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General Medical Conditions: Case Reports

Syncope in an Athlete

a Case of Infectious Mononucleosis-Induced Postural Tachycardia Syndrome

Pohlgeers, Katherine M. MD, MS; Stumbo, Jessica R. MD

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doi: 10.1249/JSR.0000000000000227
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Introduction

More than 500,000 people in the United States, particularly young girls, experience chronic orthostatic intolerance resulting in substantial morbidity affecting work, school, and recreational activities (11,34). Up to a third of patients with postural tachycardia syndrome (POTS) have frank syncopal episodes with almost daily presyncope (21,29). Syncope accounts for approximately 1% of hospital admissions and 3% of emergency department visits with mortality and morbidity rates of over 7% (21,27). However, identifying the definitive etiology and mechanism of syncope and presyncope is fairly uncommon, and treatment and management can be frustrating because of the heterogeneous pathophysiologic basis of orthostatic tachycardia in POTS (3). This report will discuss a 21-year-old division I field hockey player with infectious mononucleosis (IM)-induced POTS.

Case Report

A 21-year-old previously healthy division I field hockey player presented to her primary care physician complaining of a 2-d history of headaches. She had taken nonsteroidal anti-inflammatory drugs (NSAID) the day before evaluation, which alleviated the symptoms temporarily, allowing her to sleep. The following morning, she awoke again with a headache. Upon standing, she became light headed, nauseated, and diaphoretic. Without any recollection of the preceding events, she awoke after an unknown amount of time on the closet floor and immediately contacted her mother. Her mother arrived at her dormitory room shortly after and recalled that she was mildly confused but denied any bowel/bladder incontinence or symptoms consistent with tongue or mouth biting. Her mother contacted their primary care physician via telephone and that provider ordered an outpatient computed tomography of her head without contrast later that day, which was unremarkable. At this time, the symptoms were attributed to atypical migraines versus sinusitis and she was treated accordingly. She continued to take NSAID along with an antihistamine and took a nap for several hours that afternoon.

That evening, she had a second syncopal episode while sitting on the toilet, this time witnessed by her mother. It was reported that she experienced a complete loss of consciousness for 5 to 7 s. Immediately before the episode, she appeared extremely pale. Mom denied any jerking or seizure activity, bowel/bladder incontinence, or vomiting. Before these, she had never experienced similar syncopal events. Her athletic trainers were immediately notified, and she was subsequently evaluated the following morning by the team’s primary care sports medicine physician. During her initial evaluation, the patient was found to have a lying pulse of 67, which increased to 86 with sitting and 114 with standing. Her blood pressure was 108/76 and remained stable with no evidence of orthostatic hypotension. A physical examination was significant only for 1+ tonsillar enlargement. An electrocardiogram (ECG) revealed normal sinus rhythm with no acute ischemic changes or prolonged QT interval. She was started on an antiemetic (ondansetron) for possible atypical migraine, and it was recommended that she increase her fluid and salt intake for her tachycardia, which was presumptively secondary to dehydration. Laboratory tests included a complete blood count, a metabolic profile, Epstein-Barr virus (EBV) titers, ferritin test, iron test, total iron-binding capacity, thyroid-stimulating hormone test, and vitamin D levels. It was recommended that she avoid physical activity including all participation in field hockey and follow-up in 2 to 3 d if symptoms persisted.

She returned for follow-up 3 d later. Despite treating her with ibuprofen 600 mg three times daily, ondansetron 4 mg every 6 h, and increased fluids, her symptoms did not improve. She continued to report worsening nausea without any episodes of emesis. Again in the office, her pulse increased with positional changes (68 lying down, 86 sitting, and 110 standing) without evidence of orthostatic hypotension. Pregnancy test was negative and urinalysis obtained in the office was normal except for a specific gravity of >1.030. All laboratory results obtained at her previous visit were found to be within normal limits, except for her EBV titers, which were pending. Because her main complaint at that time was still a headache, she received promethazine and intramuscular ketorolac in hopes of combating an atypical migraine, as well as a normal saline 2-L bolus for her dehydration. She reported immediate symptomatic improvement and so was sent home with warning to go to the emergency department if symptoms returned.

The following morning, her headache and light headedness returned and reported to be even more severe. Her primary care sports medicine physician was notified, and it was decided that further evaluation was necessary with recommendation for the athlete to be seen in the emergency department. Upon arrival in the emergency department, she received a lumbar puncture, which revealed a normal opening pressure. Magnetic resonance imaging (MRI) of the brain with and without contrast was performed and showed no abnormalities. She was admitted for intravenous fluids and evaluation by cardiology and neurology subspecialists.

