two days after the onset of fever , vomiting , and diarrhea , a 10-month - old previously healthy boy was admitted with generalized tonic - clonic seizure .
brain ct , performed elsewhere , revealed the presence of symmetric low - density thalamic lesions . on admission
conventional brain mr images obtained using a 1.5-t system on the second day of hospitalization depicted symmetric distribution of t1- and t2-prolonged areas in the thalami ( fig .
* -weighted gradient - echo images ( tr / te = 800/30 , flip angle = 20 ) demonstrated low signal intensities within the thalamic lesions , suggesting acute hemorrhage ( fig .
after the intravenous administration of gadolinium - diethylene triamine penta - acetic acid , the lesions showed no abnormal enhancement .
diffusion - weighted mr imaging ( b value=1000 sec / mm ) demonstrated high signal intensity in all the lesions , though this was absent in the central portion of thalamic lesions , and other than in this same area , apparent diffusion coefficient ( adc ) mapping revealed low signal intensity ( fig .
localized proton mr spectroscopy of the thalami using a stimulated echo - acquisition mode sequence ( tr / te=3000/30 , 96 acquisitions , volume of interest=7 ml ) showed that compared with an age - matched control subject , peak intensities were higher , occurring at 2.0 - 2.5 and 0.8 - 1.5 ppm ( figs .
laboratory findings on admission showed increased serum aspartate and alanine aminotransferase levels , though those of blood ammonium and lactate were normal .
polymerase chain reaction analysis of the csf was negative for deoxynucleic acid ( dna ) of herpes simplex virus and enterovirus , and similar analysis of peripheral blood was negative for major mutations in mitochondrial dna , which would indicate mitochondrial encephalopathy with lactic acidosis and stroke - like episode ( melas ) syndrome .
his mental state improved , and on the fourth day of hospitalization he was almost alert .
follow - up brain mr imaging performed three months later revealed residual atrophic change in the previously observed lesions ; both t1- and t2-weighted images depicted small areas of high signal intensity at the center of the thalami , indicating residual subacute hemorrhage .
four days after the development of fever , cough , and rhinorrhea , a 6-month - old , previously healthy girl was admitted with generalized tonic - clonic seizure and mental change , as well as increased rigidity of the extremities .
ct images of the brain , obtained at another hospital , depicted symmetric low - density lesions in the thalami and external capsules .
conventional brain mr imaging performed on the second day of hospitalization indicated that symmetric t1- and t2-prolonged areas were present in the thalami and external capsules . t2 * -weighted gradient - echo images clearly showed that within the thalamic lesions , acute hemorrhage had occurred .
after the intravenous administration of gadolinium - diethylene triamine penta - acetic acid , the lesions showed no abnormal enhancement and adc mapping revealed areas of low signal intensity within them ( fig .
localized proton mr spectroscopy using a stimulated echo - acquisition mode sequence ( tr / te=3000/30 , 96 acquisitions , volume of interest=7 ml ) showed a small doublet at 1.33 ppm ( fig .
laboratory findings indicated slightly increased levels of serum aspartate aminotransferase , lactate , and ammonia , though the lactate level rapidly returned to normal .
polymerase chain reaction analysis of the csf was negative for dna of herpes simplex virus and enterovirus , and similar analysis of peripheral blood was negative for major mutations in mitochondrial dna .
the patient was thought to be suffering from acute necrotizing encephalopathy , and was treated with mannitol , acyclovir , and steroid .
her mental state improved and on the second day of hospitalization her level of alertness was almost normal .
the extremities gradually became less rigid , and follow - up brain mr imaging and mr spectroscopy performed one week later revealed marked improvement of the initial lesions and disappearance of the doublet at 1.33 ppm ( fig .
two days after the onset of fever , vomiting , and diarrhea , a 10-month - old previously healthy boy was admitted with generalized tonic - clonic seizure .
brain ct , performed elsewhere , revealed the presence of symmetric low - density thalamic lesions . on admission
conventional brain mr images obtained using a 1.5-t system on the second day of hospitalization depicted symmetric distribution of t1- and t2-prolonged areas in the thalami ( fig .
