Augusto Morales, MD; Andreea I. Stoichita, MD; and Jessica D. Wharton, MD

Original Research Orthostatic Intolerance and Other Autonomic Symptoms in Adolescents With Headaches Augusto Morales, MD; Andreea I. Stoichita, MD; and Jessica D. Wharton, MD From the Department of Pediatrics, Division of Pediatric Neurology, Greenville Health System, Greenville, SC (A.M.); Department of Pediatrics, Greenville Health System, Greenville, SC (A.I.S.); and Department of Pediatrics at Vanderbilt University School of Medicine, Nashville, Tenn (J.D.W.) Abstract Background: The identification of autonomic comorbidity in adolescents with headaches could provide additional treatment strategies. The objective of this study was to identify and quantify autonomic symptoms in adolescents with headaches during a clinic visit using the COMPASS 31 questionnaire. Methods: The Institutional Review Board at Greenville Health System approved chart review of 92 adolescents seen in a pediatric neurology clinic with headache or syncope. All had active orthostatic testing and completed the COMPASS 31 and SCARED questionnaires. A 40 BPM (beats per minute) heart rate increase indicated postural orthostatic tachycardia. A score of >50% was considered high for the COMPASS 31 domains. A SCARED score >24 indicated anxiety. The relationship between high scores in COMPASS 31 domains and overall headache was studied by bivariate analysis and Fisher s exact test; headache type by odds ratio; and headache frequency, anxiety, syncope, and orthostatic tachycardia by Chi-square analysis. Results: Eighty subjects had headaches, from which 65 were girls. Twelve subjects had syncope only, and 19 had both headache and syncope. Thirteen had orthostatic tachycardia; 43 had anxiety. Fifty-four subjects with headaches had high scores in the orthostatic intolerance (OI) domain, 37 in the pupillomotor domain, 17 in the vasomotor domain, and 8 in the gastrointestinal domain. OI was the only statistically significant domain when comparing subjects with and without headaches. Female sex, migraines, frequent headaches, and worsening headaches were statistically associated with OI domain high scores. Conclusions: The COMPASS 31 can be used in a busy clinic to identify and quantify OI in adolescents with headaches. Girls with migraine headaches, high headache frequency, and worsening headaches were more likely to have OI. Headache is one of the most common health problems in adolescents. They can result in significant disability, poor quality of life, and school absenteeism. 1 Adolescents with headaches are frequently refractory to pharmacologic interventions 2 and can have significant comorbidity. 3 They account for a significant number of referrals to the neurology clinic. Associations between headaches and the autonomic nervous system are well recognized. Many symptoms of migraine headaches are the result of autonomic dysfunction. Dizziness and photophobia are prominent migraine symptoms. 4 Migraineurs have a high prevalence of orthostatic intolerance (OI) and syncope. 5 Teenagers with Persistent Orthostatic Tachycardia Syndrome (POTS), a disorder of the autonomic nervous system with chronic OI, report headaches very frequently. These patients may have orthostatic headaches in which standing up or lightheadedness may trigger or worsen headaches. Impaired cerebrovascular regulation may explain orthostatic headaches. 6 20 GHS Proc. June 2017; 2 (1): 20-25

ORTHOSTATIC INTOLERANCE AND HEADACHES The mechanisms of headaches in adolescents are not well understood. Studies regarding the autonomic function in children and adolescents with headaches are limited and controversial. A sympathetic dysfunction, cranial parasympathetic dysfunction, or both has been postulated to explain migraine headaches. 