Lack of migraine in headaches of familial dysautonomia patients
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.
KeywordsFamilial 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.
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