866
DOI: 10.1590/0004-282X20130170
ARTICLE
Familial agg ega ion o clus e headache
Ag egação amilia da ce aleia em sal as
Simão C uz1, Ca olina Lemos2, José Ma ia Pe ei a Mon ei o3
1Se iço de Neu ologia, Hospi al P o . D . Fe nando Fonseca, Amado a/Sin a, Po ugal;
2UnIGENe, Ins i u o de Biologia Molecula e Celula , Uni e sidade do Po o, Po ugal; ICBAS, Ins i u o Ciências Biomédicas Abel Salaza , Uni e sidade do
Po o, Po ugal;
3Se iço de Neu ologia, CHP- HSA, Cen o Hospi ala do Po o, Hospi al de San o An ónio, Po o, Po ugal; ICBAS, Ins i u o Ciências Biomédicas Abel Salaza ,
Uni e sidade do Po o, Po o, Po ugal.
Co espondence: Simão C uz; Se iço de Neu ologia / Hospi al P o . Dou o Fe nando Fonseca; IC 19; 2720-276 Amado a - Po ugal;
E-mail: [email p o ec ed]
Con lic o in e es : The e is no con lic o in e es o decla e.
Recei ed 08 Feb ua y 2013; Recei ed in inal o m 07 June 2013; Accep ed 14 June 2013.
AbsTRACT
Se e al s udies sugges a s ong amilial agg ega ion o clus e headache (CH), bu so a none o hem ha e included subjec s wi h p obable
clus e headache (PCH) in acco dance wi h he In e na ional Classi ica ion o Headache Diso de s. Objec i e: To iden i y cases o p obable
clus e headache and o assess he amilial agg ega ion o clus e headache by including hese subjec s. Me hod: Thi y-six pa ien s a end-
ing a headache consul a ion and diagnosed wi h igeminal au onomic headaches we e subjec ed o a ques ionnai e-based in e iew. A ele-
phone in e iew was also applied o all he ela i es who we e poin ed ou as possibly a ec ed as well as o some o he emaining ela i es.
Resul s: Twen y- ou p obands ul illed he c i e ia o CH o PCH; hey had 142 i s -deg ee ela i es, o whom i e we e ound o ha e CH o
PCH, including one case o CH sine headache. The isk o i s -deg ee ela i es was obse ed o be inc eased by 35- o 46- old. Conclusion:
Ou esul s sugges a amilial agg ega ion o clus e headache in he Po uguese popula ion.
Keywo ds: clus e headache, p obable clus e headache, amilial agg ega ion, clus e headache sine headache, i s -deg ee ela i es.
REsumo
Di e sos a igos suge em uma signi ica i a ag egação amilia da ce aleia em sal as (CH) embo a nenhum enha incluído indi íduos com
p o á el ce aleia em sal as (PCH), segundo c i é ios da Classi icação In e nacional de Ce aleias (ICHD-II). Obje i o: Encon a casos de p o-
á el ce aleia em sal as e a alia a ag egação amilia da ce aleia em sal as incluindo ambém esses indi íduos. Mé odo: Foi aplicado um
ques ioná io po ele one a 36 doen es que equen a am uma Consul a de Ce aleias com diagnós ico de ce aleia igémino-au onómica.
Todos os amilia es de p imei o g au e e idos como possi elmen e a e ados e alguns dos es an es o am en e is ados po ele one. Re-
sul ados: Em 24 doen es oi diagnos icada CH ou PCH e es es inham 142 amilia es de p imei o g au, cinco dos quais o am diagnos icados
como CH ou PCH, incluindo um caso de CH sem ce aleias. O isco pa a amilia es de p imei o g au oi 35-46 ezes supe io ao da população
ge al. Conclusão: Nossos esul ados suge em a exis ência de uma ag egação amilia da ce aleia em sal as na população po uguesa.
Pala as-cha e: ce aleia em sal as, p o á el ce aleia em sal as, ag egação amilia , ce aleia em sal as sem ce aleia, amilia es de
p imei o g au.
