Approach
Orthostatic hypotension (OH) is defined as a fall in systolic blood pressure of at least 20 mmHg (at least 30 mmHg in patients with hypertension) and/or a fall in diastolic blood pressure of at least 10 mmHg within 3 minutes of standing.[1]
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]
Measurement of blood pressure
Diagnosis requires measurement of blood pressure in the supine and standing postures.[28][29] It is advisable to take multiple blood pressure measurements.[30] There is evidence to suggest that measurements made at home by the patient may be more effective in detecting OH.[31][32]
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 increase in heart rate), when there is an underlying neurogenic cause (e.g., peripheral neuropathy).[2]
These measurements, however, are rarely carried out routinely, so a careful history is crucial to identify OH as the cause of the patient's symptoms.
History
Lightheadedness is the typical symptom of OH. Other symptoms include dizziness, weakness, faintness, fatigue on exertion and dimming of the vision (tunnel vision or visual blackouts).[30]
Symptoms should not occur while supine, should get worse on standing, and should be relieved by sitting or lying down. Some patients may have difficulty recognizing or describing symptoms of OH and may present with recurrent or unexplained falls. Patients with dementia in particular may experience a gradual fading of consciousness or be unaware of losing consciousness.
Aggravating factors can often be identified, and the symptoms are often worse:
Early in the morning (because of relative volume depletion after overnight fast and pressure diuresis)
In hot environments (because of cutaneous vasodilation)
After meals (because of splanchnic blood pooling)
After standing motionless (because of decreased venous return caused by loss of muscle pump action)
During or after exercise (because of metabolic vasodilation).
Presence of neuropathy
Frequently there is a history of small-fiber neuropathy affecting the lower extremities. Typical symptoms include pain, dysesthesias (burning, tingling), and decreased sensation. The most common cause is diabetes mellitus, but any systemic disease that can cause peripheral neuropathy or amyloidosis can also produce autonomic neuropathy.
A history of an acute or subacute onset of progressive disabling OH can provide diagnostic clues. An acute pan-dysautonomia may follow a viral-like illness. Antibodies against acetylcholine nicotinic receptors that mediate neurotransmission at the level of the autonomic ganglia have been found in some of these patients.[22]
Paraneoplastic autoimmune syndromes can also cause subacute OH. The most common causes are small cell lung cancer, monoclonal gammopathies, and light-chain disease.[22]
Diagnosis of neurogenic orthostatic hypotension
Measuring heart rate alongside blood pressure is crucial in determining if an autonomic neuropathy is present. OH caused by volume depletion is associated with orthostatic tachycardia. Lack of an adequate compensatory heart rate increase (>15 bpm) in the face of profound OH (>30 mmHg fall in systolic blood pressure) is characteristic of neurogenic OH, and few conditions other than autonomic failure can explain severe OH. A sensitive cut off for diagnosing neurogenic OH is a heart rate rise <0.5 bpm per mmHg systolic blood pressure fall.[2]
In autonomic failure, the decrease in blood pressure is usually seen immediately upon standing and the heart rate fails to increase appropriately. This situation is in contrast to that seen in neurally mediated (i.e., vasovagal) syncope, in which the initial response to standing is normal, but after a variable period the patient experiences a sudden onset of hypotension together with a decrease in heart rate.
Other signs of autonomic neuropathy include erectile dysfunction (an early but nonspecific sign), worsening of constipation, urinary retention, gastroparesis, and decreased sweating (in some cases with compensatory focal hyperhidrosis). Patients with autonomic failure will often have REM sleep behavior disorder, which suggests the presence of an underlying neurodegenerative process also involving the central nervous system. Not infrequently, these patients develop Parkinson disease, dementia with Lewy bodies, or multiple system atrophy.[2][33][34]
Physical exam
Vagal modulation of heart rate is often impaired, and translates into a fixed heart rate that does not fluctuate during deep breathing (sinus arrhythmia). Parkinsonian features may be present in patients with multiple system atrophy (MSA, or Shy-Drager syndrome), although the typical parkinsonian pill-rolling tremor is usually absent. Gait abnormalities and truncal ataxia are present in patients with MSA of the cerebellar type. Subtle impairment of motor function (reduced frequency of blinking, slow/clumsy rapid alternating movements) may indicate the early stages of Parkinson disease, dementia with Lewy bodies, or multiple system atrophy. Symmetric distal sensory loss occurs in patients with diabetic neuropathy or other forms of peripheral neuropathy.
Investigations
Tilt-table testing is of limited additional value if careful orthostatic vital signs are measured, but it can aid in the diagnosis of neurally mediated (vasovagal) syncope.[35] In OH, the fall in blood pressure occurs immediately upon head-up tilt and is usually progressive, whereas in neurally mediated syncope blood pressure is initially maintained and, after a variable period, blood pressure falls abruptly, often in association with a drop in heart rate.
Autonomic function tests are useful to confirm the presence of autonomic failure and to assess its severity.[36] These tests include deep breathing, Valsalva maneuver, measures of heart rate variability, and 24-hour blood pressure monitoring.
The use of 24-hour blood pressure monitoring can be useful to find out if supine hypertension is present at night (which can occur in up to 50% of patients with autonomic failure). It can also be used to detect early morning and postprandial hypotension if patients are asked to keep a careful diary of activities.
If autonomic dysfunction is suspected, plasma norepinephrine levels may be helpful in determining the underlying cause of autonomic dysfunction. In healthy people, plasma norepinephrine levels double on the assumption of the upright posture. In contrast, this response is absent in patients with sympathetic failure (both pre- and postganglionic). Patients with autonomic disorders that affect postganglionic sympathetic nerves, such as pure autonomic failure, Parkinson disease, and diabetic neuropathy, frequently have low plasma norepinephrine levels in the supine position.[37] Patients with autonomic disorders that selectively affect preganglionic sympathetic neurons (e.g., multiple system atrophy) typically have normal plasma norepinephrine levels in the supine position.[37]
Nerve conduction studies and electromyogram can be useful for confirming the cause of OH in patients with peripheral neuropathy related to diabetes mellitus and other causes, although results can be normal in small-fiber neuropathies. Small-fiber neuropathy can be tested for by quantitative sudomotor axon reflex testing.
An antibody panel that includes the nicotinic acetylcholine receptor antibody is needed if an autoimmune process is suspected.[22]
Chest computed tomography should be performed if a paraneoplastic syndrome is suspected, often because of unintended weight loss accompanying the OH, in order to detect the primary node (which is often small) and enlarged mediastinal lymph nodes. The presence of paraneoplastic antibodies (anti-Hu, anti-Yo, anti-Ri, antiamphiphysin, anti-CV2, anti-Ma2) should be investigated.
Serum and urine electrophoresis can be performed to rule out a monoclonal gammopathy and light-chain disease.
Fat aspirate may be needed if amyloidosis is suspected.
Genetic testing for transthyretin familial amyloid polyneuropathy is available.
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