Faculty Bibliography

Objective: The purpose of this study was to determine the predictors of the improvement in orthostatic symptoms with atomoxetine. Background: We previously reported that the norepinephrine transporter inhibitor, atomoxetine, improves upright blood pressure and pre-syncopal symptoms as measured by the orthostatic hypotension symptom assessment (OHSA) in patients with neurogenic orthostatic hypotension (nOH). Design/Methods: Our sample size consisted of 101 autonomic failure patients with nOH who participated in clinical trials (NCT00223691, NCT1316666) conducted in two national referral centers for autonomic disorders (Vanderbilt Autonomic Dysfunction Center and NYU Langone Medical Center Dysautonomia Center). The analyses was performed in patients with symptomatic nOH defined as item-1 OHSA (lightheadedness) equal or more than four points. Seated blood pressure was measured in three occasions before and 60 minutes after receiving 18 mg of atomoxetine. Standing blood pressure at 1, 3, 5 and 10 minutes and OHSA questionnaire was collected before and after the atomoxetine dose. Multiple linear regression was used to test for overall linear relations between the dependent variable (OHSA score after atomoxetine) and independent variables (baseline OHSA score, age, diagnosis, baseline supine norepinephrine levels) and to assess the significance of these relations after adjustments for each covariate. Results: 47 patients (47%) met criteria for symptomatic nOH. The average age at the time of evaluation was 67+/-9 years, 47 % were males. 55% were diagnosed as pure autonomic failure, 30% as multiple system atrophy, 11% as Parkinson disease and 4% were patients with nOH of unknown etiology. Adjusted R2 for this model was 0.3, only supine norepinephrine levels (P=0.047) accurately predicted orthostatic symptoms following atomoxetine after adjusting for baseline OHSA, age and specific diagnosis. Conclusions: Supine baseline norepinephrine levels predict the improvement in symptoms produced by atomoxetine in patients with symptomatic nOH

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 dosage required to elicit a pressor response is variable. It is unknown which factors predict the magnitude of the pressor response to droxidopa. Design/Methods: We prospectively evaluated the BP response to increasing doses of droxidopa in patients with nOH. BP supine and after 3-min standing was measured before and 1-hour after 100 mg of droxidopa orally. Dosage was progressively increased until i) complete relief of symptoms, ii) supine systolic BP >180 mmHg, iii) occurrence of side effects, or iv) a dose of 600mg 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 included. 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 supine was 192+/-216 pg/ml. Maximum droxidopa dose was 212+/-102 mg (range: 100-400 mg). Droxidopa increased BP to 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, 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. Diagnosis did not predict response to droxidopa. Conclusions: Lower plasma norepinephrine levels are associated with a greater pressor response to droxidopa in nOH. This response is probably related to the degree of denervation supersensitivity. Norepinephrine levels may be useful to predict appropriate dosing of droxidopa in the clinical setting

Objective: To determine if administration of a muscarinic agonist can stimulate the secretion of tears in patients with familial dysautonomia (FD). Background: FD is frequently referred to as a disease with no tears, but the underlying reason for this alacrima is unknown. Normally, nerves in the cornea stimulate the production of tears from lacrimal glands in the eye. Whether the absent/reduced tears in FD is due to denervation or an abnormality in the lacrimal glands themselves is unclear. Design/Methods: We applied pilocarpine (4%, a parasympathetic M3 receptor agonist), topically to the eyes of 16 patients with genetically confirmed FD to stimulate the tear secretion directly in the lacrimal glands bypassing the nerve pathways. We assessed corneal sensitivity using a Cochet-Bonnet esthesiometer. Tear volume was estimated with the Schirmer test (a scaled paper strip placed in the lower eyelid and the length of moisture measured after 5 minutes). Schirmer's test was performed four times: at baseline; 30-minutes after instillation of normal saline (placebo, 2 drops); at 30-minutes; and 3-hours after pilocarpine instillation (2 drops). Results: Basal tear secretion was 6.3 +/- 2.6 mm (mean +/- SD), and 6.9 +/- 3.0 mm 30 min after placebo (p=0.395). Thirty minutes after the instillation of piloparpine, tear volume more than doubled to 19.6 +/- 8.3 mm (p<0.001); and the increased tear production persisted at 3 hours (12.6 +/- 5.1 mm; p<0.001). There was a significant positive correlation between corneal sensitivity and tear secretion at baseline (p<0.0001; R2=0.74). Conclusions: Patients with FD have functional lacrimal glands, which can be stimulated with an M3 agonist to produce tears. Basal tear secretion was directly related to corneal sensitivity. The findings suggest for the first time that tear production in patients with FD can be restored pharmacologically

