IV infusion of L-758,298 20 mg Prophylactic treatment of migraine without aura with
(n =4), 40 mg (n =4), or 60 mg (n = 39), or corresponding lisuride: a pilot study. A Cherchi, ME Stochino, A Oi,
placebo (n = 25). Headache severity, functional disability, C Chillotti, M Del Zompo. Department of Neurosciences
and meaningful relief were assessed at baseline and up to “B.B. Brodie”, University of Cagliari, Cagliari, Italy
4-6 h postdose. Additional analgesia/antiemetics were
permitted at 4 h. Adverse events were monitored through- The objective of the present study was to assess the efficacy
out the study. Statistical evidence of efficacy was based of lisuride in migraine prophylaxis. Although most studies
408 Posterpres#ltations CJZPHALALGIA18 (1998)

have focused on the involvement of serotonin in the P.46

pathogenesis of migraine, others have suggested that the
dopaminergic system is also implicated. Some authors Dihydroergqtine as long-term prophylaxis for
suggest that a dopaminergic receptor hypersensitivity migraine: one-year follow-up. F Avella , A Poli2,
exists in migraineurs. A modulation of dopaminergic L Ambrosoli3, R Girardello3. ‘Neurosurgery Division
neurotransmission with a dopamine agonist could be “SM. Loreto” Hospital, Naples, Italy; 2Biometrics/
Statistics Unit; 3D.R.S. Depart Poli Industria Chimica,
considered as a prophylactic treatment of migraine. We
S.p.A. Milan, Italy
performed a pilot study using lisuride, a dopamine agonist,
at very low doses to evaluate its efficacy as a prophylactic
Objective. The aim of this further study phase of 1 year
agent in a group of 19 patients, randomly selected, affected
was to confirm the long-term safety and efficacy of
by migraine without aura (according to IHS criteria). Our a-dihydroergocryptine mesylate (c+DHEC), an ergot deriv-
sample consisted of 17 females and 2 males, with a mean ative, in the prophylaxis of migraine without aura. Methods.
age of 30 (2144), and a mean age of onset of 13 (5-32). After a double-blind phase of 16 weeks, 46 patients (22
L&ride was administered at doses of 0.05 mg/day for a from the a-DHEC group, 24 from the placebo group)
period of 12 weeks. Patients were instructed to report suffering from frequent migraine attacks (2-6 per month)
frequency and severity of the attacks in a diary. Migraine started a further phase of 1 year with a-DHEC orally
index (frequency xintensity) of the overall sample was administered (f tablet [lo mg] once daily for the first week
measured before and after treatment and resulted in 14.4 and one tablet [20 mg] once daily for the next weeks). The
and 6.2, respectively. These two values were statistically efficacy was assessed using headache diaries (primary
analyzed with a two-tailed Wilcoxon test for paired data, efficacy variable: no. of headache attacks; secondary vari-
which showed a significant reduction of the post-treatment ables: no. of days with headache, associated symptoms
index (p =0.006). This open trial indicates that lisuride and analgesic consumption). Vital signs, adverse events,
could be considered as a prophylactic agent in the manage- laboratory examina tions were monitored to assess drug
ment of migraine. safety. Results.36/46 patients completed the l-year follow-
up, 10 patients dropping out. At the end of the 12-month
treatment with CL-DHECthe mean number of headache
attacks was 0.4kO.6 SD, thus showing a further 43%
reduction with respect to the ol-DHECmean value obtained
P.45 after the 4-month double-blind period (0.7f 1.1). Twenty-
three patients experienced no headache attacks, 11 had
Tricks to relieve migraine attacks. The report of the one attack, and 2 patients suffered from 2 attacks. Both
patients. IP Martins’, E Parreira2. Department of the number of days with headache and the analgesics
Neurology, H. St Maria, Lisbon, Portugal; 2Hospital consumption decreased. Ten patients (22%) experienced at
Fernando Ibnseca, Amadora, Portugal least one adverse event: in 5 (11%) cases it was probably
related to at-DHEC; 3 (6.5%) had to withdraw from the
Introduction. Patients often know a lot about non- trial; 1(2%) reduced the dose; and in another patient (2%)
pharmacological measures and tricks that relieve their the adverse event spontaneously disappeared. Four (9%)
headaches. Yet, with rare exceptions (Blau 1982), this patients experienced a second adverse event that caused
information is often neglected in clinical management. 1 patient to discontinue treatment. The dropout rate due
Method. In a consecutive series of patients with migraine to adverse events was 9% (4/46) (mainly nausea and
(fuIfi.UingInternational Headache Society diagnostic cri- gastric pain). No clinically relevant change in vital signs
teria of migraine with or without aura) observed by two or laboratory parameters was recorded. Conclusions. The
neurologists in an outpatient clinic, a questionnaire was findings of this long-term phase further support the use
used to find out more about those tricks. Maneuvers were of a-DHEC as prophylaxis in migraine.
classified within nine types: (a) pharmacological, @) food
(fasting, selecting specific food, etc.), (c) postural,
(d) pressure or massage to the site of pain, (e) local cold P.47
or heat, (f) sleep, (g) sensorial isolation, (h) immobiliza-
Treatment factors that conditioned transformation of
tion/movement, and (i) others. Resulfs. There were (pre-
chronic daily headache. MJA L&nez, MJ Monzon.
liminary study group) 32 patients (SM, 27F) with an
Department of Neurology, Hospital General
average age of 36.1 years who had had migraine attacks Universitario Valencia, Spain
for an average of 16.3 years. The number of maneuevers
used was 2.5 (spontaneously) and 5.9 after specific ques- Background and objecfives. Chronic daily headache (CDH)
tioning. A minority of individuals (3%) used only non- is a condition frequently dealt with at the Headache Clinic.
