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Acute lethal encephalopathy in systemic juvenile rheumatoid arthritis
Acute Lethal Encephalopathy in Systemic Juvenile Rheumatoid Arthritis Hideki Ueno, MD, PhD, Kenji Katamura, MD, PhD, Haruo Hattori, MD, PhD, Yoshimichi Yamaguchi, MD, and Tatsutoshi Nakahata, MD, PhD Macrophage activation syndrome is the most common cause of death in children with systemic juvenile rheumatoid arthritis. We present a first patient with systemic juvenile rheumatoid arthritis in which acute necrotizing encephalopathy developed as a complication of macrophage activation syndrome but not of Reye’s syndrome. The suspected mechanism of this lethal complication is discussed. © 2002 by Elsevier Science Inc. All rights reserved. Ueno H, Katamura K, Hattori H, Yamaguchi Y, Nakahata T. Acute lethal encephalopathy in systemic juvenile rheumatoid arthritis. Pediatr Neurol 2002;26:315-317.
Introduction Systemic juvenile rheumatoid arthritis is characterized by many extra-articular symptoms, such as quotidian fever accompanied by erythematous macular rash, hepatosplenomegaly, lymphadenopathy, and serositis. Occasionally its course becomes life threatening, especially when macrophage activation syndrome develops during the acute phase of the disease [1-4]. Macrophage activation syndrome has been suggested to be caused by extensively activated T cells and macrophages. The increase in the level of inflammatory cytokines secreted from these cells plays a pivotal role in this condition. Macrophage activation syndrome is characterized by sustained fever, rapid
From the Department of Pediatrics, Kyoto University Hospital, Kyoto, Japan.
© 2002 by Elsevier Science Inc. All rights reserved. PII S0887-8994(01)00394-0 ● 0887-8994/02/$—see front matter
depression of all three blood cell lines, coagulation disturbances, and elevated serum transferase values. During the active phase of systemic juvenile rheumatoid arthritis, acute encephalopathy may develop as a complication of Reye’s syndrome in the presence of high-dose therapy with nonsteroidal anti-inflammatory drugs [5], although there have been no studies reporting that acute encephalopathy develops as a complication of macrophage activation syndrome. We present a first patient with systemic juvenile rheumatoid arthritis suggesting that macrophage activation syndrome also causes lethal acute encephalopathy. Case Report A 1-year-old male was admitted for evaluation of high-grade fever accompanied by erythematous rash. He had a history of idiopathic thrombocytopenic purpura, which occurred at 3 months of age and resolved spontaneously without any medications. There was no family history of autoimmune or hematologic diseases. Two weeks before admission, a urticaria-form salmon-pink rash had appeared on his legs and arms and was not accompanied by fever. Two days before admission, body temperature elevated beyond 39°C, and he grew gradually reluctant to walk. On examination, surface lymph nodes were not significantly swollen, and the size of the liver and spleen was normal. Laboratory study revealed a mild leukocytosis of 12,100/L with 70% of neutrophils, all of which had segmented nuclei (Table 1). Rheumatoid factor was absent. Intravenous (IV) administration of antibiotics (Flomoxef and Panipenem) was ineffective to resolve fever and rash. Serologic investigations for Cytomegalovirus, Epstein-Barr virus, and Mycoplasma were negative. Multiple joints, including knee, ankle, hip, and fingers, progressively became warm and swollen, and quotidian fever appeared. C-reactive protein reached a peak of 18.3 mg/dL on day 6 after admission. Computed tomography of his neck, chest, and abdomen revealed no findings of malignancy. The synovial fluid sampled from the knee joint on day 8 had a yellowish-clouded appearance. Microscopic analysis of the fluid revealed dense infiltration of lymphocytes, although the culture was negative. Bone marrow examination revealed myeloid hyperplasia and mild hemophagocytosis. The patient was diagnosed as having systemic juvenile rheumatoid arthritis according to the criteria of the American College of Rheumatology, and treatment with aspirin, 40 mg/kg/day, was begun on day 13. Aspirin therapy failed to resolve quotidian fever even at a higher amount (60 mg/kg/day). Twelve days after the initiation of aspirin therapy, on day 24, the maculopapular rash worsened into reddish large eruptions. Physical examination revealed many swollen surface lymph nodes and hepatosplenomegaly. Laboratory tests revealed thrombocytopenia and elevation of lactic dehydrogenate and serum transferase activity, suggesting the development of macrophage activation syndrome (Table 1). Steroid therapy with 2 mg/kg/day of prednisolone was begun, and aspirin therapy was stopped. Two days after steroid therapy began, reddish large eruptions abruptly expanded to his total body and formed fusion. He became acutely ill and intemperate and suffered persistent unremitting fever. Laboratory examination re-
Communications should be addressed to: Dr. Ueno, Baylor Institute for Immunology Research, 3434 Live Oak, Dallas TX 75204. Received May 17, 2001; accepted November 12, 2001.
