Advertisement
Mayo Clinic Proceedings Home

55-Year-Old Woman With Recurrent Syncope

      A 55-year-old woman presented to the emergency department with syncope. She had a 1-month history of postural light-headedness, with 2 recent syncopal episodes. Both episodes occurred while the patient was standing and were immediately preceded by light-headedness and tunnel vision. Each episode was witnessed and did not appear to be associated with tongue biting, bowel or bladder incontinence, focal neurologic changes, jerking, or twitching. She did not recall any chest pain, palpitations, dyspnea, or diaphoresis during either syncopal episode. She regained consciousness within a minute without any confusion.
      Before her presentation to the emergency department, her primary care physician had initiated midodrine, fludrocortisone, and pyridostigmine with modest but very short-lived benefit. She was unable to get out of bed except for a brief 2-hour period following medication administration. Additional symptoms included constipation, dry eyes, and dry mouth during the previous month. She also had an unintentional 22.5-kg weight loss over the previous year. Her medical history was otherwise unremarkable. Before the onset of her symptoms, she was not taking any medications. She reported a 20-pack-year history of smoking and occasional alcohol use.
      On examination, the patient was afebrile (temperature, 36.7°C), her respiratory rate was 18 breaths/min, and her oxygen saturation was 97% while breathing room air. Orthostatic blood pressures were obtained, with the following results: 127/60 mm Hg while supine (heart rate, 62 beats/min), 85/52 mm Hg while seated (heart rate, 73 beats/min), and 54/35 mm Hg while standing (heart rate, 82 beats/min). No further abnormalities were found on cardiovascular, respiratory, or neurologic examination.
      • 1.
        On the basis of the patient's history and examination findings, which one of the following is the most likely cause of her syncope?
        • a.
          Vasovagal response
        • b.
          Sick sinus syndrome
        • c.
          Aortic stenosis
        • d.
          Postural orthostatic tachycardia syndrome
        • e.
          Orthostatic hypotension (OH)
      Vasovagal factors are a common cause of syncope, but the most frequent mechanism is a cardioinhibitory response whereby sinus pauses and bradycardia (heart rate <40 beats/min) lead to a transient drop in blood pressure.
      • Moya A.
      • Brignole M.
      • Menozzi C.
      • et al.
      International Study on Syncope of Uncertain Etiology (ISSUE) Investigators
      Mechanism of syncope in patients with isolated syncope and in patients with tilt-positive syncope.
      Similarly, sick sinus syndrome can present with syncope but is defined by alterations in heart rate, which can lead to hypotension. Although aortic stenosis can manifest in syncope, the patient's age and lack of abnormalities on cardiac examination make this an unlikely etiology.
      • Nishimura R.A.
      • Otto C.M.
      • Bonow R.O.
      • et al.
      2014 AHA/ACC guideline for the management of patients with valvular heart disease: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines.
      The absence of tachycardia on standing from a supine position effectively rules out postural orthostatic tachycardia syndrome. A drastic drop in blood pressure within 3 minutes of standing is a key feature of OH, making this the most likely cause of the patient's syncope.
      • Freeman R.
      • Wieling W.
      • Axelrod F.B.
      • et al.
      Consensus statement on the definition of orthostatic hypotension, neurally mediated syncope and the postural tachycardia syndrome.
      Initial laboratory studies revealed the following (reference ranges provided parenthetically): hemoglobin, 13.8 g/dL (12.0-15.5 g/dL); sodium, 141 mmol/L (135-145 mmol/L); potassium, 4.0 mmol/L (3.6-5.2 mmol/L); and creatinine, 0.8 mg/dL (0.6-1.1 mg/dL). Serial troponin test results were negative. Electrocardiography revealed normal sinus rhythm and no evidence of conduction block. Results of additional studies performed before admission included a normal 8 am cortisol level and corticotropin stimulation test.
      • 2.
        Which one of the following is the most likely cause of this patient's orthostatic hypotension?
        • a.
          Drug adverse effect
        • b.
          Autonomic failure
        • c.
          Volume depletion
        • d.
          Adrenal insufficiency
        • e.
          Congestive heart failure
      Orthostatic hypotension is a common adverse effect of many prescription (eg, antihypertensives) and nonprescription drugs (eg, alcohol), but our patient was not taking any medications before the onset of her syncopal episodes.
      • Perlmuter L.C.
      • Sarda G.
      • Casavant V.
      • Mosnaim A.D.
      A review of the etiology, associated comorbidities, and treatment of orthostatic hypotension.