pharmacological tricks to treat their headaches. The most In many cases CDH has evolved from episodic headache
commonly used measures were: isolation from light and in patients with analgesics abuse. The purpose of our
noise (looo/o), pressing the temples or other painful sites study is to compare treatment indications that may condi-
(73%), food avoidance or selection (22%), immobilization tion transformation of the headache. Methods. Five-
($4.6%), inducing vomiting (25%), local application of cold hundred-and-ten consecutive patients were included, 255
(46%), sleep (55%). There was no relation between fre- with migraine and 255 with CDH. Data were collected
quency, duration, or severity of the attacks and the number during the patients’initial appointments. They were asked
of maneuvers used. about the previous medical attitude of the doctor when
CJPHALALGIA 18(l!J!M) Poster presentations 409

they were attending because of their headache. The advice 1988 criteria) were studied in the period January 1997 to
they were given concerning analgesics use was also ana- February 1998. Ten percent of this population declared
lyzed; they were asked about the indication for the begin- non-use of medicines; 90% used medicines, 58% on the
ning of analgesics therapy and about the total dose. Results. advice of friends and relatives, and 43% used more than
Patients of both groups considered that they were correctly one type of medicine: nimesulide (37%), noramidopirina
treated, but they believed that their headache was treated metansulfate (15.5%), ibuprofen (6%), sumatriptan (5%),
as not an important problem. The majority of them were and other medicines (33.6%). Forty-three percent used
advised to take analgesics at the beginning of the headache, more than one medicine: noramidopirina metansulfate
but in a few cases they also received indication concerning (26.8%), nimesulide (25%), and acetylsalicylic acid, ibup-
the total quantity of medication to be taken. Conclusions. rofen, sumatriptan for the remainder. Fifty-eight percent
Physicians’attitudes may influence the evolution of head- of patients declared that their symptoms improved after
ache. If headache patients believe that their problem is consumption of the drug, while 25.9% presented a total
considered not important, they may begin using over-the- remission, but for 15.3% there was no benefit. The effect
counter medication. In the same way, if they are not of consumption of drugs was very temporary in 38.8% of
advised to limit the consumption of analgesics they could patients, lasting 1 h in 30.8% and 2 h in 29.4%. The most
common side effects were: gastralgia (25%), drowsiness
develop an analgesics-abuse headache transforming their
(12.6%), nausea and vomiting (8.8%). These results under-
episodic headache into a CDH.
line the common and misguided habit of using medicines
and the necessity of widespread dissemination of informa-
P.48 tion about the sensible use of drugs.
Migraine prophylaxis with SSRI. Experience on 100
cases. C Colucci d’Amato, V Pizza, T Marmolo, P.50
E Giordano, V Alfano. Headache Center, Faculty of Possible mechanism underlying the actions of
Medicine, Second University of Naples, Italy acupuncture and clonidine durin treatment of
migraine. AV Amelin’, VE Ivan0 3 , AA Zaitsev2, YD
The purpose of our work has been to evaluate the efficacy Ignatog, AA Skorometc*. Department of Pharmacology,
of SSRI drugs in migraine prophylaxis. One-hundred-and- S-Petersburg Medical University, L. Tolstoy str. 618, St
thirty-eight patients suffering from migraine with and Petersburg, Russia
without aura (III!? 88 criteria), divided into three groups
(A, B, C), are the sample of our study. Group A has 48 We studied the influence of acupuncture, clonidine, and
patients treated with paroxetine 20 mg/day and 20 treated both combined on plasma rotein extravasation (PPE) into
with fhmarizine 5-10 mg/day; group B has 20 patients dura mater under electric apstimulation of the right trigem-
treated with citalopram 20 mg/day and 15 patients with inal ganglion (5 min, 0.6 mA, 5 ms, 5 Hz) and also on the
flunarizine 5-10 mg/day; group C has 32 patients treated trigeminal nucleus caudalis (TNC) neuron reactions in
with fluoxetine 20 mg/day and 20 patients with placebo. response to electrical stimulation of the superior sagittal
All patients were submitted to a month’s period of phar- sinus (SSS) (0.1-10 mA, 0.5 ms, 5 Hz) in rats. The acupunc-
macological wash-out and to a 6 months’cycle of treatment ture was carried out in Sibai point (St2) and Hegu point
with monthly clinical check-up. The data were compared (Li4) for 30 min before ganglion stimulation. Activation
statistically by means of Student’s t-test. The comparative St2 resulted in blocking of the neurogenic inflammation
analysis between the basic values of index migraine and development in dura mater (the ratio decreased from
the monthly check-ups has shown a notable decrease in 1.65 kO.07 to 1.10 f 0.03 cpm/mg wet weight). Moreover,
groups A and B (p~O.05) as from the second-third month under the existing conditions, the TNC neuron activity
of treatment in the patients treated with paroxetine and provoked b SSS stimulation was inhibited. At the same
citalopram, from the first-second month in the patients time the lrli
’ uence of Li4 activation on the PPE blocking
treated with fhmarizine. In group C, in the patients treated in the dura mater was marked in smaller degree (ratio
was decreased up to 1.23 + 0.09 cpm/mg wet weight only).
with fluoxetine a significant reduction of index migraine
But the inhibition of TNC neuron activity under the
up to the third month occurred ( p < 0.05); in the patients activation of Li4 was stronger. It was found that clonidine
treated with placebo nonsignificant reduction occurred.
(0.25 and 0.5 mg/kg) had inhibited the background activity
These data, even if prelimmary and still to be confirmed of TNC neurons and their reactions in response to electrical
on the widest samples, appear to support use of the SSRI stimulation of SSS, clonidine (0.1 mg/kg) increasing the
in the preventive treatment of migraine. effect of acupuncture (the value increasing averaged
60-80% and 40-70% under activation of Li4 and St2,
P.49 correspondingly). The combination acupuncture plus clan-
idine could be promising in the treatment of migraine.
