Highly Abnormal Thermotests in Familial Dysautonomia Suggest Increased Cardiac Autonomic Risk

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J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.65.3.338 on 1 September 1998. Downloaded from 338 J Neurol Neurosurg Psychiatry 1998;65:338–343 Highly abnormal thermotests in familial dysautonomia suggest increased cardiac autonomic risk

Max J Hilz, Edwin H Kolodny, Irene Neuner, Brigitte Stemper, Felicia B Axelrod

Abstract Cardiovascular instability is a prominent mani- Objective—Patients with familial dysau- festation of familial dysautonomia, an auto- tonomia have an increased risk of sudden somal recessive disorder aVecting development death. In some patients with familial dys- and survival of sensory, sympathetic, and some autonomia, sympathetic cardiac dysfunc- parasympathetic neurons.12Both hypertensive tion is indicated by prolongation of crises and orthostatic hypotension without 34 corrected QT (QTc) interval, especially compensatory tachycardia can occur. Failure during stress tests. As many patients do of sympathetic activation with retention of not tolerate physical stress, additional parasympathetic system activity in patients indices are needed to predict autonomic with familial dysautonomia may be one of the risk. In familial dysautonomia there is a major causes of death in this population. reduction of both sympathetic neurons Survival analysis disclosed that 40% of these and peripheral small nerve ﬁbres which patients have either an unexplained death in their sleep or a sudden daytime cardiorespira- mediate temperature perception. Conse- 5 quently, quantitative thermal perception tory arrest. To date, there are no indices to identify which patients with familial dysau- test results might correlate with QTc tonomia are at risk of sudden death. Common values. If this assumption is correct, tests used to assess cardiac autonomic func- quantitative thermotesting could contri- tion, such as the Valsalva manoeuvre, deep bute to predicting increased autonomic metronomic breathing, or sustained handgrip risk. test, often cannot be applied to patients with Methods—To test this hypothesis, QTc familial dysautonomia. Because of impaired intervals were determined in 12 male and coordination and abnormal breathing pattern, eight female patients with familial dysau- many patients are unable to pace their breath- tonomia, aged 10 to 41 years (mean 21.7 ing, perform a Valsalva strain correctly, or sus- (SD 10.1) years), in supine and erect posi- tain the handgrip without simultaneous tions and postexercise and correlated with breathholding.35By contrast, measurements of warm and cold perception thresholds ECG indices such as the corrected QT interval assessed at six body sites using a Ther- (QTc) are easily performed even in patients Department of motest. Neurology, New York with poor cooperation.

