By Marcello Cherchi, MD PhD
For patients
Orthostatic intolerance is a group of conditions in which going from a lying down position to a seated or standing position causes large changes in blood pressure, or in heart rate, or both. A patient may experience those large changes in blood pressure and/or heart rate as heart racing, lightheadedness, trouble breathing, feeling faint, or actually fainting (in the sense of losing consciousness). If your doctor suspects orthostatic intolerance, then they may check several tests to figure out its subtype, and how to treat it. Some cases may be treated without medications, while others may require medications.
For clinicians
Overview
In simple terms, the phrase “orthostatic intolerance” broadly refers to symptoms that are present while in (or shortly after assuming) an upright (standing usually more than seated) position, and absent while supine or prone, and which are due to overly robust fluctuations in blood pressure and/or cardiac pulse. Such cardiovascular dysregulation sometimes occurs independently of any other discernible pathology, but more commonly occurs due to hemodynamic factors (e.g., volume depletion), or as an unintended consequence of medications, or from autonomic dysfunction secondary to a neurodegenerative process. The main forms of orthostatic intolerance (postural orthostatic tachycardia syndrome, orthostatic hypotension, orthostatic hypertension) can often be diagnosed at the bedside, but some cases may require tilt table testing. Securing the etiology of orthostatic intolerance may require more detailed autonomic testing. Treatment depends on the underlying etiology, but management can often be initiated with low-risk, non-pharmacologic interventions, progressing to pharmacologic treatment if needed.
Introduction
Orthostatic intolerance broadly refers to symptoms that are present while in (or shortly after assuming) an upright (standing usually more than seated) position, and absent while supine or prone, and which are due to overly robust fluctuations in blood pressure and/or cardiac pulse. Such cardiovascular dysregulation sometimes occurs independently of any other discernible pathology, but more commonly occurs due to hemodynamic factors (e.g., volume depletion), or as an unintended consequence of medications, or from autonomic dysfunction secondary to a neurodegenerative process. The main forms of orthostatic intolerance are:
- Postural orthostatic tachycardia syndrome (POTS), an inappropriately large increase in heart rate when going from a supine/prone position to an upright (standing typically more than sitting) position.
- Orthostatic hypotension, an inappropriately large drop in blood pressure when going from a supine/prone position to an upright (standing typically more than sitting) position.
- Orthostatic hypertension, an inappropriately large increase in blood pressure when going from a supine/prone position to an upright (standing typically more than sitting) position.
Some of these conditions can co-occur; for example, postural orthostatic tachycardia syndrome and orthostatic hypotension can occur in the same patient.
Epidemiology
The epidemiology of orthostatic intolerance varies among its subtypes (postural orthostatic tachycardia, orthostatic hypotension, orthostatic hypertension).
Genetics
Orthostatic intolerance is a general term for several subtypes of cardiovascular dysregulation (postural orthostatic tachycardia, orthostatic hypotension, orthostatic hypertension) rather than a disease in itself, and thus is not associated with specific genetic defects.
For a given subtype of orthostatic intolerance there may be specific etiologies that have been linked to particular genetic mutations. For instance, some cases of orthostatic hypotension have been linked to dopamine-beta-hydroxylase deficiency (OMIM 609312).
Pathophysiological mechanism of disease
Upon assuming an upright posture, gravity pulls blood downward; this blood in the lower (more dependent) regions of the body pools primarily in the venous system of the lower extremities and the pelvic and abdominal venous plexus. If no compensatory mechanisms offset this, then blood will tend to remain in these dependent venous structures (sometimes called “venous pooling”).
The resulting hydrostatic changes effectively bring about a higher arterial blood pressure in the more dependent portions of the body, and a lower arterial blood pressure in the higher portions of the body.
The lower arterial blood pressure in the higher portions of the body result in less distension of arterial walls, which in turn is detected by mechanoreceptors in the carotid sinuses and the aortic arch.
When those structures in the higher portions of the body detect lower arterial blood pressure, then several compensatory mechanisms are activated; the main mechanisms consist of (1) an increase in heart rate, (2) an increase in ejection fraction, and (3) constriction of peripheral blood vessels.
In orthostatic intolerance there is dysregulation of these compensatory responses; as a result, more blood remains lower in the body, and there is less blood available in the upper portions of the body for the heart to pump upward and adequately perfuse the brain. Common symptoms in this circumstance include feelings of disequilibrium, lightheadedness, faintness, or frank syncope.
Theoretical considerations
Most studies on orthostatic intolerance tacitly assume that heart rate and peripheral measurement of blood pressure (using a regular sphygmomanometer) serve as an adequate proxy for cerebral blood flow, but this assumption may be mistaken. Van Campen and colleagues (van Campen et al. 2020) studied healthy controls and chronic fatigue syndrome (myalgic encephalomyelitis) patients during tilt table testing using carotid Doppler flow studies, and reported that cerebral blood flow (as measured by carotid Doppler) could still be impaired even when assessment by traditional tilt table parameters (for orthostatic hypotension and postural orthostatic tachycardia) were normal.
Clinical presentation
A careful clinical history is important for identifying orthostatic intolerance, and sometimes distinguishing its subtypes (Goldstein and Cheshire 2017).
