Autonomic neuropathy in diabetes mellitus.
Autonomic neuropathy is a frequent and often disabling complication of diabetes mellitus. Failure to recognize symptoms in a diabetic as due to autonomic neuropathy may lead to a lot of unnecessary investigations and sometimes to wasteful treatment such as testosterone in sexual impotence. Relatively simple tests help to demonstrate the presence of autonomic neuropathyir, though a more detailed analysis needs sophisticated equipment such as a tilt-table or a pulse transducer.
The present study was undertaken to determine the frequency and pattern of autonomic neuropathy in diabetic patients.
A selective group of thirty-three well controlled diabetics (27 men and 6 women) who had had the disease for at least five years (17 had it for 10 years or longer) was investigated for the presence and the pattern of autonomic neuropathy. Their ages ranged from 36 to 76 years, with a mean of 57.8 years. Thirty-one were maturity-onset diabetics and two were juvenile diabetics. Twenty-six patients were on oral hypoglycemic drugs whereas seven were on insulin.
Before inclusion in the study, the patients were carefully screened to rule out (a) uncontrolled diabetes, (b) gross nutritional deficiency, (c) exposure to alcohol, lead, neurotoxic drugs (INH) and drugs affecting the autonomic function and (d) established disease of the major organs (heart, lungs, kidneys, central nervous system and gastro-intestinal tract) .
The selected patients were questioned about the presence of symptoms reported to be related to autonomic neuropathy viz., postural giddiness, nocturnal polyuria disturbances of bladder sphincter, constipation, diarrhoea, impotence and bouts of localized sweating. They underwent a detailed physical examination with special reference to somatic peripheral neuropathy and were finally tested for autonomic neuropathy by the following tests:
1. Orthostatic change in pulse rate: Pulse rate was counted first in the supine and then in the standing positions. A rise of less than 10 beats per minute on rising was considered abnormal.
2. Orthostatic change in blood pressure: Blood pressure in the right arm was recorded with a sphygmomanometer first with the patient supine and again after the patient had been standing for 10 minutes. Orthostatic hypotension was considered to be present if giddiness or syncope occurred along with a fall in blood pressure of at least 30/20 mm Hg.
3. Cilio-spinal reflex: The skin over the lower, lateral aspect of the neck was pinched sharply. Absence of pupillary dilatation was taken as an indication of sympathetic paralysis.
4. Pupillary response to epinephrine: Two drops of 1:1000 epinephrine solution were instilled into each eye. Dilatation of the pupils was taken as evidence of ocular sympathetic paralysis.
5. Bloodless phlebotomy: Sphygmomanometer cuffs tied around both thighs were inflated to just below the diastolic pressure for 10 minutes. A fall of more than 10 mm of Hg in the mean blood pressure (diastolic pressure + 1/3rd the pulse pressure) in the right arm was taken as an indication of autonomic neuropathy.
6. Cold-pressor test: The patient's both hands were kept immersed upto the wrists in ice-cold water for one minute. Failure of the blood pressure to rise by 16-20 mm Hg systolic and 12-15 mm Hg diastolic was taken as an indication of autonomic neuropathy.
7. Valsalva manoeuvre: The patient was asked to blow into a mercury sphygmomanometer and to maintain the pressure at about 40 mm Hg for about 30 seconds. The pulse rate and pressure were recorded using a pulse-transducer attached to the left index finger. Absence of tachycardia in phase II suggested paralysis of the cardiac sympathetic. Absence of rebound hypertension in phase IV suggested peripheral vasoconstrictor paralysis; absence of reflex bradycardia in phase IV (inspite of rebound hypertension) suggested paralysis of the cardiac parasympathetic.
8. Blood pressure response to nitroglycerine: The blood pressure was measured in the right arm before and after sublingual administration of 0.4 mg of nitroglycerine, with the patient lying supine. A fall of blood pressure by more than 15 mm Hg systolic and more than 5 mm Hg diastolic was taken as an indication of autonomic neuropathy.