During her stay, all cultures including cerebrospinal fluid and blood were normal. The cardiologist and neurologist were subsequently consulted. The cardiologist obtained an ECG and performed routine laboratory tests and recommended a stress test. The neurologist was concerned for atypical migraines and ordered an MRI of the brain with and without contrast, which was unremarkable. During these workups, her EBV titers from her outpatient clinic returned and were positive for IgM antibodies. At that time, the cardiologist recommended an electrophysiology consult to perform a tilt table test (after aggressive intravenous fluid resuscitation to eliminate dehydration as a confounding variable), which was subsequently found to be positive. Findings included an increase in the heart rate from 70 to 130 and persistently stayed above 100 during the entirety of the test. After 20 min, she experienced sinus tachycardia at 160 and a systolic blood pressure drop to 101 without syncope. She was found to be symptomatic with reports of feeling diaphoretic and light headed with worsening of previous symptoms, particularly her headache and nausea. Interestingly enough, chronic headaches are a common comorbidity in patients with POTS and orthostatic headaches also occur even in the absence of intracranial hypovolemia or cerebrospinal fluid leak (3). She was subsequently diagnosed with IM-induced POTS. Her stress test was cancelled at that time and the neurologist, agreeing with the diagnosis, did not perform any additional tests. She was sent home on 2 L of fluid daily with 3 to 5 g of daily salt intake. It was postulated that her symptoms may be reversible after the acute viral infection resolved.

Discussion

According to current criteria for adults, POTS is defined as a heart rate increase of 30 bpm or more within 10 min of standing or head-up tilt (HUT) with a standing heart rate of 120 bpm or higher (3,9). Up to half of all documented cases have antecedent viral illness (3,35,45), and the evaluation and management of POTS should be multidisciplinary (3). Typical complaints from POTS patients include poor concentration, headache, fatigue, dizziness, chest discomfort, tremor, and shortness of breath (21). Many patients report a cyclical nature of their symptoms (21). They also may report symptoms consistent with functional gastrointestinal or bladder disorders, fibromyalgia, chronic headache, and sleep disturbances (21). Up to one-third of patients experience secondary orthostatically triggered vasovagal syncope (2,3). POTS is more frequent in women (4.5/1), and most cases occur between the ages of 15 to 25 years (3) with more than 500,000 people in the United States being affected (11,34). Although the pathophysiology is not well understood, recent research suggests that physical deconditioning and a reduced standing stroke volume may be important features (11–14,19,26,30,38). Psychological factors may play a role also. Anxiety, depression, and poor sleep may all lead to relative predominance of sympathetic over vagal control of the patient’s heart rate (3). Abnormal processing of sensory information, including somatic hypervigilance and behavioral amplification, can contribute also to persistence of symptoms, including those symptoms not triggered by orthostatic stress, such as fibromyalgia, visceral pain, and chronic dizziness. Although it is common for POTS patients to have a noticeable drop in blood pressure upon standing, some patients have no change or may even experience an increase in blood pressure upon standing (6,21). Because of the presence of multiple comorbidities not directly related to the presenting orthostases (chronic fatigue, sleep disturbances, and myofascial pain) (3), as well as the pathophysiologic heterogeneity of orthostatic intolerance, these patients are difficult to recognize and pose a particular challenge in management (3). Abnormal sympathetic nervous activity or reactivity may be central to the conditions; however, there is no definitive link between the excessive tachycardia and sympathetic nervous dysfunction (21). There are several subtypes of POTS, including neuropathic POTS, hyperadrenergic POTS, volume dysregulation, and physical deconditioning (3).

In neuropathic POTS, there is indirect evidence of peripheral sympathetic denervation of the lower extremities (3,18,24). This patient population experiences venous pooling in the lower limbs secondary to impaired peripheral vasoconstriction (3). This is characterized by a loss of sweating in the feet leading to thermodysregulation and impaired increase of norepinephrine (NE) levels in response to orthostatic stress (3,18). Interestingly, there is a frequent onset after a viral illness (up to 50%), and the presence of a ganglionic acetylcholine receptor antibody in 14% of patients suggests an autoimmune etiology of neuropathic POTS (3,45). These common interacting mechanisms likely reflect changes in central nervous system areas involved in the processing of visceral and somatic nociceptive information, behavioral arousal, interoceptive awareness, and stress responses (3). Because of our patient’s recent diagnosis of IM with an acute onset (IgM+), there is high clinical suspicion that she experienced this specific subtype of POTS.

