J7ournal ofNeurology, Neurosurgery, and Psychiatry 1995;58:555-561

Acute necrotising encephalopathy of childhood:a new syndrome presenting with multifocal,symmetric brain lesions

M Mizuguchi, J Abe, K Mikkaichi, S Noma, K Yoshida, T Yamanaka, S Kamoshita

Department ofMentalRetardation and BirthDefect Research,National Institute ofNeuroscience,Kodaira, andDepartments ofPaediatrics, TokyoMetropolitan FuchuHospital andNeurological Hospital,Fuchu, JapanM MizuguchiSendai MunicipalHospital, Sendai,JapanJ AbeOhme MunicipalGeneral Hospital,Ohme, JapanK MikkaichiTokyo MetropolitanHachioji Children'sHospital, Hachioji,JapanS NomaMatsuyama ShiminHospital, Matsuyama,JapanK YoshidaYaizu MunicipalHospital, Yaizu, JapanT YamanakaUniversity ofTokyo,JapanS KamoshitaCorrespondence to:Dr M Mizuguchi,Department of MentalRetardation and Birth DefectResearch, National Instituteof Neuroscience, NCNP,4-1-1 Ogawahigashi-cho,Kodaira, 187, JapanReceived 22 July 1994and in revised form10 November 1994.Accepted 22 December 1994

AbstractThe clinicopathological features ofa previously unrecognised type ofacute encephalopathy prevalent amongJapanese children is described byreviewing the records of 13 consecutivepatients treated and 28 previouslyreported cases. The hallmark of thisencephalopathy, proposed to be a novelentity termed acute necrotisingencephalopathy of childhood, is multiple,necrotic brain lesions showing a symmet-ric distribution. The encephalopathy wasnoted in previously healthy childrenafter respiratory tract infections, withpresenting symptoms of coma, convul-sions, vomiting, hyperpyrexia, andhepatomegaly. Laboratory examinationsdisclosed liver dysfunction, uraemia,and hypoproteinaemia. The histologicalappearance of the liver was variable andnon-specific. Cerebrospinal fluid con-tained an increased amount of protein.Computed tomography and MRI showedthe presence of symmetrically distributedbrain lesions of the thalamus, cerebralwhite matter, brainstem, and cerebel-lum. Necropsy examination confirmedextensive fresh necrosis of these regionswith evidence of local breakdown of theblood-brain barrier. Based on thecharacteristic combination of clinicaland pathological findings, acute necrotis-ing encephalopathy of childhood canbe distinguished from previously knownencephalopathies, including Reye'ssyndrome.

(C Neurol Neurosurg Psychiatry 1995;58:555-561)

Keywords: acute encephalopathy; computed tomo-graphy; pathology

The introduction of CT into medical practicein the late 1 970s in Japan has led to the recog-nition of cases of an acute encephalopathyshowing unique brain pathology, which ischaracterised by the presence of multifocalbrain lesions in the bilateral thalamus, brain-stem, tegmentum, and cerebellum.The first case was reported in 1979, diag-

nosed as Reye's syndrome with unusual CTfindings.' During 1983 to 1986, five casesencountered at one of our hospitals werereported, together with the suggestion that thecondition may constitute a novel subtype ofacute encephalopathy.24 These reports may

have prompted subsequent reports of at least28 cases noted at other institutions inJapan,5-25 although the identity of the diseasehas so far remained obscure.To facilitate data acquisition, our institu-

tions have conducted a collaborative study.This report presents the results of that studyand a survey of the clinical, radiological, andpathological features of the disorder con-ducted in an effort to elucidate its identity as anovel disease entity, which we have desig-nated by the term acute necrotisingencephalopathy of childhood (ANE).

Patients and methodsFrom among patients with acute encephalo-pathy in childhood, we retrospectivelyselected those who met the following criteria:acute non-inflammatory encephalopathy withalteration in level of consciousness (CSFleucocyte count 8/mm3 or less); demonstra-tion by CT of multifocal lesions symmetricallydistributed in brain regions including thethalamus; and the absence of any otherreasonable explanation for the cerebral abnor-malities. Of the 13 such patients for whomrecords were retained at our hospitals (groupA), five have been reported previously.2-4Twenty eight additional patients at otherinstitutions for whom sufficient acute stagedata were available in the medical literature(group B) were also reviewed.5-25 The data forboth groups are described together and com-bined for the calculation of percentagesbecause of the relatively small sample size andthe similarity between the two groups.

