Orthostatic Hypotension in Parkinson Disease

Abstract

Purpose of the Review

Orthostatic hypotension (OH) is the primary manifestation of cardiovascular autonomic dysfunction in Parkinson disease (PD) and can be a prodromal feature of the disease. We review the recent progress in the field of autonomic dysfunction in PD.

Recent Findings

Individuals with isolated neurogenic OH should be followed up frequently because they may evolve into PD, dementia with Lewy bodies, or multiple system atrophy. The prevalence of OH in PD increases with disease stages, but the role of levodopa remains unclear. Measurement of supine and standing heart rate and blood pressure allows for accurate identification of neurogenic OH in the clinic.

Summary

Accurate identification of neurogenic OH in the clinic is crucial for identification of individuals who may benefit from participation in neuroprotective trials in the future. The treatment of OH in PD should be individualized and may reduce the risk of falls, cognitive impairment, and death.

There is mounting evidence of autonomic dysfunction in individuals with Parkinson disease (PD). Cardiovascular impairment, gastrointestinal dysfunction, and urinary disturbance are some of the key features of autonomic dysfunction in PD.¹ Orthostatic hypotension (OH), which is defined as a sustained drop in systolic blood pressure >20 mm Hg and/or a drop in diastolic blood pressure >10 mm Hg within 3 minutes from supine to standing, causes considerable limitations and impairment in quality of life.² OH may be neurogenic or non-neurogenic. Neurogenic OH occurs because of insufficient norepinephrine release from the sympathetic postganglionic neurons upon standing up, and it is the primary manifestation of cardiovascular autonomic dysfunction in PD.¹ It is crucial to remain updated about the most recent clinical and research aspects of this debilitating nonmotor symptom of the disease.

OH as a Prodromal Feature of PD

Several lines of evidence in the past few years have identified OH as a feature of prodromal PD.³ This observation largely stems from studies on individuals with pure autonomic failure (PAF).⁴ A prospective natural history study of individuals with PAF reported that 19/74 (25.6%) evolved into PD or dementia with Lewy bodies (DLBs) after 4 years, and 6/74 (8%) evolved into multiple system atrophy (MSA).⁴ However, this field of research is not free from controversy as a recent prospective population‐based study failed to identify an association between neurogenic OH and an increased risk of developing PD.⁵ Differences in study populations likely explain these contradictory findings. Patients diagnosed with PAF seen at specialized autonomic centers are more likely to be screened for other nonmotor features suggestive of a synucleinopathy (e.g., dream enactment behavior, anosmia, constipation, family history of PD) and may have more severe OH than in the general population. Identification of biomarkers that can predict the risk of developing PD and other autonomic synucleinopathies (DLB and MSA) in individuals with neurogenic OH is an active area of research.⁶ The major clinical implication is that patients with isolated neurogenic OH should be followed up frequently and comprehensively because those patients may benefit from participation in neuroprotective trials in the future.

Prevalence of OH in PD and Effect of Levodopa

As a prodromal feature and a bothersome nonmotor symptom of PD, attempts have been made to estimate the prevalence of OH in PD. The estimated prevalence of OH in individuals with an established clinical diagnosis of PD ranges from 30% to 65%.^7,8 OH becomes more frequent as the disease progresses.⁹ In a cohort of individuals with early PD (evaluation within 3 years of diagnosis) and mostly (79%) drug naive, Baschieri et al.¹⁰ reported that only 8% of individuals had evidence of neurogenic OH. In the same study, however, asymptomatic sympathetic impairment, which was defined by abnormal blood pressure responses to the Valsalva maneuver without OH during tilt table testing, was more common in the PD group compared with controls, and a progression of sympathetic impairment was observed with disease evolution, indicating that subclinical abnormalities on autonomic testing may precede OH in PD.¹⁰ It needs to be emphasized that in some patients, OH becomes apparent after a prolonged standing posture (>3 minutes), which is described as delayed OH. If studies explore delayed OH in PD, the estimated prevalence of overall OH may increase. Delayed OH may progress to classic OH with a high associated mortality. In a retrospective review of 10-year follow-up autonomic testing data, 26 of 48 individuals with delayed OH progressed to classic OH. Eight individuals developed PD (3 of 8 died at the time of follow-up).¹¹

Although OH primarily manifests as a feature of autonomic dysfunction in patients with PD, it has also been documented as a potential side effect of levodopa.¹² However, this issue has remained controversial because a recent meta-analysis failed to show any clear relationship between levodopa and OH in PD.¹³ This has critical clinical implications because clinicians may be reluctant to prescribe levodopa to patients with PD with OH, leading to suboptimal management of the motor symptoms. Untreated motor symptoms can also lead to immobility and physical deconditioning, which in turn further worsen the severity of OH.² Mild noradrenergic impairment can exist in PD without OH; in these individuals, levodopa may contribute to further impairment in blood pressure regulation, which can become clinically relevant in some cases. Further research is needed with a detailed investigation of the blood pressure in the same patients tested on and off levodopa. Dopamine agonist therapy has also been associated with OH, especially during initiation or up-titration, and some patients may be asymptomatic.¹⁴

