Accepted Manuscript

Overt and subclinical baroreflex dysfunction following bilateral carotid body tumor
resection: pathophysiology, diagnosis, and implications for management

Michael G.Z. Ghali, Visish M. Srinivasan, Ehab Hanna, Franco DeMonte

PII: S1878-8750(17)30246-2
DOI: 10.1016/j.wneu.2017.02.073
Reference: WNEU 5304

To appear in: World Neurosurgery

Received Date: 23 November 2016

Revised Date: 13 February 2017
Accepted Date: 15 February 2017

Please cite this article as: Ghali MGZ, Srinivasan VM, Hanna E, DeMonte F, Overt and subclinical
baroreflex dysfunction following bilateral carotid body tumor resection: pathophysiology, diagnosis, and
implications for management, World Neurosurgery (2017), doi: 10.1016/j.wneu.2017.02.073.

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 ACCEPTED MANUSCRIPT

Overt and subclinical baroreflex dysfunction following bilateral carotid body

tumor resection: pathophysiology, diagnosis, and implications for management

Michael G. Z. Ghali,1 Visish M. Srinivasan,2 Ehab Hanna,4 Franco DeMonte,2,3*

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Department. of Neurobiology & Anatomy, Drexel University College of Medicine

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2
Department of Neurosurgery, Baylor College of Medicine; and the Departments of
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Neurosurgery, and 4Head and Neck Surgery, The University of Texas M. D. Anderson Cancer

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Center, 1400 Holcombe Blvd., Houston, TX 77030

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*corresponding author

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Michael G. Z. Ghali, Ph.D.
Department of Neurobiolgy and Anatomy
Drexel University College of Medicine
2900 W. Queen Lane
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Philadelphia, PA 19129
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(703) 577-4848
mgg26@drexel.edu
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Keywords: bilateral carotid body tumors; paraganglioma; baroreflex dysfunction; baroreflex

failure syndrome
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Abstract

Carotid body paragangliomas are rare, usually benign, tumors arising from glomus cells

of the carotid body. Bilateral involvement is present in ~5% of sporadic cases and up to one-third

of familial cases. In the majority of patients undergoing bilateral resection of carotid body

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tumors (CBTs), a condition known as baroreflex failure syndrome (BFS) develops following

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resection of the second tumor characterized by headache, anxiety, emotional lability, orthostatic

lightheadedness, hypertension, and tachycardia. This is believed to result from damage to the

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carotid baroreceptor apparatus. Patients without overt cardiovascular abnormalities may have

subclinical baroreceptor dysfunction evident only on specific testing, measuring HR and

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sympathetic nerve responses to baro-loading (eg., phenylephrine) and baro-unloading (e.g.,
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Valsalva maneuver). Given the high incidence of BFS in patients undergoing bilateral resection
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of CBTs, it is suggested that operation be limited to unilateral resection of the

dominant/symptomatic lesion and non-surgical intervention (i.e., embolization, radiotherapy) on

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the contralateral side. Alternatively, refinement of surgical technique to prevent injury to

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elements of the baroreceptor apparatus may prevent this unfortunate complication of bilateral

tumor resection. We present a case of a 16 year old girl with bilateral jugular vagale and carotid
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body tumors who developed hypertension following surgical resection of her left jugular vagale

tumor and worsening of hypertension concurrent with progression, eventually requiring

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intensity-modulated radiation therapy and a resection for significant progression of her left
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jugular vagale tumor. Our case illustrates the generalizability of BFS to patients with tumors

involving the vagal baro-afferent fibers.

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Introduction

Carotid body tumors (CBTs) are (typically) benign, slow-growing tumors arising from

glomus cells, with annual incidence of 1.6 per 10,000 (Oosterwijk et al., 1996). The majority

synthesize (and some secrete) catecholamines. Some exhibit nodal or distant metastasis (Gardner

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et al., 1996; Defraigne and Limet, 1997). Proto-oncogene mutations involving c-myc, bcl-2, and

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c-jun (Wang et al., 1996), among others, have been described, as well as germline mutations in

succinate dehydrogenase (Neumayer et al., 2007). CBTs represent the most common type of

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paraganglioma and 5% present bilaterally (Dickinson et al., 1986). In familial cases (typically

autosomal dominant), bilaterality affects 26-33% of patients (Grufferman et al., 1980; Sen et al.,

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2013). Bilateral resection may cause the baroreceptor failure syndrome (BFS), with reported

prevalence of ~66% (De Toma et al., 2000).