Ueno et al: Encephalopathy in Juvenile Rheumatoid Arthritis 315
Table 1.
Discussion
Laboratory data Normal Day Day 24 Values Admission 22 (Encephalitis)
Fibrinogen (mg/dL) 200-400 Leukocytes (⫻109/L) 6-17.5 Platelets (⫻109/L) 150-400 Aspartate aminotransferase 15-55 (IU/L) Alanin aminotransferase 5-45 (IU/L) Lactic dehydrogenase 150-500 (IU/L) C-reactive protein (mg/dL) ⬍0.3
550 12.1 197 25
ND 19.7 94 138
74 11.3 50 269
17
15
27
357
2153
⬎2428
7.8
20.5
18.6
Abbreviation: ND ⫽ Not done
vealed progressive thrombocytopenia complicated by coagulation abnormality (Table 1). Notably, although the serum aspartate aminotransferase level was high, the serum ammonia level was normal, suggesting the absence of massive liver dysfunction. Serum levels of ferritin (32,099 ng/mL; normal, 7-140) and soluble interleukin-2 receptor (4,910 U/mL; age-matched normal, 341-2337 [6]) were markedly elevated, implying the increase of the level of inflammatory cytokines secreted from excessively activated lymphoid cells. In fact, serum concentrations of tumor-necrosis factor ␣ and interferon ␥ were increased to 20.5 pg/mL (normal range ⫽ less than 7.5 pg/mL) and 5.8 IU/mL (normal range ⫽ less than 0.5 IU/mL), respectively. We diagnosed these findings as evidence of exacerbation of macrophage activation syndrome. In the afternoon on that day the patient progressively lost consciousness, followed by generalized seizure and deep coma. Cranial computed tomography taken 3 hours after the seizure revealed symmetric lowdensity areas in the thalamus and brainstem tegmentum (Fig 1). The low-density areas in computed tomography markedly expanded to the whole cerebrum only over the next 5 hours. The time course and distribution in cranial lesions were identical to those of acute necrotizing encephalopathy, which is usually observed after infection with influenza A virus [7]. The patient never regained consciousness despite intensive treatments for acute necrotizing encephalopathy, and 4 days later, on day 30, he was diagnosed as clinically brain-dead.
