Faculty Bibliography

Objective: To study the rate of progression of multiple system atrophy (MSA) and assess for a potential ceiling effect of the Unified Multiple System Atrophy Rating Scale (UMSARS).
Background(s): Disease progression of MSA as measured by UMSARS varied significantly in natural history studies. Reported 1-year UMSARS-1 and UMSARS-2 progression rates ranged from 3.9 to 6.5 and 3.5 to 8.2 respectively. We hypothesize that this variability is due, at least in part, to differences in severity at enrollment and a potential ceiling effect in the scale, so that patients in more advanced stages may appear to worsen less, which would have important implications for clinical trial design.
Method(s): We analyzed the rate of change in the UMSARS in a large international cohort of well-characterized patients with a clinical diagnosis of possible or probable MSA enrolled in the Natural History Study of Synucleinopathies. Annualized progression rates were obtained using 2-year follow-up data.
Result(s): Three hundred and forty nine patients (61.4+/-7.9 years old) with MSA were enrolled. Disease duration was 4.5+/-5.1 years. 143 patients completed 1-year evaluations and 61 completed the 2-year evaluation. The 12-month progression rates were 5.4+/-5.1 for the UMSARS-I, 5.9+/-5.3 for the UMSARS-II, and 11.8+/-9.6 for the total score. The 24-month progression rates were 10.8+/-7.3 for the UMSARS-I, 12.2+/-7.9 for the UMSARSII, and 22.6+/-13.7 for the total score. Annualized progression rates were divided according to their baseline UMSARS-I and UMSARS II. There was a significant (p = 0.0153) inverse relationship between rate of progression and UMSARS-I at baseline. A similar, but not significant trend was observed with UMSARS-II at baseline.
Conclusion(s): The rate of progression as measured by UMSARS is influenced by the baseline disease severity. A possible ceiling effect should be considered when planning enrollment, power calculations, and outcome measures in clinical trials

Objective: To confirm: 1) clinical efficacy and safety of once-daily oral ampreloxetine in a 4-week double-blind (

Objective: To develop a clinical score to distinguish between the parkinsonian variant of multiple system atrophy (MSA-P) and Parkinson's disease (PD).
Background(s): The differential diagnosis between MSA-P and PD is often difficult, particularly early in the disease course.
Method(s): We compared patients with probable MSA-P and with PD with a disease duration of <3 years, selected from those who were enrolled in the Natural History Study of the Synucleinopathies, an international prospective observational study. Detailed clinical neurological, and autonomic parameters were assessed at enrollment using UMSARS part I, II and IV; Schrag quality of life (QoL) scale; burden of autonomic dysfunction by COMPASS-31 scale; smell function using the UPSIT; cardiovascular autonomic function using heart rate variability during deep-breathing, analysis of the Valsalva maneuver, orthostatic stress test, plasma catecholamine levels during supine rest and after head-up tilt; and cognitive evaluation using MoCA. Positive and negative likelihood ratios (LR) were obtained for each variable assessed. Multiple iterations of a composite score based on sequential addition of variables with the highest diagnostic accuracy were created by multiplying each variable's LR and applying a logarithmic function.
Result(s): Fifty-eight MSA-P and 53 PD patients had a disease duration of less than 3 years. The vast majority of patients had been diagnosed within the last 12 months (81% MSA-P and 66% PD patients). MSA-P patients were more frequently female (53% vs. 30% p<0.05) and younger at diagnosis (63+/-8 years vs. 71+/-8 years, p<0.001). A 7-item score comprising the bladder weighted subscore of the COMPASS-31, UMSARS's part 1, UPSIT, hyperreflexia, the motor subscore of Schrag's MSA quality of life scale, falls within 3 years of diagnosis, and new or increased snoring resulted in a ROC curve AUC of 0.983, with excellent 93% sensitivity and 98% specificity to distinguish early MSA-P from PD.
Conclusion(s): We propose a scale of 7 clinical items to distinguish early stage MSA-P from PD. It considers urinary function, olfactory function, corticospinal signs, performance of activities of daily living, motor symptoms burden on quality of life, frequent early falls and sleep disordered breathing. We are now prospectively validating the scale to determine its predictive value in our prodromal cohort. (Figure Presented)

