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Influenza-associated acute necrotizing encephalopathy in a 2-year-old American child
International Congress Series 1263 (2004) 346 – 349
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Influenza-associated acute necrotizing encephalopathy in a 2-year-old American child Michele D. Spring, Peter F. Wright * Department of Pediatric Infectious Disease, Vanderbilt University, 1161 21st Avenue South, D-7235 Medical Center North Vande, Nashville, TN 37232, USA
Abstract. Increasing numbers of cases of children with encephalopathy, associated with influenza virus infection, have recently been reported from Japan. A subset of these cases demonstrates imaging findings of bilateral thalamic and deep cerebellar nuclei necrosis consistent with acute necrotizing encephalopathy (ANE). This case report describes such a case of ANE in an American child. D 2004 Published by Elsevier B.V. Keywords: Influenza; Encephalopathy; Acute necrotizing encephalopathy
1. Introduction Influenza-associated encephalopathy is a clinical entity described primarily in the Japanese literature [1,2], manifested by an abrupt change of consciousness, often with convulsions and coma, concomitant with documented influenza infection. Certain cases of encephalopathy demonstrate bilateral thalamic and cerebellar deep nuclei hemorrhagic necrosis, hallmarks of acute necrotizing encephalopathy (ANE). The pathogenesis of both entities remains unclear, and the illnesses are not widely reported outside of Japan. We report a case of a 2-year-old American female who presented with a severe illness with clinical and radiologic characteristics of acute necrotizing encephalopathy (ANE). 2. Patient clinical presentation L.C. is a 2-year-old, previously healthy American female of Filipino descent who had a 1-day history of tactile fever, cough, and coryza. On the second day of illness, these symptoms continued, with the subsequent onset of a witnessed, generalized, tonic, clonic seizure lasting 3 min. Taken to an outside ER, the patient did regain consciousness, however, while recuperating there, her temperature rose to 42 jC and she became increasingly lethargic. She was transferred to our hospital and given ceftriaxone,
* Corresponding author. Tel.: +1-615-322-2250. E-mail addresses: [email protected] (M.D. Spring), [email protected] (P.F. Wright). 0531-5131/ D 2004 Published by Elsevier B.V. doi:10.1016/j.ics.2004.02.103
M.D. Spring, P.F. Wright / International Congress Series 1263 (2004) 346–349
347
Table 1 Complete blood count 14,800/mm3 Neutrophils Lymphocytes Monocytes 39% 205,000/mm3
Leukocyte count Leukocyte differential
Hematocrit Platelet count
93% 4% 1%
vancomycin and acyclovir. The patient’s neurologic status worsened, and she remained unresponsive with posturing and bruxism. An anti-convulsant infusion was begun and continuous EEG monitoring performed at the bedside. 3. Initial laboratory results Upon arrival to our hospital, the laboratory results obtained are indicated in Tables 1 and 2 and the ensuing paragraph. There were no significant laboratory abnormalities with the exception of a predominance of neutrophils in the peripheral blood. Cerebrospinal fluid (CSF) demonstrated 0 red blood cells/mm3 and 0 white blood cells/ mm3. Additional CSF indices indicated a glucose level of 89 mg/dl and a protein level of 26 mg/dl, both within normal range. Of note, the urinalysis and urine drug screen were also both normal. 4. Magnetic resonance imaging (MRI) results Fig. 1 demonstrates the pertinent findings from MRI imaging of the brain. A repeat MRI scan (not shown) 2 months after hospitalization did show interval evolution of the affected areas of hemorrhage. A computerized tomography (CT) scan showed hypodensities bilaterally in the basal ganglia and thalami. Magnetic Resonance Venography (MRV) and Angiography (MRA) were both negative for thrombosis. 5. Hospital course The patient was admitted to hospital and a complete evaluation of infectious causes was undertaken. Bacterial cultures of blood, spinal fluid and urine were all negative. A cerebrospinal fluid viral culture was negative as were PCR tests of the CSF for HSV 1 and 2, EBV, HHV-6, influenza and mycoplasma. Antibiotics and acyclovir were stopped after 72 h. Given the concern for possible acute disseminated encephalomyelitis, methylprednisolone at 30 mg/kg was begun intravenously on day 3 for 3 days, followed by tapered Table 2 Serum chemistries Sodium Potassium Chloride Bicarbonate Blood urea nitrogen
142 mEq/l 3.7 mEq/l 115 mEq/l 19 mEq/l 15 mg/dl
Creatinine Blood glucose SGOT (AST) SGPT (ALT) Ammonia
0.5 mg/dl 64 mg/dl 40 IU/l 23 IU/l 11 Amol/l
348
M.D. Spring, P.F. Wright / International Congress Series 1263 (2004) 346–349
Fig. 1. (A) MRI diffusion weighted imaging shows regions of restricted diffusion in the bilateral thalami and deep cerebellar nuclei bilaterally consistent with ischemia or infarction from global hypoxia. (B) MRI T2 weighted image with increased signal intensity in the bilateral thalami.
