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Acute toxic-metabolic encephalopathy in children

Author
Claudia A Chiriboga, MD, MPH
Section Editor
Marc C Patterson, MD, FRACP
Deputy Editor
Carrie Armsby, MD, MPH

INTRODUCTION

Acute toxic-metabolic encephalopathy (TME) is a condition of acute global cerebral dysfunction manifested by altered consciousness, behavior changes, and/or seizures in the absence of primary structural brain disease or direct central nervous system (CNS) infection. The causes of TME are diverse (table 1). The presentation of this condition in the infant or child may be subtle and not easily recognized. Because TME often is reversible and interruption of neuronal activity in the developing brain can have a long-lasting effect, prompt recognition and treatment are important.

An overview of the causes, clinical features, and an approach to the diagnostic evaluation and management of TME in children will be reviewed here. Neonatal encephalopathy is discussed separately. (See "Clinical features, diagnosis, and treatment of neonatal encephalopathy" and "Etiology and pathogenesis of neonatal encephalopathy".)

DEFINITION

Acute TME is a broad term used to describe a condition of acute global cerebral dysfunction manifested by altered consciousness, behavior changes, and/or seizures occurring as a consequence of systemic disorders or exposures. The term is not used to describe cerebral dysfunction due to primary brain disease, including structural pathology (eg, tumor, hemorrhage, hydrocephalus), central nervous system infection (eg, meningitis, encephalitis), or immune-mediated inflammation (eg, autoimmune encephalitis, acute disseminated encephalomyelitis) [1]. All forms of TME interfere with the function of the ascending reticular activating system and/or its projections to the cerebral cortex, thus leading to impairment of arousal and/or awareness, and/or seizures [2].

PATHOPHYSIOLOGY

Normal neuronal activity requires a balanced environment of electrolytes, water, amino acids, excitatory and inhibitory neurotransmitters, and metabolic substrates [3]. In addition, normal blood flow, normal temperature, normal osmolality, and physiologic pH are required for optimal brain function [2]. Complex systems, such as those mediating arousal and awareness and those involved in higher cognitive functions, are more likely to malfunction when the local milieu is deranged [2-4].

Despite a wide array of pathophysiologic mechanisms (table 1), the clinical manifestations of acute TME tend to be very similar because of a common final mechanism: interruption of polysynaptic pathways and altered excitatory-inhibitory amino acid balance and cerebral edema [5-8]. (See 'Specific etiologies of encephalopathy' below.)

