- Email: [email protected]
Salmonella encephalopathy successfully treated with high-dose methylpredonisolone therapy
Brain & Development 31 (2009) 782–784 www.elsevier.com/locate/braindev
Case report
Salmonella encephalopathy successfully treated with high-dose methylpredonisolone therapy Kazushi Ichikawa *, Akiko Kajitani, Akiko Tsutsumi, Saoko Takeshita Department of Pediatrics, Yokohama City University Medical Center, 4-57 Urafune-cho, Minami-ku, Yokohama 232-0024, Japan Received 6 September 2008; received in revised form 20 December 2008; accepted 27 December 2008
Abstract We present a 7-year-old boy diagnosed as having salmonella encephalopathy. He developed severe consciousness disturbance following enterocolitis. Electroencephalography showed diffuse and high-voltage slow activity but MR images of the brain were normal. Examination of inflammatory cytokines in serum and cerebrospinal fluid revealed high levels of interleukin-6, -8, and -10, and interferon gamma. Salmonella typhimurium was detected in a stool specimen. He was diagnosed as having salmonella-associated encephalopathy that had features of septic encephalopathy and quickly responded to high-dose methylpredonisolone therapy. High-dose methylpredonisolone was considered to be an effective treatment for hypercytokine-mediated S. encephalopathy. Ó 2009 Elsevier B.V. All rights reserved. Keywords: Salmonellosis; Salmonella typhimurium; Salmonella encephalopathy; Septic encephalopathy; Cytokine; High-dose methylpredonisolone
1. Introduction Non-typhi salmonella causes enterocolitis associated with food poisoning due to contaminated eggs. The clinical features of salmonellosis are abdominal cramps, diarrhea and fever. It has been known that salmonellosis is sometimes complicated by severe extraintestinal manifestations such as sepsis, meningitis, arthritis, osteomyelitis and acute encephalopathy [1]. However, there have only been a small number of reports on salmonella-associated encephalopathy. Also, the pathophysiology of salmonella-associated encephalopathy has not been disclosed sufficiently. On the other hand, an encephalopathy complicated by sepsis is referred to as septic encephalopathy, which is a common form of encephalopathy in intensive care units. It has been reported that septic encephalopathy is more likely to be caused by
*
Corresponding author. Tel.: +81 45 261 5656; fax: +81 45 243 3886. E-mail address: [email protected] (K. Ichikawa). 0387-7604/$ - see front matter Ó 2009 Elsevier B.V. All rights reserved. doi:10.1016/j.braindev.2008.12.019
mediators of inflammation such as cytokines and characteristic changes in the blood brain barrier. We present a case of salmonella encephalopathy that had a good outcome, treated with high-dose methylpredonisolone therapy. 2. Case report A Japanese boy aged 7 years developed fever, abdominal cramps and diarrhea, and drowsiness appeared 12 h after the onset of enterocolitis. He had taken a raw egg and raw fish 2 days before. His family members did not suffer from enterocolitis. There was no family history of neurological disorders and his psychomotor development had been normal. He had one convulsion and then became comatose. No meningeal sign was noted. He had a fever of 40.2 °C, blood pressure of 79/40 mmHg and a heart rate of 168 min 1. Hematological examinations revealed: white blood cell count, 5470 mm 3; hemoglobin, 13.1 g/dl; platelet count, 16.9 104 mm 3; PT, 41%; APTT, 48.1 s; fibrinogen, 457 mg/dl; D-dimer,
K. Ichikawa et al. / Brain & Development 31 (2009) 782–784
7.2 lg/ml; CRP, 12.17 mg/dl; total protein, 5.9 g/dl; albumin, 3.8 g/dl; AST, 41 U/L; ALT, 37 U/L; LDH, 266 U/L; CPK, 144 U/L; blood urea nitrogen, 24 mg/ dl; creatinine, 0.59 mg/dl; Na, 129 mEq/L; K, 3.8 mEq/ L; and Cl, 96 mEq/L. The glucose titer was 145 mg/dl and the ammonia level was 53 mg/dl. The lactate and pyruvate levels were 9.0 and 0.8 mg/dl, respectively. Blood gas analysis revealed: pH, 7.386; base excess, 4.2 mmol/L; and anion gap, +7.3 mmol/L. The serum b-hydroxybutyrate level was 95 lmol/L. The results of cerebrospinal fluid (CSF) examination of traumatic tap were as follows: leukocyte count, 16 mm 3; glucose, 78 mg/dl; protein, 108 mg/dl; lactate, 30.5 mg/dl; and pyruvate, 1.9 mg/dl. The CSF pressure was not high. The result for serum endotoxins was negative. The cytokine, i.e., interferon gamma, tumor necrosis factoralpha, and interleukin (IL)-6, -8, -10 and -1b, levels in serum were 1080.35 pg/ml, 5.34 pg/ml, 3085.86 pg/ml, 1374.19 pg/ml, 301 pg/ml and 41.11 pg/ml, respectively. Those in CSF were 29.81 pg/ml, 0 pg/ml, 1912.77 pg/ml, 1179.96 pg/ml, 14.29 pg/ml and 6.68 pg/ml, respectively. Computed tomography of the brain was normal, and electroencephalography (EEG) showed abnormally diffuse high-voltage slow activity without epileptiform