Composite Autonomic Severity Score Research Articles

A Detailed Classification of Neurogenic Orthostatic Hypotension According to the Pattern of Orthostatic Blood Pressure Drop in Patients with Orthostatic Intolerance

Background: To investigate the patterns of blood pressure (BP) decrement during the tilt, to compare the pattern of orthostatic hypotension (OH) and sympathetic index (SI) from the Valsalva maneuver (VM), and to identify whether the pattern of OH can predict the severity of autonomic failure.Methods: From January 2015 to July 2017, 551 consecutive patients with neurogenic OH were enrolled. All patients performed a standardized battery of autonomic tests, including the head-up tilt (HUT) test and VM using Finometer devices for recording beat-to-beat BP. SIs were calculated from the VM. The composite autonomic severity score (CASS) adrenergic subscore was also obtained to evaluate the severity of sympathetic adrenergic failure.Results: We classified OH into nine groups according to the patterns of orthostatic BP decrement during HUT. The two most common patterns of OH were classic stable OH (n=193) and classic OH with delayed normalization (n=102). Patients with classic stable OH and classic OH with delayed worsening had a more severe degree of sympathetic adrenergic failure as assessed with SI 5 and SI 4 from the VM, and a higher CASS adrenergic subscore than patients with other patterns of OH. There were no differences of autonomic parameters between the two delayed OH groups.Conclusions: The different patterns of orthostatic BP decrement may reflect underlying different pathophysiologic mechanisms causing OH. The pattern of orthostatic BP decrement can help to predict the degree of sympathetic adrenergic autonomic failure.

Mismatch between subjective and objective dysautonomia

Autonomic symptom questionnaires are frequently used to assess dysautonomia. It is unknown whether subjective dysautonomia obtained from autonomic questionnaires correlates with objective dysautonomia measured by quantitative autonomic testing. The objective of our study was to determine correlations between subjective and objective measures of dysautonomia. This was a retrospective cross-sectional study conducted at Brigham and Women’s Faulkner Hospital Autonomic Laboratory between 2017 and 2023 evaluating the patients who completed autonomic testing. Analyses included validated autonomic questionnaires [Survey of Autonomic Symptoms (SAS), Composite Autonomic Symptom Score 31 (Compass-31)] and standardized autonomic tests (Valsalva maneuver, deep breathing, sudomotor, and tilt test). The autonomic testing results were graded by a Quantitative scale for grading of cardiovascular reflexes, sudomotor tests and skin biopsies (QASAT), and Composite Autonomic Severity Score (CASS). Autonomic testing, QASAT, CASS, and SAS were obtained in 2627 patients, and Compass-31 in 564 patients. The correlation was strong between subjective instruments (SAS vs. Compass-31, r = 0.74, p < 0.001) and between objective instruments (QASAT vs. CASS, r = 0.81, p < 0.001). There were no correlations between SAS and QASAT nor between Compass-31 and CASS. There continued to be no correlations between subjective and objective instruments for selected diagnoses (post-acute sequelae of COVID-19, n = 61; postural tachycardia syndrome, 211; peripheral autonomic neuropathy, 463; myalgic encephalomyelitis/chronic fatigue syndrome, 95; preload failure, 120; post-treatment Lyme disease syndrome, 163; hypermobile Ehlers-Danlos syndrome, 213; neurogenic orthostatic hypotension, 86; diabetes type II, 71, mast cell activation syndrome, 172; hereditary alpha tryptasemia, 45). The lack of correlation between subjective and objective instruments highlights the limitations of the commonly used questionnaires with some patients overestimating and some underestimating true autonomic deficit. The diagnosis-independent subjective–objective mismatch further signifies the unmet need for reliable screening surveys. Patients who overestimate the symptom burden may represent a population with idiosyncratic autonomic-like symptomatology, which needs further study. At this time, the use of autonomic questionnaires as a replacement of autonomic testing cannot be recommended.

Scale for Ocular Motor Disorders in Ataxia (SODA) in Patients with Multiple System Atrophy.