                                    
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Literature review current through: Nov 2017. | This topic last updated: Nov 08, 2017.
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References
Top
  1. Parke, JT. Acute encephalopathies. In: Oski's Pediatrics. Principles and Practice, 4th ed, McMillan JA, Feigin RD, DeAngelis C, Jones MD (Eds), Lippincott, Williams & Wilkins, Philadelphia 2006. p.2258.
  2. Posner JB, Saper CB, Schiff ND, Plum F. Diagnosis of stupor and coma, 4th Ed, Plum F, Posner JB (Eds), Oxford University Press, New York 2007.
  3. Earnest MP, Parker WD. Metabolic encephalopathies and coma from medical causes. In: Management of the Acutely Ill Neurological Patient, Grotta J (Ed), Churchill Livingstone, New York 1993. p.1.
  4. Young GB, DeRubeis DA. Metabolic encephalopathies. In: Coma and Impaired Consciousness, Young GB, Ropper AH, Bolton CF (Eds), McGraw-Hill, 1998. p.307.
  5. Lipton SA, Rosenberg PA. Excitatory amino acids as a final common pathway for neurologic disorders. N Engl J Med 1994; 330:613.
  6. Baumgaertel MW, Kraemer M, Berlit P. Neurologic complications of acute and chronic renal disease. Handb Clin Neurol 2014; 119:383.
  7. Stokum JA, Gerzanich V, Simard JM. Molecular pathophysiology of cerebral edema. J Cereb Blood Flow Metab 2016; 36:513.
  8. Bolton, CF, Young, GB. Uremic encephalopathy. In: Neurological Complications of Renal Disease, Bolton, CF, Young, GB (Eds), Buttersworth, Stoneham 1990. p.44.
  9. Ransohoff RM, Schafer D, Vincent A, et al. Neuroinflammation: Ways in Which the Immune System Affects the Brain. Neurotherapeutics 2015; 12:896.
  10. Tasker RC, Acerini CL. Cerebral edema in children with diabetic ketoacidosis: vasogenic rather than cellular? Pediatr Diabetes 2014; 15:261.
  11. Chen R, Young GB. Metabolic encephalopathies. In: Baillere's Clinical Neurology, Bolton CF, Young GB (Eds), Balliere Tindall, London 1996. p.577.
  12. Jacinto SJ, Gieron-Korthals M, Ferreira JA. Predicting outcome in hypoxic-ischemic brain injury. Pediatr Clin North Am 2001; 48:647.
  13. Abend NS, Licht DJ. Predicting outcome in children with hypoxic ischemic encephalopathy. Pediatr Crit Care Med 2008; 9:32.
  14. Semmler A, Widmann CN, Okulla T, et al. Persistent cognitive impairment, hippocampal atrophy and EEG changes in sepsis survivors. J Neurol Neurosurg Psychiatry 2013; 84:62.
  15. Gofton TE, Young GB. Sepsis-associated encephalopathy. Nat Rev Neurol 2012; 8:557.
  16. Young GB, Bolton CF, Archibald YM, et al. The electroencephalogram in sepsis-associated encephalopathy. J Clin Neurophysiol 1992; 9:145.
  17. Katz ML, Volkening LK, Anderson BJ, Laffel LM. Contemporary rates of severe hypoglycaemia in youth with type 1 diabetes: variability by insulin regimen. Diabet Med 2012; 29:926.
  18. Umpierrez G, Korytkowski M. Diabetic emergencies - ketoacidosis, hyperglycaemic hyperosmolar state and hypoglycaemia. Nat Rev Endocrinol 2016; 12:222.
  19. Pugliese A, Beltramo T, Torre D. Reye's and Reye's-like syndromes. Cell Biochem Funct 2008; 26:741.
  20. Cooke DW, Plotnick L. Management of diabetic ketoacidosis in children and adolescents. Pediatr Rev 2008; 29:431.
  21. Zeitler P, Haqq A, Rosenbloom A, et al. Hyperglycemic hyperosmolar syndrome in children: pathophysiological considerations and suggested guidelines for treatment. J Pediatr 2011; 158:9.
  22. Muhsin SA, Mount DB. Diagnosis and treatment of hypernatremia. Best Pract Res Clin Endocrinol Metab 2016; 30:189.
  23. Adrogué HJ, Madias NE. Hypernatremia. N Engl J Med 2000; 342:1493.
  24. Verbalis JG. Brain volume regulation in response to changes in osmolality. Neuroscience 2010; 168:862.
  25. Cardenas JF, Bodensteiner JB. Osmotic demyelination syndrome as a consequence of treating hyperammonemia in a patient with ornithine transcarbamylase deficiency. J Child Neurol 2009; 24:884.
  26. Ranger AM, Chaudhary N, Avery M, Fraser D. Central pontine and extrapontine myelinolysis in children: a review of 76 patients. J Child Neurol 2012; 27:1027.
  27. Lin JJ, Lin KL, Hsia SH, et al. Combined central diabetes insipidus and cerebral salt wasting syndrome in children. Pediatr Neurol 2009; 40:84.
  28. Leonard J, Garrett RE, Salottolo K, et al. Cerebral salt wasting after traumatic brain injury: a review of the literature. Scand J Trauma Resusc Emerg Med 2015; 23:98.
  29. Moritz ML, Ayus JC. New aspects in the pathogenesis, prevention, and treatment of hyponatremic encephalopathy in children. Pediatr Nephrol 2010; 25:1225.
  30. Espay AJ. Neurologic complications of electrolyte disturbances and acid-base balance. Handb Clin Neurol 2014; 119:365.
  31. Ahmed MA, Martinez A, Mariam S, Whitehouse W. Chvostek's sign and hypocalcaemia in children with seizures. Seizure 2004; 13:217.
  32. Lietman SA, Germain-Lee EL, Levine MA. Hypercalcemia in children and adolescents. Curr Opin Pediatr 2010; 22:508.
