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

CLINICAL / SCIENTIFIC NOTES

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

Elcio Juliato Piovesan^I; Claudia Ferreira Sobreira^II; Rosana Herminia Scola^I; Paulo José Lorenzoni^I; Marcos Cristiano Lange^I; Lineu Cesar Werneck^I; Débora Smith^III; Stephen Silberstein^IV

^INeurology Service, Internal Medicine Department, Hospital de Clínicas, Federal University of Paraná (UFPR), Curitiba PR, Brazil

^IIDepartment of Neurology, Psychiatry and Medical Psychology, Ribeirão Preto Faculty of Medicine, University of São Paulo (USP), Ribeirão Preto SP, Brazil

^IIICardiology Service, Internal Medicine Department, Hospital de Clínicas, Federal University of Paraná (UFPR), Curitiba PR, Brazil

^IVJefferson Headache Center, Thomas Jefferson University Hospital, Philadelphia, PA, US

Migraine is a common episodic headache disorder characterized by attacks consisting of various combinations of headache, neurologic, gastrointestinal and autonomic symptoms. Autonomic symptoms, such as a cold feeling, increased urination, anorexia, diarrhea, constipation and fluid retention¹, can occur during the premonitory phase, and nausea, vomiting, diarrhea, cutaneous vasoconstriction (pallor), vasodilation (flushing), piloerection and diaphoresis can occur during the pain phase². Migraine patients with accompanying autonomic symptoms seem to experience their pain more unilateral and more severe than non autonomic migraine patients. Studies of autonomic nervous system dysfunction in migraine have been performed². Cardiovascular tests, vasomotor reactions to temperature changes and responses to pharmacological tests, and changes in biochemical parameters suggest abnormalities (hypo- or hyperfunctioning) of both the sympathetic and parasympathetic nervous systems². These inconsistent findings may be explained by different types of autonomic dysregulation. Syncope and migraine are both highly prevalent in the general population³. Both disorders occur together more frequently than chance would predict³, i.e., they are comorbid. Studies using the orthostatic (tilt) test suggest that migraine patients have vagal hyperactivity and a-sympathetic system hypoactivity². Migraineurs may have a genetic predisposition leading to autonomic nervous system (ANS) dysfunction. 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 typical 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 pathophysiology^4-6. It is not known whether the mitochondrion (encoded by the nuclear and mitochondrial genomes) is the primary site of the dysfunction, or whether the mitochondrial disturbance occur secondary to another cause⁶. Mitochondria may play a role in the genesis of migraine, especially in these groups (migraine plus autonomic symptoms)^4,5. Connecting networks exist between pain and autonomic functions in the brain (Fig 1); thus pain can produce 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 mitochondrial DNA (mtDNA) A3243G⁵ point mutation, common in patients 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 syncope (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 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 associated 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 mitochondrial DNA (mtDNA).

Tilt protocol consisted in 70º angulation during 30 minutes after a supine rest for 10 minutes. A positive result during tilt-table test was considered according to the literature^7,8. 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 described^3,9. The control group for DNA mutation consisted of two patients with MELAS. Prophylactic treatment for migraine was not used during the investigation 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 electroencephalograms. All patients had POTS and subsequent VS during the tilt-table test without pharmacologic induction. The average time to onset of symptoms was 16.4±5.2 minutes. 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 control 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 present in these patients. Why patients develop autonomic 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 triggers neuromediated syncope (Table). Autonomic-nervous-system-related syncope is common, with a life prevalence of 46% in migraineurs¹⁰. This can be confused with epilepsy. We have shown that migraine patients can develop loss of consciousness as a result of neuromediated syncope (Fig 1).

The association between migraine and abnormal mitochondrial function has been suggested on clinical, biochemical 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 migraine^4,6.

Most but not all studies have not detected mtDNA mutations in migraine patients^4,11. Despite the negative results, some speculate that mtDNA mutations could contribute to the pathogenesis of migraine⁴.

We looked for, but did not find any mtDNA MELAS A3243G point mutation, the most common mutation in mitochondrial 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.

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: [e-mail]

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Publication Dates

• Publication in this collection
  01 Apr 2008
• Date of issue
  Mar 2008