      Autonomic dysfunction leads to OH through several mechanisms, including impaired cardiovagal and peripheral adrenergic responses. Additional symptoms of autonomic dysfunction, including constipation, dry eyes, and dry mouth, were also present, making it the most likely diagnosis. Volume depletion is a common cause of OH but is unlikely in the absence of a history of vomiting, diarrhea, or hemorrhage. Aldosterone release from the adrenal glands is important in the maintenance of blood pressure and is impaired in the setting of adrenal insufficiency. However, our patient's normal cortisol level and corticotropin stimulation test results make adrenal insufficiency unlikely, as does the lack of hyponatremia or hyperkalemia. Furthermore, a more robust response to fludrocortisone would be expected in adrenal insufficiency. The patient had no history or physical examination findings suggestive of congestive heart failure.
      The patient was admitted to the inpatient medicine service for further evaluation. Computed tomography of the chest and abdomen and magnetic resonance imaging of the head detected no abnormalities. Transthoracic echocardiography revealed a mildly enlarged left atrium with mild reduction in left ventricular ejection fraction (49%).
      • 3.
        Which one of the following is the best next step in evaluation at this time?
        • a.
          Autonomic reflex testing
        • b.
          Electromyography
        • c.
          Abdominal wall fat pad aspiration
        • d.
          Positron emission tomography
        • e.
          24-Hour urinary sodium measurement
      Autonomic reflex testing, which consists of a quantitative sudomotor axon reflex test along with assessment of cardiovagal and adrenergic function, is a useful first step in evaluation of OH to confirm the presence of autonomic dysfunction, as well as to determine the severity and distribution.
      • Low P.A.
      • Tomalia V.A.
      Orthostatic hypotension: mechanisms, causes, management.
      Electromyography with nerve conduction studies are beneficial for the evaluation of an underlying peripheral neuropathy, but normal findings on sensory and motor examination make this diagnosis unlikely. Amyloidosis, which may be diagnosed through abdominal fat pad aspiration, can cause autonomic dysfunction and subsequent OH but is typically associated with other manifestations of cardiac, renal, or gastrointestinal tract disease. The patient's smoking and weight loss history are concerning for an underlying malignant neoplasm, but given the normal chest and abdominal CT findings, positron emission tomography would be unlikely to provide additional diagnostic benefit.
      • Vernino S.
      • Low P.A.
      • Fealey R.D.
      • Stewart J.D.
      • Farrugia G.
      • Lennon V.A.
      Autoantibodies to ganglionic acetylcholine receptors in autoimmune autonomic neuropathies.
      A 24-hour urinary sodium measurement can be used to verify adequate fluid and salt intake but would not help to identify the cause of the patient's autonomic failure.
      The neurology service was consulted and further testing was performed. Valsalva and tilt-table testing revealed dramatic blood pressure changes suggestive of severe autonomic dysfunction. Thermoregulatory sweat testing identified anhidrosis over the lower body, consistent with generalized autonomic failure. An antinuclear antibody screen yielded negative results. Seronegative autoimmune autonomic ganglionopathy was ultimately diagnosed, given the absence of ganglionic acetylcholine receptor autoantibodies.
      • 4.
        Which one of the following classes of medications is considered the best treatment option for this patient's symptoms?
        • a.
          Selective serotonin reuptake inhibitor
        • b.
          α1-Adrenergic receptor agonist
        • c.
          Dopamine antagonist
        • d.
          Nonsteroidal anti-inflammatory drug
        • e.
          Vasopressin analogue
      Selective serotonin reuptake inhibitors have no benefit in the treatment of OH and in fact can worsen the symptoms.
      • Perlmuter L.C.
      • Sarda G.
      • Casavant V.
      • Mosnaim A.D.
      A review of the etiology, associated comorbidities, and treatment of orthostatic hypotension.
      Midodrine, a directly acting α1-adrenergic receptor agonist, along with synthetic mineralocorticoids like fludrocortisone, has the most evidence of benefit in OH and should be the initial treatment used after failure of nonpharmacological options.
      • Low P.A.
      • Tomalia V.A.
      Orthostatic hypotension: mechanisms, causes, management.
      Antidopaminergics like metoclopramide and domperidone can provide a modest benefit in OH but are rarely used given their high risk for extrapyramidal symptoms. Nonsteroidal anti-inflammatory drugs may inhibit vasodilating prostaglandins and thus have some benefit as adjunctive agents but are not effective as monotherapy. Desmopressin preserves fluid volume and ostensibly could have some benefit, but so far, there is no evidence of efficacy in treating OH.
      During hospitalization, the patient had development of supine hypertension (blood pressure, 200/96 mm Hg) with an associated headache, and her dosage of midodrine was decreased. Further adjustments were made to the timing of her midodrine, fludrocortisone, and pyridostigmine doses in an attempt to improve the amount of time she was able to spend out of bed.
