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MRI gadolinium enhancement precedes neuroradiological findings in acute necrotizing encephalopathy
Brain & Development 35 (2013) 921–924 www.elsevier.com/locate/braindev
Case report
MRI gadolinium enhancement precedes neuroradiological findings in acute necrotizing encephalopathy Takeshi Yoshida a,⇑, Takuya Tamura b, Yuhki Nagai b, Hiroyuki Ueda c, Tomonari Awaya a, Minoru Shibata a, Takeo Kato a, Toshio Heike a a
Department of Pediatrics, Kyoto University Graduate School of Medicine, Kyoto, Japan Department of Pediatrics, Kobe City Medical Center General Hospital, Hyogo, Japan c Department of Radiology, Kobe City Medical Center General Hospital, Hyogo, Japan
b
Received 15 April 2012; received in revised form 29 October 2012; accepted 24 November 2012
Abstract We report a 2-year-old Japanese boy with acute necrotizing encephalopathy (ANE) triggered by human herpes virus-6, who presented insightful magnetic resonance imaging (MRI) findings. He was admitted due to impaired consciousness and a convulsion, 2 days after the onset of an upper respiratory infection. At admission, cranial MRI showed marked gadolinium enhancement at the bilateral thalami, brainstem and periventricular white matter without abnormal findings in noncontrast MRI sequences. On the following day, noncontrast computed tomography demonstrated homogeneous low-density lesions in the bilateral thalami and severe diffuse brain edema. The patient progressively deteriorated and died on the 18th day of admission. The pathogenesis of ANE remains mostly unknown, but it has been suggested that hypercytokinemia may play a major role. Overproduced cytokines cause vascular endothelial damage and alter the permeability of the vessel wall in the multiple organs, including the brain. The MRI findings in our case demonstrate that blood–brain barrier permeability was altered prior to the appearance of typical neuroradiological findings. This suggests that alteration of blood–brain barrier permeability is the first step in the development of the brain lesions in ANE, and supports the proposed mechanism whereby hypercytokinemia causes necrotic brain lesions. This is the first report demonstrating MRI gadolinium enhancement antecedent to typical neuroradiological findings in ANE. Ó 2012 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved. Keywords: Acute necrotizing encephalopathy; Magnetic resonance imaging; Gadolinium enhancement; Pathogenesis; Cytokine storm
1. Introduction Acute necrotizing encephalopathy (ANE) is a rare, well-defined disease characterized by fever, seizures, variable degrees of hepatic dysfunction, and rapid neurological deterioration within several days after onset of a viral infection. It is also characterized by multiple symmetrical
⇑ Corresponding author. Address: Department of Pediatrics, Kyoto University Graduate School of Medicine, 54 Kawaharacho, Shogoin, Sakyo-ku, Kyoto 606-8507, Japan. Tel.: +81 75 751 3301; fax: +81 75 752 2361. E-mail address: [email protected] (T. Yoshida).