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Methods
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Case studies and series of bilateral CBTs and BFS were identified through a comprehensive
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literature search in the PubMed database.

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CASE REPORT

A 16 year-old girl presented with postural dizziness/lightheadedness, hoarseness, chronic cough,

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and dysphagia. On examination, she had a blood pressure (BP) of 120/80 mmHg (right arm,
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sitting), a heart rate (HR) of 64 bpm, and evidence of neuropathies of the left vagus, accessory,

and hypoglossal nerves with vocal cord paresis, atrophy of the sternocleidomastoid and trapezius

muscles and atrophy and fasciculations of the left side of the tongue. Arteriography identified

bilateral glomus vagale and CBTs, the largest being the left vagale located in the jugular foramen

(Figure 1). She underwent surgical resection of the left jugular glomus vagale without change in
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her neurological examination. Postoperatively, she developed hypertension (BP 180/75 to 184/85

mmHg), with HR in the mid-nineties. She was managed with prazosin and enalapril with good

response. Over the next two years, she remained normotensive on medication. There were two

episodes of missed anti-hypertensive doses requiring urgent treatment of hypertension with BP

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as high as 220/120 mmHg. She was switched to clonidine with good response.

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Three years following surgery, tumor progression of the left vagale was noted and she

was treated with intensity-modulated radiation therapy (IMRT). Four years later, progression of

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her right caroticum/vagale was noted and it too was treated with IMRT. Eight years later,

significant progression of the left caroticum/vagale was noted and the patient required the

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addition of nifedipine for BP control. The left caroticum/vagale was subsequently resected.
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Discussion
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Bilateral carotid body tumor resection: pathophysiology of autonomic dysfunction
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Baroreflex dysfunction
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BFS has been reported by several authors following bilateral CBT resection or carotid

endarterectomy, neck trauma/irradiation, and brainstem stroke. In cases of bilateral CBTs, this
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typically follows resection of the second tumor, but not in all patients (Netterville et al., 1995).

Baroreceptors are stretch receptors concentrated in the carotid sinus and aortic arch and
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also located in the great vessels from heart to skull base (Rogers et al., 1993; Robertson et al.,
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1993a). Carotid and aortic arch baroreceptors relay via the carotid sinus (branch of cranial nerve

IX) and aortic depressor nerves (branch of cranial nerve X), respectively, to the nucleus tractus

solitarius (NTS). The carotid baroreceptor apparatus may be damaged by injury to the sinus or

nerve (Hering’s nerve) (Smit et al., 2002; Robertson et al., 1993a; De Toma et al., 2000).
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Concurrent vagal injury may compromise aortic baroreceptor function, diminishing the capacity

for compensation of carotid baroreceptor injury.

Baroreceptor activity increases with arterial blood pressure (ABP). Activation of second-

order NTS neurons by baro-afferents inhibits sympathetic and stimulates parasympathetic centers

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(Aicher et al., 2000). The NTS modulates sympathetic output by projecting to and stimulating

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the caudal ventrolateral medulla (CVLM), a vasodepressor region (Sved et al., 2000) containing

tonic and phasic inhibitory GABAergic neurons, which project to and inhibit rostral ventrolateral

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medulla (RVLM) pre-sympathetic cells projecting to preganglionic sympathetic neurons

(intermediolateral cell column; Jeske and McKenna, 1992; Gilbey and Spyer, 1993; Sved et al.,

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2000; Guyenet et al., 2001). Baroloading-activated NTS neurons stimulate phasic GABAergic
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cells in CVLM to inhibit RVLM, decreasing sympathetic tone (and thus, peripheral vascular

resistance and cardiac chronotropy/inotropy/dromotropy). Second-order NTS baroreceptor cells

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stimulate cardiac vagal pre-motor neurons in the dorsal motor nucleus of the vagus (DMNX) and
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nucleus ambiguus (NA), decreasing cardiac chronotropy/dromotropy (atrioventricular nodal

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conduction velocity), and atrial contractility. Baroreceptor unloading or denervation effects the

converse – disinhibition of RVLM and disfacilitation of DMNX/NA, with enhancement of

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sympathetic and attenuation of parasympathetic tone.

