Background

Syncope can have a variety of aetiologies and may result in falls and associated injuries.1 2

Syncope is defined as a sudden yet transient complete loss of consciousness in which the individual is unable to maintain postural tone, followed by rapid and spontaneous recovery.3 4

Standing for 2 to 3 min is usually sufficient to see the fall in blood pressure (BP) associated with syncope, however in the case presented here, BP was measured after 5 min of standing.4 Determining the underlying cause of syncopal episodes is an important diagnostic step to appropriately guide management (table 1). A relatively common cause of syncope is orthostatic hypotension (OH), which is a drop in BP of ≥20 mm Hg systolic or ≥10 mm Hg diastolic within a few minutes of standing.1 5

Neurogenic OH (nOH; that is, OH resulting from autonomic dysfunction) can be differentiated from non-neurogenic causes of OH (eg, hypovolaemia) clinically by autonomic function tests and by an insufficient compensatory heart rate (HR) increase on standing.6 7 Common clinical signs and symptoms of nOH include dizziness, lightheadedness, syncope and falls.8 Neurogenic OH is commonly comorbid with other disorders associated with autonomic dysfunction, including Parkinson’s disease (PD), multiple system atrophy, pure autonomic failure, dementia with Lewy bodies and type 2 diabetes.6 9 Neurogenic OH increases the risk of falls, which in turn interferes with activities of daily living and increases the burden of symptoms for patients and their caregivers.1 10 11

In those cases in which the aetiology of a patient’s syncope is unclear after initial evaluation and an ECG has ruled out a cardiac cause of syncope, referral for autonomic testing may aid in pinpointing the cause and guide decisions of the most appropriate steps in treating and managing the symptoms of the patient.2 12 In this context, autonomic testing should include continuous BP monitoring during prolonged head-up tilt (HUT) on a tilt table, HR in response to paced breathing and BP in response to the Valsalva manoeuvre.2 12 Decreased autonomic function, if observed, in this battery of tests indicates a neurogenic origin of OH and that the syncope is neurally mediated. Such a diagnosis should suggest a course of treatment.8 12

When the cause of syncope has been identified as OH or nOH, pharmacological management of the condition may be necessary.8 Droxidopa, a norepinephrine prodrug, is the only drug currently approved by the US Food and Drug Administration to treat symptoms of nOH in adults,8 13 whereas midodrine, an alpha−1 adrenergic agonist, is approved to treat symptoms of OH.14

Case presentation

A 62-year-old man was evaluated for a 2-year history of syncope, collapse and fluctuating BP. His medical history included Hodgkin lymphoma, lupus, type 2 diabetes mellitus, autonomic neuropathy, hypercholesterolaemia, hypothyroidism and orthostatic hypotension. He was being treated with gabapentin (300 mg, two times per day, saxagliptin (5 mg, one time per day (QD)), pravastatin (40 mg QD), levothyroxine sodium (100 mg QD), omeprazole (20 mg QD), prednisone (10 mg, every other day), midodrine (10 mg, three times per day) and fludrocortisone (0.1 mg two times per day).

At the time of his initial evaluation, the patient reported that his syncope was progressively worse over the past 3 months. Although his episodes of syncope were previously preceded by dizziness and nausea, they had begun to occur without warning. He also reported a 5-year history of orthostatic hypotension, with a supine BP of approximately 100/66 mm Hg and a standing BP as low as 50/40 mm Hg. His low standing BP and episodes of syncope persisted despite daily treatment with fludrocortisone and midodrine. Initial cardiac evaluation revealed a systolic murmur but was otherwise unremarkable. Other than OH, a clinical manifestation of possible cardiovascular autonomic dysfunction, no other signs of autonomic dysfunction were noted during examination (table 2). Additionally, the patient showed no signs of hypovolaemia (ie, extremities were not cold, moist mucous membranes, no increase in urine specific gravity) or of amyloidosis (ie, lack of tongue swelling). Negative findings on serum protein electrophoresis and fat pad biopsy confirmed the lack of amyloidosis.