lesions involving the bilateral thalami and other specific brain regions such as the putamina, brainstem tegmentum, deep white matter and cerebellum. Affected patients have high mortality rates and severe neurological sequelae [1]. This disease, first described by Mizuguchi et al., predominantly affects East Asian infants and young children, and has been sporadically reported worldwide [1,2]. The pathogenesis of ANE is mostly unknown, but several studies suggest that overproduction of cytokines, a so-called “cytokine storm”, plays a major role [3,4]. It is hypothesized that a cytokine storm, predominantly triggered by viral infection, causes vascular endothelial
0387-7604/$ - see front matter Ó 2012 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved. http://dx.doi.org/10.1016/j.braindev.2012.11.011
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T. Yoshida et al. / Brain & Development 35 (2013) 921–924
damage and alters vessel wall permeability, leading to multiple organ damage. Here we report a case of ANE triggered by human herpes virus-6 (HHV-6) infection, presenting with cranial magnetic resonance imaging (MRI) gadolinium enhancement in the absence of abnormal signals with other MRI noncontrast sequences. This suggests that alteration of blood–brain barrier (BBB) permeability is the first step in development of the brain lesions of ANE. To our knowledge, this is the first report demonstrating MRI gadolinium enhancement chronologically antecedent to the appearance of typical neuroradiological findings in ANE. 2. Case report A previously healthy 2-year-old Japanese boy was admitted to our hospital due to impaired consciousness and a generalized seizure. He had developed a highgrade fever 2 days before admission, and received cefcapene and acetaminophen under a diagnosis of upper respiratory infection. On the day of admission, he exhibited incoherent speech and a generalized seizure of 10 min duration, and was then transferred to our emergency department. On arrival, his body temperature was 38.9 °C, heart rate 206 min 1 and blood pressure 80/40 mmHg. He was severely somnolent with a Glasgow Coma Scale score of 3, but was breathing spontaneously. A neurological examination demonstrated marked hypotonia, no nuchal rigidity and normal pupillary light reflex. Laboratory blood analysis revealed the following: white blood cell, 5600 lL; C-reactive protein, 0.1 mg/dL; aspartate aminotransferase, 74 IU/L; alanine aminotransferase, 18 IU/L; lactate dehydrogenase, 427 IU/L; blood urea nitrogen, 27 mg/dL; creatinine, 0.7 mg/dL. Serum glucose and ammonia levels were within normal range, but venous lactate level was slightly elevated (2.7 mmol/L). Cerebrospinal fluid analysis showed no pleocytosis (3 cells/lL), normal protein level (19 mg/ dL) and normal glucose (106 mg/dL). A noncontrast cranial computed tomography (CT) at admission was normal (Fig. 1). Magnetic resonance imaging at admission, 6 h after mental alteration, revealed marked enhancement of the bilateral thalami and brainstem (Fig. 2A and B) on a gadoliniumenhanced T1 weighted image. Cerebral white matter was also slightly enhanced (Fig. 2B). We found no abnormalities on noncontrast sequences, including diffusion-weighted imaging (Fig. 2C), apparent diffusion coefficient (ADC) map, T1 weighted image and T2 weighted image (Fig. 2D). Shortly after admission, the patient required intubation, catecholamine support, continuous hemodiafiltration for acute renal failure and infusion of fresh frozen plasma for disseminated intravascular coagulation. He
Fig. 1. A noncontrast axial cranial computed tomography image at admission. Note that there is no significant abnormality.
Fig. 2. Cranial magnetic resonance images at admission. (A) Contrastenhanced axial T1-weighted image shows marked enhancement in the bilateral thalami. (B) Contrast-enhanced coronal T1-weighted image shows multiple symmetrical enhanced lesions, including the thalami, brainstem and cerebral white matter. (C) Axial diffusion-weighted image shows no abnormality. (D) Axial T2-weighted image shows no abnormality.
T. Yoshida et al. / Brain & Development 35 (2013) 921–924
Fig. 3. A cranial noncontrast axial computed tomography image on day after admission. Note the bilateral hypodense lesions in the thalami and the diffuse brain edema.