University Medical Results—Due to orthostatic presyncope, Based on reports that prolongation of the http://jnnp.bmj.com/ Center, 550 First six patients were unable to undergo erect QTc may be a potential marker for patients at Avenue, New York, NY and postexercise QTc interval assess- risk for arrhythmia and sudden death,6–10 10016, USA ment. The QTc interval was prolonged Glickstein et al11 studied this index in patients M J Hilz E H Kolodny (>440 ms) in two patients when supine and with familial dysautonomia and noted that a Fa B Axelrod in two additional patients when erect and significant number of patients had a prolonged postexercise. Supine QTc intervals corre- QTc, greater than 440 ms. Most patients with Department of lated significantly with thermal threshold familial dysautonomia had normal QTc inter- Neurology, University values at the six body sites and with the vals at rest, but with the challenge of head on October 2, 2021 by guest. Protected copyright. of upright tilt or exercise, by contrast with Erlangen-Nuremberg, number of sites with abnormal thermal Schwabachanlage 6, perception (Spearman’s rank correlation controls, a significant number of patients with D-91054 Erlangen, p<0.05). Abnormal Thermotest results familial dysautonomia had QTc prolongation. Germany were more frequent in the four patients However, eight of 54 patients participating in M J Hilz with QTc prolongation and the six pa- that study did not tolerate the tilt or exercise I Neuner tests. In these patients, QTc assessment is of B Stemper tients with intolerance to stress tests. Conclusion—The results suggest that im- limited use and additional non-invasive indices Correspondence to: paired thermal perception correlates with are required to evaluate autonomic risk. Professor Max J Hilz, As well as sympathetic dysfunction, patients University cardiac sympathetic dysfunction in pa- Erlangen-Nuremberg, tients with familial dysautonomia. Thus with familial dysautonomia manifest impaired Department of Neurology, temperature perception, which is due to a thermotesting may provide an alternative, 12 13 Schwabachanlage 6, D - albeit indirect, means of assessing sympa- decreased number of small nerve fibres. 91054 Erlangen, Germany. The degree of dysfunction of Aä and C fibres is Telephone 0049 9131 85 44 thetic dysfunction in autonomic disor- 44; fax 0049 9131 85 43 28. easily assessed by quantitative thermal thresh- ders. 14–16 (J Neurol Neurosurg Psychiatry 1998;65:338–343) old testing. Non-invasive psychophysical Received 4 April 1997 and in assessment of warm and cold perception final revised form 6 March 1998 Keywords: familial dysautonomia; QTc interval; quan- thresholds has proved useful in the diagnosis Accepted 16 March 1998 titative thermal testing of small fibre neuropathies of various J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.65.3.338 on 1 September 1998. Downloaded from Highly abnormal thermotests in familial dysautonomia suggest increased cardiac autonomic risk 339

Table 1 Warm and cold perception thresholds in 20 subjects was taking medication known to patients with familial dysautonomia and 90 controls at six modify the QT interval and all had normal diVerent body sites ionised serum calcium determinations on the Patients (n=20) Controls (n=90) day of the cardiac study. The initial diagnosis of Site (mean (SD)) (mean (SD) familial dysautonomia was established by Dr F Cold threshold: B Axelrod, director of the Familial Dysautono- Thenar 14.0 (8.4) 1.9 (0.8) mia Treatment and Evaluation Center, New Arm 13.8 (10.2) 1.3 (0.8) Cheek 10.2 (7.5) 1.4 (0.4) York University, New York, NY, USA. Among Calf 14.0 (9.8) 2.8 (1.9) the criteria used to establish the diagnosis of Foot 15.3 (10.3) 2.9 (1.6) familial dysautonomia were Jewish Ashkenazi Shoulder 12.0 (8.2) 1.4 (0.7) extraction, delayed development, failure to Warm threshold: Thenar 8.3 (3.3) 1.4 (0.6) thrive, episodic fevers, decreased pain and Arm 8.1 (4.0) 2.2 (1.5) temperature perception, absent deep tendon Cheek 6.6 (4.4) 0.9 (0.3) Calf 9.3 (4.0) 3.5 (2.2) reflexes, absence of overflow tears, absence of Foot 8.5 (4.4) 3.0 (1.9) fungiform papillae of the tongue, decreased Shoulder 6.9 (3.6) 1.8 (1.0) corneal reflex, increased sweating, postural In patients with familial dysautonomia all thresholds were hypotension and skin blotching and hyperten- significantly higher than in the control group (Mann-Whitney U sive crises with stress, and absent axon flare test, p<0.005). response after intradermal histamine injection. aetiologies.15–18 Correlations between impaired thermal perception and autonomic dysfunction QT MEASUREMENT have been described in diabetic, uraemic, and For QT determination, a Marquette MAC-12 19–21 alcoholic neuropathies. recorder (Marquette Electronics, Milwaukee, We hypothesised that a similar correlation WI) was set to provide a lead II rhythm strip in exists in familial dysautonomia, as there is neu- addition to a 12 lead ECG.11 25 The first ECG ropathological analogy of sympathetic ganglia was obtained after the patient was supine for 10 reduction and a decrease in peripheral small 12 13 22–24 minutes, a second after the patient was erect for nerve fibres. Analogy between thermo- five minutes, and a third immediately after the test results and QTc values would justify patient completed an exercise programme con- substitution of Thermotesting for QTc assess- sisting of stepping on and oV a 6 in high step for ment in patients intolerant to stress tests. In two minutes. this study, we therefore, compared QTc The QT interval was corrected for the intervals of patients with familial dysautonomia cardiac cycle length using Bazett’s formula26 with their warm and cold perception thresholds QTc=measured QT interval/ RR interval1/2 determined at various body sites and to the With each manoeuvre, three consecutive QT number of body sites showing abnormal intervals were measured and averaged to obtain thermal perception. a mean QTc. A prolonged QTc was defined as being>440 ms.11 27 28 Material and methods PATIENT SELECTION Twenty patients with familial dysautonomia THERMOTEST ASSESSMENT participated in the study. Informed consent Warm and cold perception thresholds were