* -weighted gradient - echo images ( tr / te = 800/30 , flip angle = 20 ) demonstrated low signal intensities within the thalamic lesions , suggesting acute hemorrhage ( fig .
after the intravenous administration of gadolinium - diethylene triamine penta - acetic acid , the lesions showed no abnormal enhancement .
diffusion - weighted mr imaging ( b value=1000 sec / mm ) demonstrated high signal intensity in all the lesions , though this was absent in the central portion of thalamic lesions , and other than in this same area , apparent diffusion coefficient ( adc ) mapping revealed low signal intensity ( fig .
localized proton mr spectroscopy of the thalami using a stimulated echo - acquisition mode sequence ( tr / te=3000/30 , 96 acquisitions , volume of interest=7 ml ) showed that compared with an age - matched control subject , peak intensities were higher , occurring at 2.0 - 2.5 and 0.8 - 1.5 ppm ( figs .
laboratory findings on admission showed increased serum aspartate and alanine aminotransferase levels , though those of blood ammonium and lactate were normal .
polymerase chain reaction analysis of the csf was negative for deoxynucleic acid ( dna ) of herpes simplex virus and enterovirus , and similar analysis of peripheral blood was negative for major mutations in mitochondrial dna , which would indicate mitochondrial encephalopathy with lactic acidosis and stroke - like episode ( melas ) syndrome .
his mental state improved , and on the fourth day of hospitalization he was almost alert .
follow - up brain mr imaging performed three months later revealed residual atrophic change in the previously observed lesions ; both t1- and t2-weighted images depicted small areas of high signal intensity at the center of the thalami , indicating residual subacute hemorrhage .
four days after the development of fever , cough , and rhinorrhea , a 6-month - old , previously healthy girl was admitted with generalized tonic - clonic seizure and mental change , as well as increased rigidity of the extremities .
ct images of the brain , obtained at another hospital , depicted symmetric low - density lesions in the thalami and external capsules .
conventional brain mr imaging performed on the second day of hospitalization indicated that symmetric t1- and t2-prolonged areas were present in the thalami and external capsules . t2 * -weighted gradient - echo images clearly showed that within the thalamic lesions , acute hemorrhage had occurred .
after the intravenous administration of gadolinium - diethylene triamine penta - acetic acid , the lesions showed no abnormal enhancement and adc mapping revealed areas of low signal intensity within them ( fig .
localized proton mr spectroscopy using a stimulated echo - acquisition mode sequence ( tr / te=3000/30 , 96 acquisitions , volume of interest=7 ml ) showed a small doublet at 1.33 ppm ( fig .
laboratory findings indicated slightly increased levels of serum aspartate aminotransferase , lactate , and ammonia , though the lactate level rapidly returned to normal .
polymerase chain reaction analysis of the csf was negative for dna of herpes simplex virus and enterovirus , and similar analysis of peripheral blood was negative for major mutations in mitochondrial dna .
the patient was thought to be suffering from acute necrotizing encephalopathy , and was treated with mannitol , acyclovir , and steroid .
her mental state improved and on the second day of hospitalization her level of alertness was almost normal .
the extremities gradually became less rigid , and follow - up brain mr imaging and mr spectroscopy performed one week later revealed marked improvement of the initial lesions and disappearance of the doublet at 1.33 ppm ( fig .
acute necrotizing encephalopathy of childhood is a distinct form of acute encephalopathy recently reported from japan ( 2 - 4 ) .
since then , similar cases in other countries have been described ( 5 - 7 ) .
