Abstract
Injury of the afferent limb of the baroreflex from neck radiation causes radiation-induced afferent baroreflex failure (R-ABF). Identification and management of R-ABF is challenging. We aimed to investigate the pattern of autonomic dysfunction on standardized autonomic testing in patients with probable R-ABF.
We retrospectively analyzed all autonomic reflex screens performed at Mayo Clinic in Rochester, MN, between 2000 and 2020 in patients with probable R-ABF. Additional tests reviewed included ambulatory blood pressure monitoring, plasma norepinephrine, and thermoregulatory sweat test (TST).
We identified 90 patients with probable R-ABF. Median total composite autonomic severity score (range 0 – 10) was 7 [IQR 6 – 7]. Cardiovascular adrenergic impairment was seen in 85 patients (94.4%); increased blood pressure recovery time after Valsalva maneuver in 71 patients (78.9%; median 17.4 sec); orthostatic hypotension (OH) in 68 patients (75.6%). Cardiovagal impairment was demonstrated by abnormal heart rate responses to deep breathing (79.5%), Valsalva ratio (87.2%), and vagal baroreflex sensitivity (57.9%). Plasma norepinephrine was elevated and rose appropriately upon standing (722 pg/mL to 1207 pg/mL). Ambulatory blood pressure monitoring revealed hypertension, postural hypotension, hypertensive surges, tachycardia, and absence of nocturnal dipping. Blood pressure lability correlated with impaired vagal baroreflex function. Postganglionic sympathetic sudomotor function was normal in most cases; the most frequent TST finding was focal neck anhidrosis (78.9%).
Standardized autonomic testing in R-ABF demonstrates cardiovascular adrenergic impairment with OH, blood pressure lability, and elevated plasma norepinephrine. Cardiovagal impairment is common, while sudomotor deficits are limited to direct radiation effects.
Keywords: baroreflex, radiation, cancer, autonomic nervous system, autonomic testing
Summary
Our study shows that autonomic laboratory evaluation can be helpful to investigate autonomic dysfunction in patients with probable R-ABF. Autonomic testing demonstrates prominent adrenergic impairment with neurogenic orthostatic hypotension, blood pressure lability, and elevated plasma norepinephrine. This study may help clinicians when identifying and/or counseling patients with probable R-ABF.
INTRODUCTION
Radiation-induced afferent baroreflex failure (R-ABF) refers to the clinical syndrome resulting from impairment of the afferent limb of the baroreflex following radiation therapy to the neck and upper chest.1 The main manifestations of R-ABF are fluctuating hypertension, orthostatic hypotension, and episodic tachycardia.1 Radiation therapy is the most common cause of afferent baroreflex failure, while other etiologies include neck surgery, trauma of the neck region, brainstem stroke or tumor, and afferent sensory neuropathy.1–4
The diagnosis of R-ABF is challenging and relies on good history taking and autonomic testing. Afferent baroreflex failure is likely an underrecognized cause of labile hypertension, syncope, and orthostatic hypotension.5 Furthermore some considerations for the management of blood pressure are unique to patients with afferent baroreflex failure and clinicians should be familiar with this syndrome to provide optimal counseling and patient care.3 Specialized tests investigating the afferent limb of the baroreflex, such as analysis of blood pressure responses during cold pressor and handgrip testing, or measurement of plasma vasopressin in the supine and upright positions, are not performed routinely.5, 6 Most institutions assess autonomic function using a routine, standardized battery of autonomic tests, the autonomic reflex screen (ARS), also for the evaluation of patients with probable R-ABF.7
Few studies, with low sample size, have reported autonomic testing in patients with R-ABF.4, 8 Over the past 20 years, a large number of patients has been referred to our institution for evaluation and testing of probable R-ABF. Therefore, we aimed to investigate the pattern of autonomic dysfunction in patients with probable R-ABF and to describe the effect of deafferentation of baroreflex on standardized autonomic testing.
