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

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.

Neurogenic orthostatic hypotension (nOH) is common in patients with neurodegenerative disorders such as Parkinson's disease, multiple system atrophy, pure autonomic failure, dementia with Lewy bodies, and peripheral neuropathies including amyloid or diabetic neuropathy. Due to the frequency of nOH in the aging population, clinicians need to be well informed about its diagnosis and management. To date, studies of nOH have used different outcome measures and various methods of diagnosis, thereby preventing the generation of evidence-based guidelines to direct clinicians towards 'best practices' when treating patients with nOH and associated supine hypertension. To address these issues, the American Autonomic Society and the National Parkinson Foundation initiated a project to develop a statement of recommendations beginning with a consensus panel meeting in Boston on November 7, 2015, with continued communications and contributions to the recommendations through October of 2016. This paper summarizes the panel members' discussions held during the initial meeting along with continued deliberations among the panel members and provides essential recommendations based upon best available evidence as well as expert opinion for the (1) screening, (2) diagnosis, (3) treatment of nOH, and (4) diagnosis and treatment of associated supine hypertension.

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.

Familial dysautonomia is an inherited autonomic disorder with afferent baroreflex failure. We questioned why despite low blood pressure standing, surprisingly few familial dysautonomia patients complain of symptomatic hypotension or have syncope. Using transcranial Doppler ultrasonography of the middle cerebral artery, we measured flow velocity (mean, peak systolic, and diastolic), area under the curve, pulsatility index, and height of the dictrotic notch in 25 patients with familial dysautonomia and 15 controls. In patients, changing from sitting to a standing position, decreased BP from 124 +/- 4/64 +/- 3 to 82 +/- 3/37 +/- 2 mmHg (p < 0.0001, for both). Despite low BP, all patients denied orthostatic symptoms. Middle cerebral artery velocity fell minimally, and the magnitude of the reductions were similar to those observed in healthy controls, in whom BP upright did not fall. While standing, patients had a greater fall in cerebrovascular resistance (p < 0.0001), an increase in pulsatility (p < 0.0001), and a deepening of the dicrotic notch (p = 0.0010), findings all consistent with low cerebrovascular resistance. No significant changes occurred in controls. Patients born with baroreflex deafferentation retain the ability to buffer wide fluctuations in BP and auto-regulate cerebral blood flow. This explains how they can tolerate extremely low BPs standing that would otherwise induce syncope.