ResultsBACKGROUND OF PATIENTSAll of the patients were Japanese children livingin the central districts of Japan. The diseaseaffected young children of both sexes, and46% of the patients were between 6 and 18months of age (table 1). The onset of diseasewas most often in the winter (51% inDecember-February). At four hospitals, suc-cessive admission of two to four patients wasnoted.'0 1221 Two such clusters, one in Sendaiin December, 1985, and the other on the out-skirts of Tokyo in March-June, 1988,21 wereassociated with epidemics of influenza A.The history was unremarkable in most of

the patients, although a minority had mildgrowth and developmental retardation (16%)or somatic anomalies (16%), such as cleftpalate with dysmorphic facies, ventricular

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Table I Clinicalfindings at the acute stage

Findings Group A Group B (%) *Age:Mean (SD) (y) 2-0 (1-3) 2-6 (2-5)Range 9 months to 5 months to

5 y 7 months 1OySex:Male 6/13 13/26 (49)Female 7/13 13/26 (51)

Prodromes:Common cold 13/13 25/26 (97)Fever (> 37 5°C) 13/13 16/20 (88)

Symptoms and signs:Coma 13/13 28/28 (100)Convulsions 13/13 21/22 (97)Vomiting 10/13 9/15 (68)Hyperpyrexia 10/12 14/17 (83)Hyperventilation 11/11 8/10 (90)Shock 5/13 4/12 (36)Diarrhoea 7/13 3/9 (45)Hepatomegaly 7/13 4/11 (46)Jaundice 0/13 0/7 (0)Decerebrate or decorticate

posture 10/13 17/18 (87)Miosis 11/11 7/12 (78)Sluggish light reflex 1/11 4/12 (22)Papilloedema 2/5 3/8 (38)Exaggerated tendon jerks 6/10 10/14 (67)Positive Babinski's sign 4/10 7/11 (52)

*Total for groups A and B.

septal defect with bilateral radial agenesis andunilateral renal hypoplasia, retention testis,and polydactyly.'0 No patient had travelledabroad. All of the cases were sporadic. Thefamily history was negative for consanguinityand neurological disorders, except in one

patient who had three paternal aunts who haddied of Ekiri, a fulminant form of acuteencephalopathy secondary to Shigella dysente-riae infection, which has now disappeared butwas prevalent in Japan until the 1950s.

SIGNS AND SYMPTOMSThe onset of the encephalopathy was pre-ceded by prodromal febrile illness with signsand symptoms of upper respiratory infection(table 1). Skin rash was noted in only one

patient (exanthem subitum).9 Antipyretics(61%), antibiotics (23%), and other drugswere prescribed, but 17% of the patientsreceived no medication. Aspirin had beentaken by only two patients. The possibility ofingestion or inhalation of toxic substances, as

well as attempted treatment with home reme-

dies, was denied by the parents. After an

interval of 0 5 to three days, without recoveryfrom the prodrome, the initial signs andsymptoms of brain dysfunction developed(table 1); these included impairment of con-

sciousness, convulsions, and recurrent vomit-ing. The level of consciousness deterioratedrapidly, with development of coma within 24hours, although one patient showed a some-

what protracted course."3 The types of convul-sions were variable, but generalised tonic or

tonic-clonic seizure were the most common

(84%). The vomitus was bloody in 32% of thepatients, but no haemorrhage at other siteswas noted. Half of the patients had mild diar-rhoea. Hepatomegaly (> 2 cm below thecostal margin) was noted either initially or

later in the course, but was unaccompaniedby visible jaundice. At the stage of coma,hyperpyrexia, hyperventilation, and decorti-cate or decerebrate posture were common

findings. The pupils showed miosis, but were

isocoric and promptly reactive to light in 78%of the patients. Mild papilloedema was pre-sent in a third of the patients. Deep tendonreflexes were mildly exaggerated andBabinski's sign was present bilaterally.Meningeal signs, abnormal involuntary move-ments, and focal neurological signs wereabsent, although in 23% of the patient'smotor signs were more accentuated on oneside than on the other.The disease reached its peak in the first few