METHODS
Patients
This study was reviewed and approved by the Mayo Clinic institutional review board and included patients who provided consent for use of their medical records for research purposes. All patients with a diagnosis of probable R-ABF who underwent ARS and who were evaluated by an autonomic disorders specialist at Mayo Clinic in Rochester, MN, between January 1, 2000, and September 1, 2020, were identified through an electronic search of the medical records. Patients were included in the study if they fulfilled the following inclusion criteria: 1) Probable diagnosis of afferent baroreflex failure confirmed by an autonomic disorders specialist based on the clinical presentation with fluctuating hypertension with or without orthostatic hypotension, orthostatic tachycardia with or without episodes of bradycardia with otherwise unexplained symptoms suggestive of impaired blood pressure and/or heart rate regulation, and 2) History of neck radiation with or without neck surgery, and 3) Standardized autonomic testing with ARS, and 4) Patient age 18 or above at time of onset of symptoms. Exclusion criteria included: 1) Patient with a diagnosis not consistent with R-ABF after review of the history and autonomic evaluation (e.g., pheochromocytoma, untreated hyperthyroidism, other secondary causes of hypertension, carcinoid syndrome). A detailed medical record review was performed by one of the author (GL, autonomic disorders clinical fellow). If the diagnostic accuracy was unclear, quality check was performed by the senior author (WS).
Clinical data
A detailed medical record review included clinical and demographic variables.
Autonomic function testing
All patients underwent standardized autonomic function testing with ARS, which tests postganglionic sympathetic sudomotor, cardiovagal, and cardiovascular adrenergic functions.7 Postganglionic sympathetic sudomotor function was assessed using quantitative sudomotor axon reflex testing (QSART).9 Resting sweat activity was defined as increased sweat volume prior to stimulation with iontophoresis. Cardiovagal function was assessed with heart rate responses to deep breathing (HRDB), heart rate responses to Valsalva maneuver (Valsalva ratio or VR), and the slope of the relationship between RR interval and blood pressure in early phase II of the Valsalva maneuver (vagal baroreflex sensitivity or BRS-V).10, 11 Cardiovascular adrenergic function was evaluated by assessing blood pressure responses to Valsalva maneuver and passive head up tilt.10 The blood pressure recovery time (PRT), the time from the nadir of the blood pressure in phase III of the Valsalva maneuver to complete return to baseline, was used as a quantitative index of baroreflex adrenergic function.12 Valsalva maneuver was performed in the supine position with head on pillow after a resting period of at least 5 minutes. A diagnosis of neurogenic orthostatic hypotension (nOH) was indicated by a sustained drop >30 mmHg in systolic blood pressure and/or >15 mmHg in diastolic blood pressure during tilt table test, a lack of reflex vasoconstriction with loss of late phase II and blood pressure over-shoot, and prolonged PRT during Valsalva maneuver.7 Blood pressure during Valsalva maneuver was assessed using a continuous non-invasive blood pressure monitoring device with a finger cuff (Finapress system). During tilt table testing, manual blood pressure with a brachial cuff placed on the right or left arm placed horizontally at the level of the heart was performed at baseline during 5 minutes of supine rest and at 30 seconds, 1, 2, 3, 5, and 10 minutes during head up tilt. Passive head-up tilt was performed at 70 degrees to minimize the effects of leg contraction. In situations where there was a large fall in blood pressure indicating imminent syncope or when the patient requested the termination of the study, the tilting was stopped at less than 10 minutes to minimize risk to patients and avoid syncope. Quantitative indices of cardiovagal and adrenergic function were compared to normative values for age and sex. Patients were instructed to discontinue medications that may interfere with autonomic function for at least 48 hours prior to autonomic function testing and abstain from alcohol and caffeine use.
