ORIGINAL ARTICLE Evaluation of Orthostatic Hypotension: Relationship of a New Self-report Instrument to Laboratory-Based Measures CCunistine ScHREZENMAIER, MI JADE A. GEHRKING, Stacy M. Hines, BS; Prue A. Low, MD; Lisa M. Beneup-Larson, PHD); aND PaoLA SaNDRON!, MD, PHD COBJECTNE: To compare moasured autonomie deficits (composite ‘autonomic severity score (CASS}) with a brief seltreport scale ‘we developed to measure severity of symptoms of orthostatic Fypotension. PATIENTS AND METHODS: Patlents were recruited In 2 phases: ‘rom August to October 2002 and in April 2004. All patients Lnderwent fll evaluation in the autonomic laboratory, ftom which 2 CASS of autonomic deficits was derived. Pationts also com- pleted the Bitom seitreport Onthostatc Grading Seale, which Inguires about symptoms of orthostatic intolerance due to ortho- ‘stati hypotension (eg, severity, frequency, and interference with daly activities). RESULTS: OF 245 patients, 97 (67%) ha orthostatic hypotension, The S.item scale demonstiated strong intemal consistency (coet- ficlont a=.94). Patients with orthostatic hypotension had signif. ‘cantly higher seores on each questionnaire Hem and CASS sub- Scores than those without orthostatic hypotension. The scale Roms correlated significantly with each ofthe CASS subscores, ‘maximally withthe CASS adrenergic subscore. CONCLUSIONS: Orthostatc hypotension is not the only cause of reduced orthostatic tolerance, and some patients may have ortho- Stati hypotension but be asymptomatic. Results of this study Indieate that this Sitem questionnare Is a reliable and valid measure of the severity of symptoms of orthostatic hypotension ‘and that It can supplement laboratory-based measures to provide 2 rapid, more complete clincal assessmont. This questionnaire would also be useful 23 brel screening device for orthostatic Intolerance to ai physicians in identifying patients who may have ‘orthostatic hypotension. rthostatic intolerance is a relatively common condi- tion for which patients are referred for evaluation in the autonomic laboratory. Although orthostatic intolerance is often thought to be synonymous with orthostatic hypo tension, the 2 conditions are not always concurrent. Some patients have orthostatic intolerance without orthostatic hypotension, such as those with postural tachycardia syn- drome’; conversely, some patients with orthostatic hy- potension may not have symptoms of orthostatic intoler- ance because of expanded cerebral autoregulation that maintains adequate cerebral perfusion despite a decrease in ‘blood pressure (BP). A standardized laboratory-based scale® developed by fone of the authors (P.A.L.) to measure the severity of 30 Mayo Cin Proc. * March 2005;803}:330:334 + autonomic deficits by using autonomie function tests and 2 comprehensive self-report questionnaire® assessing auto- ‘nomic symptoms in general have been validated, However, no study has specifically evaluated the relationship be- tween the severity of orthostatic intolerance due to ortho- static hypotension as perceived by patients (symptoms) and | our laboratory-based scoring system (deficits). We posit | that the frequency and severity of symptoms of orthostatic intolerance are overall highly correlated with the degree of adrenergic dysfunction. To test such a hypothesis, we com- pared the laboratory-measured autonomic deficits (com- posite autonomic severity score [CASS with a brief self- report scale we developed to rate the severity of orthostatic intolerance PATIENTS AND METHODS Data were collected in 2 stages. In the first stage, we collected data from a consecutive series of patients with neurogenic orthostatic hypotension who were seen in the Mayo Clinic Autonomic Reflex Laboratory in Rochester, ‘Minn, from August to October 2002. Orthostatic hypoten- sion was defined as a sustained reduction in systolic BP of 20 mm Hg or greater within 3 minutes of head-up tilt The second stage consisted of a consecutive series of patients referred to the Mayo Autonomic Reflex Laboratory in April 2004, except for those