SMALL-FIBER NEUROPATHY WITH CARDIAC DENERVATION IN POSTURAL TACHYCARDIA SYNDROME CARL-ALBRECHT HAENSCH, MD,1 MARCO TOSCH, MD,2 ISTVAN KATONA, MD,3 JOACHIM WEIS, MD,3 and STEFAN ISENMANN, MD4 1
Department of Neurology, Kliniken Maria Hilf M€ onchengladbach, Faculty of Health, University of Witten/Herdecke, Viersenerstrasse 450, D-41063 M€ onchengladbach, Germany 2 Department of Nuclear Medicine, HELIOS-Klinikum Wuppertal, University of Witten/Herdecke, Witten, Germany 3 Institute of Neuropathology, Medical Faculty, RWTH Aachen University, Aachen, Germany 4 Autonomic Laboratory, Department of Neurology and Clinical Neurophysiology, HELIOS-Klinikum Wuppertal, University of Witten/ Herdecke, Witten, Germany Accepted 18 March 2014 ABSTRACT: Introduction: Postural tachycardia syndrome (POTS) is a disorder of orthostatic intolerance characterized by excessive tachycardia of unknown etiology. Our objective in this study was to evaluate the correlation between C-fiber involvement as shown by skin biopsy and adrenergic cardiac metaiodobenzylguanadine (MIBG) uptake in POTS patients. Methods: Skin biopsies of 84 patients with POTS were examined by Protein Gene Product 9.5 (PGP9.5) immunohistochemistry and were compared with MIBG myocardial scintigraphy imaging data. Results: Mean intraepidermal nerve fiber (IENF) density was in the lower normal age-adjusted range, 7.2 6 2.9/mm (normal 7/mm), and was slightly below the normal range in 45% of POTS patients. MIBG uptake was reduced in 21% of patients. Low IENF density correlated with reduced cardiac MIBG uptake (r 5 0.39, P 5 0.001). Conclusions: A subset of neuropathic POTS patients may harbor mild small fiber neuropathy with abnormalities of unmyelinated nerve fibers in the skin associated with reduced myocardial postganglionic sympathetic innervation. Muscle Nerve 50: 956–961, 2014
Postural orthostatic tachycardia syndrome (POTS) is defined in patients by an excessive increase in heart rate by >30 beats/minute within 10 minutes of becoming upright, or to absolute levels of >120 beats/minute without a gradual drop in blood pressure. It is associated with symptoms of orthoThese include lightstatic intolerance.1,2 headedness, weakness, palpitations, tremulousness, and, in more severe cases, presyncope and syncope. POTS can be quite debilitating due to significant limitations in activities of daily living. Young, otherwise healthy women are most commonly affected. The pathogenetic mechanism of the condition is unclear. Several major subtypes of primary POTS have been described. The majority of patients with POTS have preserved autonomic
Abbreviations: BP, blood pressure; HM, heart/mediastinum; HR, heart rate; IENF, intraepidermal nerve fiber; MIBG, metaiodobenzylguanine; NET, norepinephrine transporter; POTS, postural tachycardia syndrome; PGP9.5, Protein Gene Product 9.5; SPECT, single-photon emission computed tomography; VM, Valsava maneuver Key words: autonomic disorder; cardiac denervation; orthostatic intolerance; postural tachycardia syndrome; small fiber neuropathy Correspondence to: C.-A. Haensch; e-mail: carl-albrecht.haensch@ mariahilf.de C 2014 Wiley Periodicals, Inc. V
Published online 20 March 2014 in Wiley Online Library (wileyonlinelibrary. com). DOI 10.1002/mus.24245
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function. Neuropathic POTS comprises a subgroup with length-dependent denervation of sympathetic fibers of the lower extremities.3,4 Thermoregulatory sweat testing may provide evidence of small fiber neuropathy. Abnormalities of sudomotor autonomic function could reflect an underlying neural deficit that also impairs cardiovascular autonomic innnervation. Impaired postganglionic sudomotor function indicates autonomic C-fiber involvement. One study using sympathetic microneurography in POTS suggested sympathetic denervation.5 Scintigraphy with 123I-metaiodobenzylguanidine (MIBG) visualizes and quantifies sympathetic innervation in vivo and reflects the relative distribution of adrenergic neurodensity and function.6 Because MIBG structurally resembles norepinephrine, it enters neuroendocrine cells by an active uptake mechanism and is stored in the neurosecretory granules, resulting in a specific concentration in contrast to cells of other tissues. MIBG reflects uptake and storage in postganglionic and presynaptic terminals similar to those of the endogenous neurotransmitter norepinephrine. Cardiac MIBG scintigraphy allows autonomic neuropathy to be detected in the early stages of diabetes mellitus, familial amyloid polyneuropathy,7 and Parkinson disease.8 Recently, we showed reduced myocardial uptake of MIBG in 20% of POTS patients, indicating dysfunction of postganglionic adrenergic innervation.9,10 Protein Gene Product 9.5 (PGP9.5) immunohistochemistry of skin biopsies has emerged as a valuable tool to analyze autonomic innervation morphologically.11,12 The loss of autonomic nerve fibers was shown in Ross syndrome and in familial dysautonomia (Riley–Day syndrome)13 and other peripheral neuropathies.14–25 Measurement of intraepidermal axon density is now used to diagnose neuropathies and to assess the distribution and severity of denervation.26 In a study of a small group of 8 POTS patients, intraepidermal nerve fiber (IENF) density was in the normal range, but 3 of the 8 had some morphological abnormalities, including bulbous swelling of intraepidermal unmyelinated fibers.14 MUSCLE & NERVE
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In this study we investigated whether C-fiber involvement and cardiac denervation could be detected in a larger retrospective cohort of POTS patients. Our second objective was to evaluate the correlation between C-fiber involvement, as shown by skin biopsy and adrenergic cardiac MIBG uptake. METHODS
In a retrospective study, a total of 84 patients were included who had been referred for evaluation of chronic orthostatic intolerance to the Autonomic Laboratory of the Department of Neurology, HELIOS-Klinikum Wuppertal, University of Witten/Herdecke between 2009 and 2012 (Table 1). A diagnosis of POTS was made by the presence of orthostatic intolerance symptoms associated with a heart rate increase of 30 beats/min or a rate that exceeded 120 beats/min within the first 10 minutes of standing or upright tilt in the absence of other chronic debilitating disorders, prolonged bed rest, or medications that could impair vascular or autonomic tone. Clinical examination was normal in all patients. The patients did not take any medication except for oral contraceptives. No patient had diabetes or previous cardiac disease. All patients had normal blood cell counts, electrolyte analysis, and resting electrocardiography. Twenty-four-hour urinary sodium secretion was estimated to exclude hypovolemia. The primary endpoint of the study was to evaluate the decrease in IENF density and to correlate small fiber neuropathy with reduced cardiac MIBG uptake. The cardiovascular autonomic function tests were based on blood pressure and heart rate at rest and after various stimulations under standardized environmental conditions at 20 C. All tests were performed in the morning after fasting for 4 hours. All patients abstained from tobacco and caffeine use on the day of the study. Patients took no dietary supplements. Finger arterial pressure was measured beat-to-beat continuously and noninvasively using the volume clamp method with the Portapres device (TNO TPD, Amsterdam, The Netherlands). The cuff was placed on the second phalanx of the third finger. A synchronous recording of a standard 4-channel electrocardiograph and respiratory effort measured by thoracic strain gauges and of the Portapres signal were performed simultaneously with a FAN device (Schwarzer GmbH, Munich, Germany). The FAN device records heart rate variability based on the standard recording techniques and algorithms used in autonomic function studies.27 After a 5minute rest phase, head-up tilt-table testing at a Autonomic Testing.