Composite autonomic severity score (CASS) was derived from ARS. CASS is a validated instrument that quantifies the severity and distribution of autonomic failure and is composed of three subdomains: sudomotor (score range 0–3), cardiovagal (0–3), and adrenergic (0–4). The total CASS ranges from 0 to 10, with 10 indicating severe autonomic failure.7
Thermoregulatory sweat test (TST) was used to investigate the central and peripheral thermoregulatory system.13
Other ancillary testing
Ambulatory 24 hour blood pressure monitoring were reviewed. The standard deviation of systolic blood pressure was used as an index of blood pressure variability (values were obtained during activity, sleep, and the full 24-hour period). Hypertension was defined by sustained systolic blood pressure >140 millimeters of mercury (mm Hg) and/or diastolic blood pressure >90 mm Hg during 24-hour blood pressure recording.14 Hypertensive crisis was defined by a severe increase in systolic blood pressure >180 mm Hg and/or diastolic blood pressure >120 mm Hg during 24-hour blood pressure recording.14 A blood pressure surge during recording was defined by an abrupt increase in systolic blood pressure >30mmHg for more than 2 consecutive measurements, whereas loss of nocturnal fall in blood pressure was defined by obvious blunted or absent nocturnal blood pressure decline according to the clinician.
Laboratory variables included supine and orthostatic norepinephrine levels performed as part of plasma catecholamine testing.
Statistics
Summary statistics were used to describe demographic and clinical variables including mean (standard deviation), median (interquartile range, IQR) and frequency (percentage). Categorical variables were analyzed using χ2 test or Fisher exact test, as appropriate. Continuous variables were compared using Student t-test or Wilcoxon rank-sum test, as appropriate.
The Pearson correlation coefficient was used to evaluate the linear relationship between independent variables including HRDB, VR, the baroreflex cardiovagal sensitivity, PRT, the change in plasma norepinephrine, the orthostatic change in systolic blood pressure during tilt, and the standard deviation of the systolic blood pressure during 24-hour recording. The statistical software was IBM Corp. Released 2017. IBM SPSS Statistics for Windows, Version 25.0. Armonk, NY: IBM Corp.
Data availability
Anonymized data will be shared by request from any qualified investigator.
RESULTS
We identified 90 patients (73 men [81.1%]) with probable R-ABF. Patients’ characteristics are shown in Table 1. Patients with probable R-ABF frequently had significant comorbidities related to prior radiation treatment including dysphagia, brachial plexopathy, and cranial neuropathy (Table 1). Patients with probable R-ABF frequently underwent adjuvant surgery (N = 63) and/or chemotherapy (N = 47) as part of the treatment of the underlying cancer (Table 1). History of head and neck cancer was reported in 87 patients while 3 patients had neck radiation for other reasons (acne, streptococcal infection with rheumatic fever, and metastatic non-small cell lung cancer). Patients were referred from the autonomic clinic or the hypertension clinic. Indications for referral included labile hypertension and/or symptoms of orthostatic intolerance (e.g., orthostatic dizziness, syncope).
Table 1.
Demographics of patients with radiation-induced afferent baroreflex failure
| N | 90 |
| Age at diagnosis (years), median [Q1 – Q3] | 64 [58.4 – 69.4] |
| Sex, M (%) | 73 (81.1) |
| Follow-up (years), median [Q1 – Q3] | 7.2 [4.2 – 10.4] |
| Comorbidities, N (%) | |
| Dysphagia | 61 (67.8) |
| Feeding tube | 44 (48.8) |
| Hypothyroidism | 59 (65.5) |
| Brachial plexopathy | 18 (20) |
| Cranial neuropathy | 33 (36.6) |
| Carotid stenosis / occlusion | 29 (32.2) |
| Stroke | 20 (22.2) |
| Ischemic stroke | 19 |
| Hemorrhagic stroke | 1 |
| CHF | 5 (5.6) |
| CKD | 20 (22.2) |
| Diabetes | 15 (16.6) |
| Neck cancer, N (%) | 87 (96.6) |
| Neck radiation, N (%) | 90 (100) |
| Dose of radiation (centigray), median, [Q1 – Q3] | 6000 [3605 – 6897] |
| Duration of radiation treatment (months), median [Q1 – Q3] | 1.5 [1.3 – 2.0] |
| Neck surgery, N (%) | 63 (70.0) |
| Chemotherapy, N (%) | 47 (52.2) |
| Latency (time from radiation to symptom onset, in years), median [Q1 – Q3] | 7.2 [4.1 – 12.4] |
Abbreviations: CKD = chronic kidney disease, CHF = chronic heart failure, M = male, Q1 = first quartile, Q3 = third quartile.