referred for complex regional pain syndrome (who undergo a different set of tests). These patients may or may not have had orthostatic hypotension, Reasons for referral included spells, peripheral neuropa- thies, gastrointestinal dysmotility problems, dizziness, fa- tigue, and autonomic disorders in general (proved or sus- pected). Demographics and medication information were 1th Ruanonie Dsorers Center, Deparment of Newog. Moyo Cie allege of Medel, Rocreste, Mon. Dr Sevenenm row wth od Masrilans Unersiy, Munich, Gormary ‘oe sty was supsotedn pat by grants 823 BRASS? (PS), NS32862, 1nS42253, ana NSAGS04 (PAL), ard T32 HOOTAAT (LM.8.L) fom the Naconalisttutes of eats and MOL RRODGES ror the Mayo ine Gone {ines Reser Canter idl opis of this tie ate not vale Aatress cotespandece to aol Sandor, MD, 0, auton Dror Cone, Mayo Cine Coes Wetcine, 200 Fret St SW, Roatestr, MN S905 (ermal: pseoren enaroe (©2005 Mayo Foundation for Model Paton and Research mayocinicproceedngs.comextracted from the medical records. Additionally, the labo- ratory staff routinely reviewed medication status at the time of testing, All patients completed a standardized Autonomic Re- flex Seren (ARS) that includes continuous noninvasive monitoring of heart rate and BP during 5 minutes of supine rest, followed by 5 minutes of hend-up tilt (70°) ‘The ARS consists of a battery of noninvasive laboratory tests of known sensitivity, specificity, reproducibility, and clinical elevance used to evaluate cardiovagal, adrenersi ‘and postganglionic sudomotor function The severity of autonomic deficit, quantified for each participant using ARS, was converted to CASS, which corrects for the con- founding effects of age and sex. Participants also com- pleted a 5-item questionnaire (Self-report Orthostatic Grading Seale [OGS]) that we developed to provide a subjective grading scale of the severity of orthostatic intol- cance in patients with orthostatic hypotension. Our auto- nomic laboratory technicians were available to answer any ‘question that the patients may have had while completing the questionnaire Miasunes Orthostatic Grading Scale, Our S.item self-eport questionnaire was designed on the basis of questions rou- tinely asked by clinicians and researchers specializing in autonomic disorders during initial consultation with pa- tients who have orthostatic hypotension. The 5 questions address frequency and severity of orthostatic symptoms, relationship of symptoms to orthostatic stressors, and the impact of symptoms on activites of daily living and stand- ing time (Table 1). Respondents rate each item on a scale cof 0 to 4. Adding the scores forthe individual items creates total score. ‘Composite Autonomic Severity Score. We quantified severity of autonomic deficit with the objective 10-point CASS (Appendix 1), which is based on ARS. Primary components include the quantitative sudomotor axon re- flex test, orthostatic BP and heart rate responses t tlt, heart rate response to deep breathing, the Valsalva ratio, and beat-to-beat BP response to the Valsalva maneuver, tlt, and deep breathing. The range for CASS is 0 (no deficit) to 10 (maximal deficit). Patients with a subscore of 3 or less on CASS have mild autonomic failure, those with subscores of 7 to 10 have severe autonomic failure, and those with scores between these 2 ranges have moderate autonomic failure. ‘StarisicaL ANALYSES ‘We evaluated the internal consistency of the OGS with coefficient cand used factor analysis to examine the factor structure of the scale, Descriptive statistics include mean EVALUATION OF ORTHOSTATIC HYPOTENSION TABLE 1. Settreport Orthostatic Grading Seale T. Frequency of orotate symptoms 0 never or rarely experince orotic symptoms when T stand up 1 Lsometines experience orthostatic symptoms when Tstsbd 9p 2 Leften experience onbosatic symptoms when I standup 5 Lunualy expenence onhost smptons when Tsp 4 Latways experience onhosttie symp when I stand uP 2. Severity of onhostatc symptoms ° 1 To notexpesence eres syptons when I standup experience mild orthostatic