Clus e headache (CH) is a o m o igeminal au o-
nomic headache de ined by a se o c i e ia ha include
a se e e, unila e al pain, usually loca ed a ound he o -
bi , combined wi h disau onomic mani es a ions a ec-
ing he same egion, and usually accompanying he pain1.
The In e na ional Classi ica ion o Headache Diso de s
(ICHD-II) also ecognizes he concep o p obable clus-
e headache (PCH), which equi es he ul illmen o all
CH c i e ia bu one. Cases p esen ing wi h hese “incom-
ple e” o ms ha e al eady been epo ed, and in some o
hese, a con e sion in o a “comple e” o m o ice- e sa
has occu ed2,3. The es ima e o he p e alence o CH
among he gene al popula ion anges om 56 o 401 pe
100.0004-11. A Po uguese popula ion-based s udy ound
one indi idu al wi h CH and one case o PCH among a sample
o 2008 subjec s12.
Familial agg ega ion o his disease has been he subjec o
a leas ou s udies; he esul s ha e sugges ed an inc eased
isk o i s -deg ee ela i es anging om 14- o 45- old when
compa ed o he gene al popula ion13-16. These s udies inclu-
ded only he pa ien s and ela i es ul illing he comple e se
o c i e ia o CH.
Based on he esul s o his s udy he ollowing hypo hesis
eme ged: i bo h CH and PCH cases we e included, a s onge
867
Simão C uz e al. Clus e headache
amilial agg ega ion could be de e mined. Such indings
would p obably con ibu e o s eng hening he in e es in
inding possible gene ic ac o s implied in he pa hogenesis
o his disease.
The main objec i es o his s udy we e o ind cases o
PCH including CH sine headache among ela i es and o
e alua e he amilial agg ega ion o a b oade spec um o
CH in a sample o he Po uguese popula ion.
mEThod
Pa ien ’s selec ion
F om he popula ion e alua ed in he Ou pa ien Hea -
dache Clinic o Hospi al San o An ónio (Po o, Po ugal) du-
ing he las 15 yea s, 77 consecu i e and un ela ed pa ien s
suspec ed o ha ing a igeminal au onomic headache we e
selec ed.
da a collec ion
The i s s ep was o con ac he pa ien s in o de o
e alua e a s uc u ed ques ionnai e o allow he ul illmen o
he diagnos ic c i e ia o CH. The con ac was made by ele-
phone and du ing he con ac he pa ien s we e asked i hei
i s -deg ee ela i es (pa en s, siblings, and o sp ing) ha e
e e had a headache simila o hei own o , al e na i ely, i
hei ela i es ha e e e expe ienced pa oxisms o disau o-
nomic ea u es compa ible wi h CH, e en in he absence o
he headache i sel . Finally, he elephone numbe o he i s -
deg ee ela i es was eques ed. The second s age o his s udy
consis ed o in e iewing he i s -deg ee ela i es o sc een
hem o ecu en headaches and, in case o a posi i e in-
ding, o y o ma ch he symp oms wi h he diagnos ic c i e-
ia o CH. The deceased ela i es e e ed by he p obands as
suspec s we e no conside ed as such. Only 12 o he ela i es
no conside ed suspec s we e a ailable o in e iew. None o
he 20 in e iewed ela i es we e obse ed and examined by
a neu ologis . The e o e, possible seconda y causes o hei
symp oms we e no excluded.
Familial agg ega ion
E alua ion o CH amilial agg ega ion was based on he
concep o ela i e isk (RR), which was calcula ed om he
a io be ween he likelihood o ha ing an a ec ed ela i e
conside ing an a ec ed pa ien , and he likelihood o ha ing
a andom a ec ed indi idual in he gene al popula ion. The
la e co esponds o he p e alence o he disease among
he gene al popula ion. Fo his pu pose, he es ima ion ob-
ained om a Po uguese popula ion-based s udy12 was used.
