LANGE, Marcos Cristiano

LORENZONI, Paulo José

PIOVESAN, Elcio Juliato

SCOLA, Rosana Herminia

SILBERSTEIN, Stephen

SMITH, Débora

SOBREIRA, Claudia Ferreira

WERNECK, Lineu Cesar

Biblioteca Digital da Produção Intelectual da Universidade de São Paulo (BDPI/USP)

Arq Neuropsiquiatr 2008;66(1):77-79
 77
EPISODIC MIGRAINE ASSOCIATED WITH POSTURAL  
ORTHOSTATIC TACHYCARDIA SYNDROME  
AND VASOVAGAL SYNCOPE
Migraine triggers neuromediated syncope
Elcio Juliato Piovesan1, Claudia Ferreira Sobreira2, Rosana Herminia Scola1, Paulo José Lorenzoni1, 
Marcos Cristiano Lange1, Lineu Cesar Werneck1, Débora Smith3, Stephen Silberstein4
MIGRâNEA EPISóDICA ASSOCIADA COM SíNDROME DA TAqUICARDIA ORTOSTáTICA POSTURAL E SíNCOPE VASOVAGAL: MIGRâNEA DESEN­
CADEIA SíNCOPE NEUROMEDIADA
1Neurology Service, 3Cardiology Service,  Internal Medicine Department, Hospital de Clínicas, Federal University of Paraná (UFPR), Curitiba PR, Brazil; 
2Department of Neurology, Psychiatry and Medical Psychology, Ribeirão Preto Faculty of Medicine, University of São Paulo (USP), Ribeirão Preto SP, 
Brazil; 4Jefferson Headache Center, Thomas Jefferson University Hospital, Philadelphia, PA, USA. 
Received 2 August 2007, received in final form 29 November 2007. Accepted 5 January 2008.
Dr. Elcio Juliato Piovesan – Hospital de Clínicas da UFPR - Rua General Carneiro 181 / 12 andar / Sala 1236 - 80060-900 Curitiba PR - Brasil. E-mail: 
piovesan@avalon.sul.com.br
Migraine is a common episodic headache disorder 
characterized by attacks consisting of various combina-
tions of headache, neurologic, gastrointestinal and auto-
nomic symptoms. Autonomic symptoms, such as a cold 
feeling, increased urination, anorexia, diarrhea, constipa-
tion and fluid retention1, can occur during the premoni-
tory phase, and nausea, vomiting, diarrhea, cutaneous va-
soconstriction (pallor), vasodilation (flushing), piloerec-
tion and diaphoresis can occur during the pain phase2. 
Migraine patients with accompanying autonomic symp-
toms seem to experience their pain more unilateral and 
more severe than non autonomic migraine patients. Stud-
ies of autonomic nervous system dysfunction in migraine 
have been performed2. Cardiovascular tests, vasomotor 
reactions to temperature changes and responses to phar-
macological tests, and changes in biochemical parame-
ters suggest abnormalities (hypo- or hyperfunctioning) of 
both the sympathetic and parasympathetic nervous sys-
tems2. These inconsistent findings may be explained by 
different types of autonomic dysregulation. Syncope and 
migraine are both highly prevalent in the general popu-
lation3. Both disorders occur together more frequently 
than chance would predict3, i.e., they are comorbid. Stud-
ies using the orthostatic (tilt) test suggest that migraine 
patients have vagal hyperactivity and α-sympathetic sys-
tem hypoactivity2. Migraineurs may have a genetic predis-
position leading to autonomic nervous system (ANS) dys-
function. The link between migraine and abnormal ANS 
function is unclear. ANS dysfunction may be involved in 
both increased susceptibility to migraine headaches and 
increased response to triggers. Migraine patients with typ-
ical autonomic symptoms, such as postural orthostatic 
tachycardia syndrome (POTS) and vasovagal syncope (VS), 
as well as patients with migraine with prolonged aura, are 
potential candidates for genetic studies4. Mitochondrial 
dysfunction may play a role in migraine pathophysiolo-
gy4-6. It is not known whether the mitochondrion (encod-
ed by the nuclear and mitochondrial genomes) is the pri-
mary site of the dysfunction, or whether the mitochon-
drial disturbance occur secondary to another cause6. Mi-
tochondria may play a role in the genesis of migraine, es-
pecially in these groups (migraine plus autonomic symp-
toms)4,5. Connecting networks exist between pain and au-
