Faculty Bibliography

Multiple system atrophy (MSA) is a neurodegenerative disorder characterized by a combination of autonomic failure, cerebellar ataxia, and parkinsonism. Laryngeal stridor is an additional feature for MSA diagnosis, showing a high diagnostic positive predictive value, and its early occurrence might contribute to shorten survival. A consensus definition of stridor in MSA is lacking, and disagreement persists about its diagnosis, prognosis, and treatment. An International Consensus Conference among experts with methodological support was convened in Bologna in 2017 to define stridor in MSA and to reach consensus statements for the diagnosis, prognosis, and treatment. Stridor was defined as a strained, high-pitched, harsh respiratory sound, mainly inspiratory, occurring only during sleep or during both sleep and wakefulness, and caused by laryngeal dysfunction leading to narrowing of the rima glottidis. According to the consensus, stridor may be recognized clinically by the physician if present at the time of examination, with the help of a witness, or by listening to an audio recording. Laryngoscopy is suggested to exclude mechanical lesions or functional vocal cord abnormalities related to different neurologic conditions. If the suspicion of stridor needs confirmation, drug-induced sleep endoscopy or video polysomnography may be useful. The impact of stridor on survival and quality of life remains uncertain. Continuous positive airway pressure and tracheostomy are both suggested as symptomatic treatment of stridor, but whether they improve survival is uncertain. Several research gaps emerged involving diagnosis, prognosis, and treatment. Unmet needs for research were identified.

INTRODUCTION: Familial dysautonomia (FD) is a progressive neurogenetic disease with carrier rate as high as 1 in 18 persons in European Jews of Polish origin. Clinical hallmarks include cardiovascular instability, spinal deformities, renal dysfunction, alacrima, ataxia, and impaired nociception. Physical or emotional stress may elicit autonomic crises characterized by hypertension and vomiting. Despite profound sensory deficits, GI perturbations are frequently reported by FD patients. While the incidence of inflammatory bowel disease (IBD) and FD is unknown, concurrence is underreported given increased frequency of both diseases in Ashkenazi Jews. CASE DESCRIPTION/METHODS: We report a 33-year-old female with FD and ulcerative colitis who presented with one week of abdominal pain and bloody diarrhea. She had been maintained on balsalazide. Colonoscopy one year prior revealed endoscopic and histologic remission. On physical examination, her abdomen was tender in the lower quadrants. A CT scan revealed pancolitis. Stool studies resulted negative. Her CRP was 58.4 mg/L and albumin was 2.4 g/dL. A flexible sigmoidoscopy noted Mayo endoscopic score 3 in the rectum and CMV staining was negative. The patient was started on IV steroids. Her hospital course was complicated by ileus, parainfluenza infection, and MSSA bacteremia with a pacemaker lead vegetation, requiring extraction. Lack of optimal clinical response to treatment on hospital day five led to consideration of alternative treatments with careful attention to her underlying FD. A subtotal colectomy with end ileostomy was unfavorable due to concern for volume loss. Infliximab and cyclosporine were opposed due to infection risk and later exhibiting possible nephrotoxicity. During this discussion the patient improved enough to be transitioned to oral steroids with a plan to initiate vedolizumab as an outpatient. On recent colonoscopy she had achieved mucosal healing. DISCUSSION: This is the first case of UC in a FD patient reported. Given myriad GI symptoms in the later diagnosis it can be hard to distinguish disease-related from treatment-related events. Due to the gut-specificity of vedolizumab, infection risk is considerably reduced compared to that of other biologics and is the most favorable option in the setting of underlying FD. This case highlights the difficulty encountered when treating IBD in the setting of systemic illness and underscores the need to carefully consider management options to enhance patient outcomes. (Figure Presented)