Use of the drugs for the attack. Study of 400 patients.
V Pizza, T Marmolo, E Giordano, V Alfano,
F Napoleone, A Nasta, C Colucci d’Amato. Headache P.51
Center, Faculty of Medicine, Second University of Eflicacy and safety of rizatriptan versus standard care
Naples, Naples, Italy lon -term treatment for migraine. GA Block’,
sstein’ A Polis’ SA Reines’ ME Smith’. IWest
Using a detailed questionnaire, we sought to verify the Point, PA, &A; ~‘Francisco, CA, USA
habit of drug consumption in migraine attacks. Four-
hundred patients (72% females, mean age 34.8 years, range Rizatriptan is a novel, selective 5HT1,,,, ret or agonist
13-57) affected by migraine with and without aura (IHS with a rapid onset of action after oral dosing ‘p’
or the acute
410 Poster presentations CEPHALALGIA 18 (1998)

treatment of migraine. We conducted a long-term (up to developed for the acute treatment of migraine. Background.
one year) multicenter, randomized study in 1831 patients The objective of this study was to identify the lowest
treating >46,000 attacks to compare the efficacy and effective dose and further assess the tolerability of frova-
tolerability of rizatriptan 5 mg and 10 mg with standard triptan in patients during an acute migraine attack.
care medications (primarily sumatriptan) routinely used Methods. A randomized, double-blind, placebo-controlled
for the acute treatment of migraine attacks. Both doses of study was conducted in 695 patients (age range 18 to 65
rizatriptan were highly effective, without evidence of years). Patients were randomized to receive a single oral
tachyphylaxis. Rizatriptan 10 mg was consistently superior dose of placebo or VML2510.5 mg, 1 mg, 2.5 mg, or 5 mg,
(p ~0.05) both to the 5-mg dose and to standard care, in a 1: 1: 1: 1: 1 ratio. Efficacy was defined as the portion
providing relief in 90% of attacks, with 50% pain free, by of patients whose headache decreased in severity from
2 h after dosing. The most common dose-related adverse severe or moderate (MS Grades 3 or 2) to mild or none
events were nausea, somnolence, and asthenia/fatigue. (IHS Grades 1 or 0) at 2 h after dosing. Results. Males (90)
Based on this large, multicenter, long-term trial, rizatriptan and females (SOB),mean age 41.4 years, were treated. At
appears to be an important new oral agent for the acute 2 h, response rates for 2.5 mg and 5 mg were 38% (p =
treatment of migraine. 0.047) and 37% (p=O.O64) compared to placebo, 25%.
Doses of 0.5 mg and 1 mg were not superior to placebo.
At 4 h, response rates for 2.5 mg and 5 mg were twofold
P.52 higher 68% and 67% (p <0.005) than placebo, 33%. The
24 h recurrence rates were 17% for placebo and 10% for
Phazmacokinetics of Frovatriptan WML 25l/SB 2095091
frovatiptan. There was a small dose response effect for
in healthy young and elderly male and female subjects.
P Buchanl , C Keywood’, C Ward2. ‘Vanguard Medica the incidence of treatment emergent adverse events (28%
Guildford, UK; Tovance, Leeds, UK placebo, 33%-48% for frovatriptan). Conclusion. Frova-
triptan 2.5 mg was identified as the lowest effective
Frovatriptan (proposed INN), a potent, cerebroselective dose.
5HT,,/1, receptor agonist being developed for acute treat-
ment of migraine, was administered orally as single doses
of 2.5 mg (proposed therapeutic dose) to groups of healthy
young (21-37 years) and elderly (65-77 years) subjects,
each consisting of 6 males and 6 females. Frovatriptan was P.54
well tolerated in all subjects. Frovatriptan concentrations, Histamine therapy of chronic daily headache having
measured by LC/MS/MS, were -2-fold higher in blood the features of transformed migraine. M Nicolodi,
than in plasma at equilibrium, irrespective of gender and PL Del Bianco, F Sicuteri. Inter-university Centre of
age. Mean blood C,, of 4.2 ng.mL-i (young males), Neurochemistry and Clinical Pharmacology of Idiopathic
7.0 ng.mL-’ (young females), 5.7 ng.mL-l (elderly males) Headache and Department of Internal Medicine,
and 8.6 ng.mL-’ (elderly females) was achieved 2-4 h after University of Florence, Florence, Italy
administration in 96% of subjects. The corresponding mean
blood AUC(,,,, values were 46,94,73, and 115 ng.h.mL-‘. In rodents, histamine induces analgesia when intracerebrov-
The trend towards higher blood concentrations in older entricularly injected. We proved that histamine induces pain
subjects compared to young, and in females compared to indirectly by causing bradykinin production. A chronic expo-
males, remained even after bodyweight correction. sure to histamine evokes receptor changes in the different
Intravenous studies in the young indicated that these subtypes of histamine receptors (Hl, H2, H3). These changes
differences could be attributed partly to greater bioavail- seem to evoke desensitization of receptors in the periphery
ability and partly to lower clearance in females than in and to strengthen histammergic analgesia in the CNS.