  33. Thompson MD, Henry RK. Myxedema Coma Secondary to Central Hypothyroidism: A Rare but Real Cause of Altered Mental Status in Pediatrics. Horm Res Paediatr 2016.
  34. Swee du S, Chng CL, Lim A. Clinical characteristics and outcome of thyroid storm: a case series and review of neuropsychiatric derangements in thyrotoxicosis. Endocr Pract 2015; 21:182.
  35. Anglin RE, Rosebush PI, Mazurek MF. The neuropsychiatric profile of Addison's disease: revisiting a forgotten phenomenon. J Neuropsychiatry Clin Neurosci 2006; 18:450.
  36. Furtado A, Hsu A, La Colla L, Zuccoli G. Arterial blood pressure but not serum albumin concentration correlates with ADC ratio values in pediatric posterior reversible encephalopathy syndrome. Neuroradiology 2015; 57:721.
  37. Squires RH Jr, Shneider BL, Bucuvalas J, et al. Acute liver failure in children: the first 348 patients in the pediatric acute liver failure study group. J Pediatr 2006; 148:652.
  38. Alonso EM, Sokol RJ, Hart J, et al. Fulminant hepatitis associated with centrilobular hepatic necrosis in young children. J Pediatr 1995; 127:888.
  39. Hussain E, Grimason M, Goldstein J, et al. EEG abnormalities are associated with increased risk of transplant or poor outcome in children with acute liver failure. J Pediatr Gastroenterol Nutr 2014; 58:449.
  40. Kamat P, Kunde S, Vos M, et al. Invasive intracranial pressure monitoring is a useful adjunct in the management of severe hepatic encephalopathy associated with pediatric acute liver failure. Pediatr Crit Care Med 2012; 13:e33.
  41. Scott TR, Kronsten VT, Hughes RD, Shawcross DL. Pathophysiology of cerebral oedema in acute liver failure. World J Gastroenterol 2013; 19:9240.
  42. Iyer RS, Chaturvedi A, Pruthi S, et al. Medication neurotoxicity in children. Pediatr Radiol 2011; 41:1455.
  43. Kossoff EH, Bergey GK, Freeman JM, Vining EP. Levetiracetam psychosis in children with epilepsy. Epilepsia 2001; 42:1611.
  44. Neuhut R, Lindenmayer JP, Silva R. Neuroleptic malignant syndrome in children and adolescents on atypical antipsychotic medication: a review. J Child Adolesc Psychopharmacol 2009; 19:415.
  45. Yip L, Dart RC, Gabow PA. Concepts and controversies in salicylate toxicity. Emerg Med Clin North Am 1994; 12:351.
  46. Clark I, Whitten R, Molyneux M, Taylor T. Salicylates, nitric oxide, malaria, and Reye's syndrome. Lancet 2001; 357:625.
  47. Gleeson JG, duPlessis AJ, Barnes PD, Riviello JJ Jr. Cyclosporin A acute encephalopathy and seizure syndrome in childhood: clinical features and risk of seizure recurrence. J Child Neurol 1998; 13:336.
  48. Bhattacharyya S, Darby RR, Raibagkar P, et al. Antibiotic-associated encephalopathy. Neurology 2016; 86:963.
  49. Zwiener RJ, Ginsburg CM. Organophosphate and carbamate poisoning in infants and children. Pediatrics 1988; 81:121.
  50. Trope I, Lopez-Villegas D, Cecil KM, Lenkinski RE. Exposure to lead appears to selectively alter metabolism of cortical gray matter. Pediatrics 2001; 107:1437.
  51. Belay ED, Bresee JS, Holman RC, et al. Reye's syndrome in the United States from 1981 through 1997. N Engl J Med 1999; 340:1377.
  52. Ninove L, Daniel L, Gallou J, et al. Fatal case of Reye's syndrome associated with H3N2 influenza virus infection and salicylate intake in a 12-year-old patient. Clin Microbiol Infect 2011; 17:95.
  53. Sullivan KM, Belay ED, Durbin RE, et al. Epidemiology of Reye's syndrome, United States, 1991-1994: comparison of CDC surveillance and hospital admission data. Neuroepidemiology 2000; 19:338.
  54. Lee JH, Hung HY, Huang FY. Kawasaki disease with Reye syndrome: report of one case. Zhonghua Min Guo Xiao Er Ke Yi Xue Hui Za Zhi 1992; 33:67.
  55. Wei CM, Chen HL, Lee PI, et al. Reye's syndrome developing in an infant on treatment of Kawasaki syndrome. J Paediatr Child Health 2005; 41:303.
  56. Helmstaedter C, Elger CE, Lendt M. Postictal courses of cognitive deficits in focal epilepsies. Epilepsia 1994; 35:1073.
  57. Biton V, Gates JR, dePadua Sussman L. Prolonged postictal encephalopathy. Neurology 1990; 40:963.
  58. Lim M, Hacohen Y, Vincent A. Autoimmune encephalopathies. Pediatr Clin North Am 2015; 62:667.
  59. Al-Twaijri WA, Shevell MI. Pediatric migraine equivalents: occurrence and clinical features in practice. Pediatr Neurol 2002; 26:365.
  60. Pelzer N, Blom DE, Stam AH, et al. Recurrent coma and fever in familial hemiplegic migraine type 2. A prospective 15-year follow-up of a large family with a novel ATP1A2 mutation. Cephalalgia 2016.
  61. Bates D. The management of medical coma. J Neurol Neurosurg Psychiatry 1993; 56:589.
  62. Painter MJ, Alvin J. Neonatal Seizures. Curr Treat Options Neurol 2001; 3:237.
  63. Nagarajan L, Ghosh S. The role of the video-EEG in neonates with seizures. In: Neonatal Seizures: Current Management and Future Challenges, Nagarajan L (Ed), Mac Keith Press, London 2016.
  64. Helbok R, Olson DM, Le Roux PD, et al. Intracranial pressure and cerebral perfusion pressure monitoring in non-TBI patients: special considerations. Neurocrit Care 2014; 21 Suppl 2:S85.