1053
EVIDENCE OF VAGAL NEUROPATHY IN CHRONIC ALCOHOLICS R. H. JOHNSON E. A. WHITESIDE
G. DUNCAN D. G. LAMBIE
Wellington Clinical School of Medicine, Wellington Hospital, Wellington 2, New Zealand
Autonomic function was tested in healthy control subjects and 20 chronic alcoholic patients with varying degrees of alcohol-related peripheral and central neurological damage. The alcoholics were divided into two groups according to the severity of their symptoms and signs. The alcoholic subjects had no postural hypotension. However, heart-rate responses to Valsalva’s manœuvre, deep breathing, change in posture, baroreceptor stimulation, and atropine were lower in those alcoholics with a greater degree of peripheral and central nervous damage than in the less severely affected alcoholics and the controls. These results suggest that chronic vagal damage may be a feature of alcoholic polyneuropathy.
Summary
Introduction CLINICAL symptoms of chronic autonomic dysfunction the cardiovascular system are not common in alcoholic patients, although acute alcoholism may cause i temporary orthostatic hypotension. A study of the sympathetic nervous system in chronic alcoholics found no significant disturbance of blood-pressure control, which correlated well with the absence of pathology in the greater splanchnic nerve, although impaired sweating occurred in a glove-and-stocking distribution in patients with chronic alcoholic neuropathy.2 There was no clear evidence of parasympathetic failure. However, parasympathetic vagalnerve degeneration has been described in three chronic alcoholics at necropsy, one of whom also had damage to nerves of the sympathetic trunk.3 In the present study we investigated the circulatory reflexes of chronic alcoholic patients for evidence of parasympathetic
affecting
vagal damage. Subjects
and Methods
Subjects 6 healthy male controls aged 39 to 51 years (mean 46 years) and 20 chronic alcoholic men aged 33 to 69 years (mean 50 years) were studied. 2 of the controls were abstainers and 4 drank alcohol not more than once a week. The alcoholics were all undergoing rehabilitation and had abstained from alcohol for 2 weeks to 3 years (mean 6 months) at the time of the study. They formerly drank 100 to 300 g ethyl alcohol daily for 12 to 40 years. None of the subjects had clinical symptoms of hypertension or heart disease, but the alcoholic patients had varying degrees of alcohol-related
-
neurological damage (see table). Clinical Assessment
:
along
a
Autonomic Tests Postural change. -The subject lay on a tipping table. After 15 min of supine rest the subject’s blood pressure (BP) and heart rate (HR) were recorded three times with a standard arm sphygmomanometer and electrocardiograph (ECG). The subject was then rapidly tipped in 2-3 s until standing, and BP was recorded at 30 s intervals for 2 min (or longer if BP had not stabilised). Mean BP was calculated as diastolic pressure + 1/3 (systolic - diastolic pressure). HR was continuously monitored during and after tipping at a fast chart speed (50 mm/s), and the 30 : 15 ratio was calculated, as the ratio of the R-R interval at beat 30 after standing (approximate time of longest interval) to the R-R interval at beat 15 after standing (approximate time of shortest interval). The test was repeated twice and the highest 30 : 15 ratio obtained was accepted. The test was carried out as described by Ewing,4except that in our patients the heart-rate change was measured after tipping rapidly in 2-3 s. They then stood on a foot-board attached to the table. Valsalva manœuvre.-The subject was studied supine and trained to maintain an expiratory pressure of 40 mm Hg for 10 s by blowing through a mouthpiece and tubing attached to an anaeroid manometer. A small leak was provided in the manometer tubing to prevent the subject maintaining pressure with the cheek muscles. During each recorded Valsalva manoeuvre HR was monitored continuously throughout and for 30 s after release of pressure, on the ECG at a fast chart speed (50 mm/s). The Valsalva ratio was calculated as the ratio of the longest R-R interval after the manceuvre to the shortest R-R interval during the manœuvre.5 The test was repeated twice and the highest ratio accepted. Deep breathing.-The subject was trained to breathe deeply at a rate of 6 breaths/min while supine. HR was then monitored continuously on the ECG at 50 mm/s as the subject breathed deeply for at least 1 min. The heart-rate change with breathing was then calculated from the average maximum R-R interval during deep expiration and the average minimum R-R interval during deep inspiration. This was carried out as described by Wheeler and Watkins,except that heart-rate changes were measured from an ECG rather than an instantaneous heart-rate meter. Baroreceptor stimulation.-The baroreceptors were stimulated by application of negative pressure to the subject’s neck with apparatus as described by Eckberg et al. A suction control unit attached to a vacuum source was used to create rapidly (within 0 - 5 s) a suction pressure of - 50 mm Hg within the neck collar. The negativepressure stimulus was introduced in the latter two-thirds of the cardiac cycle and maintained for at least 5 s. The changes in R-R interval for five beats from the onset of suction were measured, and the best of three periods of neck suction was accepted. The subjects stopped breathing during neck suction to prevent respiration influencing the R-R interval responses. Atropine test. -Atropine (1. 8 mg) was administered intravenously at a rate of 0 - 6 mg/ml/min, with an interval of 1 min between successive 0 - 6 mg doses. HR was monitored throughout infusion of atropine and until the HR reached a maximum (5 to 10 min). The maximum change in HR from rest was calculated.
