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1 Neurologic Complications of Medical Disease C13 Neurologic Complications of Medical Disease C13, April 22, 2017 10.30 am – 12.30 pm AAN Annual Meeting, Boston, MA, April 22—April 28, 2017 Overview of the Interface of Neurology & Medicine: An Update 04/22/2017, 10.30 am – 11.45 am Neeraj Kumar MD Rochester, MN PULMONOLOGY – NEUROLOGY Central mechanisms control ventilation. The CNS regulates ventilation through chemoreceptors (central and peripheral) which are sensitive to changes in pO2, pCO2, and blood pH. Chemoreceptors provide feedback to brain respiratory centers which drive respiratory rhythms.1 Hypoxia or hypercarbia result in cerebral blood vessel dilation and increased cerebral blood flow. Acute Hypoxia Acute Respiratory Failure o Acute respiratory failure is defined by a drop in pO2 below 60 mm Hg or a rise in pCO2 over 50 mm Hg. o Neurologic manifestations depend on the onset, duration, and severity of hypoxia. Symptoms range from anxiety, confusion, somnolence, and delirium to impaired consciousness and coma. Tremors or myoclonus may be seen. Prolonged hypoxia as seen in cardiopulmonary arrest may result in a hypoxic ischemic encephalopathy. The cortex, hippocampus, and Purkinje cells are vulnerable to the effects of hypoxia. Severity of neurologic manifestations correlates with acidosis and hypercarbia.2 Absent pupillary reflexes at initial examination predict a low likelihood of regaining consciousness.3 Survivors of cardiac arrest often have memory deficits and executive dysfunction.4 Altitude sickness o High-altitude sickness refers to the abrupt onset, in a non-acclimatized person at 2500 m or higher, of headache plus one of the following: nausea, vomiting, anorexia, insomnia, dizziness, somnolence, or fatigue.5, 6 Neurologic manifestations can include mental status change, ataxia, cranial nerve palsies, retinal hemorrhage, and papilledema. Development is related to rate of ascent, absolute altitude, and individual physiologic responses. The “tight- fit” hypothesis suggests the young are more predisposed to develop the condition because the lack of cerebral atrophy results in a propensity to develop cerebral edema and raised intracranial pressure. Treatment modalities include descent to a lower altitude, supplemental oxygen, hyperbaric chambers, acetazolamide, and dexamethasone.5 Chronic Hypoxia Chronic Respiratory Failure o Chronic hypoxia and hypercarbia associated with chronic respiratory failure can cause headache and mental status changes. An acute rise in pCO2 is much more deleterious than a gradual rise. Papilledema and rarely seizures and focal neurologic signs may be present. Giving high concentration of oxygen is harmful because it decreases ventilatory drive by reducing stimulus to the carotid body. This in turn worsens hypercarbia and related symptoms.7 Hypoventilation Obesity Hypoventilation Syndrome (Pickwickian Syndrome) o The hallmark of this condition is chronic hypercarbia and obesity with dyspnea and cor pulmonale.7 Blunted respiratory drive and mechanical pressure on the chest wall result in alveolar hypoventilation. Cognitive changes and hypersomnolence may be present. 1 Ondine curse o Though probably initially used in context of bulbar polio, the term is used for various brainstem disorders that affect respiration such as infarcts or tumors. Though it has classically been used to refer to failure of automatic respiration, it is also used in context of central hypoventilation syndrome & sleep apnea.8 Sleep Disordered Breathing o Sleep disordered breathing or sleep apnea is defined by episodic cessation of breathing for at least 10 seconds (apnea) or a decrease in airflow with a drop in hemoglobin saturation of at least 4% (hypopnea). In general 5 or more apneic or hypopneic episodes per hour are required to make the diagnosis.9 o Obstructive (OSA), central (CSA), and mixed forms are recognized. o OSA is the most common form. The daytime neurologic manifestations of the sleep fragmentation that accompany sleep apnea include headache, mood and personality change, fatigue, inattention, decreased processing speed, and memory difficulties. o An association between OSA and idiopathic intracranial hypertension has been reported in men.10 The nocturnal hypercarbia-related cerebral vasodilation is believed to result in increased intracranial pressure. o CSA is diagnosed when there is failure of ventilatory effort in response to apnea. CSA has been linked to medullary lesions, genetic, and paraneoplastic disorders.11, 12 Congenital central hypoventilation is characterized by a blunted response to hypercapnia with decreased ventilation during sleep. Mutations in PHOX2B, a gene responsible for maturation of the neural crest and formation of facial structures, have been identified in this condition.11, 13 