A clinical scale fully dedicated to evaluating ocular motor abnormalities is required for now. We investigated the utility of a recently developed Scale for Ocular motor Disorders in Ataxia (SODA) in patients with multiple system atrophy (MSA). We prospectively assessed SODA in consecutive patients with MSA between August 2021 and August 2023 at the Korea University Medical Center. The results of the clinical exam-based SODA were compared with those measured using video-oculography (VOG-guided SODA). We also compared the findings with other established clinical scales targeting patients with MSA, including the Unified Multiple System Atrophy Rating Scale (UMSARS) I-II, Movement Disorder Society-Unified Parkinson's Disease Rating Scale motor part (UPDRS-III), Scale for Assessment of Rating of Ataxia (SARA), Composite Autonomic Symptom Score-31 (COMPASS-31), and Composite Autonomic Severity Score (CASS). Twenty patients were enrolled in our study (17 with cerebellar-type MSA and three with Parkinson-type MSA). Scores ranged from 1 to 14 (median [interquartile range (IQR)] = 8 [5-10]). Among the subscales, saccades had a median score of 2.5 (IQR = 1-3), followed by ocular pursuit (1 [0-1]), nystagmus (1 [0-2]), saccadic intrusions (1 [0-1]), vestibulo-ocular reflex (VOR) (0.5 [0-1]), ocular alignment (0 [0-1]), and VOR cancellation (1 [0-1]). The clinical-exam-based SODA (p = 0.020) and VOG-guided SODA (p = 0.034) positively correlated with disease duration. No correlation was found between clinical exam-based SODA and other scales. Skew deviation, gaze-evoked nystagmus, VOR cancellation, and smooth pursuit had the highest precision among the items. Ocular misalignment and spontaneous and positional nystagmus were frequently false positive and were poorly detected with clinical exam-based SODA. Six patients with repeated evaluation exhibited higher scores, along with deterioration documented on other clinical scales. The SODA can reliably predict neurodegeneration as an additional clinical surrogate in MSA.

Clinical Characteristics and Outcomes in Young-Onset Multiple System Atrophy.

Young-onset multiple system atrophy (YOMSA) is defined as the onset of multiple system atrophy (MSA) before the age of 40 years old. YOMSA is rare and there is much uncertainty of the phenotype and natural history in patients with YOMSA. The objective is to evaluate the characteristics and disease course of patients with YOMSA. We retrospectively reviewed medical records of patients with MSA who were evaluated at all Mayo Clinic sites from 1998 to 2021. We identified patients with YOMSA and evaluated clinical characteristics, autonomic function testing results, and disease course. Of 1496 patients with a diagnosis of clinically probable or clinically established MSA, 20 patients had YOMSA. The median age of onset was 39.1 (interquartile range [IQR] = 37.1, 40.1) years; 13 patients (65%) were male. MSA-parkinsonism was the most common subtype (65%). The median duration of symptom onset to YOMSA diagnosis was 4.9 (IQR = 3.7, 9) years. At the time of medical record review, 17 patients were deceased with a median survival of 8.3 (IQR = 7, 10.9) years. Univariate analysis showed that initial onset of autonomic failure predicted unfavorable survival (hazard ratio = 2.89, P = 0.04) compared to those who presented with motor impairment only at onset. At the time of YOMSA diagnosis, composite autonomic severity score was available in 19 patients with a median of 5 (IQR = 4, 6.5). YOMSA resembles MSA in most aspects including phenotype and prognosis, although the diagnosis is usually delayed. The presence of autonomic failure at symptom onset may be a poor predictor for survival.

Composite autonomic severity scoring in spinocerebellar ataxia type 1 and 2

ObjectivesThe aim of the present study was to evaluate the integrity of autonomic nervous system in spinocerebellar ataxia (SCA) type 1 and 2 patients using battery of autonomic function tests and their comprehensive scoring using composite autonomic severity score (CASS). Material and methodsBattery of autonomic function test comprising of cardiovascular (baroreflex dependent and non-baroreflex dependent) and sudomotor functions were assessed in age and gender-matched SCA1 (n = 31), SCA2 (n = 40) patients along with healthy controls (n = 40). To assess the grade of autonomic abnormalities, the composite autonomic severity score (CASS) was computed using the results of the standard autonomic function tests. ResultsWe found reduction in baroreflex dependent autonomic reactivity parameters predominantly a significant fall of systolic blood pressure (<0.001) and lower 30:15 ratio (<0.001) during head up tilt in both the SCA1 and SCA2 as compared to controls. On sudomotor assessment, distal leg latency of sweat response was prolonged in SCA1 than SCA2 patients. Moderate generalized autonomic failure was commonly found amongst SCA1 (80.65%) and SCA2 (85%) patients. Severe autonomic failure was found to be more in SCA1 (6.45%) than SCA2 (2.50%) patients. ConclusionsCardiovascular autonomic function assessment in SCA1 and SCA2 patients revealed a significant impairment in the baroreflex loop integrity. Severity scoring using CASS suggests the existence of moderate autonomic failure in majority of both SCA1 and SCA2 patients.