Standardized autonomic testing revealed cardiovascular adrenergic impairment in 85 patients (94.4%), which was almost invariably severe resulting in OH; increased PRT (>6 sec) was seen in 71 patients (78.9%) with a median 17.4 sec. Median CASS adrenergic score was 4 (Table 2). Cardiovagal impairment was evident in most patients, and the median CASS vagal score was 2 (Table 2). Sudomotor function was assessed with QSART in all patients, and TST in 42 patients. Postganglionic sympathetic sudomotor function was normal in most cases; the median CASS sudomotor was 0 (Table 2). The most common distribution of anhidrosis on TST was focal anhidrosis of the neck area (see illustrative example in Figure 1).
Table 2.
Results of standardized autonomic testing, thermoregulatory sweat test, plasma norepinephrine and 24-hour blood pressure monitoring in patients with radiation-induced afferent baroreflex failure
| Autonomic reflex screen, N (%) | 90 (100) |
| CASS sudomotor, median [Q1 – Q3] | 0 [0 – 1] |
| CASS cardiovagal, median [Q1 – Q3] | 2 [2 – 3] |
| CASS adrenergic, median [Q1 – Q3] | 4 [4 – 4] |
| CASS total, median [Q1 – Q3] | 7 [6 – 7] |
| Abnormal HRDB compared to normative values, N (%) | 70/88 (79.5) |
| Abnormal VR compared to normative values, N (%) | 75/86 (87.2) |
| Abnormal BRS-V compared to normative values, N (%) | 44/76 (57.9) |
| PRT (sec), median [Q1 – Q3] | 17.4 [9.9 – 26.2] |
| Supine SBP (mmHg), median [Q1 – Q3] | 144 [130 – 168] |
| Supine DBP (mmHg), median [Q1 – Q3] | 80 [74 – 89.5] |
| OH, N (%) | 68 (75.6) |
| ΔSBP 3min (mmHg), median [Q1 – Q3] | −60 [−80 – −54] |
| ΔSBP 5min (mmHg), median [Q1 – Q3] | −38 [−62 – −19] |
| ΔHR 3min (bpm), median [Q1 – Q3] | +10 [+4 – +12] |
| ΔHR 5min (bpm), median [Q1 – Q3] | +7 [+3 – +12.5] |
| Thermoregulatory sweat test, N (%) | 38 (42.2) |
| Percentage of anhidrosis, N (%) | |
| 0% | 2 (5.3) |
| 1 – 25% | 24 (63.1) |
| 25 – 50% | 7 (18.4) |
| 50 – 75% | 3 (7.9) |
| > 75% | 2 (5.3) |
| Plasma NE, N (%) | 19 (21.1) |
| Plasma supine NE (pg/mL), mean (SD) | 722 (643) |
| Plasma standing NE (pg/mL), mean (SD) | 1207 (1239) |
| 24-hour blood pressure monitoring, N (%) | 76 (84.5) |
| Hypertension, N (%) | 63 (70.0) |
| Postural hypotension, N (%) | 54 (60.0) |
| Hypertensive surge, N (%) | 50 (55.6) |
| Number of surges, median [Q1 – Q3] | 1 [0–2] |
| Minimal SBP during the day (mmHg), median [Q1 – Q3] | 80 [71 – 89] |
| Maximal SBP during the day (mmHg), median [Q1 – Q3] | 184 [174 – 201] |
| SD of SBP during activity (mmHg), median [Q1 – Q3] | 23 [20 – 28] |
| SD of SBP during sleep (mmHg), median [Q1 – Q3] | 16 [14 – 24] |
| SD of SBP total (mmHg), median [Q1 – Q3] | 22 [20 – 29] |
| Loss of BP dipping at night, N (%) | 39 (43.3) |
Abbreviations: bpm = beats per minute, BP = blood pressure, BRS-V = baroreflex cardiovagal sensitivity, CASS = Composite Autonomic Scoring Scale, DBP = diastolic blood pressure; HR = heart rate, HRDB = heart rate responses to deep breathing, NE = norepinephrine, OH = orthostatic hypotension, PRT = blood pressure recovery time, Q1 = first quartile, Q3 = third quartile, SBP = systolic blood pressure, SD = standard deviation, VR = Valsalva ratio
Figure 1. Thermoregulatory sweat test in an illustrative patient with post radiation afferent baroreflex failure.