Postural Tachycardia Syndrome
Table 1. Demographic and clinical data. Number of patients
84
Mean age (years) Men/women Heart rate supine (bpm) Heart rate upright (bpm) Heart rate change (bpm) Hyperadrenergic POTS Valsalva ratio Systolic blood pressure increase, phase IV, Valsalva maneuver (mm Hg)
28 6 10.5 25/59 75 6 11.2 121 6 13.4 45 6 10.2 24 2.01 6 0.42 34 6 20
70 upright position within 20 seconds with an electrically driven tilt-table was performed for 10 minutes. Hyperadrenergic POTS was defined as POTS associated with a systolic blood pressure (BP) increment 10 mm Hg during tilt-table testing in the 70 position.28 The Valsalva maneuver (VM) was performed by asking the subjects to blow into a mouthpiece attached to an aneroid pressure gauge at a pressure of 40 mm Hg and to endure pressure for 15 seconds. The VM was performed with the patient supine. The subjects performed a series of maneuvers until 2 reproducible arterial blood pressure responses were obtained. The Valsalva ratio of heart rate (HR) was calculated from the maximum HR during or shortly after straining and the minimum HR in the overshoot phase IV. Systolic blood pressure increase in phase IV was assessed and compared with baseline average BP for each patient. Between each test, a return of cardiovascular parameters to baseline was awaited.29–31 MIBG Scintigraphy. Myocardial adrenergic function was analyzed by imaging with MIBG using the SPECT technique. For imaging of cardiac adrenergic innervation, scintigraphy was performed by injection of 180 MBq MIBG (GE Healthcare Buchler, Braunschweig, Germany) after blocking iodine uptake in the thyroid gland with a total of 300 mg perchlorate. To allow for clearance of non-specific tissue uptake, data were acquired 5 hours after injection. After obtaining a planar static image, single-photon emission computed tomography (SPECT) was performed using a dual-headed gamma camera (Hawkeye; GE Medical Systems, Solingen, Germany) equipped with low-dose computed tomography for image fusion and correction of attenuation (which was not used in this study). Thirty projections of 40 seconds each were acquired over a 180 rotation. The data were stored in a 64 3 64 matrix and reconstructed iteratively. Cardiac MIBG uptake was assessed qualitatively for heart visualization on planar studies by nuclear medicine specialists who were unaware of the autonomic function status. On the planar MUSCLE & NERVE
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images, regions of interest were drawn over the heart and mediastinum by 3 independent investigators to calculate the heart/mediastinum (H/M) ratio. The mediastinum is used as reference in our laboratory because it contains few sympathetic nerves. MIBG uptake was measured, on average, after 5:05 hours (range 4:36–5:28 hours). The H/M ratio was compared with the normal range of >1.7, as derived from earlier investigations.6,9 Reproducibility of the region drawings by 3 independent investigators is high, with a maximum error of about 5%. Three-millimeter skin punch biopsies were obtained approximately 15 cm proximal to the left lateral malleolus. The specimens were fixed in Zamboni solution and processed using standard diagnostic protocols, as described elsewhere.13,32 In short, in all cases, 6 consecutive 40– 50-lm cryostat sections were stained against PGP9.5 (rabbit polyclonal antibody; Ultraclone, UK). Immunoreactivity was visualized using Alexa Fluor 488 (Invitrogen)-labeled goat anti-rabbit secondary antibodies. IENF density was determined according to standardized counting rules described elsewhere,33 counting only continuous fibers that clearly cross the epidermal basement membrane to the epidermis. Epidermal length was measured using the scale bar in the microscope eyepiece calibrated with a standardized scale bar slide, and the IENF density was calculated. Patients with IENF density lower than the fifth percentile of the appropriate age and gender group, as determined from the literature, were considered to have small fiber neuropathy.34 In addition, the number of axons showing focal swellings >1.5 lm in diameter was counted. The presence of such swellings can be observed in many if not all skin biopsies, and we consider it normal if it affects 1.5 lm, and 6 of these patients (13%) showed swelling ratios >10%. For sweat gland innervation, a severe reduction was found in 7 patients, which correlated more closely with reduced MIBG uptake (2.08 vs. 1.80; P 5 0.001) and low IENF density (7.5 vs. 3.59; P < 0.001). IENF density showed a mild correlation with age [odds ratio 1.06 (1.01–1.11); P 5 0.009]. The swelling ratio (number of axons with swellings >1.5 lm / number of all intraepidermal axons) did not correlate with MIBG uptake or results of the autonomic function tests. MIBG uptake after 5 hours was reduced in 21% of patients compared with the normal range for heart/mediastinum ratio, 1.7. Low IENF density correlated with reduced cardiac MIBG uptake (Spearman r 5 0.39, P 5 0.001, 2tailed; Fig. 1). The degree of accordance between the 2 methods was slight (kappa 5 0.105). The odds ratio for a pathological finding due to age was 1.06 for IENF density (P 5 0.009) and 1.02 for MIBG uptake (not statistically significant). No correlation was found for MIBG uptake and age. Multivariate analysis of heart rate at rest and during tilt-table testing indicated no significant risk factor for abnormal IENF density or reduced MIBG uptake. Patients with hyperadrenergic POTS had significantly lower IENF density (5.56 vs. 7.82; P 5 0.001) and MIBG uptake (1.88 vs 2.13; P 5 0.01). Clinically, only nausea was found more often in POTS patients with reduced IENF density (Table 2). MUSCLE & NERVE