7 The identification of different types of autonomic symptoms in adolescents with headaches may be helpful to better diagnose a certain type of headache syndrome. It may also identify comorbid states that may provide additional treatment strategies to the physician treating adolescents with headaches. A comprehensive assessment of autonomic symptoms and functions is usually achieved using established questionnaires. Typically, these questionnaires are extensive and require computer analysis for score generation. They are used in autonomic disorder centers and are not easily completed on a single visit to a busy pediatric neurology/headache clinic. At the Mayo Clinic, a refined and abbreviated composite autonomic symptom score (COMPASS), based on the well-established 169 questions of the Autonomic Symptom Profile, 8 has been developed and consists of only 31 questions that address 6 autonomic domains. These include OI, as well as vasomotor, secretomotor, gastrointestinal, bladder, and pupillomotor dysfunction. This new questionnaire is user friendly, broadly applicable, and easy to administer in a short time without the need for computer analysis. Known as the COMPASS 31, it provides a global autonomic severity score, and specific domain scores that are clinically and scientifically meaningful. Higher scores indicate a larger number of symptoms, increased severity of symptoms, or symptom progression in each domain. 9 The objective of this study was to identify and quantify autonomic symptoms in adolescents with headaches during a routine visit to the pediatric neurology clinic. Methods Following Institutional Review Board approval, chart review of 92 consecutive adolescent patients seen in the pediatric neurology clinic with complaints of headache or syncope was conducted. The patients were seen between January 1, 2013 April 24, 2015. Patients were referred to the clinic because of the severity of their headaches and failure to respond to standard treatment by their primary care pediatrician. Subjects were evaluated with a clinical history, physical exam, and neurologic exam. In addition, during a single visit, these subjects had an autonomic/psychogenic evaluation that included active orthostatic testing at the bedside, completion of the COM- PASS 31 self-assessment autonomic symptom questionnaire, and completion of the Screen for Child Anxiety Related Emotional Disorders (SCARED) questionnaire. 10 During the chart review, the presence or absence of headache, syncope, and OI symptoms was noted. Headaches were first classified according to the International Classification of Headache Disorders 3 (ICHD3). They were grouped into 1 of 3 headache groups, which included tension-type headache, migraine headache, and daily persistent headache. Subjects with syncope and no headaches were used as a control group of patients with autonomic dysfunction but no headaches. Headache symptom duration was classified as recent (<3 months), subacute (3 6 months) and chronic (>6 months). Headaches were also classified as frequent (>7 headaches in a 15-day period), worsening (increase frequency over the last 3 months), improving (decreased frequency over the last 3 months), and transforming (changing headache type). The COMPASS 31 and the SCARED questionnaires were completed consecutively by the patient in the examining room. A score of >50% on each domain of the COMPASS 31 was considered a high score indicative of significant autonomic symptoms in each domain. A total score of 25 or more in the SCARED questionnaire was considered positive and indicative of anxiety. Active bedside orthostatic testing was performed by a nurse in the examining room after a rest period of 20 minutes in which the patient was lying supine. Blood pressure and heart rate were noted while supine, then immediately after standing, and again at 5 and 10 minutes. Presence or absence of orthostatic symptoms was noted. An increase in heart rate of 40 BPM (beats per minute), systolic hypotension of 20 mmhg, or diastolic hypotension of 10 mmhg were considered significant during active bedside orthostatic testing. The relationship between high scores in COM- PASS 31 domains and overall headache was studied by bivariate analysis and Fisher s exact test; headache type by odds ratio; and headache frequency, anxiety, syncope, and orthostatic tachycardia by Chi-square analysis. GHS Proc. June 2017; 2 (1): 20-25 21

Results Figure 1 Patient characteristics: headache type. Number of patients 60 50 40 30 20 10 0 Demographics and Chart Review Ninety-two consecutive subjects were studied. There were 65 females and 27 males ages 12 18 years (mean age of 15 years). Eighty subjects (88%) had recurrent headaches, 66 (83%) had chronic headaches, and 50 (63%) had a high headache frequency. Nineteen (23%) had headache and syncope, while 14 subjects (18%) had headaches only with no syncope or symptoms of OI. Fifty subjects (63%) had migraine headaches; 14 subjects (18%) had tension-type headaches. Thir- Figure 2 Patient characteristics: anxiety, total score, and anxiety subsets according to SCARED