dosing of oral prednisone. The patient remained poorly responsive with extensor posturing. On day 5 of hospitalization, two viral cultures taken from the nasopharynx on the day of admission grew influenza A, identified as A/Caledonia/H1N1. PCR from the nasopharnyx was positive for influenza A and negative for PIV 3 and influenza B. A convalescent sera showed an HAI rise to H1N1 from < 1:8 to 1:512. Amantidine and oseltamivir were administered via nasogastric tube for 5 days, in addition to a 5-day course of intravenous immunoglobulin at 400 mg/kg/day. The patient remained hospitalized for 19 days. After transfer to a rehabilitation facility, she was able to regain gross motor control and single word communication. Twelve weeks after her initial presentation, her mental status returned to baseline, but she continued to have difficulty with ambulation. The subtype was found to be H1N1/New Caledonia, and the hemagglutination inhibition titers (HAI) to H1N1 were < 1:8 in the acute phase and 1:512 in the chronic phase. 6. Discussion Acute necrotizing encephalopathy (ANE), first described in 1995, is characterized by symmetrical brain lesions involving the thalami, cerebral periventricular white matter and cerebellar medulla [1]. It is often associated with influenza infection, but has also been found in infections with HHV-6 and measles. In a recent case series of 148 patients with influenza-associated encephalopathy, Morishima et al. [2] found the majority of patients were healthy children less than five years of age with documented influenza A infection, predominantly of the H3N2 subtype. In this series, 10% of the children demonstrated head imaging findings consistent with ANE. The pathogenesis of ANE and influenza-associated encephalopathy remains largely unknown. Cerebrospinal fluid indices often do not demonstrate pleocytosis, and as with our patient, viral culture or PCR for influenza virus is often negative [1,2]. Histopathologic
M.D. Spring, P.F. Wright / International Congress Series 1263 (2004) 346–349
349
specimens of the brain from patients with ANE demonstrate diffuse edema, perivascular hemorrhage, and necrosis of neurons and glial cells, and viral antigen is not detected. Cytokines, in particular IL-6, IL-10 and TNF-alpha, have been implicated in the pathogenesis of influenza-associated encephalopathy, although the exact mechanism remains to be elucidated [3]. Given the preponderance of cases in Japan, Asian heritage or local environmental factors may contribute to the development of ANE or encephalopathy [our patient was of Filipino descent]. However, in 2002, eight cases of influenza-related encephalopathy were reported in the state of Michigan in the United States [4]. The mortality rate of influenzaassociated encephalopathy ranges from 15% to 30%. With the large numbers of cases in Japan, and possible increasing numbers in the United States, ANE and influenzaassociated encephalopathy should be recognized as a serious complication of influenza infection. Further studies to elucidate the pathogenesis of this entity are needed. Acknowledgements We would like to thank the patient and her family as well as Hendrik Weitkamp, M.D., Terrence Brogan, M.D. and Sharon Tollefson. References [1] M. Mizuguchi, et al., Acute necrotizing encephalopathy of childhood: a novel form of acute encephalopathy prevalent in Japan and Taiwan, Brain Develop. 19 (1997) 81 – 92. [2] T. Morishima, et al., Encephalitis and encephalopathy associated with an influenza epidemic in Japan, CID 35 (2002) 512 – 517. [3] J. Kawada, et al., Cytokine responses in patients with influenza-associated encephalopathy, JID 188 (2003) 690 – 698. [4] N.J. Wilkins, et al., Severe morbidity and mortality associated with influenza in children and young adults— Michigan, 2003, MMWR 52 (2003) 837 – 840.