Seventeen patients had one or more symptoms. Nine patients complained of nocturnal polyuria. Eight had impotence. Seven had postural giddiness and only 2 had constipation. Disturbances of bladder sphincter, diarrhoea or bouts of localised sweating were not seen in any patient.
Nine patients (27.4%) had no objective evidence of autonomic neuropathy. Frequency of abnormal responses to tests of autonomic function is depicted in [Table 1]. Twenty-four (72.3%) had abnormal responses to between one and four tests. The most frequent abnormalities were (a) absence of adequate tachycardia on standing up and (b) an abnormal fall of blood pressure after sublingual nitroglycerine. Each test was positive in 15 (57.7%) patients; at least one of them was positive in 20 (77%) patients whereas both tests were positive in 10 (38.5%) patients.
More than half of the asymptomatic patients had objective evidence of autonomic neuropathy, while 90% of symptomatic patients had abnormal responses to the tests.
Sixteen patients had both somatic peripheral neuropathy and autonomic neuropathy. Ten patients had autonomic but not somatic neuropathy, whereas 3 patients had somatic but not autonomic neuropathy. Only 2 patients had neither neuropathy present.
Six out of 8 patients in the 36 to 50 years age group, 11 out of 13 in 50-59 year age group and 9 out of 12 in the age group of 60 and above had autonomic neuropathy. Thirteen out of 16 patients having diabetes for 5-9 years and 13 out of 17 patients with diabetes of more than 10 years were found to have autonomic neuropathy. Thus the frequency of autonomic neuropathy bore no relationship to the age of the patient or to the duration of diabetes in excess of 5 years.
Out of the seven patients who comlained of giddiness and blackout on standing, only 3 showed objective evidence of postural hypotension. This might be because of the stringent criteria adopted in this study.
One patient had evidence of failure of peripheral vasoconstrictor mechanism as suggested by an abnormal fall in blood pressure during bloodless phlebotomy and following nitroglycerine, by absence of rebound hypertension during phase IV and Valsalva manoeuvre and by giddiness on arising from the recumbent posture. However, he did not have sufficient fall of blood pressure on standing to merit the diagnosis of postural hypertension.
Four patients had evidence of healed, past, painless myocardial infarction. None of them was in failure nor on digitalis. In 3 of them, there was evidence of autonomic neuropathy.
Abnormal pupillary response to epinephrine was the only evidence of autonomic neuropathy in one patient.
Autonomic neuropathy is frequent in diabetics. Some evidence of it was found in 26 out of 33 (78.8%) patients in this study: 24 had at least one test abnormal; nine of them were asymptomatic. But, of the 17 who had symptoms, only two did not show abnormal response to any test. Bhatia et al found evidence of autonomic neuropathy (either symptoms or an abnormal response to Valsalva manoeuvre or both) in 29 out of 100 patients they studied.
Sexual impotence was the commonest symptom met with in this study, followed closely by nocturnal polyuria. Sexual impotence is now recognized to be a common and sometimes the only manifestation of autonomic neuropathy. Plasma testosterone levels and testicular biopsy have been reported to be normal in impotent diabetics and testosterone has not been found effective in alleviating it. It would thus appear to be neurogenic in origin. It has been reported that bladder function which is also dependent on intact sacral autonomic pathways is often abnormal in impotent diabetics. Nocturnal polyuria is believed to be due to exaggeration of sympathetic hypofunction during sleep. Disturbances of bladder sphincter are sometimes the earliest symptoms of autonomic neuropathy in diabetics but in general, they are seen in the more advanced cases; they were not seen in this study.
Gastro-intestinal manifestations of autonomic neuropathy have been reported in diabetes: nausea and vomiting due to diminished gastric motility; diarrhoea and nocturnal fecal incontinence due to exaggerated sympathetic hypofunction during sleep; and asymptomatic, functional disturbances of the gall bladders and the esophagus.,  None of these was seen in this study.