days. High fever lasted for two to five days.Systemic hypotension developed in the severecases.6 13 18 Despite treatment, death occurredin 28% of the patients. In the survivingpatients, the recovery of consciousness wasfirst noted on the sixth to the 1 0th day.Although improvement of neural functionscontinued for several months, most patientshad residual neurological sequelae, such asspastic tetraplegia with rigidity (63% of thesurvivors), severe mental delay (63%), andepileptic seizures (24%).5 In milder cases,there were focal signs such as hemiparesis(four patients),'122 slurred or scanning speech,intention tremor, or ataxia, or both(four patients),'920 and abducens nerve palsy(one patient).'9 Compared with the motorsigns, cognitive functions showed goodrecovery."'3 9 2122 Recurrence of acute episodesor subsequent further deterioration was notencountered during the follow up period.

LABORATORY FINDINGSBiochemical examinations of blood on admis-sion showed increases in serum aspartateaminotransferase (95%, range 56-11 480IU/1), alanine aminotransferase (81%, range10-12 300 IU/1), lactate dehydrogenase(87%), creatine kinase (48%), and blood ureanitrogen (90%), but not in creatinine (16%).Increased blood ammonia (6%) and totalbilirubin (13%) were rare. The serum calciumconcentration was slightly depressed (50%),and sodium was in the low normal range.There was no hypoglycaemia (3%). Metabolicacidosis of variable degree was present (88%).Increases in blood concentrations of lactate(19%; range 4-8-19-2 mg/dl) and pyruvate(38%; range 04-1-51 mg/dl) were occasionaland slight.

During the first two days after admission,the biochemical abnormalities progressed. In55% of the patients, hypoproteinaemia devel-oped during this period,'0 to as low as 3-6 g/dlin the most severe case. In the survivingpatients, the first evidence of normalisation oflaboratory values was seen on the third tosixth day, and complete normalisation withinthree to five weeks.

Haematological examinations showed norapid decrease in haemoglobin concentration(0%). In the acute period, low platelet count(50%), prolonged prothrombin time or partialthromboplastin time (38%), decreased fib-rinogen (54%), and increased fibrin degrada-tion products (57%) were detected in severecases, although not to the degree that theyfulfilled the criteria for disseminated intra-vascular coagulation. Serological examination

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Acute necrotising encephalopathy ofchildhood: a new syndrome presenting with multifocal, symmetric brain lesions

Table 2 Computed tomography findings

Findings Group A Group B (%) *Brain contour on initial CT:Oedema 9/13 16/21 (74)Atrophy 1/3 1/21 (6)

Distribution of lesions:Thalamus and internal capsulet 13/13 28/28 (100)Cerebral white matter: 8/13 15/21 (68)Cerebellum§ 11/13 13/21 (71)Pons and/or midbrainll 12/13 12/20 (73)Other brain regions 0/13 0/28 (0)

Residual lesions:Cerebral atrophy 6/7 9/13 (75)Small thalamic hypodensity 4/7 12/16 (70)Multiple white matter cysts 4/7 4/12 (42)

*Total for groups A and B; tposterior limb; $periventricular region; §medullary substancearound the dentate nucleus; Iltegmentum.

Fisgure 1 (C Tfindings in a female patient, 1 year and 3 months of age. On the secondday of illness (top), multiple, symmetric hypodense areas in the thalamus, cerebellum, andbrainstem are already apparent. The periventricular white matter shows slight reduction ofattenuation. On the eighth day (middle), the density of the lesions is further decreased, andthe thalamic lesions contain tiny hyperdense dots. The cerebrum is slightly atrophic. On the41st day (bottom), the hypodense areas are reduced in size, but remain as cystic lesions.The cerebrum shows severe atrophy.

showed positive C reactive protein (76%) anda modest increase of erythrocyte sedimenta-tion rate (42%). During their stay in hospitalsignificant increases in antibody titres forinfluenza A' 21 (five patients; 24%) and cox-ackie A9 (one patient) was detected.Rotavirus was isolated from the stool of twopatients, and influenza B from the pharynx oftwo patients.6 Polymerase chain reactionanalysis on the CSF of five patients failed todetect herpes virus DNA. Bacteriologicalstudies of blood, CSF, and stool specimensyielded negative results.The findings for urine were unremarkable

except for transient proteinuria (50%) andhaematuria (33%). Serum and urine analysisof amino acids and organic acids disclosed nospecific abnormalities (both 0%).7 014 Serumcarnitine and urine acylcarnitine concentra-tions were normal (two patients).