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Table 2. Characteristics of POTS patients with and without reduced cardiac MIBG uptake and low IENF density. POTS patients
Number of patients Mean age (years) Men/women Duration of illness (months) Dizziness Light-headedness Presyncope Fatigue or weakness Chest pain Syncope Headache Palpitations Exercise intolerance Decreased concentration Tilt-table–induced syncope Nausea Blurred vision
Cardiac MIBG uptake
Cardiac MIBG uptake and IENF density
IENFD
All
Reduced
Normal
Reduced
Normal
Reduced
Normal
84 28 25/59 14.9 77 34 28 8 8 31 20 35 7 2 4 21 18
18 31 4/14 19.0 17 7 4 1 3 10 6 10 1 1 0 9 2
66 28 21/45 13.8 60 27 24 7 5 21 14 25 6 1 4 12 16
37 31 14/23 9.9 35 15 11 3 3 12 11 13 3 1 1 14* 8
47 26 11/36 18.8 42 19 17 5 5 19 9 22 4 1 3 7 10
10 29 3/7 11.4 10 3 1 0 1 4 4 6 1 1 0 6 1
39 24 10/29 16.9 35 15 14 4 4 13 7 18 4 1 3 4 9
*Significant difference from normal group (t-test, 2-tailed; P 5 0.02).
DISCUSSION
This study was designed to correlate the sympathetic and somatic C-fiber innervation of the epidermis and myocardial 123I-MIBG uptake for cardiac sympathetic neuroimaging in POTS patients. The original idea follows recently published studies in which these techniques were applied to study the sympathetic innervation in other neurological diseases. Recently, we described altered sympathetic cardiac innervation as demonstrated by MIBG myocardial scintigraphy in 20% of POTS patients.9 Our results have been confirmed in this study with a larger cohort in which we noted a reduced MIBG uptake in 21% of patients. Diminished MIBG myocardial uptake indicates reduction of local myocardial sympathetic innervation. Several clinical observations have suggested the presence of distal denervation.33 In addition, abnormal quantitative sudomotor axon reflex test results indicated postganglionic sympathetic dysfunction. Epidermal skin biopsy using anti-PGP9.5 immunohistochemistry is a useful test for investigation of small-caliber sensory nerves, including autonomic nerve fibers in peripheral neuropathies.12,13,15 IENF density was below threshold in 45% of POTS patients. Increased numbers of focal epidermal axon swellings were observed in 6 of 47 patients at a time when IENF density was (still) in the normal range in many patients, suggesting an early stage of degeneration of the affected fibers. We found a modest age-related decrease of skin innervation, which is in line with IENF density studies done on control groups.12,34–36 Sweat gland innervation is predominantly sympathetic Postural Tachycardia Syndrome
cholinergic, not sympathetic adrenergic, but it may be associated more closely with a diffuse autonomic neuropathy. The reductions of MIBG uptake and IENF density were mostly quite mild. It is possible that the combination of both abnormalities, especially when mild, is not very common or is difficult to assess with currently available methodology. In addition, the correlation between reduced MIBG uptake and low IENF density, although statistically significant, was relatively modest (Spearman r 5 0.39, P 5 0.001, 2-tailed). This may suggest that the disorder involves not only autonomic but also somatic C-fibers. It is theoretically possible that abnormal function of the norepinephrine transporter (NET) itself may lead to similar findings in POTS patients who have failed to accumulate MIBG. However, NET dysfunction is rare.37 Moreover, decreased (albeit slightly) innervation of the skin encourages the view that we have identified a partial sympathetic dysfunction.37–40 POTS is currently defined as a syndromic dysautonomia with a change in autonomic nervous system function. The exact causes of POTS are unknown. It is almost certainly a heterogeneous disorder with variable etiology and pathophysiology.41 In POTS, orthostatic intolerance seems to be associated with a “patchy” dysautonomia, which results in orthostatic pooling of blood in the splanchnic and dependent circulations and activation of the remaining cardiac sympathetic system, causing tachycardia upon standing.42 Most attempts to explain the pathophysiology of POTS have focused on an increased release or other abnormalities in synaptic clearance of norepinephrine in response to the change from a supine to MUSCLE & NERVE