tonomic functions in the brain (Fig 1); thus pain can pro-
duce autonomic symptoms. 
We describe a group of patients in whom autonomic 
symptoms (POTS and VS) occurred only during migraine 
attacks. We also studied the presence of the mitochondri-
al DNA (mtDNA) A3243G5 point mutation, common in pa-
tients with mitochondrial encephalomyopathy with lactic 
acidosis and stroke-like episodes (MELAS). 
METHOD
Six patients with migraine attacks associated with postural 
orthostatic tachycardia syndrome followed by vasovagal syn-
cope (4 females aged 28.05±8.21 years and 2 males aged 31.21±5 
years) were selected from our migraine patient group (n= 3215). 
Only patients who had more than 20 percent of their migraine 
attacks associated with POTS and VS after the onset of pain 
were studied. Three patients had visual aura during some of their 
migraine attacks. The average age when they experienced their 
Arq Neuropsiquiatr 2008;66(1)
78
Episodic migraine
Piovesan et al.
first attack was 17.23±3.20 years; the average number of attacks 
was 2.3±1.2 per month. Patients with other autonomic symptoms 
or with isolated POTS, isolated VS, or POTS plus VS not associ-
ated with migraine were excluded. All six patients were studied 
using brain magnetic resonance imaging, electroencephalograms, 
tilt-table test and analysis of the A3243G point mutation in mi-
tochondrial DNA (mtDNA).
Tilt protocol consisted in 70o angulation during 30 minutes 
after a supine rest for 10 minutes. A positive result during tilt-ta-
ble test was considered according to the literature7,8. Analysis of 
the A-to-G mutation at position 3243 of the mtDNA was done by 
the PCR-RFLP (polymerase chain reaction/restriction fragment 
length polymorphism) method using DNA from peripheral blood 
lymphocytes, as previously described3,9. The control group for 
DNA mutation consisted of two patients with MELAS. Prophy-
lactic treatment for migraine was not used during the investiga-
tion protocol. All subjects provided written informed consent, 
as required by appropriate local (Human Ethical committee of 
Universidade Federal do Paraná) committees on the protection 
of research subjects. 
RESULTS
All patients had normal MRIs and electroencepha-
lograms. All patients had POTS and subsequent VS dur-
ing the tilt-table test without pharmacologic induction. 
The average time to onset of symptoms was 16.4±5.2 min-
utes. Only two patients had headache during the tilt-table 
test. Both cases related that headache is different of the 
usual migraine attacks. We found an association between 
migraine, POTS and VS in 0.18% of our migraine patients. 
The A3243G mutation was not detected by the PCR-RFLP 
method in our six migraineurs with migraine/POTS/VS, 
but was detected in the two MELAS patients in the con-
trol group (see Table, Figs 2 and 3). 
DISCUSSION
Our group of migraine patients present autonomic 
symptoms such as POTS and VS after pain onset. DNA 
studies showed that the A3243G point mutation was not 
Fig 1. Interaction between migraine and autonomic symptoms: (Step 1) 
primary nociceptive activation of the dura mater; (Step 2) activation 
of the ventrolateral periaqueductal gray substance (PAG); (Step 3) in-
hibitory behavior of the ventrolateral PAG over the trigeminal nu-
cleus caudalis; (Step 4) balance between different excitatory and in-
hibitory potentials and activation of the thalamus.
Table. Case descriptions: clinical features; headache intensity measured according to the visual analogue scale (VAS); frequency (in per-
cent) of postural orthostatic tachycardia syndrome (POTS) and vasovagal syncope (VS) symptoms; results of the tilt-table test and time 
to onset of autonomic symptoms; and results of DNA testing (see Fig 1).
Case Gender Age Age at 
first attack 
(years)
Attacks 
per month
First 
symptoms 
VAS
Frequency of 
subsequent 
symptoms
Tilt-table test DNA
(A3243G point 
mutation)
