The many faces of autonomic failure in multiple system atrophy

Orthostatic hypotension, gastrointestinal symptoms, urinary disturbances, and erectile dysfunction are well recognized as autonomic features by movement disorders specialists dealing with patients with Parkinson’s disease (PD) and atypical parkinsonian disorders such as multiple system atrophy (MSA). These symptoms are the consequence of direct or indirect involvement of the central and peripheral autonomic nervous systems. Autonomic dysfunction in form of orthostatic hypotension and urinary dysfunction is a core feature of current consensus clinical diagnosis criteria for MSA. Albeit mild in intensity, signs of urinary dysfunction, constipation, and orthostatic hypotension are also prevalent in untreated patients with PD. Moreover, patients with rapid eye movement sleep behavioral disorder more frequently report mild urinary disturbances and constipation as well as mild to severe erectile dysfunction, keeping in mind that a significant number of these patients will eventually be diagnosed as PD, MSA, or Lewy body dementia. As PD progresses, autonomic dysfunction becomes more severe with symptomatic orthostatic hypotension, urinary incontinence, and constipation requiring laxatives occurring in 48%, 71%, and 40% of PD patients 20 years after disease onset. Autonomic dysfunction is correlated with healthrelated quality of life (Hr-QoL) in MSA. It also highly correlates with Hr-QoL in PD patients, in particular with gastrointestinal, urinary, and thermoregulatory symptoms but also to a lesser degree with cardiovascular and sexual complaints. This is true for early and later stages of PD. Remarkably, the correlation is stronger between Hr-QoL and autonomic dysfunction than motor signs as assessed by the Unified PD Rating Scale. Classically, it is believed that autonomic dysfunction is a result of preganglionic dysfunction in MSA and postganglionic impairment in PD. Recent evidence has challenged this view because mild to moderate loss of tyrosine hydroxylase immunoreactive fibers in the pericardium is observed on postmortem assessment in some MSA patients and cardiac [123I]-meta-iodobenzylguanidine (MIBG) uptake is decreased in up to one third of MSA patients, independent of disease duration and severity. Beyond gastrointestinal, cardiovascular, and urinary complaints, autonomic dysfunction in MSA and PD may affect pupillomotor functioning, respiration, and thermoregulation, the latter may present as hypoor hyperhidrosis, cold or heat intolerance. Some of these additional autonomic features, in particular respiratory disturbances, may precede cardiovascular and urinary dysfunctions for many years in MSA patients. On thermoregulatory sweat testing (TST), MSA patients show more pronounced anhidrosis when compared with PD patients with a distinct topographical distribution pattern, that is, regional and progressive anhidrosis in MSA versus ganglionic and/or postganglionic length-dependent denervation in PD. Central thermoreceptors, located in the preoptic anterior hypothalamus, and peripheral thermoreceptors, in the skin, viscera and spinal cord, relay information to the central thermoregulatory control center in the hypothalamus. Sweat glands are innervated by sympathetic, unmyelinated, or poorly myelinated C-fibers with cholinergic neurotransmission. Different techniques have been described to assess sudomotor function such as TST, quantitative sudomotor axon reflex testing (QSART), silicone impressions, sympathetic skin response, and quantitative direct and indirect axon reflex testing. The TST evaluates the integrity of the entire central and peripheral sudomotor circuitry; it measures the sweat response to increasing body temperature with a dye that covers the skin of the assessed patient and that changes its color in the presence of moisture. The QSART assesses postganglionic sudomotor function by measuring sweat production after local stimulation of sympathetic nerves via iontophoresis of a cholinergic agent. -----------------------------------------------------------*Correspondence to: Prof. Wassilios G. Meissner, Institute of Neurodegenerative Diseases, University Bordeaux, 146 rue L eo Saignat, 33076 Bordeaux Cedex, France; wassilios.meissner@chu-bordeaux.fr