symptoms whe I tnd up experience moderate orthostatic symptoms when | stand up and Sometimes have casi back down for eit experience severe ones symptoms when [standup and “Fequenty ave to sit back down fori 4 Toxpiiene severe orbostte symp whea Tstnd up and ‘lary fin it do noes ack down Conditions ender which orthostatic symptoms accur (0 Tnever or arety experience ortostatc symptoms under any 1 Liometimes experience onthastati symptoms under cern ‘ondtions, soch as profonged standing, 2 mel, exertion (Ga, walking) or when exposed to heat 3, ot day ot bah, hotshowes) 1 often experience etostatc symptoms under cetan conditions, Sich as prolonged standing, a meal, exertion (e, walking), thon exposed to het (a, hot day, ht ba, Ao shower) Tuuatly experience ontosttesympoms wader certain “onditions, ch as prolonged staring, 2 mel, xerion (ce, walking) ce when exposed teat ep, hot day ot bath, tot shower) 4 Lalwess experience cethostae symptoms when I and up the ‘peciic editions do no mater 4. Aesvtes of dai ving 10 My ortostatic symptoms do no imterfre wit ati of ily Tivng (eg, work, chores, dressing, thing) 1 My ontostticsympoms mid interfere with stv of daily living (eg, work, chores, dessing uthing) 2. My orthostatic syroplons moderately inefere with activites of duly living eg, work, chores, dressing, ating) ‘3 My orthostatic symptoms severely interfere with activities of daily ving eg, Woek chores, cessing, bashing) 44 Myonhostatc symptoms severely inerire wit cies of dhl ving (ep, work chores, desing, bathing) 1am ed or wheelchair ound Because o ny symone 5. Standing time (0° On mort occasions, I cn stands long a neestry without experiencing enbosiaic symptoms 1) Onmost occasions, Lean stand more than 15 minate fore ‘experiencing oosatic symptoms 2 Onmoxt occasions, can tan 5-14 minutes before experiencing ott symptoms 3. Onmost occasions. Tan stand 1-4 mime before experiencing those symptoms 4 On most occasions, can stand es than minute before xpeiening oostati syptoms (SD) for the OGS and median (interquartile range) for CASS. The / test was used to examine group differences on the OGS, and the Wilcoxon rank sum test was used (0 ‘examine group differences on CASS. Spearman correla- tions were used to examine the relationship among the OGS items, CASS subscores, and systolic BP response to hhead-up tilt. P<.0S was considered statistically significant. [Mayo Clin Proc. + March 2005;80/3):530-334 + www mayoctinicproceedings com 331_EVALUATION OF ORTHOSTATIC HYPOTENSION TABLE 2, Vales on the Orthostatic Grading Scale and ‘Composite Autonomic Severity Score for Patients ‘with and Without Orthostatte Hypotension* ‘Oreste hypotension With Witout G57) rs) Pale 196(132) 085¢.03) — <001 Tsc93) 190¢105) — <001 198035 08303) <001 E75(132)052(080) — <001 191d) 123168) “OL 9320546) $4415.10) <001 Composite Avionomic Seventy Score, median (Goterquar ans Sodooior 200(200) 0.00100) .05). However, the treated group scored significantly higher on all 5 questionnaire items (Gable 4). We also compared patients with orthostatic hy- potension who were taking drugs known to cause ortho- static hypotension vs those who were not. The 2 groups did not differ significantly on any of the 5 questionnaire items (for all, P>-05), The group not taking medications the could cause orthostatic hypotension had a higher CAS adrenergic subscore (median, 3.00 vs 2.00; P=.02). There were no significant differences in CASS cardiovagal or CASS sudomotor subscores between the 2 groups. DISCUSSION ‘To our knowledge, this isthe first study to compare a self- report grading scale for orthostatic intolerance in patients with putative orthastatic hypotension to laboratory-mea- sured composite score of autonomic deficits. The simple 5- item questionnaire proved (© be of good intemal consis- tency and demonstrated a unitary factor structure. It also ‘had robust correlations with autonomic deficits (CASS), resulting in good sensitivity and specificity compared to the CASS adrenergic subscore, The strongest correlation was, as expected, with the