Faculty Bibliography

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.

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

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

Objectives: (1) To determine if measuring alpha-synuclein in exosomes from neurons and oligodendrocytes can distinguish between healthy controls and patients with Parkinson disease (PD) or multiple system atrophy (MSA). (2) To test whether analyzing alpha-synuclein in neuronal and oligodendroglial exosomes can distinguish between PD and MSA. Background: Developing reliable biomarkers that can distinguish among synucleinopathies is an urgent public health need. In particular PD and atypical Parkinsonian disorders are often misdiagnosed at early stages. Exosomes are nano-sized vesicles shed by most cells, which carry biomolecules of the parent cell and provide a rich source of biomarkers. Recently, alpha-synuclein was shown to transfer via exosomes suggesting that measuring alpha-synuclein in brain-derived exosomes could serve as a biomarker for synucleinopathies. Methods: Neuronal and oligodendroglial exosomes were isolated from serum of 50 healthy individuals, 50 patients with PD, and 24 patients with MSA. a-Synuclein concentration was measured using electrochemiluminescence ELISA. Results: Significantly higher concentrations of alpha-synuclein were found in both neuronal and oligodendroglial exosomes from patients than in controls. a-Synuclein in oligodendroglial exosomes distinguished patients with MSA from healthy controls with 100.0% sensitivity and 96% specificity. The absolute values of alpha-synuclein in neuronal and oligodendroglial exosomes provided moderate separation between the PD and MSA groups, yet the individual ratio between the two cell types allowed separating the two disease groups with 91.7% sensitivity and 86.0% specificity. Conclusion: a-Synuclein in brain-derived blood exosomes provides a sensitive biomarker for distinguishing patients with MSA from healthy controls and from patients with PD using a simple blood test

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 define which factors predict the pressor response to droxidopa in patients with neurogenic orthostatic hypotension (nOH). Background: Droxidopa, a synthetic norepinephrine precursor, was recently approved to treat symptomatic nOH. The pressor response is variable with some patients responding to doses of 100 mg while others requiring up to 600 mg three times/day. It is not known which factors predict the magnitude of the pressor response to droxidopa. Methods: We prospectively evaluated the BP response to increasing doses of droxidopa in patients with nOH in an outpatient setting. BP supine and after 3-min standing was measured before and 1-h after oral administration of 100 mg of droxidopa. Droxidopa was progressively increased until (1) complete relief of symptoms, (2) supine systolic BP[180 mmHg, (3) occurrence of side effects, or (4) the maximum dose of 600 mg was reached. Results: Sixteen subjects with nOH (6 with Parkinson disease, 5 with pure autonomic failure-PAF-, 3 with autoimmune autonomic ganglionopathy-AAG-, and 2 with multiple system atrophy) were evaluated. Mean BP was 126 +/- 28/72 +/- 11 mmHg supine, and 89 +/- 19/53 +/- 15 mmHg after 3-min standing (fall of 37/18 mmHg). Mean plasma norepinephrine while supine was 192 +/- 216 pg/ml. Maximum droxidopa dose during the titration was 212 +/- 102 mg (range 100-400 mg). Droxidopa increased BP to an average of 148 +/- 53/90 +/- 13 mmHg supine and 135 +/- 38/66 +/- 16 mmHg after 3-min standing (p<=0.001). Plasma norepinephrine levels were inversely correlated with higher systolic BP after-3 min standing following droxidopa treatment (R2 = 0.42; p = 0.023). Four patients (3 with AAG and 1 with PAF) with very low plasma norepinephrine levels (<=90 pg/ml) experienced transient nausea, vomiting, and abdominal pain during titration with dosages of 200 mg. In these patients, treatment with 100 mg/day was effective and well tolerated. Diagnostic categories did not predict response to droxidopa. Conclusions: In patients with nOH, lower plasma norepinephrine levels are associated with a greater pressor response to droxidopa. This response is probably related to the degree of denervation supersensitivity. Supine norepinephrine levels may be useful to predict appropriate dosing of droxidopa in the clinical setting

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.

Introduction: Patients with pure autonomic failure (PAF) typically present with symptoms of sympathetic insufficiency, with anhidrosis frequently reported. We here report an unusual patient with PAF who presented with cold-induced sweating. Methods: Case report. Results: A 73-year-old man had a 5-year history of frequent lightheadedness, dizziness and syncope on standing. He also had erectile dysfunction, nocturia, constipation, and dream reenactment. He also reported a significant increase in sweating in his torso, back, and both arms (particularly the left) induced by cold temperatures. Autonomic testing showed a supine hypertension (193/105 mmHg) with resting bradycardia (50 bpm). Blood pressure overshoot after release of the Valsalva strain was absent, indicating impaired baroreflex-mediated sympathetic activation. After 14-min of head-up tilt his blood pressure had dropped to 124/83 mmHg with a blunted increase in heart rate to 73 bpm. His norepinephrine levels failed to increase appropriately upon head-up tilt (supine 376 pg/mL; tilted 404 pg/mL), indicating a neurogenic cause for his orthostatic hypotension. Electrochemical skin conductance was reduced in palms and soles. An iodine-starch test was performed with a room temperature of 90degreeF and repeated after the temperature was decreased to 78degreeF. When the ambient temperature was reduced, the starch powder turned dark purple, more intensely in the left side, indicating the release of sweat. Conclusion: Cold-induced sweating can be a manifestation of autonomic failure. Possible mechanisms include cold-induced sudomotor supersensitivity triggered by the remaining fibers innervating the sweat glands

Background: Symptoms of psychosis, including hallucinations and delusions, are relatively frequent in Parkinson disease and Lewy body dementia, particularly in patients receiving levodopa and dopamin-ergic agonists. However, the prevalence of psychosis in multiple system atrophy (MSA) is unknown. We aimed to determine the prevalence and characteristics of psychotic symptoms in patients with MSA, and factors associated with their development. Methods: Consecutive patients with probable MSA without previous history of psychiatric disorders were prospectively enrolled in a longitudinal observational study. The presence of hallucinations and delusions was determined during a standardized clinical interview and quantified with the Scale for the Assessment of Positive Symptoms in Parkinson disease (SAPS-PD). Patients also underwent full evaluation of visual acuity, cognition (Montreal Cognitive Assessment, MoCA), motor function and disease severity [United Multiple System Atrophy Rating Scale (UMSARS)]. Results: Of the 31 consecutive patients with probable MSA (17 men; mean age 64 +/- 8 years; 13 MSA-P and 14 MSA-C), 6 (19%) had positive symptoms of psychosis including delusions and/or hallucinations. All but one patient had the cerebellar phenotype of the disease (MSA-C). Auditory hallucinations occurred in 4 patients, visual hallucinations in 4, persecutory delusions in 3, and jealousy delusions in 3. No patients reported somatic or tactile hallucinations. Psychosis symptoms were extremely severe and refractory to treatment in 2 cases with MSA-C, both of whom died within 12 months of psychosis onset. Psychotic symptoms were not associated with levodopa or other antiparkinsonian medication treatment, visual acuity, cognitive score, depression score, or duration of illness. Conclusions: Psychotic symptoms occur in *20% of patients with MSA, the vast majority of whom have MSA-C. Severe refractory psychotic symptoms appear to be associated with poor prognosis (death < 1 year). Our results suggest that psychotic symptoms in MSA are unrelated to visual system abnormalities