discharges (Fig. 1). We diagnosed him as having acute encephalopathy associated with bacterial enterocolitis, and then he was managed with ventilator support in an intensive care unit. He was treated with high-dose methylpredonisolone at the dose of 30 mg/kg daily for three consecutive days. Mannitol and edaravon were simultaneously administered for 8 and 5 days, respectively. Antibacterial agents, ceftriaxone and fosfomycin, were administered intravenously. Magnetic resonance images of the brain on the second and fifth hospital days were normal. Single photon emission computed tomography of the brain 8 days after hospitalization showed no abnormalities. Salmonella typhimurium, a non-typhi salmonella species, was cultured from a stool, but the result for a blood culture and CSF culture were nega-
Fig. 1. EEG on first day of hospitalization showing diffuse and highvoltage slow activity in background.
783
tive. His consciousness had become normal by the third day and the EEG on the eighth days was normal. He could leave the hospital 12 days after admission without any sequelae. 3. Discussion Non-typhi salmonella infection is estimated to affect approximately 5000–10,000 per year in Japan, as reported by the Ministry of Health, Labour and Welfare of Japan. S. encephalopathy is a rare extraintestinal manifestations of salmonellosis. The clinical features of the encephalopathy include rapidly progressive brain dysfunction, such as consciousness disturbance and convulsions, subsequent to salmonella enteritis without severe dehydration or abnormality of electrolytes. The pathophysiology of the encephalopathy has not been disclosed, but an effect of endotoxins and cytokines on the central nervous system is speculated [2–4]. The present case showed severe consciousness disturbance a few hours following enteritis that was typical in salmonellaassociated encephalopathy previously reported. Septic encephalopathy has been reported as a common form of encephalopathy among patients in intensive care units. A diagnosis of septic encephalopathy requires impairment of the mental state and other neurological manifestations with evidence of extracranial infection. The involvement of hypoxemia, hypotension and peripheral organ failure should be excluded [5,6]. The pathophysiology of septic encephalopathy is likely to be multifactorial, but it was recently reported that systemic inflammatory mediators or a breakdown of the blood brain barrier have adverse effects on the brain [7]. Our case showed a systemic septic state with salmonella enterocolitis and his serum cytokine levels were high, especially those of IL-6, -8, and -10, and interferon c. Furthermore, the cytokines in the CSF also exhibiting high levels were the same as those in the serum. Although the CSF sample had contamination of the blood, we speculated the inflammatory cytokines were extremely high level in itself because of different proportions of each cytokine in the serum and CSF. Though there have been some reports of S. encephalopathy, it is presumed that S. encephalopathy involves various clinical courses, radiological findings and outcomes. Most cases of S. encephalopathy recover with antibacterial agents, however, 20% of the cases are left with some sequelae and 10% die, according to some previous reports. There has been no report about the effectiveness of steroids for S. encephalopathy. The present case, diagnosed as having salmonella-associated encephalopathy, had features of septic encephalopathy in terms of elevation of cytokines and normal MR images. Our case quickly recovered from the consciousness disturbance, which seemed to be earlier than in other reported cases that had not been treated with steroids, and he left without
784
K. Ichikawa et al. / Brain & Development 31 (2009) 782–784
any sequelae despite extremely high cytokine levels in the CSF [8]. Since a hypercytokine state induces some brain damage, it should be meaningful to use steroids as dexamethasone therapy for bacterial meningitis, as high-dose methylpredonisolone for influenza-associated encephalopathy [9,10]. High-dose methylpredonisolone should be tried as a treatment for S. encephalopathy, with adequate use of antibacterial agents, which is subsequently complicated by hypercytokinemia due to sepsis. In conclusion, a case of S. encephalopathy was reported. Some cases of S. encephalopathy are presumed to having features of septic encephalopathy. High-dose methylpredonisolone is a suitable treatment for hypercytokine-mediated S. encephalopathy. References [1] Hohmann EL. Nontyphoidal salmonellosis. Clin Infect Dis 2001;32:263–9. [2] Arii J, Tanabe Y, Miyake M, Mukai T, Matsuzaki M, Niinomi N, et al. Clinical and pathologic characteristics of nontyphoidal Salmonella encephalopathy. Neurology 2002;58:1641–5.
