Clinical Rheumatology

, Volume 32, Issue 3, pp 403–407 | Cite as

Valproate-induced hyperammonaemia superimposed upon severe neuropsychiatric lupus: a case report and review of the literature

Case Based Review


This paper presents a case of systemic lupus erythematosus (SLE) with neuropsychiatric features, where the outcome was influenced by the development of hyperammonaemia, probably induced by sodium valproate. A case of severe SLE occurring in a 20-year-old Maori girl is described. Her disease had been characterised by neuropsychiatric features for several years, culminating in persistent seizure activity at the time of her final presentation. Her management with anticonvulsants was complicated by the development of intractable hyperammonaemia which contributed to irreversible clinical deterioration. We have reviewed the English literature for reports of valproate-related hyperammonaemia which has often been described in the setting of seizure and mood disorders. This is the first case where it has been reported, superimposed upon severe neuropsychiatric SLE (NP-SLE). The mechanism by which valproate induces hyperammonaemia remains incompletely understood but is likely to relate to the urea cycle. Under normal metabolic conditions, acyl-CoA is transported into the mitochondria via a carnitine transport system. It is then converted to acetyl-CoA via β-oxidation and eventually to N-acetyl glutamate. This pathway can be interrupted by the introduction of sodium valproate, leading to a reduction of free coenzyme A, acetyl-CoA and carnitine, and resulting in the decreased availability of cofactors necessary for the function of the urea cycle. As this is the primary means of ammonia metabolism, serious elevation in serum ammonia levels may occur in patients on this anticonvulsant medication. In this patient with active NP-SLE, the combined autoimmune and metabolic brain insult contributed to a fatal outcome.


Anticonvulsants Hyperammonaemia Sodium valproate Systemic lupus erythematosus 




Supplementary material

10067_2012_2150_MOESM1_ESM.docx (30 kb)
ESM 1 (DOCX 29.6 kb)