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an upright position.40 Genetic or acquired deficits in norepinephrine inactivation may underlie hyperadrenergic states that lead to orthostatic intolerance. The results of sympathetic skin response and quantitative testing of the sudomotor axon reflex suggest that autonomic denervation of the legs may be another underlying mechanism.42 Distal autonomic C-fiber status was examined histologically by Singer et al. in skin biopsies from a group of 8 POTS patients.14 IENF density was found to be normal in their group, but normative values were different at that time compared with those in use now. Nevertheless, most of the nerve fiber density values considered abnormal in our study were only slightly below the normal range. Results of a recent study on a smaller group of POTS patients demonstrated that about half (9 of 20) had mildly reduced IENF,43 which is in line with the results obtained from our larger cohort. In the recent article by Gibbons et al.,43 the results of an analysis of axonal swelling density were not reported; however, in the study by Singer et al.,14 3 of 8 biopsies showed some morphologic skin nerve fiber abnormalities. These included bulbous swellings of intraepidermal unmyelinated axons. Such swellings were also increased in number in a subset of patients in our study. It has been recognized increasingly that such swellings may be present in normal subjects, although normative values have thus far not been established clearly. Still, application of an arbitrary threshold of 10% revealed that 13% of the POTS patient biopsies available for this analysis showed a considerable increase in the number of such swellings.32 Taken together, skin biopsy results indicate that minor abnormalities in skin innervation exist in a subgroup of POTS patients. The finding of hypersensitivity to infusion of norepinephrine into veins of the foot, despite high plasma catecholamine concentrations, suggests that denervation hypersensitivity of the veins of the legs is involved.42,44 Carson et al. showed that a selective peripheral noradrenergic lesion can result in an elevated heart rate in rats.45 They suggested that loss of distal sympathetic innervation could produce an exaggerated sympathetic response in innervated tissues such as the heart, resulting in tachycardia. b-Adrenergic supersensitivity has been proposed as a mechanism of POTS and, indeed, bsupersensitivity to the chronotropic effects of isoproterenol has been reported. Therefore, the sympathetic denervation of the heart that was detected by MIBG SPECT in POTS patients may produce supersensitivity of the heart itself with exaggerated tachycardia while standing. This study is limited by its retrospective nature and potential referral bias. In addition, a more 960
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thorough quantification of the changes in autonomic innervation could include a semiquantitative analysis of dermal blood vessel walls, of the arrector pili muscles, and of hair follicles, as well as quantitative evaluation of sweat gland innervation.46 The skin biopsy study was also limited by the fact that only half of the skin biopsies (47 of 84) were available for detailed quantitative analysis of axonal swellings. MIBG SPECT was not performed with attenuation correction, and the SPECT data were used only to visualize the heart. No semiquantification (e.g., compared with a normal group, segmentation, etc.) was performed. The H/M ratio was measured only on planar images. In some instances, higher uptake in the myocardium may be caused by uptake in the left lobe of the liver. It is possible that the results could show higher sensitivity and specificity if the SPECT images were used for the quantification (without overlay by liver, etc.). These technical questions will need to be investigated in a future study. In conclusion, in this study we have demonstrated morphological and functional evidence supporting the notion that mild neuropathic changes contribute to the development of POTS in a considerable percentage of patients. Autonomic evaluation, including MIBG SPECT and skin biopsy, may be useful to identify patients who belong to this neuropathic POTS subgroup. These results underscore the heterogeneity of POTS. The statistical analysis was performed with the support of H. Niggemann, commercial statistician in Jena, Germany. REFERENCES 1. Haensch CA, Isenmann S. Postural orthostatic tachycardia syndrome: current concepts in pathophysiology, diagnosis and therapeutic options [in German]. Fortschr Neurol Psychiatry 2011;79:117–122. 2. Grubb BP, Kanjwal Y, Kosinski DJ. The postural tachycardia syndrome: a concise guide to diagnosis and management. J Cardiovasc Electrophysiol 2006;17:108–112. 3. Kimpinski K, Figueroa JJ, Singer W, Sletten DM, Iodice V, Sandroni P, et al. A prospective, 1-year follow-up study of postural tachycardia syndrome. Mayo Clin Proc 2012;87:746–752. 4. Schondorf R, Low PA. Idiopathic postural orthostatic tachycardia syndrome: an attenuated form of acute pandysautonomia? Neurology 1993;43:132–137. 5. Bonyhay I, Freeman R. Sympathetic nerve activity in response to hypotensive stress in the postural tachycardia syndrome. Circulation 2004;110:3193–3198. 6. Haensch CA, Lerch H, Jorg J, Isenmann S. Cardiac denervation occurs independent of orthostatic hypotension and impaired heart rate variability in Parkinson’s disease. Parkinsonism Relat Disord 2009;15:134–137. 7. Nagasaka T, Togashi S, Watanabe H, Iida H, Nagasaka K, Nakamura Y, et al. Clinical and histopathological features of progressive-type familial amyloidotic polyneuropathy with TTR Lys54. J Neurol Sci 2009;276:88–94. 8. Haensch CA. Heart trouble comes early in Parkinson’s disease before blood pressure falls. Eur J Neurol 2011;18:201–202. 9. Haensch CA, Lerch H, Schlemmer H, Jigalin A, Isenmann S. Cardiac neurotransmission imaging with 123I-meta-iodobenzylguanidine in postural tachycardia syndrome. J Neurol Neurosurg Psychiatry 2010; 81:339–343. 10. Haensch CA, Lerch H, Jigalin A, Schlemmer H, Isenmann S. Cardiac denervation in postural tachycardia syndrome. Clin Auton Res 2008; 18:40–42.
