Eye (1987) 1, 496-499

Autonomic Neuropathy in Proliferative Diabetic Retinopathy

CHARLES V. CLARK Edinburgh

Summary Autonomic nerve function was assessed in 28 diabetic patients with proliferative retinopathy and 61 age- and sex-matched control subjects, using a series of tests based upon cardiovascular reflex responses to standardised stimuli. Autonomic neuropathy was present in 75 per cent of diabetics with proliferative retinopathy, compared with 5.2 per cent of the control group. The implications of a significant association between cardiovascular autonomic neuropathy and proliferative dia­ betic retinopathy are discussed.

Autonomic neuropathy has an insidious onset The aim of the present study was to assess which precludes accurate identificationdue to systemic autonomic control of cardiovascular the compensatory mechanisms inherent function in diabetic patients with abnormal within the autonomic nervous system. Until retinal microsvascular proliferation-pro­ comparatively recently, tests of autonomic liferative retinopathy. function have been extremely difficult to interpret and almost impossible to quantify. A series of simple, non-invasive tests based Patients and Methods upon cardiovascular reflexeshave been devel­ After informed consent had been obtained, cardio­ vascular autonomic nerve function was assessed in oped during the past 15 years, permitting 28 diabetic patients with proliferative retinopathy accurate, objective and reproducible (mean age 50. 8±14. 3 years) and 61 age- and sex­ measurement of autonomic nerve func­ matched control subjects (mean age 53 .1±1O. 1 tion.1.2•3,4,5,6 As in all reflex assessments, the years) . The diabetic group comprised 21 subjects subject's output reaction is measured follow­ with IDDM (mean age 46. 0±12. 9 years) and 7 ing application of a standardised input stim­ subjects with NIDDM (mean age 65. 8±6. 5 years) . ulus. Results are based upon blood pressure The mean duration of diabetes was 20. 9±8. 8 years: and heart-rate responses to a variety of stim­ IDDM (23. 6±7.3 years) ; NIDDM (12. 6±7. 9 uli, the relative importance of each compo­ years) . The control group consisted of hospital staff nent of the reflex having been determined by and patients attending an ophthalmic casualty selective pharmacological autonomic block­ department who were subsequently determined to have no detectable abnormality. Subjects with ade. Evidence to date confirmsthat these tests medical disorders predisposing to autonomic nerve reflect damage elsewhere in the autonomic dysfunction, or taking medication with effects on nervous system, and represent generalised the autonomic nervous system, were excluded from autonomic nerve function. 7.8,9 the study. A standard series of cardiovascular

From Department of Ophthalmology, U nive rsity of Edinburgh, Princess Alexandra Eye Pavilion, Edinburgh Correspondence to: Mr. C. V. Clark, MD FRCS, Moorfields Eye Hospital, City Road, London ECI V 2PD Presented at the Moorfields Alumni Meeting, January 1987. AUTONOMIC NEUROPATHY IN PROLIFERATIVE DIABETIC RETINOPATHY 497