  1. 1.
    Churg J, Sobin LH (1982) Renal diseases: classification and atlas of glomerular disease. Igaku-Shoin, TokyoGoogle Scholar
  2. 2.
    American College of Rheumatology (ACR) (1999) The American College of Rheumatology nomenclature and case definitions for neuropsychiatric lupus syndrome. Arthritis Rheum 42(4):599–608CrossRefGoogle Scholar
  3. 3.
    Hanly JG, Walsh NM, Sangalang V (1992) Brain pathology in systemic lupus erythematosus. J Rheumatol 19(5):732–741PubMedGoogle Scholar
  4. 4.
    Sterling G, West MD (1996) Lupus and the central nervous system. Curr Opin Rheumtol 8:408–414CrossRefGoogle Scholar
  5. 5.
    Hanly JG, Harrison MJ (2005) Management of neuropsychiatric lupus. Best Pract Res Clin Rheumatol 19(5):799–821PubMedCrossRefGoogle Scholar
  6. 6.
    Sanna G, Bertolaccini ML, Cuadrado MJ et al (2005) Neuropsychiatric manifestations in systemic lupus erythematosus: prevalence and association with antiphospholipid antibodies. J Rheumatol 30(5):985–992Google Scholar
  7. 7.
    DeGiorgio LA, Konstantinov KN, Lee SC, Hardin JA, Volpe BT, Diamond B (2001) A subset of lupus anti-DNA antibodies cross-reacts with the NR2 glutamate receptor in systemic lupus erythematosus. Nat Med 7:1189–1193PubMedCrossRefGoogle Scholar
  8. 8.
    Campostrini R, Zaccara G, Rossi L, Paganini M, Dorigotti A, Zappoli R (1985) Valproate-induced hyperammonaemia in two epileptic identical twins. J Neurol 232:167–168PubMedCrossRefGoogle Scholar
  9. 9.
    Kulick SK, Kramer DA (1993) Hyperammonemia secondary to valproic acid as a cause of lethargy in a postictal patient. Ann Emerg Med 22:610–612PubMedCrossRefGoogle Scholar
  10. 10.
    Oechsner M, Steen C, Sturenburg HJ, Kohlschutter A (1998) Hyperammonaemic encephalopathy after initiation of valproate therapy in unrecognized ornithine transcarbamylase deficiency. J Neurol Neurosurg Psychiatry 64:680–682PubMedCrossRefGoogle Scholar
  11. 11.
    Blindauer KA, Harrington G, Morris GL, Ho K (1998) Fulminant progression of demyelinating disease after valproate-induced encephalopathy. Neurology 51:292–295PubMedCrossRefGoogle Scholar
  12. 12.
    Vossler DG, Wilensky AJ, Cawthon DF et al (2002) Serum and CSF glutamine levels in valproate-related hyperammonemic encephalopathy. Epilepsi 43(2):154–159CrossRefGoogle Scholar
  13. 13.
    Ziyeh S, Thiel T, Spreer J, Klisch J, Schumacher M (2002) Valproate-induced encephalopathy: assessment with MR imaging and 1H MR spectroscopy. Epilepsia 43(9):1101–1105PubMedCrossRefGoogle Scholar
  14. 14.
    Feil D, Chuang K, Sultzer DL (2002) Valproate-induced hyperammonemia as a cause of altered mental status. Am J Geriatr Psychiatr 10(4):476–478Google Scholar
  15. 15.
    O’Neill M, Dubrey RW, Grocott-Mason RM (2002) Valproate encephalopathy and hyperammonaemia. Postgrad Med J 78:316–318PubMedCrossRefGoogle Scholar
  16. 16.
    Lokrantz CM, Eriksson B, Rosen I, Asztely F (2004) Hyperammonemic encephalopathy induced by a combination of valproate and pivmecillinam. Acta Neurol Scand 109:297–301PubMedCrossRefGoogle Scholar
  17. 17.
    Mallet L, Babin S, Morais JA (2004) Valproic acid-induced hyperammonemia and thrombocytopenia in an elderly woman. Ann Pharmacother 38:1643–1647PubMedCrossRefGoogle Scholar
  18. 18.
    Latour P, Biraben A, Polard E et al (2004) Drug induced encephalopathy in six epileptic patients: topiramate? valproate? or both? Hum Psychopharmacol Clin Exp 19:193–203CrossRefGoogle Scholar
  19. 19.
    Cuturic M, Abramson RK (2005) Acute hyperammonemic coma with chronic valproic acid therapy. Ann Pharmacother 39:2119–2123PubMedCrossRefGoogle Scholar
  20. 20.
    Soares-Fernandes JP, Machado A, Ribeiro M, Ferreira C, Figueiredo J, Rocha JF (2006) Hippocampal involvement in valproate-induced acute hyperammonemic encephalopathy. Arch Neurol 63:1202–1203PubMedCrossRefGoogle Scholar
  21. 21.
    Pradeep R (2008) Valproate monotherapy induced-delirium due to hyperammonemia: a report of three adult cases with different types of presentation. Indian J Psychiatr 50(2):121–123CrossRefGoogle Scholar
  22. 22.
    Gerstner T, Buesing D, Longin E et al (2006) Valproic acid induced encephalopathy—19 new cases in Germany from 1994 to 2003—a side effect associated to VPA-therapy not only in young children. Seizure 15:443–448PubMedCrossRefGoogle Scholar
  23. 23.
    Gomceli YB, Kutlu G, Cavdar L, Sanivar F, Inan LE (2007) Different clinical manifestations of hyperammonemic encephalopathy. Epilepsy Behav 10(4):583–587PubMedCrossRefGoogle Scholar
  24. 24.
    Chan YC, Tse ML, Lau FL (2007) Two cases of valproic acid poisoning treated with l-carnitine. Hum Exp Toxicol 26:967–969PubMedCrossRefGoogle Scholar
  25. 25.
    McCall M, Bourgeois JA (2004) Valproic acid induced hyperammonaemia: a case report. J Clin Psychopharmacol 24(5):521–526PubMedCrossRefGoogle Scholar
  26. 26.