KEY POINTS/CONCLUSIONS:Individuals with Hereditary Sensory & Autonomic Neuropathy type III (HSAN III), also known as Riley-Day syndrome or Familial Dysautonomia, do not have functional muscle spindle afferents but do have essentially normal cutaneous mechanoreceptors Lack of muscle spindle feedback from the legs may account for the poor proprioception at the knee and the ataxic gait typical of HSAN III Given that functional muscle spindle afferents are also absent in the upper limb, we assessed whether proprioception at the elbow was likewise compromised Passive joint angle matching showed that proprioception was normal at the elbow, suggesting that individuals with HSAN III rely more on cutaneous afferents around the elbow ABSTRACT: Hereditary Sensory & Autonomic Neuropathy type III (HSAN III) is a rare neurological condition that features a marked ataxic gait that progressively worsens over time. We have shown that functional muscle spindle afferents are absent in the upper and lower limbs in HSAN III, and we have argued that this may account for the ataxia. We recently used passive joint angle matching to demonstrate that proprioception of the knee joint is very poor in HSAN III but can be improved towards normal by application of elastic kinesiology tape across the knee joints, which we attribute to the presence of intact cutaneous mechanoreceptors. Here we assessed whether proprioception was equally compromised at the elbow joint, and whether it could be improved through taping. Proprioception at the elbow joint was assessed using passive joint angle matching in 12 HSAN III patients and 12 age-matched controls. There was no difference in absolute error, gradient or correlation coefficient of the relationship between joint angles of the reference and indicator arms. Unlike at the knee, taping did not improve elbow proprioception in either group. Clearly, the lack of muscle spindles compromised proprioception at the knee but not at the elbow, and we suggest that the HSAN III patients rely more on proprioceptive signals from the skin around the elbow. This article is protected by copyright. All rights reserved.

Afferent lesions of the arterial baroreflex occur in familial dysautonomia. This leads to excessive blood pressure variability with falls and frequent surges that damage the organs. These hypertensive surges are the result of excess peripheral catecholamine release and have no adequate treatment. Carbidopa is a selective DOPA-decarboxylase inhibitor that suppresses catecholamines production outside the brain. To learn whether carbidopa can inhibit catecholamine-induced hypertensive surges in patients with severe afferent baroreflex failure, we conducted a double-blind randomized crossover trial in which patients with familial dysautonomia received high dose carbidopa (600 mg/day), low-dose carbidopa (300 mg/day), or matching placebo in 3 4-week treatment periods. Among the 22 patients enrolled (13 females/8 males), the median age was 26 (range, 12-59 years). At enrollment, patients had hypertensive peaks to 164/116 (range, 144/92 to 213/150 mm Hg). Twenty-four hour urinary norepinephrine excretion, a marker of peripheral catecholamine release, was significantly suppressed on both high dose and low dose carbidopa, compared with placebo (P=0.0075). The 2 co-primary end points of the trial were met. The SD of systolic BP variability was reduced at both carbidopa doses (low dose: 17±4; high dose: 18±5 mm Hg) compared with placebo (23±7 mm Hg; P=0.0013), and there was a significant reduction in the systolic BP peaks on active treatment (P=0.0015). High- and low-dose carbidopa were similarly effective and well tolerated. This study provides class Ib evidence that carbidopa can reduce blood pressure variability in patients with congenital afferent baroreflex failure. Similar beneficial effects are observed in patients with acquired baroreflex lesions.

PURPOSE/OBJECTIVE:The primary objective of this study was to examine the relationship of longitudinal changes in autonomic symptom burden and longitudinal changes in activities of daily living (ADLs); a secondary analysis examined the impact of depressive symptoms in this relationship. METHODS:Data were retrieved from the Parkinson's Progression Markers Initiative (PPMI), a dataset documenting the natural history of newly diagnosed Parkinson's disease (PD). The analysis focused on data from baseline, visit 6 (24 months after enrollment), and visit 12 (60 months after enrollment). The impact of longitudinal changes in autonomic symptom burden on longitudinal changes in ADLs function was examined. A secondary mediation analysis was performed to investigate whether longitudinal changes in depressive symptoms mediate the relationship between longitudinal changes in autonomic symptom burden and ADLs function. RESULTS:Changes in autonomic symptom burden, cognitive function, depressive symptoms, and motor function all correlated with ADLs. Only changes in ADLs and depression were found to be associated with changes in autonomic symptom burden. We found that longitudinal change in autonomic symptoms was a significant predictor of change in ADLs at 24 and 60 months after enrollment, with the cardiovascular subscore being a major driver of this association. Mediation analysis revealed that the association between autonomic symptoms and ADLs is partially mediated by depressive symptoms. CONCLUSIONS:Longitudinal changes in autonomic symptoms impact ADLs function in patients with early signs of PD, both directly and indirectly through their impact on depressive symptoms. Future investigation into the influence of treatment of these symptoms on outcomes in PD is warranted.