Diffusion tensor imaging in congenital central hypoventilation syndrome has identified myelin injury in the brainstem and cerebellum.14 o Patients with neuromuscular disorders are prone to both OSA and CSA. Neuromuscular disorders associated with pulmonary complications and sleep disordered breathing include Charcot – Marie Tooth, amyotrophic lateral sclerosis, postpolio syndrome, myotonic dystrophy, myasthenia gravis, acid maltase deficiency, and Duchenne muscular dystrophy.15, 16 Diaphragmatic weakness, bulbar weakness, respiratory muscle weakness and probably impaired chemosensitivity are all contributing factors. Hyperventilation Acute o Hyperventilation can be seen in a broad spectrum of conditions: pain, sepsis, cardiopulmonary disease, pregnancy, CNS tumors, anxiety, medications, and metabolic derangement.17 Hyperventilation results in a decreased pCO2 which in turn causes respiratory alkalosis and decreased plasma calcium. Clinical manifestations of acute hyperventilation include dizziness, perioral and distal paresthesias, carpopedal spasm, and tetany. Chronic o Chronic hyperventilation can be more difficult to diagnose. Clinical manifestations include nonspecific symptoms like fatigue, dizziness, and anxiety. The hyperventilation test can help make a diagnosis (see if symptoms are reproduced by deep breathing for 3 minutes or increasing ventilation to 60 breaths per minute).18, 19 This test should not be done in cardiopulmonary or cerebrovascular disease, sickle cell anemia, or hyperviscosity states. Adult-onset Acid Maltase deficiency 20-23 The enzyme acid α glucosidase (GAA) degrades lysosomal glycogen. Deficiency of this enzyme results in an autosomal recessive disorder called Pompe’s disease (also called glycogen-storage disease type II or acid maltase deficiency). The classic infantile form is associated with glycogen deposition in the heart, skeletal muscle, and respiratory muscles. The resulting cardiomyopathy, hypotonia, and respiratory failure results in death in infancy. Children and adults have glycogen deposition in the skeletal and respiratory muscles. This results in a limb-girdle myopathy and respiratory failure. A recent study noted that in a large cohort of unselected adult patients with hyperCKemia and/or limb- girdle muscular weakness the prevalence of late-onset Pompe disease was 2.4%.24 2 In 2006, based on the results of an open-label study of infantile-onset Pompe’s disease, enzyme- replacement therapy with alglucosidase α (a recombinant human GAA) was approved for all patients with Pompe’s disease.25 More recently a randomized, controlled trial in late-onset Pompe’s disease showed improved walking distance and stabilization of pulmonary function over a 18-month period.26 References: 1. Eldridge FL. Central nervous system and chemoreceptor factors in control of breathing. Chest 1978;73:256-258. 2. Kilburn KH. Neurologic Manifestations of Respiratory Failure. Arch Intern Med 1965;116:409-415. 3. Levy DE, Caronna JJ, Singer BH, Lapinski RH, Frydman H, Plum F. Predicting outcome from hypoxic-ischemic coma. JAMA 1985;253:1420-1426. 4. Lim C, Alexander MP, LaFleche G, Schnyer DM, Verfaellie M. The neurological and cognitive sequelae of cardiac arrest. Neurology 2004;63:1774-1778. 5. Hackett PH, Roach RC. High-altitude illness. N Engl J Med 2001;345:107-114. 6. Dreibelbis JE, Jozefowicz RF. Neurologic complications of respiratory disease. Neurol Clin 2010;28:37-43. 7. Piper AJ, Grunstein RR. Current perspectives on the obesity hypoventilation syndrome. Curr Opin Pulm Med 2007;13:490- 496. 8. Nannapaneni R, Behari S, Todd NV, Mendelow AD. Retracing "Ondine's curse". Neurosurgery 2005;57:354-363; discussion 354-363. 9. Broderick M, Guilleminault C. Neurological aspects of obstructive sleep apnea. Ann N Y Acad Sci 2008;1142:44-57. 10. Wall M, Purvin V. Idiopathic intracranial hypertension in men and the relationship to sleep apnea. Neurology 2009;72:300- 301. 11. Sasaki A, Kanai M, Kijima K, et al. Molecular analysis of congenital central hypoventilation syndrome. Hum Genet 2003;114:22-26. 12. Gomez-Choco MJ, Zarranz JJ, Saiz A, Forcadas MI, Graus F. Central hypoventilation as the presenting symptom in Hu associated paraneoplastic encephalomyelitis. J Neurol Neurosurg Psychiatry 2007;78:1143-1145. 13. Weese-Mayer DE, Berry-Kravis EM, Zhou L, et al. Idiopathic congenital central hypoventilation syndrome: analysis of genes pertinent to early autonomic nervous system embryologic development and identification of mutations in PHOX2b. Am J Med Genet A 2003;123A:267-278. 14. Kumar R, Macey PM, Woo MA, Alger JR, Harper RM. Diffusion tensor imaging demonstrates brainstem and cerebellar abnormalities in congenital central hypoventilation syndrome. Pediatr Res 2008;64:275-280. 15. Dhand UK, Dhand R. Sleep disorders
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