      • 5.
        When counseling the patient at discharge, which one of the following is the best suggestion to prevent further syncopal episodes?
        • a.
          Magnesium supplementation
        • b.
          Lower the head of the bed at night
        • c.
          Wear knee-high compression stockings throughout the day
        • d.
          Limit exercise
        • e.
          Cross legs and contract bilateral thigh muscles on standing
      Supplementation with magnesium has not been found to be beneficial in OH. There is no evidence to support lowering the head of the bed in the prevention of syncope. However, elevating the head of the bed to 30 degrees has been found to help minimize supine hypertension. Compression stockings have limited benefit in OH, given the small volume of venous blood in the lower extremities. Abdominal binders should be recommended instead.
      • Low P.A.
      • Tomalia V.A.
      Orthostatic hypotension: mechanisms, causes, management.
      Mild physical exercise reduces venous pooling and should be recommended. Exercises that allow a supine or sitting position are preferred. Physical countermaneuvers are instrumental for the prevention of syncopal episodes. Isometric contraction of the muscles of the thighs and calves increases the total peripheral resistance and maintains normal blood pressure.
      Our patient was instructed on lifestyle modifications and physical countermaneuvers and was subsequently discharged with a treatment regimen of midodrine, fludrocortisone, and pyridostigmine. A 3-month course of intravenous immunoglobulin immunotherapy is planned.

      Discussion

      Orthostatic hypotension, defined as a reduction of systolic blood pressure of at least 20 mm Hg or diastolic blood pressure of at least 10 mm Hg within 3 minutes of standing, can be devastating to one's functionality and has been reported to independently increase mortality.
      • Freeman R.
      • Wieling W.
      • Axelrod F.B.
      • et al.
      Consensus statement on the definition of orthostatic hypotension, neurally mediated syncope and the postural tachycardia syndrome.
      • Verwoert G.C.
      • Mattace-Raso F.U.
      • Hofman A.
      • et al.
      Orthostatic hypotension and risk of cardiovascular disease in elderly people: the Rotterdam study.
      Although common in elderly patients, OH is a relatively uncommon cause of syncope in younger patients, occurring in approximately 0.5% to 6% of patients under the age of 60 years.
      • Task Force for the Diagnosis and Management of Syncope of the European Society of Cardiology (ESC)
      Guidelines for the diagnosis and management of syncope (version 2009).
      Orthostatic hypotension has a broad differential diagnosis, including autonomic disorders, as illustrated in this case. Commonly, OH is related to medications (especially alcohol, antihypertensives, antidepressants, antipsychotics, antiparkinsonism drugs, and phosphodiesterase inhibitors).
      • Perlmuter L.C.
      • Sarda G.
      • Casavant V.
      • Mosnaim A.D.
      A review of the etiology, associated comorbidities, and treatment of orthostatic hypotension.
      Another common cause is volume depletion, especially in the setting of prolonged diarrhea or vomiting. Aging itself is associated with decreased baroreceptor sensitivity, which may lead to OH in 10% to 30% of elderly community-dwelling individuals.
      • Rubenstein L.Z.
      Falls in older people: epidemiology, risk factors and strategies for prevention.
      Less commonly, cardiac pump failure (arrhythmias or valvular disease) or adrenal insufficiency can cause some degree of OH. Autonomic disorders, such as those related to Parkinson disease, diabetes mellitus, amyloidosis, multiple system atrophy, pure autonomic failure, and autoimmune autonomic ganglionopathy, are an important and heterogeneous group of diseases that can lead to OH.
      Management of OH can be divided into nonpharmacological and pharmacological treatments. Nonpharmacological management includes abdominal binders, which cause compression of splanchnic-mesenteric veins to help reduce venous pooling, thus lessening the decrease in blood pressure associated with standing. Water bolus treatment (two 8-oz glasses of water in rapid succession) has been found to transiently increase blood pressure by 20 mm Hg for 1 to 2 hours and may attenuate postprandial OH.
      • Shannon J.R.
      • Diedrich A.
      • Biaggioni I.
      • et al.
      Water drinking as a treatment for orthostatic syndromes.
      Physical countermaneuvers lead to increased muscle pressor response and include standing on tiptoes, crossing legs and squeezing, and contracting calf and thigh muscles on standing. Elevating the head of the bed by 30 degrees helps prevent supine hypertension. Increasing intake of fluid (1.5-2.0 L/d) and salt (up to 4-6 g/d) remains crucial in the prevention of OH.
