Faculty Bibliography

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

Background: Reduced pain and temperature sensation with varying degrees of autonomic dysfunction are characteristic features of patients with hereditary sensory and autonomic neuropathies (HSAN). At least seven HSAN phenotypes have been described for which 14 gene mutations have been identified. In many patients presenting with congenital sensory and autonomic deficits, however, traditional genetic testing is unable to detect genetic mutations. Objective: To identify novel genetic causes of congenital impaired sensation to pain with autonomic dysfunction with whole exome sequencing and evaluate genotype-phenotype correlations. Methods: We enrolled 10 patients with impaired or absent sensation to pain and temperature sensation with onset at birth without a previously identified molecular diagnosis from a HSAN gene panel. We performed detailed phenotypic assessment including presentation, autonomic testing, and comprehensive neurological and ophthalmo-logical examinations. Whole exome sequencing was performed in all patients as well as in, at least, one family member. Results: In 9 of 10 (90%) patients with congenital impaired pain sensation, we identified variants predicted to be pathogenic in NGF (n = 2, siblings), SMPDL3A (n = 2, siblings), SCN11A (n = 1), SCN10A (n = 1), SCN9A (n = 1), LIFR (n = 1), and TECPR2 (n = 1). Only in one patient, whole exome sequencing was not useful to identify potential pathogenic variants. Autonomic deficits included anhidrosis (SCN9A, NGF), hypohidrosis (TECPR2), hyperhidrosis (SCN11A, SCN10A, TECPR2, LIFR), alacrima or hypolacrima (SMPDL3A, TECPR2, LIFR), neurogenic dysphagia (TECPR2, SMPDL3A, SCN11A), gastroesophageal reflux (SCN11A), vomiting episodes (LIFR), and central sleep apnea (TECPR2). The subject with LIFR had episodes of hypertension, tachycardia, severe hyperhidrosis and hypernatremia. Sensorineural hearing loss was present in TECPR2 and one of the subjects with SMPDL3A. Conclusions: We characterize and expand the genetic landscape of HSAN, and demonstrate the feasibility of genetic diagnosis with clinically whole exome sequencing in 90% of our cohort

Background: The arterial baroreflex buffers blood pressure to prevent it from rising or falling excessively. Afferent baroreflex failure occurs in patients with genetic or acquired lesions of the afferent (sensory) baroreceptor nerves relaying information to the brain or within the central connections of the medulla. Patients with afferent baroreflex failure have extremely volatile high and quite low pressures. Review of the literature reveals that acquired forms of afferent baroreflex failure have never been described in children or young adults. Aim: To define the cause, clinical spectrum, and treatment of acquired baroreflex failure in children and young adults. Methods: We prospectively studied consecutive pediatric and young adult patients (<30 years old) who were diagnosed with afferent baroreflex failure. Each patient underwent a detailed clinical history, neurological examination, autonomic testing, plasma catecholamine measurements, and ambulatory blood pressure monitoring. Results: We identified 6 patients (3 males and 3 females; age range: 11-28 years old). All presented with severe, labile hypotension with syncope and hypertension often accompanied by headache, and flushing. Office blood pressure ranged from a maximum of 198/138 to 143/90 mmHg and a minimum of 70/40 to 102/68 mmHg. Plasma norepinephrine levels failed to increase appropriately during head-up. On ambulatory monitoring, 24-h systolic blood pressure standard deviation was markedly exaggerated (from 17.5 to 20.8 mmHg). In all cases, patients had excessive pressor and tachycardic responses to cognitive arousal (mental-arithmetic). The underlying causes of the afferent baroreflex failure included surgery and radiotherapy of head or neck cancer (n = 4), posterior reversible leukoencephalopathy (n = 1), and Moebius syndrome (n = 1). Conclusions: Acquired afferent baroreflex failure should be considered in children and young adults with otherwise unexplained labile hypertension, particularly in those with a history of head or neck cancer

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