questionnaire. Number of patients 50 45 40 35 30 25 20 15 10 Migraine Tension type Daily persistent Mixed teen (16%) had daily persistent headaches, and 3 subjects (4%) had headaches with mixed features. The control group consisted of 12 subjects (13%) with syncope and no headaches (Fig. 1). SCARED Questionnaire Forty-three subjects (52%) with headaches had a high total score of 25 or more, indicative of anxiety. Thirty-one subjects (39%) had scores that may indicate panic disorder or significant somatic symptoms. Twenty-nine (35%) had scores that may indicate general anxiety disorder. Twenty-six (33%) had scores that may indicate separation anxiety. Thirty (38%) had scores that may indicate social anxiety. Forty subjects (50%) had scores that may indicate significant school avoidance (Fig. 2) Active Bedside Orthostatic Intolerance Testing Thirty subjects (38%) with headaches had 1 or more symptoms during testing. Twenty-four reported dizziness or lightheadedness. Six had a headache, 3 of whom reported an orthostatic headache. Two subjects had nausea, while 2 others had numbness. One subject had tinnitus, and 1 felt hot. There were no cases of syncope. Two had systolic hypotension and extreme dizziness. In these 2 patients, testing was discontinued after determination of hypotension. Thirteen subjects (16%) had an increase in heart rate of more than 40 BPM, indicative of orthostatic tachycardia. Five of these subjects had symptoms. Fifteen subjects had symptoms and no abnormalities noted in blood pressure or pulse during testing. COMPASS 31 Data Of the 80 patients with headaches, 54 subjects (68%) had a high score for the OI domain. Only 5 subjects (6%) did not report OI symptoms. Twenty-seven subjects (34%) had a high score for the pupillomotor domain, while only 10 subjects (13%) had no symptoms in this domain. Seventeen subjects (21%) had a high score for vasomotor domain; 54 (68%) had no symptoms in this domain. Eight subjects (10%) had a high score for gastrointestinal domain, and 8 (10%) had no symptoms in this domain. Two subjects (3%) had high scores in the secretomotor domain, while 54 (68%) had no symptoms in this domain. No subjects had high scores for bladder domain; 63 (79%) had no symptoms at all in this domain. 5 0 Total score Panic/somatic symptoms Generalized anxiety Separation anxiety Social anxiety School avoidance From the 12 subjects in the control group, 2 subjects had a high score in the OI domain, and 2 subjects had no symptoms in this domain. When subjects with headache were compared to the 22 GHS Proc. June 2017; 2 (1): 20-25

ORTHOSTATIC INTOLERANCE control group, OI was the only COMPASS 31 domain that was significant (P =.001) (Table 1). High Score on the Orthostatic Intolerance Domain of COMPASS 31 Of the 54 subjects with headaches and high scores on the OI domain, 46 (82%) were girls. Thirty-five subjects (62.5%) had migraine headaches, 36 (64.3%) had frequent headaches, and 20 (37.7%) had worsening headaches. When compared with subjects with headaches and low OI scores, the following categories were significant: female sex (P =.002), migraine headaches (P =.005), high headache frequency (P =.017), and worsening headaches (P =.019). A history of syncope, high anxiety scores on the SCARED questionnaire, or OI in heart rate during active bedside orthostatic testing was not found to be significant between these 2 groups (Table 2). Discussion We studied adolescents referred to a subspecialty clinic with a longstanding history of frequent headaches with comorbidities of syncope and anxiety. The female sex preponderance noted in our study is not unusual in adolescents with headaches. 11 We used the COMPASS 31 questionnaire to identify and quantify autonomic dysfunction. All subjects had standard active orthostatic testing at the bedside to document OI features and also completed the SCARED questionnaire to study the possible effects of anxiety on the results. Most subjects had autonomic symptomatology noted on the different domains of COMPASS 31. Significantly high scores indicative of high symptom frequency, symptom severity, and symptom progression were noted only in the OI domain. Many subjects had high scores in the pupillomotor and vasomotor domains, but these did not achieve statistical significance. Less-than-expected scores in the pupillomotor domain may result from a dilution effect of the number of patients who had non-migraine headaches. Very few