Autonomic Neuropathy as a Predictor of Morbidity and Mortality in People Living with HIV: A Retrospective, Longitudinal Cohort Study (P9-9.006)

<h3>Objective:</h3> This study aimed to evaluate whether HIV-AN is predictive of important adverse clinical outcomes. <h3>Background:</h3> HIV-associated autonomic neuropathy (HIV-AN) is common, however, its clinical impact is unclear. It is known that the composite autonomic severity score (CASS) is associated with markers of morbidity such as the Veterans Affair Cohort Study (VACS) index. Additionally, it is known that cardiovascular autonomic neuropathy due to diabetes is associated with poor cardiovascular outcomes. <h3>Design/Methods:</h3> The electronic medical records of HIV-infected participants who underwent autonomic function tests at the Mount Sinai Hospital between April 2011 and August 2012 were reviewed. The cohort was stratified into those who had no or mild autonomic neuropathy (HIV-AN [-], CASS&lt;/=3) and those with moderate or severe autonomic neuropathy (HIV-AN [+], CASS&gt;3). The primary outcome was a composite of the incidence of death from any cause, new major cardiovascular or cerebrovascular event, or development of severe renal or hepatic disease. Time to event analysis was performed. <h3>Results:</h3> 111 of 114 participants had follow-up data (median follow up for HIV-AN[-] was 94.00 months and HIV-AN[+] was 81.29 months) and were analyzed. Participants were followed until March 1^st, 2020. The HIV-AN[+] group (N=42) was significantly associated with the presence of hypertension, higher HIV-1 viral load, and more abnormal liver function. 17 (40.48%) events occurred in the HIV-AN[+] group, and 11 (15.94%) occurred in the HIV-AN[−] group. 6 (14.29%) cardiac events occurred in the HIV-AN[+] group, whereas 1 (1.45%) occurred in the HIV-AN[−] group. The other subgroups of the composite outcome had a similar trend. The adjusted Cox proportional hazards model showed that the presence of HIV-AN predicted our composite outcome (HR 3.85, CI 1.61–9.20). <h3>Conclusions:</h3> HIV-AN is associated with the development of severe morbidity and mortality in people living with HIV. People living with HIV with autonomic neuropathy may benefit from closer cardiac, renal, and hepatic surveillance. <b>Disclosure:</b> Dr. Kwon has nothing to disclose. Mr. Lawrence has nothing to disclose. Mr. Figueroa has nothing to disclose. The institution of Dr. Robinson Papp has received research support from NIH. Dr. Robinson Papp has received publishing royalties from a publication relating to health care.

Characteristics and Outcome of Patients with Young-Onset Multiple System Atrophy (P8-11.005)

<h3>Objective:</h3> To evaluate the characteristics and disease course of patients with young-onset multiple system atrophy (YOMSA). <h3>Background:</h3> YOMSA is defined as the onset of MSA before age 40 years. There is limited information about the disease course and outcome in these patients. <h3>Design/Methods:</h3> We retrospectively reviewed medical records of all patients with a diagnosis of clinically established or clinically probable MSA who were evaluated at all Mayo Clinic sites from 1998 to 2021. We identified patients who were ≤40 years at time of disease onset. We evaluated clinical characteristics, disease course, and autonomic function testing results. Composite Autonomic Severity Score (CASS) was calculated based on autonomic testing. <h3>Results:</h3> Of 1496 patients with a diagnosis of clinically established or probable MSA, 20 patients had YOMSA. The mean age of onset was 38.61 (±2.16) years; 13 patients (65%) were male. MSA-parkinsonism was the most common subtype (65%). At the time of medical record review, 15 patients were deceased with a mean age of death of 47.88 (±3.83) years. The median duration of disease course (onset to death) and onset to diagnosis were 7.67 [IQR: 6.36, 10.23] and 4.90 [IQR: 3.70, 8.61] years, respectively. Patients with autonomic symptoms at the time of disease onset had a shorter disease course compared to those without autonomic complaints (6.60 years versus 10.74 years; p=0.037). At the time of YOMSA diagnosis, thermoregulatory sweat test was performed in 17 patients with a median of 88% anhidrosis; CASS was available in 19 patients with a median of 5 [IQR: 4, 6.5]. Genetic evaluations were performed in 6 patients with no revealing results. <h3>Conclusions:</h3> Patients with YOMSA are often diagnosed late in the disease course. Those with autonomic symptoms at the time of disease onset have a more rapid course compared to those with initial motor-only presentation. <b>Disclosure:</b> Dr. Badihian has nothing to disclose. The institution of Dr. Savica has received research support from ACADIA Pharmaceuticals, Inc. Dr. Adler has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Amneal. Dr. Adler has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Avion. Dr. Adler has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for CND Life Sci. Dr. Adler has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Jazz. Dr. Adler has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Precon. Dr. Adler has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Neurocrine. The institution of Dr. Adler has received research support from NIH. The institution of Dr. Adler has received research support from Michael J. Fox Foundation. The institution of Dr. Adler has received research support from Arizona Biomedical Research Commission. Dr. Adler has received publishing royalties from a publication relating to health care. Dr. Wszolek has received personal compensation in the range of $5,000-$9,999 for serving as an Editor, Associate Editor, or Editorial Advisory Board Member for Polish Neurological Society/Via Medica. Dr. Jackson has nothing to disclose. Dr. Benarroch has nothing to disclose. Dr. Sandroni has nothing to disclose. Dr. Low has nothing to disclose. Dr. Singer has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Amneal. Dr. Singer has received personal compensation in the range of $500-$4,999 for serving as a Consultant for UniQure. The institution of Dr. Singer has received research support from NIH. The institution of Dr. Singer has received research support from FDA. Dr. Singer has received intellectual property interests from a discovery or technology relating to health care. Dr. Coon has nothing to disclose.