While baroreceptor afferents increase discharge frequency proportionally to absolute rise

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of ABP, NTS unit firing rate codes for the rate of rise of ABP (dP/dt), rather than absolute
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stretch (Rogers et al., 1993). Patients suffering from BFS, thus, cannot sense and respond

appropriately to alterations of absolute ABP (decreased baroreflex gain) or rate of rise. This

leads to a baseline hypersympathetic and hypoparasympathetic state with hypertension and

tachycardia not adequately compensated by intact aortic baroreceptor inputs. Moreover,

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increased sympathetic activity stimulates renin secretion from the juxtaglomerular apparatus

(Coote et al., 1972), leading to increased angiotensin II (ATII; Hughes-Jones et al., 1949). ATII

potentiates sympathetic activity by depolarizing sympathetic ganglia (Dendorfer et al., 2002) and

blunts the baroreflex by direct actions on the area postrema (Bishop and Sanderford, 2000).

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Chemoreceptor dysfunction

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The first author reporting on bilateral CBT resection described not post-operative

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hypertension (Birrell, 1952), but rather reduced respiratory response to hypoxia, an expected

result of chemo-denervation. Importantly, chemoreceptors are diffusely-distributed in the carotid

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bodies, aortic arch, pulmonary vasculature, and retroperitoneum. Patients undergoing bilateral
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glomectomy for asthma also experience significantly reduced response to hypoxia (Wood et al.,

1965) and central CO2 chemosensitivity (Dahan et al., 2007), suggesting important modulation
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of central chemoreception by peripheral chemoreceptors. Zikk et al. (1983) describe a patient
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developing apneic episodes and BFS following bilateral CBT resection, the former presumably

due to loss of peripheral chemoreceptor function. Alveolar hypoventilation has been reported
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following unilateral excision of a CBT in a patient with bilateral tumors (Roncoroni et al., 1993),
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as well as postoperative respiratory depression (Baraka, 1994). Experimental chemoreceptor

ablation in dogs causes blunted hypoxic respiratory responses, arterial desaturation, and
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secondary polycythemia, but no abnormalities of ABP or HR (Gilfillan, 1967). In contrast, a

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study investigating chemoreceptor function following bilateral CBT removal failed to reveal

perturbations in peripheral chemoreflex sensitivity or sleep-disordered breathing (van Hulsteijn

et al., 2014). These findings are consistent with the hypothesis that BFS secondary to bilateral

CBT resection results from dysfunction of baroreceptors rather than chemoreceptors.

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Hypoglycemia and baroreflex sensitivity

Novel insights have been provided by Limberg and colleagues (2015) on the interactions

of hypoglycemia, chemoreceptors, and the baroreflex. It is well known that hypoglycemia,

sensed by chemoreceptors, diminishes baroreflex sensitivity. It was hypothesized by this group

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that following bilateral resection of CBTs, rendering the glomi caroticus dysfunctional,

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hypoglycemia-mediated attenuation of baroreflex sensitivity would be reduced. Indeed, in

patients having undergone bilateral CBT resection, hypoglycemia caused a depressor response

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with failure to increase HR; control subjects maintained ABP and demonstrated a tachycardic

response to hypoglycemia. Direct RVLM glucosensitivity (Verberne and Sartor, 2010) appears

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insufficient to compensate for this. Thus, a plethora of autonomic abnormalities should be
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anticipated in the patient undergoing bilateral CBT resection.
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Clinical presentation
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CBTs present as asymptomatic unilateral neck masses. They may compress and cause
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dysfunction of cranial nerves IX, X, or XII. Secretion of catecholamines may cause a

hypersympathetic state and impingement on the baroreceptor apparatus may result in

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dysregulation of baseline and/or reflex control of ABP.

BFS presents with headache, anxiety, emotional lability, tachycardia, hypertension,

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orthostatic lightheadedness, and/or hypotensive episodes (Table 1). Characteristically, patients

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develop marked dysautonomia following resection of the second tumor. Hypertension ensues 24-

72 hours post-operatively, concurrently with tachycardia, headache, anxiety, and emotional

lability (Gur and Katz, 2010). BFS has been reported following removal of a unilateral CBT

secondary to injury to the carotid sinus nerve (Gómez Esteban et al., 2004), as well as following

resection of a CBT and contralateral vagal paraganglioma (Díez Porres et al., 2003).
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Patients with baroreflex dysfunction may exhibit sustained elevations of resting ABP,

episodic hypertension, and/or increased BP variability. Episodes of hypotension may also occur,

especially with sedation or orthostasis (Robertson et al., 1993b). Baroreflex dysfunction, strictly

defined, entails inability to appropriately attenuate/augment sympathetic activity and HR in

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response to elevations/decreases in ABP. Patients with severe dysfunction may or may not

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exhibit elevated baseline ABP. Timmers and colleagues (2003a) systematically investigated this,

showing that patients with normal ABP post-operatively following bilateral CBT removal still

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exhibit baroreflex dysfunction (in contrast to an earlier study by the same group [Smit et al.