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29. Vogel ER, Sandroni P, Low PA. Blood pressure recovery from Valsalva maneuver in patients with autonomic failure. Neurology 2005; 65:1533–1537. 30. Vogel ER, Corfits JL, Sandroni P, Sletten DM, Benarroch EE, Fealey RD, et al. Effect of position on valsalva maneuver: supine versus 20 degree position. J Clin Neurophysiol 2008;25:313–316. 31. Sandroni P, Benarroch EE, Low PA. Pharmacological dissection of components of the Valsalva maneuver in adrenergic failure. J Appl Physiol 1991;71:1563–1567. 32. Weis J, Katona I, Muller-Newen G, Sommer C, Necula G, Hendrich C, et al. Small-fiber neuropathy in patients with ALS. Neurology 2011;76:2024–2029. 33. Peltier AC, Garland E, Raj SR, Sato K, Black B, Song Y, et al. Distal sudomotor findings in postural tachycardia syndrome. Clin Auton Res 2010;20:93–99. 34. Ebenezer GJ, Hauer P, Gibbons C, McArthur JC, Polydefkis M. Assessment of epidermal nerve fibers: a new diagnostic and predictive tool for peripheral neuropathies. J Neuropathol Exp Neurol 2007;66:1059–1073. 35. Lauria G, Bakkers M, Schmitz C, Lombardi R, Penza P, Devigili G, et al. Intraepidermal nerve fiber density at the distal leg: a worldwide normative reference study. J Peripher Nerv Syst 2010;15:202–207. 36. Bakkers M, Merkies IS, Lauria G, Devigili G, Penza P, Lombardi R, et al. Intraepidermal nerve fiber density and its application in sarcoidosis. Neurology 2009;73:1142–1148. 37. Shannon JR, Flattem NL, Jordan J, Jacob G, Black BK, Biaggioni I, et al. Orthostatic intolerance and tachycardia associated with norepinephrinetransporter deficiency. N Engl J Med 2000;342:541–549. 38. Mustafa HI, Robertson D. Beyond postural tachycardia syndrome. J Neurol Neurosurg Psychiatry 2010;81:237–238. 39. Bayles R, Harikrishnan KN, Lambert E, Baker EK, Agrotis A, Guo L, et al. Epigenetic modification of the norepinephrine transporter gene in postural tachycardia syndrome. Arterioscler Thromb Vasc Biol 2012;32:1910–1916. 40. Robertson D, Shannon JR, Biaggioni I, Ertl AC, Diedrich A, Carson R, et al. Orthostatic intolerance and the postural tachycardia syndrome: genetic and environment pathophysiologies. Pflugers Arch 2000;441:R48–51. 41. Thieben MJ, Sandroni P, Sletten DM, Benrud-Larson LM, Fealey RD, Vernino S, et al. Postural orthostatic tachycardia syndrome: the Mayo Clinic experience. Mayo Clin Proc 2007;82:308–313. 42. Jacob G, Costa F, Shannon JR, Robertson RM, Wathen M, Stein M, et al. The neuropathic postural tachycardia syndrome. N Engl J Med 2000;343:1008–1014. 43. Gibbons CH, Bonyhay I, Benson A, Wang N, Freeman R. Structural and functional small fiber abnormalities in the neuropathic postural tachycardia syndrome. PLoS One 2013;8:e84716. 44. Streeten DH, Anderson GH Jr, Richardson R, Thomas FD. Abnormal orthostatic changes in blood pressure and heart rate in subjects with intact sympathetic nervous function: evidence for excessive venous pooling. J Lab Clin Med 1988;111:326–335. 45. Carson RP, Appalsamy M, Diedrich A, Davis TL, Robertson D. Animal model of neuropathic tachycardia syndrome. Hypertension 2001; 37:1357–1361. 46. Luo KR, Chao CC, Chen YT, Huang CM, Yang NC, Kan HW, et al. Quantitation of sudomotor innervation in skin biopsies of patients with diabetic neuropathy. J Neuropathol Exp Neurol 2011;70:930–938.
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Department of Neurology, Kliniken Maria Hilf M€ onchengladbach, Faculty of Health, University of Witten/Herdecke, Viersenerstrasse 450, D-41063 M€ onchengladbach, Germany 2 Department of Nuclear Medicine, HELIOS-Klinikum Wuppertal, University of Witten/Herdecke, Witten, Germany 3 Institute of Neuropathology, Medical Faculty, RWTH Aachen University, Aachen, Germany 4 Autonomic Laboratory, Department of Neurology and Clinical Neurophysiology, HELIOS-Klinikum Wuppertal, University of Witten/ Herdecke, Witten, Germany Accepted 18 March 2014 ABSTRACT: Introduction: Postural tachycardia syndrome (POTS) is a disorder of orthostatic intolerance characterized by excessive tachycardia of unknown etiology. Our objective in this study was to evaluate the correlation between C-fiber involvement as shown by skin biopsy and adrenergic cardiac metaiodobenzylguanadine (MIBG) uptake in POTS patients. Methods: Skin biopsies of 84 patients with POTS were examined by Protein Gene Product 9.5 (PGP9.5) immunohistochemistry and were compared with MIBG myocardial scintigraphy imaging data. Results: Mean intraepidermal nerve fiber (IENF) density was in the lower normal age-adjusted range, 7.2 6 2.9/mm (normal 7/mm), and was slightly below the normal range in 45% of POTS patients. MIBG uptake was reduced in 21% of patients. Low IENF density correlated with reduced cardiac MIBG uptake (r 5 0.39, P 5 0.001). Conclusions: A subset of neuropathic POTS patients may harbor mild small fiber neuropathy with abnormalities of unmyelinated nerve fibers in the skin associated with reduced myocardial postganglionic sympathetic innervation. Muscle Nerve 50: 956–961, 2014
Postural orthostatic tachycardia syndrome (POTS) is defined in patients by an excessive increase in heart rate by >30 beats/minute within 10 minutes of becoming upright, or to absolute levels of >120 beats/minute without a gradual drop in blood pressure. It is associated with symptoms of orthoThese include lightstatic intolerance.1,2 headedness, weakness, palpitations, tremulousness, and, in more severe cases, presyncope and syncope. POTS can be quite debilitating due to significant limitations in activities of daily living. Young, otherwise healthy women are most commonly affected. The pathogenetic mechanism of the condition is unclear. Several major subtypes of primary POTS have been described. The majority of patients with POTS have preserved autonomic
Abbreviations: BP, blood pressure; HM, heart/mediastinum; HR, heart rate; IENF, intraepidermal nerve fiber; MIBG, metaiodobenzylguanine; NET, norepinephrine transporter; POTS, postural tachycardia syndrome; PGP9.5, Protein Gene Product 9.5; SPECT, single-photon emission computed tomography; VM, Valsava maneuver Key words: autonomic disorder; cardiac denervation; orthostatic intolerance; postural tachycardia syndrome; small fiber neuropathy Correspondence to: C.-A. Haensch; e-mail: carl-albrecht.haensch@ mariahilf.de C 2014 Wiley Periodicals, Inc. V
Published online 20 March 2014 in Wiley Online Library (wileyonlinelibrary. com). DOI 10.1002/mus.24245