was empirically treated with antibacterials, pulsed methylprednisolone (30 mg/kg/day for 3 days) and variable vitamins. His pupils became fixed and dilated 14 h after the emergence of neurological symptoms. On the following day, a noncontrast CT demonstrated homogeneous low-density lesions in the bilateral thalami and severe diffuse brain edema (Fig. 3). On the fifth day after admission, small macules appeared on the trunk and proximal extremities. Serum polymerase chain reaction for HHV-6 on the fourth day of admission was positive (250,000 copies/mL) and serum HHV-6 IgM antibody testing by enzyme immunoassay on the 12th day was positive. All metabolic analyses, such as organic acids in the urine, amino acids in the blood and urine, and acylcarnitine in the blood, were normal. From these findings, we diagnosed ANE associated with HHV-6 infection. The patient progressively deteriorated and died of refractory bacterial pneumonia on the 18th day of hospitalization. Autopsy was not performed. 3. Discussion We report a 2-year-old boy with ANE associated with HHV-6 infection. He exhibited characteristic MRI findings, marked gadolinium enhancement at the bilateral thalami, brainstem and periventricular white matter without abnormal signals in noncontrast
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sequences, on the first day that he presented neurological symptoms. A hallmark of ANE is symmetrical bilateral thalamic lesions that often show multiple concentric structures. Neuropathologically, the center of the thalamic lesion demonstrates tissue necrosis and extravasation of plasma-like substances from vessels is observed at the periphery [5]. In a report of MRI signals in ANE, the outer portions of thalamic lesions showed decreased ADC values, representing cytotoxic edema, and the outermost portions showed increased ADC values, representing vasogenic edema [6]. These findings indicate altered permeability of the BBB at the area surrounding the necrotic lesion. However, it is unclear whether such an alteration of permeability is a primary cause of the brain lesions or a secondary phenomenon from tissue necrosis in the adjacent areas. Some authors have proposed that uncontrolled production of cytokines, a “cytokine storm”, is critical in the pathogenesis of ANE [3,4]. A cytokine storm causes vascular endothelial damage and alteration of vessel wall permeability across the whole body. This is consistent with the fact that patients with ANE often have systemic symptoms including shock, acute renal failure or disseminated intravascular coagulation. A few reports demonstrate that interleukin-6 and tumor necrosis factor (TNF)-a are markedly increased during the acute stage of ANE associated with influenza virus infection [4,7]. Furthermore, TNF-a has been shown to participate in the alteration of BBB permeability during various neuroinflammatory events such as sepsis or bacterial meningitis [8]. Thus, we hypothesized that a highly elevated level of cytokines causes endothelial damage of cerebral vessels and breakdown of BBB, leading to brain edema and, finally, necrotic lesions of ANE. The MRI findings in the presented case showed gadolinium enhancement preceding the emergence of typical neuroradiological findings of ANE. Gadolinium enhancement is generally considered a specific indicator of altered BBB permeability [9]. Usually BBB hyperpermeability results in vasogenic edema, which is associated with T2 prolongation or increased ADC value. Since our case’s MRI was examined early in the course, vasogenic edema was not yet developed, still less cytotoxic edema or necrosis. For this reason, no abnormal signal was observed on T2-weighted image or ADC map. Thus, our case demonstrated altered BBB permeability chronologically antecedent to brain edema or necrotic change. This suggests that an alteration of BBB permeability is the first step in development of the brain lesions of ANE, and supports the hypothesis that hypercyotokinemia is a primary cause of necrotic brain lesions. Therefore, therapies that control cytokine production or vessel wall permeability might alleviate neurological sequelae of ANE. Okumura et al. indicated some efficacy of early steroid therapy to children with ANE [10].
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T. Yoshida et al. / Brain & Development 35 (2013) 921–924
As to gadolinium enhancement in ANE, Wong et al. reported that contrast enhancement was found in eight (66%) of 12 patients [11]. Enhancement of lesions in ANE may depend on timing of MRI or severity of the case, but ANE in itself may be attributed to heterogeneous pathogenic mechanisms. To our knowledge, this is the first report demonstrating MRI gadolinium enhancement antecedent to typical neuroradiological findings in ANE. This case might clarify the pathogenesis of brain lesions of ANE. Despite the best efforts of clinicians, prognoses of patients with ANE are far from satisfactory. To fully elucidate the pathogenesis of ANE and improve prognosis of patients with ANE, accumulation of further cases is required. References [1] Mizuguchi M, Abe J, Mikkaichi K, Noma S, Yoshida K, Yamanaka T, et al. Acute necrotising encephalopathy of childhood: a new syndrome presenting with multifocal, symmetric brain lesions. J Neurol Neurosurg Psychiatry 1995;58: 555–61. [2] Kirton A, Busche K, Ross C, Wirrell E. Acute necrotizing encephalopathy in Caucasian children: two cases and review of the literature. J Child Neurol 2005;20:527–32.