Table I. Cardiovascular autonomic function tests during the 5 beats before lying to the shortest during the 10 beats after lying down. Parasympathetic nerve function i. Heart-rate variation during deep breathing ii. Immediate heart-rate response to standing Sympathetic nerve function iii. Immediate heart-rate response to lying Systolic blood pressure response to standing iv. Valsalva manoeuvre A fall in blood pressure is precipitated by gravita­ Sympathetic nerve function tional pooling of blood in the lower extremities. i. Systolic blood pressure response to standing Significant fluctuations in blood pressure during ii. Diastolic blood pressure response to sustained alteration in posture is prevented by an intact bar­ isometric muscular contraction oreflex arc, effecting peripheral and splanchnic vas­ oconstriction via sympathetic efferent nerves. The immediate difference between systolic blood pres­ sure lying and standing is the postural change in autonomic function tests are shown in Table 1. blood pressure. These are simple, non-invasive tests, without known side-effects, however there are potential All subjects were in normal sinus rhythm, an complications in this particular group of patients essential prerequisite to cardiovascular autonomic which required modification of the standard function assessment. methods. Valsalva manoeuvre and raising blood Long-term glycaemic control was assessed by pressure-as occurs in the diastolic blood pressure glycosylated haemoglobin, using a micro-column response to sustained isometric muscle con­ technique,14 and an estimation of renal function traction-involve a rare, potential risk of vitreous was obtained by measurement of plasma haemorrhage in subjects with retinal neo­ creatinine .15 vascularisation, and therefore these tests were omitted. The test regimen employed in prolifera­ Statistical analysis tive retinopathy was therefore: Comparisons were made between the results of the Parasympathetic nerve function control group and diabetic patients with prolifera­ (i) Heart-rate variation during deep breathing tive retinopathy; significance was assessed by Stu­ There are many different techniques of assessing dent's unpaired t test. Results are expressed as respiratory sinus arrhythmia;IO.11.12.13 one of the mean ±SEM. standard methods is to request the subject to breathe at a rate of 6 deep breaths/minute. whilst recording a continuous electrocardiogram. In Results normal subjects, a relative tachycardia occurs The results of cardiovascular autonomic func­ during inspiration, with a relative bradycardia tion assessment in 28 diabetic patients with during expiration. Maximum and minimum R-R proliferative retinopathy and 61 age- and sex­ intervals are measured and expressed as beats/min­ matched control subjects are shown in Table ute, and the final result is the mean of the differ­ II. Results of all parasympathetic nerve func­ ences between maximum and minimum heart­ tion tests were significantly lower in diabetics rates. with proliferative retinopathy than the control (ii) Immediate heart-rate response to standing During alteration in posture from lying to standing group, with significance at the 0.1 per cent a characteristic cardiovascular reflex response level. Sympathetic nerve function was not sig­ occurs under vagal control, consisting of an initial nificantlydifferent. Age-adjusted normal tol­ tachycardia, maximal at about the 15th beat after erance intervals in the control group were standing, followed by a relative bradycardia around calculated for each individual test by linear the 30th beat. R-R intervals are measured to deter­ regression analysis; the data were fitted mine the shortest around the 15th beat and longest according to various mathematical models at about beat 30, and the result expressed as the using the computer programme SPSSx on an 30: 15 ratio. IBM 4341 computer to obtain a normal distri­ Immediate heart-rate response to lying (iii) bution on age, thus permitting determination A similar, though distinctly separate reflex occurs during alteration in posture from standing to lying. of tolerance intervals.16 Values below the A tachycardia occurs during the 3rd-4th beat after 2.5th percentile were arbitrarily designated commencing the manoeuvre; the reflex is repre­ abnormal. In every test of autonomic nerve sented by the ratio of the longest R-R interval function, abnormal values were significantly 498 CHARLES V. CLARK

Table II. Results of cardiovascular autonomic function assessment in 28 diabetic patients with proliferative diabetic retinopathy and 61 age- and sex-matched control subjects (Group mean values ± SEM)

Control group PDR Significance

Parasympathetic nerve function i. Heart-rate variation (beats/min) 18. 24±0. 93 1O. 08±1. 42 p0.05

Table III. The proportion of diabetics with proliferative retinopathy and control subjects with abnormal results of cardiovascular autonomic nerve function, defined by the age-adjusted normal tolerance limit at the lower 2.5th percentile

Control group PDR Parasympathetic nerve function i. Heart-rate variation 1. 3% 64.3% ii. 30:15 ratio 2. 6% 11.1% iii. S:L ratio 1. 3% 25. 0% Sympathetic nerve function Postural hypotension 2. 6% 28. 6%

elevated in diabetics with proliferative reti­ provides an accurate and quantifiable nopathy (Table III). measurement of a nervous system previously Autonomic dysfunction is defined as an virtually impossible to isolate. Heart-rate is abnormal result of at least one autonomic determined by the autonomic nervous system, function test. By this criterion, the prevalence and represents a balance between sympa­ of parasympathetic neuropathy in prolifera­ thetic and parasympathetic effects.17.18 tive diabetic retinopathy was 67.9 per cent, Although each test may be used individually, with sympathetic neuropthy in 28.6 per cent of the application of a series of tests provides a patients, compared with values in the control detailed assessment of systemic autonomic group of 2.6 per cent respectively. Neuropa­ nerve function. thy involving both parasympathetic and sym­ Diabetes mellitus is the commonest cause pathetic nerves was present in 21.5 per cent of of autonomic neuropathy in this country; diabetics with proliferative retinopathy; no approximately 17-30 per cent of randomly member of the control group had evidence of selected diabetics have abnormal autonomic both parasympathetic and sympathetic function, a prevalence confirmed by several neuropathy. large studies. 5.19.20,21 By definition,this popula­ Glycosylated haemoglobin was moderately tion will include patients with proliferative elevated in diabetics with proliferative reti­ retinopathy, and therefore the prevalence in nopathy (10.3±0.42 per cent; normal range diabetics without retinopathy is propor­ 6.0-8.5 per cent). Serum creatinine levels tionately less. Cardiovascular autonomic neu­ were not excessively abnormal in the diabetic ropathy is present in 75 per cent of diabetic group (104.5±8.31 flmolll; normal range subjects with proliferative retinopathy, which 55-110 flmolll); abnormal results were pres­ is the highest prevalence of secondary autono­ ent in only 5 diabetic patients. mic neuropathy recorded to date. Glycaemic control and renal function were not exces­ Discussion sively abnormal in these patients, and there­ Clinical assessment of autonomic nerve func­ fore this could not be considered merely a tion based upon cardiovascular reflex tests manifestation of severity of diabetes. AUTONOMIC NEUROPATHY IN PROLIFERATIVE DIABETIC RETINOPATHY 499

