in herpes simplex encephalitis ( hse ) , the gray matter of the temporal and frontal lobes is 
 predominantly destroyed by many foci of hemorrhage and necrosis .
the lesions usually begin either unilaterally or bilaterally in the 
 medial temporal cortex with bilateral spread along limbic pathways to the orbital frontal lobe 
 and insular cortex .
parietal , occipital , brainstem , internal capsule , and cingulate gyrus 
 involvement often occurs with further spread , but the basal ganglia and lobar white matter are 
 relatively spared . here , we report a case of 
 hse with basal ganglia and white matter involvement evident on mri during the acute stage , which 
 presented with unusual and severe progression .
when there was no response to medical management 
 of hse , we had to use surgical decompression .
pathological findings of hse during the acute 
 stage indicated involvement of the white matter . to our knowledge , this is the first report 
 which shows both mr and pathological findings in the white matter during the acute stage of 
 hse .
a previously healthy 51-year old male presented with the sudden onset of generalized tonic 
 clonic convulsion . after two hours he was admitted to our hospital .
the convulsion had 
 terminated spontaneously after thirty minutes . on admission , he had no headache , was not 
 vomiting , and had a low - grade fever of 37.4c .
there were no obvious motor or sensory 
 abnormalities , and his reflexes were equal bilaterally in both the upper and lower limbs . 

mri on admission ( three hours after onset ) was 
 normal on t1 , t2 , diffusion - weighted ( dw ) and fluid - attenuated inversion recovery ( flair ) 
 images .
one hour after admission , clonic convulsion in his right arm emerged without impaired 
 consciousness .
the focal seizure could not be controlled by diazepam , phenytoin and midazolam 
 infusion .
this refractory focal seizure persisted until day 3 without other neurological focal 
 signs , and a second mri on day 2 was normal on t1 , t2 , dw , flair , and gadolinium - enhanced t1 
 images .
electroencephalography ( eeg ) on day 2 showed left parietal focal slow 
  activity without epileptiform discharge .
titers for common viruses 
 ( hivs , epstein - barr , cytomegalovirus , herpes zoster , and herpes simplex ) , bacteria , and 
 toxoplasmosis were negative .
tests for autoantibodies ( antinuclear , anti - deoxyribonucleic acid , 
 and anti - ribonucleoprotein antibodies ) , lupus erythematosus factor , syphilis serology , 
 p - and canca were all negative .
cerebrospinal fluid ( csf ) examination on day 3 showed no abnormality , 
 and no herpes simplex virus ( hsv ) dna was demonstrated by polymerase chain reaction ( pcr ) . 

cytology and culture of the csf for bacteria , tuberculous bacillus , and fungi were negative .
axial dw and flair images on day 4 
 revealed high - intensity areas in the left frontal cortex ( figure 
 1a ) .
the clonic seizure in the right arm changed to myoclonic status in the mouth , 
 diaphragm , and right arm . additionally , respiratory failure necessitated artificial ventilation 
 under anesthesia .
continuous propofol infusion did not suppress the myoclonic status migrating 
 around the four limbs , from the right arm to the right leg , the right leg to the left arm , and 
 the left arm to the left leg , every other day .
after the myoclonus in the left leg disappeared , 
 myoclonic status persisted in the diaphragm alone .
high - dose barbiturate therapy instead of 
 propofol did not resolve this intractable myoclonic status in the diaphragm .
eeg on day 7 
 revealed a burst - suppression pattern observed during barbiturate coma .
axial dw and flair images on day 9 revealed high - intensity areas ; bilaterally widespread in frontoparietal cortex , medial 
 temporal lobe , insula , and putamen with left - sided predominance , additionally in the frontal 
 orbital lobes bilaterally , in the left caudate nucleus , and the thalamus ( figure 1b ) . on lumbar
puncture , csf pressure was 400 mm h2o , cell count 
 was 16/mm ( 56% mononuclear cells ) , csf protein concentration and glucose were normal at 27 and 98 mg / dl ( blood glucose 115 mg / dl ) , respectively , and the pcr result was positive for hsv-1 dna .
a diagnosis of hse was made , and acyclovir was administered on day 9 , but did not suppress the emergence of the diaphragmatic myoclonic status .
fever increased to high - grade , and coma persisted , so artificial ventilation did not require sedation .
axial dw and flair images on day 16 , compared with the previous mri , demonstrated more widespread lesions indicating frontoparietal involvement , progression of left thalamic high - intensity areas , and swelling sufficient to cause midline shift to the right and distortion of the lateral ventricle ( figure 1c ) . 