[3] Mizuguchi M, Yamanouchi H, Ichiyama T, Shiomi M. Acute encephalopathy associated with influenza and other viral infections. Acta Neurol Scand 2007;115(Suppl.):45–56. [4] Ichiyama T, Isumi H, Ozawa H, Matsubara T, Morishima T, Furukawa S. Cerebrospinal fluid and serum levels of cytokines and soluble tumor necrosis factor receptor in influenza virusassociated encephalopathy. Scand J Infect Dis 2003;35:59–61. [5] Mizuguchi M, Hayashi M, Nakano I, Kuwashima M, Yoshida K, Nakai Y, et al. Concentric structure of thalamic lesions in acute necrotizing encephalopathy. Neuroradiology 2002;44:489–93. [6] Albayram S, Bilgi Z, Selcuk H, Selcuk D, C ¸ am H, Kocßer N, et al. Diffusion-weighted MR imaging findings of acute necrotizing encephalopathy. Am J Neuroradiol 2004;25:792–7. [7] Aiba H, Mochizuki M, Kimura M, Hojo H. Predictive value of serum interleukin-6 level in influenza virus-associated encephalopathy. Neurology 2001;57:295–9. [8] Tsao N, Hsu HP, Wu CM, Liu CC, Lei HY. Tumour necrosis factor-alpha causes an increase in blood–brain barrier permeability during sepsis. J Med Microbiol 2001;50:812–21. [9] Kassner A, Thornhill R. Measuring the integrity of the human blood–brain barrier using magnetic resonance imaging. Methods Mol Biol 2011;686:229–45. [10] Okumura A, Mizuguchi M, Kidokoro H, Tanaka M, Abe S, Hosoya M, et al. Outcome of acute necrotizing encephalopathy in relation to treatment with corticosteroids and gammaglobulin. Brain Dev 2009;31:221–7. [11] Wong AM, Simon EM, Zimmerman RA, Wang HS, Toh CH, Ng SH. Acute necrotizing encephalopathy of childhood: correlation of MR findings and clinical outcome. Am J Neuroradiol 2006;27:1919–23.
Case report
MRI gadolinium enhancement precedes neuroradiological findings in acute necrotizing encephalopathy Takeshi Yoshida a,⇑, Takuya Tamura b, Yuhki Nagai b, Hiroyuki Ueda c, Tomonari Awaya a, Minoru Shibata a, Takeo Kato a, Toshio Heike a a
Department of Pediatrics, Kyoto University Graduate School of Medicine, Kyoto, Japan Department of Pediatrics, Kobe City Medical Center General Hospital, Hyogo, Japan c Department of Radiology, Kobe City Medical Center General Hospital, Hyogo, Japan
b
Received 15 April 2012; received in revised form 29 October 2012; accepted 24 November 2012
Abstract We report a 2-year-old Japanese boy with acute necrotizing encephalopathy (ANE) triggered by human herpes virus-6, who presented insightful magnetic resonance imaging (MRI) findings. He was admitted due to impaired consciousness and a convulsion, 2 days after the onset of an upper respiratory infection. At admission, cranial MRI showed marked gadolinium enhancement at the bilateral thalami, brainstem and periventricular white matter without abnormal findings in noncontrast MRI sequences. On the following day, noncontrast computed tomography demonstrated homogeneous low-density lesions in the bilateral thalami and severe diffuse brain edema. The patient progressively deteriorated and died on the 18th day of admission. The pathogenesis of ANE remains mostly unknown, but it has been suggested that hypercytokinemia may play a major role. Overproduced cytokines cause vascular endothelial damage and alter the permeability of the vessel wall in the multiple organs, including the brain. The MRI findings in our case demonstrate that blood–brain barrier permeability was altered prior to the appearance of typical neuroradiological findings. This suggests that alteration of blood–brain barrier permeability is the first step in the development of the brain lesions in ANE, and supports the proposed mechanism whereby hypercytokinemia causes necrotic brain lesions. This is the first report demonstrating MRI gadolinium enhancement antecedent to typical neuroradiological findings in ANE. Ó 2012 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved. Keywords: Acute necrotizing encephalopathy; Magnetic resonance imaging; Gadolinium enhancement; Pathogenesis; Cytokine storm
1. Introduction Acute necrotizing encephalopathy (ANE) is a rare, well-defined disease characterized by fever, seizures, variable degrees of hepatic dysfunction, and rapid neurological deterioration within several days after onset of a viral infection. It is also characterized by multiple symmetrical
⇑ Corresponding author. Address: Department of Pediatrics, Kyoto University Graduate School of Medicine, 54 Kawaharacho, Shogoin, Sakyo-ku, Kyoto 606-8507, Japan. Tel.: +81 75 751 3301; fax: +81 75 752 2361. E-mail address: [email protected] (T. Yoshida).