(2002)] showing above-average BP at rest). However, patients had attenuated HR and muscle

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sympathetic nerve activity responses to phenylephrine compared to control subjects.
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Additionally, there was diminished HR rise in response to Valsalva maneuver during phase 2.

Thus, baroreflex dysfunction occurred in response to both baro-loading and –unloading.

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Moreover, baroreflex control of sympathetic nerve discharge involves activity of carotid, aortic,
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and cardiopulmonary baroreceptors, whereas that of HR appears to primarily depend on carotid

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baroreceptors (Timmers et al., 2003a).

The classic definition of BFS with overt resting ABP and HR abnormalities (Robertson et
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al., 1993a) likely reflects a manifestation of severely perturbed baroreflex function to the extent

that tonic inhibition of ABP by baroreceptor afferents is lost (Robertson et al., 1993a). In most
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cases, baroreflex dysfunction occurs transiently post-operatively following removal of the

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second CBT (Timmers et al., 2003a,b). BP also becomes highly sensitive to minimal stressors

(e.g., mental activity), with pressor responses up to 190-230/90-120 mmHg (Smit et al., 2002).

However, baroreflex dysfunction following bilateral operative intervention in the carotid

bifurcation is typically subclinical, reflecting abnormal responses to changes in ABP, rather than
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altered set-point, which may be well-preserved by aortic and other baroreceptors (Timmers et al.,

2003a). Cardiovascular dysfunction in these patients can be detected by ABP Holter monitoring

demonstrating abnormalities in resting ABP and increased BP variability. Baroreflex dysfunction

can be tested directly using transfer function analysis and indirectly by spectral analysis of

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electrocardiogram R-R intervals and systolic BP demonstrating power attenuation in the low-

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and high-frequency bands. In addition to a complete history, review of medications, and physical

examination, tests to rule out secondary causes of hypertension (e.g., renal artery stenosis and

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parenchymal disease, pheochromocytoma, other endocrinopathies) should be performed.

Our patient presented initially with lower cranial nerve palsies (hoarseness, dysphagia)

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and dysautonomia (postural lightheadedness). She was normotensive, indicating preserved
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capacity to maintain normal static ABP, although dynamic BP control was not tested. Following

resection of the patient's left jugular glomus vagale, she exhibited marked hypertension, possibly
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consequent to left-sided injury to vagal baroreceptor afferents, requiring and well-controlled with
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prazosin and enalapril. Evidencing the significance of her baroreflex dysfunction, two instances
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of missed doses were associated with severe hypertensive episodes (220/120 mmHg). She was

subsequently switched to and well-controlled on clonidine. Progression of left then right-sided

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tumors required treatments with IMRT. BP destabilized once more concurrently with further

progression of her left caroticum/vagale tumor, requiring the addition of nifedipine.

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Our case is remarkable for baroreflex dysfunction following unilateral tumor resection
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and progression of baroreflex dysfunction concurrently with tumor progression. Baroreflex

dysfunction manifesting after resection of only the left-sided lesion may reflect concurrent right-

sided involvement rendering that carotid baroreceptor apparatus incapable of compensating for

the contralateral resection. Our case also highlights the shared pathogenesis of baroreflex
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dysfunction from a tumor involving vagal nerve baro-afferents relaying carotid sinus pressure

with that of a CBT directly involving the carotid sinus receptor cells and distal afferents relaying

arterial stretch information. Concomitant and concurrent involvement of left- and right- jugular

vagal and carotid body regions undoubtedly added to our patient’s progression of ABP

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regulatory dysfunction.