RR was s a is ically de e mined using a uni a ia e analysis
o ca ego ical a iables (c2 es ). The le el o signi icance was
se a 95% and amilial agg ega ion was conside ed i he RR
was g ea e han one.
E hical issues
A le e con aining he necessa y in o ma ion abou his
s udy was sen o all o he 77 pa ien s. The E hics Commi ee
o Hospi al San o An ónio app o ed he p ojec .
REsuLTs
I was no possible o ob ain any esponse om 41 o he
ini ial 77 pa ien s due o se e al easons such as dea h (2),
e usal o collabo a e (6), and inco ec con ac de ails (33).
O he 36 subjec s in e iewed, 7 we e excluded because hei
headache did no sa is y he c i e ia o any o he igeminal
au onomic headaches. The emaining 29 pa ien s we e classi-
ied as ollows: 22 as ha ing CH (82% wi h an episodic pa e n
and 18% wi h ch onic CH), 2 as PCH and 5 as sho -las ing
unila e al neu algi o m headache a acks wi h conjunc i al
injec ion and ea ing (SUNCT). Only he 24 pa ien s wi h CH
o PCH we e conside ed in he subsequen s a is ical analysis.
Se en y-nine pe cen o hese pa ien s we e male (Table 1),
and he mean age o onse was 34 yea s (s anda d de ia ion:
15,39), anging om 11 o 70 yea s.
The 24 p obands wi h CH o PCH had a o al o 142 i s -
deg ee ela i es. Fi e pa ien s (21%) had a posi i e amily his-
o y, wi h 10 possible cases among he g oup o ela i es. O
he 142 ela i es, 20 (14%) we e in e iewed, including 8 ou
o he 10 p e iously designa ed ( he o he s had died). Th ee o
hese ma ched he c i e ia o CH and wo we e classi ied as
PCH acco ding o he ICHD-II. None o he unsuspec ed ela-
i es had CH o PCH (Figu e 1).
Two scena ios we e conside ed when calcula ing he RR
(Table 2). In he i s scena io, o all he a iables implied in
he equa ion, bo h CH and PCH subjec s we e included. In
he second scena io, only hose indi iduals wi h CH we e
conside ed. Fi s -deg ee ela i es o p obands wi h CH we e
es ima ed as ha ing a 35- o 46- old inc eased isk o ha ing
CH compa ed wi h he gene al popula ion. Bo h alues a e
s a is ically signi ican (p<0.05).
Cases among he a ec ed amilies
The i e a ec ed ela i es belonged o he amilies o only
h ee p obands.
One o hese p obands was a 58-yea -old emale who
had an episodic CH o 15 yea s. She had wo sis e s; one
aged 56 yea s and he o he aged 61 yea s. The o me had
Table 1. Demog aphic cha ac e is ics o p obands.
Numbe o
p obands (%)
Age Age o onse
Mean Range Mean Range
To al 24 51 18-76 34 11-70
Male 19 (79) 49 18-76 31 11-65
Female 5 (21) 56 44-74 43 17-70
868 A q Neu opsiquia 2013;71(11):866-870
symp oms o 30 yea s, ul illing all he c i e ia o CH excep
o he du a ion: she men ioned pe iods o pain las ing be -
ween 2 and 3 days. The second sis e seemed o be a case o
CH sine headache. She denied ecu en headaches, bu des-
c ibed se e al episodes las ing abou 30 min, du ing which
she complained o conjunc i al injec ion, ea ing, and p osis
exclusi ely a ec ing he le eye, wi hou any appa en p e-
cipi an . The p oband men ioned ha hei mo he displayed
simila mani es a ions bu she had al eady died and was no
conside ed as an a ec ed ela i e.
The second p oband was a 55-yea -old male desc ibing
an episodic CH. He had ou siblings, including wo males
who also ul illed all he c i e ia o CH.