lesions involving the bilateral thalami and other specific brain regions such as the putamina, brainstem tegmentum, deep white matter and cerebellum. Affected patients have high mortality rates and severe neurological sequelae [1]. This disease, first described by Mizuguchi et al., predominantly affects East Asian infants and young children, and has been sporadically reported worldwide [1,2]. The pathogenesis of ANE is mostly unknown, but several studies suggest that overproduction of cytokines, a so-called “cytokine storm”, plays a major role [3,4]. It is hypothesized that a cytokine storm, predominantly triggered by viral infection, causes vascular endothelial
0387-7604/$ - see front matter Ó 2012 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved. http://dx.doi.org/10.1016/j.braindev.2012.11.011
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T. Yoshida et al. / Brain & Development 35 (2013) 921–924
damage and alters vessel wall permeability, leading to multiple organ damage. Here we report a case of ANE triggered by human herpes virus-6 (HHV-6) infection, presenting with cranial magnetic resonance imaging (MRI) gadolinium enhancement in the absence of abnormal signals with other MRI noncontrast sequences. This suggests that alteration of blood–brain barrier (BBB) permeability is the first step in development of the brain lesions of ANE. To our knowledge, this is the first report demonstrating MRI gadolinium enhancement chronologically antecedent to the appearance of typical neuroradiological findings in ANE. 2. Case report A previously healthy 2-year-old Japanese boy was admitted to our hospital due to impaired consciousness and a generalized seizure. He had developed a highgrade fever 2 days before admission, and received cefcapene and acetaminophen under a diagnosis of upper respiratory infection. On the day of admission, he exhibited incoherent speech and a generalized seizure of 10 min duration, and was then transferred to our emergency department. On arrival, his body temperature was 38.9 °C, heart rate 206 min 1 and blood pressure 80/40 mmHg. He was severely somnolent with a Glasgow Coma Scale score of 3, but was breathing spontaneously. A neurological examination demonstrated marked hypotonia, no nuchal rigidity and normal pupillary light reflex. Laboratory blood analysis revealed the following: white blood cell, 5600 lL; C-reactive protein, 0.1 mg/dL; aspartate aminotransferase, 74 IU/L; alanine aminotransferase, 18 IU/L; lactate dehydrogenase, 427 IU/L; blood urea nitrogen, 27 mg/dL; creatinine, 0.7 mg/dL. Serum glucose and ammonia levels were within normal range, but venous lactate level was slightly elevated (2.7 mmol/L). Cerebrospinal fluid analysis showed no pleocytosis (3 cells/lL), normal protein level (19 mg/ dL) and normal glucose (106 mg/dL). A noncontrast cranial computed tomography (CT) at admission was normal (Fig. 1). Magnetic resonance imaging at admission, 6 h after mental alteration, revealed marked enhancement of the bilateral thalami and brainstem (Fig. 2A and B) on a gadoliniumenhanced T1 weighted image. Cerebral white matter was also slightly enhanced (Fig. 2B). We found no abnormalities on noncontrast sequences, including diffusion-weighted imaging (Fig. 2C), apparent diffusion coefficient (ADC) map, T1 weighted image and T2 weighted image (Fig. 2D). Shortly after admission, the patient required intubation, catecholamine support, continuous hemodiafiltration for acute renal failure and infusion of fresh frozen plasma for disseminated intravascular coagulation. He
Fig. 1. A noncontrast axial cranial computed tomography image at admission. Note that there is no significant abnormality.