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Imaging

Ultrasound and color Doppler ultrasound are effective at diagnosing CBTs (Demattè et

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al., 2012). Computed tomographic scanning reveals an intensely-enhancing well-circumscribed

mass (Casselman et al., 1987). MRI evaluates extent of tumor (characteristically T1 hypointense

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and T2 hyperintense) spread and possible involvement of the intracranial cavity (Wang et al.,
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2011). Conventional catheter (or magnetic resonance [Arriaga et al., 1992; Biliciler et al., 1992])
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angiography reveals prominent vascular supply from the external carotid, vertebral, and

thyrocervical arteries (Rosen et al., 1981; Gur and Katz, 2010) and is the definitive diagnostic
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modality (Kraus et al., 1990).

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Bilaterality is evident on imaging in cases involving both carotid bodies. In the case of a

single angiographically-detected CBT, evaluation of the contralateral carotid bifurcation by the

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same is indicated in familial cases due to high incidence of bilaterality. Since CBTs may present

as contralateral neck tenderness without mass, this presentation is also an indication for imaging
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of that side (Sugarbaker et al., 1971). Radionuclide angiography appears to be an effective and
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safer alternative to conventional angiography in work-up of CBTs (Laird et al., 1983). Patients
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with familial paragangliomas may benefit from undergoing whole body Indium pentetreotide

scanning (Myssiorek and Palestro, 1998).

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Management

CBTs are generally treated via surgical resection. Previously reported mortality

approached 13%. The most common post-operative sequel is cranial nerve injury (e.g., cranial

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nerves IX, X, XII) (incidence 0-70%; Williams et al., 1992). Small tumors are readily excisable,

whereas progressive growth may result in encasement of vascular structures. Tumors larger than

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5 cm are associated with greater likelihood of neurovascular complications (Meyer et al., 1986).

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Surgical advances have reduced incidence of cerebrovascular accident (2-3%) and mortality (0.5-

1%; Netterville et al., 1995; Mitchell et al., 1996). Dissection is performed subadventitially in the

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carotid bifurcation, wherein lie baroreceptors and chemoreceptors, which may underlie, in part,
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post-operative dysfunction of the same. Use of a surgical shunt and electroencephalographic

monitoring are advisable for large tumors (Kraus et al., 1990; Fachinetti et al., 1991).
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Preoperative deployment of an internal carotid artery (ICA) stent may help preserve patency
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(Konishi et al., 2011; McDougall et al., 2012; Piazza et al., 2013), especially with concomitant

CBT and/or carotid stenosis (Smeds and Jacobs, 2013). Preparation of a saphenous vein graft
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may become necessary should reconstruction of the ICA become requisite (Zikk et al., 1983;
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Reyt et al., 1992).

Embolization may be used as pre-operative adjunctive or definitive therapy, the former

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being shown to reduce operative duration and blood loss (DuBois et al., 1987; Işik et al., 2006;
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Morita et al., 2012; Power et al., 2012; Kalani et al., 2013). Combination of embolization (to

reduce tumor size) and stenting (to facilitate dissection) is effective for resection of bilateral

CBTs, especially in patients failing a temporary ICA balloon test occlusion (Ong et al., 2014).

Radiation therapy has also been used effectively to treat bilateral CBTs and is indicated for

large/inoperable tumors (Mendenhall et al., 1986; Valdagni and Amichetti, 1990; Guedea et al.,
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1991; Cooper et al., 1998) or may be used adjunctively (Alaoui et al., 2007). We used IMRT

successfully following the initial surgical resection of the left jugular vagale tumor to control

progression of left- and right-sided lesions. Perhaps if surgical resection was performed

alternatively, more severe BP perturbations refractory to pharmacologic therapy would have

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become manifest.

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The patient with bilateral CBTs presents a management dilemna. Dysfunction of the

baroreflex may cause pre-operative dysregulation of ABP (Table 1). Moreover, carotid region

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surgery may effect intra- and post-operative BP fluctuations, which must be anticipated and

aggressively managed with vigilant monitoring and sodium nitroprusside as necessary

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(Robertson et al., 1993a). If the carotid sinuses or other elements of the baroreceptor apparatus
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are injured bilaterally, the patient may experience long-term baroreflex dysfunction.

Recommended treatment for this condition includes clonidine (centrally-acting alpha-2 agonist)
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to reduce sympathetic outflow, beta-blockers, and benzodiazepines (for anxiety). Fludrocortisone
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may be used to prevent hypovolemia and BP lability.

