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Acute toxic-metabolic encephalopathy in children

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


Acute toxic-metabolic encephalopathy (TME) is a condition of acute global cerebral dysfunction resulting in altered consciousness, behavior changes, or seizures, which is not due to primary structural brain disease (eg, tumor or hemorrhage) or infection [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].  

TME usually is a consequence of systemic disorders and, therefore, the causes are diverse. The presentation of this condition in the newborn, 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.


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].

The pathophysiology of acute toxic-metabolic encephalopathy (TME) usually is multifactorial and varies according to etiology. TME generally results from cytotoxic injury or disruption of neurotransmission [1]. Causes of cytotoxic injury include:

Disruption of energy production by inadequate cerebral blood flow, or lack of oxygen or glucose.


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Literature review current through: Dec 2016. | This topic last updated: Mon Jun 22 00:00:00 GMT+00:00 2015.
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  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. Bolton, CF, Young, GB. Uremic encephalopathy. In: Neurological Complications of Renal Disease, Bolton, CF, Young, GB (Eds), Buttersworth, Stoneham 1990. p.44.
  6. Chen R, Young GB. Metabolic encephalopathies. In: Baillere's Clinical Neurology, Bolton CF, Young GB (Eds), Balliere Tindall, London 1996. p.577.
  7. Lipton SA, Rosenberg PA. Excitatory amino acids as a final common pathway for neurologic disorders. N Engl J Med 1994; 330:613.
  8. Bates D. The management of medical coma. J Neurol Neurosurg Psychiatry 1993; 56:589.
  9. Bleck TP, Smith MC, Pierre-Louis SJ, et al. Neurologic complications of critical medical illnesses. Crit Care Med 1993; 21:98.
  10. Painter MJ, Alvin J. Neonatal Seizures. Curr Treat Options Neurol 2001; 3:237.
  11. Plum F, Posner JB. The Diagnosis of Stupor and Coma, FA Davis Company, Philadelphia 1982. p.177.
  12. American Academy of Pediatrics: Committee on Child Abuse and Neglect. Shaken baby syndrome: rotational cranial injuries-technical report. Pediatrics 2001; 108:206.
  13. Bolton CF, Young GB, Zochodne DW. The neurological complications of sepsis. Ann Neurol 1993; 33:94.
  14. Eidelman LA, Putterman D, Putterman C, Sprung CL. The spectrum of septic encephalopathy. Definitions, etiologies, and mortalities. JAMA 1996; 275:470.
  15. Kirkham FJ. Non-traumatic coma in children. Arch Dis Child 2001; 85:303.
  16. Levy DE, Caronna JJ, Singer BH, et al. Predicting outcome from hypoxic-ischemic coma. JAMA 1985; 253:1420.
  17. Jacinto SJ, Gieron-Korthals M, Ferreira JA. Predicting outcome in hypoxic-ischemic brain injury. Pediatr Clin North Am 2001; 48:647.
  18. Becker DJ, Ryan CM. Hypoglycemia: a complication of diabetes therapy in children. Trends Endocrinol Metab 2000; 11:198.
  19. Glasgow JF, Middleton B. Reye syndrome--insights on causation and prognosis. Arch Dis Child 2001; 85:351.
  20. White NH. Diabetic ketoacidosis in children. Endocrinol Metab Clin North Am 2000; 29:657.
  21. Rosenbloom AL. Intracerebral crises during treatment of diabetic ketoacidosis. Diabetes Care 1990; 13:22.
  22. 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.
  23. Cronan K, Kost SI. Renal and electrolyte emergencies. In: Textbook of Pediatric Emergency Medicine, 5th ed, Fleisher G, Ludwig S, Henretig FM (Eds), Lippincott Williams and Wilkins, Philadelphia 2006. p.873.
  24. Oddie S, Richmond S, Coulthard M. Hypernatraemic dehydration and breast feeding: a population study. Arch Dis Child 2001; 85:318.
  25. Conley SB. Hypernatremia. Pediatr Clin North Am 1990; 37:365.
  26. Adrogué HJ, Madias NE. Hypernatremia. N Engl J Med 2000; 342:1493.
  27. De Petris L, Luchetti A, Emma F. Cell volume regulation and transport mechanisms across the blood-brain barrier: implications for the management of hypernatraemic states. Eur J Pediatr 2001; 160:71.
  28. Strange K. Regulation of solute and water balance and cell volume in the central nervous system. J Am Soc Nephrol 1992; 3:12.
  29. Lee JH, Arcinue E, Ross BD. Brief report: organic osmolytes in the brain of an infant with hypernatremia. N Engl J Med 1994; 331:439.
  30. Kahn A, Brachet E, Blum D. Controlled fall in natremia and risk of seizures in hypertonic dehydration. Intensive Care Med 1979; 5:27.