Fig. 2. Cranial magnetic resonance images at admission. (A) Contrastenhanced axial T1-weighted image shows marked enhancement in the bilateral thalami. (B) Contrast-enhanced coronal T1-weighted image shows multiple symmetrical enhanced lesions, including the thalami, brainstem and cerebral white matter. (C) Axial diffusion-weighted image shows no abnormality. (D) Axial T2-weighted image shows no abnormality.
T. Yoshida et al. / Brain & Development 35 (2013) 921–924
Fig. 3. A cranial noncontrast axial computed tomography image on day after admission. Note the bilateral hypodense lesions in the thalami and the diffuse brain edema.
was empirically treated with antibacterials, pulsed methylprednisolone (30 mg/kg/day for 3 days) and variable vitamins. His pupils became fixed and dilated 14 h after the emergence of neurological symptoms. On the following day, a noncontrast CT demonstrated homogeneous low-density lesions in the bilateral thalami and severe diffuse brain edema (Fig. 3). On the fifth day after admission, small macules appeared on the trunk and proximal extremities. Serum polymerase chain reaction for HHV-6 on the fourth day of admission was positive (250,000 copies/mL) and serum HHV-6 IgM antibody testing by enzyme immunoassay on the 12th day was positive. All metabolic analyses, such as organic acids in the urine, amino acids in the blood and urine, and acylcarnitine in the blood, were normal. From these findings, we diagnosed ANE associated with HHV-6 infection. The patient progressively deteriorated and died of refractory bacterial pneumonia on the 18th day of hospitalization. Autopsy was not performed. 3. Discussion We report a 2-year-old boy with ANE associated with HHV-6 infection. He exhibited characteristic MRI findings, marked gadolinium enhancement at the bilateral thalami, brainstem and periventricular white matter without abnormal signals in noncontrast
923
sequences, on the first day that he presented neurological symptoms. A hallmark of ANE is symmetrical bilateral thalamic lesions that often show multiple concentric structures. Neuropathologically, the center of the thalamic lesion demonstrates tissue necrosis and extravasation of plasma-like substances from vessels is observed at the periphery [5]. In a report of MRI signals in ANE, the outer portions of thalamic lesions showed decreased ADC values, representing cytotoxic edema, and the outermost portions showed increased ADC values, representing vasogenic edema [6]. These findings indicate altered permeability of the BBB at the area surrounding the necrotic lesion. However, it is unclear whether such an alteration of permeability is a primary cause of the brain lesions or a secondary phenomenon from tissue necrosis in the adjacent areas. Some authors have proposed that uncontrolled production of cytokines, a “cytokine storm”, is critical in the pathogenesis of ANE [3,4]. A cytokine storm causes vascular endothelial damage and alteration of vessel wall permeability across the whole body. This is consistent with the fact that patients with ANE often have systemic symptoms including shock, acute renal failure or disseminated intravascular coagulation. A few reports demonstrate that interleukin-6 and tumor necrosis factor (TNF)-a are markedly increased during the acute stage of ANE associated with influenza virus infection [4,7]. Furthermore, TNF-a has been shown to participate in the alteration of BBB permeability during various neuroinflammatory events such as sepsis or bacterial meningitis [8]. Thus, we hypothesized that a highly elevated level of cytokines causes endothelial damage of cerebral vessels and breakdown of BBB, leading to brain edema and, finally, necrotic lesions of ANE. The MRI findings in the presented case showed gadolinium enhancement preceding the emergence of typical neuroradiological findings of ANE. Gadolinium enhancement is generally considered a specific indicator of altered BBB permeability [9]. Usually BBB hyperpermeability results in vasogenic edema, which is associated with T2 prolongation or increased ADC value. Since our case’s MRI was examined early in the course, vasogenic edema was not yet developed, still less cytotoxic edema or necrosis. For this reason, no abnormal signal was observed on T2-weighted image or ADC map. Thus, our case demonstrated altered BBB permeability chronologically antecedent to brain edema or necrotic change. This suggests that an alteration of BBB permeability is the first step in development of the brain lesions of ANE, and supports the hypothesis that hypercyotokinemia is a primary cause of necrotic brain lesions. Therefore, therapies that control cytokine production or vessel wall permeability might alleviate neurological sequelae of ANE. Okumura et al. indicated some efficacy of early steroid therapy to children with ANE [10].