The patient underwent radiation therapy of the neck for metastatic small cell lung cancer. He also underwent adjuvant left radical neck dissection. He developed complications from radiation therapy including cranial nerve X and XI neuropathy as well as esophageal stenosis. The thermoregulatory sweat test revealed an area of anhidrosis over the left neck and shoulder, corresponding to prior radiation (total anhidrosis area = 2%).
Baroreflex deafferentation was suggested by low VR in 87.2% of patients (Table 2). BRS-V was calculated in 76 patients, whereas regressing the beat-to-beat blood pressure against heart period could not be performed reliably in 14 patients. Median BRS-V was low and abnormal compared to normative value for age and sex in 44 (57.9%) patients (Table 2). Abnormal HRDB with normal VR was seen in 4/86 patients (4.6%), whereas abnormal VR with normal HRDB was seen in 9/86 patients (10.5%). There was a significant association between HRDB and VR responses (R = 0.65, p <0.001). A normal VR was seen in 11 patients (12.2%). Analysis of blood pressure responses during the Valsalva maneuver in these 11 patients revealed an excessive drop in blood pressure during early phase II in 7 patients, whereas 4 patients had normal blood pressure and heart rate responses on autonomic testing.
Twenty-four hour blood pressure monitoring was obtained in 76 patients (84.4%) and demonstrated hypertension, postural hypotension, hypertensive surges, and absence of nocturnal fall in blood pressure in most patients (Table 2). Bradycardia was not detected on ABPM but was reported in the medical chart of one patient. Plasma norepinephrine was elevated in the supine position and surged further upon standing (Table 2). Fifteen patients (78.9%) had elevated upright norepinephrine >600 pg/mL.
There was no correlation between the change in plasma norepinephrine and BRS-V, PRT, the magnitude of blood pressure change during tilt, or the standard deviation of systolic blood pressure during 24-hour monitoring. The standard deviation of systolic blood pressure during activity, sleep, and 24-hours all correlated with BRS-V (R = −0.27, p = 0.007; R = −0.26, p = 0.05; and R = −0.31, p = 0.01 respectively), however, it did not correlate with PRT. The magnitude of change in systolic blood pressure at 1 minute during tilt was correlated with PRT (R = −0.3, p = 0.007), whereas the magnitude of change systolic in blood pressure at 5 minutes during tilt was correlated with BRS-V (R = 0.25, p = 0.04).
DISCUSSION
We present a large series of standardized autonomic testing in patients with probable R-ABF. The main findings are those of prominent cardiovascular adrenergic impairment with nOH, and blood pressure lability. Cardiovagal impairment is commonly associated, while sudomotor dysfunction is limited to local radiation effects. Plasma norepinephrine is high in patients with probable R-ABF but does not correlate with indices of baroreflex function or blood pressure lability. However, higher blood pressure variability is associated with more impaired baroreflex sensitivity. Probable R-ABF is therefore characterized by a hyperadrenergic form of nOH with relative preservation and disinhibition of sympathetic efferent pathways.