  31. Blum D, Brasseur D, Kahn A, Brachet E. Safe oral rehydration of hypertonic dehydration. J Pediatr Gastroenterol Nutr 1986; 5:232.
  32. Albanese A, Hindmarsh P, Stanhope R. Management of hyponatraemia in patients with acute cerebral insults. Arch Dis Child 2001; 85:246.
  33. Arieff AI, Ayus JC, Fraser CL. Hyponatraemia and death or permanent brain damage in healthy children. BMJ 1992; 304:1218.
  34. Nishiyama S. Hypercalcemia in children: an overview. Acta Paediatr Jpn 1997; 39:479.
  35. Kelly DA. Acute liver failure. Indian J Pediatr 1999; 66:S104.
  36. Alonso EM, Sokol RJ, Hart J, et al. Fulminant hepatitis associated with centrilobular hepatic necrosis in young children. J Pediatr 1995; 127:888.
  37. Alper G, Jarjour IT, Reyes JD, et al. Outcome of children with cerebral edema caused by fulminant hepatic failure. Pediatr Neurol 1998; 18:299.
  38. Lockwood AH. Neurologic complications of renal disease. Neurol Clin 1989; 7:617.
  39. Sánchez-Carpintero R, Narbona J, López de Mesa R, et al. Transient posterior encephalopathy induced by chemotherapy in children. Pediatr Neurol 2001; 24:145.
  40. Dietemann JL, Botelho C, Nogueira T, et al. [Imaging in acute toxic encephalopathy]. J Neuroradiol 2004; 31:313.
  41. Sandoval C, Kutscher M, Jayabose S, Tenner M. Neurotoxicity of intrathecal methotrexate: MR imaging findings. AJNR Am J Neuroradiol 2003; 24:1887.
  42. Ty EB, Rothner AD. Neuroleptic malignant syndrome in children and adolescents. J Child Neurol 2001; 16:157.
  43. Yip L, Dart RC, Gabow PA. Concepts and controversies in salicylate toxicity. Emerg Med Clin North Am 1994; 12:351.
  44. Clark I, Whitten R, Molyneux M, Taylor T. Salicylates, nitric oxide, malaria, and Reye's syndrome. Lancet 2001; 357:625.
  45. 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.
  46. Patchell RA. Neurological complications of organ transplantation. Ann Neurol 1994; 36:688.
  47. Zwiener RJ, Ginsburg CM. Organophosphate and carbamate poisoning in infants and children. Pediatrics 1988; 81:121.
  48. 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.
  49. Lim M, Hacohen Y, Vincent A. Autoimmune encephalopathies. Pediatr Clin North Am 2015; 62:667.
  50. Dalmau J, Gleichman AJ, Hughes EG, et al. Anti-NMDA-receptor encephalitis: case series and analysis of the effects of antibodies. Lancet Neurol 2008; 7:1091.
  51. Gable MS, Sheriff H, Dalmau J, et al. The frequency of autoimmune N-methyl-D-aspartate receptor encephalitis surpasses that of individual viral etiologies in young individuals enrolled in the California Encephalitis Project. Clin Infect Dis 2012; 54:899.
  52. Houtrow AJ, Bhandal M, Pratini NR, et al. The rehabilitation of children with anti-N-methyl-D-aspartate-receptor encephalitis: a case series. Am J Phys Med Rehabil 2012; 91:435.
  53. Florance NR, Davis RL, Lam C, et al. Anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis in children and adolescents. Ann Neurol 2009; 66:11.
  54. Haberlandt E, Bast T, Ebner A, et al. Limbic encephalitis in children and adolescents. Arch Dis Child 2011; 96:186.
  55. Suleiman J, Brenner T, Gill D, et al. VGKC antibodies in pediatric encephalitis presenting with status epilepticus. Neurology 2011; 76:1252.
  56. Hacohen Y, Wright S, Waters P, et al. Paediatric autoimmune encephalopathies: clinical features, laboratory investigations and outcomes in patients with or without antibodies to known central nervous system autoantigens. J Neurol Neurosurg Psychiatry 2013; 84:748.
  57. Hurwitz ES, Nelson DB, Davis C, et al. National surveillance for Reye syndrome: a five-year review. Pediatrics 1982; 70:895.
  58. Pugliese A, Beltramo T, Torre D. Reye's and Reye's-like syndromes. Cell Biochem Funct 2008; 26:741.
  59. 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.
  60. Hurwitz ES, Barrett MJ, Bregman D, et al. Public Health Service study on Reye's syndrome and medications. Report of the pilot phase. N Engl J Med 1985; 313:849.
  61. 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.
  62. Smith ET Jr, Davis GJ. Medium-chain acylcoenzyme-A dehydrogenase deficiency. Not just another Reye syndrome. Am J Forensic Med Pathol 1993; 14:313.
  63. Santer R, Schmidt-Sommerfeld E, Leung YK, et al. Medium-chain acyl CoA dehydrogenase deficiency: electron microscopic differentiation from Reye syndrome. Eur J Pediatr 1990; 150:111.
  64. Schrör K. Aspirin and Reye syndrome: a review of the evidence. Paediatr Drugs 2007; 9:195.
  65. 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.
  66. 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.