subjects had high scores in the gastrointestinal and secretomotor domain, and none in the bladder domain. Lack of bladder symptoms is likely because this autonomic domain is mainly controlled by the caudal parasympathetic system. The absence of high scores in other autonomic domains suggests that headaches in adolescents may not be associated with a widespread dysautonomia. OI can be defined by the inability to tolerate the upright posture because of signs and symptoms that are relieved by lying down. OI is manifested by lightheadedness, blurred vision, decreased Table 1 COMPASS 31 domain high scores in subjects with headaches and controls. High Score (>50%) in COMPASS 31 Domain No. Headache N = 80 Control N = 12 P value Orthostatic intolerance 56 54 2.001 Vasomotor 18 17 1.44 Secretomotor 2 2 0.99 Gastrointestinal 9 8 1.99 Bladder 0 - - - Pupillomotor 28 27 1.09 Table 2 Subjects with high score on OI domain versus low scores and other subject characteristics. No. Total, N 92 OI High Score N = 56 OI Low Score N = 36 P value Gender, no. (%).002 Girls 65 46 (82.1) 19 (52.8) Type of headache, no. (%).005 No headache 12 2 (3.6) 10 (27.8) Migraine 50 35 (62.5) 15 (41.7) Tension headache 14 7 (12.5) 7 (19.4) Daily persistent 13 9 (16.1) 4 (11.1) Headache frequency (within 15 day period), no. (%) 7 days 50 36 (64.3) 14 (38.8). 017 Tachycardia >40 BPM, no. (%).95 Yes 13 8 (14.3) 5 (13.8) Syncope, no. (%).92 Present 19 13 (23.2) 6 (16.7) Total anxiety score, no. (%).10 High score 43 30 (53.6) 13 (36.1) Change in headache symptoms, no. (%) Transformation 60 30 (56.6) 30 (83.3) Worsening 25 20 (37.7) 5 (13.9) Improvement 2 1 (1.9) 1 (2.8) BPM, beats per minute.019 GHS Proc. June 2017; 2 (1): 20-25 23

Acknowledgment The authors acknowledge the valuable assistance of Nirav T. Patil, MBBS, MPH, who provided consultation and performed the statistical analyses. We are also grateful for the additional services provided by our clinic nurses. Abbreviations and Acronyms OI = orthostatic intolerance; POTS = Postural Orthostatic Tachycardia Syndrome; COMPASS = Composite Autonomic Symptom Scale; ASP = Autonomic Symptom Profile; SCARED = Screen for Children Anxiety Related Emotional Disorders; ICHD3 = International Classification of Headache Disorders 3; BPM = beats per minute Correspondence Address to: Augusto Morales MD, Greenville Health System, Department of Pediatrics, Division of Pediatric Neurology, 200 Patewood Dr, Suite A350, Greenville, SC 29615 (amorales@ghs.org) hearing, vertigo, and altered cognition. Some patients experience sudden syncope shortly after standing up or after prolonged standing. 12 OI may be the manifestation of multiple underlying mechanisms. OI is noted in subjects with migraine, dysautonomia, 13 peripheral neuropathy, 14 POTS, 15 chronic fatigue syndrome, 16 and genetic conditions. 17 OI can also occur after excessive recumbence, deconditioning, and hypovolemia. 18 OI symptoms are also noted in psychogenic dizziness. 19 The evaluation of patients with OI requires a methodical search for the mechanism involved as treatment will greatly depend on the etiology. 20 Bedside active orthostatic testing and Head-Up Tilt testing are frequently used to demonstrate orthostatic hypotension or orthostatic tachycardia. A tachycardia of more than 40 BPM is necessary for a diagnosis of POTS in adolescents. The scope of our study did not address all possible causes for OI. Orthostatic hypotension and postural orthostatic tachycardia were studied with active bedside orthostatic testing. Sixteen percent of our patients had orthostatic tachycardia, while 3% had orthostatic hypotension. Therefore, a small number of our subjects could be characterized as having POTS and having orthostatic hypotension. The rest of the subjects, despite having similar clinical profiles of subjects with POTS, could not be diagnosed with this condition. It is possible that they may have a milder, early, or similar form of this common autonomic condition. OI could also be the result of additional stress to the regulatory capabilities of the circulatory system imposed by frequent headaches. The questions of the COMPASS 31 focused on daily life OI symptom severity and References 1. Krogh AB, Larsson B, Linde M. Prevalence and disability of headache among Norwegian adolescents: a cross-sectional school-based study. Cephalalgia. 2015;35:1181-91. 2. Powers SW, Coffey CS, Chamberlin LA, et al. Trial of amitriptyline, topiramate, and placebo for pediatric migraine. N Engl J Med. 2017;376:115-23. 