Faculty Bibliography

Objective: To study the rate of progression of multiple system atrophy (MSA) and assess for a potential ceiling effect of the Unified Multiple System Atrophy Rating Scale (UMSARS).
Background(s): Disease progression of MSA as measured by UMSARS varied significantly in natural history studies. Reported 1-year UMSARS-1 and UMSARS-2 progression rates ranged from 3.9 to 6.5 and 3.5 to 8.2 respectively. We hypothesize that this variability is due, at least in part, to differences in severity at enrollment and a potential ceiling effect in the scale, so that patients in more advanced stages may appear to worsen less, which would have important implications for clinical trial design.
Method(s): We analyzed the rate of change in the UMSARS in a large international cohort of well-characterized patients with a clinical diagnosis of possible or probable MSA enrolled in the Natural History Study of Synucleinopathies. Annualized progression rates were obtained using 2-year follow-up data.
Result(s): Three hundred and forty nine patients (61.4+/-7.9 years old) with MSA were enrolled. Disease duration was 4.5+/-5.1 years. 143 patients completed 1-year evaluations and 61 completed the 2-year evaluation. The 12-month progression rates were 5.4+/-5.1 for the UMSARS-I, 5.9+/-5.3 for the UMSARS-II, and 11.8+/-9.6 for the total score. The 24-month progression rates were 10.8+/-7.3 for the UMSARS-I, 12.2+/-7.9 for the UMSARSII, and 22.6+/-13.7 for the total score. Annualized progression rates were divided according to their baseline UMSARS-I and UMSARS II. There was a significant (p = 0.0153) inverse relationship between rate of progression and UMSARS-I at baseline. A similar, but not significant trend was observed with UMSARS-II at baseline.
Conclusion(s): The rate of progression as measured by UMSARS is influenced by the baseline disease severity. A possible ceiling effect should be considered when planning enrollment, power calculations, and outcome measures in clinical trials

Background/UNASSIGNED:In the current consensus diagnostic criteria, the diagnosis of probable multiple system atrophy (MSA) is based solely on clinical findings, whereas neuroimaging findings are listed as aid for the diagnosis of possible MSA. There are overlapping phenotypes between MSA-parkinsonian type and Parkinson's disease, progressive supranuclear palsy, and dementia with Lewy bodies, and between MSA-cerebellar type and sporadic adult-onset ataxia resulting in a significant diagnostic delay and misdiagnosis of MSA during life. Objectives/UNASSIGNED:In light of an ongoing effort to revise the current consensus criteria for MSA, the Movement Disorders Society Multiple System Atrophy Study Group performed a systematic review of original articles published before August 2019. Methods/UNASSIGNED:We included articles that studied at least 10 patients with MSA as well as participants with another disorder or control group for comparison purposes. MSA was defined by neuropathological confirmation, or as clinically probable, or clinically probable plus possible according to consensus diagnostic criteria. Results/UNASSIGNED:We discuss the pitfalls and benefits of each diagnostic test and provide specific recommendations on how to evaluate patients in whom MSA is suspected. Conclusions/UNASSIGNED:This systematic review of relevant studies indicates that imaging and autonomic function tests significantly contribute to increasing the accuracy of a diagnosis of MSA.

Von Economo neurons (VENs) and fork cells are principally located in the anterior cingulate cortex (ACC) and the frontoinsular cortex (FI). Both of these regions integrate inputs from the autonomic nervous system (ANS) and are involved in decision-making and perception of the emotional states of self and others. Familial dysautonomia (FD) is an orphan disorder characterized by autonomic dysfunction and behavioral abnormalities including repetitive behavior and emotional rigidity, which are also seen in autism spectrum disorder. To understand a possible link between the ANS and the cortical regions implicated in emotion regulation we studied VENs and fork cells in an autonomic disorder. We determined the densities of VENs, fork cells, and pyramidal neurons and the ratio of VENs and fork cells to pyramidal neurons in ACC and FI in 4 FD patient and 6 matched control brains using a stereologic approach. We identified alterations in densities of VENs and pyramidal neurons and their distributions in the ACC and FI in FD brains. These data suggest that alterations in migration and numbers of VENs may be involved in FD pathophysiology thereby supporting the notion of a functional link between VENs, the ANS and the peripheral nervous system in general.