axial fluid - attenuated inversion recovery ( flair ) images : ( a ) on day 4 , showing high signal intensity in the left frontal cortex , and ( b ) on day 9 , showing high signal intensity in the frontoparietal cortex bilaterally , medial temporal lobe , insula , and putamen with left - sided predominance , and in the frontal orbital lobe bilaterally , left caudate nucleus , and thalamus .
the high - intensity areas in the gray matter shown on day 9 increased : ( c ) on day 16 , except in the basal ganglia ( caudate nucleus , putamen ) , especially in the left thalamus , which caused midline shift to the right , and ( d ) on day 23 , extending to the white matter , causing an increased midline shift to the right and cerebral edema . 
 
axial fluid - attenuated inversion recovery ( flair ) images : ( a ) on day 4 , showing high signal intensity in the left frontal cortex , and ( b ) on day 9 , showing high signal intensity in the frontoparietal cortex bilaterally , medial temporal lobe , insula , and putamen with left - sided predominance , and in the frontal orbital lobe bilaterally , left caudate nucleus , and thalamus .
the high - intensity areas in the gray matter shown on day 9 increased : ( c ) on day 16 , except in the basal ganglia ( caudate nucleus , putamen ) , especially in the left thalamus , which caused midline shift to the right , and ( d ) on day 23 , extending to the white matter , causing an increased midline shift to the right and cerebral edema .
cerebral edema worsened , and adjunctive immunosuppressive ( steroid pulse therapy and 
 intravenous immunoglobulin ) and high - dose anti - edematous therapies were added .
csf examination 
 on day 20 revealed a 37/m cell count ( 65% mononuclear cells ) and protein 
 concentration of 340 mg / dl .
axial dw and flair images on day 23 showed high - intensity areas in 
 the white matter adjacent to the affected gray matter , and cerebral edema worsened 
 catastrophically ( figure 1d ) .
one hour after the mri was 
 performed ( on day 23 ) , sudden hypotension and mydriasis emerged , which suggested cerebral 
 herniation .
surgical decompression resolved 
 the cerebral herniation , and rescued our patient from death . despite this , coma , diaphragmatic myoclonic status , and
histological examination detected perivascular infiltration of lymphocytes and 
 destruction of basic structure ( figure 2a , b ) .
obvious edema , demyelination and axonal reduction were not seen ( figure 2c , d ) . 

figure 2microscopic findings of the biopsied tissue in the left frontal lobe ( a , b , c , d ) . ( a ) and ( b , arrows ) : perivascular infiltration of lymphocytes and destruction of basic structure , which confirmed non specific inflammatory change , hematoxylin - eosin stain ,  10 and 40 , respectively . ( c ) : no obvious demyelination , kluver - barrera stain , 10 .
( d ) : no definite axonal reduction or swelling , bodian stain , 10 . 
 
