Journal of Neural Transmission

, Volume 120, Issue 3, pp 399–402 | Cite as

Lack of migraine in headaches of familial dysautonomia patients

  • Boris Shihman
  • Israel Steiner
  • Ivelin Yovchev
  • Channa Maayan
Translational Neurosciences - Original Article


Familial Dysautonomia (FD) is an autosomal recessive genetic disease where autonomic and sensory functions are defective affecting many body systems including the vascular. Plasma level of the neurotransmitter Calcitonin Gene Related Peptide (CGRP) is decreased in FD patients. This compound has been implicated to take part in the pathogenesis of migraine. We aimed to evaluate the symptoms of headaches in FD patients and to test the hypothesis that these patients will have a low incidence of migrainous headache. Sixty-five FD patients were evaluated by a medical headache questionnaire. Mean age was 23.73 + 10.82 years (mean 21 years) and there were 37 males (57 %).Thirty-eight patients (58.5 %) described having episodic headache conforming to criteria of tension headache, and in 17 of those 38 (44.7 %) headache were dependent on changes in blood pressure, except from one patient who had complaints that matched diagnosis of acephalic migraine. None of the patients had symptoms compatible with migraine or cluster headache. Results show that the headache is a very common complaint in FD, there is lack of migraine symptoms in this group. This might be attributed to defective sensory innervation and deficiency of CGRP. FD could be regarded as a human model for CGRP deficiency when studying the pathogenesis of migraine.


Familial dysautonomia Headache Migraine Calcitonin Gene Related Peptide 


Familial Dysautonomia (FD, the Riley-Day syndrome), is an autosomal recessive condition occurring almost exclusively among Ashkenazi Jews. Its incidence in this population is 1:3,703 live births with a carrier frequency of 1:32 (Maayan et al. 1987). The genetic defect has been mapped to a mutation in an intronic nucleotide substitution that alters the splicing of the IKBKAP-derived transcript on chromosome 9q (Slaugenhaupt et al. 2001; Anderson et al. 2001). Clinical manifestations arise secondary to autonomic and sensory nervous system defects and include malfunctions in most body systems (Gold-von Simson and Axelrod 2006). There is gastrointestinal dysfunction, cardiovascular instability with extreme blood pressure variations, orthopedic problems as well as dysautonomic crises manifested as hypertensive episodes, nausea, vomiting, blotching, restlessness and sweating for variable degrees of time. Patients suffer from altered sensitivity to pain and temperature and absence of corneal reflex, lack of overflow tears and growth retardation (Gold-von Simson and Axelrod 2006). Treatment advances have changed the prognosis so that more than 50 % of FD patients survive beyond 15 years of age (Axelrod et al. 2002).

The neuro-anatomical basis of FD consists of decreased size of sympathetic and parasympathetic ganglia (Aguayo et al. 1971; Pearson and Pytel 1978a, b; Pearson et al. 1978; Grover-Johnson and Pearson 1976), reduction in non-myelinated (C fibers) and in small diameter myelinated axons (A fibers) and their neurons. These neurons are involved in the nociceptive pain sensation and in the autonomic nervous system centrally and peripherally. They function by several neuropeptide transmitters which include Calcitonin Gene-Related Peptide (CGRP) and substance P, neurokinines A and K, Somatostatin and Vasoactive Intestinal Peptide. CGRP is released from activated sensory neurons, is involved in the sensory neurotransmission and has a potent vasodilatory effect (Recober and Russo 2009).

Headache is the most prevalent neurological disorder affecting up to 47 % of the adult population, with about 10 % the of people suffering from migraine (Jensen and Stovner 2008). The risk of migraine in family members of migraine probands is 50 % higher than that in family members of controls (Stewart et al. 1997).

One of the promising developments of migraine pathophysiology has been the discovery of the role of CGRP, a potent vasodilator in causing vascular headache (Benemei et al. 2007; Doods et al. 2007; Sprenger and Goadsby 2009; Olesen 2001). Findings showed that CGRP blood plasma level is reduced in FD patients (Maayan et al. 2001). We therefore conducted this study to examine headache in general, and migraine in particular in FD patients.

Materials and methods

Sixty-five FD patients above 6 years of age whose diagnosis was established by signs, symptoms and positive histamine test and confirmed genetically, were enrolled into this study. All patients were diagnosed and are followed at the Israeli Familial Dysautonomia Center at the Hadassah-Hebrew University Mount Scopus, Jerusalem. The Institutional Review Board approved this study.