Statistics The results for the groups of alcoholic patients and normal controls were compared with Student’s t-test.
of Neurological Damage
The alcoholic patients were examined and scored one for each of the following neurological abnormalities: 1. Absent ankle jerks. 2. Absent vibration sense (128 c/s) at the ankles. 3. Amnesia (inability to repeat six serial numbers). 4. Dementia (inability to recall date or home address or to do "100 minus 7" test). 5. A positive tandem gait (instability in walking heel to toe
The patients were then divided into two groups on the basis of their clinical score-group 1 with clinical score <3 and group 2 with clinical score 3.
straight line).
Results Clinical Assessment When the alcoholic patients were examined, their drinking histories and clinical scores were obtained. The patients were then divided into two groups on the basis of their clinical scores (see table). Group-1 alcoholics had a clinical score of< 3 and consisted of 13 patients (mean age 47±9), 6 with a
1054 CLINICAL DETAILS AND ABNORMALITIES IN TESTS OF VAGAL FUNCTION IN ALCOHOLIC PATIENTS AND CONTROLS I
I
I
regular and7 with a bout drinking habit of 100-300 g (mean 243 g) daily ethanol of 12-30 years’ (mean 21 years) duration. Group-2 alcoholics had a clinical score of≥, 3 and consisted of 7 patients (mean age 53±10 years), with a regular drinking habit of 150-350 g (mean 242 g) daily ethanol of 20-40 years’ (mean 29 years’) duration. The mean ages of the patients in the two groups were not significantly different, nor were they significantly different from the mean age of the controls. The daily ethanol intakes of the two alcoholic groups were not significantly different, but the alcoholics in group 2 had a significantly longer (p< 0. 02) drinking history than those of
significantly less in group-2 alcoholics than normal subjects (p<0 . 001) and group-1 alcoholics (p
group 1.
beat-to-beat variation below the lower normal limit of 15
were
beats/min.6
Autonomic Tests Postural change.-The mean BP of normal subjects and the groups of alcoholics before rapid head uptilt are illustrated in fig. 1, and the resting HR are given in the table. The HR changes (30 : 15 ratios) with tipping are shown in fig. 2. There were no significant differences in BP, either supine or after tilting, between controls and either group of alcoholics, nor between group-1 and group-2 alcoholics, and there was no evidence of postural hypotension in any subject; alcoholic subjects tended to show less increase in mean BP on standing than did controls, but this difference was not significant (p>O. 1). There were no significant differences in resting HR between normal subjects and either alcoholic groups, nor between group-1 and group-2 alcoholics. However, the 30 : 15 ratios were significantly less in group-2 alcoholics than in normal subjects (p
Fig. I-Changes in mean blood-pressure on tilting in normal subjecc. and group- and group-2 alcoholic patients.
1055
1 22 Normal
Alcoholic
Fig. 2-Heart-rate change (30 :15 ratio) after tilting from lying position in normal subjects and group-1 and group-2 alcoholic patients. Normal range
responses. The normal range of increase in R-R interval with neck suction is uncertain but, taking 80 ms as the lower limit of normal, 4 alcoholic patients showed abnormal responses. 1 subject (patient 14) showed no response of HR to neck
suction.