Macrophage activation syndrome is a serious complication of systemic juvenile rheumatoid arthritis associated with considerable morbidity and death and requires prompt recognition and treatment [1-4]. In typical cases of macrophage activation syndrome, patients with chronic conditions become acutely ill with persistent fever, mental status changes, lymphadenopathy, hepatosplenomegaly, and often have easy bruising and mucosal bleeding. Laboratory examinations reveal profound depression of all three blood cell lines, low erythrocyte sedimentation rate, elevated serum liver enzyme values, and coagulation abnormalities. In our patient, we diagnosed macrophage activation syndrome in light of clinical manifestations and laboratory tests exhibiting hypofibrinogemia and thrombocytopenia. Markedly increased levels of serum ferritin, serum soluble interleukin-2 receptor, and inflammatory cytokines, such as interferon ␥ and tumor necrosis factor ␣, supported the status of hypercytokinemia, which has been suggested to play a pivotal role in the development of macrophage activation syndrome. A milder form of macrophage activation syndrome may have already been present before day 24, the day on which macrophage activation syndrome was suggested to be exacerbated, given that levels of serum ferritin and interferon ␥ had already demonstrated a mild increase on day 4 (3,621 ng/mL and 1.0 IU/mL, respectively). In addition, bone marrow examination performed on day 8 revealed some hemophagocytic histiocytes, which directly exhibited the hyperactivated status of macrophages. During the course of aspirin therapy, macrophage activation syndrome developed suddenly into fulminant form, which was resistant to steroid therapy at a conventional dose. Many triggers for macrophage activation syndrome have been proposed, including gold therapy, nonsteroidal anti-inflammatory drugs, and viral infections [1-4,8,9]. In our patient, there is
Figure 1. Cranial computed tomography revealed acute necrotizing encephalopathy. Low-density areas appeared symmetrically in the thalamus and brainstem tegmentum.
316
PEDIATRIC NEUROLOGY
Vol. 26 No. 4
a possibility that aspirin accelerated the exacerbation of macrophage activation syndrome. In aspirin therapy in juvenile rheumatoid arthritis, however, hepatic dysfunction is generally observed only when the serum salicylate levels are greater than 25 mg/dL. In consideration of the fact that the serum salicylate level was not high (4.63 mg/dL), 2 days before cessation of aspirin therapy, it is not conceivable that salicylate alone triggered the exacerbation of macrophage activation syndrome. Alternatively, macrophage activation syndrome may have developed along with the exacerbation of systemic juvenile rheumatoid arthritis itself, without any trigger. There was no evidence or symptoms of current or recent viral infection. Two days after the initiation of steroid therapy, acute encephalopathy developed, causing generalized seizure and deep coma, followed by brain death only a few days later. Cranial computed tomography revealed symmetric low-density areas in the thalamus, which expanded into the whole cerebrum over several hours. These dramatic clinical and radiologic changes are observed in acute necrotizing encephalopathy [7]. Acute necrotizing encephalopathy was recently established as a novel disease entity and is frequently observed after viral infections, such as influenza viruses and human herpesvirus. Acute necrotizing encephalopathy has often been confused with Reye’s syndrome because no significant difference in laboratory examinations, except for the absence of hyperammonemia and lactic acidemia in acute necrotizing encephalopathy, has been present. The most striking difference between these two entities is revealed by radiologic findings. Acute necrotizing encephalopathy is characterized by multifocal gray matter lesions in the thalamus, brainstem tegmentum, and cerebellar dentate nucleus during the acute phase [7]. In contrast, radiologic findings in Reye’s syndrome are essentially limited to brain edema [10]. Thus in our patient, the changes in radiologic findings strongly suggested the development of acute necrotizing encephalopathy, not of Reye’s syndrome. Given that recent reports have demonstrated the possible involvement of hypercytokinemia, including interferon ␥ and tumor necrosis factor ␣, in the development of acute necrotizing encephalopathy [11], it is conceivable that macrophage activation
syndrome complicating systemic juvenile rheumatoid arthritis may cause acute necrotizing encephalopathy. This is the first report of a patient with systemic juvenile rheumatoid arthritis in which lethal acute encephalopathy may have been induced by macrophage activation syndrome, but not by Reye’s syndrome. High-dose parenteral steroid administration is the usual treatment strategy for macrophage activation syndrome. It has been reported, however, that macrophage activation syndrome can be treated more effectively by cyclosporine A [1,2]. We conclude that early diagnosis and appropriate therapy of macrophage activation syndrome is necessary to avoid this dreadful complication.