Similarly, duration of diabetes was relatively 8 Ewing DJ, Campbell IW, Clarke BF: The natural history of diabetic autonomic neuropathy. Quart unremarkable. J Med 1980, 49: 95-108. In conciusion, this study has demonstrated 9 Campbell IW, Heading RC, Tothill P, Buist TAS, a significant association between cardio­ Ewing DJ, Clarke BF: Gastric emptying in dia­ vascular autonomic neuropathy and prolifera­ betic autonomic neuropathy. Gut 1977, 18: 462-7. tive diabetic retinopathy. The exact nature of 10 Murray A, Ewing DJ, Campbell IW, Neilson JMM, this relationship remains to be defined, how­ Clarke BF: R-R interval variations in young ever severe impairment of autonomic control male diabetics. Br Heart J 1975,37: 882-5. II Gundersen HJC, Neubauer B: A long-term diabetic of the cardiovascular system may be a contrib­ autonomic nervous abnormality. Reduced varia­ uting factor to the development of retinal neo­ tions in resting heart rate measured by a simple vascularisation in diabetes mellitus. and sensitive method. Diabetologia 1977, 13: 137-40. 12 Bennett T, Farquhar IK, Hosking DJ, Hampton JR: I thank Dr D. J. Ewing, Univer�ity of Edinburgh, Assessment of methods for estimating autonomic for advice relating to Autonomic Functional nervous control of the heart in patients with Assessment. diabetes mellitus. Diabetes 1978, 27: 1167-74. 13 Wheeler T, Watkins PJ: Cardiac denervation in diabetes. Br Med J 1973, iv: 584-6. References 14 Baron MD, Shenouda FS, Sonksen PH: Micro­ I Ewing DJ, Borsey DQ, Bellavere F, Clarke BF: column method of HbAI determination. Lancet Cardiac autonomic neuropathy in diabetes: com­ 1980, i: 1114-6. parison of measures of R-R interval variation. 15 Gabriel R: Time to scrap creatinine clearance? Br Diabetologia 1981, 21: 18-24. Med J 1986, 293: 1119-20. 2 Levin AB: A simple tests of cardiac function based 16 Nie NH: A complete guide to SPSSx language and upon the heart-rate changes induced by the Val­ operations New York: McGraw Hill, 1983. salva manoeuvre. Am J Cardiol1966,18: 90-9. 17 Higgins CB, Vatner SF, Braunwald E: Parasympath­ 3 Ewing DJ, Campbell IW, Murray A, Neilson JMM, etic control of the heart. Pharmacal Rev 1973,25: Clarke BF: Immediate heart-rate response to 119-55. standing: simple test for autonomic neuropathy 18 Levy MN: Sympathetic-parasympathetic interac­ in diabetes. Br Med J 1978, i: 145-7. tions in the heart. Circ Res 1971, 29: 437-45. 4 Bellavere, F, Ewing DJ: Autonomic control of the 19 Hulper B, Willms B: Investigations of autonomic immediate heart-rate response to lying down. diabetic neuropathy of the cardiovascular Clin Sci 1982, 62: 57-64. system. In: FA Gries, HJ Freund, F Rabe and H 5 Ewing DJ, Irving JB, Kerr F, Wildsmith JAW, Berger (eds). Aspects of autonomic neuropathy Clarke BF: Cardiovascular responses to sus­ in diabetes. New York: George Thieme Verlag, tained handgrip in normal subjects and in 1980: 77-80. 20 patients with diabetes mellitus. Clin Sci Mol Med Dyrberg T, Benn J, Christiansen JS, Hilsted J, 1974, 46: 295-306. Nerup J: Prevalence of diabetic autonomic neu­ 6 Hilsted J, Galbo H, Christensen NJ, Parving H-H, ropathy measured by simple bedside tests. Benn J: Haemodynamic changes during graded Diabetologia 1981, 20: 190-4. exercise in patients with diabetic autonomic neu­ 21 Chipps DR, Kraegen EW, Zelenka GS, McNamara ropathy. Diabetologia 1982,22: 318-23. ME, Chisholm DJ: Cardiac beat to beat varia­ 7 Ewing DJ, Campbell IW, Burt AA, Clarke BF: Vas­ tion: age related changes in the normal popula­ cular reflexes in diabetic autonomic neuropathy. tion and abnormalities in diabetics. Aust NZ J Lancet 1973, ii: 1354-6. Med 1981,11: 614-20.