The patients and their parents were asked to answer a medical headache questionnaire. The information consisted of past medical history, data on headache, type of attacks, duration, associated symptoms and therapy. Results of brain imaging when available were obtained. Family members were asked to measure blood pressure of patients during headaches.

Headaches were classified according to the International Classification of Headache disorders, second edition (2004).


The 65 FD patients studied included 37 males (56.9 %). The age ranged from 6 years and 4 months to 48 years and 2 months, mean 23.73 + 10.82 years with mean age of 21 years. None of the 65 FD patients reported typical migraine headaches. One patient had several attacks of aura associated with visual phenomena with increased blood pressure but without headache and was classified as having acephalic migraine. Thirty-nine (60 %) patients had headaches during FD crisis consisting of elevated BP with bouts of nausea and vomiting.

Thirty-eight from 65 FD patients (58.5 %), 20 of them males (52.6 %), suffered from headaches. The headache was described as pressure type headache of mild to moderate intensity with diffuse localization more prominent in the frontal region. No aura was reported. Eleven patients with headaches had family history of migraine (including two pairs of siblings) (28.9 %).

Headache during drastic changes in blood pressure occurred in 17 patients (44.7 %). In six it took place during blood pressure increase, in four it happened while blood pressure was decreased, and in seven it occurred both during either increase or decrease of blood pressure. This type of headache may conform to the designation of “headache attributed to disorders of homeostasis” (Headache Classification Subcommittee of the International Headache Society 2004) if regarded as secondary headache but may be classified as tension type headache if considered a primary headache disorder.

Brain imaging was done on 12 from 38 FD patients with headaches (31.6 %) and the results did not identify any structural source or cause for the headaches.

Fundus examination did not show increased intracranial pressure in any patient. None of the patients had sinusitis. Eight patients (21 %) had vision defects which were corrected by glasses, and one patient was near blind.


In this cohort of 65 FD patients, we found no typical migraine symptoms although the patients experienced intracranial pain sensation. More than half of them complained of headache mainly related to severe hemodynamic changes. One patient had acephalic migraine. Our finding of lack of migraine symptoms in FD patients might be of importance in the clinical setup of FD, to the mechanisms related to intracranial pain sensation in these patients and also relevant as a clinical model to the pathophysiology of migraine in general.

FD patients have decreased serum level of CGRP. The pain of migraine originates from intracranial blood vessels that are innervated by sensory nerves storing several neurotransmitters. CGRP is one of them and is found both in the pericranial vascular nerves and the trigeminal ganglia (Edvisson and Ho 2010).

FD is associated with several biochemical features. Thus, both substance P and CGRP are reduced in FD. CGRP is a potent dilator of cerebral and dural blood vessels (Jansen-Olesen et al. 1996) and might play an important role in the pathophysiological mechanisms of migraine (Benemei et al. 2007; Doods et al. 2007; Sprenger and Goadsby 2009; Rapoport 2010). CGRP can induce migraine in patients who are prone to migraine (lassen et al. 2002; Hansen et al. 2010) and in a mouse model (Russo et al. 2009). Plasma and saliva levels of CGRP are reported to be elevated in migraine (Jang et al. 2011). Intracranial blood vessels dilate in response to intravenous CGRP, a phenomenon that is reversed by triptans (Asghar et al. 2010).

Recent years have seen major advances in the treatment of migraine (Rapoport 2010). The understanding of the role of CGRP in primary headaches and migraine paved the way to the development of rational therapy such as CGRP receptor antagonists which would have less cardiovascular side effects as compared to triptans (Olesen et al. 2004). At present, there are two CGRP antagonists effective in the treatment of migraine attacks, Olcegepant (Olesen et al. 2004) administered intravenously and Telcagepant orally (MKO970) (Ho et al. 2008). It is possible that anti-CGRP receptor drugs will serve not only for acute treatments but as also migraine prophylactic medicines.

The present finding of the absence of migraine symptoms in FD might be related to the reduced plasma levels of CGRP in these patients’ populations and is another evidence to the role of CGRP in the pathogenesis of migraine.It would be interesting to examine the rate of migraine in similar conditions to FD such as HSAN II and IV where the underlying molecular basis is yet not delineated.