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function. Neuropathic POTS comprises a subgroup with length-dependent denervation of sympathetic fibers of the lower extremities.3,4 Thermoregulatory sweat testing may provide evidence of small fiber neuropathy. Abnormalities of sudomotor autonomic function could reflect an underlying neural deficit that also impairs cardiovascular autonomic innnervation. Impaired postganglionic sudomotor function indicates autonomic C-fiber involvement. One study using sympathetic microneurography in POTS suggested sympathetic denervation.5 Scintigraphy with 123I-metaiodobenzylguanidine (MIBG) visualizes and quantifies sympathetic innervation in vivo and reflects the relative distribution of adrenergic neurodensity and function.6 Because MIBG structurally resembles norepinephrine, it enters neuroendocrine cells by an active uptake mechanism and is stored in the neurosecretory granules, resulting in a specific concentration in contrast to cells of other tissues. MIBG reflects uptake and storage in postganglionic and presynaptic terminals similar to those of the endogenous neurotransmitter norepinephrine. Cardiac MIBG scintigraphy allows autonomic neuropathy to be detected in the early stages of diabetes mellitus, familial amyloid polyneuropathy,7 and Parkinson disease.8 Recently, we showed reduced myocardial uptake of MIBG in 20% of POTS patients, indicating dysfunction of postganglionic adrenergic innervation.9,10 Protein Gene Product 9.5 (PGP9.5) immunohistochemistry of skin biopsies has emerged as a valuable tool to analyze autonomic innervation morphologically.11,12 The loss of autonomic nerve fibers was shown in Ross syndrome and in familial dysautonomia (Riley–Day syndrome)13 and other peripheral neuropathies.14–25 Measurement of intraepidermal axon density is now used to diagnose neuropathies and to assess the distribution and severity of denervation.26 In a study of a small group of 8 POTS patients, intraepidermal nerve fiber (IENF) density was in the normal range, but 3 of the 8 had some morphological abnormalities, including bulbous swelling of intraepidermal unmyelinated fibers.14 MUSCLE & NERVE
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In this study we investigated whether C-fiber involvement and cardiac denervation could be detected in a larger retrospective cohort of POTS patients. Our second objective was to evaluate the correlation between C-fiber involvement, as shown by skin biopsy and adrenergic cardiac MIBG uptake. METHODS
In a retrospective study, a total of 84 patients were included who had been referred for evaluation of chronic orthostatic intolerance to the Autonomic Laboratory of the Department of Neurology, HELIOS-Klinikum Wuppertal, University of Witten/Herdecke between 2009 and 2012 (Table 1). A diagnosis of POTS was made by the presence of orthostatic intolerance symptoms associated with a heart rate increase of 30 beats/min or a rate that exceeded 120 beats/min within the first 10 minutes of standing or upright tilt in the absence of other chronic debilitating disorders, prolonged bed rest, or medications that could impair vascular or autonomic tone. Clinical examination was normal in all patients. The patients did not take any medication except for oral contraceptives. No patient had diabetes or previous cardiac disease. All patients had normal blood cell counts, electrolyte analysis, and resting electrocardiography. Twenty-four-hour urinary sodium secretion was estimated to exclude hypovolemia. The primary endpoint of the study was to evaluate the decrease in IENF density and to correlate small fiber neuropathy with reduced cardiac MIBG uptake. The cardiovascular autonomic function tests were based on blood pressure and heart rate at rest and after various stimulations under standardized environmental conditions at 20 C. All tests were performed in the morning after fasting for 4 hours. All patients abstained from tobacco and caffeine use on the day of the study. Patients took no dietary supplements. Finger arterial pressure was measured beat-to-beat continuously and noninvasively using the volume clamp method with the Portapres device (TNO TPD, Amsterdam, The Netherlands). The cuff was placed on the second phalanx of the third finger. A synchronous recording of a standard 4-channel electrocardiograph and respiratory effort measured by thoracic strain gauges and of the Portapres signal were performed simultaneously with a FAN device (Schwarzer GmbH, Munich, Germany). The FAN device records heart rate variability based on the standard recording techniques and algorithms used in autonomic function studies.27 After a 5minute rest phase, head-up tilt-table testing at a Autonomic Testing.
Postural Tachycardia Syndrome
Table 1. Demographic and clinical data. Number of patients
84
Mean age (years) Men/women Heart rate supine (bpm) Heart rate upright (bpm) Heart rate change (bpm) Hyperadrenergic POTS Valsalva ratio Systolic blood pressure increase, phase IV, Valsalva maneuver (mm Hg)
28 6 10.5 25/59 75 6 11.2 121 6 13.4 45 6 10.2 24 2.01 6 0.42 34 6 20
70 upright position within 20 seconds with an electrically driven tilt-table was performed for 10 minutes. Hyperadrenergic POTS was defined as POTS associated with a systolic blood pressure (BP) increment 10 mm Hg during tilt-table testing in the 70 position.28 The Valsalva maneuver (VM) was performed by asking the subjects to blow into a mouthpiece attached to an aneroid pressure gauge at a pressure of 40 mm Hg and to endure pressure for 15 seconds. The VM was performed with the patient supine. The subjects performed a series of maneuvers until 2 reproducible arterial blood pressure responses were obtained. The Valsalva ratio of heart rate (HR) was calculated from the maximum HR during or shortly after straining and the minimum HR in the overshoot phase IV. Systolic blood pressure increase in phase IV was assessed and compared with baseline average BP for each patient. Between each test, a return of cardiovascular parameters to baseline was awaited.29–31 MIBG Scintigraphy. Myocardial adrenergic function was analyzed by imaging with MIBG using the SPECT technique. For imaging of cardiac adrenergic innervation, scintigraphy was performed by injection of 180 MBq MIBG (GE Healthcare Buchler, Braunschweig, Germany) after blocking iodine uptake in the thyroid gland with a total of 300 mg perchlorate. To allow for clearance of non-specific tissue uptake, data were acquired 5 hours after injection. After obtaining a planar static image, single-photon emission computed tomography (SPECT) was performed using a dual-headed gamma camera (Hawkeye; GE Medical Systems, Solingen, Germany) equipped with low-dose computed tomography for image fusion and correction of attenuation (which was not used in this study). Thirty projections of 40 seconds each were acquired over a 180 rotation. The data were stored in a 64 3 64 matrix and reconstructed iteratively. Cardiac MIBG uptake was assessed qualitatively for heart visualization on planar studies by nuclear medicine specialists who were unaware of the autonomic function status. On the planar MUSCLE & NERVE