References [1] Ravelli A, De Benedetti F, Viola S, Martini A. Macrophage activation syndrome in systemic juvenile rheumatoid arthritis successfully treated with cyclosporine. J Pediatr 1996;128:275-8. [2] Mouy R, Stephan JL, Pillet P, Haddad E, Hubert P, Prieur AM. Efficacy of cyclosporine A in the treatment of macrophage activation syndrome in juvenile arthritis: Report of five cases. J Pediatr 1996;129: 750-4. [3] Stephan JL, Zeller J, Hubert P, Herbelin C, Dayer JM, Prieur AM. Macrophage activation syndrome and rheumatic disease in childhood: A report of four new cases. Clin Exp Rheumatol 1993;11:451-6. [4] Prieur AM, Stephan JL. Macrophage activation syndrome in rheumatic diseases in children. Rev Rhem [Engl Ed] 1994;61:385-8. [5] Ulshen MH, Grand, RJ, Crain JD, Gelfand EW. Hepatotoxicity with encephalopathy associated with aspirin therapy in rheumatoid arthritis. J Pediatr 1978;93:1034-7. [6] Komp DM, Shapio E, McNamara J. Soluble interleukin-2 receptor in childhood non-Hodgkin’s lymphoma [letter]. Blood 1988;71: 1172-4. [7] Mizuguchi M. Acute necrotizing encephalopathy of childhood: A novel form of acute encephalopathy prevalent in Japan and Taiwan. Brain Dev 1997;19:81-92. [8] Hadchouel M, Prieur AM, Grisccelli C. Acute hemorrhagic, hepatic, and neurologic manifestations in juvenile rheumatoid arthritis: Possible relationship to drugs or infection. J Pediatr 1985;106:561-6. [9] Everson GW, Krenzelok EP. Chronic salicylism in a patient with juvenile rheumatoid arthritis. Clin Pharm 1986;5:334-41. [10] Evans H, Bourgeois CH, Comer DS, Keschamras N. Brain lesions in Reye’s syndrome. Arch Pathol 1970;90:543-6. [11] Yokota S, Imagawa T, Miyamae T, et al. Hypothetical pathophysiology of acute encephalopathy and encephalitis related to influenza virus infection and hypothermia. Pediatr Int 2000;42:197-203.
Ueno et al: Encephalopathy in Juvenile Rheumatoid Arthritis 317
Introduction Systemic juvenile rheumatoid arthritis is characterized by many extra-articular symptoms, such as quotidian fever accompanied by erythematous macular rash, hepatosplenomegaly, lymphadenopathy, and serositis. Occasionally its course becomes life threatening, especially when macrophage activation syndrome develops during the acute phase of the disease [1-4]. Macrophage activation syndrome has been suggested to be caused by extensively activated T cells and macrophages. The increase in the level of inflammatory cytokines secreted from these cells plays a pivotal role in this condition. Macrophage activation syndrome is characterized by sustained fever, rapid
From the Department of Pediatrics, Kyoto University Hospital, Kyoto, Japan.