Most patients in this series have evidence of chaotic blood pressure regulation. Blood pressure lability with volatile hypertension characterizes R-ABF.3 Abrupt increase in sympathetic activity without immediate regulation or inhibition by the arterial baroreflex is thought to be responsible for blood pressure surges in R-ABF.6 This is supported by commonly reported triggers during which sympathetic outflow is increased such as mental or physical stress.1, 6 High supine and upright plasma norepinephrine in the current study also argues for increased sympathetic tone. The correlations between indices of blood pressure variability and baroreflex function suggest that failure of blood pressure regulation at the baroreceptor level with insufficient compensation from non-baroreflex mechanisms of blood pressure regulation (e.g., central influences, humoral factors, cardiopulmonary reflex, chemoreflex, metaboreflex) contribute to blood pressure lability in R-ABF.15
Standardized autonomic testing suggested evidence of nOH in the majority of patients with probable R-ABF. Previous studies have reported that nOH is not seen in the majority of patients with afferent baroreflex failure possibly because of sparing of the cardiopulmonary stretch receptors or vestibulo-sympathetic responses bypassing the afferent baroreflex limb.1, 3, 16, 17 The results of the current study suggest that nOH might be underrecognized and that most patients with probable R-ABF eventually develop nOH. The PRT is a validated index of adrenergic baroreflex function and can differentiate groups with different degrees of autonomic failure from controls.12 The pathophysiological mechanisms responsible for nOH in patients with R-ABF is not fully understood. The sympathetic efferent pathways are mostly preserved and the degree of baroreflex impairment is only weakly correlated with the degree of nOH in R-ABF, which suggests other contributing factors. Orthostatic hypotension is likely multifactorial in patients with R-ABF with the contribution of intravascular volume depletion and impaired regulation through baroreflex afferents.
The orthostatic increment in plasma norepinephrine provides a neurochemical index of baroreflex-sympathoneural function.18 In patients with probable R-ABF, plasma norepinephrine is elevated and increases appropriately upon standing. This is different from other conditions with nOH where plasma norepinephrine is low (e.g., pure autonomic failure) and/or does not rise appropriately upon standing (e.g., multiple system atrophy).19 Therefore, R-ABF represents a condition characterized by hyperadrenergic nOH. Previous studies have reported normal to high plasma norepinephrine in R-ABF.1, 20 A retrospective study identified 19 subjects with hyperadrenergic nOH, including patients with diabetes, Parkinson disease, and idiopathic orthostatic hypotension.21 In that study, subjects with hyperadrenergic nOH had less severe adrenergic impairment compared to typical nOH patients and the authors postulated that hyperadrenergic nOH may be a precursor to typical nOH.21 Hyperadrenergic nOH has been thought to be related to partial autonomic neuropathy or decreased clearance of norepinephrine coupled with impaired norepinephrine sensitivity.21, 22 We present a new group of patients with hyperadrenergic nOH. In R-ABF, normal to high supine plasma norepinephrine levels suggest relative preservation of the sympathetic efferent pathway, with dysregulation and inappropriate stimulation due to an impaired baroreflex-mediated negative feedback loop. The preserved orthostatic increase in plasma norepinephrine appears paradoxical and may reflect residual baroreflex function and effects from central commands or from the vestibulo-sympathetic reflex leading to activation of sympathetic postganglionic neurons in the standing position.23 The lack of correlation between plasma norepinephrine and variables on 24-hour blood pressure monitoring and autonomic testing further suggests an important contribution of pathways independent of the baroreflex.
Direct effects of radiation on the sweat glands over the neck region were obvious in most cases of probable R-ABF. Radiation therapy affects sweat gland function independently of skin changes, with a radiation dose relationship.24, 25 Furthermore, radiation induces skin fibrosis, reducing tissue perfusion over time that further worsens the quality and function of the irradiated skin26. Large areas of anhidrosis of the neck and upper chest may have clinical consequences with compensatory hyperhidrosis elsewhere and heat intolerance.
