Investigations
1st investigations to order
posture test
Test
The initial test to diagnose orthostatic hypotension (OH). Blood pressure should be measured supine or sitting, and after standing for 3 minutes.[29] A fall in systolic blood pressure of at least 15 mmHg can be used when measuring orthostatic vitals from the seated, rather than supine, posture.[27]
It is advisable to take multiple BP measurements.[30] There is evidence to suggest that measurements made at home by the patient may be more effective in detecting OH.[31]
Heart rate should be recorded at the same time as the blood pressure measurements, as the expected tachycardia in response to hypotension is blunted (typically less than 15 bpm in heart rate) when there is an underlying neurogenic cause (e.g., peripheral neuropathy).[2]
These measurements, however, are rarely done routinely, so a careful history is crucial to suspect OH as the cause of the patient's symptoms.
In patients who have OH caused by impaired autonomic cardiovascular reflexes, the increase in heart rate that accompanies the fall in blood pressure is typically diminished (<10 bpm). However, in some patients, particularly those with multiple system atrophy, the heart rate may increase as much as 20 bpm when the fall in blood pressure is profound. Thus, the ratio of heart rate increase to the blood pressure fall is a more precise measure of baroreflex impairment.
A normal rise in heart rate accompanying the fall in blood pressure is typical of patients with depletion of intravascular volume (from dehydration or haemorrhage) or impaired vasoconstrictor tone (usually caused by drugs).
Result
systolic blood pressure falls >20 mmHg (>30 mmHg in patients with hypertension) and diastolic blood pressure falls >10 mmHg within 3 minutes of standing upright; a heart rate increase <0.5 bpm per mmHg systolic blood pressure fall indicates a neurogenic cause
Investigations to consider
tilt-table test
Test
Can be useful when orthostatic hypotension (OH) is not detected during the posture test and the patient gives a history suggestive of OH.
Blood pressure and heart rate (by means of RR intervals on ECG) are measured continuously in the supine position and during passive head-up tilt (usually at 60°).
Upright tilt induces a progressive fall in blood pressure in patients with impaired autonomic cardiovascular reflexes. The increase in heart rate is either absent or abnormally low considering the magnitude of the blood pressure fall.
A fall in blood pressure on head-up tilt accompanied by a large rise (>25 bpm) in heart rate suggests dehydration or impaired vasomotor tone (e.g., varicose veins), frequently as a result of the use of antihypertensive drugs.
Maintenance of blood pressure on upright posture rules out chronic severe OH (i.e., autonomic failure). It does not, however, rule out the possibility of OH that occurs only with aggravating factors such as eating (postprandial hypotension) or exercise. If postprandial hypotension is suspected, the tilt-table test can be repeated after a carbohydrate-rich meal.
Delayed OH can also occur, and requires prolonged tilt (of up to 40 minutes).
Result
beat-to-beat recordings of blood pressure and heart rate reveal an immediate and progressive decline in blood pressure with a small increase in heart rate on head-up tilt
plasma noradrenaline (norepinephrine)
Test
Patients with autonomic disorders that affect post-ganglionic sympathetic nerves, such as pure autonomic failure and diabetic neuropathy, frequently have low plasma noradrenaline (norepinephrine) levels in the supine position.[37] In contrast, patients with autonomic disorders that selectively affect pre-ganglionic sympathetic neurons (e.g., multiple system atrophy) typically have normal plasma noradrenaline (norepinephrine) levels in the supine position.[37]
In normal people, plasma noradrenaline (norepinephrine) levels double on the assumption of the upright posture. In contrast, this response is absent in patients with sympathetic failure (both pre- and post-ganglionic).
Result
blunted increase in noradrenaline (norepinephrine) on standing; plasma noradrenaline (norepinephrine) levels <150 pg/mL usually indicate a severe peripheral neuropathy
deep breathing
Test
Heart rate variability during deep paced breathing (6 breaths/min) is performed as part of a battery of autonomic tests in patients with suspected dysautonomias.
Normally, during inspiration, heart rate increases (RR intervals shorten) and during expiration heart rate decreases (RR intervals lengthen). Diminished variation in RR intervals during inspiration and expiration indicates an abnormality in parasympathetic outflow to the heart. Heart rate variability diminishes with age and is decreased in patients with parasympathetic neuropathy (most frequently due to diabetes). The degree of heart rate variability impairment in diabetes correlates with morbidity and mortality.
This test cannot be interpreted in patients with pacemakers; the test can be difficult to interpret in patients with frequent arrhythmias.
Result
diminished beat-to-beat variation on ECG during inspiration and expiration
Valsalva manoeuvre
Test
The Valsalva manoeuvre is a standard test performed in patients with suspected dysautonomia. It is performed by having the patient blow forcefully, maintaining a pressure of 40 mmHg for 15 seconds. The decrease in venous return and stroke volume lowers blood pressure during strain, and elicits sympathetic activation and partial restoration of blood pressure and compensatory tachycardia. Upon release, venous return and cardiac output is restored on a vasoconstricted vascular bed leading to a blood pressure overshoot and reflex bradycardia.
In normal subjects, the magnitude of the blood pressure and heart rate response during and after release of the strain decrease with age.