microscopic findings of the biopsied tissue in the left frontal lobe ( a , b , c , d ) .
( a ) and ( b , arrows ) : perivascular infiltration of lymphocytes and destruction of basic structure , which confirmed non specific inflammatory change , hematoxylin - eosin stain ,  10 and 40 , respectively .
( d ) : no definite axonal reduction or swelling , bodian stain , 10 .
subsequently , axial dw and flair images on day 30 displayed the extensive white matter lesions 
 extending into the lower midbrain and pons despite surgical decompression ( figure 3a ) .
resolution of high - grade fever coincided with amelioration of 
 diaphragmatic myoclonic status , while coma and decorticate states persisted . at four months 
 after onset , this patient remained in a comatose and decerebrate state under artificial 
 ventilation .
two 
 years after onset , an axial flair image showed cerebral atrophy , severe ventricular dilatation 
 and multiple cystic changes ( 3b ) . 

figure 3axial flair images : ( a ) after surgical decompression showing high signal intensity in the frontotemporoparietal lobes bilaterally , left occipital lobe , basal ganglia bilaterally , left midbrain , and pons , and ( b ) two years after onset showing cerebral atrophy , severe ventricular dilatation , and cystic change in the frontal lobes , with left - sided predominancy , and in the left thalamus . 
 