      Pharmacological options for OH are limited, with midodrine (an α1-agonist; initial dose, 2.5 mg 3 times daily) and fludrocortisone (a synthetic mineralocorticoid; initial dose, 0.1 mg/d) having the greatest evidence to support their use.
      • Low P.A.
      • Tomalia V.A.
      Orthostatic hypotension: mechanisms, causes, management.
      Other medications such as pyridostigmine, caffeine, nonsteroidal anti-inflammatory drugs, and erythropoietin may also be considered as adjunctive therapies but have less evidence to support their use.
      • Gupta V.
      • Lipsitz L.A.
      Orthostatic hypotension in the elderly: diagnosis and treatment.
      L-dihydroxyphenylserine (droxidopa, a synthetic norepinephrine precursor; initial dose, 100 mg 3 times daily) is a newer agent that has been approved by the US Food and Drug Administration for the treatment of neurogenic OH.
      • Kaufmann H.
      L-dihydroxyphenylserine (Droxidopa): a new therapy for neurogenic orthostatic hypotension; the US experience.
      In addition to the aforementioned medications, disease-specific therapy should be aimed at the underlying etiology of OH.
      As illustrated in this case, OH is an important cause of syncope and can be related to medications (such as alcohol and antihypertensives), volume depletion, or autonomic failure, the latter of which can be further categorized by anatomic location (brain, spinal cord, or peripheral neuropathy) and primary vs secondary disease. Identifying the etiology of OH is important because disease-specific treatments for OH depend on the underlying cause, but general measures to reduce and prevent OH exist. Low and Tomalia
      • Low P.A.
      • Tomalia V.A.
      Orthostatic hypotension: mechanisms, causes, management.
      proposed a useful mnemonic for remembering the key features of treatment for OH, which is “A to F”: abdominal binders, boluses of water, countermaneuvers, drugs, elevating head of bed, and fluids.

      References

        • Moya A.
        • Brignole M.
        • Menozzi C.
        • et al.
        • International Study on Syncope of Uncertain Etiology (ISSUE) Investigators
        Mechanism of syncope in patients with isolated syncope and in patients with tilt-positive syncope.
        Circulation. 2001; 104: 1261-1267
        • Nishimura R.A.
        • Otto C.M.
        • Bonow R.O.
        • et al.
        2014 AHA/ACC guideline for the management of patients with valvular heart disease: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines.
        J Am Coll Cardiol. 2014; 63 ([published correction appears in J Am Coll Cardiol. 2014;63(22):2489]): e57-e185
        • Freeman R.
        • Wieling W.
        • Axelrod F.B.
        • et al.
        Consensus statement on the definition of orthostatic hypotension, neurally mediated syncope and the postural tachycardia syndrome.
        Auton Neurosci. 2011; 161: 46-48
        • Perlmuter L.C.
        • Sarda G.
        • Casavant V.
        • Mosnaim A.D.
        A review of the etiology, associated comorbidities, and treatment of orthostatic hypotension.
        Am J Ther. 2013; 20: 279-291
        • Low P.A.
        • Tomalia V.A.
        Orthostatic hypotension: mechanisms, causes, management.
        J Clin Neurol. 2015; 11: 220-226
        • Vernino S.
        • Low P.A.
        • Fealey R.D.
        • Stewart J.D.
        • Farrugia G.
        • Lennon V.A.
        Autoantibodies to ganglionic acetylcholine receptors in autoimmune autonomic neuropathies.
        N Engl J Med. 2000; 343: 847-855
        • Verwoert G.C.
        • Mattace-Raso F.U.
        • Hofman A.
        • et al.
        Orthostatic hypotension and risk of cardiovascular disease in elderly people: the Rotterdam study.
        J Am Geriatr Soc. 2008; 56: 1816-1820
        • Task Force for the Diagnosis and Management of Syncope of the European Society of Cardiology (ESC)
        Guidelines for the diagnosis and management of syncope (version 2009).
        Eur Heart J. 2009; 30: 2631-2671
        • Rubenstein L.Z.
        Falls in older people: epidemiology, risk factors and strategies for prevention.
        Age Ageing. 2006; 35: ii37-ii41
        • Shannon J.R.
        • Diedrich A.
        • Biaggioni I.
        • et al.
        Water drinking as a treatment for orthostatic syndromes.
        Am J Med. 2002; 112: 355-360
        • Gupta V.
        • Lipsitz L.A.
        Orthostatic hypotension in the elderly: diagnosis and treatment.
        Am J Med. 2007; 120: 841-847
        • Kaufmann H.
        L-dihydroxyphenylserine (Droxidopa): a new therapy for neurogenic orthostatic hypotension; the US experience.
        Clin Auton Res. 2008; 18: 19-24