Faculty Bibliography

When cerebral blood flow falls below a critical limit, syncope occurs and, if prolonged, ischemia leads to neuronal death. The cerebral circulation has its own complex finely tuned autoregulatory mechanisms to ensure blood supply to the brain can meet the high metabolic demands of the underlying neuronal tissue. This involves the interplay between myogenic and metabolic mechanisms, input from noradrenergic and cholinergic neurons, and the release of vasoactive substrates, including adenosine from astrocytes and nitric oxide from the endothelium. Transcranial Doppler (TCD) is a non-invasive technique that provides real-time measurements of cerebral blood flow velocity. TCD can be very useful in the work-up of a patient with recurrent syncope. Cerebral autoregulatory mechanisms help defend the brain against hypoperfusion when perfusion pressure falls on standing. Syncope occurs when hypotension is severe, and susceptibility increases with hyperventilation, hypocapnia, and cerebral vasoconstriction. Here we review clinical standards for the acquisition and analysis of TCD signals in the autonomic laboratory and the multiple methods available to assess cerebral autoregulation. We also describe the control of cerebral blood flow in autonomic disorders and functional syndromes.

Dysfunction of the autonomic nervous system afflicts most patients with Parkinson disease and other synucleinopathies such as dementia with Lewy bodies, multiple system atrophy, and pure autonomic failure, reducing quality of life and increasing mortality. For example, gastrointestinal dysfunction can lead to impaired drug pharmacodynamics causing a worsening in motor symptoms, and neurogenic orthostatic hypotension can cause syncope, falls, and fractures. When recognized, autonomic problems can be treated, sometimes successfully. Discontinuation of potentially causative/aggravating drugs, patient education, and nonpharmacological approaches are useful and should be tried first. Pathophysiology-based pharmacological treatments that have shown efficacy in controlled trials of patients with synucleinopathies have been approved in many countries and are key to an effective management. Here, we review the treatment of autonomic dysfunction in patients with Parkinson disease and other synucleinopathies, summarize the nonpharmacological and current pharmacological therapeutic strategies including recently approved drugs, and provide practical advice and management algorithms for clinicians, with focus on neurogenic orthostatic hypotension, supine hypertension, dysphagia, sialorrhea, gastroparesis, constipation, neurogenic overactive bladder, underactive bladder, and sexual dysfunction. © 2018 International Parkinson and Movement Disorder Society.

OBJECTIVE:Blunted tachycardia during hypotension is a characteristic feature of patients with autonomic failure, but the range has not been defined. This study reports the range of orthostatic heart rate (HR) changes in patients with autonomic failure caused by neurodegenerative synucleinopathies. METHODS:Patients evaluated at sites of the U.S. Autonomic Consortium (NCT01799915) underwent standardized autonomic function tests and full neurological evaluation. RESULTS:We identified 402 patients with orthostatic hypotension (OH) who had normal sinus rhythm. Of these, 378 had impaired sympathetic activation, i.e., neurogenic OH, and based on their neurological examination were diagnosed with Parkinson disease, dementia with Lewy bodies, pure autonomic failure or multiple system atrophy. The remaining 24 patients had preserved sympathetic activation and their OH was classified as non-neurogenic, due to volume depletion, anemia or polypharmacy. Patients with neurogenic OH had twice the fall in systolic blood pressure (SBP) [-44±25 vs. -21±14 mmHg (mean±SD), p<0.0001] but only one third of the increase in HR than those with non-neurogenic OH (8±8 vs. 25±11 bpm, p<0.0001). A ΔHR/ΔSBP ratio of 0.492 bpm/mmHg had excellent sensitivity (91.3%) and specificity (88.4%) to distinguish between patients with neurogenic vs. non-neurogenic OH (AUC=0.96, p<0.0001). Within patients with neurogenic OH, HR increased more in those with multiple system atrophy (p=0.0003), but there was considerable overlap with patients with Lewy body disorders. INTERPRETATION/CONCLUSIONS:A blunted HR increase during hypotension suggests a neurogenic cause. A ΔHR/ΔSBP ratio lower than 0.5 bpm/mmHg is diagnostic of neurogenic OH.