Autonomic nervous system involvement in chronic inflammatory demyelinating polyradiculoneuropathy: a literature review.

Although dysautonomia is a well-recognized complication of acute demyelinating polyradiculoneuropathy, it is rarely reported and evaluated in chronic demyelinating neuropathies. The purpose of this review is to search and synthesize the current literature on the prevalence and type of autonomic dysfunction (AD) in chronic inflammatory demyelinating polyradiculoneuropathy (CIDP). PubMed and Web of Science were searched for studies reporting AD in CIDP. Twelve studies, including 346 patients with CIDP, were found eligible for the review. Seven studies used autonomic tests only as an additional component of the comprehensive clinical evaluation, and found that dysautonomia in CIDP may indicate the presence of a comorbid disease (e.g., diabetes) and facilitate the differentiation of CIDP from other neuropathies (e.g., amyloid neuropathy). Five studies performed quantitative assessment of autonomic function in CIDP as a primary goal. Two studies have used the Composite Autonomic Severity Score (CASS) to assess severity and distribution of dysautonomia. The reported prevalence of dysautonomia in CIDP during quantitative assessment of autonomic function ranged from 25 to 89%, depending on the battery of tests used, with CASS not exceeding 4 points. The abnormalities in autonomic tests indicated both sympathetic and parasympathetic dysfunction and did not correlate with the duration, severity and variant of CIDP. Clinical or subclinical involvement of the ANS has been shown to be common and relatively mild in CIDP. The impact of autonomic impairment on disability and of its possible response to therapy in CIDP needs to be further investigated.

Autonomic Neuropathy as a Predictor of Morbidity and Mortality in People Living With HIV: A Retrospective, Longitudinal Cohort Study.

HIV-associated autonomic neuropathy (HIV-AN) is common; however, its clinical effect is unclear. Previously, it was shown that the composite autonomic severity score is associated with markers of morbidity such as the Veterans Affair Cohort Study index. In addition, it is known that cardiovascular autonomic neuropathy due to diabetes is associated with poor cardiovascular outcomes. This study aimed to evaluate whether HIV-AN is predictive of important adverse clinical outcomes. The electronic medical records of HIV-infected participants who underwent autonomic function tests at the Mount Sinai Hospital between April 2011 and August 2012 were reviewed. The cohort was stratified into those who had no or mild autonomic neuropathy (HIV-AN [-], CASS ≤3) and those with moderate or severe autonomic neuropathy (HIV-AN [+], CASS >3). The primary outcome was a composite of the incidence of death from any cause, new major cardiovascular or cerebrovascular event, or development of severe renal or hepatic disease. Time-to-event analysis was performed using Kaplan-Meier analysis and multivariate Cox proportional hazards regression models. One hundred eleven of 114 participants had follow-up data (median follow-up for HIV-AN (-) was 94.00 months, and HIV-AN (+) was 81.29 months) and were included in the analysis. Participants were followed until March 1, 2020. The HIV-AN (+) group (N = 42) was significantly associated with the presence of hypertension, higher HIV-1 viral load, and more abnormal liver function. Seventeen (40.48%) events occurred in the HIV-AN (+) group, and 11 (15.94%) occurred in the HIV-AN (-) group. Six (14.29%) cardiac events occurred in the HIV-AN (+) group, whereas 1 (1.45%) occurred in the HIV-AN (-) group. The other subgroups of the composite outcome had a similar trend. The adjusted Cox proportional hazards model showed that the presence of HIV-AN predicted our composite outcome (HR 3.85, CI 1.61-9.20). These findings suggest that HIV-AN is associated with the development of severe morbidity and mortality in people living with HIV. People living with HIV with autonomic neuropathy may benefit from closer cardiac, renal, and hepatic surveillance.

Reduced cardiovagal baroreflex sensitivity is associated with postural orthostatic tachycardia syndrome (POTS) and pain chronification in patients with headache.