males. The mean blood terminal elimination half-life was Histamine therapy was performed in 680 migraine sufferers,
substantially longer than other triptans, at 20 to 25 h. healthy except for headache. Patients were diagnosed using
Despite the higher blood levels observed in females com- the following criteriaz (i) Daily chronic headache associated
pared to males and in elderly compared to young, dosage with over-imposed migraine attack (more than 1
adjustment is considered unnecessary since higher doses attack/month) for 2 years at least, (ii) analgesics over-
(up to 40 mg) have been well tolerated in female migraine use/abuse for 12 months at least, (iii) refractoriness to con-
patients and a dose of 2.5 mg appeared equally effective ventional prophylactic therapies (i.e., propranolol, methyser-
in males and females in Phase Il studies. gide, or flunarizine). On a daily basis patients had to fill out
a pain diary, where pain was rated on a O-4 VAS. The plan
of the study included a l-year period during which conven-
P.53 tional therapies were administered. Patients who did not
A low-dose range-finding study of frovatriptan, a report a benefit greater than 30% volunteered for histamine
potent selective 5HTlD agonist for the acute treatment therapy. During a l-year follow-up period, conventional
of migraine. J Goldstein’, A Elkind2, C Keywood3, therapies were given Histamine was administered as short;
J Klapper4, R Ryan5. ‘San Francisco, CA, USA; ?Mount lasting treatment (15 days). Doses increased from
Vernon, NY, USA; 3Guildford, Surrey, UK; ‘Denver, CO, 2 pg/kg/day to 70 wg/kg/day/iv slow infusion. In 5% of
USA; %t Louis, MO, USA the patients the therapy induced a marked (over 70%) relief
for 1 year; in 62% the benefit (over 50%) lasted 2.3
Objecfive. Frovatriptan (VMLZl/SB209509) is a potent, months f 1.7 SD. The remain patients reported no less than
specific, cerebroselective 51-IT1B,1r,receptor agonist being 40% relief versus conventional therapies. The described
CEPHALALGIA 18 (1998) Posterpresentations 411

therapy seems to enlighten the relevance of histaminergic opted to tail off SV after 12-36 months of treatment.
analgesia in transformed migraine. Within 6-12 weeks of withdrawal, 70% experienced more
frequent headaches. SV was restarted with improvement.
Almost all patients complained of weight gain; seven
P.55 developed fine bilateral finger tremor and two complained
Unusual indomethacin responsive headaches. of excessive hair loss. No other serious adverse effects
S Solomon, LC Newman. Headache Unit, Montefiore were observed and plasma drug monitoring indicated
Medical Center, 111 East 210 St. Bronx, NY, USA good compliance. Conclusion. SV appears to be an effective
long-term prophylactic agent for migraine and it is fairly
Infruduction.We report a case of bilateral daily headache well tolerated by migraine patients.
responsive to indomethacin and review other cases respons-
ive to indomethacin. Case report. A 46-year-old man experi-
P.57
enced a continuous bilateral non-throbbing headache of mild
to moderate intensity for 15 months. There were no associ- Efficacy and tolerability of nimesulide &cyclodestrine
ated autonomic symptoms. However, severe exacerbation of versus naproxen sodium in prophylactic treatment of
pain occurred for 1-2 h after straining, coughing, or sneezing. menstrual migraine. A Leo, A Lieto, D D’Alessio,
The headache did not respond to many acute and prophy- L Lieto. Headache Center Operative Unit of
lactic medications; he did not take daily analgesics. The initial Cerebrovascular Diseases, S.G. Moscati Hospital,
diagnosis was new onset chronic daily headache with exacer- Avellino, Italy
bation evoked by coughing or straining. To treat the exacerba-
tions, indomethacin was presc&ed The daily headache We evaluated efficacy and tolerability of nimesulide
disappeared within 45 min of taking*indomethacin and he Bcyclodestrine versus naproxen sodium in prophylactic
remained headache-free while taking the drug. Discussion. treatment of menstrual migraine (MM). Design-Methods. 50
The first headaches responsive to indomethacin were of short women with MM diagnosed according to IHS criteria and
duration, e.g., chronic paroxysmal hemicrania and cough fuhXing MacGregor criteria for MM (migraine attacks
and exertional headache. Later, a rare headache of long which regularly occur on or between days -2 to + 3 of
duration hemicrania continua, was found to be indomethacin the menstrual cycle and at no other time), received in an
responsive. One case of so-called bilateral hemicrania con- open, randomized study prophylactic treatment from day
tinua has been reported. Our patient with continuous bilat- -5 to day + 5 of the expected day of menses. 25 patients
eral headache also responded dramatically to indomethacin. received naproxen sodium 1100 mg/day p.o. and 25
Conclusion.Indomethacin is typically effective for headaches patients received nimesulide B-cyclodestrine BOO/dayp.o.
of short duration, particularly those that are unilateral. The for three menstrual cycles. All 50 patients received suma-
medication is also effective for a continuous unilateral head- triptan 50mg p-o. as acute headache treatment. Results.
ache (hemicrania continua) and very rarely for continuous Reduction or disappearance of migraine attacks was
bilateral headache. A therapeutic trial of indomethacin is reported from 17 (68%) patients receiving naproxen
warranted for new onset chronic daily headache and for sodium and in 18 (72%) patients receiving nimesulide
more common forms of chronic daily headache that have P-cyclodestrine. Side effects (especially gastrointestinal dis-
been unresponsive to currently recommended medications. tress) were reported by 13 (52%) patients in the group
receiving naproxen sodium and 7 (28%) in the group
receiving nimesulide P-cyclodestrine. Headache relief
P.56 was reported in 33 (66%) patients receiving sumatriptan
Long-term ef6icacy and tolerance of sodium valproate in 50 mg p.0. as acute treatment for migraine. ConcZusion.
the prophylaxis of migraine headache. K Ghose. Nimesulide P-cyclodestrine is as effective as naproxen
Department of Pharmacology, University of Otago, sodium in prophylactic treatment of MM but is better
Dunedin, New Zealand tolerated. Nimesulide Pcycloclestrine appears to offer the
optimal ratio of efficacy to tolerability.
Aim of investigation. Sodium valproate (SV) is now consid-
ered to be an effective prophylactic agent for migraine.