In hyperadrenergic POTS, between 30% and 60% of patients have increased central sympathetic drive with plasma NE levels of 600 pg·mL−1 or more (3). They also experience fluctuating blood pressure in response to HUT, as well as episodes of tachycardia, hypertension, and hyperhidrosis (3,25,43,45). The possibility of a catecholamine-secreting tumor such as a pheochromocytoma or an autoimmune etiology such as hyperthyroidism should be considered (3). Secondary hyperadrenergic POTS also has been associated with mast cell activation disorders (3,37). Neuronal reuptake of noradrenaline via the cell membrane NET (uptake 1) is the main means of inactivation of noradrenaline and a key factor in regulation of noradrenaline to myocardial adrenoceptors (7,21). It has been demonstrated that a defect in NET may be involved in the pathophysiology of POTS (21,36). By selectively blocking NET in healthy individuals, a phenotype that resembled POTS was demonstrated (21,36). Because our patient did not demonstrate these specific symptoms and never had hypernatremia, this subtype was deemed very unlikely in our specific case.

Hypovolemia secondary to volume dysregulation should be considered with the diagnosis of POTS. In one study, 28.9% of patients excreted less than 100 mEq·L−1 of sodium in 24 h (3,45) and a large subgroup experienced low plasma, total blood volumes, and red cells (3,33,42,44), illustrating a compensatory physiologic mechanism that differs from chronic dehydration in which the body retains sodium, thus retaining water, to prevent further dehydration. After saline loading, the affected patient’s urinary sodium increased and symptoms improved (23). Angiotensin-converting enzyme 2 activity has been shown to be reduced in these patients with inappropriately high plasma angiotensin II levels (3,42). Although NSAID use also can alter the angiotensin cascade, our patient was not chronically on any anti-inflammatories, nor did she ever have hyponatremia. Excessive exercise leading to dehydration as well as hypovolemia secondary to excess fluid loss from vomiting and diarrhea also should be considered (3). Again, because our patient did not experience any recent gastroenteritis or other conditions leading to dehydration with such an acute presentation, this subtype also was considered highly unlikely.

Regardless of the underlying pathophysiology, physical deconditioning is an important factor in the development of orthostatic symptoms (3,19,26). These patients exhibit greater and more persistent tachycardia when upright, reduced left ventricular mass, reduced stroke volume, and reduced peak oxygen uptake during and after exercise compared with control subjects (3,12,26). The phenomenon of deconditioning also decreases the response to the vasoconstrictor baroreceptor reflex (3,4,17) and vestibulosympathetic reflex (3,6). Our patient was a highly competitive and active division I athlete making this subtype highly unlikely. She had not recently experienced any injury leading to a long period of inactivity with secondary deconditioning.

Peak oxygen uptake (V˙O2 peak) is generally lower in these patients suggesting a lower physical fitness level (11). Compared with healthy, sedentary individuals matched for age and sex, POTS patients were found to have lower stroke volume and higher heart rate for each level of absolute workload (11,38). However, when expressed at the relative workload (percent of V˙O2peak), no differences in heart rate response were found, suggesting no intrinsic abnormality of heart rate regulation during exercise in POTS patients (11,17). It was found that POTS patients as well as their healthy counterparts had a similar linear correlation between cardiac output and V˙O2 during submaximal and maximal exercises indicating that POTS patients have a normal ability to increase cardiac output for the oxygen demand as well as peripheral use of oxygen (11,38). It has been postulated also that there are sex-specific differences exaggerated in POTS and that women born with small hearts, albeit normal range, were more susceptible to develop POTS (4,11,12). Conversely, decreased myocardial load and work secondary to physiologic adaptation to the reduced physical activity level also could account for these findings (11).

Diagnosis

POTS is one of the most common manifestations of orthostatic intolerance (3,24,25). Current criteria for adults are defined by a heart rate increase of 30 bpm or more within 10 min of standing or HUT (3,9) and a standing heart rate of 120 bpm or higher (3). For patients with a low resting heart rate or structural cardiac abnormalities, these criteria may not be applicable (3). For individuals aged 12 to 19 years, the required heart rate increment is at least 40 bpm (3,9). The observed orthostatic tachycardia may be accompanied with symptoms consistent with cerebral hypoperfusion (blurred vision, light headedness, cognitive difficulties, and generalized weakness) and sympathetic hyperactivity (chest pain, palpitations, and tremulousness) that are relieved by recumbency (3). For those patients that experience symptoms on standing or HUT but do not fulfill the heart rate criteria, the term orthostatic intolerance is used (3,30).