Non-cephalgic symptoms including orthostatic intolerance, fatigue, and cognitive impairment, are common in patients with chronic headache disorders and may result from alterations in the autonomic nervous system. However, little is known about the function of autonomic reflexes, which regulate cardiovascular homeostasis and cerebral perfusion in patients with headache. Autonomic function testing data from patients with headache collected between January 2018 and April 2022 was retrospectively analyzed. Through review of EMR we determined headache pain chronicity and patient self-report of orthostatic intolerance, fatigue, and cognitive impairment. Composite Autonomic Severity Score (CASS), CASS subscale scores, and cardiovagal and adrenergic baroreflex sensitivities were used to quantify autonomic reflex dysfunction. Descriptive analyses (Mann-Whitney-U or χ2, as appropriate) determined associations between autonomic reflex dysfunction and POTS as well as chronic headache. Binomial logistic regression adjusted for age and sex. Spearman's rank correlation determined the association between the total CASS score and the number of painless symptoms reported by each participant. We identified 34 patients meeting inclusion criteria, of whom there were 16 (47.0%) with orthostatic intolerance, 17 (50.0%) with fatigue, 11 (32.4%) with cognitive complaints, and 11 (32.4%) with Postural Orthostatic Tachycardia Syndrome (POTS). The majority of participants had migraine (n = 24, 70.6%), were female (n = 23, 67.6%) and had a chronic (>15 headache days in a month) headache disorder (n = 26, 76.5%). Reduced cardiovagal baroreflex sensitivity (BRS-V) independently predicted chronic headache [aOR: 18.59 (1.16, 297.05), p = 0.039] and POTS [aOR: 5.78 (1.0, 32.5), p = 0.047]. The total CASS was correlated with the total number of non-painful features in the expected direction (r = 0.46, p = 0.007). Abnormal autonomic reflexes may play an important role in pain chronification and the development of POTS in patients with headache.

Physiological and clinical impact in the carotid baroreceptor function following the surgical management of bilateral carotid body tumors.

The bilateral presentation of Carotid Body Tumors (CBT) is rare; the surgical resection of these masses remains the mainstay management due to the malignant potential. We aim to describe, classify, and quantify baroreceptor failure (BRF) after the surgical management of patients with bilateral CBT to better understand the clinical consequences. Retrospective review of patients that underwent bilateral CBT resection to assess the changes in baroreceptor function. We describe the clinical events associated to BRF after surgery, baseline patient's demographics, characteristics, comorbidities. Additionally, clinical and a quantitative evaluation of baroreceptor sensitivity were conducted using the Composite Autonomic Severity Score (CASS). From 1986 to 2020, a total 146 CBT resections were performed in 132 patients in our institution. Tumors were removed bilaterally in staged procedures in seven patients with a mean age of 61years (Standard Deviation 11), six (85%) were females, and there was no family history of paragangliomas. The clinical presentation were palpable masses in 5 (71%), and odynophagia in 2 (29%) cases; malignant histopathology following surgery was found in one case. BRF occurred in one patient after unilateral CBT resection, consisting of bradycardia and a 40s asystole that was not previously associated to BR sensitivity. Three (43%) patients presented BRF in the immediate postoperative period of the contralateral CBT excision, consisting of volatile hypertensive crisis in two cases, and supraventricular tachycardia in one. All the patients developed (100%) chronic baroreceptor sensitivity symptoms consisting in syncope, vertigo and fatigue in 4 (57%), tachycardia in 2 (28%), and orthostatic headache in one (14%). Autonomic testing showed mixed sympathetic and parasympathetic failure in five (71%), severe sympathetic failure in 1 (14%), and parasympathetic dysfunction in one patient (14%). Postoperative autonomic assessment confirmed BRF in all studied patients that underwent staged bilateral CBT resection with mixed, sympathetic, and parasympathetic dysfunction. Further studies are necessary to evaluate the incidence and physiological mechanisms of these sequelae to anticipate possible complications and offer the appropriate perioperative management.

Generalised autonomic failure as a prognostic factor in systemic light-chain (AL) amyloidosis

Background In the present study, it was investigated whether autonomic dysfunction could predict prognosis in light-chain (AL) amyloidosis patients. Patients and methods Seventy-two patients with biopsy-proven AL amyloidosis were included and underwent an autonomic function test (AFT) between January 2016 and June 2019. Autonomic failure was evaluated using the Composite Autonomic Severity Score (CASS). Survival curves and the three-year overall survival (OS) rate were estimated using the Kaplan–Meier curve, and the Cox proportional hazards regression method was used to evaluate the variables that influenced survival. Results Autonomic dysfunction was observed in 69 (96%) patients with AL amyloidosis, and the three-year OS rate was 67%. Generalised autonomic failure (GAF) was observed in 31 (43%) patients. In the Kaplan–Meier curve, the three-year OS rates in patients with sudomotor dysfunction or GAF were lower than that in control patients (35 vs. 84%, and 33 vs. 81%, respectively). In Cox proportional hazards regression model, female, bone marrow plasma cell percentage, left ventricular systolic dysfunction, and GAF were significant independent variables associated with survival. Conclusion The results of this study indicate that GAF on the AFT is an independent adverse prognostic factor for survival in AL amyloidosis patients.