[3] Minami K, Yanagawa T, Okuda M, Suzuki H, Tamura A, Izumi G, et al. Cerebrospinal fluid cytokines in Salmonella urbana encephalopathy. Tohoku J Exp Med 2004;203: 129–32. [4] Fujita Y, Sakurai Y, Yoshida K, Shima M, Yoshioka A. A child with non-typhoidal Salmonella encephalopathy. Syounika Rinsho 2008;61:1035–40, [in Japanese]. [5] Davis NWS, Sharief MK, Howard RS. Infection-associated encephalopathies – their investigation, diagnosis, and treatment. J Neurol 2006;253:833–45. [6] Papadopoulos MC, Davis DC, Moss RF, Tighe D, Bennett ED. Pathophysiology of septic encephalopathy: a review. Crit Care Med 2000;28:3019–24. [7] Davis DC. Blood–brain barrier breakdown in septic encephalopathy and brain tumors. J Anat 2002;200:639–46. [8] Ichiyama T, Morishima T, Isumi H, Matsufuji H, Matsubara T, Furukawa S. Analysis of cytokine levels and NF-jB activation in peripheral blood mononuclear cells in influenza virus-associated encephalopathy. Cytokine 2004;27:31–7. [9] Yokota S, Imagawa T, Miyamae T, Ito S, Nakajima S, Nezu A, et al. Hypothetical pathophysiology of acute encephalopathy and encephalitis related to influenza virus infection and hypothermia therapy. Pediatr Int 2000;42:197–203. [10] Chaudhuri A. Adjunctive dexamethasone treatment in acute bacterial meningitis. Lancet 2004;3:54–62.
Case report
Salmonella encephalopathy successfully treated with high-dose methylpredonisolone therapy Kazushi Ichikawa *, Akiko Kajitani, Akiko Tsutsumi, Saoko Takeshita Department of Pediatrics, Yokohama City University Medical Center, 4-57 Urafune-cho, Minami-ku, Yokohama 232-0024, Japan Received 6 September 2008; received in revised form 20 December 2008; accepted 27 December 2008
Abstract We present a 7-year-old boy diagnosed as having salmonella encephalopathy. He developed severe consciousness disturbance following enterocolitis. Electroencephalography showed diffuse and high-voltage slow activity but MR images of the brain were normal. Examination of inflammatory cytokines in serum and cerebrospinal fluid revealed high levels of interleukin-6, -8, and -10, and interferon gamma. Salmonella typhimurium was detected in a stool specimen. He was diagnosed as having salmonella-associated encephalopathy that had features of septic encephalopathy and quickly responded to high-dose methylpredonisolone therapy. High-dose methylpredonisolone was considered to be an effective treatment for hypercytokine-mediated S. encephalopathy. Ó 2009 Elsevier B.V. All rights reserved. Keywords: Salmonellosis; Salmonella typhimurium; Salmonella encephalopathy; Septic encephalopathy; Cytokine; High-dose methylpredonisolone
1. Introduction Non-typhi salmonella causes enterocolitis associated with food poisoning due to contaminated eggs. The clinical features of salmonellosis are abdominal cramps, diarrhea and fever. It has been known that salmonellosis is sometimes complicated by severe extraintestinal manifestations such as sepsis, meningitis, arthritis, osteomyelitis and acute encephalopathy [1]. However, there have only been a small number of reports on salmonella-associated encephalopathy. Also, the pathophysiology of salmonella-associated encephalopathy has not been disclosed sufficiently. On the other hand, an encephalopathy complicated by sepsis is referred to as septic encephalopathy, which is a common form of encephalopathy in intensive care units. It has been reported that septic encephalopathy is more likely to be caused by