.1 -03.
stimulation.-The mean R-R interval for normal and alcoholic subjects are shown in fig. responses 5 (9 out of 13 group-1 subjects and all 7 group-2 subjects being tested). There was considerable variation in individual responses, particularly in normal subjects (maximum increase in R-R interval 80-113 ms), making statistical comparison difficult. Nevertheless, the alcoholic subjects showed a smaller increase in R-R interval than normal subjects, and group-2 alcoholics displayed the smallest
Baroreceptor
Atropine.-The changes in HR after intravenous atropine in normal and alcoholic subjects are shown in fig. 6. The alcoholics in group 2 showed significantly lower HR and group-1 responses than normal subjects (p<0-001) alcoholics (p<0’001), there was no significant difference between group-1 alcoholics and normal subjects. 9 of 17 alcoholics showed HR responses to atropine below 30 beats per min. Patients were regarded as having vagal neuropathy if they showed abnormalities in two or more of the tests described above. By this criterion 1 patient of 13 in group-1 and 6 patients of 7 in group-2 had vagal neuropathy. There was thus a highly significant (x2 = 11-22, p<0’ 001) difference
Fig. 5-Increases in heart-rate during the first five beats after onset of Fig. 3-Valsalva ratio in normal subjects alcoholic patients. Normal range 1 - 50.
and
group-1
and
group-2
neck suction.
Means of results for 6 normal alcoholics in group-2.
subjects,
9 alcohohcs in
group-1
and 7
1056
Fig. 6-Heart-rate response to atropine (1-8 mg i.v.) subjects and group-1 and group-2 alcoholic patients.
than controls when doing graded exercise.9 In addition. studies of diabetic subjects with abnormal cardiovascular reflexes have revealed a poor prognosis. Of 37 diabetic patients with signs of autonomic neuropathy who were followed for 21f2 years, 5007o died in that period.’° The cause of increased mortality is unknown, but one factor may be damage to respiratory reflexes. Page and Watkins Ireported 12 unexplained respiratory arrests in diabetic subjects with autonomic neuropathy. Subjects with autonomic neuropathy probably have a diminished hypoxic drive to ventilation. experimentally the ventilatory response to hypoxia can be inhibited by vagal blockage. 12 Low et al .,2 in a study of alcoholics with clinical and electrophysiological signs of peripheral neuropathy, found an abnormally low Valsalva ratio in 2 of 9 patients studied but considered that this could be related to differences in age and resting blood-pressure in their subjects. In our study 7 of 13 patients with peripheral neuropathy showed an abnormal Valsalva ratio. In our subjects there was no statistical difference in age or in resting BP, and the differences maybe related to their degree of sympathetic and parasympathetic damage. In our study, patients showing abnormalities in Valsalva ratio and in other tests had not only peripheral neuropathy but also damage to the central nervous system; clinical findings of neurological damage are not reported by Low et aI.,2 but their patients probably showed less severe nervous damage than did the subjects described here. Myers et aI.l3 found no "blunting" of the Valsalva reponse in any of 44 alcoholics, and in these patients also there was no parasympathetic denervation of the iris. 16 of their patients had evidence of peripheral neuropathy, including depressed ankle jerks, but no information is given on other neurological
in normal
Normal range 30 beats/mm.
between the two groups, confirming that vagal neuropathy is seen only in those alcoholic patients with major nervous
damage. The results of tests ofvagal function showed generally good (see table). However, for the 30 : 15 ratio, 4 patients showed normal results who were classed as having vagal neuropathy by other results; stimulation of carotid baroreceptors by neck suction also failed to show abnormalities in 3 patients. Tests of HR changes with atropine, Valsalva manoeuvre, and deep breathing agreed well; correlating results of measured values in all subjects (controls and patients) from all tests, the best correlations were found between HR increase with atropine and Valsalva ratio or HR change with deep breathing (r 0 - 744 andr = 0 - 679 respectively, p
agreement
=
Discussion
