Faculty Bibliography

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.

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.

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.

BACKGROUND:Despite innovations in left ventricular assist devices (LVAD) technology, stroke remains a leading cause of morbidity and mortality in this population. Major clinical trials of LVAD have used various definitions and approaches to measuring stroke outcomes which may limit comparison of stroke risk between different devices. METHODS:Data from the five major LVAD randomized, controlled, trials was abstracted to compare definitions of stroke (composite, ischemic, hemorrhagic and disabling) and stroke event rates across trials. Methodological limitations and suggestions to improve research and clinical practices for stroke and LVAD were identified. RESULTS:Comparison of stroke events across LVAD clinical trials is confounded by methodological variability including heterogeneity in stroke definitions, non-standardized evaluation of stroke etiology, oversimplification of stroke severity classification, and inconsistent event rate reporting due to data censoring at the time of death or transplant. Variability in the study of stroke in LVAD patients limits the ability to compare devices and design prevention strategies to mitigate stroke risk. CONCLUSIONS:Based on this review, we propose that future clinical trials: 1) utilize standardized stroke definitions and define stroke subtypes, 2) ensure that neurologists are integrated in study design and event adjudication, 3) include more thorough evaluations of stroke etiology using multimodality techniques, and 4) adopt the National Institutes of Health Stroke Scale to define stroke severity.

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.

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.

PURPOSE OF REVIEW/OBJECTIVE:This article reviews the management of orthostatic hypotension with emphasis on neurogenic orthostatic hypotension. RECENT FINDINGS/RESULTS:Establishing whether the cause of orthostatic hypotension is a pathologic lesion in sympathetic neurons (ie, neurogenic orthostatic hypotension) or secondary to other medical causes (ie, non-neurogenic orthostatic hypotension) can be achieved by measuring blood pressure and heart rate at the bedside. Whereas fludrocortisone has been extensively used as first-line treatment in the past, it is associated with adverse events including renal and cardiac failure and increased risk of all-cause hospitalization. Distinguishing whether neurogenic orthostatic hypotension is caused by central or peripheral dysfunction has therapeutic implications. Patients with peripheral sympathetic denervation respond better to norepinephrine agonists/precursors such as droxidopa, whereas patients with central autonomic dysfunction respond better to norepinephrine reuptake inhibitors. SUMMARY/CONCLUSIONS:Management of orthostatic hypotension is aimed at improving quality of life and reducing symptoms rather than at normalizing blood pressure. Nonpharmacologic measures are the key to success. Pharmacologic options include volume expansion with fludrocortisone and sympathetic enhancement with midodrine, droxidopa, and norepinephrine reuptake inhibitors. Neurogenic supine hypertension complicates management of orthostatic hypotension and is primarily ameliorated by avoiding the supine position and sleeping with the head of the bed elevated.