The hi d p oband, a emale aged 45 yea s, p esen ed an
episodic CH and had a 51-yea -old b o he who also ul illed
all he c i e ia o episodic CH.
dIsCussIon
The demog aphic cha ac e is ics o he pa ien s inclu -
ded in his s udy we e simila o hose widely epo ed. The
male: emale a io was ound o be app oxima ely 4:1, hus
sligh ly highe han ha desc ibed by mos au ho s17,18. The
age o onse is also supe io o wha has been epo ed. While
mos pa ien s p esen hei i s ea u es a ound he hi d de-
cade o li e, he p obands in his s udy had hei ini ial symp-
oms abou a decade la e . The indings o he wo pa ien s
who began complaining o CH symp oms a an uncommon
age (11 and 70 yea s) a e no ewo hy, al hough simila cases
ha e been p e iously epo ed19. The p opo ion o episodic
and ch onic pa e ns o CH in his sample (app oxima ely 4:1)
is also conco dan wi h mos s udies20.
The high numbe o cases ma ching he c i e ia o
SUNCT in his s udy is unexpec ed, as his ype o headache
is desc ibed as e y uncommon. Acco ding o some au ho s,
he e may be some sha ed aspec s in he physiopa hology o
he igeminal au onomic headaches21. Fu he mo e, he e
a e some case epo s o success ul usage o d ugs like e a-
pamil (mos commonly used in CH) in pa ien s wi h SUNCT22.
While hese indings may sugges some o e lap be ween CH
and SUCNT, i seems mo e likely ha he exceedingly high
numbe o cases in ou s udy may be due o he o igin o ou
sample (a e ia y headache clinic).
One o he mos impo an aspec s o amilial agg ega ion
s udies is he choice o he p e alence es ima ion, because a
small p e alence can lead o an o e es ima ion o he ela-
i e isk and ice- e sa. We used he da a om a Po uguese
popula ion-based s udy12 ha epo ed one case o CH and
ano he o PCH among 2008 indi iduals, hus ob aining a
p e alence o app oxima ely 50/100.000, i only CH cases a e
included. This es ima ion is simila o hose ob ained in he
wo San Ma ino s udies5,6 ha used a ho ough me hodology
and epo ed he ollowing alues: 56 and 69/100.000. Thus,
he p e alence used in ou s udy seems o be a good indica o
o he p e alence o CH in sou he n Eu ope.
Table 2. Rela i e isk o i s -deg ee ela i es o pa ien s wi h clus e headache and p obable clus e headache.
Cases included RR 95% CI
P e alence Rela i es ( o al) Rela i es (a ec ed)
1s scena io
Condi ion To ul ill all o all bu one
diagnos ic c i e ia
Should be ela ed o a p oband
who ul ills all o all bu one
diagnos ic c i e ia
To ul ill all o all bu
one diagnos ic c i e ia
35.21a14.56–85.14
Value 1:1000 142 5
2nd scena io
Condi ion To ul ill all he
diagnos ic c i e ia
Should be ela ed o a p oband
who ul ills all he c i e ia
To ul ill all he
diagnos ic c i e ia
46.15a14.58–146.09
Value 0.5/1000 130 3
RR: ela i e isk; CI: con idence in e al.
a Fo bo h RR alues, p<0.05.
CH: clus e headache; PCH: p obable clus e headache.
Figu e 1. Flow cha showing p obands and i s -deg ee
ela i es wi h hei clinical diagnosis.
22 subjec s wi h CH 2 cases o PCH
142 i s deg ee
10 e e ed by
he p obands as
suspec s
132 non
suspec s
8 in e iewed 2 no
in e iewed
(deceased)
12
in e iewed
120 no
in e iewed
9 denied
ecu en
headaches
3 had o he
ypes o
headache
3 had o he
ypes o
headache
2 cases
o PCH
3 cases
o CH
869
Simão C uz e al. Clus e headache
Conside ing he epo s o cases p esen ing wi h PCH ha
la e de eloped a CH3 o ice- e sa2, as well as he sugges ion
o a b oade clinical spec um o CH, i seemed app op ia e
o include indi iduals who p esen wi h PCH, and no jus
CH, in epidemiological s udies. In ou i s scena io we ob-
ained a RR o 35 and o he second a 46- old inc eased isk
o i s -deg ee ela i es. The di e ence be ween bo h alues
may be pa ially explained by he lowe p e alence used in
he second scena io. Thus, he hypo hesis o a highe RR wi h
he inclusion o PCH subjec s was no con i med.