© 2002 by Elsevier Science Inc. All rights reserved. PII S0887-8994(01)00394-0 ● 0887-8994/02/$—see front matter
depression of all three blood cell lines, coagulation disturbances, and elevated serum transferase values. During the active phase of systemic juvenile rheumatoid arthritis, acute encephalopathy may develop as a complication of Reye’s syndrome in the presence of high-dose therapy with nonsteroidal anti-inflammatory drugs [5], although there have been no studies reporting that acute encephalopathy develops as a complication of macrophage activation syndrome. We present a first patient with systemic juvenile rheumatoid arthritis suggesting that macrophage activation syndrome also causes lethal acute encephalopathy. Case Report A 1-year-old male was admitted for evaluation of high-grade fever accompanied by erythematous rash. He had a history of idiopathic thrombocytopenic purpura, which occurred at 3 months of age and resolved spontaneously without any medications. There was no family history of autoimmune or hematologic diseases. Two weeks before admission, a urticaria-form salmon-pink rash had appeared on his legs and arms and was not accompanied by fever. Two days before admission, body temperature elevated beyond 39°C, and he grew gradually reluctant to walk. On examination, surface lymph nodes were not significantly swollen, and the size of the liver and spleen was normal. Laboratory study revealed a mild leukocytosis of 12,100/L with 70% of neutrophils, all of which had segmented nuclei (Table 1). Rheumatoid factor was absent. Intravenous (IV) administration of antibiotics (Flomoxef and Panipenem) was ineffective to resolve fever and rash. Serologic investigations for Cytomegalovirus, Epstein-Barr virus, and Mycoplasma were negative. Multiple joints, including knee, ankle, hip, and fingers, progressively became warm and swollen, and quotidian fever appeared. C-reactive protein reached a peak of 18.3 mg/dL on day 6 after admission. Computed tomography of his neck, chest, and abdomen revealed no findings of malignancy. The synovial fluid sampled from the knee joint on day 8 had a yellowish-clouded appearance. Microscopic analysis of the fluid revealed dense infiltration of lymphocytes, although the culture was negative. Bone marrow examination revealed myeloid hyperplasia and mild hemophagocytosis. The patient was diagnosed as having systemic juvenile rheumatoid arthritis according to the criteria of the American College of Rheumatology, and treatment with aspirin, 40 mg/kg/day, was begun on day 13. Aspirin therapy failed to resolve quotidian fever even at a higher amount (60 mg/kg/day). Twelve days after the initiation of aspirin therapy, on day 24, the maculopapular rash worsened into reddish large eruptions. Physical examination revealed many swollen surface lymph nodes and hepatosplenomegaly. Laboratory tests revealed thrombocytopenia and elevation of lactic dehydrogenate and serum transferase activity, suggesting the development of macrophage activation syndrome (Table 1). Steroid therapy with 2 mg/kg/day of prednisolone was begun, and aspirin therapy was stopped. Two days after steroid therapy began, reddish large eruptions abruptly expanded to his total body and formed fusion. He became acutely ill and intemperate and suffered persistent unremitting fever. Laboratory examination re-
Communications should be addressed to: Dr. Ueno, Baylor Institute for Immunology Research, 3434 Live Oak, Dallas TX 75204. Received May 17, 2001; accepted November 12, 2001.
Ueno et al: Encephalopathy in Juvenile Rheumatoid Arthritis 315
Table 1.
Discussion
Laboratory data Normal Day Day 24 Values Admission 22 (Encephalitis)
Fibrinogen (mg/dL) 200-400 Leukocytes (⫻109/L) 6-17.5 Platelets (⫻109/L) 150-400 Aspartate aminotransferase 15-55 (IU/L) Alanin aminotransferase 5-45 (IU/L) Lactic dehydrogenase 150-500 (IU/L) C-reactive protein (mg/dL) ⬍0.3
550 12.1 197 25
ND 19.7 94 138
74 11.3 50 269
17
15
27
357
2153
⬎2428
7.8
20.5
18.6
Abbreviation: ND ⫽ Not done
vealed progressive thrombocytopenia complicated by coagulation abnormality (Table 1). Notably, although the serum aspartate aminotransferase level was high, the serum ammonia level was normal, suggesting the absence of massive liver dysfunction. Serum levels of ferritin (32,099 ng/mL; normal, 7-140) and soluble interleukin-2 receptor (4,910 U/mL; age-matched normal, 341-2337 [6]) were markedly elevated, implying the increase of the level of inflammatory cytokines secreted from excessively activated lymphoid cells. In fact, serum concentrations of tumor-necrosis factor ␣ and interferon ␥ were increased to 20.5 pg/mL (normal range ⫽ less than 7.5 pg/mL) and 5.8 IU/mL (normal range ⫽ less than 0.5 IU/mL), respectively. We diagnosed these findings as evidence of exacerbation of macrophage activation syndrome. In the afternoon on that day the patient progressively lost consciousness, followed by generalized seizure and deep coma. Cranial computed tomography taken 3 hours after the seizure revealed symmetric lowdensity areas in the thalamus and brainstem tegmentum (Fig 1). The low-density areas in computed tomography markedly expanded to the whole cerebrum only over the next 5 hours. The time course and distribution in cranial lesions were identical to those of acute necrotizing encephalopathy, which is usually observed after infection with influenza A virus [7]. The patient never regained consciousness despite intensive treatments for acute necrotizing encephalopathy, and 4 days later, on day 30, he was diagnosed as clinically brain-dead.