PURPOSE/OBJECTIVE:Neurogenic orthostatic hypotension is a prominent and disabling manifestation of autonomic dysfunction in patients with hereditary transthyretin (TTR) amyloidosis affecting an estimated 40-60% of patients, and reducing their quality of life. We reviewed the epidemiology and pathophysiology of neurogenic orthostatic hypotension in patients with hereditary TTR amyloidosis, summarize non-pharmacologic and pharmacological treatment strategies and discuss the impact of novel disease-modifying treatments such as transthyretin stabilizers (diflunisal, tafamidis) and RNA interference agents (patisiran, inotersen). METHODS:Literature review. RESULTS:Orthostatic hypotension in patients with hereditary transthyretin amyloidosis can be a consequence of heart failure due to amyloid cardiomyopathy or volume depletion due to diarrhea or drug effects. When none of these circumstances are apparent, orthostatic hypotension is usually neurogenic, i.e., caused by impaired norepinephrine release from sympathetic postganglionic neurons, because of neuronal amyloid fibril deposition. CONCLUSIONS:), a synthetic norepinephrine precursor, has shown efficacy in controlled trials of neurogenic orthostatic hypotension in patients with hereditary TTR amyloidosis and is now approved in the US and Asia. Although they may be useful to ameliorate autonomic dysfunction in hereditary TTR amyloidosis, the impact of disease-modifying treatments on neurogenic orthostatic hypotension is still uninvestigated.

PURPOSE/OBJECTIVE:To assess the urodynamic findings in patients with Parkinson disease (PD) with overactive bladder symptoms. METHODS:We performed a retrospective chart review of all PD patients who were seen in an outpatient clinic for lower urinary tract symptoms (LUTS) between 2010 and 2017 in a single-institution. Only patients who complained of overactive bladder (OAB) symptoms and underwent a video-urodynamic study for these symptoms were included. We excluded patients with neurological disorders other than PD and patients with voiding LUTS but without OAB symptoms. RESULTS:We included 42 patients (29 men, 13 women, 74.5±8.1 years old). Seven patients (16.7%) had a postvoid residual (PVR) bladder volume >100 mL and only one reported incomplete bladder emptying. Detrusor overactivity (DO) was found in all 42 patients (100%) and was terminal in 19 (45.2%) and phasic in 22 patients (52.4%). Eighteen patients had detrusor underactivity (DU) (42.3%). Later age of PD diagnosis was the only parameter associated with DU (P=0.02). Patients with bladder outlet obstruction (BOO) were younger than patients without BOO (70.1 years vs. 76.5 years, P=0.004), had later first sensation of bladder filling (173.5 mL vs. 120.3 mL, P=0.02) and first involuntary detrusor contraction (226.4 mL vs. 130.4 mL, P=0.009). CONCLUSION/CONCLUSIONS:DO is almost universal in all patients with PD complaining of OAB symptoms (97.1%). However, a significant percentage of patients also had BOO (36.8%), DU (47%), and increased PVR (16.7%) indicating that neurogenic DO may not be the only cause of OAB symptoms in PD patients.

: Supine hypertension commonly occurs in patients with neurogenic orthostatic hypotension due to autonomic failure. Supine hypertension promotes nocturnal sodium excretion and orthostatic hypotension, thus, interfering with quality of life. Perusal of the literature on essential hypertension and smaller scale investigations in autonomic failure patients also suggest that supine hypertension may predispose to cardiovascular and renal disease. These reasons provide a rationale for treating supine hypertension. Yet, treatment of supine hypertension, be it through nonpharmacological or pharmacological approaches, may exacerbate orthostatic hypotension when patients get up during the night. Fall-related complications may occur. More research is needed to define the magnitude of the deleterious effects of supine hypertension on cardiovascular, cerebrovascular, and renal morbidity and mortality. Integration of more precise cardiovascular risk assessment, efficacy, and safety data, and the prognosis of the underlying condition causing autonomic failure is required for individualized management recommendations.

PURPOSE/OBJECTIVE:Familial dysautonomia (FD) is a rare autosomal recessive disease that affects the development of sensory and autonomic neurons, including those in the cranial nerves. We aimed to determine whether conventional brain magnetic resonance imaging (MRI) could detect morphologic changes in the trigeminal nerves of these patients. METHODS:Cross-sectional analysis of brain MRI of patients with genetically confirmed FD and age- and sex-matched controls. High-resolution 3D gradient-echo T1-weighted sequences were used to obtain measurements of the cisternal segment of the trigeminal nerves. Measurements were obtained using a two-reader consensus. RESULTS:in controls (P < 0.001). No association between trigeminal nerve area and age was found in patients or controls. CONCLUSIONS:Using conventional MRI, the caliber of the trigeminal nerves was significantly reduced bilaterally in patients with FD compared to controls, a finding that appears to be highly characteristic of this disorder. The lack of correlation between age and trigeminal nerve size supports arrested neuronal development rather than progressive atrophy.