1 Female 36 16 3 Headache 
(VAS-8)
25% POTS 
and VS
Positive  
20 min after
Absent
2 Female 19 14 2 Headache
(VAS-9)
22% POTS 
and VS
Positive  
18 min after
Absent
3 Female 22 16 4 Headache
(VAS-9)
29% POTS 
and VS
Positive  
15 min after
Absent
4 Female 35 21 3 Headache
(VAS-10)
31% POTS 
and VS
Positive 
18 min after
Absent
5 Male 36 11 2 Headache 
(VAS-8)
24% POTS 
and VS
Positive 
22 min after
Absent
6 Male 24 22 2 Headache
(VAS-8)
22% POTS 
and VS
Positive 
27 min after
Absent
Arq Neuropsiquiatr 2008;66(1)
 79
Episodic migraine
Piovesan et al.
present in these patients. Why patients develop autonom-
ic symptoms, such as vasovagal syncope, during migraine 
attacks is not clear3. A small subset of patients develop 
autonomic disorders only after the onset of migraine 
headache. In these patients migraine pain probably trig-
gers neuromediated syncope (Table). Autonomic-nervous-
system-related syncope is common, with a life prevalence 
of 46% in migraineurs10. This can be confused with epi-
lepsy. We have shown that migraine patients can develop 
loss of consciousness as a result of neuromediated syn-
cope (Fig 1). 
The association between migraine and abnormal mi-
tochondrial function has been suggested on clinical, bio-
chemical and neuroradiological grounds1. A few studies 
have examined mtDNA mutations in high risk subgroups 
of migraineurs: patients with migraine with or without 
aura selected from pedigrees with a maternal mode of 
transmission, patients with cluster headache, patients 
with migrainous cerebral infarction, and patients with 
sporadic hemiplegic migraine4,6. 
Most but not all studies have not detected mtDNA 
mutations in migraine patients4,11. Despite the negative re-
sults, some speculate that mtDNA mutations could con-
tribute to the pathogenesis of migraine4. 
We looked for, but did not find any mtDNA MELAS 
A3243G point mutation, the most common mutation in mi-
tochondrial diseases. MELAS typically presents with severe 
migraine-like symptoms, and the A3243G mutation was 
previously found in 6% of migraine patients from another 
subgroup (with juvenile occipital migraine stroke)3-5,12,13.
The physiologic link between migraine and autonomic 
dysfunctions probably occurs in the PAG (specifically, in 
the ventrolateral region) and hypothalamus. Nociceptive 
input may, trigger an inhibitory reaction from the PAG 
to the trigeminal nucleus caudalis, triggering secondary 
sympathoinhibition. In our study, 0.18% of the migraine 
patients had coexistant POTS and VS during their migraine 
attacks. No mitochondrial dysfunction (mtDNA A3243G 
point mutation) was detected in this group.
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present in the two MELAS control subjects.
Fig 3. Tilt-table test; SAP, systolic arterial pressure; DAP, diastolic ar-
terial pressure; AAP, average arterial pressure; CF, cardiac frequency.


Migrânea episódica associada com síndrome da taquicardia ortostática postural e síncope vasovagal: migrânea desencadeia síncope neuromediada

Universidade de São Paulo

Arquivos de Neuro-Psiquiatria

RCAAP - Repositório Científico de Acesso Aberto de Portugal

Elcio Juliato Piovesan

Claudia Ferreira Sobreira

Rosana Herminia Scola

Paulo José Lorenzoni

Marcos Cristiano Lange

Lineu Cesar Werneck

Débora Smith

Stephen Silberstein

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Episodic migraine associated with postural orthostatic tachycardia syndrome and vasovagal syncope: migraine triggers neuromediated syncope Migrânea episódica associada com síndrome da taquicardia ortostática postural e síncope vasovagal: migrânea desencadeia síncope neuromediada

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Migrânea episódica associada com síndrome da taquicardia ortostática postural e síncope vasovagal: migrânea desencadeia síncope neuromediada

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