P.58
However, very few published reports are available about
its long-term efficacy and safety in migraine patients. I The pharmacokinetics, safety, and tolerability of oral
would like to present information on the first 100 migraine eletriptan in subjects with impaired hepatic function.
patients who received prophylactic SV for 24-60 months. KA Milton’, TJ Buchanan’, G Haug-Pihale*, K-H Molz*.
Methuds. Forty-one (28F) migraine patients with aura and ‘Pfizer Central Research, Sandwich, Kent, UK; *Apex
59 (42F) migraine patients without aura, who previously Research, Munich, Germany
showed limited response to other medication, received
400-1000 mg SV daily for 12 weeks. Eighty-two patients In man, eletriptan is extensively and rapidly metabolized
who showed a 40% or greater reduction in the migraine by the liver, and hepatic impairment may thus modify its
frequency continued with long-term SV. They were pharmacokinetics. The safety, tolerability, and pharmaco-
assessed in a clinic at 12-24 week intervals and patients kinetics of oral eletriptan (40 mg or 80 mg) were investi-
kept a diary. At each attendance, venous blood was taken gated in 12 male patients (33 to 43 years; 60-104 kg) with
for serum SV level and routine blood tests. Results. SV moderate chronic stable hepatic cirrhosis (Child-Pugh
was stopped in 24 patients during the first 24 weeks for Classification grade A or B), and compared with those for
loss of beneficial effect or adverse effects. Sixteen patients 12 age- and weight-matched healthy subjects (37 to 64
412 Poster presentations CEPHALALGIA 18 (1998)

years; 66-96 kg) in an open, single-dose, parallel-group P.60

study. One hepatically impaired subject with inexplicably
low plasma levels and his matched pair were excluded The Dharmacokinetics of oral eletriutan, and its
from the analysis. The elimination rate constant for eletrip- ex&tion into breast milk in norm& h&thy, nursing
tan (b) was significantly reduced (to 0.094 /h) with an women. AK Shah’, L Laboy-Goral’, TA Morse’, KA
increase in the associated half-life (t& to 7.4 h for the Milton’. ‘Pfizer Central Research, Groton, CT, USA;
cirrhotic patients compared to healthy subjects b 0.111 *Pfizer Central Research, Sandwich, Kent, UK
/h and t,/, 6.3 h, p ~0.05). This was reflected by an
increased systemic exposure to, eletriptan with a 35% Eletriptan, a potent and selective agonist at 5HTiB11n
increase in AUC (2234 ng.h/ml in cirrhotic group versus receptors, is currently under clinical investigation as an
1661 ng.h/mI; p < 0.05) but no significant change in C-. acute treatment for migraine using oral doses up to 80 mg.
Values for T,, and plasma protein binding (f,) were The excretion of eletriptan into breast milk and its pharm-
comparable in both groups. Transient elevations in blood acokinetics following oral dosing (80 mg) have been evalu-
pressure were observed in both groups following eletrip- ated in an open, non-comparative, non-randomized single-
tan dosing, but there were no statistically significant dose study involving eight normal, healthy, nursing female
subjects (24 to 34 years; 51-90 kg), who were at least 1
differences in the maximum increase from baseline, or in
month postpartum. Eletriptan was rapidly absorbed,
the AUEC of changes from baseline, for systolic or diastolic
reaching mean maximum plasma levels at 1.9 h. The time
blood pressure between the two groups. There were no
course of the breast milk concentrations followed the
serious adverse events in either group. In conclusion,
plasma concentrations suggesting passive diffusion of ele-
hepatic impairment is associated with a small increase in
triptan from the plasma into the breast milk. Maximum
the systemic exposure to eletriptan following oral dosing levels of eletriptan in breast milk were achieved approxi-
due to a reduction in eletriptan elimination. Eletriptan was mately 25 min later than plasma with mean T,, of 2.3 h
well tolerated in these subjects with hepatic impairment. and values for C-, AUC, and AUC in breast milk were
alI annroximatelv 25% of nlasma values. The mean elim-
inat& half-live; of eletri&an in breast milk and plasma
were 3.7 h and 4.7 h, rest&tivelv. The average am&ant of
eletriptan excreted i&to breast milk over 24 hvwas 12.9 pg
P.59 corresponding to 0.02% of the 80 mg dose administered.
The pharmacokinetic and pharmacodynamic Eletriptan w& well tolerated and there were no serious
interactions of oral eletriptan and propranolol in adverse events. In conclusion, the data from this study
healthy volunteers. KA Milton, L Tan, R Love. Pfizer indicate that very small amounts of eletriptan are excreted
into breast milk.
Central Research, Sandwich, Kent, UK

Breakthrough migraine attacks can still occur in patients

receiving prophylactic therapy such as propranolol, and
these often require additional acute treatment. The effect of P.61
7 days’pm-treatment with propranolol(80 mg, twice daily)
Arising of headache in the Srst five years of life.
on the pharmacokinetics and pharmacodynamics of a single
D Moscato, Childhood Headache Center, S. Charles
oral eletriptan dose (80 mg) has therefore been investigated
Nancy ID1 Hospital, Via Aurelia 275, Rome, Italy
in a double-blind, placebo-controlled crossover study invol-
ving 12 healthy volunteers of either sex (20-34 years). In recent years, the percentage of headache-suffering chiI-
Propranolol pm-treatment was associated with a slightly dren aged less than 5 years showing up at our center has
slower elimination of eletriptan (tld of 5.2 h versus 4.9 h for increased considerably compared with preceding years.