Standardized autonomic testing can suggest involvement of the afferent limb of the baroreflex. A previous study has reported reduced VR with normal HRDB in the same 6 patients suggesting an isolated afferent lesion.4 The HRDB is a reliable test of cardiovagal function, however, baroreflex function only contributes partially to HRDB responses, which are mainly driven by other mechanisms, including the Hering-Breuer and Bainbridge reflexes.7 On the other hand, the VR is mainly dependent on afferent baroreflex stimulation and is modulated by blood pressure alterations, cardiac and peripheral sympathetic functions, and norepinephrine response.7 Abnormal values of both HRDB and VR may indicate concomitant destruction of parasympathetic efferent vagal fibers because of injury from surgery and/or radiation and/or chemotherapy or associated comorbidities.27 It is possible that most patients with probable R-ABF in our study had non-selective baroreflex failure with involvement of parasympathetic efferent nerves protecting the heart from excessive bradycardia.28
Although insufficient reciprocal changes in heart rate in response to changes in blood pressure are to be expected with R-ABF, a minority of patients had normal VR in this study. The excessive blood pressure stimulus during early phase II seen in most of these patients may explain spuriously “normal” VR values. Intravascular volume depletion and / or impairment of the adrenergic limb of the baroreflex may both contribute to an excessive drop in blood pressure during the Valsalva maneuver. Only 4 patients had normal blood pressure and heart rate responses on autonomic testing; these patients may have had mild R-ABF causing erratic blood pressure on 24-hour recording but no clear abnormality on autonomic function testing. Furthermore, we are looking at 95th percentile of normal values, and a result within that range may still be abnormal for an individual. Alternatively, we cannot exclude another unidentified cause of blood pressure dysregulation in these patients.
Our study has several limitations. Specialized tests to confirm involvement of the afferent limb of the baroreflex were not performed, however, pharmacological challenges (e.g., phenylephrine or sodium nitroprusside), measurements of plasma vasopressin, and evaluation of the cardiovascular response to physiological or psychological stimuli that utilize alternative afferent pathways are not performed routinely. Furthermore, due to the retrospective nature of this study, we cannot rule out residual effects from antihypertensive medications used in 62% of the patients in this cohort, even though patients are routinely instructed to hold medications that could interfere with the results prior to autonomic testing. There is also the possibility of referral bias because patients with probable R-ABF are more likely to be referred to the autonomic clinic when they experience symptoms of OH. In our experience, R-ABF is a rare condition and the majority of patients who undergo neck radiation do not develop R-ABF. Studies including patients with well-defined R-ABF (i.e., involvement of the afferent lib of the baroreflex confirmed by pharmacological challenges) and controls who received the same dose of neck radiation would be helpful to shed light on the pathogenesis of R-ABF. The CASS score is not validated for diagnosing afferent baroreflex failure; however, there is no validated autonomic score for R-ABF. The CASS score was derived as a standardized general measure of autonomic dysfunction that is not specific for R-ABF. For each index of baroreflex cardiovagal and cardiovascular adrenergic function we had a large normative database balanced by age and sex. Finally, our study did not include a control group with other causes of hypertension.
Perspective
Patients with probable R-ABF present with prominent cardiovascular adrenergic impairment with hyperadrenergic neurogenic orthostatic hypotension and blood pressure lability. Impaired cardiovagal baroreflex function is associated with higher blood pressure variability. This study provides insights into the autonomic manifestations of R-ABF and may help clinicians when identifying and/or counseling patients with this syndrome.
CONCLUSION
Standardized autonomic testing in patients with probable R-ABF demonstrates prominent adrenergic impairment with neurogenic OH, blood pressure lability, and paradoxically elevated plasma norepinephrine. Cardiovagal impairment is commonly associated, while sudomotor deficits are limited to direct radiation effects.
NOVELTY AND SIGNIFICANCE.
“What is new?”
Most patients with probable R-ABF have evidence of neurogenic orthostatic hypotension.
Blood pressure variability may be related to vagal baroreflex impairment.
“What Is Relevant?”
R-ABF should be suspected in patients with history of neck cancer treated by radiation who present with labile hypertension and symptoms of orthostatic hypotension (e.g., postural dizziness, syncope).
Source of funding:
Supported by NIH (P01NS44233, U54NS065736, K23NS075141, R01 FD004789, R01 NS092625), Cure MSA Foundation, and Mayo Funds.
Footnotes
Disclosure: The Corresponding Author affirms that none of the authors has a conflict of interest.
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Associated Data
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Data Availability Statement
Anonymized data will be shared by request from any qualified investigator.