A precise clinical history should be obtained during initial evaluation of POTS patients, which include the timing of the onset, precipitating or aggravating factors, fluid and caffeine intake, level of physical activity, current drug therapy, and sleep pattern (3). Patients should then undergo neurologic and cardiac examination in addition to orthostatic vital signs (3). It is imperative to exclude primary cardiac causes of inappropriate tachycardia with ECG, as well as possible Holter monitoring, and echocardiogram (3). Screening HUT table testing has been shown to be helpful with patients experiencing syncope of an unknown cause, including POTS (1,3), and should be ordered as an initial test. Because of limited sensitivity/specificity, this is not beneficial as a diagnostic tool but better served as a screening test in order to differentiate POTS from other forms of orthostatic intolerance. Plethysmographic blood pressure and heart rate monitoring allows examination of the beat-to-beat systolic and diastolic blood pressure and heart rate responses during HUT to improve test sensitivity and reduce false-positive rates (3). In individual cases, additional laboratory investigations may be necessary. Serum cortisol levels in both AM and PM can be considered to evaluate for any underlying hyperadrenergic states including Cushing’s disease and acute stress reactions, a thyroid cascade to evaluate for dysregulation of thyroid hormones, plasma and urinary metanephrines to detect a pheochromocytoma, serum tryptase and urinary methylhistamine to detect mast cell activation disorders, and even MRI of the head for patients with orthostatic headaches (3). For those patients with multiple associated nonorthostatic symptoms, a behavioral medicine evaluation may prove to be beneficial (3).

Treatment

The treatment for POTS should be focused on patient education. Many patients have unrealistic expectations about the benefits of treatments and become frustrated (3). Most patients require volume expansion with adequate daily water (1.5 to 2 L) and sodium intake (3). Diuretics should be avoided in POTS patients, most notably alcohol and caffeine (3,28). Maintaining an adequate cerebral blood flow by using vasovagal maneuvers, i.e., leg crossing, making a fist, or active contraction of abdominal or buttock muscles, can be beneficial (3) as well as wearing support garments such as compression stockings or abdominal binders (3,41).

In 2014, Figueroa et al. (8) expected to show that normal saline infusion before exercise would decrease heart rate; however, no effect was observed. They postulated that an acute saline infusion was not sufficient, and more chronic treatments may be needed to improve exercise capacity (8). Furthermore, the treatment groups were not randomized so any beneficial effect of saline may have been confounded by prolonged fatigue or training effect (8).

Exercise training is extremely beneficial to POTS patients by improving cardiovascular responses. In 2010 and 2011, Fu et al. (11–13) found that 53% of patients that completed a 3-month exercise training program no longer met the criteria for diagnosis of POTS; however, the severity of the POTS symptoms was a major factor limiting patients’ exercise tolerance (11). It also was noted that many patients initially exercised too vigorously leading to a worsening of symptoms (3). It has been recommended that patients start with a recumbent cycle and gradually increase over 6 to 8 wk (3). Light strengthening exercises for the major muscle groups using weight machines provide added benefit (3).

Pharmacologic agents also can be used to treat POTS. The mineralocorticoid, fludrocortisone, promotes intravascular volume expansion (3,10); however, in patients with a history of migraine headaches, this can exacerbate headache and vertigo (3). The alpha1-adrenergic agonist, midodrine (5,15), elicits peripheral vasoconstriction and reduces venous pooling but can increase the risk of urinary retention in patients with bladder disorders (3). Beta-blockers such as propanolol (15,31) and bisoprolol (3,10,47) can be used to control excessive tachycardia. These medications can exacerbate fatigue and exercise intolerance and can cause hypotension in patients with preexisting low intravascular volume (3). Pyridostigmine (3,20,32,40) is a cholinesterase inhibitor which can prolong the phasic effects of acetylcholine on the autonomic ganglia, potentiating vagal effects on standing (3). Pyridostigmine potentiates muscarinic receptor activation in the gastrointestinal tract and can cause vomiting, nausea, abdominal cramps, diarrhea, and detrusor hyperactivity (3). Because of the adverse effect profile of medications and the large majority of patients being young with multiple comorbidities such as chronic fatigue syndrome, depression, and fibromyalgia, pharmacologic interventions are reserved for those cases resistant to fluid and salt loading.

Conclusion

In this case, conservative measures were initiated at the onset of diagnosis. The patient was discharged with strict dietary guidelines that included 2 to 3 L of water intake along with 3 g of salt daily. It was recommended she avoid caffeine and alcohol. Cardiology, neurology, and electrophysiology consults all concurred that her diagnosis of POTS would most likely be reversible with the resolution of her acute viral illness. She was treated conservatively for IM and was held from contact sports and heavy lifting until 6 wk of follow-up. Current guidelines recommend supportive therapy only for IM with steroid administration considered only in cases of airway compromise (22). Treatment with antiviral agents has not shown any benefit to date (22). At her 6 wk of follow-up, her symptoms had completely resolved and she had not experienced any additional syncopal episodes. She was cleared at that time to return to physical activity at a reduced exertional level allowing her to slowly return to her baseline. At the final follow-up, she was back to full activity with no return of symptoms.

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