was obtained according to the declaration of psychophysically determined with a Somedic http://jnnp.bmj.com/ Helsinki, with a parent signing for patients less Thermotest™ (Somedic, Stockholm, Sweden), than 21 years of age. Twelve patients were male a modification of the “Marstock” device.14 29 and eight were female. They ranged in age from The thermodes operate on the Peltier principle 10 to 41 years (mean 21.7 (SD 10.1) years). All applying continuously increasing ramp-like were ambulatory patients followed up annually temperature stimuli to the tested skin area at a at the dysautonomia centre. None of the temperature change rate of 1°C/s. Simultane- ously, a thermocouple attached to the stimulat- Table 2 Frequency of impaired warm and cold perception in 20 patients with familial dysautonomia tested at six diVerent body sites ing surface continuously registers instantane- on October 2, 2021 by guest. Protected copyright. ous temperature changes within 0.1°C. Data Pathological Thermal Thermal Thermal Incomplete Paradoxical are digitally displayed on a monitor and stored thresholds hypoaesthesia dysaesthesia anaesthesia perception perception (n=20) (n=20) (n=20) (n=20) (n=20) (n=20) on hard disk. Thermal stimuli are generated at randomised4sto10sintervals (Senselab™, Site of cold stimulation: Foot1512732 Somedic, Sweden) with preset stimulation lim- Calf1662512 its, a minimum of 5°C and a maximum of Thenar1773232 45°C. Thermal stimulation started from a Forearm 20 9 1523 Shoulder 18 6 1632 baseline of 32°C. Once the subject signals Cheek1761541 stimulus perception, the temperature returns Site of warm stimulation: to baseline. Foot1450711 Calf1633631 Warm and cold perception thresholds were Thenar20122132 determined by the “method of limits”, which is Forearm 19 8 0371 comparable with the determination of hearing Shoulder 18 9 0621 30 Cheek1771621 thresholds by means of a Békésy audiometer. Warm or cold stimuli are steadily increased The number of patients with pathological thresholds represents the sum of patients with thermal until the subject indicates stimulus perception hypoaesthesia, dysaesthesia, or paradoxical sensation, and patients with absent or incomplete perception of repeated stimuli. No patient presented with hyperaesthesia. Incomplete perception was by pressing a button. This ends stimulation and defined as perceiving< five of the stimuli applied for each threshold determination. reverses the thermode temperature to the J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.65.3.338 on 1 September 1998. Downloaded from 340 Hilz, Kolodny, Neuner, et al

) thresholds at the six body sites, but also to the ° K ( number of abnormal perception sites found in No perception within range of stimulation each patient. The level of signiﬁcance was set at p<0.05. Data were analysed by a commercially 25 available statistical program (SYSTAT, Evan- ston, IL, USA). 20 15 Results Spearman R = 0.6 10 Values for QTc were prolonged in four of the p < 0.005 20 patients.The QTc was prolonged in two 5 y = 0.184x – 64.9 patients when supine. A third patient devel-