Spinal tap disclosed high CSF pressure.Concentrations of protein (78%) and myelinbasic protein (83%) in CSF wereincreased,202' 25 whereas CSF lactate andpyruvate concentrations were normal (0%and 17% respectively).7 21 25 During convales-cence, all the CSF findings returned tonormal.

ELECTROPHYSIOLOGICAL FINDINGSThe EEG at the acute stage was dominated bydiffuse 1-6 Hz slow waves except in braindead patients (100%). Paroxysmal activitieswere rare in the initial record (18%),"3 '4 butwere common in the follow up EEG severalweeks later. The auditory brainstem responsewas diminished or abolished (86%).7 18

NEURORADIOLOGICAL FINDINGSIn all the patients, CT showed the presence ofmultiple low density areas in the brain (fig 1).The lesions were not seen in the two patientsexamined early in the lethargic state,' butwere apparent within 12 hours after the onsetof coma (100%). The brain was oedematousin most patients, but mild atrophy was notedin a few (table 2). The distribution of thehypodense lesions was almost symmetric andwas similar in all the patients (table 2).Supratentorial lesions included most of thethalamus, the posterior limb of the internalcapsule, and the posterior part of the lenticularnucleus. The periventricular white matter ofthe cerebrum was also affected. Infratentoriallesions were distributed in the cerebellarmedullary substance around the dentatenucleus and the tegmentum of the pons ormidbrain. Other brain regions were notaffected in any patient. The thalamic lesionswere enhanced by contrast materials in 27%of the patients.

During the first week of illness, the thala-mic lesions became mottled, and the cerebralwhite matter lesions became more hypodense.During subsequent weeks, the thalamic andinfratentorial lesions became smaller and thecerebrum more atrophic. Five patients ingroup B showed positive contrast enhance-ment at this stage, notably ring like enhance-ment of the margin of the thalamic

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Figure 2 MRIfindings in a male patient, 1 year and 3 months of age. Tl (left) and T2(right) weighted images on the fourth day (top and middle) and 23rd day (bottom) ofillness show symmetric lesions in the thalamus, internal capsule, lenticular nucleus,periventricular white matter, cerebellum, and pons. The infratentorial and cerebral whitematter lesions in this patient are small. At the initial MRI (fourth day), the signalintensity observedfor the lesions is low on Tl weighted images and high on T2 weightedimages. At the subsequent MRI (23rd day), the centre and periphery of the thalamic andlenticular lesions show hyperintensity on both Tl and T2 weighted images, suggestive ofhaemorrhagic change.

lesions.7 1321 24 In one patient, the white matterlesions were also stained.'3 During convales-cence, there were residual findings such as

cerebral atrophy, small thalamic hypodensi-ties, and multiple cysts in the white matter. Inone patient, calcification was noted in thethalamus.

Magnetic resonance imaging studies were

performed in the more recent cases (threepatients in group A and 11 patients in groupB).'3 16 Although low signal intensity of the

lesions was found on TI weighted images andhigh intensity on T2 weighted images, thethalamic lesions in all patients included areasof high signal intensity on both T1 and T2weighted images (fig 2). In two patients, thehigh intensity had consisted solely of minutedots during the initial two to four days butbecame larger and coalescent during subse-quent weeks.23 In the other patients, an ovalarea of high intensity in the centre and a ringlike zone of high intensity along the marginwere prominent as early as the first week ofillness.19 21 In no patient was intravascularthrombosis demonstrated.

LIVER PATHOLOGYHistological examinations were performed ontissue specimens obtained at biopsy (fourpatients in group A and 10 patients in groupB)9 17-1921 23 or at necropsy (two patients eachin groups A and B).617 In no specimen wasnecrosis, bile stasis, or inflammatory infiltratefound. In many of these patients, the hepato-cytes were swollen or contained intracytoplas-mic vacuoles that stained positively forlipids.69 1821 Fatty changes were moderate orsevere in 61% of the patients,69 1821 but wereminimal or absent in the others.'4 21 23 The dis-tribution of lipid droplets was variable, beingperiportal, centrilobular, or diffuse. Electronmicroscopic examination showed mitochon-drial swelling and mild pleiomorphism in 58%of the patients,6 9 21 but normal findings in theothers.'8 There was no evidence of furtherabnormalities, such as decrease in matrix den-sity, loss of intramitochondrial dense bodies,or ameboid deformation.

