Faculty Bibliography

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:To assess the relationship between depressive symptoms and self-perceived severity of autonomic dysfunction in patients with multiple system atrophy (MSA). METHODS:Cross-sectional evaluation of patients with MSA who underwent autonomic testing, Unified MSA Rating Scale (UMSARS)-1 and -2, rating of the presence and severity of depressive symptoms (Zung scale), quality of life (SF-36), body vigilance, anxiety (Spielberger's anxiety scale), severity of autonomic dysfunction with the Composite Autonomic Symptoms Score (COMPASS-31), and severity of orthostatic hypotension (OH) symptoms with the Orthostatic Hypotension Questionnaire (OHQ). RESULTS:Fifty-eight patients (32 women) with probable MSA (aged 61.8 ± 8.6 years; disease duration 4.3 ± 2.1 years) were studied. Forty patients (69%) had symptoms of depression in the Zung scale. Age, disease duration, and motor disability were similar in those with and without symptoms of depression. Despite a similar orthostatic blood pressure fall, the severity of orthostatic symptoms was higher in patients with symptoms of depression (p = 0.004). Depression scores were associated with higher burden of autonomic symptoms (R = 0.401, p = 0.02), specifically with the COMPASS-31 items related to orthostatic intolerance (R = 0.337, p = 0.045), and with the OHQ (R = 0.529; p < 0.001). A multivariable regression model including age, sex, UMSARS, and drop in systolic blood pressure upon head-up tilt as covariates showed that the burden of depressive symptoms was independently associated with the OHQ score: for every 1-unit increase in the Zung depression score, there was a 1.181-point increase in the total OHQ score. CONCLUSIONS:In patients with MSA, depressive symptoms worsen the perceived severity of autonomic symptoms in general and orthostatic hypotension in particular. Our findings have implications for clinical trial design.

INTRODUCTION/BACKGROUND:In addition to neurogenic orthostatic hypotension (nOH), patients with synucleinopathies frequently have hypertension when supine. The long-term consequences of both abnormalities are difficult to disentangle. We aimed to determine if supine hypertension is associated with target organ damage and worse survival in patients with nOH. METHODS:Patients with nOH due to multiple system atrophy (MSA), Parkinson disease (PD), or pure autonomic failure (PAF) were classified into those with or without supine hypertension (systolic BP of at least 140 mmHg or diastolic BP of at least 90 mmHg). Organ damage was assessed by measuring cerebral white matter hyperintensities (WMH), left ventricular hypertrophy (LVH), and renal function. We prospectively followed patients for 30 months (range: 12-66 months) and recorded incident cardiovascular events and all-cause mortality. RESULTS:Fifty-seven patients (35 with probable MSA, 14 with PD and 8 with PAF) completed all evaluations. In addition to nOH (average fall 35 ± 21/17 ± 14 mmHg, systolic/diastolic, mean ± SD), 38 patients (67%) had supine hypertension (systolic BP > 140 mmHg). Compared to those without hypertension, patients with hypertension had higher blood urea nitrogen levels (P = 0.005), lower estimated glomerular filtration rate (P = 0.008), higher prevalence of LVH (P = 0.040), and higher WMH volume (P = 0.019). Longitudinal follow-up of patients for over 2 years (27.1 ± 14.5 months) showed that supine hypertension was independently associated with earlier incidence of cardiovascular events and death (HR = 0.25; P = 0.039). CONCLUSIONS:Supine hypertension in patients with nOH was associated with an increased risk for target organ damage, cardiovascular events, and premature death. Defining management strategies and safe blood pressure ranges in patients with nOH remains an important research question.

Background and aims: Dementia is considered a nonsupportive diagnostic feature for multiple system atrophy (MSA). Nevertheless, post-mortem verified dementia with Lewy bodies and Parkinson's disease masquerade as MSA. Cognitive impairment (CI), especially executive dysfunction, may occur in MSA patients. It is, however, unclear whether CI manifests in early disease stages.
Objective(s): To compare the prevalence of CI in MSA versus other Lewy Body disorders (LBD), including dementia with Lewy bodies and Parkinson's disease, in early (<3 years from symptom onset) versus more advanced disease stages (>=3 years from symptom onset).
Method(s): A total of 364 patients (LBD: n=83; MSA: n=281) of the natural history study of synucleinopathies register have been analysed. Consensus diagnostic criteria for dementia with Lewy bodies, Parkinson's disease and MSA were applied. To assess CI, the Montreal Cognitive Assessment (MoCA) has been used.
Result(s): In early disease stages, median MoCA scores did not differ significantly between MSA and LBD. In advanced disease stages, MSA patients had a significantly higher median MoCA score compared to LBD patients (27 versus 25, p=0.006). Comparison of the median MoCA Scores of LBD versus MSA patients at early and advanced disease stages
Conclusion(s): In patients with longer disease duration severity of CI helps to differentiate LBD from MSA

Background and aims: Distinguishing neurogenic orthostatic hypotension (nOH) from other causes of blood pressure (BP) instability is of pivotal importance in clinical practice. Norcliffe-Kaufmann et al. recently showed that when the ratio between the heart rate increase and the systolic BP fall after 3 minutes of passive head-up tilt (HUT) is <0.492, this indicates nOH. Here we aimed at validating this nOH ratio with standard arm-cuff BP measurements upon active standing (AS).
Method(s): We screened all patients who had undergone cardiovascular autonomic function testing at the Innsbruck Medical University between January 2008 and September 2019.
Result(s): We included 51 patients (27 with Parkinson's disease, 22 with multiple system atrophy) diagnosed with orthostatic hypotension either upon AS or HUT. 49 patients showed no BP overshoot after the Valsalva maneuver and were thus classified as having nOH. Out of these, 27 patients showed a systolic BP fall >=20mmHg in both the HUT and the AS and were considered for further analysis. The nOH ratio was <0.492 for 20 patients during HUT and for 19 patients during the AS. The sensitivity of the nOH ratio for neurogenic OH was therefore 74% upon HUT and 70% upon AS. The correlation between the nOH-ratio upon HUT and AS was strong (rho=0.86, p<0.001).
Conclusion(s): A nOH ratio <0.492 evaluated with standard arm-cuff heart rate and BP measurements has a good sensitivity for nOH both upon HUT and AS. This ratio can be therefore used as bedside nOH screening measure, if no tilt-test facilities are available