Cold threshold at the thenar 0 oped prolongation when erect and a fourth 380 400 420 440 460 480 postexercise. QTc interval supine (ms) Supine QTc intervals ranged from 387 ms to Significant correlation between cold perception thresholds at 467 ms (mean 417 (SD 18.7) ms), erect QTc the thenar and supine QTc intervals in 20 patients with intervals ranged from 395 ms to 483 ms (mean familial dysautonomia. Open triangles indicate normal cold perception. Filled symbols indicate impaired cold perception. 417.2 ( SD 21.3) ms) and postexercise QTc Symbols above the dotted line represent patients with cold intervals from 398 ms to 465 ms (mean 417.7 anaesthesia. Diamonds represent the three patients who had (SD 21.8) ms). However, an erect QTc interval a cardiac arrest within 12 months after the study. could only be determined in 15 patients and a baseline. The diVerence between the signalled postexercise QTc interval in 14 patients. One peak and the baseline temperature is regis- patient could not stand or exercise because of tered. bilateral Charcot knee joints. Presyncopal Each warm or cold stimulus was applied five symptoms developed in four patients when times. In addition, catch trials with one or two they assumed the erect position and in a fifth null stimuli were added to the five warm or cold patient after exercise. stimuli. Warm or cold thresholds were deter- All participants had a reaction time<0.1 s in mined as the average of the five peak to baseline the test preceeding thermal threshold assess- diVerences. Heat pain thresholds were not ment. Thermotest results were abnormal in all evaluated separately as too many patients or patients, but were more impaired in patients parents did not agree to heat stimulation. with prolonged QTc than in those with normal Thresholds were determined at six body sites: QTc values, and even worse in the six patients at the cheek, at the shoulder 1.5–2.5 cm above intolerant to standing or exercise. In all the midpoint of the scapular spine, at the distal patients, thermal thresholds at the six tested volar forearm 3 cm proximal to the wrist, at the sites were higher than in the control group thenar, at the distal medial calf 4–5 cm above (Mann-Whitney U test: p<0.005). There was the medial malleolus in the L4 dermatome, and no consistent pattern of impaired thermal sen- at the lateral dorsum of the foot in the area sation (tables 1 and 2). The degree of threshold innervated by the sural nerve. A 2.5 cm×5.0 cm increase varied from one body site to the other, thermode was used for testing at the shoulder, and the number of abnormal perception sites forearm, calf, and foot. A 1.5 cm×2.5 cm ther- diVered from one patient to another. The mode was used at the cheek and thenar. frequency of abnormal temperature perception Thresholds were compared with normative age was highest at the thenar and the distal volar related data established in 90 healthy controls forearm. At these sites, either cold or warm http://jnnp.bmj.com/ aged 10 to 42 years (52 male, 38 female; mean sensation was altered in all 20 patients. The site 23.7 (10.6) years). Thermal perception was with the lowest frequency of abnormal results considered abnormal if thresholds exceeded was the feet. Here, thresholds were abnormal in mean normative values by more than 2 SD, if 75% of the patients. patients did not perceive all of the five repeated In the 20 patients, perception of the five warm or cold stimuli, or if they reported para- stimuli applied for threshold averaging at each doxical sensations or dysaesthesias. Before of the six tested sites was incomplete in 15% of testing, we established that no patient was tak- the warm and in 13.3% of the cold threshold on October 2, 2021 by guest. Protected copyright. ing medication with central nervous eVects determinations. Moreover, the individual vari- inducing drowsiness and biassing cooperation. ability of the five repeated stimuli was signifi- With a temperature change rate of 1°C/s and cantly higher in patients than in controls. At the a 0.1–0.2°C accuracy of the Thermotest, a diVerent sites, variability of warm and cold reaction time of 0.1–0.2 s is suYcient for perception was twofold to 14-fold higher in threshold assessment. To familiarise the study patients than in controls—that is, the threshold participants with the task of quickly responding reproducibility was significantly lower in pa- to a stimulus, and to ensure adequate reaction tients than in controls (Mann-Whitney U test time, we performed a simple test which had p<0.005). previously proved useful in children.31 The In the four patients with prolonged QTc participants were instructed to tap on the intervals, warm and cold perception was abnor- examiner´s knee as quickly as possible after the mal at all of the six tested sites apart from one examiner had touched their own knee. A stop- patient with normal warm perception at the watch was used to assure that reaction time did foot. Ây contrast, patients with normal QTc not exceed 0.1 s. intervals showed normal warm perception at To correlate QTc intervals with the severity 15.6% of the tested sites and normal cold of thermal perception dysfunction, QTc values perception at 17.7% of the sites. Similarly, in were not only compared to warm and cold the six patients with familial dysautonomia J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.65.3.338 on 1 September 1998. Downloaded from Highly abnormal thermotests in familial dysautonomia suggest increased cardiac autonomic risk 341

