Short Communication
Can novel non-invasive autonomic tests help discriminate between pure autonomic failure and multiple system atrophy?

https://doi.org/10.1016/j.autneu.2021.102773Get rights and content

Abstract

Background

Pure autonomic failure (PAF) and multiple system atrophy (MSA) are rare disorders causing severe autonomic failure. Their initially similar clinical presentation may lead to years of diagnostic difficulties. Improving the differentiation would have an important impact on patients and families in view of better prediction of disease progression.

Objective

To investigate whether several new non-invasive autonomic tests are beneficial in discriminating between PAF and MSA.

Methods

Patients and controls underwent two tests examining the autonomic innervation of the skin (Sudoscan and water-induced skin wrinkling) and one test measuring retinal nerve fiber layer thickness in the eye.

Results

The skin vasomotor tests yielded differences between the disease and control groups, but did not discriminate between PAF and MSA. No differences in retinal nerve fiber layer thickness were found between the groups.

Conclusion

The tests applied in this study may help to confirm autonomic failure but did not support the differential diagnosis between PAF and MSA.

Introduction

Autonomic failure (AF) concerns diminished function of the autonomic nervous system (ANS). One of its most debilitating symptoms is ‘neurogenic orthostatic hypotension’ (nOH) (Freeman, 2008).

Pure autonomic failure (PAF) and multiple system atrophy (MSA) cause severe AF with pronounced nOH (Fanciulli and Wenning, 2015). The similar initial clinical presentation of both diseases makes it often impossible to differentiate PAF and MSA for several years, leaving patients in diagnostic uncertainty. The usual approach then is to observe the development of the disease: when motor symptoms appear, MSA is more likely, and when isolated AF persists for at least five years, PAF is more likely (Fanciulli and Wenning, 2015; Kaufmann and Biaggioni, 2003; Gilman et al., 2008). Lately, several studies have shown that within four years up to 34% of patients, initially diagnosed with PAF, phenoconvert to a central nervous system synucleinopathy including MSA (8–10%), Parkinson's Disease (PD) or dementia with Lewy bodies (DLB) (Singer et al., 2017; Kaufmann et al., 2017).

Tools to shorten the time to differentiate PAF and MSA would have important implications for patients and families, by reducing uncertainty with regards to prognosis and possibly reducing resource demands.

We report on several non-invasive tests to evaluate their utility for differential diagnosis between PAF and MSA, including vasomotor function of the skin and optical coherence tomography of the retina (OCT).

Sympathetic autonomic innervation of the skin was previously investigated in patients with PAF and MSA, using a sudorometer measuring the sweat production in response to several stimuli (Singer et al., 2017). The study showed a preserved sweat production in MSA and reduced to absent sweating in PAF, but has not been replicated yet (Asahina et al., 2009).

Another method to assess vasomotor function is to measure skin wrinkling upon immersion of the hands in warm water (Wilder-Smith, 2015). Water induced skin wrinkling (WISW) has been shown to be useful in diagnosing small fiber neuropathy, a condition that includes pathology of skin nerve fibres (Wilder-Smith and Chow, 2003).

Another promising technique to examine the autonomic nervous system is to study the retinal nerve fiber layer (RNFL) using OCT. The RNFL is a superficial retinal layer containing axons. Thinning of this layer has been investigated in various disorders, including alpha-synucleinopathies. Although it is not known which neurons or axons are affected in the retina in MSA, previous studies showed a fairly widespread neuronal damage: Fischer et al. (Fischer et al., 2011; Fischer et al., 2013) as well as Albrecht et al. (Albrecht et al., 2012) and Schneider et al. (Schneider et al., 2014) reported a significantly thinner RNFL in MSA patients compared to controls, but no difference between patients with PD and controls. To our knowledge such studies have not been performed yet in PAF.

Our working hypothesis for the two skin tests was that we expected preserved function in MSA, given that it is primarily a disorder of the central autonomic nervous system, and attenuated function in PAF, as a primarily peripheral disorder. As retinal vessels are not under autonomic control, we expected the RNFL to be normal in PAF and thinned in MSA (Bennett et al., 2015).

Section snippets

Patients and controls

The study protocol was reviewed and approved by the medical ethical committee of the Leiden University Medical Centre and complied with the declaration of Helsinki and its later amendments. Written informed consent was obtained from all participants. We recruited participants of 18 years and older from the outpatient departments of Syncope and Autonomic Disorders and Movement Disorders of the Leiden University Medical Centre.

We included patients with PAF and MSA according to the consensus

Patients and controls

We included nine patients with PAF, 10 with MSA and 10 healthy controls. Clinical features of both groups are described in Table 1. Median disease duration for PAF was 10.5 years reported from symptoms onset until the performed tests, and 6 years for the MSA group.

One subject with MSA withdrew consent prior to the tests. One WISW test was not performed for one patient due to a planning error. Baseline characteristics of the two disease groups and controls are summarized in Table 2.

Sudoscan

Sudomotor

Discussion

We found that the two autonomic skin tests, i.e. sweating and skin wrinkling, discriminated between patients and controls, but failed to differentiate between MSA and PAF groups. RNFL proved normal in both patient groups. We selected the tests on their putative different susceptibility to peripheral or central autonomic damage, as PAF generally affects peripheral autonomic nerve fibres, whereas MSA mainly involves the central autonomic nervous system.

As for Sudoscan results, we confirmed the

Ethical standards

The study protocol was reviewed and approved by the medical ethical committee of the Leiden University Medical Centre and have therefore been performed in accordance with the ethical standards laid down in the 1964 Declaration of Helsinki and its later amendments. Written informed consent was obtained from all participants.

Declaration of competing interest

The authors declare that they have no conflict of interest.

All authors contributed to the study conception and design. Material preparation, data collection and analysis were performed by [Mirjam Datema], [Martijn Tannemaat], [Sylvie Steenmeijer] and [Boriana Gagaouzova]. The first draft of the manuscript was written by [Boriana Gagaouzova] and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.

References (23)

  • E.A. Coon et al.

    Anhidrosis in multiple system atrophy involes pre- and postganglionic sudomotor dysfunction

    Mov. Disord.

    (2017)
  • Cited by (3)

    View full text