Epidemiology, Diagnosis, and Management of Neurogenic Orthostatic Hypotension

Abstract

Background: Orthostatic hypotension (OH) is a sustained fall in blood pressure on standing which can cause symptoms of organ hypoperfusion. OH is associated with increased morbidity and mortality and leads to a significant number of hospital admissions particularly in the elderly (233 per 100,000 patients over 75 years of age in the US). OH can be due to volume depletion, blood loss, large varicose veins, medications, or due to defective activation of sympathetic nerves and reduced norepinephrine release upon standing (i.e., neurogenic OH).

Methods and findings: Literature review. Neurogenic OH is a frequent and disabling problem in patients with synucleinopathies such as Parkinson disease, multiple system atrophy, and pure autonomic failure, and is commonly associated with supine hypertension. Several pharmacological and non-pharmacological therapeutic options are available.

Conclusions: Here we review the epidemiology, diagnosis, and management of neurogenic OH, and provide an algorithm for its treatment emphasizing the importance of removing aggravating factors, implementing non-pharmacologic measures, and selecting appropriate pharmacological treatments.

Keywords: Autonomic failure; Droxidopa; Multiple system atrophy; Parkinson disease; Supine hypertension; Synucleinopathies.

Figure 1

Neurotransmitter disorders in Parkinson's disease. Motor dysfunction is mainly caused by a dopaminergic deficit in basal ganglia neurons. Dopamine deficit can be treated with oral administration of the dopamine precursor l‐dopa or with direct dopaminergic agonists. Defective vasoconstriction leading to neurogenic orthostatic hypotension is a result of impaired release of norepinephrine from postganglionic sympathetic terminals. Norepinephrine deficit can be treated with oral administration of the norepinephrine precursor droxidopa or with direct adrenergic agonists such as midodrine.

Figure 2

Blood pressure (BP) and cerebral blood flow in a patient with neurogenic orthostatic hypotension. The upper tracing displays blood flow velocity as measured by transcranial Doppler ultrasound of the middle cerebral artery (MCA), which is proportional to cerebral blood flow. The lower tracing shows continuous BP recorded with plethysmography. When the patient is in the supine position, BP is normal (120/85 mm Hg) and MCA velocity (Vm) is 55 cm/s, indicating normal cerebral blood flow. When the patient stands, BP drops rapidly to 68/55 mm Hg and cerebral blood flow falls by nearly 50% as shown by Vm down to 28 cm/s. The patient becomes symptomatic, feels faint, and is unable to remain standing (indicated by a swirl). The patient then sits and his BP increases to 95/62 mm Hg. Although this BP value is still low, the patient is not symptomatic because Vm increased to 46 cm/s, indicating almost normal cerebral blood flow. This tracing shows that for a patient to become asymptomatic, BP does not need to return to normal values but only to increase above the lower limit of cerebral autoregulation.

Figure 3

Treatment algorithm in patients with neurogenic orthostatic hypotension. Removal of aggravating factors and initiation of nonpharmacological measures must always predate pharmacological agents.

Figure 4

Mechanism of action of drugs for neurogenic orthostatic hypotension. Commonly used short‐acting vasoconstrictor agents include midodrine, an α‐1‐adrenergic receptor agonist; and droxidopa, an artificial aminoacid, which is converted to norepinephrine (NE) by the enzyme aromatic aminoacid decarboxylase (AAAD) in the postganglionic sympathetic terminal, but also extraneurally in other organs (eg, kidney). Less commonly used, pyridostigmine, an acetylcholinesterase inhibitor, enhances cholinergic (ACho) transmission in the pre‐ to postganglionic synapse of the sympathetic pathways, but its pressor effect is less consistent. Atomoxetine is a norepinephrine transporter (NET) inhibitor that increases norepinephrine levels; clinical trials are underway to ascertain whether chronic treatment with atomoxetine exerts a significant pressor effect in patients with nOH. Fludrocortisone (not shown) is a mineralocorticoid that retains sodium and water, therefore increasing intravascular volume. CNS, central nervous system.