Recognition of Neurogenic OH in the Clinic

Considering the growing recognition of autonomic dysfunction as one of the debilitating nonmotor symptoms of PD, the clinicians must be familiar with the diagnosis of various forms of OH (neurogenic vs non-neurogenic). OH can easily be identified in the clinic, and, ideally, every patient with PD should have supine and standing blood pressure and heart rate measurements during clinic visits. A decreased heart rate response to OH is a surrogate marker of a neurogenic etiology.¹⁵ This is opposed to non-neurogenic causes of OH such as intravascular volume loss, physical deconditioning, or heart failure, which may resolve when the underlying cause is corrected. In a prospective study of 423 patients, neurogenic OH was reliably distinguished from other causes of OH when the ratio of orthostatic heart rate changes over systolic blood pressure changes at 3 minutes of tilt was <0.5 beats/min per mm Hg.¹⁵ Importantly, this ratio has been validated at the bedside when patients were actively standing.¹⁶

Consequences of OH in PD

In the past few years, numerous studies have explored the effect of OH on PD. Higher prevalence of autonomic dysfunction has been associated with a diffuse malignant phenotype of PD.¹⁷ The presence of OH in PD is associated with more rapid disease progression, shorter survival time, and falls.^18,19 Association of OH with cognitive impairment in PD has also been a prime area of research. It has been demonstrated that patients with PD with OH perform poorly in specific neuropsychological tests during the upright posture compared with the supine position.²⁰ Longitudinal follow-up of patients with PD with and without OH also demonstrated an association between OH and cognitive impairment.²¹ This association is speculated to be secondary to recurrent cerebral hypoperfusion.²² The presence of OH early in the disease process may also support the hypothesis that some individuals with PD have a more widespread involvement across peripheral and central nervous system locations.²³ Further studies are necessary to investigate the effects of early identification and treatment of OH in PD for clinical outcomes (i.e., motor progression, evolution of nonmotor symptoms, falls, hospitalization, institutionalization, and mortality).

Treatment: Recent Advances, Failures, and Future Directions

Nonpharmacological management is often recommended as a first-line treatment in the management of OH in PD. Patient's convenience or safety should be considered (e.g., comorbid severe heart failure may limit fluid and salt intake). Nonpharmacological interventions work by expanding blood volume (increasing fluid intake to at least 2 L per day and increasing salt intake to 5–10 g daily), decreasing nocturnal pressure natriuresis (raising the head of the bed), decreasing venous pooling (using waist-high compression stockings or an abdominal binder, strengthening of the core musculature or leg muscles with recumbent exercise), or inducing a pressor response (drinking a bolus of cold water). The pharmacologic management of OH should be individualized (Table). Fludrocortisone at a low dose can be helpful in combination with adequate hydration and liberalizing dietary sodium; however, it can worsen supine hypertension, and serum potassium and renal function should be monitored frequently.²⁴ Droxidopa and midodrine are potential alternative therapy and are the only drugs approved by the Food and Drug Administration for the treatment of neurogenic OH.²⁴ Droxidopa is most beneficial in patients with low supine plasma norepinephrine levels (<200 pg/mL).²⁵ Pyridostigmine, a reversible inhibitor of acetylcholinesterase, increases the availability of acetylcholine to bind to muscarinic or nicotinic receptors. Therefore, it has the potential to enhance both sympathetic ganglionic and parasympathetic ganglionic and postganglionic functions. Pyridostigmine has the advantage of increasing sympathetic adrenergic tone on demand upon standing, whereas it should be silent under conditions of low sympathetic tone without the risk of supine hypertension. The pressor effect of pyridostigmine might be suboptimal compared with other drugs in patients with moderate-to-severe autonomic failure.²⁶ Nevertheless, pyridostigmine may be a good option for patients with OH and constipation because it can improve both. Norepinephrine transporter inhibition is a mechanism that is being studied to increase blood pressure in patients with PD with OH. In a recent study, Kaufmann et al.²⁷ reported the safety and efficacy of ampreloxetine to treat neurogenic OH in synucleinopathies in a small phase II clinical trial. This study demonstrated that ampreloxetine was well tolerated and improved orthostatic symptoms and seated/standing blood pressure with little change in supine blood pressure.²⁷ Unfortunately, a press release from the company announced the failure of the phase III study because of a lack of efficacy (unpublished data at the time of writing the manuscript). We now await the results of another phase II trial investigating the effect of atomoxetine in the symptomatic management of neurogenic OH (ClinicalTrials.gov: NCT02796209). Patients with neurogenic OH can have supine hypertension, which also requires treatment.²⁴ Most patients have normal seated blood pressures. Therefore, it is important to consider the 24-hour blood pressure profile and not use the sitting blood pressure as a target to assess treatment efficacy.

Table.

Pharmacologic Management of Orthostatic Hypotension in Parkinson Disease

FIVE NEW THINGS

1. The evaluation of patients with neurogenic OH should include screening for nonmotor features classically associated with synucleinopathies and a complete neurologic examination to look for evidence of parkinsonism or cerebellar dysfunction.

2. The prevalence of OH in PD increases with increasing disease stages. Further studies are required to investigate the role of levodopa in patients with PD with OH and the prevalence of delayed OH.

3. Clinicians can easily recognize neurogenic OH in the clinic by measuring supine and standing heart rate and blood pressure (Δ HR:ΔBP <0.5 indicates neurogenic OH).

4. The presence of OH in PD may reflect a more malignant phenotype with rapid progression and is associated with increased morbidity and mortality.

5. The treatment of OH in PD should be individualized.

Appendix. Authors

Study Funding

The authors report no targeted funding.

Disclosure

Dr. G. Lamotte serves as the managing editor of the journal Clinical Autonomic Research. The authors report no other relevant disclosures. Full disclosure form information provided by the authors is available with the full text of this article at Neurology.org/cp.