0626 Nocturnal Pulse Event Frequency in Multiple System Atrophy: An Exploratory Pilot Study

Abstract Introduction Risk of sudden death in multiple system atrophy (SuD-MSA) is greatest during sleep. Mechanisms underlying SuD-MSA may involve impaired brainstem arousal and cardiovascular responses to hypercapnia in MSA patients. We hypothesized that nocturnal arousal-related tachycardia events are reduced in MSA patients. We analyzed whether nocturnal pulse event frequency was altered in patients with MSA compared to patients with sleep disordered breathing without MSA utilizing portable overnight oximetry. Methods We retrospectively analyzed 46 probable MSA and 46 age-sex matched patients with sleep disordered breathing (SDB) without MSA, excluding patients receiving cardioactive medications. Nocturnal oxyhemoglobin desaturation indices (ODI) and pulse event indices (PEI) were automatically recorded for all patients using portable overnight oximetry. We calculated a PEI/ODI ratio to determine the relationship between probable breathing-related arousals and pulse rate change. Cardiovagal function was assessed by heart rate to deep breathing and Valsalva ratio in patients with MSA and Composite Autonomic Severity Score was assigned. Group comparisons were made with non-parametric tests. Multivariable regression explored relationships between oximetry variables and clinical characteristics. Results Average age at overnight oximetry was 62.9 ± 7.7 years. Total respiratory events between MSA patients compared with OSA controls were similar (95.0 ± 118.6 vs 73.5± 54.2, p=0.61). Total pulse events were lower in MSA than OSA controls without MSA (25.5±44.2 vs 111.6±120.2, p&amp;lt;0.001), as were pulse events per hour (3.1 ± 5.3 vs. 12.8 ± 10.8, p &amp;lt;0.001). The ratio of PEI/ODI was lower in MSA than OSA patients without MSA (p&amp;lt;0.001). Twelve (26%) MSA patients had zero pulse rate events, while all OSA patients without MSA had at least 1 pulse rate event (p&amp;lt;0.001). The number of pulse events was not associated with severity of cardiovagal dysfunction on daytime autonomic function testing. Conclusion Patients with MSA have fewer pulse rate events when compared with SDB patients without MSA, despite similar overall respiratory event frequency. The number of pulse events was not explained by severity of daytime autonomic dysfunction in those with MSA. Whether nocturnal pulse event response to sleep disordered breathing is a marker of disease severity or plays a role in SuD-MSA deserves further study. Support (If Any)

Interpreting resting heart rate variability in complex populations: the role of autonomic reflexes and comorbidities.

Resting heart rate variability (HRV) is an important biomarker linking mental health to cardiovascular outcomes. However, resting HRV is also impaired in autonomic neuropathy, a common and underdiagnosed complication of common medical conditions which is detected by testing autonomic reflexes. We sought to describe the relationship between autonomic reflex abnormalities and resting HRV, taking into consideration medical comorbidities and demographic variables. Participants (n=209) underwent a standardized autonomic reflex screen which was summarized as the Composite Autonomic Severity Score (CASS) and included measures of reflexive HRV, e.g., heart rate with deep breathing (HRDB). Resting HRV measures were: pNN50 (percentage of NN intervals that differ by>50ms) and cvRMSSD (adjusted root mean square of successive differences). In univariate analyses, lower resting HRV was associated with: older age, higher CASS, neuropathy on examination, hypertension, diabetes, chronic obstructive pulmonary disease, chronic kidney disease, and psychiatric disease. Adaptive regression spline analysis revealed that HRDB explained 27% of the variability in resting HRV for participants with values of HRDB in the normal range. Outside this range, there was no linear relationship because: (1) when HRDB was low (indicating autonomic neuropathy), resting HRV was also low with low variance; and (2) when HRDB was high, the variance in resting HRV was high. In multivariate models, only HRDB was significantly independently associated with cvRMSSD and pNN50. Subclinical autonomic neuropathy, as evidenced by low HRDB and other autonomic reflexes, should be considered as a potential confounder of resting HRV in research involving medically and demographically diverse populations.

The Utility of COMPASS-31 Questionnaire to Predict Autonomic Dysfunction in Patients With Cervical/Upper Thoracic Compressive Myelopathy.