the clinico - radiological features of our cases closely correspond to the diagnostic criteria suggested by mizuguchi ( 1 ) , namely clinical findings of acute encephalopathy following febrile prodromata , rapid deterioration in the level of consciousness , and convulsions ; laboratory findings which indicate an absence of csf pleocytosis , together with frequently increased csf protein and serum aminotransferase levels but no increase in blood ammonia ; characteristic neuroimaging findings ; and the exclusion of similar disease . among the characteristic neuroimaging findings , symmetric lesions in the thalami were most constant , being observed in all reported cases ( 1 - 8 ) .
bilateral tegmental involvement of the brain stem was the second most common finding , present in about 60% of cases .
neuropathologically , the lesions occurring in acute necrotizing encephalopathy have been described as having a concentric or laminar structure ( 9 ) .
perivascular petechial hemorrhage and necrosis of neurons and glial cells occurred in the center of lesions , and in the outer portion , all vessels were congested and acutely swollen oligodendrocytes were observed . along the edge of lesions , the pathologic findings were extravasation mainly around the arteries and myelin pallor .
the diffusion mr imaging findings of acute necrotizing encephalopathy have previously been reported ( 8) .
the adc value was found to be initially lower than normal , indicating decreased water diffusibility , a very useful finding in differentiating acute necrotizing encephalopathy from acute demyelinating encephalomyelitis ; this low adc value seen during the acute phase slowly increased during follow - up studies . in our cases ,
a low adc was observed , except in the central portion of thalamic lesions , where adc was high .
the causes of adc decrease during the acute phase of acute necrotizing encephalopathy are not clear , though it is most likely due to swollen neuroglial cells within the lesions , as in acute ischemic infarctions , or to the swelling of myelin .
supportive evidence for this is the presence of swollen oligodendrocytes or myelin pallor , revealed by pathologic examination .
another possible cause is the presence of acute petechial hemorrhage within a lesion , particularly a thalamic lesion . it is well known that diffusion mr imaging reveals the lower than normal adc caused by acute hemorrhage ( 10 ) , but the adc decrease seen in non - hemorrhagic lesions is difficult to explain .
we believe , therefore , that the cytotoxic edema occurring in neuroglial cells and possible swelling of myelin is the dominant cause of adc decrease in acute necrotizing encephalopathy . in the brain , decreased adc is observed most frequently in cases involving hyperacute infarction , but rarely in status epilepticus , hemiplegic migraine or venous infarction .
acute necrotizing encephalopathy is a further example of a brain disorder in which a lower adc is found in the involved areas , and in most clinical situations this decrease involves significant neuroglial damage .
we speculate that the degree and extent of adc decrease can be used to predict brain damage or the clinical outcome in patients with acute necrotizing encephalopathy , and our experience , though limited to only two cases , supports this possibility . in the first patient , in whom the adc of thalamic lesions showed a greater decrease ,
there was more significant morphologic damage and a poorer clinical outcome , as shown at follow - up , than in the second , whose adc of thalamic lesions was only slightly decreased . in both our cases , the central high adc area surrounded by a thick , rim - like area of low adc in the thalami correlated closely with the pathologic findings of lesions with a concentric or laminar structure , as mentioned above . in severe cases of acute necrotizing encephalopathy , rapid neuroglial cell death or
necrosis may occur in the central portion of a lesion , surrounded by a less severely damaged zone , pathological change which can be clearly demonstrated by diffusion mr imaging . in milder cases , as in our second patient
, brain damage may be less severe and the pathological change occurring may be seen at diffusion mr imaging as a slight decrease in adc .
the proton mr spectroscopic findings of acute necrotizing encephalopathy have previously been reported ( 5 , 8) .
follow - up studies showed that a small lactate peak seen at initial mr spectroscopy had rapidly returned to within the normal range ( 8) , and we also observed this change in our second patient . in our first case , we noted that peak intensities were higher at 2.0 - 2.5 ppm , a finding not reported in previous proton mr spectroscopic studies of this disease .