Localized bouts of sweating on the face during eating are reported to be diagnostic of diabetic autonomic neuropathy.  They were not seen in this study.
The cardiovascular manifestations of autonomic neuropathy appear to be the most widely studied ones and justifiably so because they are likely to be potentially lethal. Postural giddiness and syncope are the only autonomic symptoms referable to the cardiovascular systems and were seen in 21.2% of the patients in this study. Hypoglycemia, defective peripheral vasoconstriction, defective catecholamine release and impaired baroreceptor afferent mechanism have all been proposed as contributory factors in such postural syncope. Absence of rebound hypertension in phase IV of Valsalva response (suggesting defective vasoconstriction), subnormal response to cold pressor test (suggesting defective catecholamine release) and failure of reflex bradycardia during phase IV of Valsalva response inspite of rebound hypertension (suggesting defective cardiac parasympathetic innervation) were seen in 12.1%, 30.3% and 15.2% of the patients respectively. Abnormal response to nitroglycerine (45.5%) and inadequate rise of pulse rate on standing up (45.5%) were the two commonest abnormalities on objective testing. By contrast, orthostatic change in blood pressure was abnormal in only 9.1% of the patients.
Many workers have reported various disturbances in the cardiovascular responses in diabetics when studied in a variety of sophisticated ways., , ,  Page et al have reported an unexpectedly high occurrence of sudden cardiorespiratory deaths during and after surgery in diabetics with evidence of autonomic neuropathy. Such patients, if spotted before surgery, would benefit from close monitoring during surgery.
Painless myocardial infarction was seen in four patients. Three of them had evidence of autonomic neuropathy. Relative mildness or atypical nature of pain,  and even its absence are well known when diabetics get myocardial infarction. A recent histopathological study has demonstrated typical lesions of neuropathy in the nerve fibres of the heart in diabetics with painless myocardial infarcts but not in controls nor in diabetics with painful infarcts. Thus, absence of pain in myocardial infarction in diabetics may well be due to a lesion of the afferent nerves that conduct pain.
Thus, it will be seen that the cardiovascular system bears the brunt of autonomic neuropathy in diabetics and this may be responsible for certain disabling symptoms, painless myocardial infarction and even sudden death during surgery. It is, therefore, desirable to evaluate in detail the cardiovascular and autonomic status of all diabetics before major surgery.
Abnormal responses to eye tests were seen in 24% of the patients in this study. By using sophisticated electronic gadgetary, Smith et a1 found pupillary abnormalities in all the diabetics they studied. The contribution of such changes to the visual difficulties in the diabetics needs to be assessed.
Measurement of orthostatic change in the pulse rate, and change in blood pressure following nitroglycerine were both abnormal in 38.5% of the patients in this study; at least one of them was abnormal in 77% of the patients. This makes us feel that they can be used as simple bedside screening tests for autonomic neuropathy.
More than half the patients who had no symptoms suggestive of autonomic neuropathy had evidence of it on objective testing. Only two patients who had symptoms had no abnormal test. Autonomic neuropathy was present in 10 out of 12 patients who had no evidence of somatic peripheral neuropathy; Keen has reported similar findings. The frequency of autonomic neuropathy was not related to the age of the patient nor to the duration of diabetes above 5 years. This is consistent with the findings of Ellenberg.
Once autonomic abnormalities are present, they are permanent. sometimes showing progressive deterioration but rarely, if ever, improving. They can affect multiple organ systems in the body, can cause disabling symptoms and have a lethal potential. It is therefore, necessary to be constantly aware of them and to screen the diabetics periodically, and most certainly pre-operatively. Therein lies their safety.
It must be pointed out that the high frequency of symptoms and signs of autonomic neuropathy seen in this study may not be extrapolated to the entire diabetic population as the group studied was a selective one.