BRAIN PATHOLOGYPermission to perform necropsy was obtainedfor two patients each in groups A and B.6 Inthe three patients who were in the acute stageat necropsy (duration of illness six to 48hours), the brain was the only organ showingspecific pathological changes, which weresimilar in all three. The brains were oedema-tous on gross examination, but there was nocerebral herniation. The main branches of thecerebral arteries and veins were intact. Onsectioning (fig 3A), all of the lesions that hadbeen seen on CT showed pronounced soften-ing. Central lesions in the thalamus and brain-stem tegmentum showed dark browndiscoloration and petechial haemorrhage.Peripheral lesions in the periventricular whitematter of the cerebrum, corpus callosum,dentate nuclei, and surrounding white matterof the cerebellum showed loss of the normallustre of the white matter. Microscopic exami-nation of the lesions by haematoxylin andeosin and myelin stains showed congestion,loosening, and poor staining of tissue (fig 3B)and necrosis of neurons and glial cells, butthere was no proliferation of reactive astro-cytes or microglial cells. A silver impregnationmethod showed concomitant loss of axons.Around the small arteries, veins, and capillar-ies, extravasation of erythrocytes was seen inthe central lesions (fig 3C) and a plasma likesubstance was present in the peripheral

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Acute necrotising encephalopathy of childhood: a new syndrome presenting with multifocal, symmetric brainlesions55

Figure 3 Necropsyfindings for the brain of amale patient, 1 year and 9months of age, who died onthe first day of illness. (A)Gross appearance of theunfixed brain section. Thebrain is oedematous; thethalamus and lenticularnucleus are softened anddiscoloured dark brown;and the periventricularwhite matter and corpuscallosum are also softened.(B) A periventricularlesion, abutting thecingulate gyrus (rightupper) and involving partof the corpus callosum(right lower), isdemonstrated as a sharplydemarcated area of myelinpallor (7uxol fast blue).(C) In the thalamic lesionthere are: loosening of thetissue, petechialhaemorrhage, andscattered cells with darklystained nuclei. (D) In thecerebral white matterlesion, extravasation of aplasma like substance isnoted around a vein (Cand D, haemawoxylin andeosin).

B~~~~~~~~~~~T:

cI.,

cystic lesion in the midbrain (fig 4B). Onhistological examination, the dorsal half of thethalamus and adjacent corpus striatumshowed multiple necrotic foci filled with lipidladen macrophages (fig 4C). In the otherlesions of the grey matter, such as the ventralhalf of the thalamus, severe loss of neuronsand myelin sheaths were present together withgliosis. Fibrous gliosis was also noted alongthe walls of cavities in the white matter andthe midbrain.

At both the acute and chronic stages, theboundaries of the lesions were sharply definedbut were irrespective of those of normal struc-tures. Outside the affected areas, there wereno abnormal findings except for mildischaemic change in neurons.

WN:'

4~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~......

lesions (fig 3D). Except for occasional nuclear

pyknosis of the endothelial cells, no notable

change of blood vessels, such as deposition of

fibrinoid materials or infiltration of inflamma-

tory cells in the perivascular space, was noted.

T'he walls of arteries and veins appeared intact

by elastic-van Gieson and connective tissue

stains, and the vascularity was normal by reti-

culin stains.

T'he brain of a patient who died after one

year of persistent vegetative state'4 was

atrophic with enlargement of the ventricles.

T'he thalami and basal ganglia showed soften-

ing, microcavitation, or brown discoloration.