the peak is usually caused by the glutamate / glutamine complex within the brain , and it is well known that cerebral glutamine is increased in the presence of hyperammonemia ( 11 ) . because of the absence of hyperammonemia in our first case , it is less likely that the peak was due to increased cerebral glutamine , and we speculate that it may , instead , have been due mainly to increased cerebral glutamate . glutamate is a well - known excitatory neurotransmitter but can cause excitotoxic neuronal damage if excessive amounts are released into the synaptic cleft .
it is , therefore , tempting to explain the neuronal damage occurring in acute necrotizing encephalopathy in terms of glutamate - mediated excitotoxicity .
an increase in glutamate was not , however , observed in our second case or in those previously reported , suggesting that it may be transient or depend on the severity of the disease . in our first case ,
another interesting mr spectroscopic finding was the broad peak occurring at 0.8 - 1.5 ppm .
as the increased peak intensities were broad rather than a narrow doublet at 1.33 ppm , we believe that most are due to mobile lipids , the increase of which may result from cell membrane damage or disintegration ; pathological evidence which supports this hypothesis is the neuroglial cell necrosis occurring at the center of the lesions .
this was not , however , observed in the second case , in which diffusion mri demonstrated a slightly decreased adc and the clinical outcome was good .
we consider that the combined increase in the glutamate / glutamine complex and mobile lipids is a spectroscopic sign suggesting significant neuroglial damage in the investigated regions . at follow - up
t1-weighted imaging , subacute perivascular petechial hemorrhage has been detected ( 1 - 3 , 6 , 7 ) , and in our cases , t2 * -weighted gradient - echo imaging detected acute petechial hemorrhage in the center of the thalamic lesions ; t2-weighted images obtained during the acute phase showed homogeneous high signal intensity and the presence of hemorrhage was not detected . small petechial hemorrhage may , however , be obscured within the lesions on t2-weighted images , and t2 * -weighted gradient - echo imaging may help characterize the lesions by identifying central hemorrhage during the acute phase . in acute necrotizing encephalopathy ,
the infectious organisms identified are almost always viruses , and so an antiviral agent such as acyclovir is used for treatment .
another widely used agent is steroid , which has an anticytokine effect , and since the effect of hypothermia is similar , it too has recently been used in the treatment of patients with acute necrotizing encephalopathy ( 12 ) .
such anticytokine therapies are based on the observation that in the csf and serum of patients with this disease , proinflammatory cytokine levels , including those of interleukin-6 and tumor necrosis factor- , increase . in this report , we have described two cases of acute necrotizing encephalopathy examined by diffusion mr imaging and proton mr spectroscopy , as well as routine brain mr imaging .
diffusion mr imaging revealed a more prominent decrease of adc in the first patient , who had more severe brain damage and a poorer clinical outcome than the second .
proton mr spectroscopy demonstrated increased glutamate / glutamine complex and mobile lipids in the first case and only a small increase of lactate in the second , less severe , case .
we conclude that diffusion mr imaging and proton mr spectroscopy may provide useful information not only for diagnosis , but also for estimating the severity and clinical outcome of acute necrotizing encephalopathy .
 in this report , we describe the findings of diffusion mr imaging and proton mr spectroscopy in two infants with acute necrotizing encephalopathy in which there was characteristic symmetrical involvement of the thalami . 
 diffusion mr images of the lesions showed that the observed apparent diffusion coefficient ( adc ) decrease was more prominent in the first patient , who had more severe brain damage and a poorer clinical outcome , than in the second . 
 proton mr spectroscopy detected an increase in the glutamate / glutamine complex and mobile lipids in the first case but only a small increase of lactate in the second . 
 diffusion mr imaging and proton mr spectroscopy may provide useful information not only for diagnosis but also for estimating the severity and clinical outcome of acute necrotizing encephalopathy . 
CASE REPORTS
Case 1
Case 2
DISCUSSION