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Earlier opinion favored resection of both tumors in cases of bilateral CBTs, as

hypertension typically improved with time and was not severe (Sugarbaker et al., 1971; Shedd et
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al., 1990). However, recent investigators report post-operative hypertension up to 280 mmHg

systolic following bilateral resection. Given their frequent benignity and slow-growth, as well as
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occasional spontaneous regression (Hammer et al., 2012), a more conservative approach to

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bilateral CBTs may be prudent (van der Mey et al., 1992; De Toma et al., 2000; Elghozi et al.,

2001; Moroni et al., 2012). The risk of iatrogenic bilateral cranial nerve palsies, especially with

large tumors, seems to favor unilateral resection of the dominant tumor and close observation of

the contralateral tumor, with radiotherapy for symptoms and/or progression (Demir et al., 2014).
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As a counterpoint, meticulous surgical technique avoiding injury to the baroreceptor apparatus

may avoid BFS (Hamilton and Barros D’Sa, 1987) and other complications (Marchesi et al.,

1997) altogether. For example, Hamilton and Barros D'Sa (1987) report on a series of 5 patients

with bilateral CBTs who underwent surgical resection without development of overt baroreflex

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dysfunction.

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Conclusion

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In conclusion, bilateral resection of CBTs frequently causes overt or subclinical

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baroreflex dysfunction, as a result of injury to the carotid baroreceptor apparatus. These patients

exhibit headache, anxiety, and/or emotional lability, as well as abnormalities of resting ABP,
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increased ABP variability, tachycardia, orthostasis, and episodes of hypotension. In some cases,

baroreflex dysfunction improves, perhaps through compensation by aortic or other extra-carotid

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baroreceptors. In many patients, however, BFS persists and causes a significant decline in quality
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of life. Thus, it is recommended that bilateral surgical resection for CBTs be reserved for

symptomatic patients, with unilateral resection of the dominant lesion and treatment of the
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contralateral tumor with non-surgical alternatives, such as embolization or radiotherapy.

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Conflicts of interest: none

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Figure Legends

Figure 1. A) Axial post contrast CT angiogram at the level of the carotid bifurcation
reveals bilateral carotid body tumors (arrows), the larger of the two on the right. B)

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Axial post contrast CT angiogram at level of body of C2 reveals bilateral glomus
vagale tumors(arrows) the larger of the two on the left. C) Coronal CT angiogram
reveals the rostrocaudal extent of the bilateral paragangliomas.

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Author (s) Age, Presentation Imaging Course Management of BFS

Gender
Sugarbaker 24, M Tender L neck mass, DSA: left large CBT, R small CBT. Uncomplicated resection of R CBT; L CBT resected 5 months later. Post-op HTN Conservative
et al., 1971 prominent tender R (160/110)/tachycardia (140); 1 year later BP – 144/86, HR – 70
carotid bulb without
palpable mass

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Zikk et al., 26, F Neck swelling - R CBT resected, carotid bifurcation bridged by saphenous vein graft; subadventitial -
1983 dissection of L CBT and removal, ECA sacrificed; tear in L carotid bifurcation repaired;
CN XII preserved; post-op recurrent apneic episodes; sustained HTN (170-240)/(110-
140)/tachycardia (130), L CN XII paresis

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Ridge et al., 47, M Bilateral neck CT and DSA: b/l CBT Resection of L (7.6 x 4 x 3 cm) tumor and part of CN X; subclinical L vocal cord palsy 6 Calcium channel
1993 swelling weeks post-op; embolization (ascending pharyngeal and superior thyroid arteries) of R blocker
tumor (two fragments: 5 x 3.2 x 2.2 and 3.3 x 2.4 x 2.5 cm); resection of R tumor with

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ECA; post-op BP labile (SBP 90 to > 200 mmHg) partially controlled w/ phenylephrine
and nitroprusside, but eventually normalized.
Boyle et al., 31, F Bilateral neck DSA: b/l CBT Resection of R then L CBT 4 months apart; within 4 days, intermittent frontal headache, Analgesics for
1995 swelling persistent tachycardia (140), and intermittent HTN (SBP range 100-150/60-100 mmHg); headache

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left CN XII neurapraxis; 1 mo. post-op. palpitations, flushing, frontal headaches, episodes
of LOC with severe HTN (likely HTN encephalopathy)
De Toma et 47, F Painless mobile L Doppler US: hypoechnoic Resection of right then left tumor 1 week apart; asx after removal of 1st tumor, following Clonidine/Nifedipine