Neurogenic orthostatic hypotension (nOH) is among the most debilitating nonmotor features of patients with Parkinson's disease (PD) and other synucleinopathies. Patients with PD and nOH generate more hospitalizations, make more emergency room visits, create more telephone calls/mails to doctors, and have earlier mortality than those with PD but without nOH. Overall, the health-related cost in patients with PD and OH is 2.5-fold higher compared with patients with PD without OH. Hence, developing effective therapies for nOH should be a research priority. In the last few decades, improved understanding of the pathophysiology of nOH has led to the identification of therapeutic targets and the development and approval of two drugs, midodrine and droxidopa. More effective and safer therapies, however, are still needed, particularly agents that could selectively increase blood pressure only in the standing position because supine hypertension is the main limitation of available drugs. Here we review the design and conduct of nOH clinical trials in patients with PD and other synucleinopathies, summarize the results of the most recently completed and ongoing trials, and discuss challenges, bottlenecks, and potential remedies.

Acute-onset and severe sensory and autonomic deficits with no motor dysfunction, typically preceded by a febrile illness, with poor recovery, and often fatal outcome are the hallmark features of acute sensory and autonomic neuronopathy (ASANN). Pathologically and electrophysiologically, ASANN is characterized by an extensive ganglionopathy affecting sensory and autonomic ganglia with preservation of motor neurons. Consequently, patients, usually children or young adult, develop acute-onset profound widespread loss of all sensory modalities resulting in automutilations, as well as autonomic failure causing neurogenic orthostatic hypotension, neurogenic underactive bladder, and gastroparesis and constipation. The diagnosis is clinical with support of nerve conduction studies and autonomic testing, as well as spinal cord magnetic resonance imaging showing characteristic posterior cord hyperintensities. Although the presumed etiology is immune-mediated, further studies are required to clarify the physiopathology of the disease. We here performed a systematic review of the epidemiology, pathophysiology, diagnosis, and management of ASANN, with three representative cases that recently presented at our clinic. All three patients had the typical clinical manifestations of ASANN but in different combinations, illustrating the variable phenotype of the disorder. Immunosuppression is seldom effective. Management options are limited to supportive and symptomatic care with the goal of minimizing complications and preventing death.

Head and neck tumors can affect afferent baroreceptor neurons and either interrupt or intermittently increase their signaling, causing blood pressure to become erratic. When the afferent fibers of the baroreflex are injured by surgery or radiotherapy or fail to develop as in familial dysautonomia, their sensory information is no longer present to regulate arterial blood pressure, resulting in afferent baroreflex failure. When the baroreflex afferents are abnormally activated, such as by paragangliomas in the neck, presumably by direct compression, they trigger acute hypotension and bradycardia and frequently syncope, by a mechanism similar to the carotid sinus syndrome. We describe our observations in a large series of 23 patients with afferent baroreflex dysfunction and the cardiovascular autonomic features that arise when the sensory baroreceptor neurons are injured or compressed. The management of afferent baroreceptor dysfunction is limited, but pharmacological strategies can mitigate blood pressure swings, improve symptoms, and may reduce hypertensive organ damage. Although rare, the prevalence of afferent baroreflex dysfunction appears to be increasing in middle-aged men due to human papillomavirus related oropharyngeal cancer.

A 10-year-old girl presented with ileus, urinary retention, dry mouth, lack of tears, fixed dilated pupils, and diffuse anhidrosis 7-days after a febrile illness. We hypothesized that her syndrome was due to autoimmunity against muscarinic acetylcholine receptors, blocking their activation. Using an indirect enzyme-linked immunosorbent assay for all five muscarinic receptors (M₁ -M₅ ) we identified in the patient's serum antibodies that selectively bound to M₃ receptors. In-vitro functional studies confirmed that these autoantibodies selectively blocked M₃ receptor activation. Thus, autoantibodies against M₃ acetylcholine receptors can cause acute postganglionic cholinergic dysautonomia. This article is protected by copyright. All rights reserved.