Objective: The Movement Disorder Society (MDS)-endorsed MSA study group (MODIMSA) identified a need to develop a systematic review on diagnostic tests in patients with multiple system atrophy (MSA). Background: The diagnosis of MSA is a primarily clinical exercise, despite development of numerous ancillary tests that differ in their diagnostic performance, availability and costs. Design/methods: We systematically reviewed original reports published before December 2016 with at least 10 MSA subjects per study defined by post-mortem verification, clinically probable, or clinically probable plus possible MSA according to consensus criteria and at least one reference group of diseased subjects. Results: A total of 363 relevant citations on diagnostic tests in MSA were critically analyzed. Cardiovascular autonomic tests and bladder ultrasonography contribute to the diagnosis of autonomic failure. None of the fluid biomarkers is sufficiently robust for the diagnosis of MSA, since most of the assays are not standardized and commercially available for wider testing. CoQ2 mutation testing is recommended in familial Japanese MSA-cerebellar cases. Screening for MSA mimic genes should be considered to refine clinical diagnosis. Visual interpretation of conventional MRI by experts, quantitative assessment of regional cerebral atrophy, diffusion imaging, iron sensitive sequences and automated techniques for quantitative MRI analysis are useful, but diagnostic accuracy of different MRI abnormalities across the studies is highly variable. [18F]FDG-PET, [123I]IBZM-SPECT, cardiac [123I]MIBG-SPECT and certain neuropsychological tests may also aid, but are not sufficient for the diagnosis of MSA. Reported data regarding neuroendocrine tests, external sphincter electromyography, transcranial parenchymal sonography, video polysomnography, levodopa challenge test, olfactory testing and skin and enteric biopsy are inconsistent. Conclusion: Based on this comprehensive literature review, several investigative measures may assist in the diagnostic work-up of patients with suspected MSA. The best current guidelines for MSA diagnosis are still clinical phenotype and inexorable progression

Objective: We investigated whether activation of afferent and central baroreceptor pathways could differentiate between Lewy body disorders and MSA. Background: Clinical distinction between multiple system atrophy (MSA) and Lewy body disorders with motor involvement (Parkinson disease [PD] and dementia with Lewy bodies [DLB]) is sometimes challenging. Methods: Cross-sectional study including 35 patients with probable or possible MSA and 24 patients with Lewy body disorders (20 with PD and 4 with DLB). All subjects had neurogenic orthostatic hypotension. Subjects underwent complete autonomic testing with measurement of plasma levels of catecholamines and vasopressin after 10-min in the resting supine position and after 10-min of passive head-up tilt. Results: Thirty-five patients with probable MSA (22 MSA-C, 13 MSA-P) and 24 patients with Lewy body disorders (20 with PD, 4 with DLB) were included. All patients had documented neurogenic orthostatic hypotension. In patients with PD and DLB upright tilt induced marked hypotension and a significant increase in plasma vasopressin (from 0.82 +/- 0.77 to 4.85 +/- 13.9 pmol/l in PD (p = 0.0027); from 1.18 +/- 0.81 to 5.1 +/- 3.76 pmol/l in DLB (p = 0.11). In patients with MSA, upright tilt also elicited profound hypotension but circulating levels of vasopressin did not increase significantly (from 0.51 +/- 0.08 to 0.70 +/- 0.71 pmol/l, p = 0.092). Plasma norepinephrine did not increase significantly on head-up tilt in any of the subjects. A plasma vasopressin concentration during upright tilt of<=0.8 pmol/l in a patient with neurogenic orthostatic hypotension had a sensitivity of 91%, a specificity of 64%, and a negative predictive value of 83.3% for a diagnosis of MSA. Conclusions: Our results indicate that afferent and central baroreceptor pathways involved in vasopressin release are preserved in Lewy body disorders but impaired in MSA. Thus a patient with a vasopressin when standing of[0.8 pg/ml makes a diagnosis of MSA unlikely