T'here were multiple cystic lesions in the

periventricular white matter of the cerebrum

(fig 4A). In the brainstem of this patient, con-

siderable atrophy of the tegmentum was pre-

sent at both the mesencephalic and pontine

levels. There were bilateral symmetric,

necrotic lesions in the pontine tegmentum

and cerebellar medullary substance, and a

DiscussionThe clinical, radiological, and pathologicalfeatures of the encephalopathy described inthis report constitute an unusual but charac-teristic pattern that we believe warrantsrecognition of ANE as a distinct clinico-pathological entity. Although the individualclinical or laboratory findings in ANE may beseen in a wide range of disorders, includingoverwhelming bacterial and viral infections,fulminant hepatitis, toxic shock, haemolytic-uraemic syndrome, other toxin induced dis-eases-, Reye's syndrome, haemorrhagic shockand encephalopathy syndrome, and heat-stroke, none of these conditions are associatedwith the symmetric brain lesions seen inANE. Multifocal haemorrhagic or non-haemorrhagic infarcts have been found in thebrains of patients with haemolytic-uraemicsyndrome and haemorrhagic shock andencephalopathy syndrome., but they areusually asymmetric.27 Moreover, the cardi-nal clinical and laboratory findings in ANEare clearly distinct from the features of thesediseases, with the sole exception of Reye'ssyndrome.

T'he differentiation of ANE from Reye'ssyndrome has presented much difficulty in thepatients who have very high transaminase val-ues or fatty change of the liver, some of whomwere initially thought to have Reye's syn-drome.1'468917 1821 25 There are certain differ-ences, however., between ANE and Reye'ssyndrome; diarrhoea and increased CSF pro-tein are common in ANE but are rare inReye's syndrome, patients with ANE do notpresent certain metabolic features of Reye'ssyndrome such as hyperammonaemia andhypoglycaemia,2 and, unlike Reye's syn-drome, ANE is not associated with varicella asan antecedent infection. With regard to theliver pathology, the combination ofencephalopathy and fatty liver change alone isnot conclusive evidence warranting the diag-nosis of Reye's syndrome. Fatty change in theliver has been regarded by some investigatorsas an incidental and non-specific finiding inReye like encephalopathies.29 This view seemsto hold true in ANE., as the number and dis-tribution of lipid droplets are highly variableamong the patients. Moreover, the severe

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560~~~~~~~~~~~~~~~~Mizuguchi,Abe, Mikkaichi, Noma, Yoshida, Yamanaka, Kamoshita

4...

n1

Figure 4 Gross necropsy findings for the brain of a female patient who hadc

encephalopathy at the age of 8 months, one year before her death. (A) The cel

atrophy, pigmentation (brown) of the thalamus, and the presence of multipleCthe white matter surrounding the lateral ventricle. (B) The brainstem shows si

atrophy of the tegmentum, where cysts and necrotic (brown) lesions are presen,

symmetrically. Symmetric lesions are also noted in the cerebellum. (C) In the

lesion, there are macrophage filled, necrotic foci (left) and perivascular aggrego

macrophages (arrows). The rest of the tissue shows severe gliosis (haematoxylieosin).

distortion of mitochondria typical

syndrome30 is absent.

The most important features ofthe symmetric brain lesions, which

the early stage of coma and shov

pathological features. The acute sta

ogy in ANE can be summarised

oedema and necrosis involving boit]

white matter. Local breakdown of

brain barrier is indicated by the extof erythrocytes in the thalamic Ic

that of a plasma like substance in ti

white matter lesions; both of these necropsyfindings are compatible with the local signalpatterns seen on MRI. The increase in CSFprotein may be additional evidence for thedefective baffler. At the acute stage, there areno reactive changes of inflammatory cells,glial cells, or blood vessels. Absence of suchreactions differentiates ANE from Wemnicke'sand Leigh's encephalopathies, and resultsfrom the short clinical course of ANE. UnlikeLeigh's encephalopathy, ANE shows afulminant and monophasic course withoutexception.From the radiological and pathological

standpoints, ANE should be differentiatedfrom other acute disorders that may producebilateral lesions in the cerebral deep greymatter, including Leigh's encephalopathy andrelated mitochondrial cytopathies, glutaricacidaemia, methylmalonic acidaemia,Wemnicke's encephalopathy, carbon monox-ide poisoning, infantile bilateral striatal necro-sis, acute disseminated encephalomyelitis,acute haemorrhagic leucoencephalitis (alsoreferred to as "acute necrotising haemorrhagicencephalopathy"), and other types ofencephalitis, vasculitis, arterial or venousinfarction, and the effects of severe hypoxia orhead trauma. Of these, the metabolic disor-ders can be excluded based on biochemicalstudies, and the intoxications based on clini-Cal history. Infantile bilateral striatal necrosisshows a different distribution, the corpusstriatum being affected most severely.3"3Although it may occasionally be difficult torule out encephalitides solely on clinicalgrounds, the brain pathology in ANE is notcompatible with inflammatory disorders. Forexample, the brain lesions in ANE lackperivascular and meningeal inflammation,necrosis of blood vessels, and asymmetric dis-tribution, features that are typical of acutehaemorrhagic leucoencephalitis.33The brain lesions in ANE cannot be