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al., 2000 neck mass hypervascular L-sided mass; DSA: b/l resection of second tumor, severe HTN (240/130)/tachycardia (120), headache, nausea, for HTN post-op;
CBT vomiting, flushing long-term controlled
with clonidine, β-
blockers, and

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benzodiazepine
Elghozi et 46, M R neck mass, 1980, DSA: R CBT (1980); L CBT (1999) Right ICA ligation in 1980, patient developed prolonged dysphonia; Left ECA ligation in Clonidine
al., 2001 L neck mass, 1999 2000; post-operative severe headache and HTN to 300/180 mmHg, dysphagia; clonidine
effective for HTN managing arterial HTN (trials of beta-blockers and calcium channel

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antagonists were also attempted)
Smit et al., 45, F - - Resection of both tumors two months apart at age 35; patient developed headache,
2002**
63, F - -
TE orthostatic lightheadedness, and labile HTN refractory to anti-hypertensives
Resection of R tumor at age 23, development and resection of L tumor 40 years later;
headache, lightheadedness, dysphagia (superior laryngeal nerve injury)
63, F - - Resection of L then R tumor 3 months apart; headaches, HTN, orthostatic
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lightheadedness, cutaneous flushing
41, F Globus, dysphagia - Resection of R then L tumor 1 year apart; headache, flushing, nervousness, Moxonidine,
tremulousness; episodic hypertension, emotional lability, orthostatic lightheadedness atenolol,
chlorthalidone
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Timmers et 44, F Neck swelling R 2.5 cm CBT; L 1.0 cm CBT Removal of tumors 1 year apart; long-term persistent signs/symptoms of baroreflex N/A
al., 2003 failure
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58, F Neck swelling R 1.5 cm CBT; L 2.0 cm tumor Removal of tumors ~1 month apart, radiotherapy; asymptomatic baroreflex dysfunction; Chlorthalidone,
cervical plexus injury atenolol, moxonidine
44, F Neck swelling R 3.0 cm tumor; L 4.0 cm tumor Removal of tumors ~1 year apart, asymptomatic baroreflex dysfunction N/A
62, F Neck swelling R 2.0 cm tumor; L 3.0 cm tumor Removal of tumors ~1 year apart, asymptomatic baroreflex dysfunction N/A
36, M Neck swelling R 1.5 cm tumor; L 2.0 cm tumor Removal of tumors ~1 year apart, transient signs/symptoms of baroreflex failure Atenolol
Işik et al., 46, M Bilateral neck MRI: L 2.5 x 2.0 x 2.0 cm CBT; R 3.0 Removal of R CBT using subadventitial resection technique with R CN X, XII palsy; L
2006 swelling x 2.0 x 2.5 cm CBT; DSA: CBT removed 1 month later. One year post-op, 6-month history of headache,
hypervascular mass, splaying of ICA hypertension, and tachycardia; elevated urine catecholamines, metanephrines,
and ECA normetanephrine, vanillylmandelic acid, 131I MIBG scan showed left adrenal
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pheochromocytoma, tumor resected; non-paroxysmal hypertension persisted post-

operatively
Maturo and 38, M MRI: b/l carotid paragangliomas, Resection of R carotid then L carotid and jugulotympanic body tumors 1 year apart; 1 Clonidine,
Brennan, L jugulotympanic paraganglioma month post-operatively developed headache, facial flushing, diaphoresis, HTN (SBP > clonazepam
2006 200), controlled with labetalol and nitroprusside, then switched to clonidine and terazosin
Erem et al., 45, M Headache, Pheochromocytoma (PSH of bilateral Prior resection of b/l CBT; resection of pheochromocytoma; urine catecholamines,

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2006 palpitations, carotid body tumor removal) metanephrines, and normetanephrines normalized following resection; non-paroxysmal
sweating, HTN sustained
paroxysmal HTN,
postural hypotension

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Díaz- - Neck swelling CT: bilateral carotid body tumors Embolization and resection of right then left CBT, 1 month apart; post-operative HTN Clonidine,
Molina et (SBP > 200) / tachycardia (> 160), headache, episodes of hypotension, cutaneous benzodiazepine
al., 2010 flushing, emotional lability, diaphoresis