In conclusion, headache is a very common complaint in FD patients and is associated with abnormal alterations of blood pressure and hemodynamic changes. The lack of migraine symptoms in this group might be attributed to the defective sensory innervation and in particular deficiency of CGRP. Thus, FD could be regarded as a human model for CGRP deficiency when studying the pathogenesis of migraine.



Dr. Steiner and Dr. Maayan conceived the project, designed the study and wrote the manuscript. Dr. Shihman interviewed the patients and analyzed the data. Dr.Yovchev collected data from the clinical charts.

Prof. Steiner serves on the editorial boards of the Journal of Neurovirology, the Journal of Neurological Sciences, and Medicine Neurology (Hebrew); serves on a data safety monitoring board for Actelion Pharmaceuticals Ltd. And Hoffmann-La Roche Ltd; and has received research support from the Israel Science Foundation and the Israeli Ministry of Health Chief Scientist.

Dr. Shihman, Dr. Maayan and Dr. Yovchev have nothing to disclose.


  1. Aguayo AJ, Nair CP, Bray GM (1971) Peripheral nerve abnormalities in the Riley-Day syndrome. Findings in a sural nerve biopsy. Arch Neurol 24:106–116PubMedCrossRefGoogle Scholar
  2. Anderson SL, Coli R, Daly IW, Kichula EA, Rork MJ, Volpi SA, Ekstein J, Rubin BY (2001) Familial dysautonomia is caused by mutations of the IKAP gene. Am J Hum Genet 68:753–758PubMedCrossRefGoogle Scholar
  3. Asghar MS, Hansen AE, Kapijimpanga T, van der Geest RJ, van der Koning P, Larsson HB, Olesen J, Ashina M (2010) Dilation by CGRP of middle meningeal artery and reversal by sumatriptan in normal volunteers. Neurology 75:1520–1526PubMedCrossRefGoogle Scholar
  4. Axelrod FB, Goldberg JD, Ye XY, Maayan C (2002) Survival in familial dysautonomia: impact of early intervention. J Pediatr 141:518–523PubMedCrossRefGoogle Scholar
  5. Benemei S, Nicoletti P, Capone JA, Geppetti P (2007) Pain pharmacology in migraine: focus on CGRP and CGRP receptors. Neurol Sci 28(Suppl 2):S89–S93PubMedCrossRefGoogle Scholar
  6. Doods H, Arndt K, Rudolf K, Just S (2007) CGRP antagonists: unravelling the role of CGRP in migraine. Trends Pharmacol Sci 28:580–587PubMedCrossRefGoogle Scholar
  7. Edvisson I, Ho TW (2010) CGRP receptor antagonism and migraine. Neurotherapeutics 7:164–175CrossRefGoogle Scholar
  8. Gold-von Simson G, Axelrod FB (2006) Familial dysautonomia: update and recent advances. Curr Probl Pediatr Adolesc Health Care 36:218–237PubMedCrossRefGoogle Scholar
  9. Grover-Johnson N, Pearson J (1976) Deficient vascular innervation in familial dysautonomia, an explanation for vascular instability. Neuropathol Appl Neurobiology 2:217–224CrossRefGoogle Scholar
  10. Hansen JM, Hauge AW, Olesen J, Ashina M (2010) Calcitonin gene-related peptide triggers migraine-like attacks in patients with migraine with aura. Cephalalgia 30:1179–1186PubMedCrossRefGoogle Scholar
  11. Headache Classification Subcommittee of the International Headache Society (2004) The International Classification of Headache Disorders 2nd edition. Cephalalgia 24(Suppl 1):9–160Google Scholar
  12. Ho TW, Ferrari MD, Dodick DW, Galet V, Kost J, Fan X, Leibensperger H, Froman S, Assaid C, Lines C, Koppen H, Winner K (2008) Efficacy and tolerability of MK-9074 (telcagepant), a new oral antagonist of calcitonin gene-related peptide receptor, compared with zolmitriptan for acute migraine: a randomized, placebo-controlled, parallel-treatment trial. Lancet 372:2115–2123PubMedCrossRefGoogle Scholar
