Parkinson's disease (PD) is a progressive neurodegenerative disorder characterised by motor dysfunction ( parkinsonism) and several non-motor features. Dysautonomia is a significant non-motor feature as well as a neuropsychiatric symptom. Autonomic dysfunction can occur even in the early stages of PD, often preceding the onset of the classic motor symptoms of PD. The patterns of autonomic features in PD are different from other parkinsonian disorders. Detection of autonomic dysfunction may therefore be helpful in diagnosing PD in the early or pre-motor stages, and/or in differentiating it from other parkinsonian disorders, such as multiple system atrophy and progressive supuranuclear palsy. The aim of this review is to describe aspects of autonomic dysfunction, including symptoms, assessment and pathophysiology, resulting from autonomic impairment in PD and other parkinsonian syndromes.

Non-motor symptoms are now commonly recognized in Parkinson’s disease (PD) and can include dysautonomia. Impairment of cardiovascular autonomic function can occur at any stage of PD but is typically prevalent in advanced stages or related to (anti-Parkinsonian) drugs and can result in atypical blood pressure (BP) readings and related symptoms such as orthostatic hypotension (OH) and supine hypertension. OH is usually diagnosed with a head-up-tilt test (HUT) or an (active) standing test (also known as Schellong test) in the laboratory, but 24 h ambulatory blood pressure monitoring (ABPM) in a home setting may have several advantages, such as providing an overview of symptoms in daily life alongside pathophysiology as well as assessment of treatment interventions. This, however, is only possible if ABPM is administrated correctly and an autonomic protocol (including a diary) is followed which will be discussed in this review. A 24-h ABPM does not only allow the detection of OH, if it is present, but also the assessment of cardiovascular autonomic dysfunction during and after various daily stimuli, such as postprandial and alcohol dependent hypotension, as well as exercise and drug induced hypotension. Furthermore, information about the circadian rhythm of BP and heart rate (HR) can be obtained and establish whether or not a patient has a fall of BP at night (i.e., “dipper” vs. non-“dipper”). The information about nocturnal BP may also allow the investigation or detection of disorders such as sleep dysfunction, nocturnal movement disorders, and obstructive sleep apnea, which are common in PD. Additionally, a 24-h ABPM should be conducted to examine the effectiveness of OH therapy. This review will outline the methodology of 24 h ABPM in PD, summarize findings of such studies in PD, and briefly consider common daily stimuli that might affect 24 h ABPM.

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Objective The objective of this study was to evaluate patients with ganglionic acetylcholine receptor antibody (gAChR‐Ab) positive autoimmune autonomic ganglionopathy using a multimodal testing protocol to characterize their full clinical phenotype and explore biomarkers to quantify immunotherapy response. Methods We conducted a cohort study of 13 individuals (7 women, 21–69 years of age) with autonomic failure and gAChR‐Ab >100 pM identified between 2005 and 2019. From 2018, all patients were longitudinally assessed with cardiovascular, pupillary, urinary, sudomotor, lacrimal and salivary testing, and Composite Autonomic Symptom Score (COMPASS‐31) autonomic symptom questionnaires. The orthostatic intolerance ratio was calculated by dividing change in systolic blood pressure over time tolerated on head‐up tilt. Eleven patients received immunotherapy. Results At first assessment, all 13 patients had cardiovascular and pupillary impairments, 7 of 8 had postganglionic sudomotor dysfunction, 9 of 11 had urinary retention and xeropthalmia, and 6 of 8 had xerostomia. After immunotherapy, there were significant improvements in orthostatic intolerance ratio (33.3 [17.8–61.3] to 5.2 [1.4–8.2], p = 0.007), heart rate response to deep breathing (1.5 [0.0–3.3] to 4.5 [3.0–6.3], p = 0.02), pupillary constriction to light (12.0 [5.5–18.0] to 19.0 [10.6–23.8]%, p = 0.02), saliva production (0.01 [0.01–0.05] to 0.08 [0.02–0.20] g/min, p = 0.03), and COMPASS‐31 scores (52 to 17, p = 0.03). Orthostatic intolerance ratio correlated with autonomic symptoms at baseline (r = 0.841, p = 0.01) and following immunotherapy (r = 0.889, p = 0.02). Immunofluorescence analyses of skin samples from a patient 32 years after disease onset showed loss of nerve fibers supplying the dermal autonomic adnexa and epidermis, with clear improvements following immunotherapy. Interpretation Patients with autoimmune autonomic ganglionopathy demonstrated objective evidence of widespread sympathetic and parasympathetic autonomic failure, with significant improvements after immunotherapy. Quantitative autonomic biomarkers should be used to define initial deficits, guide therapeutic decisions, and document treatment response. ANN NEUROL 2021;89:753–768