www.ics-elsevier.com
Influenza-associated acute necrotizing encephalopathy in a 2-year-old American child Michele D. Spring, Peter F. Wright * Department of Pediatric Infectious Disease, Vanderbilt University, 1161 21st Avenue South, D-7235 Medical Center North Vande, Nashville, TN 37232, USA
Abstract. Increasing numbers of cases of children with encephalopathy, associated with influenza virus infection, have recently been reported from Japan. A subset of these cases demonstrates imaging findings of bilateral thalamic and deep cerebellar nuclei necrosis consistent with acute necrotizing encephalopathy (ANE). This case report describes such a case of ANE in an American child. D 2004 Published by Elsevier B.V. Keywords: Influenza; Encephalopathy; Acute necrotizing encephalopathy
1. Introduction Influenza-associated encephalopathy is a clinical entity described primarily in the Japanese literature [1,2], manifested by an abrupt change of consciousness, often with convulsions and coma, concomitant with documented influenza infection. Certain cases of encephalopathy demonstrate bilateral thalamic and cerebellar deep nuclei hemorrhagic necrosis, hallmarks of acute necrotizing encephalopathy (ANE). The pathogenesis of both entities remains unclear, and the illnesses are not widely reported outside of Japan. We report a case of a 2-year-old American female who presented with a severe illness with clinical and radiologic characteristics of acute necrotizing encephalopathy (ANE). 2. Patient clinical presentation L.C. is a 2-year-old, previously healthy American female of Filipino descent who had a 1-day history of tactile fever, cough, and coryza. On the second day of illness, these symptoms continued, with the subsequent onset of a witnessed, generalized, tonic, clonic seizure lasting 3 min. Taken to an outside ER, the patient did regain consciousness, however, while recuperating there, her temperature rose to 42 jC and she became increasingly lethargic. She was transferred to our hospital and given ceftriaxone,
* Corresponding author. Tel.: +1-615-322-2250. E-mail addresses: [email protected] (M.D. Spring), [email protected] (P.F. Wright). 0531-5131/ D 2004 Published by Elsevier B.V. doi:10.1016/j.ics.2004.02.103
M.D. Spring, P.F. Wright / International Congress Series 1263 (2004) 346–349
347
Table 1 Complete blood count 14,800/mm3 Neutrophils Lymphocytes Monocytes 39% 205,000/mm3
Leukocyte count Leukocyte differential
Hematocrit Platelet count
93% 4% 1%
vancomycin and acyclovir. The patient’s neurologic status worsened, and she remained unresponsive with posturing and bruxism. An anti-convulsant infusion was begun and continuous EEG monitoring performed at the bedside. 3. Initial laboratory results Upon arrival to our hospital, the laboratory results obtained are indicated in Tables 1 and 2 and the ensuing paragraph. There were no significant laboratory abnormalities with the exception of a predominance of neutrophils in the peripheral blood. Cerebrospinal fluid (CSF) demonstrated 0 red blood cells/mm3 and 0 white blood cells/ mm3. Additional CSF indices indicated a glucose level of 89 mg/dl and a protein level of 26 mg/dl, both within normal range. Of note, the urinalysis and urine drug screen were also both normal. 4. Magnetic resonance imaging (MRI) results Fig. 1 demonstrates the pertinent findings from MRI imaging of the brain. A repeat MRI scan (not shown) 2 months after hospitalization did show interval evolution of the affected areas of hemorrhage. A computerized tomography (CT) scan showed hypodensities bilaterally in the basal ganglia and thalami. Magnetic Resonance Venography (MRV) and Angiography (MRA) were both negative for thrombosis. 5. Hospital course The patient was admitted to hospital and a complete evaluation of infectious causes was undertaken. Bacterial cultures of blood, spinal fluid and urine were all negative. A cerebrospinal fluid viral culture was negative as were PCR tests of the CSF for HSV 1 and 2, EBV, HHV-6, influenza and mycoplasma. Antibiotics and acyclovir were stopped after 72 h. Given the concern for possible acute disseminated encephalomyelitis, methylprednisolone at 30 mg/kg was begun intravenously on day 3 for 3 days, followed by tapered Table 2 Serum chemistries Sodium Potassium Chloride Bicarbonate Blood urea nitrogen
142 mEq/l 3.7 mEq/l 115 mEq/l 19 mEq/l 15 mg/dl
Creatinine Blood glucose SGOT (AST) SGPT (ALT) Ammonia
0.5 mg/dl 64 mg/dl 40 IU/l 23 IU/l 11 Amol/l
348
M.D. Spring, P.F. Wright / International Congress Series 1263 (2004) 346–349
Fig. 1. (A) MRI diffusion weighted imaging shows regions of restricted diffusion in the bilateral thalami and deep cerebellar nuclei bilaterally consistent with ischemia or infarction from global hypoxia. (B) MRI T2 weighted image with increased signal intensity in the bilateral thalami.
