Respiratory care in familial dysautonomia: Systematic review and expert consensus recommendations

Abstract

Background Familial dysautonomia (Riley-Day syndrome, hereditary sensory autonomic neuropathy type-III) is a rare genetic disease caused by impaired development of sensory and afferent autonomic nerves. As a consequence, patients develop neurogenic dysphagia with frequent aspiration, chronic lung disease, and chemoreflex failure leading to severe sleep disordered breathing. The purpose of these guidelines is to provide recommendations for the diagnosis and treatment of respiratory disorders in familial dysautonomia. Methods We performed a systematic review to summarize the evidence related to our questions. When evidence was not sufficient, we used data from the New York University Familial Dysautonomia Patient Registry, a database containing ongoing prospective comprehensive clinical data from 670 cases. The evidence was summarized and discussed by a multidisciplinary panel of experts. Evidence-based and expert recommendations were then formulated, written, and graded using the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) system. Results Recommendations were formulated for or against specific diagnostic tests and clinical interventions. Diagnostic tests reviewed included radiological evaluation, dysphagia evaluation, gastroesophageal evaluation, bronchoscopy and bronchoalveolar lavage, pulmonary function tests, laryngoscopy and polysomnography. Clinical interventions and therapies reviewed included prevention and management of aspiration, airway mucus clearance and chest physical therapy, viral respiratory infections, precautions during high altitude or air-flight travel, noninvasive ventilation during sleep, antibiotic therapy, steroid therapy, oxygen therapy, gastrostomy tube placement, Nissen fundoplication surgery, scoliosis surgery, tracheostomy and lung lobectomy. Conclusions Expert recommendations for the diagnosis and management of respiratory disease in patients with familial dysautonomia are provided. Frequent reassessment and updating will be needed.

Chemoreflex failure and sleep-disordered breathing in familial dysautonomia: Implications for sudden death during sleep

“…ELP-1 deficiency in FD affects the development of primary sensory (afferent) neurons, resulting in a complex neurological phenotype. Impaired development of primary sensory nerves results in reduced pain and temperature sensation, absent deep tendon reflexes and gait ataxia (Macefield et al, 2011), optic neuropathy (Mendoza-Santiesteban et al, 2017), and neurogenic dysphagia contributing to chronic lung disease (Kazachkov et al, 2018;Palma et al, 2018). In addition, abnormal development of mechano-and chemosensory neurons results in baro-and chemoreflex failure with orthostatic hypotension, paroxysmal hypertension, and abnormal control of heart rate and ventilatory responses to hypoxia and hypercapnia (Norcliffe- Kaufmann et al, 2010;Norcliffe-Kaufmann et al, 2016).…”

“…These are relatively frequent in children with FD after crying or laughing and can result in severe hypotension, hypoxia, and decerebrate posturing before breathing resumes (Maayan et al, 2015). In addition, during respiratory infections, patients with FD have no compensatory tachypnea, and can suffer hypotension and syncope in low oxygen environments, such as high altitude, airplane travel, and underwater swimming (Kazachkov et al, 2018).…”

“…This finding has key clinical implications: episodes of hypercapnia not associated with apneas might be missed in polysomnography studies that do not include EtCO 2 monitoring. Expert consensus guidelines now recommend EtCO 2 monitoring in all sleep studies performed in patients with FD (Kazachkov et al, 2018).…”

“…This laryngeal closure reflex has been implicated in the pathogenesis of sudden-infant death syndrome (Cummings, 2016;Horne, 2018), and could potentially play a role in sleep-disordered breathing in FD. These factors may contribute to prolonged apnea, as well as poor tolerance of environments with low partial pressure of oxygen, such as pressurized airplane cabins and high altitude (Kazachkov et al, 2018).…”

“…The finding that untreated sleep apnea and fludrocortisone are independent risk factors for SUDS in patients with FD has important therapeutic implications. Early identification of sleep abnormalities with polysomnography and implementation of non-invasive ventilation with CPAP or BiPAP when required are now encouraged in expert consensus guidelines for the diagnosis and management of respiratory disorders in FD (Kazachkov et al, 2018).…”