Objective: To describe three cases with acute autonomic and sensory neuropathy (AASN). Background: AASN is considered a very rare variant of immune-mediated acute peripheral neuropathy or ganglionopathy. Only a few cases have been documented in the literature so far. Design/Methods: Case series. Results: Three previously healthy subjects (11-year-old male; 11-year-old female; 37-year-old female), all of Asian ancestry, presented with acute and severe sensory and autonomic deficits shortly after a brief gastrointestinal or respiratory febrile illness. Autonomic disturbances included vomiting, diarrhea, anhidrosis, abdominal cramps, neurogenic pain, dry mouth and eyes, non-reactive mid-sized pupils, and dizziness upon standing and syncope. Sensory disorders included decreased perception for all sensory modalities with widespread patchy distribution and significant sensory ataxia. Impaired motor control with dysphagia was interpreted as reduced muscle power and prompted an early diagnosis of Guillain-Barre syndrome. Symptoms progressed for a few days and later stabilized. Neurological examination revealed very depressed or absent deep tendon, corneal, and gag reflexes with preserved muscle power. Corneal exam showed paracentral and inferior corneal opacities due to exposure keratopathy and dry eye. Nerve conduction studies showed extremely reduced or absent sensory nerve action potentials with normal motor nerve conduction and F waves. Cardiovascular autonomic evaluation showed decreased heart rate variability, orthostatic hypotension without compensatory tachycardia and very low or absent plasma norepinephrine levels. Spinal cord MRI showed extensive T2 hyperintensities of the posterior cords. Patient #1 had positive anti-sulfatide antibodies. One year after onset, recovery of sensory impairment was poor, and autonomic dysfunction was ameliorated with symptomatic treatment. Conclusions: This is the second largest case series ever reported of patients with AASN, an immune-mediated disorder mostly affecting Asian subjects. Patients are usually misdiagnosed, which delays the start of appropriate therapy

BACKGROUND: Multiple system atrophy (MSA) is a rare, adult-onset, rapidly progressive fatal synucleinopathy that primarily affects oligodendroglial cells in the brain. Patients with MSA only rarely have visual complaints, but recent studies of the retina using optical coherence tomography (OCT) showed atrophy of the peripapillary retinal nerve fiber layer (RNFL) and to a lesser extent the macular ganglion cell layer (GCL) complex. METHODS: We performed a literature review and meta-analysis according to the preferred reporting items for systematic reviews and meta-analyses guidelines for studies published before January 2017, identified through PubMed and Google Scholar databases, which reported OCT-related outcomes in patients with MSA and controls. A random-effects model was constructed. RESULTS: The meta-analysis search strategy yielded 15 articles of which 7 met the inclusion criteria. The pooled difference in the average thickness of the RNFL was -5.48 mum (95% CI, -6.23 to -4.73; p < 0.0001), indicating significant thinning in patients with MSA. The pooled results showed significant thinning in all the specific RNFL quadrants, except in the temporal RNFL quadrant, where the thickness in MSA and controls was similar [pooled difference of 1.11 microm (95% CI, -4.03 to 6.26; p = 0.67)]. This pattern of retinal damage suggests that MSA patients have preferential loss of retinal ganglion cells projecting to the magnocellular pathway (M-cells), which are mainly located in the peripheral retina and are not essential for visual acuity. Visual acuity, on the other hand, relies mostly on macular ganglion cells projecting to the parvocellular pathway (P-cells) through the temporal portion of the RNFL, which are relatively spared in MSA patients. CONCLUSION: The retinal damage in patients with MSA differs from that observed in patients with Parkinson disease (PD). Patients with MSA have more relative preservation of temporal sector of the RNFL and less severe atrophy of the macular GCL complex. We hypothesize that in patients with MSA there is predominant damage of large myelinated optic nerve axons like those originating from the M-cells. These large axons may require higher support from oligodendrocytes. Conversely, in patients with PD, P-cells might be more affected.

Study Objectives: Sudden unexpected death during sleep (SUDS) is the most common cause of death in patients with familial dysautonomia, an autosomal recessive disease characterized by sensory and autonomic dysfunction. It remains unknown what causes SUDS in these patients and who is at highest risk. We tested the hypothesis that SUDS in FD is linked to sleep-disordered breathing. Methods: We retrospectively identified patients with familial dysautonomia who died suddenly and unexpectedly during sleep and had undergone polysomnography within the 18-month period prior to death. For each case, we sampled one age-matched surviving subject with familial dysautonomia that had also undergone polysomnography within the 18-month period prior to study. Data on polysomnography, EKG, ambulatory blood pressure monitoring, arterial blood gases, blood count, and metabolic panel were analyzed. Results: Thirty-two deceased cases and 31 surviving controls were included. Autopsy was available in 6 cases. Compared with controls, subjects with SUDS were more likely to be receiving treatment with fludrocortisone (odds ratio; 95% confidence interval) (OR 29.7; 4.1-213.4), have untreated obstructive sleep apnea (OR 17.4; 1.5-193) and plasma potassium levels < 4 mEq/L (OR 19.5; 2.36-161), but less likely to use non-invasive ventilation at night (OR 0.19; 0.06-0.61). Conclusions: Initiation of non-invasive ventilation when required, and discontinuation of fludrocortisone treatment may reduce the high incidence rate of SUDS in patients with familial dysautonomia. Our findings contribute to the understanding of the link between autonomic, cardiovascular, and respiratory risk factors in sudden unexpected death during sleep.

BACKGROUND: Droxidopa, a prodrug of norepinephrine, was approved for treatment of neurogenic orthostatic hypotension (nOH) due to primary autonomic disorders based on 3 randomized double-blind studies. We performed safety and efficacy analyses of this pooled dataset (n = 460). METHODS: Efficacy was assessed using Orthostatic Hypotension Questionnaire (OHQ) scores (composite and individual items). Safety and tolerability were also examined. RESULTS: Droxidopa improved virtually all nOH symptom scores compared with placebo, significantly reducing OHQ composite score (-2.68 +/- 2.20 vs -1.82 +/- 2.34 units; P < 0.001), dizziness/lightheadedness score (-3.0 +/- 2.9 vs -1.8 +/- 3.1 units; P < 0.001), and 3 of 5 other symptom assessments (visual disturbances, weakness, and fatigue [P