Investigations

Autonomic function testing was performed to determine whether the OH was neurogenic in origin. Tilt table testing revealed a BP drop from 112/68 mm Hg (HR, 74 bpm) after 6 min in the supine position to 76/60 mm Hg (83 bpm) within 2 min of tilt to the 80° head-up position; this BP drop was accompanied by dizziness and weakness at 2 min of tilt and presyncope at 4 min of tilt. Continuous recording with transcranial Doppler during tilt testing indicated no changes in mean cerebral blood flow. ECG tracings during the HR with deep breathing test (paced breathing at six breaths per minute) showed an expiration/inhalation ratio of 1.02, which is abnormal for the patient’s age and sex, indicating depressed baseline autonomic tone and decreased vagal tone. Valsalva testing (measured at 40 mm Hg) revealed a Valsalva ratio of 1.15, which is also abnormal for the patient’s age and sex. Taken together, the results of autonomic testing were consistent with a diagnosis of idiopathic nOH for this patient.

Treatment

The patient was prescribed droxidopa (100 mg two times per day) to treat symptoms of nOH. Treatment with droxidopa was reduced to 100 mg QD because of nocturnal hypertension, for which he was prescribed a nitroglycerin patch as needed (0.2 mg, transdermal). The patient continued to take both fludrocortisone and midodrine.

Outcome and follow-up

After initiating treatment with droxidopa, the patient reported he no longer lost consciousness on standing, although he still experienced some symptoms of presyncope, such as lightheadedness. One year after initiating droxidopa treatment, these improvements were maintained. The mitigation of his symptoms has improved his activities of daily living and decreased the burden of nOH on both the patient and his caregivers.

Discussion

Determination of the underlying mechanism of syncope is critical for choosing an appropriate treatment and management protocol.12 A proposed diagnostic algorithm should include a detailed patient history and physical examination (including supine and standing BP measurements and an ECG; figure 1).12 If determination of the mechanism of syncope is inconclusive after initial examinations, then autonomic function testing is warranted.2 12

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Figure 1

Diagnostic algorithm and treatment options for neurogenic orthostatic hypotension. BP, blood pressure; CHF, congestive heart failure; DBP, diastolic BP; HR, heart rate; MI, myocardial infarction; nOH, neurogenic orthostatic hypotension; OH, orthostatic hypotension; SBP, systolic BP.

The underlying causes of nOH can be varied, and there are multiple factors to be considered in the management of nOH, especially in the face of comorbid conditions. A case report identified amyloidosis as a potential cause in a patient who presented with autonomic nervous system impairment and OH with systemic organ involvement including gastrointestinal and kidney dysfunction.15 In two other case reports, patients with PD and cardiac conditions presented with dizziness, lightheadedness and fatigue, and were subsequently diagnosed with nOH.16 17 In one of these cases, the patient was initially suspected to have bradycardia because the symptoms overlap with those seen in nOH and was referred for a pacemaker before diagnostic testing for nOH was even considered.16 Thus, it is imperative for clinicians to screen for nOH when patients present with non-specific symptoms like dizziness and lightheadedness, even when there are other comorbidities present.

Autonomic function testing, including HUT, HR with deep breathing and response to the Valsalva manoeuvre, can determine whether orthostatic syncope is neurogenic in origin.2 12

Although the standard supine-to-standing BP test is more commonly used and can be performed in many clinical settings, HUT testing on a tilt table has several advantages.8 When secured to the tilt table, HUT is markedly safer for patients who experience syncope on standing.2 Passive HUT eliminates the potential confound of compensatory muscle contraction, leading to a more sensitive test.2 Abnormal response to the HR with deep breathing test or to the Valsalva manoeuvre indicates autonomic dysfunction is likely causing orthostatic symptoms. In the current case, autonomic testing led to an efficient diagnosis of nOH, which allowed for implementation of appropriate pharmacological intervention.

When the first treatment for nOH does not relieve symptom burden, it is important to continue to seek a symptom-alleviating treatment.8 The goal of treatment is to restore physical capabilities and reduce potentially dangerous symptoms, not to normalise BP.8 The patient in this case study experienced improved quality of life once his symptoms were successfully treated with droxidopa.