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T. Yoshida et al. / Brain & Development 35 (2013) 921–924
As to gadolinium enhancement in ANE, Wong et al. reported that contrast enhancement was found in eight (66%) of 12 patients [11]. Enhancement of lesions in ANE may depend on timing of MRI or severity of the case, but ANE in itself may be attributed to heterogeneous pathogenic mechanisms. To our knowledge, this is the first report demonstrating MRI gadolinium enhancement antecedent to typical neuroradiological findings in ANE. This case might clarify the pathogenesis of brain lesions of ANE. Despite the best efforts of clinicians, prognoses of patients with ANE are far from satisfactory. To fully elucidate the pathogenesis of ANE and improve prognosis of patients with ANE, accumulation of further cases is required. References [1] Mizuguchi M, Abe J, Mikkaichi K, Noma S, Yoshida K, Yamanaka T, et al. Acute necrotising encephalopathy of childhood: a new syndrome presenting with multifocal, symmetric brain lesions. J Neurol Neurosurg Psychiatry 1995;58: 555–61. [2] Kirton A, Busche K, Ross C, Wirrell E. Acute necrotizing encephalopathy in Caucasian children: two cases and review of the literature. J Child Neurol 2005;20:527–32.
[3] Mizuguchi M, Yamanouchi H, Ichiyama T, Shiomi M. Acute encephalopathy associated with influenza and other viral infections. Acta Neurol Scand 2007;115(Suppl.):45–56. [4] Ichiyama T, Isumi H, Ozawa H, Matsubara T, Morishima T, Furukawa S. Cerebrospinal fluid and serum levels of cytokines and soluble tumor necrosis factor receptor in influenza virusassociated encephalopathy. Scand J Infect Dis 2003;35:59–61. [5] Mizuguchi M, Hayashi M, Nakano I, Kuwashima M, Yoshida K, Nakai Y, et al. Concentric structure of thalamic lesions in acute necrotizing encephalopathy. Neuroradiology 2002;44:489–93. [6] Albayram S, Bilgi Z, Selcuk H, Selcuk D, C ¸ am H, Kocßer N, et al. Diffusion-weighted MR imaging findings of acute necrotizing encephalopathy. Am J Neuroradiol 2004;25:792–7. [7] Aiba H, Mochizuki M, Kimura M, Hojo H. Predictive value of serum interleukin-6 level in influenza virus-associated encephalopathy. Neurology 2001;57:295–9. [8] Tsao N, Hsu HP, Wu CM, Liu CC, Lei HY. Tumour necrosis factor-alpha causes an increase in blood–brain barrier permeability during sepsis. J Med Microbiol 2001;50:812–21. [9] Kassner A, Thornhill R. Measuring the integrity of the human blood–brain barrier using magnetic resonance imaging. Methods Mol Biol 2011;686:229–45. [10] Okumura A, Mizuguchi M, Kidokoro H, Tanaka M, Abe S, Hosoya M, et al. Outcome of acute necrotizing encephalopathy in relation to treatment with corticosteroids and gammaglobulin. Brain Dev 2009;31:221–7. [11] Wong AM, Simon EM, Zimmerman RA, Wang HS, Toh CH, Ng SH. Acute necrotizing encephalopathy of childhood: correlation of MR findings and clinical outcome. Am J Neuroradiol 2006;27:1919–23.