placebo pm-treatment) and a smaII increase in the systemic We tried to ascertain the relevant causes. The study was
exposure to eletriptan with a larger AUC (133% of placebo performed on 25 children (15 ETTH, 10 MI, 1Of. 15m,
pre-treatment value; p ~0.01) but no significant change in range 3/5 years) and on 25 (17 ETTI-I, 9MI, 14f. llm.,
C,- (p = 0.464). Values for T_ were comparable after both range 6/9 years). We reviewed in arrears some parameters
pm-treatments ( p =0&E). Treatment with propranolol for 7 that seemed significant for growing up age: headache
days reduced systolic and diastolic blood pressure and pulse familiarity, the behavioral aspect at birth (delivery, feed-
rate compared with placebo. A small increase in diastolic ing, gaseous colics), sleep disturbances (sleep walking,
blood pressure was seen after eletriptan. Diastolic blood bruxism, etc.) and the child’s relationship with the member
pressure was significantlylower following propranolol treat- of his family (real or assumed absence of an important
ment with a propranolol/placebo difference for maximum family figure, both parents working, full-time school
change in diastolic blood pressure of 5.2 mmHg (p -cO.Ol). attendance). While for events at birth, such as sleep dis-
The combination of propranolol and eletriptan was well turbances and headache’s familiarity, no differences were
tolerated and the adverse event profile of eletriptan following noted; the absence of either parents (G&21%), both parents
propranolol was sin&r to that of eletriptan following pla- working (62-27%), and school attendance (71-38%) were
cebo. In conclusion, the results of this study indicate that found significantly different. We, therefore, believe that
propranolol treatment produces a small reduction in the notwithstanding the fact that the available data are few,
clearance of eletriptan probably due to a reduction in its the psychic discomfort, considered under the form lack of
metabolism resulting in smaIl increases in AUC and plasma love, may be the leading cause of early arising of headache.
half-life. These data also confirm that in growing up age, no
CEPHALALGIA 18 (1998) Poster presentations 413

essential difference exists between the two pathologies, polymerase chain reaction (RT-PCR). Immunocy~oc~mistry.
but almost a continuum between the same. CGRP immunoreactive (-ir) neurons occurred in high
numbers positivity in 36-40% of all neuronal cells of the
trigeminal ganglion and distributed homogeneously
P.62 throughout the ganglia. A smaller number of the neurons
showed SP-(18%), NOS-(15%) and PACAP-(20%)~ir.
Relationship between cell volume and extracellular
Double immunostaining revealed that only few CGRP-ir,
potential during spreading depression. MI Smith,
less than 5% of the neurons, were NOS positive. The
M Evans, AA Parsons, CD Benham. Neuroscience
majority of the CGRP- and SP-ir somata were small and
Research, SmithKline Beecham Pharmaceuticals, Third
medium sized. C-PON immunoreactive neurons were not
Avenue, Harlow, Essex, CM19 5AW, UK
visible in the ganglia. Autofluorescent lipofuscins were
present within perikarya as a characteristic of adult human
The temporal relationship between cell volume and meta-
nervous tissue. In situ hybridization. CGRP mRNA was
bolic activation is poorly understood. The aim of the
found in a large portion of the trigeminal neurons. RT-
present study was to investigate cellular volume changes
PCR. Agarose gel electrophoresis of the RT-PCR products
during spreading depression (SD) in the rat cortex in vitro.
from human tigeminal ganglia demonstrated products of
This study utilized 300 um coronal rat brain cortical slices
the expected size (339 bp) corresponding to ml?NA encod-
superfused with artificial CSF at 30°C. Slices were placed
ing the CGRPl receptor mRNA. Positive reaction for
on an inverted microscope and illuminated from above
human NPY Y1 and VIP1 receptors were also seen.
through a red h filter. Changes in light transmission
intensity (LTI) were recorded with an intensified camera.
SD stimulation was by micro-injections of 3OOmM Kc1
-250 microns below the pial surface, every 30 min, with P.64
SD activity verified by DC potential. Five SD events could First human dose study with LY334370, a selective
be elicited over 120 min. Mean DC amplitude of SD was
5HTIP agonist. D Gossen, J-M de Suray, C Onkelinx.
30 +2.3 mV. LTI changes indicative of cell swelling were
Lilly Development Centre, Clinical Pharmacology, 11 rue
biphasic. The initial phase produced a 15.2 +0.4% LTI
Granbonpre, 1348 Mont-Saint-Guibert, Belgium.
increase spreading concentrically through superficial cor-
tical structures to a depth of ~500 m, coincident with
Background and object&s. LY334370 is a serotonin analogue
DC deflections. The second phase produced an 18.1 f 0.5% that was selected on the basis of its high activity and
increase in LTI spreading from the pial surface to a depth selectivity towards the 5HTlp receptor, its high potency in
of 500 p. Both LTI phase changes were significant from
a neurogenic inflammation model and its lack of contractile
baseline ( p (0.05, ANOVA). MK-801 produced a dose-
activity in the saphenous vein model. This study was the
related inhibition of SD amplitude. At 108 @I, amplitude
first administration to man of LY334370. Methods. Part 1
was reduced to 4 + 0 mV ( p < 0.05, ANOVA). Similarly, the was a subject-blind, investigator-blind, placebo-controlled
degree of LTI increase was also significantly inhibited in
study involving multiple panels of 9 male subjects who
both initial (7.1+ 1.2%) and second (11.3f2.3%) phases received single oral doses of LY334370. Part 2 was an open
( p ~0.05, ANOVA). This study shows that SD produces
label, randomized balanced cross-over study involving 6
changes consistent with increased cell volume in a biphasic
males and 6 females who received LY334370 p-o. once in
sequence, the first coincident with depolarization. These
fasting conditions and once 30 min after the beginning of
changes in volume descend to subcortical layers.
a standardized fatty breakfast. Safety was assessed by
means of clinical examinations, ECG records, cardiac mon-
itoring, laboratory tests and the record of symptoms.
