Faculty Bibliography

Background/UNASSIGNED:The Global Multiple System Atrophy Registry (GLOMSAR) was established in 2013. It is an online patient-reported contact registry open and free that relies on self-reported diagnosis by the patient or caregiver. Objectives/UNASSIGNED:To report the demographics of patients enrolled in GLOMSAR and the results of an ancillary online symptom questionnaire. Methods/UNASSIGNED:Patients enrolled in GLOMSAR were invited to complete a custom-designed online questionnaire about disease onset and symptom prevalence. Results/UNASSIGNED:At the time of writing, there were 1083 participants in GLOMSAR, of which 33% (365) completed the questionnaire. The onset and frequency of most symptoms was similar to those reported in the literature in physician-reported studies. Some were understudied or not typically associated with multiple system atrophy (MSA), including reduced female sexual sensation (55%), forgetfulness (60%), pseudobulbar affect (37%), olfactory changes (36%), and visual hallucinations (21%). Conclusions/UNASSIGNED:Patient-reported studies and ancillary online questionnaires are valid, underused research tools useful to advance our knowledge on understudied MSA features and highlight the patients' voice.

Multiple system atrophy (MSA) is a rare neurodegenerative disease that is characterized by neuronal loss and gliosis in multiple areas of the central nervous system including striatonigral, olivopontocerebellar and central autonomic structures. Oligodendroglial cytoplasmic inclusions containing misfolded and aggregated α-synuclein are the histopathological hallmark of MSA. A firm clinical diagnosis requires the presence of autonomic dysfunction in combination with parkinsonism that responds poorly to levodopa and/or cerebellar ataxia. Clinical diagnostic accuracy is suboptimal in early disease because of phenotypic overlaps with Parkinson disease or other types of degenerative parkinsonism as well as with other cerebellar disorders. The symptomatic management of MSA requires a complex multimodal approach to compensate for autonomic failure, alleviate parkinsonism and cerebellar ataxia and associated disabilities. None of the available treatments significantly slows the aggressive course of MSA. Despite several failed trials in the past, a robust pipeline of putative disease-modifying agents, along with progress towards early diagnosis and the development of sensitive diagnostic and progression biomarkers for MSA, offer new hope for patients.

Orthostatic hypotension is an unusually large decrease in blood pressure on standing that increases the risk of adverse outcomes even when asymptomatic. Improvements in haemodynamic profiling with continuous blood pressure measurements have uncovered four major subtypes: initial orthostatic hypotension, delayed blood pressure recovery, classic orthostatic hypotension, and delayed orthostatic hypotension. Clinical presentations are varied and range from cognitive slowing with hypotensive unawareness or unexplained falls to classic presyncope and syncope. Establishing whether symptoms are due to orthostatic hypotension requires careful history taking, a thorough physical examination, and supine and upright blood pressure measurements. Management and prognosis vary according to the underlying cause, with the main distinction being whether orthostatic hypotension is neurogenic or non-neurogenic. Neurogenic orthostatic hypotension might be the earliest clinical manifestation of Parkinson's disease or related synucleinopathies, and often coincides with supine hypertension. The emerging variety of clinical presentations advocates a stepwise, individualised, and primarily non-pharmacological approach to the management of orthostatic hypotension. Such an approach could include the cessation of blood pressure lowering drugs, adoption of lifestyle measures (eg, counterpressure manoeuvres), and treatment with pharmacological agents in selected cases.

Despite its increasing recognition and extensive research, there is no unifying hypothesis on the pathophysiology of the postural tachycardia syndrome. In this cross-sectional study, we examined the role of fear conditioning and its association with tachycardia and cerebral hypoperfusion upon standing in 28 patients with postural tachycardia syndrome (31 ± 12 years old, 25 women) and 21 matched controls. We found that patients had higher somatic vigilance (p = 0.0167) and more anxiety (p < 0.0001). They also had a more pronounced anticipatory tachycardia right before assuming the upright position in a tilt-table test (p = 0.015), a physiologic indicator of fear conditioning to orthostasis. While standing, patients had faster heart rate (p < 0.001), higher plasma catecholamine levels (p = 0.020), lower end-tidal CO2 (p = 0.005), and reduced middle cerebral artery blood flow velocity (p = 0.002). Multi-linear logistic regression modeling showed that both epinephrine secretion and excessive somatic vigilance predicted the magnitude of the tachycardia and the hyperventilation. These findings suggest that the postural tachycardia syndrome is a functional psychogenic disorder in which standing may acquire a frightful quality, so that even when experienced alone, it elicits a fearful conditioned response. Heightened somatic anxiety is associated with and may predispose to a fear-conditioned hyperadrenergic state when standing. Our results have therapeutic implications.