  13. Jang MU, Park JW, Kho HS, Chung SC, Chung JW (2011) Plasma and saliva levels of nerve growth factor and neuropeptides in chronic migraine patients. Oral Dis 17:187–193PubMedCrossRefGoogle Scholar
  14. Jansen-Olesen J, Mortensen A, Edvinsson I (1996) Calcitonon gene-related peptide is released from capsaicin-sensitive nerve fibers and induces vasodilation of human cerebral arteries concomitant with activation of adnyl cyclase. Cepahalalgia 16:310–316CrossRefGoogle Scholar
  15. Jensen R, Stovner LJ (2008) Epidemiology and comorbidity of headache. Lancet Neurol 7:354–361PubMedCrossRefGoogle Scholar
  16. Lassen LH, Haderslev PA, Jacobsen VB, Iversen HK, Sperling B, Olesen J (2002) CGRP may play a causative role in migraine. Cephalalagia 22:54–61CrossRefGoogle Scholar
  17. Maayan C, Kaplan E, Shachar S, Godfrey S (1987) Incidence of familial dysautonomia in Israel 1977–1981. Clin Genet 32:106–108PubMedCrossRefGoogle Scholar
  18. Maayan C, Becker Y, Gesundheit B, Girgis SI (2001) Calcitonin gene related peptide in familial dysautonomia. Neuropeptides 35:189–195PubMedCrossRefGoogle Scholar
  19. Olesen J (2001) CGRP in migraine. Cephalalgia 31:638CrossRefGoogle Scholar
  20. Olesen J, Diener HC, Hussted IW, Goadsby PJ, Hall D, Meier U, Pollentier S, Lesko LM, BIBN 4096 BS Clinical Proof of Concept Study Group (2004) Calcitonin gene-related peptide receptor antagonist BIBN 4096 BS for the acute treatment of migraine. N Eng J Med 350:1104–1110CrossRefGoogle Scholar
  21. Pearson J, Pytel BA (1978a) Quantitative studies of sympathetic ganglia and spinal cord intermedio-lateral gray columns in familial dysautonomia. J Neurol Sci 39:47–59PubMedCrossRefGoogle Scholar
  22. Pearson J, Pytel BA (1978b) Quantitative studies of ciliary and sphenopalatine ganglia in familial dysautonomia. J Neurol Sci 39:123–130PubMedCrossRefGoogle Scholar
  23. Pearson J, Pytel BA, Grover-Johnson N, Axelrod F, Dancis J (1978) Quantitative studies of dorsal root ganglia and and neuropathologica observations on spinal cords in familial dysautonomia. J Neurol Sci 35:77–92PubMedCrossRefGoogle Scholar
  24. Rapoport AM (2010) New acute treatments for headache. Neurol Sci 31(Suppl 1):129–132CrossRefGoogle Scholar
  25. Recober A, Russo AF (2009) Calcitonin gene-related peptide: an update on the biology. Curr Opin Neurol 22:241–246PubMedCrossRefGoogle Scholar
  26. Russo AF, Kuburas A, Kaiser EA, Raddant AC, Recober AA (2009) Potential Preclinical Migraine Model: CGRP-Sensitized Mice. Mol Cell Pharmacol 1:264–270PubMedGoogle Scholar
  27. Slaugenhaupt SA, Blumenfeld A, Gill SP et al (2001) Tissue-specific expression of a splicing mutation in the IKBKAP gene causes familial dysautonomia. Am J Hum Genet 68:598–605PubMedCrossRefGoogle Scholar
  28. Sprenger T, Goadsby PJ (2009) Migraine pathogenesis and state of pharmacological treatment options. BMC Med 7:71PubMedCrossRefGoogle Scholar
  29. Stewart WF, Staffa J, Lipton RB, Ottman R (1997) Familial risk of migraine: a population-based study. Ann Neurol 41:166–172PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag Wien 2012

Authors and Affiliations

  • Boris Shihman
    • 1
    • 3
  • Israel Steiner
    • 1
    • 4
  • Ivelin Yovchev
    • 2
  • Channa Maayan
    • 2
  1. 1.Neurological Sciences UnitHadassah-Hebrew University Hospital, Mount ScopusJerusalemIsrael
  2. 2.Department of PediatricsIsraeli Familial Dysautonomia Center, Hadassah-Hebrew University Hospital, Mount ScopusJerusalemIsrael
  3. 3.Department of NeurologyRabin Medical CenterPetah-TikvaIsrael
  4. 4.Department of NeurologyRabin Medical Center-Beilinson CampusPetah TiqvaIsrael

Personalised recommendations