Table 3 Comparison of QTc supine values to the individual number of body sites manifesting abnormal thermal perception in 20 patients with familial dysautonomia

Body sites with Body sites with Intolerance to tilt abnormal warm abnormal cold Body sites with abnormal (+) or stair stepping Patient No perception (n) perception (n) warm or cold perception (n) QTc supine (ms) (†) 1324387 2324398 3436399 4344401 5666404 6424406 7345406+† 8212410 9445415 10 2 4 5 415 11 4 2 4 418 + † 12 3 4 4 420 13 6 5 6 420 14 5 4 6 422 15 6 5 6 423 (16) (6) (6) (6) (423) (+†) 17 4 4 4 429 + † (18) (6) (6) (6) (429) (†) (19) (6) (6) (6) (455) 20 6 4 6 467 +†

The number of body sites with abnormal warm or cold thresholds found in each patient correlates with the QTc supine values. QTc supine values v number of sites with abnormal cold perception: Rs = 0.57; p<0.01. QTc supine values v number of sites with abnormal warm perception: Rs = 0.59; p<0.001. QTc supine values v number of sites with abnormal warm or cold perception: Rs = 0.46; p<0.05. Numbers in parentheses refer to the three patients who had cardiac arrest within 12 months after study.

intolerant of standing or exercise, warm and cold conduction as well as thermal sensory function perception was abnormal at all tested sites are impaired to a similar extent. The degree to whereas the 14 other patients with familial dys- which patients are aVected varies considerably. autonomia had normal perception for warmth at To date, no one has developed a clinical means 19% of the sites and for cold at 20.2% of the of assessing severity of disease or method of sites. Moreover, the six patients presented with predicting patients at increased risk of sudden warm anaesthesia at 36.1% of the sites and cold death. Prolongation of the QTc interval is con- anaesthesia at 33.3% of the sites compared with sidered an indicator of cardiac risk,6–10 25 and only 19% warm and 21.4% cold anaesthesia orthostatic presyncope indicates autonomic sites in the 14 patients tolerating physical stress. dysregulation.4 32–34 Our study shows that highly In all patients with familial dysautonomia, ther- abnormal Thermotest results may be a predic- mal threshold values of the six tested sites corre- tor of increased cardiac autonomic risk. Ther- lated with the supine QTc interval. However, the motest results correlated with supine QTc Spearman’s rank correlation coeYcient (Rs) interval values in all 20 patients, but coeY- varied for warm and cold thresholds and from cients of correlation varied between 0.43 and one body site to another between 0.43 and 0.71 0.71. However, patients with prolongation of (p<0.05)(ﬁgure). the QTc interval and especially patients Supine QTc intervals correlated with the intolerant of standing and exercise had Thermo-