P.63
Results. The results indicate that LY334370 was very well
Messenger molecules and receptor mRNA in the tolerated and adverse events did not appear to be related
human trigeminal ganglion. J Tajti, R Uddman, to study drug. There were no clinically significant changes
F Sundler, S Moller, L Edvinsson. Department of Internal in ECG, vital signs, or laboratory tests compared to base-
Medicine, University Hospital of Lund, Sweden. line. LY334370 was rapidly and extensively absorbed with
a & between 1 and 2 h and an apparent elimination half-
In order to analyse in detail the messenger molecules that life of about 15 h. Pharmacokinetic parameters did not
might be involved in the trigemino-vascular mechanisms differ significantly between males and females, were linear
and in the pathophysiology of migraine, we have examined with dose and were minimally affected by food.
the neuropeptide distribution in the human trigeminal Conclusions. LY334370 in single oral doses is readily
ganglion with immunohistochemistry and CGRP mRNA absorbed and very well tolerated up to 400 mg in healthy
with in situ hybridization. In addition, peptide receptor subjects. Further studies have been undertaken to evaluate
mRNA distribution was studied with reverse transcriptase its efficacy during acute migraine attacks.
Author Index

AaRonen, K. 381 Cerbo, R. 382 Genicot, R. 399

Accornero, N. 387 CeruIlo, A. 395 Gerber, W.D. 397
Afra, J. 388 (2), 397,399 Chaturvedi, S. 381 Gessa, G.L. 389
Ahrens, S.P. 392 Chen, F.J. 383 Ghirmai, S. 384
AI-Sayed, F. 397 Cherchi, A. 389,407 Ghose, K. 380,391
AIbert, A. 399 ChiIIotti, c. 407 Giacovazzo, M. 401,402,404,411
Alberti, A. 383 Chopp, M. 383 GiI-Gouveia, R.S. 396
AIfano, v. 409 (2) Cittadini, E. 383 Gillies, S. 392
AmbrosoIi, L. 408 Ciusani, E. 391 Giordano, E. 409 (2)
AmeIin, A.V. 409 Colantoni, 0. 385,403 Girardello, R. 408
Antonaci, F. 384 Cologne, D. 395,396 Goadsby, P.J. 399,402 (2)
Aranyi, Z.S. 398 Colucci d’Amato, C. 409 (2) GoebeII, H. 381
Ariano, c. 391 Connor, HE. 392 Goldstein, J. 385,393,404,409,410
ArmeIIino, J.J. 385 Cortelli, P. 395 Gossen, D. 413
Attanasio, A. 387,391,400 Couch, J. 381,383,385 Grattan, D. 391
Aurora, S. 388,397 coutin, P. 399 Grazzi, L. 391,400
AveIIa, F. 408 Guidetti, V. 391
d’Alessio, D. 411 Guitera, V. 379
Bahra, A. 402 D’Amico, D. 387,391,400 Guido, M. 389
Balm, T-K. 392 Davenport, A.P. 405
Barbanti, P. 382 De Benedetti, G. 387 H&naItien, M.L. 381
Barontini, M. 401 de Fee, A. 387 Hafferl, A. 380
Battikha, J.P. 385 De Marinis, M. 387 Hall, L.D. 400
Baudesson, G. 387 De Martino, G. 385 Haque, M.A. 383
Beattie, D.T. 392 De Pasqua, V. 389 Hasse, L.A. 379
Benham, C.D. 413 de Suray, J.-M. 413 Haug-Pihale, G. 411
Berry, D. 391 De Tommaso, M. 389 I-BE, R-G. 401,405
Bertin, L. 392 Del Bianco, P.L. 399,410 Hoffman H.D., 385
Bianchi, A. 385,403 Del Zompo, M. 389,407 Holtmann, G. 381
Block, G.A. 406,409 DeIage, A. 387 Hoppu, K. 381
Blumenthal, H. 385 Diamond, S. 392 Hoskin, K.L. 402
Bocchetta, A. 389 Diener, H.C. 381 Houston, G.C. 400
Bockhorst, K.H.J. 400 Dobashi, K. 403 Huang, C.L.H. 400
Boers, P.M. 400 Dodick, D.W. 395 Huston, J. 395
BoIIig, G. 405 Donaldson, C. 400 Hyland, R. 404
BonucceBi U. 390 Dowson, A.J. 398, 406
Boyce, M.J. 405 Igarashi, H. 403
Edvinsson, L. 413
Bousser, M.-G. 378 Ignatov, YuD. 409
EIkind, A. 410
Boyer, S. 383 Iosca, L. 386
Erba, N. 391
Breslau, N. 379 Ivanov, V.E. 409
Ertsey, C.S. 398
Britch, K. 393
Evans, M. 413
B&ton, J.W. 395 James, M.F. 400
Brown, R.D. 395 Fabbrini, G. 382 Jelencsik, I. 398
Buchan, P. 410 Fernandez, F.J. 406 (2) Jiang, K. 392
Buchel, C. 402 Ferraris, A. 400 Jones, B.C. 404
Buchanan, T.J. 411 Ferrer, P. 406 (2) Jonkman, A. 402
Bulgheroni, M. 384 Figuerola, M. 401 Juhra, C. 405
Buhner, D. 402 Fiore, G. 404
Bussone, G. 387,391,400 Fletcher, P.E. 406 Karwautz, A. 380