dosing of oral prednisone. The patient remained poorly responsive with extensor posturing. On day 5 of hospitalization, two viral cultures taken from the nasopharynx on the day of admission grew influenza A, identified as A/Caledonia/H1N1. PCR from the nasopharnyx was positive for influenza A and negative for PIV 3 and influenza B. A convalescent sera showed an HAI rise to H1N1 from < 1:8 to 1:512. Amantidine and oseltamivir were administered via nasogastric tube for 5 days, in addition to a 5-day course of intravenous immunoglobulin at 400 mg/kg/day. The patient remained hospitalized for 19 days. After transfer to a rehabilitation facility, she was able to regain gross motor control and single word communication. Twelve weeks after her initial presentation, her mental status returned to baseline, but she continued to have difficulty with ambulation. The subtype was found to be H1N1/New Caledonia, and the hemagglutination inhibition titers (HAI) to H1N1 were < 1:8 in the acute phase and 1:512 in the chronic phase. 6. Discussion Acute necrotizing encephalopathy (ANE), first described in 1995, is characterized by symmetrical brain lesions involving the thalami, cerebral periventricular white matter and cerebellar medulla [1]. It is often associated with influenza infection, but has also been found in infections with HHV-6 and measles. In a recent case series of 148 patients with influenza-associated encephalopathy, Morishima et al. [2] found the majority of patients were healthy children less than five years of age with documented influenza A infection, predominantly of the H3N2 subtype. In this series, 10% of the children demonstrated head imaging findings consistent with ANE. The pathogenesis of ANE and influenza-associated encephalopathy remains largely unknown. Cerebrospinal fluid indices often do not demonstrate pleocytosis, and as with our patient, viral culture or PCR for influenza virus is often negative [1,2]. Histopathologic
M.D. Spring, P.F. Wright / International Congress Series 1263 (2004) 346–349
349
specimens of the brain from patients with ANE demonstrate diffuse edema, perivascular hemorrhage, and necrosis of neurons and glial cells, and viral antigen is not detected. Cytokines, in particular IL-6, IL-10 and TNF-alpha, have been implicated in the pathogenesis of influenza-associated encephalopathy, although the exact mechanism remains to be elucidated [3]. Given the preponderance of cases in Japan, Asian heritage or local environmental factors may contribute to the development of ANE or encephalopathy [our patient was of Filipino descent]. However, in 2002, eight cases of influenza-related encephalopathy were reported in the state of Michigan in the United States [4]. The mortality rate of influenzaassociated encephalopathy ranges from 15% to 30%. With the large numbers of cases in Japan, and possible increasing numbers in the United States, ANE and influenzaassociated encephalopathy should be recognized as a serious complication of influenza infection. Further studies to elucidate the pathogenesis of this entity are needed. Acknowledgements We would like to thank the patient and her family as well as Hendrik Weitkamp, M.D., Terrence Brogan, M.D. and Sharon Tollefson. References [1] M. Mizuguchi, et al., Acute necrotizing encephalopathy of childhood: a novel form of acute encephalopathy prevalent in Japan and Taiwan, Brain Develop. 19 (1997) 81 – 92. [2] T. Morishima, et al., Encephalitis and encephalopathy associated with an influenza epidemic in Japan, CID 35 (2002) 512 – 517. [3] J. Kawada, et al., Cytokine responses in patients with influenza-associated encephalopathy, JID 188 (2003) 690 – 698. [4] N.J. Wilkins, et al., Severe morbidity and mortality associated with influenza in children and young adults— Michigan, 2003, MMWR 52 (2003) 837 – 840.