total number of sites showing abnormal warm test results significantly more abnormal than http://jnnp.bmj.com/ or cold perception. The number of abnormal those of the patients with normal supine, post- warm or cold thresholds at all the tested body tilt, or postexercise QTc intervals. Three of our sites correlated with QTc supine intervals at Rs patients had a cardiac arrest within 12 months. values of 0.59 and 0.57 respectively (p<0.05; One of these patients had a prolonged supine table 3). QTc interval and the other two developed All patients underwent follow up examina- presyncope with physical stress. All three tions within 12 months of the study. Within this patients had highly abnormal Thermotest year, three of the patients had a cardiac arrest. results suggesting that they had pronounced on October 2, 2021 by guest. Protected copyright. Two of these patients had been unable to impairment of both autonomic function and undergo QTc interval determination when thermal perception. erect or postexercise. In the third patient, the Thermotest results showed that the distribu- supine QTc interval had been prolonged. In all tion of small fibre dysfunction varies individu- three, warm and cold perception was docu- ally and does not follow a rather predictable mented as abnormal at each of the six tested pattern as seen in dying-back neuropathies. sites. The three patients either could not Thermal perception was more often impaired perceive the applied thermal stimuli or had at the upper than the lower limbs. However, highly raised thresholds. our Thermotest findings are consistent with various neuropathological studies of sural Discussion nerves, dorsal root, and sympathetic ganglia The cause of increased frequency of sudden showing that the major pathological process in death in the familial dysautonomia population familial dysautonomia is one of insuYcient has not been elucidated. Postmortem examin- development rather than postnatal ation has never disclosed cardiac abnormali- degeneration.212132324 As the failure of small ties. As familial dysautonomia is a disorder that nerve fibre development varies individually, the primarily aVects small fibre development and pattern of thermal perception also varies from function, it is likely that sympathetic cardiac one patient to another and might aZict the J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.65.3.338 on 1 September 1998. Downloaded from 342 Hilz, Kolodny, Neuner, et al