In patients with impaired autonomic cardiovascular reflexes, blood pressure falls progressively and markedly during forced expiration and the heart rate increases little. A failure of the blood pressure to increase (overshoot) after releasing the strain indicates sympathetic dysfunction, with an abnormality in the sympathetic outflow to the blood vessels. Blood pressure also takes longer to return to baseline levels after release of the strain.
The Valsalva manoeuvre requires continuous blood pressure monitoring, and a significant degree of patient cooperation and the ability to generate the strain pressure. If the patient is not able to perform the manoeuvre adequately, the result cannot be interpreted.
Result
failure of the blood pressure to recover during strain, and to overshoot after release
nerve conduction studies and electromyogram (EMG)
Test
Nerve conduction studies and EMG can be abnormal in diabetes mellitus and in other forms of peripheral neuropathy, but they can be normal in small-fibre neuropathies.
Result
reduction in sensory nerve conduction velocity; muscle denervation
quantitative sudomotor axon reflex test (QSART)
Test
QSART examines the integrity of peripheral sympathetic cholinergic function, which may be affected in patients with generalised autonomic failure, and absence of sweat production suggests a problem with peripheral autonomic nerves.
Result
absence or decrease of sweat production
heart rate variability
Test
Continuous ECG traces show a variation in RR intervals, reflecting changes in autonomic outflow to the sinoatrial node. Spectral analysis of RR variability in predefined high-frequency (HF) bands (0.15 Hz up to 0.40 Hz) and low-frequency (LF) bands (0.04 Hz up to 0.14 Hz) are complementary ways of measuring autonomic (sympathetic and parasympathetic) innervation to the sinoatrial node.
To standardise values, RR intervals should be measured for 500 seconds during quiet supine rest. Ectopic beats need to be removed from the tracings.
Decreased heart rate variability at the predefined bands suggests impaired sympathetic or parasympathetic outflow.
The variability in heart rate decreases with age and reduced fitness levels. Heart rate variability is also reduced in patients with disorders that affect autonomic function (e.g., diabetes mellitus, Parkinson's disease, multiple system atrophy). In patients with impaired autonomic reflexes, there is often a reduction in overall power in the HF and LF bands of heart rate variability.
Time domain measures of heart rate variability (including standard deviation, root mean squared standard deviation, and percentage of sequential RR intervals that differ by 50 milliseconds or more) are also diminished.
These tests cannot be used as a standalone measure to diagnose autonomic dysfunction.
Result
decreased heart rate variability
24-hour blood pressure monitoring
Test
Ambulatory blood pressure monitoring should be ordered in patients with a history suggesting symptomatic orthostatic hypotension (OH), particularly when OH is not detected during regular autonomic testing.
Ambulatory monitoring involves intermittent recordings of blood pressure (and heart rate) over 24 hours while the patient is awake and asleep. Patients should keep a diary in which they record symptoms, meal times, medications, posture, and sleep time.
Normally, there is a fall both in blood pressure and in heart rate at night during sleep. In patients with impaired autonomic reflexes this night-time 'dipping' is often absent; 50% of patients have hypertension during the night. Ambulatory blood pressure monitoring can also identify episodes of hypotension not seen during testing in the surgery. Ambulatory monitoring is useful to detect episodes of hypotension that occur only after meals or after exercise.
Ambulatory recordings allow correlation between symptoms and blood pressure values and are a useful tool to guide the treatment.
Result
episodes of low blood pressure, either when standing or after eating; absence of the normal night-time 'dipping' in blood pressure
autoimmune antibodies
Test
The presence of paraneoplastic antibodies (anti-Hu, anti-Yo, anti-Ri, anti-amphiphysin, anti-CV2, anti-Ma2) suggests a paraneoplastic disorder.
In patients with acute or subacute onset of orthostatic hypotension (OH) who have risk factors for breast or lung cancer or have had sudden weight loss, the autoimmune antibody panel should be used to rule out a paraneoplastic syndrome.
Autoantibodies against the nicotinic ganglionic receptors occur in some patients and result in severe OH. These patients have an autoimmune autonomic ganglionopathy.
More than half of patients presenting with acute or subacute OH, accompanied by other autonomic abnormalities such as gastrointestinal dysfunction, are seronegative (i.e., no known pathogenic antibodies are detected).
Result
high antibody titres
chest CT
Test
In a patient with orthostatic hypotension found to have high autoimmune antibodies, chest CT can rule out small cell lung carcinoma as the underlying source of the paraneoplastic antibodies by visualising small nodules that would be undetectable by x-ray, or enlarged lymph nodes.
If the chest CT is negative in such a patient, other cancer screens should be carried out (e.g., breast, ovary).
However, paraneoplastic syndromes can occur without a detectable tumour mass.
Result
tumour mass detected on chest CT as a source of paraneoplastic antibodies
serum and urine electrophoresis
Test
Gammopathies can be associated with autonomic neuropathies.
A normal serum electrophoresis does not rule out light-chain disease, and urine electrophoresis may be required.
Result
high levels of monoclonal proteins
fat-pad biopsy
Test
Amyloid deposits can result in polyneuropathy and orthostatic hypotension.
Result
amyloid deposits in fat
genetic testing
Test
Genetic testing may be used for suspected transthyretin familial amyloid polyneuropathy, which can cause autonomic dysfunction and orthostatic hypotension.
Genes can be tested by direct sequencing.
Result
positive
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