Correspondence

Hyperammonemic Encephalopathy in Multiple Myeloma

N Engl J Med 2002; 346:1674-1675May 23, 2002

Article

To the Editor:

We report the development of hyperammonemic encephalopathy in a patient with multiple myeloma.

A 43-year-old woman with stage IIIA light-chain multiple myeloma presented to the hospital with lethargy and a left molar mass. She had not received chemotherapy during the four months before admission. On physical examination, the patient was alert, oriented, and afebrile, with a left-sided upper molar mass measuring 5 by 6 cm. Electrolyte, blood urea nitrogen, creatinine, and calcium levels were unremarkable. Biopsy of the left molar mass revealed a plasmacytoma. The patient became increasingly confused during her hospital course. Computed tomography (CT) and magnetic resonance imaging of the head were negative. A lumbar puncture showed only mildly increased intracranial pressure. The results of chest radiography and cultures of blood, cerebrospinal fluid, and urine were unremarkable. Further evaluation revealed a primary respiratory alkalosis with a secondary metabolic acidosis (pH, 7.66; carbon dioxide, 11 mmol per liter; and bicarbonate, 14 mmol per liter) and an elevated ammonia level (172 μmol per liter). Liver-function tests and abdominal CT showed no evidence of hepatic dysfunction. The patient had not received salicylates.

Renal dialysis was begun. The patient's mental status improved, but elevated ammonia levels quickly recurred between dialysis treatments (Figure 1Figure 1Serum Ammonia Levels before and after Treatment with Hemodialysis and Chemotherapy in a Patient with Multiple Myeloma.). Therapy with cyclophosphamide (2 g given intravenously for two days) led to a reduction in ammonia levels to less than 10 μmol per liter over a period of five days without dialysis and a concurrent marked decrease in the size of the plasmacytoma. The patient's mental status returned to normal, and the respiratory alkalosis cleared. Ammonia levels remained below 50 μmol per liter for four weeks.

Our patient's encephalopathy was most likely due to hyperammonemia. Hyperammonemia has infrequently been reported after bone marrow transplantation and high-dose chemotherapy.1 She had not previously received high-dose chemotherapy, and her last treatment with vincristine, doxorubicin, and dexamethasone had been administered more than four months before admission. The striking and persistent reduction in ammonia levels within five days after cyclophosphamide infusion and the concurrent decrease in the size of the plasmacytoma suggest an association between the production of ammonia and the myeloma. We are aware of only very rare reports of such an association.2,3 One instance involved in vitro production of ammonia by a human myeloma cell line.2 In patients with multiple myeloma and altered mental status without a clear cause, primary hyperammonemic encephalopathy should be considered in the differential diagnosis.

Lawrence Kwan, M.D.
Clifford Wang, M.D.
Santa Clara Valley Medical Center, San Jose, CA 95128

Lee Levitt, M.D.
Stanford University School of Medicine, Stanford, CA 94305
lee.levitt@hhs.co.santa-clara.ca.us

3 References

1. 1

   Mitchell RB, Wagner JE, Karp JE, et al. Syndrome of idiopathic hyperammonemia after high-dose chemotherapy: review of nine cases. Am J Med 1988;85:662-667
   CrossRef | Web of Science | Medline

2. 2

   Otsuki T, Yamada O, Sakaguchi H, et al. In vitro excess ammonia production in human myeloma cell lines. Leukemia 1998;12:1149-1158
   CrossRef | Web of Science | Medline

3. 3

   Martinelli G, Peccatori F, Ullrich B, Ghielmini M, Roggero E, Goldhirsch A. Clinical manifestation of severe hyperammonaemia in patients with multiple myeloma. Ann Oncol 1997;8:811-811
   CrossRef | Web of Science | Medline

Citing Articles (8)

Citing Articles

1. 1

   Ido Laish, Ziv Ben Ari. (2011) Noncirrhotic hyperammonaemic encephalopathy. Liver International 31:9, 1259-1270
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2. 2

   Ari Auron, Patrick D. Brophy. (2011) Hyperammonemia in review: pathophysiology, diagnosis, and treatment. Pediatric Nephrology
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   Orhan Turken, C. Basekim, A. Haholu, B. Karagoz, O. Bilgi, A. Ozgun, Y. Kucukardalı, Y. Narin, Y. Yazgan, E. G. Kandemir. (2009) Hyperammonemic encephalopathy in a patient with primary hepatic neuroendocrine carcinoma. Medical Oncology 26:3, 309-313
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   Klaus H. Metzeler, Stefan Boeck, Birgit Christ, Andreas Hausmann, Hans-Joachim Stemmler, Klaus G. Parhofer, Helmut Ostermann, Wolfgang Hiddemann, Jan Braess. (2009) Idiopathic hyperammonemia (IHA) after dose-dense induction chemotherapy for acute myeloid leukemia: Case report and review of the literature. Leukemia Research 33:7, e69-e72
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5. 5

   Junji Ikewaki, Masao Ogata, Tomoyuki Imamura, Kazuhiro Kohno, Toshiyuki Nakayama, Jun-Ichi Kadota. (2009) Development of hyperammonemic encephalopathy in patients with multiple myeloma may be associated with the appearance of peripheral blood myeloma cells. Leukemia & Lymphoma 50:4, 667-669
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6. 6

   C. Shenoy. (2007) Hyperammonaemic encephalopathy in plasma cell leukaemia. Internal Medicine Journal 37:11, 784-786
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7. 7

   Louise Nott, Timothy J. Price, Ken Pittman, Kevin Patterson, Janice Fletcher. (2007) Hyperammonemia encephalopathy: An important cause of neurological deterioration following chemotherapy. Leukemia & Lymphoma 48:9, 1702-1711
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8. 8

   Yuri Kim, Jin Seok Kim, Sun Young Park, In Hae Park, June-Won Cheong, Seung Tae Lee, Yoo Hong Min, Jee Sook Hahn, Jeong-Hae Kie. (2005) A Case of Serum Amino Acid Disturbance with Hyperammonemia in Patient with Primary Amyloidosis. The Korean Journal of Hematology 40:1, 54
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