*
Corresponding author. Tel.: +81 45 261 5656; fax: +81 45 243 3886. E-mail address: [email protected] (K. Ichikawa). 0387-7604/$ - see front matter Ó 2009 Elsevier B.V. All rights reserved. doi:10.1016/j.braindev.2008.12.019
mediators of inflammation such as cytokines and characteristic changes in the blood brain barrier. We present a case of salmonella encephalopathy that had a good outcome, treated with high-dose methylpredonisolone therapy. 2. Case report A Japanese boy aged 7 years developed fever, abdominal cramps and diarrhea, and drowsiness appeared 12 h after the onset of enterocolitis. He had taken a raw egg and raw fish 2 days before. His family members did not suffer from enterocolitis. There was no family history of neurological disorders and his psychomotor development had been normal. He had one convulsion and then became comatose. No meningeal sign was noted. He had a fever of 40.2 °C, blood pressure of 79/40 mmHg and a heart rate of 168 min 1. Hematological examinations revealed: white blood cell count, 5470 mm 3; hemoglobin, 13.1 g/dl; platelet count, 16.9 104 mm 3; PT, 41%; APTT, 48.1 s; fibrinogen, 457 mg/dl; D-dimer,
K. Ichikawa et al. / Brain & Development 31 (2009) 782–784
7.2 lg/ml; CRP, 12.17 mg/dl; total protein, 5.9 g/dl; albumin, 3.8 g/dl; AST, 41 U/L; ALT, 37 U/L; LDH, 266 U/L; CPK, 144 U/L; blood urea nitrogen, 24 mg/ dl; creatinine, 0.59 mg/dl; Na, 129 mEq/L; K, 3.8 mEq/ L; and Cl, 96 mEq/L. The glucose titer was 145 mg/dl and the ammonia level was 53 mg/dl. The lactate and pyruvate levels were 9.0 and 0.8 mg/dl, respectively. Blood gas analysis revealed: pH, 7.386; base excess, 4.2 mmol/L; and anion gap, +7.3 mmol/L. The serum b-hydroxybutyrate level was 95 lmol/L. The results of cerebrospinal fluid (CSF) examination of traumatic tap were as follows: leukocyte count, 16 mm 3; glucose, 78 mg/dl; protein, 108 mg/dl; lactate, 30.5 mg/dl; and pyruvate, 1.9 mg/dl. The CSF pressure was not high. The result for serum endotoxins was negative. The cytokine, i.e., interferon gamma, tumor necrosis factoralpha, and interleukin (IL)-6, -8, -10 and -1b, levels in serum were 1080.35 pg/ml, 5.34 pg/ml, 3085.86 pg/ml, 1374.19 pg/ml, 301 pg/ml and 41.11 pg/ml, respectively. Those in CSF were 29.81 pg/ml, 0 pg/ml, 1912.77 pg/ml, 1179.96 pg/ml, 14.29 pg/ml and 6.68 pg/ml, respectively. Computed tomography of the brain was normal, and electroencephalography (EEG) showed abnormally diffuse high-voltage slow activity without epileptiform discharges (Fig. 1). We diagnosed him as having acute encephalopathy associated with bacterial enterocolitis, and then he was managed with ventilator support in an intensive care unit. He was treated with high-dose methylpredonisolone at the dose of 30 mg/kg daily for three consecutive days. Mannitol and edaravon were simultaneously administered for 8 and 5 days, respectively. Antibacterial agents, ceftriaxone and fosfomycin, were administered intravenously. Magnetic resonance images of the brain on the second and fifth hospital days were normal. Single photon emission computed tomography of the brain 8 days after hospitalization showed no abnormalities. Salmonella typhimurium, a non-typhi salmonella species, was cultured from a stool, but the result for a blood culture and CSF culture were nega-
Fig. 1. EEG on first day of hospitalization showing diffuse and highvoltage slow activity in background.