upper limbs equally or more often than the perform Valsalva manoeuvres or other tests lower limbs.32 such as a sustained handgrip manoeuvre33 44 Thermotest results are not a direct indicator requiring prolonged and steady coordination of autonomic dysfunction, but previous studies and cooperation. of diabetic, uraemic, or alcoholic patients Patients with normal supine QTc intervals describe similarities between dysfunctions of but intolerance of stress tests require further temperature perception and autonomic evaluation of cardiac risk. Two of our patients regulation.19–21 In familial dysautonomia, the who had a cardiac arrest could not undergo finding of such clinical similarities is supported QTc stress tests. Therefore, alternative tests by a similar degree of neuropathological supporting the cardiac risk evaluation but abnormality in peripheral small nerve fibres requiring only little physical cooperation are and sympathetic ganglia. In familial dysau- desirable. tonomia, there is a reduction of unmyelinated Thermotesting provides a non-invasive alter- sural nerve fibres to 5%-15% of the normal native that requires no physical eVort. The number and of neuron somas in the Gasserian method of limits29 45 46 used in this study needs and spinal ganglia to 50% of normal, and neu- only slight patient cooperation; is easy to ron somas in cervical and thoracical sympa- understand and thus yields highly reproducible thetic ganglia are reduced to 27–37% of the results even in preschool children.31 In abun- normal number.12 13 22–24 The decrease in pe- dant studies the algorithm has proved useful in ripheral small fibres is clinically reflected by quantifying peripheral small fibre impaired thermal perception,12 14 24 32 and the dysfunction.14 15 18 29 45 47 48 Verdugo and Ochoa reduction of cervical and thoracic ganglia described as many as 36 diVerent combinations accounts for cardiac autonomic of impaired thermal sensation patterns.14 dysfunction,23 35 36 which might be recognised In patients with familial dysautonomia, clinically by prolonged QTc interval values. In Thermotesting assesses the most prominent Romano-Ward long QT syndrome, an imbal- peripheral nerve dysfunction and thus refines ance of left and right cervicothoracic sympa- the clinical grading of the disease. Thermotest- thetic activity is assumed to induce prolonga- ing might also be useful for long term follow up tion of the QT interval.37–39 studies. Most importantly, our results show In patients with familial dysautonomia, that highly abnormal Thermotest results are an determination of QTc intervals provides im- indirect suggestion of advanced cardiac auto- portant information. Abnormal QTc intervals nomic dysfunction and merit further evalua- were detected in 20% of our patients. Glick- tion of cardiac function stein et al reported QTc prolongation in 33% of 54 patients with familial dysautonomia with an 1 Mahloudji M, Brunt PW, McKusick VA. Clinical age distribution similar to our group (mean 24 neurological aspects of familial dysautonomia. J Neurol Sci 11 1969;11:383–95. (8.7) years). Limitations of QTc assessment 2 Pearson J, Axelrod FB, Dancis J. Current concepts of seem to account for the diVerent incidences. dysautonomia: neurologic defects. Ann NY Acad Sci 1974; 228:288–300. Eighty five per cent of patients studied by 3 Axelrod FB, Nachtigall R, Dancis J. Familial dysautonomia: Glickstein et al could stand and exercise diagnosis, pathogenesis and management. In: Schulman I, ed. Advances in pediatrics. Chicago: Year Book, 1974;21:75– compared with only 70% of our group. We 96. assume that Glickstein et al11 were able to show 4 Ziegler MG, Lake R, Kopin IJ. Deficient sympathetic response in familial dysautonomia. N Engl J Med a higher incidence of QTc prolongation 1976;294:630–3. because more of their patients were able to tol- 5 Axelrod FB, Abularrage JJ. Familial dysautonomia: a http://jnnp.bmj.com/ prospective study of survival. J Pediatr 1982;101:234–6. erate stress tests. Stress tests are essential to 6 Jervell A, Lange-Nielsen F. Congenital deaf mutism: unveil cardiac conduction abnormalities. In functional heart disease with prolongation of the QT interval and sudden death. Am Heart J 1957;54:59–68. their control group (mean 24.7 (7.6) years), 7 Romano C, Gemme G, Pongiglione R. Aritmie cardiache Glickstein et al found no QTc intervals exceed- rare delléta´ pediatrica. Il Accessi sincopali fibrillazione ventricolare parossistica. Clin Pediatr 1963;45:656–83. ing 440 ms at rest, but one of the controls had 8 Ward OC. A new familial cardiac syndrome in children. a QTc prolongation of 452 ms after standing.11 Journal of the Irish Medical Association 1964;54:103–6. 9 Moss AJ, Schwartz PJ. Sudden death and the idiopathic long Several previous studies show the need for QT syndrome. Am J Med 1979;66:6–7. stress tests to unmask prolongation of the QTc 10 Moss AJ, Schwartz PJ, Crampton RS, et al. The long QT on October 2, 2021 by guest. Protected copyright. 40 41 40 syndrome: a prospective international study. Circulation interval. Shimizu et al reported normal 1985;1:17–21. supine QTc values in five of 11 patients with 11 Glickstein JS, Schwartzman D, Friedman D, et al. Abnormalities of the corrected QT-interval in familial Romano-Ward syndrome(45.5%). With physi- dysautonomia: an indicator of autonomic dysfunction. J cal exercise all patients showed prolongation of Pediatr 1993;6:925–8. 40 42 12 Aguayo AJ, Nair CPV, Bray GM. Peripheral nerve the QTc interval. Gonin et al and Sivieri et abnormalities in the Riley-Day syndrome: findings in a al43 reported that supine QTc values often fail sural nerve biopsy. Arch Neurol 1971;24:106–16. 13 Pearson J, Dancis J, Axelrod F, et al. The sural nerve in to disclose diabetic cardiac autonomic neu- familial dysautonomia. J Neuropathol Exp Neurol 1975;34: ropathy which had been diagnosed with other 413–25. 14 Verdugo R, Ochoa JL. Quantitative somatosensory thermot- cardiovascular function tests such as Valsalva est. 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