    Davison AS, Milan AM, Roberts NB (2011) The consequences of valproate overdose. Clin Chem 57(9):1223–1238CrossRefGoogle Scholar
  27. 27.
    Gomez-Ibanez A, Urrestarazu-Bolumburu E, Viteri-Torres C (2011) Hyperammonemic encephalopathy related to valproate, phenobarbital, and topiramate synergism. Epilepsy Behav 21(4):480–482PubMedCrossRefGoogle Scholar
  28. 28.
    Prins MC, van Meijel JJ (2011) A case of hyperammonaemic encephalopathy due to valproic acid. Neth J Med 69(9):389–391PubMedGoogle Scholar
  29. 29.
    LaBuzetta JN, Yao JZ, Bourque DL, Zivin J (2010) Adult nonhepatic hyperammonemia: a case report and differential diagnosis. Am J Med 123(10):885–891PubMedCrossRefGoogle Scholar
  30. 30.
    Eze E, Workman M, Donley B (1998) Hyperammonemia and coma developed by a woman treated with valproic acid for affective disorder. Psychiatr Serv 49:1358–1359PubMedGoogle Scholar
  31. 31.
    Barrueto F, Hack JB (2001) Hyperammonemia and coma without hepatic dysfunction induced by valproate therapy. Acad Emerg Med 8:999–1001PubMedCrossRefGoogle Scholar
  32. 32.
    Stewart J (2008) A case of hyperammonemic encephalopathy after 11 years of valproate therapy. J Clin Psychopharmcol 28(3):361–362CrossRefGoogle Scholar
  33. 33.
    Wadzinski J, Franks R, Roane D, Bayard M (2007) Valproate-associated hyperammonemic encephalopathy. J Am Board Fam Med 20:499–502PubMedCrossRefGoogle Scholar
  34. 34.
    Raby WN (1997) Carnitine for valproic acid-induced hyperammonemia. Am J Psychiatry 154(8):1168–1169PubMedGoogle Scholar
  35. 35.
    Panikkar GP, Gilman SM (1999) Valproate-induced hyperammonemia in the psychiatric setting: 2 cases. J Clin Psychiatry 60:557–559PubMedCrossRefGoogle Scholar
  36. 36.
    Elgudin L, Hall Y, Schubert D (2003) Ammonia induced encephalopathy from valproic acid in a bipolar patient: case report. Int J Psychiatry Med 33:91–96PubMedCrossRefGoogle Scholar
  37. 37.
    Eubanks AL, Aguirre B, Bourgeois JA (2008) Severe acute hyperammonemia after brief exposure to valproate. Psychosomatics 49:82–83PubMedCrossRefGoogle Scholar
  38. 38.
    Abreu LN, Issler C, Lafer B (2009) Valproate-induced reversible pseudoatrophy of the brain and hyperammonemic encephalopathy in a bipolar patient. Aust N Z J Psychiatr 43:484–485CrossRefGoogle Scholar
  39. 39.
    Shan JC, Hsieh MH, Liu CC, Wen CC, Liu CM (2010) Clinical alertness to valproic acid-induced hyperammonemia—two case reports. J Psychopharmacol 24(6):943–945PubMedCrossRefGoogle Scholar
  40. 40.
    Rupasinghe J, Jasinarachchi M (2011) Progressive encephalopathy with cerebral oedema and infarctions associated with valproate and diazepam overdose. J Clin Neurosci 18(5):710–711PubMedCrossRefGoogle Scholar
  41. 41.
    Settle EC Jr (1995) Valproic acid-associated encephalopathy with coma. Am J Psychiatry 152(8):1236–1237PubMedGoogle Scholar
  42. 42.
    Kimmel RJ, Irwin SA, Meyer JM (2005) Valproic acid-associated hyperammonemic encephalopathy: a case report from the psychiatric setting. Int Clin Psychopharmacol 20:57–58PubMedCrossRefGoogle Scholar
  43. 43.
    Carr RB, Shrewsbury K (2007) Hyperammonemia due to valproic acid in the psychiatric setting. Am J Psychiatry 164(7):1020–1027PubMedCrossRefGoogle Scholar
  44. 44.
    Hung CC, Li TM, Wei IH, Huang CC (2011) The real mechanism of VPA-induced hyperammonemia remains unknown. Gen Hosp Psychiatr 33(1):84, e3-4CrossRefGoogle Scholar
  45. 45.
    Reif A, Leonhard C, Mobner R, Lesch KP, Fallgatter AJ (2004) Encephalopathy and myoclonus triggered by valproic acid. Prog Neuropsychopharmacol Biol Psychiatr 28:1061–1063CrossRefGoogle Scholar
  46. 46.
    Stewart JT (2005) Treatment of valproate-induced hyperammonemia. J Am Geriatr Soc 53:1080PubMedCrossRefGoogle Scholar
  47. 47.
    Khoo CL, Naik S, Lua R, Chai SB, Liew A, Sim K (2010) Valproate-induced hyperammonemia in mental retardation: a case report and review of the literature. Prog Neuropsychpharmacol Biol Psychiatr 34:561–562CrossRefGoogle Scholar
  48. 48.
    Starer J, Chang G (2010) Hyperammoneic encephalopathy, valproic acid, and benzodiazepine withdrawal: a case series. Am J Drug Alcohol Abuse 36:98–101PubMedCrossRefGoogle Scholar
  49. 49.
    Mittal V, Muralee S, Tampi RR (2009) Valproic acid-induced hyperammonemia in the elderly: a review of the literature. Case Report Med 2009:802121Google Scholar
  50. 50.
    Ott CA, Campbell N, Dworek EA (2007) Valproic acid-induced hyperammonaemia in a patient with schizoaffective disorder. J Pharm Prac 20(1):82–92CrossRefGoogle Scholar

Copyright information

© Clinical Rheumatology 2012

Authors and Affiliations

  1. 1.Department of Rheumatology, Greenlane Clinical CentreAuckland District Health BoardAucklandNew Zealand
  2. 2.Department of Molecular Medicine and PathologyUniversity of AucklandAucklandNew Zealand

Personalised recommendations