Physical examination
As mentioned earlier, orthostatic intolerance refers to symptoms that are present while in (or shortly after assuming) an upright (standing usually more than seated) position, and absent while supine or prone, and which are due to overly robust fluctuations in blood pressure and/or cardiac pulse. The specific diagnostic criteria for each subtype (postural orthostatic tachycardia, orthostatic hypotension, orthostatic hypertension) are occasionally revised, and have been promulgated in published subspecialty concensus statements.
Ocular motor examination
Ocular motor examination generally does not provide evidence to support or refute a diagnosis of orthostatic intolerance, or to distinguish the subtype of orthostatic intolerance.
Testing: auditory
Auditory testing generally does not provide evidence to support or refute a diagnosis of orthostatic intolerance, or to distinguish the subtype of orthostatic intolerance.
Testing: vestibular
There is accumulating evidence (Bogle et al. 2022; Carter and Ray 2008; Kerman et al. 2000; Yates 1992; Yates et al. 2014) from physiologic (Yates and Miller 1998) and clinical (Furman et al. 1998) studies that responses of the autonomic nervous system are influenced by vestibular afferent signaling. There is also evidence that vestibular lesions can influence autonomic function (Yates and Bronstein 2005). Despite recognition of this relationship, vestibular testing does not yet play a role in confirming or disproving autonomic disorders. The main role of vestibular testing in these patients is to exclude vestibular disorders.
Testing: other
Tilt table testing (TTT) can secure a diagnosis of orthostatic intolerance and identify the subtype (postural orthostatic tachycardia syndrome, orthostatic hypotension, orthostatic hypertension).
A home device for continuous blood pressure monitoring (usually dispensed by cardiology) may also be helpful, particularly if the patient can maintain a corresponding symptom log.
Imaging
Imaging of the neuraxis generally does not provide evidence to support or refute a diagnosis of orthostatic intolerance, nor does it usually help distinguish its subtype. Specific exceptions to this include imaging for spinal cord injuries, some of which can interfere with autonomic function.
Histopathology
Histopathological studies generally do not provide evidence to support or refute a diagnosis of orthostatic intolerance, nor to distinguish its sutbype. Specific exceptions include post-mortem histopathology in neurodegenerative disorders (such as multiple system atrophy) that are associated with autonomic dysfunction.
Differential diagnosis
The differential diagnosis of orthostatic intolerance includes the three main categories (postural orthostatic tachycardia, orthostatic hypotension, orthostatic hypertension), as well as other diseases that can cause positionally-triggered disequilibrium, such as benign paroxysmal positional vertigo (BPPV).
Management
The various subtypes of orthostatic intolerance (postural orthostatic tachycardia, orthostatic hypotension, orthostatic hypertension) share some management strategies, but the overlap is incomplete.
Given that studies have demonstrated an imperfect correlation between tilt table test results and cerebral blood flow (as measured by carotid Doppler) (van Campen et al. 2020), in cases where clinical suspicion remains high for an orthostatic disorder (despite normal tilt table test results), there is still some rationale for empiric treatment.
Prognosis
The prognosis of orthostatic intolerance depends on the subtype and specific etiology.
References
Bogle JM, Benarroch E, Sandroni P (2022) Vestibular-autonomic interactions: beyond orthostatic dizziness. Curr Opin Neurol 35: 126-134. doi: 10.1097/WCO.0000000000001013
Carter JR, Ray CA (2008) Sympathetic responses to vestibular activation in humans. Am J Physiol Regul Integr Comp Physiol 294: R681-8. doi: 10.1152/ajpregu.00896.2007
Furman JM, Jacob RG, Redfern MS (1998) Clinical evidence that the vestibular system participates in autonomic control. J Vestib Res 8: 27-34.
Goldstein DS, Cheshire WP, Jr. (2017) The autonomic medical history. Clin Auton Res 27: 223-233. doi: 10.1007/s10286-017-0425-7
Kerman IA, McAllen RM, Yates BJ (2000) Patterning of sympathetic nerve activity in response to vestibular stimulation. Brain Res Bull 53: 11-6. doi: 10.1016/s0361-9230(00)00303-8
van Campen C, Verheugt FWA, Rowe PC, Visser FC (2020) Cerebral blood flow is reduced in ME/CFS during head-up tilt testing even in the absence of hypotension or tachycardia: A quantitative, controlled study using Doppler echography. Clin Neurophysiol Pract 5: 50-58. doi: 10.1016/j.cnp.2020.01.003
Yates BJ (1992) Vestibular influences on the sympathetic nervous system. Brain Res Brain Res Rev 17: 51-9. doi: 10.1016/0165-0173(92)90006-8
Yates BJ, Bolton PS, Macefield VG (2014) Vestibulo-sympathetic responses. Compr Physiol 4: 851-87. doi: 10.1002/cphy.c130041
Yates BJ, Bronstein AM (2005) The effects of vestibular system lesions on autonomic regulation: observations, mechanisms, and clinical implications. J Vestib Res 15: 119-29.
Yates BJ, Miller AD (1998) Physiological evidence that the vestibular system participates in autonomic and respiratory control. J Vestib Res 8: 17-25.