Although, as Low and others found,2severe damage to the sympathetic nervous system, with orthostatic hypotension, is rare in alcoholics, we have found that abnormalities in parasympathetic nervous control of the HR are common in alcoholics with clinical signs of brain damage and peripheral neuropathy. A study on alcoholics with peripheral neuropathy found reduced oesophageal motility, which, it was speculated, might be due to vagal dysfunction.8 Novak and Victor3described 4 alcoholic patients with severe nervous damage in whom dysphagia and hoarseness were prominent symptoms; post-mortem examination of 3 of these patients revealed substantial degeneration of the vagus nerves comparable to the changes seen in peripheral nerves. Our study shows that vagal damage in alcoholics may be exhibited clinically (as is found in diabetics with peripheral neuropathy) in abnormalities of cardiovascular reflexes and HR response to atropine. This is important, for a vagal neuropathy could contribute to poor exercise tolerance. Diabetics with autonomic neuropathy have been found to show less change in heart-rate and a lower tolerable workload
deficits. ,
Comparing results of different tests of vagal function in the present study, we can draw some conclusions about the relative value of these tests in the diagnosis of autonomic neuropathy. It can be seen from the table that there was generally good agreement between results of all tests, although in tests of 30 :15 ratio, deep breathing, and baroreceptor stimulation there was in each case at leastI subject who showed normal results despite showing abnormalities in two or more other tests. The tests of immediate HR response to postural change and stimulation of carotid baroreceptors by neck suction appeared less satisfactory. The insensitivity of the test of HR response to tipping is surprising; Ewing et al. found the 30:15 ratio to be abnormal in all diabetics with autonomic neuropathy, and a study of autonomic neuropathy in patients on chronic be a more sensitive haemodialysis found the 3015 ratio to 14 test than the Valsalva-manoeuvre ratio. It is possible that the heart-rate response to tipping, as carried out in the present study, is a less sensitive test than the heart-rate response to standing, which was the method used by Ewing. Tests of Valsalva’s manoeuvre and intravenous atropine both showed abnormal results for all patients who, as judged from overall results, had autonomic neuropathy, but in the former case there were 3 patients, and in the latter case 1 patient, who might be judged as "false positives". The HR change with atropine is probably the most sensitive test of vagal neuropathy, but Valsalva’s manoeuvre or deep
breathing are almost equally satisfactory and, being noninvasive, are preferable. Chronic vagal damage is a not-uncommon feature 0:’ alcoholic polyneuropathy. It can be easily diagnosed or measuring HR responses to Valsalva’s manceuvre or dee
1057
breathing; measurement of HR response to standing, although a satisfactory test in diabetics, may not indicate the true prevalence of autonomic neuropathy associated with alcoholism. Further studies will be needed to establish the importance of vagal damage in mortality associated with alcoholism. This work was supported by a grant from the Alcoholic Liquor Advisory Council of New Zealand. D. G. L. was in receipt of a grant from Reckitt & Colman (New Zealand) Ltd.
Requests for reprints
should be addressed
to
R. H.
J.
REFERENCES
1. Barraclough MA, Sharpey-Schafer EP Hypotension from absent circulatory reflexes. 2 3. 4
5. 6 7.
Lancet 1963; i: 1121-26. Low PA, Walsh JC, Huang CY, McLeod JG. The sympathetic nervous system in alcoholic neuropathy. A clinical and pathological study. Brain 1975; 98: 357-64. Novak DJ, Victor M. The vagus and sympathetic nerves in alcoholic neuropathy. Arch Neurol 1974; 30: 273-84. Ewing DJ, Campbell JW, Murray A, Neilson JMM, Clarke BF Immediate heart-rate response to standing: simple test for autonomic neuropathy in diabetes. Br Med J 1978; i: 145-47. Levin AB. A simple test of cardiac function based upon the heart rate changes induced by the Valsalva manoeuvre. Am J Cardiol 1966; 18: 90-99. Wheeler T, Watkins PJ. Cardiac denervation in diabetes. Br Med J 1973; iv: 584-86. Eckberg DL, Cavanagh MS, Mark AL, Abboud FM. A simplified neck suction device for activation of carotid baroreceptors. J Lab Clin Med 1975; 85: 167-73.
8. Winship DH, Caflisch CR, Zboralske FF, Hogan WJ. Deterioration of oesophageal peristalsis in patients with alcoholic neuropathy Gastroenterology 1968; 55: 173-78. 9. Hilsted
Calbo H, Christensen NJ Impaired cardiovascular responses to graded in diabetic autonomic neuropathy. Diabetes 1979; 28: 313-19. Ewing DJ, Campbell JW, Clarke BF. Mortality in diabetic autonomic neuropathy. Lancet 1976; i: 601-03. Page MM, Watkins PJ. Cardiorespiratory arrest and diabetic autonomic neuropathy. Lancet 1978; i: 14-16.. Phillipson EA, Hickey RF, Bainton CR, Nadel JA. Effect of vagal blockade on regulation of breathing in conscious dogs. J Appl Physiol 1970; 29: 475-79. Myers W, Willis K, Reeves A. Absence of parasympathetic denervation of the iris in alcoholics. J Neurol Neurosurg Psychiat 1979; 42: 1018-19. Bach C, Iaina A, Eliahou HE. Autonomic nervous system disturbance in patients on chronic hemodialysis. Israel J Med Sci 1979; 15: 761-64.