CASS adrenergi¢ subscore, followed by the cardiovagal subscore and then the sudo- ‘motor subscore. The correlation between the questionnaire and sudomotor function may appear surprising because sudomotor function certainly does not affect orthostatic tolerance. However, adrenergic failure in most patients is March 2005;90(3):330-334 + www mayoclincprocedings.com[EVALUATION OF ORTHOSTATIC HYPOTENSION TABLE 3. Spearman Correlations forthe Orthostatie Grading Seale Items, Systolle Blood Pressure Response to Head Up Tit, ‘and Composite Autonome Scoring System Subscores (N=145)" Change Orthotic esting systolic ee Gnding Sak, e blood pressuret- Compost As Seoring Sis quston 123 S—Toul_ (aug) Sudomotor Cariowagal_ Adrenergic Toul 1 re a ae 18 26 364 res 2 Te Th aT 218 215 36t ae Rt 3 on a9 is 22s Bat ait 4 oH ast 8 30 38h ag aR 5 sit ‘00 15 175 20523 ‘To 16 23 tt ao att equency of sympromsy 2 = seve of symptoms; 3 = symptoms with onhosae sree, 4= inerfesnee wih acer of dally ving 5 = standing ime {Prom basin to heap it at 70°. spe peas. part of generalized autonomic failure; thus, cardiovagal and sudomotor deficits occur concurrently. Among the 5 items on the questionnaire, the level of interference with activities of daily living showed the strongest correlation, ‘with the CASS subscores. This information emphasized the impact that orthostatic hypotension has on patients’ activi- ties of daily living since we specifically asked patients to rate solely how orthostatic hypotension/orthostatic intoler~ tance affects their activities of daily living. However, some ‘patients, such as those diagnosed as having multiple system atrophy or Parkinson disease, may have severe extrapyra- ‘midal and other neurologic deficits (such as postural insta- bility) that may render it difficult to isolate the effect of orthostatic hypotension from symptoms due to these defi cits. Therefore, we expected a less robust correlation with this specific item. Conversely, the weakest correlation oc- curred between standing time and CASS subscores. This could be explained by the fact that symptoms of orthostatic hypotension are due to cerebral hypoperfusion, Patients who develop orthostatic hypotension slowly may adjust © itthrough expansion oftheir cerebral autoregulation range! and may remain asymptomatic despite major orthostatic changes. ‘Of note, orthostatic hypotension isnot the only cause of reduced orthostatic tolerance. Because the purpose of the questionnaire was to evaluate orthostatic symptoms due to orthostatic hypotension specifically, we excluded patients ‘who had orthostatic intolerance due to postural tachycardia syndrome. A few patients with normal tests reported orthostatic intolerance that was thought to be due to pos- tural instability, vertigo, or metabolic abnormalities or to a nonorganic basis. As we had presumptive but no definite diagnosis, these patients were included in the analysis (in the group without orthostatic hypotension) ‘Medications can ameliorate, aggravate, or occasionally ccause orthostatic symptoms. For autonomic function tests, Mayo Clin Proc. + Marek 2005;80(3):330-334 + patients are instructed to discontinue any medication known to affect BP or sweating before being tested in the autonomic laboratory. Nonetheless, such medications could potentially affect the self-reported orthostatic symp- toms. Of interest is the observation that patients who re- ceived treatment for their orthostatic hypotension symp- ‘toms scored significantly higher on the questionnaire than those who did not, although the 2 groups did not differ in their autonomic deficits (CASS). Such a finding is not surprising and likely reflects the fact that the decision to treat orthostatic hypotension is often based on patients” TABLE 4 Values onthe Orthostatic Grading Seale ‘and Composite Autonomie Seveity Score {or Patients With Orthostatc Hypotension Who Are or Aro Not Taking Antinypotonsive Medication* ‘Onhostati ypovension ‘Taking Not uking medietion medision 8) (069) Pale ‘rosie Grading Scaled ‘nein (SD) 7 2maoy 1650.32)