Macrophage activation syndrome is a serious complication of systemic juvenile rheumatoid arthritis associated with considerable morbidity and death and requires prompt recognition and treatment [1-4]. In typical cases of macrophage activation syndrome, patients with chronic conditions become acutely ill with persistent fever, mental status changes, lymphadenopathy, hepatosplenomegaly, and often have easy bruising and mucosal bleeding. Laboratory examinations reveal profound depression of all three blood cell lines, low erythrocyte sedimentation rate, elevated serum liver enzyme values, and coagulation abnormalities. In our patient, we diagnosed macrophage activation syndrome in light of clinical manifestations and laboratory tests exhibiting hypofibrinogemia and thrombocytopenia. Markedly increased levels of serum ferritin, serum soluble interleukin-2 receptor, and inflammatory cytokines, such as interferon ␥ and tumor necrosis factor ␣, supported the status of hypercytokinemia, which has been suggested to play a pivotal role in the development of macrophage activation syndrome. A milder form of macrophage activation syndrome may have already been present before day 24, the day on which macrophage activation syndrome was suggested to be exacerbated, given that levels of serum ferritin and interferon ␥ had already demonstrated a mild increase on day 4 (3,621 ng/mL and 1.0 IU/mL, respectively). In addition, bone marrow examination performed on day 8 revealed some hemophagocytic histiocytes, which directly exhibited the hyperactivated status of macrophages. During the course of aspirin therapy, macrophage activation syndrome developed suddenly into fulminant form, which was resistant to steroid therapy at a conventional dose. Many triggers for macrophage activation syndrome have been proposed, including gold therapy, nonsteroidal anti-inflammatory drugs, and viral infections [1-4,8,9]. In our patient, there is
Figure 1. Cranial computed tomography revealed acute necrotizing encephalopathy. Low-density areas appeared symmetrically in the thalamus and brainstem tegmentum.