Background: Depressive symptoms are common in patients with multiple system atrophy (MSA). We aimed to determine the prevalence of depression in MSA and its impact on quality of life and disease progression. Methods: MSA patients enrolled in a natural history study to determine the natural progression of disease. Patients completed psychiatric (Zung Depression scale, Spielberg's anxiety scale and Body vigilance scale) and autonomic (OHQ, COMPASS, UMSARS-I and II, SCOPA-Autonomic and SF36 Quality of life scale) rating scales, and underwent autonomic and cardiovascular assessments at baseline, and then followed at regular intervals for repeat assessments. Results: Forty-five MSA patients (mean age 61.8 years, 4.3 years disease duration) were included. Thirty patients (67%) scored as having depression on the Zung depression scale (15 mild, 13 moderate, and 2 severe). Seventy-three percent had orthostatic hypotension (OH). Depressed patients had higher trait/state anxiety and body vigilance scores than non-depressed patients. Depressed patients had significantly higher OHQ scores on each of the 6 OHSA items and each of the OHDAS items (OH interference with activities of standing and walking). Trait-anxiety and depression correlated with OHSA and OHDAS items. Depressed patients reported greater OHQ scores for the same amount of blood pressure change than nondepressed. Linear regression showed significant effect of depression on progression of UMSARS-II scores. Depression correlated with orthostatic and urinary function symptoms on the COMPASS scale. Conclusion: Depression is common in MSA and is associated with faster disease progression and higher burden of autonomic symptoms. Recognizing and treating depression may improve quality of life and ameliorate symptoms

Objective: To evaluate the efficacy of droxidopa on symptoms of neurogenic orthostatic hypotension (nOH) and activities of daily living using the Orthostatic Hypotension Questionnaire (OHQ) in patients with multiple system atrophy (MSA). Background: Droxidopa is an oral prodrug of norepinephrine with demonstrated efficacy in patients with primary autonomic failure (pure autonomic failure, MSA, and Parkinson disease) who have nOH. Design/Methods: We conducted a subset analysis of data from three droxidopa (Studies NOH301, NOH302, NOH303) clinical trials which enrolled over 400 patients with primary autonomic failure, including 95 patients with MSA, 56 of which were randomized into double-blind treatment periods of the studies. Changes in symptoms of nOH and in symptom impact on activities of daily living were measured via the OHQ. Safety was measured via the incidence and severity of adverse events. Results: There were statistically significant (P<=0.05) improvements in OHQ composite score after droxidopa treatment versus placebo in the combined analysis of Studies NOH301 and NOH302, although the total number of MSA patients was relatively small. Patients treated with droxidopa demonstrated numerically greater improvements than placebo-treated patients in nine of ten OHQ items. Standing systolic blood pressure improved with droxidopa treatment. Data suggests that 4-6 weeks of treatment may be required to reach full symptomatic benefit with the drug. Importantly, despite the progressive nature of MSA, the symptomatic and blood pressure benefits were maintained through 3 months of open label extension treatment. Droxidopa was well tolerated and safe in MSA patients and the overall population. Conclusions: Droxidopa was shown in this post hoc, subset analysis to be a useful therapy for the treatment and management of nOH in MSA patients, providing symptomatic relief associated with improvement in standing blood pressure and an excellent safety profile

Objectives: To report the preliminary results of the GLOMSAR survey for MSA. Background: Multiple system atrophy (MSA) is a rare fatal synucleinopathy characterized by Parkinsonian, pyramidal, cerebellar, and autonomic features in any combination. The GLObal MSA Registry (GLOMSAR) was established as an online contact registry for patients with MSA. Methods: Members of the Autonomic Disorders Consortium developed a web-based questionnaire comprising of 40-item with yes/no questions to evaluate the chronology and full spectrum of symptoms of MSA. GLOMSAR registrants were contacted by email on April 26 2017 and the survey was administered by the NIH's Rare Diseases Clinical Research Network (RDCRN). Results: Within 7 days, 155 registrants with MSA completed all 40 questions. Mean age was 62 years (range 30-92) and 58% were male. Frequent presenting symptoms were difficultly moving (28%), trouble with blood pressure or urination (23%), REM sleep behavior disorder (i.e., dream reenactment 23%) and falls (14%). Sixty-eight percent had been treated with levodopa and 30% experienced some benefit from it. Fifty-five percent reported using a wheelchair. Urinary incontinence was present in 65 and 30% required intermittent or indwelling urinary catheterization. Constipation occurred in 78%. Visual problems were reported in 65%. Of men, 91% reported erectile dysfunction; of women, 65% reported decreased genital sensation. Other findings included a high prevalence of depression (59%), hallucinations (21%) and a history of head trauma/concussion (22%). Conclusion: The GLOMSAR contact registry and web-based MSA survey are feasible ways to reach patients with MSA. This may be useful to support clinical research in this rare disease