The p e ious ou published amilial agg ega ion s udies
epo ed an inc eased isk o i s -deg ee ela i es anging
om app oxima ely 14- o 45- old13-16.
Bo h Russell e al.13, in Denma k, and Leone e al.14, in
I aly, used a simila me hodology and de e mined a RR o 14.1
and 39, espec i ely, o i s -deg ee ela i es. We can iden i y
a leas ou impo an di e ences when compa ing hese
s udies wi h ou s. Fi s ly, in hese s udies, only he possibly
a ec ed ela i es we e in e iewed. Ano he di e ence has
o do wi h he non-inclusion o PCH subjec s. Fu he mo e,
hey included deceased ela i es as long as he desc ip ion
p o ided by he p obands was de ailed enough o classi-
y hem acco ding o ICHD. Finally, he p e alence used in
he se s udies (69/100.000) was only sligh ly highe han he
one conside ed o ou equi alen scena io (50/100.000). The
samples used by hese au ho s we e a la ge han ou s and
he con idence in e als we e conside ably na owe , gi ing
an impo an consis ency o hei esul s.
In F ance, El Am ani e al.15 in oduced wha seems o be
a me hodological ad an age: all i s -deg ee ela i es we e
di ec ly in e iewed by a neu ologis . In he o he s udies,
including ou s, some a ec ed ela i es may ha e been los
because o a possible unde epo ing by he p obands.
Kud ow and Kud ow16, wi h a No h-Ame ican sample,
ound a RR o 45. Howe e , he amily his o y p o ided by he
p obands was no con i med by a di ec in e iew wi h he
ela i es, which may ha e led o an o e es ima ion o RR.
The mos impo an limi a ion o ou s udy is he small
numbe o subjec s included, which wi hd aws some consis-
ency o ou esul s, especially when compa ed wi h simila
s udies. Fu he mo e, ou sample was collec ed om a e -
ia y cen e , and hus a di ec ex apola ion o he gene al
popula ion canno be done.
Only a small p opo ion (14%) o he i s -deg ee ela i es
was in e iewed in his s udy and he emaining ela i es
we e conside ed o be una ec ed (acco ding o he in o -
ma ion p o ided by he p obands). Howe e , aking in o ac-
coun he possibili y ha he e could ha e been some a ec-
ed ela i es among hose no in e iewed, hei inclusion in
he equa ion would ha e esul ed in an e en g ea e RR. Also,
i his calcula ion was made using only he ela i es who we e
in e iewed, he RR alue would ha e been highe . Thus, his
limi a ion may ha e lead o an unde es ima ion o he RR in
his s udy.
Telephonic in e iews ha e been desc ibed as a alid ins-
umen in amilial agg ega ion s udies and p e alence s ud-
ies23,24, pa icula ly because hey allow he cla i ica ion o
di icul o ambiguous ques ions. So he use o elephone in-
e iews seems o be an impo an ad an age o ou s udy.
Ano he posi i e aspec is he use o a p e alence es ima ion
ob ained om a simila popula ion.
Finally, o he bes o ou knowledge, ou s udy is he i s
one ha includes indi iduals wi h PCH, which seems o be a
majo ad an age gi en he epo s o a b oade spec um o
he disease. Al hough we ha e no con i med a g ea e RR
wi h his addi ion, ou esul s p o ide signi ican e idence o
a s ong amilial agg ega ion, hus ein o cing he heo y o a
gene ic basis o CH. In he u u e, a la ge s udy wi h a simi-
la me hodology may be impo an o suppo hese esul s.
Acknowledgmen s
The au ho s would like o hank D . Ângela Timó eo
and D . José Ba os o e iewing he manusc ip and o
hei sugges ions.
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