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images, regions of interest were drawn over the heart and mediastinum by 3 independent investigators to calculate the heart/mediastinum (H/M) ratio. The mediastinum is used as reference in our laboratory because it contains few sympathetic nerves. MIBG uptake was measured, on average, after 5:05 hours (range 4:36–5:28 hours). The H/M ratio was compared with the normal range of >1.7, as derived from earlier investigations.6,9 Reproducibility of the region drawings by 3 independent investigators is high, with a maximum error of about 5%. Three-millimeter skin punch biopsies were obtained approximately 15 cm proximal to the left lateral malleolus. The specimens were fixed in Zamboni solution and processed using standard diagnostic protocols, as described elsewhere.13,32 In short, in all cases, 6 consecutive 40– 50-lm cryostat sections were stained against PGP9.5 (rabbit polyclonal antibody; Ultraclone, UK). Immunoreactivity was visualized using Alexa Fluor 488 (Invitrogen)-labeled goat anti-rabbit secondary antibodies. IENF density was determined according to standardized counting rules described elsewhere,33 counting only continuous fibers that clearly cross the epidermal basement membrane to the epidermis. Epidermal length was measured using the scale bar in the microscope eyepiece calibrated with a standardized scale bar slide, and the IENF density was calculated. Patients with IENF density lower than the fifth percentile of the appropriate age and gender group, as determined from the literature, were considered to have small fiber neuropathy.34 In addition, the number of axons showing focal swellings >1.5 lm in diameter was counted. The presence of such swellings can be observed in many if not all skin biopsies, and we consider it normal if it affects 1.5 lm, and 6 of these patients (13%) showed swelling ratios >10%. For sweat gland innervation, a severe reduction was found in 7 patients, which correlated more closely with reduced MIBG uptake (2.08 vs. 1.80; P 5 0.001) and low IENF density (7.5 vs. 3.59; P < 0.001). IENF density showed a mild correlation with age [odds ratio 1.06 (1.01–1.11); P 5 0.009]. The swelling ratio (number of axons with swellings >1.5 lm / number of all intraepidermal axons) did not correlate with MIBG uptake or results of the autonomic function tests. MIBG uptake after 5 hours was reduced in 21% of patients compared with the normal range for heart/mediastinum ratio, 1.7. Low IENF density correlated with reduced cardiac MIBG uptake (Spearman r 5 0.39, P 5 0.001, 2tailed; Fig. 1). The degree of accordance between the 2 methods was slight (kappa 5 0.105). The odds ratio for a pathological finding due to age was 1.06 for IENF density (P 5 0.009) and 1.02 for MIBG uptake (not statistically significant). No correlation was found for MIBG uptake and age. Multivariate analysis of heart rate at rest and during tilt-table testing indicated no significant risk factor for abnormal IENF density or reduced MIBG uptake. Patients with hyperadrenergic POTS had significantly lower IENF density (5.56 vs. 7.82; P 5 0.001) and MIBG uptake (1.88 vs 2.13; P 5 0.01). Clinically, only nausea was found more often in POTS patients with reduced IENF density (Table 2). MUSCLE & NERVE
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Table 2. Characteristics of POTS patients with and without reduced cardiac MIBG uptake and low IENF density. POTS patients
Number of patients Mean age (years) Men/women Duration of illness (months) Dizziness Light-headedness Presyncope Fatigue or weakness Chest pain Syncope Headache Palpitations Exercise intolerance Decreased concentration Tilt-table–induced syncope Nausea Blurred vision
Cardiac MIBG uptake
Cardiac MIBG uptake and IENF density
IENFD
All
Reduced
Normal
Reduced
Normal
Reduced
Normal
84 28 25/59 14.9 77 34 28 8 8 31 20 35 7 2 4 21 18
18 31 4/14 19.0 17 7 4 1 3 10 6 10 1 1 0 9 2
66 28 21/45 13.8 60 27 24 7 5 21 14 25 6 1 4 12 16
37 31 14/23 9.9 35 15 11 3 3 12 11 13 3 1 1 14* 8
47 26 11/36 18.8 42 19 17 5 5 19 9 22 4 1 3 7 10
10 29 3/7 11.4 10 3 1 0 1 4 4 6 1 1 0 6 1
39 24 10/29 16.9 35 15 14 4 4 13 7 18 4 1 3 4 9
*Significant difference from normal group (t-test, 2-tailed; P 5 0.02).
DISCUSSION
This study was designed to correlate the sympathetic and somatic C-fiber innervation of the epidermis and myocardial 123I-MIBG uptake for cardiac sympathetic neuroimaging in POTS patients. The original idea follows recently published studies in which these techniques were applied to study the sympathetic innervation in other neurological diseases. Recently, we described altered sympathetic cardiac innervation as demonstrated by MIBG myocardial scintigraphy in 20% of POTS patients.9 Our results have been confirmed in this study with a larger cohort in which we noted a reduced MIBG uptake in 21% of patients. Diminished MIBG myocardial uptake indicates reduction of local myocardial sympathetic innervation. Several clinical observations have suggested the presence of distal denervation.33 In addition, abnormal quantitative sudomotor axon reflex test results indicated postganglionic sympathetic dysfunction. Epidermal skin biopsy using anti-PGP9.5 immunohistochemistry is a useful test for investigation of small-caliber sensory nerves, including autonomic nerve fibers in peripheral neuropathies.12,13,15 IENF density was below threshold in 45% of POTS patients. Increased numbers of focal epidermal axon swellings were observed in 6 of 47 patients at a time when IENF density was (still) in the normal range in many patients, suggesting an early stage of degeneration of the affected fibers. We found a modest age-related decrease of skin innervation, which is in line with IENF density studies done on control groups.12,34–36 Sweat gland innervation is predominantly sympathetic Postural Tachycardia Syndrome
cholinergic, not sympathetic adrenergic, but it may be associated more closely with a diffuse autonomic neuropathy. The reductions of MIBG uptake and IENF density were mostly quite mild. It is possible that the combination of both abnormalities, especially when mild, is not very common or is difficult to assess with currently available methodology. In addition, the correlation between reduced MIBG uptake and low IENF density, although statistically significant, was relatively modest (Spearman r 5 0.39, P 5 0.001, 2-tailed). This may suggest that the disorder involves not only autonomic but also somatic C-fibers. It is theoretically possible that abnormal function of the norepinephrine transporter (NET) itself may lead to similar findings in POTS patients who have failed to accumulate MIBG. However, NET dysfunction is rare.37 Moreover, decreased (albeit slightly) innervation of the skin encourages the view that we have identified a partial sympathetic dysfunction.37–40 POTS is currently defined as a syndromic dysautonomia with a change in autonomic nervous system function. The exact causes of POTS are unknown. It is almost certainly a heterogeneous disorder with variable etiology and pathophysiology.41 In POTS, orthostatic intolerance seems to be associated with a “patchy” dysautonomia, which results in orthostatic pooling of blood in the splanchnic and dependent circulations and activation of the remaining cardiac sympathetic system, causing tachycardia upon standing.42 Most attempts to explain the pathophysiology of POTS have focused on an increased release or other abnormalities in synaptic clearance of norepinephrine in response to the change from a supine to MUSCLE & NERVE