783
tive. His consciousness had become normal by the third day and the EEG on the eighth days was normal. He could leave the hospital 12 days after admission without any sequelae. 3. Discussion Non-typhi salmonella infection is estimated to affect approximately 5000–10,000 per year in Japan, as reported by the Ministry of Health, Labour and Welfare of Japan. S. encephalopathy is a rare extraintestinal manifestations of salmonellosis. The clinical features of the encephalopathy include rapidly progressive brain dysfunction, such as consciousness disturbance and convulsions, subsequent to salmonella enteritis without severe dehydration or abnormality of electrolytes. The pathophysiology of the encephalopathy has not been disclosed, but an effect of endotoxins and cytokines on the central nervous system is speculated [2–4]. The present case showed severe consciousness disturbance a few hours following enteritis that was typical in salmonellaassociated encephalopathy previously reported. Septic encephalopathy has been reported as a common form of encephalopathy among patients in intensive care units. A diagnosis of septic encephalopathy requires impairment of the mental state and other neurological manifestations with evidence of extracranial infection. The involvement of hypoxemia, hypotension and peripheral organ failure should be excluded [5,6]. The pathophysiology of septic encephalopathy is likely to be multifactorial, but it was recently reported that systemic inflammatory mediators or a breakdown of the blood brain barrier have adverse effects on the brain [7]. Our case showed a systemic septic state with salmonella enterocolitis and his serum cytokine levels were high, especially those of IL-6, -8, and -10, and interferon c. Furthermore, the cytokines in the CSF also exhibiting high levels were the same as those in the serum. Although the CSF sample had contamination of the blood, we speculated the inflammatory cytokines were extremely high level in itself because of different proportions of each cytokine in the serum and CSF. Though there have been some reports of S. encephalopathy, it is presumed that S. encephalopathy involves various clinical courses, radiological findings and outcomes. Most cases of S. encephalopathy recover with antibacterial agents, however, 20% of the cases are left with some sequelae and 10% die, according to some previous reports. There has been no report about the effectiveness of steroids for S. encephalopathy. The present case, diagnosed as having salmonella-associated encephalopathy, had features of septic encephalopathy in terms of elevation of cytokines and normal MR images. Our case quickly recovered from the consciousness disturbance, which seemed to be earlier than in other reported cases that had not been treated with steroids, and he left without
784
K. Ichikawa et al. / Brain & Development 31 (2009) 782–784
any sequelae despite extremely high cytokine levels in the CSF [8]. Since a hypercytokine state induces some brain damage, it should be meaningful to use steroids as dexamethasone therapy for bacterial meningitis, as high-dose methylpredonisolone for influenza-associated encephalopathy [9,10]. High-dose methylpredonisolone should be tried as a treatment for S. encephalopathy, with adequate use of antibacterial agents, which is subsequently complicated by hypercytokinemia due to sepsis. In conclusion, a case of S. encephalopathy was reported. Some cases of S. encephalopathy are presumed to having features of septic encephalopathy. High-dose methylpredonisolone is a suitable treatment for hypercytokine-mediated S. encephalopathy. References [1] Hohmann EL. Nontyphoidal salmonellosis. Clin Infect Dis 2001;32:263–9. [2] Arii J, Tanabe Y, Miyake M, Mukai T, Matsuzaki M, Niinomi N, et al. Clinical and pathologic characteristics of nontyphoidal Salmonella encephalopathy. Neurology 2002;58:1641–5.
[3] Minami K, Yanagawa T, Okuda M, Suzuki H, Tamura A, Izumi G, et al. Cerebrospinal fluid cytokines in Salmonella urbana encephalopathy. Tohoku J Exp Med 2004;203: 129–32. [4] Fujita Y, Sakurai Y, Yoshida K, Shima M, Yoshioka A. A child with non-typhoidal Salmonella encephalopathy. Syounika Rinsho 2008;61:1035–40, [in Japanese]. [5] Davis NWS, Sharief MK, Howard RS. Infection-associated encephalopathies – their investigation, diagnosis, and treatment. J Neurol 2006;253:833–45. [6] Papadopoulos MC, Davis DC, Moss RF, Tighe D, Bennett ED. Pathophysiology of septic encephalopathy: a review. Crit Care Med 2000;28:3019–24. [7] Davis DC. Blood–brain barrier breakdown in septic encephalopathy and brain tumors. J Anat 2002;200:639–46. [8] Ichiyama T, Morishima T, Isumi H, Matsufuji H, Matsubara T, Furukawa S. Analysis of cytokine levels and NF-jB activation in peripheral blood mononuclear cells in influenza virus-associated encephalopathy. Cytokine 2004;27:31–7. [9] Yokota S, Imagawa T, Miyamae T, Ito S, Nakajima S, Nezu A, et al. Hypothetical pathophysiology of acute encephalopathy and encephalitis related to influenza virus infection and hypothermia therapy. Pediatr Int 2000;42:197–203. [10] Chaudhuri A. Adjunctive dexamethasone treatment in acute bacterial meningitis. Lancet 2004;3:54–62.