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.

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.

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

BACKGROUND:Chronic lung disease is a leading cause of premature death in patients with familial dysautonomia (FD). A significant number of patients have obstructive airway disease, yet it is not known whether this is pharmacologically reversible. METHODS:We conducted a double-blind, placebo-controlled, randomized clinical trial comparing the beta 2 agonist albuterol with the muscarinic blocker ipratropium bromide in patients homozygous for the IKBKAP founder mutation. Albuterol, ipratropium bromide, and placebo were administered on 3 separate days via nebulizer in the seated position. Airway responsiveness was evaluated using spirometry and impulse oscillometry 30 min post dose. Cardiovascular effects were evaluated by continuous monitoring of blood pressure, RR intervals, cardiac output, and systemic vascular resistance. RESULTS:A total of 14 patients completed the trial. Neither active agent had significant detrimental effects on heart rate or rhythm or blood pressure. Albuterol and ipratropium were similar in their bronchodilator effectiveness causing significant improvement in forced expiratory volume in 1-s (FEV1, p = 0.002 and p = 0.030). Impulse oscillometry measures were consistent with a reduction in total airway resistance post nebulization (resistance at 5 Hz p < 0.006). CONCLUSION/CONCLUSIONS:Airway obstruction is pharmacologically reversible in a number of patients with FD. In the short term, both albuterol and ipratropium were well tolerated and not associated with major cardiovascular adverse events.

Objective: The Multiple System Atrophy (MSA) Criteria Revision Steering Group identified the weaknesses of current set of diagnostic criteria for MSA and discussed a need for its revision. Background: Typically MSA is diagnosed half way through its clinical disease course. However, early diagnosis is critical if any diseasemodifying treatment is to be applied. Methods: The Steering Group includes investigators experienced in Parkinsonian, cerebellar, autonomic, neuroimaging, sleep, genetic and postmortem aspects of MSA. Shortcomings of the current diagnostic criteria for MSA were addressed through the personal communication. Results: The first criteria for MSA diagnosis were published in 1989, the first Consensus Criteria in 1998, and the second Consensus Criteria in 2008. A study of "red flags" was also published in 2008 but the results not incorporated into the criteria. In a recent large autopsy study by Koga et al., 2015 38% of cases diagnosed in life with MSA did not have it, the largest misdiagnosed group having dementia with Lewy bodies. In a study examining validity of Consensus Criteria (Osaki et al., 2009), sensitivity for MSA diagnosis was 41% for possible and 18% for probable at first visit, whereas at last visit these figures were 92 and 63% respectively. There is clearly a need for improved sensitivity and specificity of diagnosis of MSA, especially at its earliest stages. Conclusions: It is time in 2018 to revisit and revise the Consensus Criteria for the diagnosis of MSA

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: 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

OBJECTIVE:To assess vestibular function in patients with familial dysautonomia (FD), a hereditary sensory and autonomic neuropathy - caused by a mutation in the IKBKAP gene (c.2204 + 6 T>C) - and characterized by marked gait ataxia. METHODS:Cervical and vestibular evoked myogenic potentials (cVEMPs and oVEMPs) were recorded from the sternocleidomastoid (SCM) and extraocular muscles in 14 homozygous patients, 2 heterozygous patients, and 15 healthy controls during percussion of the forehead. RESULTS:cVEMP and oVEMP amplitudes were significantly lower, and peak latencies significantly delayed, in the FD patients. There were no differences in overall EMG during attempted maximal voluntary contractions of the SCM muscle, suggesting intact efferent function. The two heterozygotes with a minor haplotype missense (R696P) mutation in exon 19 of the IKBKAP gene had cVEMP responses less affected than the homozygous. CONCLUSIONS:The founder mutation in the IKBKAP gene affects the development of vestibular afferent pathways, leading to attenuated cVEMPs. SIGNIFICANCE/CONCLUSIONS:Vestibular abnormalities may contribute to the gait ataxia in FD.