axial flair images : ( a ) after surgical decompression showing high signal intensity in the frontotemporoparietal lobes bilaterally , left occipital lobe , basal ganglia bilaterally , left midbrain , and pons , and ( b ) two years after onset showing cerebral atrophy , severe ventricular dilatation , and cystic change in the frontal lobes , with left - sided predominancy , and in the left thalamus .
typically , mri abnormalities in hse are seen in the temporal and frontal lobes , and the basal 
 ganglia and white matter are relatively spared
. early diagnosis of hse is difficult because of 
 the finding of a normal mri or a purely extra - temporal involvement .
clinical diagnosis is 
 suggested by the febrile patient with focal neurologic signs , and the most important factor in 
 the diagnosis of hse is the consideration of this diagnostic possibility .
hence , if hse is suspected , treatment should be 
 started before a definitive diagnosis is made .
early administration of antiviral therapy is the 
 only parameter that can be modified to improve the prognosis of the patient with hse . in our case ,
mri and csf examinations were normal until day 3 , and the initial abnormal dw and 
 flair images on day 4 revealed purely extra - temporal involvement , which delayed antiviral therapy .
first , the initial lesion was seen in the left frontal cortex , and extended to have an unusual distribution into the basal ganglia , i.e. , from purely extra - temporal involvement , which are usually spared in hse . additionally , mri on days 9 and 16 showed thalamic involvement . in infectious encephalitis , bilateral involvement of the basal ganglia and thalamus is characteristic of flavivirus encephalitis , like japanese encephalitis .
therefore this case suggested that mr findings , which displayed purely extra - temporal involvement in the early stage and subsequently basal ganglia and thalamic involvement , did not rule out hse conclusively .
second , mri revealed the extensive white matter involvement adjacent to the affected gray matter , in parallel with monophasic clinical worsening .
this white matter involvement appeared on day 23 , during the acute stage . in this report
, acute stage means the stage of the illness where the symptoms are the most severe before recovery .
this acute white matter involvement revealed high - intensity areas on dw and flair images , and especially markedly high intensities on dw images .
several reports have described white matter lesions that appeared several weeks or months after the onset of illness , not during the acute stage like the present case but during the subacute or chronic stage .
the delayed white matter lesions appeared with or without deterioration of conditions after the discontinuation of the acute stage , which developed independently of the affected gray matter lesions .
there have been no reports regarding intensities on dw images in delayed white matter 
 involvement .
the mechanism underlying the delayed white matter lesions has not been elucidated , 
 and an immune - mediated complication , such as edema or demyelination , is suspected .
besides , another two mechanisms are possible : the 
 occurrence of late - onset symptoms of the initial viral infection , and recurrence of viral 
 replication ( as a result of incomplete treatment of the initial hse or by selection of clones of 
 an acyclovir - resistant virus ) .
one autopsy 
 study of hse with delayed white matter involvement showed diffuse edema , without demyelination 
 or viral inclusion .
another biopsy study of 
 hse with delayed white matter involvement revealed cell - mediated demyelination without 
 reactivation of the hsv infection . in the 
 present case
, the acute white matter involvement appeared adjacent to the affected gray matter 
 with high intensities on dw images .
the speculated mechanism of the acute white matter 
 involvement was direct invasion of hsv different from that with the delayed change .
on the other hand , it was postulated at the autopsy 
 that focal perivascular myelin destruction in the white matter , without recovery , was dependent 
 on the immune response .
that is to say , the 
 speculated mechanism underlying either the delayed or acute white matter involvement of hse has 
 been controversial .
microscopic findings of the biopsied tissue obtained in acute white matter 
 involvement demonstrated perivascular infiltration and destruction of basal structure , which 
 confirmed non specific inflammatory changes .
a brain biopsy was carried out on day 23 , after 
 acyclovir administration , which demonstrated some of the neurons to be immunohistochemically 
 positive for hsv-1 antigen .
thus we could not conclude that the acute white matter involvement 
 was not a result of direct invasion of hsv .
obvious edema , demyelination , axonal reduction , and 
 swelling , which could suggest the mechanism underlying the white matter involvement of hse 
 during the acute stage , were not seen .
there was a discrepancy between nonspecific pathological 
 findings and the unusual clinical course of the present hse , including mr findings .
hence , it is 
 still unclear from the histology whether the acute white matter involvement is because of direct 
 invasion of hse , like the affected gray matter , or secondary inflammatory change or both , but 
 combination therapy with antiviral therapy and immunosuppressive therapy did not control the 
 condition .
although the white matter involvement had not extended into the medulla oblongata on 
 mri , prolonged respiratory failure necessitated artificial ventilation .
therefore , it was 
 possible that the respiratory centers located in the medulla oblongata were injured despite 
 there being no corresponding involvement on mri .
the present case resulted in neurologic deterioration because of cerebral edema and herniation 
 despite antiviral , immunosuppressive , and anti - edematous therapies .
emergency decompressive 
 craniectomy prevented death as a result of cerebral herniation , but lead to severe neurological 
 sequelae .
matthew et al . ( reported by adamo and deshaies , 2008 ) discussed cases 
 of infectious encephalitis including hse , which resulted in excellent recovery after surgical 
 decompression .
the reason that surgical 
 decompression did not lead to improvement in the present case may be attributed to the 
 devastating white matter involvement , sufficient to extend into the brainstem and cause injury 
 to the respiratory center even after surgical decompression .
if extensive progression into the 
 white matter could have been prevented , the sequelae would not have been as severe as in the 
 present case .
therefore , further investigation of the mechanism underlying the white matter 
 involvement of hse during the acute stage is needed .
   we report a 51-year old male with herpes simplex encephalitis ( hse ) showing unusual 
 progression and magnetic resonance ( mr ) findings . 
 the initial neurological manifestation of 
 intractable focal seizure with low - grade fever persisted for three days , and rapidly coma , 
 myoclonic status , and respiratory failure with high - grade fever emerged thereafter . 
 the 
 polymerase chain reaction ( pcr ) result of cerebrospinal fluid ( csf ) was positive for hsv-1 dna . 
 in the early stage , mr images ( mri ) 
 were normal . on subsequent mr diffusion - weighted ( dw ) and 
 fluid - attenuated inversion recovery ( flair ) images , high - intensity areas first appeared in the 
 left frontal cortex , which was purely extra - temporal involvement , and extended into the basal 
 ganglia , then the white matter , which are relatively spared in hse . 
 antiviral therapy and 
 immunosuppressive therapy did not suppress the progression of hse , and finally severe cerebral 
 edema developed into cerebral herniation , which required emergency decompressive craniectomy . 
 
 histological examination of a biopsy specimen of the white matter detected perivascular 
 infiltration and destruction of basic structure , which confirmed non specific inflammatory 
 change without obvious edema or demyelination . 
 the present case shows both mr and pathological 
 findings in the white matter in the acute stage of hse . 
Introduction
Case Report
Discussion