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an upright position.40 Genetic or acquired deficits in norepinephrine inactivation may underlie hyperadrenergic states that lead to orthostatic intolerance. The results of sympathetic skin response and quantitative testing of the sudomotor axon reflex suggest that autonomic denervation of the legs may be another underlying mechanism.42 Distal autonomic C-fiber status was examined histologically by Singer et al. in skin biopsies from a group of 8 POTS patients.14 IENF density was found to be normal in their group, but normative values were different at that time compared with those in use now. Nevertheless, most of the nerve fiber density values considered abnormal in our study were only slightly below the normal range. Results of a recent study on a smaller group of POTS patients demonstrated that about half (9 of 20) had mildly reduced IENF,43 which is in line with the results obtained from our larger cohort. In the recent article by Gibbons et al.,43 the results of an analysis of axonal swelling density were not reported; however, in the study by Singer et al.,14 3 of 8 biopsies showed some morphologic skin nerve fiber abnormalities. These included bulbous swellings of intraepidermal unmyelinated axons. Such swellings were also increased in number in a subset of patients in our study. It has been recognized increasingly that such swellings may be present in normal subjects, although normative values have thus far not been established clearly. Still, application of an arbitrary threshold of 10% revealed that 13% of the POTS patient biopsies available for this analysis showed a considerable increase in the number of such swellings.32 Taken together, skin biopsy results indicate that minor abnormalities in skin innervation exist in a subgroup of POTS patients. The finding of hypersensitivity to infusion of norepinephrine into veins of the foot, despite high plasma catecholamine concentrations, suggests that denervation hypersensitivity of the veins of the legs is involved.42,44 Carson et al. showed that a selective peripheral noradrenergic lesion can result in an elevated heart rate in rats.45 They suggested that loss of distal sympathetic innervation could produce an exaggerated sympathetic response in innervated tissues such as the heart, resulting in tachycardia. b-Adrenergic supersensitivity has been proposed as a mechanism of POTS and, indeed, bsupersensitivity to the chronotropic effects of isoproterenol has been reported. Therefore, the sympathetic denervation of the heart that was detected by MIBG SPECT in POTS patients may produce supersensitivity of the heart itself with exaggerated tachycardia while standing. This study is limited by its retrospective nature and potential referral bias. In addition, a more 960
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thorough quantification of the changes in autonomic innervation could include a semiquantitative analysis of dermal blood vessel walls, of the arrector pili muscles, and of hair follicles, as well as quantitative evaluation of sweat gland innervation.46 The skin biopsy study was also limited by the fact that only half of the skin biopsies (47 of 84) were available for detailed quantitative analysis of axonal swellings. MIBG SPECT was not performed with attenuation correction, and the SPECT data were used only to visualize the heart. No semiquantification (e.g., compared with a normal group, segmentation, etc.) was performed. The H/M ratio was measured only on planar images. In some instances, higher uptake in the myocardium may be caused by uptake in the left lobe of the liver. It is possible that the results could show higher sensitivity and specificity if the SPECT images were used for the quantification (without overlay by liver, etc.). These technical questions will need to be investigated in a future study. In conclusion, in this study we have demonstrated morphological and functional evidence supporting the notion that mild neuropathic changes contribute to the development of POTS in a considerable percentage of patients. Autonomic evaluation, including MIBG SPECT and skin biopsy, may be useful to identify patients who belong to this neuropathic POTS subgroup. These results underscore the heterogeneity of POTS. The statistical analysis was performed with the support of H. Niggemann, commercial statistician in Jena, Germany. REFERENCES 1. Haensch CA, Isenmann S. Postural orthostatic tachycardia syndrome: current concepts in pathophysiology, diagnosis and therapeutic options [in German]. Fortschr Neurol Psychiatry 2011;79:117–122. 2. Grubb BP, Kanjwal Y, Kosinski DJ. The postural tachycardia syndrome: a concise guide to diagnosis and management. J Cardiovasc Electrophysiol 2006;17:108–112. 3. Kimpinski K, Figueroa JJ, Singer W, Sletten DM, Iodice V, Sandroni P, et al. A prospective, 1-year follow-up study of postural tachycardia syndrome. Mayo Clin Proc 2012;87:746–752. 4. Schondorf R, Low PA. Idiopathic postural orthostatic tachycardia syndrome: an attenuated form of acute pandysautonomia? Neurology 1993;43:132–137. 5. Bonyhay I, Freeman R. Sympathetic nerve activity in response to hypotensive stress in the postural tachycardia syndrome. Circulation 2004;110:3193–3198. 6. Haensch CA, Lerch H, Jorg J, Isenmann S. Cardiac denervation occurs independent of orthostatic hypotension and impaired heart rate variability in Parkinson’s disease. Parkinsonism Relat Disord 2009;15:134–137. 7. Nagasaka T, Togashi S, Watanabe H, Iida H, Nagasaka K, Nakamura Y, et al. Clinical and histopathological features of progressive-type familial amyloidotic polyneuropathy with TTR Lys54. J Neurol Sci 2009;276:88–94. 8. Haensch CA. Heart trouble comes early in Parkinson’s disease before blood pressure falls. Eur J Neurol 2011;18:201–202. 9. Haensch CA, Lerch H, Schlemmer H, Jigalin A, Isenmann S. Cardiac neurotransmission imaging with 123I-meta-iodobenzylguanidine in postural tachycardia syndrome. J Neurol Neurosurg Psychiatry 2010; 81:339–343. 10. Haensch CA, Lerch H, Jigalin A, Schlemmer H, Isenmann S. Cardiac denervation in postural tachycardia syndrome. Clin Auton Res 2008; 18:40–42.
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