Frackowiak, R.S.J. 402 KathpaI, G.S. 386
Cabarrocas, X. 406 (2) Frediani, F. 387 Kawashima, E. 406
Campos, J. 396 Freitag, F.G. 392 Keywood, C. 384,410 (2)
Canitano, R. 391 Fusco, B.M. 385,403 Kienbacher, Ch. 380
Cao, Y. 388 Kippes, C.M. 379
Cadin, A. 400 GabrieIIi, M. 404 KIapper, J. 410
Caronti, B. 382 GaIIai, V. 383 Konno, S. 383
Carpenter, T.A. 400 GaIIi, F. 391 Kroner-Herwig B. 405
Cassano, G.B. 390 Gambaccini, G. 390 Kropp, P. 397
CastiBo, J. 379 Gasbarrini, A. 387,404 Kunke, R.S. 379
Catania, A. 400 Gerard, P. 397 Kurth, T. 381
416 Author Index CEPHALALGIA 18 (1998)

Laboy-Goral, L. 412 OnkeIinx, C. 413 Schuhz, L.R. 379

Lainez, M.J.A. 398,408 OQuinn, s. 403 Sciruicchio, v. 389
Lambert, G.A. 400 Oi, A. 407 Serim, M. 380
Landgrebe, B.H. 386,407 Shah, A.K. 412
Lanfranchi,s. 384 Padron, A. 399 Shaw, D. 405
LasaIandra, M. 402 Pait, D-G. 403 Sheftell, F.D. 403
Lenzi, G.L. 382 Paiva, T. 395 Sicuteri, F. 390, 392, 399, 410
Leo, A. 411 Pahnas, M.A. 389 Silberstein, S. 393
Leone, M. 387,391,400 Panebianco, D. 406 Siniatchkin M. 397 (2)
Leston, J.A. 401 Papadakis, N. 400 Skorometc, A.A. 409
Lieto, A. 411 Parra, J. 398 Smith, D. 401
Lieto, L. 411 Parreira, E. 395, 396 (2), 408 Smith, J.M. 400
Lipari, M. 402 Parsons, A.A. 400,413 Smith, M.E. 409
Lipton, R.B. 377, 380,385 Pascali, M.P. 382 Smith, MI. 400,413
Longmore, J. 401,405 PascuaI, J. 379 Smith, R. 379
Love, R. 412 Pavao-Martins I. 396 Solomon, S. 379,411
Lucetti, c. 390 Pavese, N. 390 Steiner, T-J. 385
Peatfield, R.C. 390 ’ Stephani, U. 397
Pecori Giraldi, J. 387 Stewart, W.F. 380
Maertens de Noordhout, A. 397 Pedri, S. 390 Stirparo, G. 401,402
Maguire, J-J. 405 Peiro, C. 398 S&chino, M-E. 407
Main, A.D. 398 Piccardi, M.P. 389 Storer, J. 399
Manzoni, G.C. 395,396 Pickard, J.D. 405 Sundler, F. 413
Marazziti, D. 390 Pinessi, L. 386,387 Swann, M. 381
Margishvih, G.M. 383 Pitari, G.M. 385
Marmolo, T. 409 (2) Pizza, V. 409 (2) Tajti, J. 413
MarteIIetti, P. 401,402 PodoII, K. 377 Tan, E. 405
Martinez, V. 398 Poli, A. 408 Tan, L. 412
Martins, I.P. 395,396 (2), 408 Polis, A. 409 Tome, A. 396
Mascia, A. 388 (2), 389, 397,399 Ponti, M. 389 Toni, C. 390
Maskell, L. 405 Ponzetto, A. 387 Tore& P. 395,3%
Mau, J. 405 Pothmann, R. 405
May, A. 402 Pradaher, A. 387 Uddman, R. 413
Mazzotta, G. 383 Proietti-Cecchini, A. 388 Unno, Y. 403,406
McCleverty, P. 404 Puca, F.M. 389 VaIfre, V. 386
Mengozzi, G. 382 Vein, A. 397
Meyer, J.S. 383 Rainero, I. 386,387
Vikingstad, E. 388
MiIIson, D.S. 406 Rapoport, A. 384
Visser, W.H. 392
Milton, K.A. 405,411,412 (2) Ravishankar, K. 382
Vogtmann, T. 405
Mitchell, R.J. 404 Razzaque, Z. 405
Volpe, A.R. 399
MoIIer, S. 413 Reines, S.A. 392,409
Voon, M.L. 380
MoIIicone, A. 387 Rhodes, K. 390
Vormbaum, I. 405
MoIz, K.H. 411 Ricci, A. 382
Moncada, S. 378 RinaIdi, C. 402 Ward, C. 410
Montagna, P. 395 Robert, M. 406 (2) Ward, P. 392
Monzon, M.J. 398,408 Ruju, F. 383 Warrington S. 405
Morgan, P. 404 Ruoff, G-E. 392 Watson, C. 403
Morse, T.A. 412 Ryan, R. 410 Welch, K.M.A. 379,383,388,397
Moscato, D. 412 Wessely, P. 380
Moschiano, F. 387,391 Sandor, P.S. 388, 389 Wiggins, G. 388
Munoz, P. 379 Saito, E. 406 Williams, E.J. 408
Sakai, F. 403,406 Winter, P. 403
Salomone, S. 403 Wiiber, Ch. 380
Napoleone, F. 409 Sancho, J. 398 Wober-Bingol, C. 380
Nappi, G. 384 Sandrini,G. 384 Wood, M. 390
Nasta, A. 409 Santarelh, S. 387
Nattero, G. 382 SarchieIIi, P. 383 Xing,D. 400
Neufang-Hiiber, J. 381 SasaneIIi, G. 389
Newman, L.C. 411 Saturnino, c. 385,403 Zagami, AS. 400
Nicolodi, M. 384,390,392,399, 410 Savi, L. 386,387 Zaitsev, A.A. 409
Niven, B. 380,391 Sawyer, J. 380 Zayas, J.M. 406 (2)
Norman, B. 406 Schieroni, F. 391 Zebenholzer, K. 380
Norris, L. 397 Schneider, S. 405 Zhai, Q.H. 383
Nuti, A. 390 Schoenen, J. 388 (2), 389, 397, 399 Zicari, A. 402