J,
exercise
10. 11 12 13 14
Introduction THYROID microsomal antibodies (TMA) in serum correlate with lymphoid infiltration of the thyroid gland 1,2 and are detected in most patients with Hashimoto’s thyroiditis and Graves’ disease. However, the diagnostic and pathogenetic significance of TMA is not clear since some studies have shown a population frequency of up to 12% and even higher in the elderly.3-9 Furthermore, TMA may be associated with viral disease, or with other, non-thyroid autoimmune diseases, including pernicious anaemia, insulindependent diabetes mellitus, and myasthenia gravis2,11.13 We have made use of the long-term multidisciplinary health survey of the population of Busselton, Western Australia, to study the diagnostic value of the finding of TMA in a normal population. Features studied were the time course of TMA over a six year period, and the relationship to serum thyroid stimulating hormone (TSH).
Population and Methods Population Busselton is a rural community with an adult population of approximately 8600. Since 1966 the population has been taking part in a longitudinal multidisciplinary health survey in which between 3000 and 4000 adults provide blood samples for study and answer -health questionnaires every three years. The population was tested for TMA in 1969 and 1975.’4 This study is based on 2838 respondents tested in 1975, and the 1587 who
were
also tested in 1969.
Questionnaire The questionnaire in 1969, 1972, and 1975 included the following questions: (a) Have you ever had any thyroid disease? (b) If yes, please indicate whether overactive thyroid, underactive thyroid, enlarged gland or goitre, other thyroid disease? (c) Have you ever been treated for a thyroid condition? (d) If yes, was this by neck operation, radioactive iodine or tablets? The questionnaires also asked for details of recent drug medication. These questions were used to obtain an indication of the general health of the respondents. Immunofluorescence
DIAGNOSTIC SIGNIFICANCE OF THYROID MICROSOMAL ANTIBODIES IN RANDOMLY SELECTED POPULATION B. R. HAWKINS R. L. DAWKINS H. G. BURGER I. R. MACKAY
P. S. CHEAH S. WHITTINGHAM Y. PATEL T. A. WELBORN
Departments of Clinical Immunology, Rheumatology, and Endocrinology, Sir Charles Gairdner Hospital, Queen Elizabeth II Centre, Nedlands, Western Australia; Clinical Research Unit, Walter & Eliza Hall Institute for Medical Research, Parkville, Victoria; and Monash University Department of Medicine, and Medical Research Centre, Prince Henry’s Hospital, Medical
Melbourne
TMA were defined by reactions with human thyroid tissue resected from blood group 0 patients undergoing surgery for thyroid hyperplasia. The immunofluorescence procedures are described elsewhere. 8,14
Serum TSH The double antibody radioimmunoassay of Patel et al. 10 was used establish serum TSH on subjects found to have TMA in the 1969 and/or 1975 surveys, and a control group of 117 healthy adult subjects who were negative to TMA (56 female, 61 male). In the control group the mean TSH was 1 - 0 mU/1 (range 0 - 2 - 13 - 6). 2 (1 - 7%) of the 117 controls had a TSH (61 and 13 -6 mU/1) above the upper limit of the reference range (3 - 6 mU/1) used in local hospital to
practice. Analysis recorded on computer punch cards and analysed on 73’ computer. The Statistical Package for the Social Sciences was used to determine frequency distributions and to obtain cross-tabulations and chi-square indices of heterogeneity. Data
Summary
A
longitudinal study among the population
of Busselton, Western Australia, has identified individuals with persistent and transient thyroid microsomal antibodies (TMA). 59 (72%) of 82 subjects with persistent TMA, 18 (72%) of 25 with recently developed TMA, and 12(23%) of 53 with transient antibody were found have subclinical
hypothyroidism, as indicated by high thyroid stimulating hormone concentrations. This study reveals the high specificity, sensitivity, and predictive value of persistent or recently acquired TMA. to
serum
a
were
’Cyber
Results
Prevalence
of TMA
In the 1975 survey, 190
(6-7%) of the 2838 subjects tested for The TMA. positive prevalence was 9 - 8% in females and 2 - 801o in males =52.9, p