Faculty Bibliography

He who studies medicine without books sails an uncharted sea, but he who studies medicine without patients does not go to sea at all." (William Osler, Canadian physician 1849-1919) David H. Streeten was a master clinician with an astute eye for observation. His work was never far from the bedside describing patient's signs and symptoms in exquisite detail. I also never wandered far from the bedside. My favorite tools have always been a reflex hammer, an EKG and a Finapres. At their core, neurologists are observers and listeners, they love to watch and recognize human phenomenology. Thinking about the diseases I studied I realize that my interest for each of them was sparked by the encounter with an affected patient that made a big impression. They were 5 particular patients that I remember vividly. Each of them taught me something I did not know, kept me awake many nights and shaped my career. I will tell you some of their stories at the 2017's Streeten Memorial Lecture at the American Autonomic Society

Background: Allgrove syndrome (triple A syndrome) is a rare autosomal recessive disorder first described by endocrinologist Jeremy Allgrove in 1978 in two siblings with adrenal insufficiency, achalasia, and alacrima. Onset is usually within the first decade of life. Other features include adrenocorticotropic hormone (ACTH) unresponsiveness, and varying degrees of neurologic dysfunction. In 2002, mutations in the AAAS gene located on chromosome 12q13, which encodes for the nuclear pore protein ALADIN, were reported as the cause of the disease. The autonomic features of the disorder remain poorly understood with only ~ 100 cases in the literature, most of which were described before the availability of genetic testing. Methods: Case series of 2 patients with genetically confirmed Allgrove syndrome. Results: Case # 1: 9-year-old girl of East Indian descent presented with alacrima since birth. At age 6, she developed adrenal insufficiency manifesting as hyperpigmentation and fatigue. Genetic testing confirmed she was homozygous for the pathogenic variant c.1432C>T p.Arg478Ter. The patient had no achalasia and neurological exam was normal. Cardiovascular autonomic testing was normal. Case # 2: 39-year-old Hispanic woman presented with alacrima, achalasia, ACTH resistance, and sensorimotor polyneuropathy at the age of 13 years. Autonomic testing revealed adrenergic impairment with orthostatic hypotension together with cholinergic dysfunction and decreased heart rate variability. Genetic testing confirmed two heterozygous mutations: 1) Heterozygous Exon 6, R155P, base 464 CGT to CCT; 2) Heterozygous IVSC14 + 1G to A. Mutation 1 had not been previously reported. Conclusions: Allgrove syndrome is a rare pediatric-onset disorder with variable presentation. Neurological signs (autonomic dysfunction, hyperreflexia, dysarthria, ataxia, sensory impairment, weakness, cognitive deficits) and ACTH resistance may only manifest after many years or decades. As the number of genetically confirmed cases grows, there is a need to understand the autonomic phenotype, which should perhaps be considered the 4th A

Cardiovascular autonomic dysfunctions, including neurogenic orthostatic hypotension, supine hypertension and post-prandial hypotension, are relatively common in patients with Parkinson disease. Recent evidence suggests that early autonomic impairment such as cardiac autonomic denervation and even neurogenic orthostatic hypotension occur prior to the appearance of the typical motor deficits associated with the disease. When neurogenic orthostatic hypotension develops, patients with Parkinson disease have an increased risk of mortality, falls, and trauma-related to falls. Neurogenic orthostatic hypotension reduces quality of life and contributes to cognitive decline and physical deconditioning. The co-existence of supine hypertension complicates the treatment of neurogenic orthostatic hypotension because it involves the use of drugs with opposing effects. Furthermore, treatment of neurogenic orthostatic hypotension is challenging because of few therapeutic options; in the past 20 years, the US Food and Drug Administration approved only two drugs for the treatment of this condition. Small, open-label or randomized studies using acute doses of different pharmacologic probes suggest benefit of other drugs as well, which could be used in individual patients under close monitoring. This review describes the pathophysiology of neurogenic orthostatic hypotension and supine hypertension in Parkinson disease. We discuss the mode of action and therapeutic efficacy of different pharmacologic agents used in the treatment of patients with cardiovascular autonomic failure.

BACKGROUND: Orthostatic hypotension (OH) is a sustained fall in blood pressure on standing which can cause symptoms of organ hypoperfusion. OH is associated with increased morbidity and mortality and leads to a significant number of hospital admissions particularly in the elderly (233 per 100,000 patients over 75 years of age in the US). OH can be due to volume depletion, blood loss, large varicose veins, medications, or due to defective activation of sympathetic nerves and reduced norepinephrine release upon standing (i.e., neurogenic OH). METHODS AND FINDINGS: Literature review. Neurogenic OH is a frequent and disabling problem in patients with synucleinopathies such as Parkinson disease, multiple system atrophy, and pure autonomic failure, and is commonly associated with supine hypertension. Several pharmacological and non-pharmacological therapeutic options are available. CONCLUSIONS: Here we review the epidemiology, diagnosis, and management of neurogenic OH, and provide an algorithm for its treatment emphasizing the importance of removing aggravating factors, implementing non-pharmacologic measures, and selecting appropriate pharmacological treatments.

PURPOSE: To report the use of intranasal dexmedetomidine, an alpha2-adrenergic agonist for the acute treatment of refractory adrenergic crisis in patients with familial dysautonomia. METHODS: Case series. RESULTS: Three patients with genetically confirmed familial dysautonomia (case 1: 20-year-old male; case 2: 43-year-old male; case 3: 26-year-old female) received intranasal dexmedetomidine 2 mcg/kg, half of the dose in each nostril, for the acute treatment of adrenergic crisis. Within 8-17 min of administering the intranasal dose, the adrenergic crisis symptoms abated, and blood pressure and heart rate returned to pre-crises values. Adrenergic crises eventually resumed, and all three patients required hospitalization for investigation of the cause of the crises. CONCLUSIONS: Intranasal dexmedetomidine is a feasible and safe acute treatment for adrenergic crisis in patients with familial dysautonomia. Further controlled studies are required to confirm the safety and efficacy in this population.

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