Patients with cervical/upper thoracic compressive myelopathy may have autonomic dysfunction. The composite autonomic severity score (CASS) is the gold standard test to detect autonomic dysfunction, and the self-rated composite autonomic system scale (COMPASS-31) questionnaire is a screening tool to diagnose autonomic dysfunction. This study compared the COMPASS-31 and modified CASS scores for the detection of autonomic dysfunction in patients with compressive myelopathy. Patients with cervical/upper thoracic compressive myelopathy scheduled for decompressive surgery completed a COMPASS-31 questionnaire and underwent autonomic function tests to calculate the modified CASS score before surgery. Forty-two patients were included in the study; 19 (45.2%) had mild autonomic dysfunction, 5 (11.9%) had moderate autonomic dysfunction, and 18 (42.9%) had severe autonomic dysfunction. Median (interquartile range) of modified CASS and COMPASS-31 scores were 19 (6.33) and 3 (2.5), respectively. There was a positive correlation between modified CASS and COMPASS-31 scores ( r =0.43; P =0.004). Receiver operating characteristic curve analysis confirmed that COMPASS-31 had fair accuracy for prediction of moderate to severe autonomic dysfunction (area under the curve, 0.74; 95% confidence interval, 0.64-0.82; P =0.009). A cut-off of 30 for total COMPASS-31 score had a sensitivity of 52.2% and specificity of 89.5% to detect moderate to severe autonomic dysfunction, with positive and negative predictive values of 85.7% and 60.7%, respectively. Patients with cervical/upper thoracic compressive myelopathy had varying degrees of autonomic dysfunction based on the modified CASS. There was a positive correlation between the modified CASS and COMPASS-31 questionnaire. A COMPASS-31 score of >30 30 could be utilized to predict moderate to severe autonomic dysfunction in patients with compressive myelopathy.

Standardized Autonomic Testing in Patients With Probable Radiation-Induced Afferent Baroreflex Failure.

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. We identified 90 patients with probable R-ABF. Median total composite autonomic severity score (range, 0-10) was 7 (interquartile range, 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 seconds), and orthostatic hypotension 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 (722-1207 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 thermoregulatory sweat test finding was focal neck anhidrosis (78.9%). Standardized autonomic testing in R-ABF demonstrates cardiovascular adrenergic impairment with orthostatic hypotension, blood pressure lability, and elevated plasma norepinephrine. Cardiovagal impairment is common, while sudomotor deficits are limited to direct radiation effects.

Small Fiber Neuropathy Incidence, Prevalence, Longitudinal Impairments, and Disability.

There are limited population-based data on small fiber neuropathy (SFN). We wished to determine SFN incidence, prevalence, comorbid conditions, longitudinal impairments, and disabilities. Test-confirmed patients with SFN in Olmsted, Minnesota, and adjacent counties were compared 3:1 to matched controls (January 1, 1998-December 31, 2017). Ninety-four patients with SFN were identified, with an incidence of 1.3/100,000/y that increased over the study period and a prevalence of 13.3 per 100,000. Average follow-up was 6.1 years (0.7-43 years), and mean onset age was 54 years (range 14-83 years). Female sex (67%), obesity (body mass index mean 30.4 vs 28.5 kg/m2), insomnia (86% vs 54%), analgesic-opioid prescriptions (72% vs 46%), hypertriglyceridemia (180 mg/dL mean vs 147 mg/dL), and diabetes (51% vs 22%, p < 0.001) were more common (odds ratio 3.8-9.0, all p < 0.03). Patients with SFN did not self-identify as disabled with a median modified Rankin Scale score of 1.0 (range 0-6) vs 0.0 (0-6) for controls (p = 0.04). Higher Charlson comorbid conditions (median 6, range 3-9) occurred vs controls (median 3, range 1-9, p < 0.001). Myocardial infarctions occurred in 46% vs 27% of controls (p < 0.0001). Classifications included idiopathic (70%); diabetes (15%); Sjögren disease (2%); AL-amyloid (1%); transthyretin-amyloid (1%); Fabry disease (1%); lupus (1%); postviral (1%); Lewy body (1%), and multifactorial (5%). Foot ulcers occurred in 17, with 71% having diabetes. Large fiber neuropathy developed in 36%, on average 5.3 years (range 0.2-14.3 years) from SFN onset. Median onset Composite Autonomic Severity Score (CASS) was 3 (change per year 0.08, range 0-2.0). Median Neuropathy Impairment Scale (NIS) score was 2 at onset (range 0-8, change per year 1.0, range -7.9 to +23.3). NIS score and CASS change >1 point per year occurred in only AL-amyloid, hereditary transthyretin-amyloid, Fabry, uncontrolled diabetes, and Lewy body. Death after symptom onset was higher in patients with SFN (19%) vs controls (12%, p < 0.001), 50% secondary to diabetes complications. Isolated SFN is uncommon but increasing in incidence. Most patients do not develop major neurologic impairments and disability but have multiple comorbid conditions, including cardiovascular ischemic events, and increased mortality from SFN onsets. Development of large fiber involvements and diabetes are common over time. Targeted testing facilitates interventional therapies for diabetes but also rheumatologic and rare genetic forms.