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Onan et al., 43, F Bilateral neck Right 7.8 x 5 x 4.5 cm tumor; left 5 x 3 Resection of both tumors 1 week apart; post-operative HTN episodes to 220/140, Clonidine,
2010 swelling x 2 cm tumor tachycardia to 130, headache, vomiting, skin flushing, episodes of hypotension and metoprolol, sedative
bradycardia; long-term patient developed episodic HTN (2/mo.)
Gur and 41, M Bilateral neck CT: Right 2.2 x 2.5 cm left 4.7 x 6 cm Uncomplicated resection L CBT; R CBT resected 8 months later, HTN (160/120) / β-blockers, clonidine

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Katz, 2010 swelling tachycardia (140) POD 1, asx
Konishi et 35, F Bilateral neck MRI: b/l CBT encasing ECA and ICA; Stainless steel stent placed 3 months pre-operatively in L ICA; L CBT, ECA, and Conservative
al., 2011 swelling, dysphonia R 3.0 x 3.0 x 4.5 cm, L 3.5 x 3.5 x 4.5 branches resected; 10 months later, right ICA stented. 3 months later, R CBT resected

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cm; DSA: intense tumor blush with ligation of ECA and branches; postoperative HTN (160/70)/tachycardia (120). At
discharge, BP 130/80, HR (100-110); BP and HR normalize by 1 year.
Boscarino - Neck swelling Bilateral carotid body tumors; vagal Hypertension following removal of second carotid body tumor; recurrent laryngeal nerve β-blockers, clonidine
et al., 2014 paraganglioma palsy following removal of vagal paraganglioma

M
Ghali et al., 16, F Orthostatic bilateral glomus vagale and carotid Resection of L jugular glomus vagale
postop HTN; good response to Prazosin + enalapril
2016 dizziness; vagal, body tumors; L vagal in jugular prazosin+enalapril, normotensive for 2 years; 2 episodes severe HTN (220/120) with
clonidine

spinal accessory, and foramen (largest) missed anti-hypertensive doses
switched to clonidine with good response. Progression Clonidine +

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hypoglossal of L vagale 3 years following initial surgery
treated with IMRT
progression of R nifedipine
neuropathies caroticum/vagale 4 years later
treated with IMRT
significant progression of L
caroticum/vagale 8 years later
required nifedipine for BP control
L
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Table 1. Baroreflex failure syndrome following bilateral carotid body tumor resection. Netterville et al. (1995) additionally report on two patients who developed BFS following bilateral resection of
carotid body tumors, although individual patient demographics and presentation are not reported. Limberg et al., (2015) report on five patients undergoing bilateral carotid body tumor resection, but did
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not report individual patient demographics and presentation (3 M, 2 F; mean age 40:5 yrs). ** study reports on patients presenting with baroreflex dysfunction following bilateral carotid body resection
(bCBR). Sanli et al., 2012 report on a patient undergoing bCBR who developed baroreflex failure syndrome. Ferrante et al. (2015) report on a patient who developed arterial HTN following bCBR.
HTN, hypertension; BFS, baroreflex failure syndrome; BP, blood pressure; b/l, bilateral; CN X, vagus nerve X; CBT, carotid body tumor; CN XII, hypoglossal nerve; SBP, systolic blood pressure; HR,
heart rate; ICA, internal carotid artery; IMRT, intensity-modulated radiation therapy; ECA, external carotid artery; MIBG, metaiodobenzylguanidine; R, right; L, left.
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BFS, baroreflex failure syndrome

BP, blood pressure

CVLM, caudal ventrolateral medulla

DMNX, dorsal motor nucleus of the vagus nerve

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dP/dt, rate of rise of arterial pressure with respect to time

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ECA, external carotid artery

GABA, gamma-aminobutyric acid

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HR, heart rate

ICA, internal carotid artery

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MIBG, metaiodobenzylguanidine

NA, nucleus ambiguus

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NTS, nucleus tractus solitarius
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PNMT, phenylethanolamine N-methyltransferase
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RVLM, rostral ventrolateral medulla

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SBP, systolic blood pressure

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Conflicts of interest: none.

Michael G. Z. Ghali, Ph.D.

Department of Neurobiology and Anatomy
Drexel University College of Medicine

Visish M. Srinivasan, M.D.

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Department of Neurosurgery
Baylor College of Medicine

Franco DeMonte, M.D.

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Departments of Neurosurgery, Head and Neck Surgery
Baylor College of Medicine
The University of Texas M.D. Anderson Cancer Center

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Ehab Hanna, M.D.
Department of Head and Neck Surgery
The University of Texas M.D. Anderson Cancer Center

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