316
PEDIATRIC NEUROLOGY
Vol. 26 No. 4
a possibility that aspirin accelerated the exacerbation of macrophage activation syndrome. In aspirin therapy in juvenile rheumatoid arthritis, however, hepatic dysfunction is generally observed only when the serum salicylate levels are greater than 25 mg/dL. In consideration of the fact that the serum salicylate level was not high (4.63 mg/dL), 2 days before cessation of aspirin therapy, it is not conceivable that salicylate alone triggered the exacerbation of macrophage activation syndrome. Alternatively, macrophage activation syndrome may have developed along with the exacerbation of systemic juvenile rheumatoid arthritis itself, without any trigger. There was no evidence or symptoms of current or recent viral infection. Two days after the initiation of steroid therapy, acute encephalopathy developed, causing generalized seizure and deep coma, followed by brain death only a few days later. Cranial computed tomography revealed symmetric low-density areas in the thalamus, which expanded into the whole cerebrum over several hours. These dramatic clinical and radiologic changes are observed in acute necrotizing encephalopathy [7]. Acute necrotizing encephalopathy was recently established as a novel disease entity and is frequently observed after viral infections, such as influenza viruses and human herpesvirus. Acute necrotizing encephalopathy has often been confused with Reye’s syndrome because no significant difference in laboratory examinations, except for the absence of hyperammonemia and lactic acidemia in acute necrotizing encephalopathy, has been present. The most striking difference between these two entities is revealed by radiologic findings. Acute necrotizing encephalopathy is characterized by multifocal gray matter lesions in the thalamus, brainstem tegmentum, and cerebellar dentate nucleus during the acute phase [7]. In contrast, radiologic findings in Reye’s syndrome are essentially limited to brain edema [10]. Thus in our patient, the changes in radiologic findings strongly suggested the development of acute necrotizing encephalopathy, not of Reye’s syndrome. Given that recent reports have demonstrated the possible involvement of hypercytokinemia, including interferon ␥ and tumor necrosis factor ␣, in the development of acute necrotizing encephalopathy [11], it is conceivable that macrophage activation
syndrome complicating systemic juvenile rheumatoid arthritis may cause acute necrotizing encephalopathy. This is the first report of a patient with systemic juvenile rheumatoid arthritis in which lethal acute encephalopathy may have been induced by macrophage activation syndrome, but not by Reye’s syndrome. High-dose parenteral steroid administration is the usual treatment strategy for macrophage activation syndrome. It has been reported, however, that macrophage activation syndrome can be treated more effectively by cyclosporine A [1,2]. We conclude that early diagnosis and appropriate therapy of macrophage activation syndrome is necessary to avoid this dreadful complication.
References [1] Ravelli A, De Benedetti F, Viola S, Martini A. Macrophage activation syndrome in systemic juvenile rheumatoid arthritis successfully treated with cyclosporine. J Pediatr 1996;128:275-8. [2] Mouy R, Stephan JL, Pillet P, Haddad E, Hubert P, Prieur AM. Efficacy of cyclosporine A in the treatment of macrophage activation syndrome in juvenile arthritis: Report of five cases. J Pediatr 1996;129: 750-4. [3] Stephan JL, Zeller J, Hubert P, Herbelin C, Dayer JM, Prieur AM. Macrophage activation syndrome and rheumatic disease in childhood: A report of four new cases. Clin Exp Rheumatol 1993;11:451-6. [4] Prieur AM, Stephan JL. Macrophage activation syndrome in rheumatic diseases in children. Rev Rhem [Engl Ed] 1994;61:385-8. [5] Ulshen MH, Grand, RJ, Crain JD, Gelfand EW. Hepatotoxicity with encephalopathy associated with aspirin therapy in rheumatoid arthritis. J Pediatr 1978;93:1034-7. [6] Komp DM, Shapio E, McNamara J. Soluble interleukin-2 receptor in childhood non-Hodgkin’s lymphoma [letter]. Blood 1988;71: 1172-4. [7] Mizuguchi M. Acute necrotizing encephalopathy of childhood: A novel form of acute encephalopathy prevalent in Japan and Taiwan. Brain Dev 1997;19:81-92. [8] Hadchouel M, Prieur AM, Grisccelli C. Acute hemorrhagic, hepatic, and neurologic manifestations in juvenile rheumatoid arthritis: Possible relationship to drugs or infection. J Pediatr 1985;106:561-6. [9] Everson GW, Krenzelok EP. Chronic salicylism in a patient with juvenile rheumatoid arthritis. Clin Pharm 1986;5:334-41. [10] Evans H, Bourgeois CH, Comer DS, Keschamras N. Brain lesions in Reye’s syndrome. Arch Pathol 1970;90:543-6. [11] Yokota S, Imagawa T, Miyamae T, et al. Hypothetical pathophysiology of acute encephalopathy and encephalitis related to influenza virus infection and hypothermia. Pediatr Int 2000;42:197-203.
Ueno et al: Encephalopathy in Juvenile Rheumatoid Arthritis 317