Vasovagal syncope with mild versus moderate autonomic dysfunction: a 13-year single-center experience

BackgroundAn adequate large-scale pediatric cohort based on nationwide administrative data is lacking in Korea.PurposeThis study aimed to differentiate patients with VVS by autonomic dysfunction severity using the composite autonomic severity score (CASS) and compare the clinical manifestations and prognosis between patient subgroups.MethodsWe retrospectively reviewed the medical records of 66 VVS patients divided into 3 groups by CASS. To compare the differences between these groups, we analyzed VVS type, triggers, prodromal symptoms, management of syncope, and prognosis between patients with mild versus moderate autonomic dysfunction.ResultsOf our 66 patients with VVS, 41 had mild autonomic dysfunction (62.1%) and 25 had moderate autonomic dysfunction (37.9%). We found no significant intergroup differences in age, sex, inducible factor (P=0.172), prodromal symptoms, laboratory findings, head-up tilt test, type of syncope, or prognosis (P=0.154).ConclusionWe found no evidence that autonomic dysfunction degree is affected by VVS characteristics, test findings, parameters, or prognosis; therefore, no further evaluations are needed to classify autonomic dysfunction severity.

Ala97Ser transthyretin amyloidosis-associated polyneuropathy, clinical and neurophysiological profiles in a Thai cohort

BackgroundAla97Ser transthyretin amyloidosis-associated polyneuropathy (ATTRA97S-PN) is a rare form of inherited polyneuropathy, usually manifesting with late-onset (> 50) progressive polyneuropathy. This mutation is mostly prevalent in Taiwanese and Han-Chinese individuals. The aim of this study was to describe the clinical and comprehensive neurophysiological profiles of ATTRA97S-PN in Thai patients.MethodsThe clinical profiles and serial neurophysiologic studies (nerve conduction study (NCS), quantitative sensory test (QST), and comprehensive autonomic function test (AFT)) of symptomatic ATTRA97S-PN patients who had been followed-up at King Chulalongkorn Memorial Hospital during 2010–2020 were retrospectively reviewed.ResultsNine symptomatic patients (55.6 % were male) from four unrelated families were included. All were Thais of mixed Thai Chinese descent. The mean age of onset was 48.3 (32–60) years. The mean age at diagnosis was 54.8 (33–66) years. Three patients developed early-onset (< 40y) polyneuropathy. The mean Neuropathy Impairment Score was 41.33 (10–92) at diagnosis. Sensory (9/9) and autonomic (9/9) neuropathies were more frequent than motor neuropathy (5/9), which appeared in the late stage of disease. Hypoesthesia in the feet, and gastrointestinal autonomic symptoms were frequently reported as the initial symptoms. The course of neuropathy progressed over years to decades. The worsening of neuropathy tended to progress faster once motor nerves were affected in both clinical and neurophysiological aspects. Concurrent cardiac amyloidosis was found in 6/9 patients. NCS showed length-dependent sensorimotor axonal polyneuropathy in 5/9 patients, and median neuropathy at the wrist (mostly bilateral) in 7/9 patients. QST showed abnormalities in the vibratory detection threshold, the cold detection threshold and the heat pain sensation in 8/9, 8/9 and 7/7 tested patients, respectively. AFT results were abnormal in all. The mean composite autonomic severity score was 5 (3–9).ConclusionsThis clinical study is the first of ATTRA97S-PN in Thai patients. The mixed polyneuropathy-cardiopathy phenotype was the most common manifestation. In this cohort, the age of onset was lower, and the course of neuropathy was relatively longer, than that in previous studies. Some patients may develop early-onset polyneuropathy. This mutation has not yet been documented in any population other than Han Chinese-related populations, probably suggesting a founder effect. Further studies are warranted.

Comparison of baroreflex sensitivity indices with standard tests of autonomic nervous system function

ObjectiveIn order to further evaluate clinical usefulness of α- and β-adrenergic components of the baroreflex sensitivity (BRS) index, the aim of this study was to compare them to standardized measures of the autonomic dysfunction. MethodsIn 275 participants (mean age 40.57 ± 15.19, range 18 to 89 years, 76.4% females) referred for testing of the autonomic nervous system, α-BRSa, β-BRSa and BRSv were compared to heart rate (HR) and blood pressure (BP) values, adrenergic and cardiovagal indices of the Composite Autonomic Severity Score (CASS) and heart rate variability (HRV) parameters. Resultsα-BRSa showed statistically significant positive correlation with HR in the supine position and negative with the adrenergic index. β-BRSa showed statistically significant negative correlation with tests for parasympathetic nervous system function. BRSv showed statistically significant negative correlation with all HR and BP parameters and positive with all HRV parameters. In a univariable logistic regression analysis, α-BRSa was a negative predictor (Exp(B) 0.866, 95% CI 0.782–0.959, p = 0.006, respectively) of the pathological adrenergic index. To differentiate between subjects with normal and pathological adrenergic index, the optimal cutoff for α-BRSa was found to be 6.741, which gave a sensitivity of 61.0% and a specificity of 56.0%. ConclusionBRSa indices showed a good correlation with standard measures of ANS function. The most promising test was α-BRSa, which performed well as a α adrenergic receptors mediated sympathetic nervous system marker.