Parkinson's disease with autonomic failure and MSA patients had similar circadian BP patterns suggesting that autonomic dysfunction influences abnormal BP circadian patterns similarly in these disorders. The higher sensitivity and specificity in detecting OH using a systolic BP fall of >20 mmHg compared to a diastolic BP fall of >10 mmHg during the standing test supports its usefulness to assess autonomic function in MSA and PD.

In this review, we describe the wide clinical spectrum of features that can be seen in multiple system atrophy (MSA) with a focus on the premotor phase and the non-motor symptoms providing an up-to-date overview of the current understanding in this fast-growing field. First, we highlight the non-motor features at disease onset when MSA can be indistinguishable from pure autonomic failure or other chronic neurodegenerative conditions. We describe the progression of clinical features to aid the diagnosis of MSA early in the disease course. We go on to describe the levels of diagnostic certainty and we discuss MSA subtypes that do not fit into the current diagnostic criteria, highlighting the complexity of the disease as well as the need for revised diagnostic tools. Second, we describe the pathology, clinical description, and investigations of cardiovascular autonomic failure, urogenital and sexual dysfunction, orthostatic hypotension, and respiratory and REM-sleep behavior disorders, which may precede the motor presentation by months or years. Their presence at presentation, even in the absence of ataxia and parkinsonism, should be regarded as highly suggestive of the premotor phase of MSA. Finally, we discuss how the recognition of the broader spectrum of clinical features of MSA and especially the non-motor features at disease onset represent a window of opportunity for disease-modifying interventions.

The discovery of genetic links between alpha-synuclein and PD has opened unprecedented opportunities for research into a new group of diseases, now collectively known as synucleinopathies. Autonomic dysfunction, including cardiac sympathetic denervation, has been reported in familial forms of synucleinopathies that have Lewy bodies at the core of their pathogenesis. SNCA mutations and multiplications, LRRK2 disease with Lewy bodies as well as other common, sporadic forms of idiopathic PD, MSA, pure autonomic failure, and dementia with Lewy bodies have all been associated with dysautonomia. By contrast, in familial cases of parkinsonism without Lewy bodies, such as in PARK2, the autonomic profile remains normal throughout the course of the disease. The degeneration of the central and peripheral autonomic systems in genetic as well as sporadic forms of neurodegenerative synucleinopathies correlates with the accumulation of alpha-synuclein immunoreactive-containing inclusions. Given that dysautonomia has a significant impact on the quality of life of sufferers and autonomic symptoms are generally treatable, a prompt diagnostic testing and treatment should be provided. Moreover, new evidence suggests that autonomic dysfunction can be used as an outcome prediction factor in some forms of synucleinopathies or premotor diagnostic markers that could be used in the future to define further research avenues. In this review, we describe the autonomic dysfunction of genetic synucleinopathies in comparison to the dysautonomia of sporadic forms of alpha-synuclein accumulation and provide the reader with an up-to-date overview of the current understanding in this fast-growing field. © 2018 International Parkinson and Movement Disorder Society.