3. Blaauw BA, Dyb G, Hagen K, et al. The relationship of anxiety, depression, and behavioral problems with recurrent headache in late adolescence a Young- Hunt follow-up study. J Headache Pain. 2015;16:10. 4. Drummond PD. Relationships among migrainous, vascular, and orthostatic symptoms. Cephalalgia. 1982; 2:157-61. 5. Thijs RD, Kruit MC, van Buchem MA, Ferrari MD, Launer LJ, van Dijk JG. Syncope in migraine: the frequency do not address whether OI symptoms are related to headaches. The subjects with significant OI in our study had headaches of high frequency or worsening frequency, and the majority had migraine headaches. High headache/migraine frequency may cause excessive recumbence, deconditioning, and frequent vomiting that may lead to hypovolemia causing OI by these indirect mechanisms. Psychogenic issues are always a concern when dealing with patients with OI symptoms and refractory headaches. In our study, there were a large number of subjects with anxiety and panic/ somatic symptom disorders. Anxiety was present in patients with high OI scores and in patients with low OI scores and did not have a significant statistical effect. Conclusion In this study, OI was frequently noted in adolescents with headaches. The COMPASS 31 is an instrument that can be easily used in a busy clinic to identify and quantify OI. Girl patients with migraine headaches, high headache frequency, and worsening headaches were more likely to have OI. Early diagnosis of OI using minimally invasive procedures available in an outpatient clinic can provide the physician a better understanding of the usually complex problems that adolescents with headaches experience. Once OI has been identified, a careful evaluation may identify the mechanisms of OI in each patient, providing an additional treatment approach that is likely to improve the quality of life for the adolescent with headaches. population-based CAMERA study. Neurology. 2006;66:1034-7. 6. Khurana R, Eisenberg L. Orthostatic and non-orthostatic headache in postural tachycardia syndrome. Cephalalgia. 2010;31:409-15. 7. Yakinci C, Mungen B, Er H, Durmaz Y, Karabiber H. Autonomic nervous system function in childhood migraine. Pediatrics International. 1999;41:529-533. 8. Suarez GA, Opfer-Gehrking TL, Offord KP, Atkinson EJ, O Brien PC, Low PA. The autonomic symptom profile: a new instrument to assess autonomic symptoms. Neurology. 1999;52:523-8. 9. Sletten DM, Suarez GA, Low PA, Mandrekar J, Singer W. COMPASS 31: a refined and abbreviated composite autonomic symptom score. Mayo Clin Proc. 2012;87:1196-201. 24 GHS Proc. June 2017; 2 (1): 20-25

ORTHOSTATIC INTOLERANCE AND HEADACHES 10. Muris P, Merckelbach H, van Brakel A, Mayer B, van Dongen L. The screen for child anxiety related emotional disorders (SCARED): relationship with anxiety and depression in normal children. Personality and Individual Differences. 1998;24:451-6. 11. Huguet A, Tougas ME, Hayden J, et al. Systematic review of childhood and adolescent risk and prognostic factors for recurrent headaches. J Pain. 2016;17:855-73. 12. Stewart JM. Common syndromes of orthostatic intolerance. Pediatrics. 2013;131:968-80. 13. Grubb BP, Kosinski. Syncope resulting from autonomic insufficiency syndromes associated with orthostatic intolerance. Med Clin North Am. 2001;85:457-72. 14. Novak V, Freimer ML, Kissel JT, et al. Autonomic impairment in painful neuropathy. Neurology 2001;56:861-8. 15. Freeman R, Wieling W, Axelrod FB, et al. Consensus statement on the definition of orthostatic hypotension, neutrally mediated syncope and the postural tachycardia syndrome. Clin Auton Res.2011;21:69-72. 16. Stewart JM, Gewitz MH, Weldon A, Arlievsky N, Li K, Munoz J. Orthostatic intolerance in adolescent chronic fatigue syndrome. Pediatrics. 1999;103:116-21. 17. De Wandele I, Rombaut L, De Backer T, et al. Orthostatic intolerance and fatigue in the hypermobility type of Ehlers-Danlos syndrome. Rheumatology. 2016;55:1412-20. 18. Stewart JM Chronic orthostatic intolerance and the postural tachycardia syndrome (POTS). J Pediatrics. 2004;145:725-30. 19. Blad H, Lamberts RJ, van Dijk JG, Thijs RD. Tilt-induced vasovagal syncope and psychogenic pseudosyncope. Neurology. 2015;85:2006-10. 20. Qubty W, Kedia S. Dizziness and orthostatic intolerance in pediatric headache patients. Semin Pediatr Neurol. 2016;23:71-8. GHS Proc. June 2017; 2 (1): 20-25 25