ascribed to incidental circulatory accidentssuch as hypoxia or ischaemia, as has beenpointed out by some previous authors whomade the diagnosis of Reye's syndrome,7'1 inwhich the gross neuropathological findingsare essentially limited to brain oedema.34

ontrcted Diffuse cerebral hypoxia can result in sym-rebrmsows metric damage to the bilateral deep grey mat-

cavities in ter, but such a pathomechanism is excludedelective by the clinical course in many of the patients;It ~~the CT lesions appear early in the absence of

thalamichyoiisheiepsdsLoaisamarates Of hyoi-sheiepsdsLoaisama

in and due to hypoperfusion of the branches of thebilateral posterior cerebral arteries has beenproposed, with speculated compression of the

in Reye's arteries caused by transtentorial herniation.' 15

This explanation, however, is refuted by theANE are presence of lesions beyond the territory of theiappear at posterior cerebral artery, the absence of anyv constant sign of brain oedema on the initial CT scan inige pathol- 26% of the patients, and the absence of cere-Ias acute bral hemniation in the necropsied brains.h grey and Thrombotic occlusion of large cerebral arter-the blood- ies or veins is another possibility. In excep-travasation tional cases, in which the lesions were~sions and restricted to the thalamus and lenticularie cerebral nucleus, it is possible that bilateral infarction

560

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Acute necrotising encephalopathy of childhood: a new syndrome presenting with multifocal, symmetric brain lesions

developed due to thrombosis of the internalcerebral veins, great cerebral vein of Galen, orstraight sinus.24 36 In most of the cases, how-ever, a thrombotic mechanism is not tenablebecause of the lack of CT or MRI evidence,the intact vessels found on postmortem exam-inations, and the more extensive distributionof lesions than the territories fed by a singleartery or those drained by a single vein.

Although the basis for the distributionremains obscure, the affected areas generallycorrespond to the zones irrigated by the ter-minal branches of the intracerebral arteriesand to the regions where TI and T2relaxation times on MRI decline early innormal development,37 implicating regionaldifferences in blood flow and myelination asthe factors responsible for the selectivevulnerability.

Because biochemical studies have so farprovided no promising clue as to the patho-genesis of ANE, further epidemiologicalinvestigations are needed. The geographicaldistribution ofANE is noteworthy. It is by nomeans uncommon among Japanese children,and there are reports of adult cases showingsimilar pathological findings, that may repre-sent a variant of ANE.38 By contrast, we haveso far failed to find any reports of similar casesoccurring outside Japan. We hope that thisreport will serve to alert paediatric neurolo-gists and neuropathologists in countries otherthan Japan, where there may be as yetunrecognised cases of ANE. Detailed epi-demiological, clinical, and pathological investi-gations may shed light on the aetiology of thisdevastating disorder.

We thank Drs Rinmei Fukuda, Masaki Hoshiyama, KunioKaneshi, Hajime Katayama, Eiji Kurihara, Akira Kusakari,and Mineko Matsuo for clinical evaluations, Drs NobuhikoAoki and Akira Yagishita for radiological interpretations, andDrs Koken Kinjo and Toshihiro Nishida for pathologicalinvestigations.

1 Mizuta R, Izumi H, Takeuchi S, et al. A case of Reye'ssyndrome with elevation of influenza A, CF antibody.Japanese Journal of Pediatrics 1979;32:2144-9. (InJapanese.)

2 Aoki N, Kaneshi K, Mizuguchi M, Kurihara E. Computedtomography in acute toxic encephalopathy-Report ofthree cases with symmetrical low density areas in thethalamus and the cerebellum. No To Hattatsu1983;15:345-9. (In Japanese.)

3 Aoki N. Acute toxic encephalopathy with symmetrical lowdensity areas in the thalami and the cerebellum. ChildsNerv Syst 1985;1:62-5.

4 Mizuguchi M, Kamoshita S. Neuropathology of Reye syn-drome. Journal of Pediatnrc Practice 1986;49:1027-35. (InJapanese.)

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