chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids ( clippers ) is an inflammatory disorder in the central nervous system ( cns ) with distinct clinical , radiological , and pathological features .
although the radiological lesions were reported to be located predominantly in the pons , brachium pontis , and cerebellum , other adjacent structures such as the white matter and spinal cord were very recently reported as involved regions in clippers . in this study , we report a case of clippers presenting with intracranial epstein  barr virus ( ebv ) infection and diffuse white matter involvement .
a 37-year - old male was diagnosed with mediastinal hodgkin 's lymphoma ( lymphocyte predominance type ) at the age of 26 , and then obtained complete remission after treatment and remained free of relapse for 11 years .
he was admitted with 7 months history of mental disorder , and 20 days history of gait and limb ataxia , dysphagia , and cough .
the diagnosis of clippers was established based on the findings of punctate and nodular enhancing lesions in the bilateral pons , the basal ganglia , the mid - brain , the pontine brachium , and diffuse white matter in magnetic resonance imaging ( mri ) , together with cd3 t - lymphocytic inflammatory infiltration in perivascular and parenchymal area revealed by bilateral parietal lobe brain biopsy .
also , our patient exhibited a good response to steroid therapy and remained free of relapse for 5 months .
clippers might be an autoimmune disorder , and intracranial ebv - infection raises the possibility that ebv - associated autoimmunity is associated with clippers pathogenesis .
chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids ( clippers ) is a recently defined immune - mediated and treatable central nervous system ( cns ) inflammatory disease with distinct clinical , radiological , and pathological characteristics .
clippers patients present with a favorable but dependent response to steroids therapy and show a punctate and nodular pattern of gadolinium enhancement  peppering  in the pons , brainstem , white matter , and other adjacent structures .
several studies suggested that clippers is an autoimmune disorder , but the related evidence still remains deficient .
now , we report a case of clippers patient confirmed by clinical , radiological , and pathological characteristics .
interestingly , a significantly elevated load of epstein  barr virus ( ebv ) dna was detected in his cerebrospinal fluid ( csf ) .
this presentation raises the possibility that ebv - associated immunity dysfunction may be related to the pathogenesis of clippers .
as far as we perceive , this is the first case of clippers with cns ebv infection .
a 37-year - old male was diagnosed with mediastinal hodgkin 's lymphoma ( lymphocyte predominance type ) at the age of 26 .
after treated with abvd ( adriamycin , bleomycin , vinblastine , dacarbazine ) , he obtained complete remission and remained free of relapse for 11 years .
seven months prior to admission , he described sadness when feeling tough in his career . meanwhile , with the irritability , aypnia , and reduction of speech , he found the unwillingness of communication with others .
after treated with escitalopram oxalate , risperidone , and sertraline , he gradually emerged symptoms of mania , which is characterized by increased grandiloquent speech and less need for sleep .
diagnosed with bipolar disorder at the local hospital , he was given vpa - mg , buspirone and clonazepam , and then obtained an improvement .
one month ago , he subacutely developed gait and limb ataxia featured by unstable walking and clumsy hand movements .
he also had a generalized seizure ( tonic ) 2 weeks before admission , and then developed headache , shortness of breath , and somnolence . on admission , the patient 's temperature was normal .
neurological examination revealed the right abducens nerve palsy and limited left eyeball movement to any direction .
appearance of hoarseness , dysphagia , and cough had been noticed , with apparent pharyngeal reflex decreased .
muscle strength scores of bilateral upper and lower limbs were 4 on the medical research council scale .
the leukocytoclastic vasculitis was excluded because no palpable purpura , urticarial plaques , vesicles , bullae , or pustule was noted , nor were signs of joints injury or gastrointestinal injury .
fever , malaise , weight loss , arthralgias , and myalgias were not detected in this case .
hematuria and proteinuria were absent in this case . nor was any suspicious pulmonary hemorrhage noted .
laboratory investigations revealed that the patient had normal complete and differential blood count , sedimentation rate , c - reactive protein , thyroid hormone , renal and liver function . serum immunological study , antinuclear antibodies , double - stranded dna antibodies , and antibodies against extractable nuclear antigens were all negative .
paraneoplastic autoantibodies panels including anti - hu , anti - cv2 , anti - ma2 , anti - ri and anti - voltage - gated k channels were negative .
nmda igg , ampa1 igg , ampa2 igg , lgl1 igg , caspr2 igg , and gaba b receptor igg were all negative .
serum igg and/or igm of human immunodeficiency virus , hepatitis b virus , syphilis , and herpes simplex virus were all negative .
barr nuclear antigens ( ebnas ) antibody and epstein  barr viral capsid antigen igg ( ebvca - igg > 22  ru / ml ) but negative for epstein  barr viral capsid antigen igm ( ebvca - igm > 22  ru / ml ) , suggesting a possible history of ebv infection .
the level of ebv dna in the blood ( < 5000 copies ) was also specified to rule out chronic active ebv disease ( caebv ) in this young patient .
csf examination revealed mildly elevated protein levels ( 1.3  g / l , normal 0.150.40 
notably , an elevated load of ebv - dna was detected in csf by pcr as 2.01    10 copies ( normal < 5000 copies ) .
brain magnetic resonance imaging ( mri ) showed hyperintense signal on t2-weighted images , associated with patchy gadolinium enhancement on t1-weighed images in the bilateral pons , the basal ganglia , the midbrain , the pontine brachium , and diffuse white matter ( fig .
the clinical and mri findings could suggest other disorders , such as neurosarcoidosis , cns vasculitis , autoimmune encephalitis , histiocytosis and paraneoplastic disease .
bilateral parietal lobe brain biopsy revealed lymphocytic inflammatory infiltration in perivascular and parenchymal area ( fig .
1c ) , consisting primarily of cd3 t lymphocytes ( fig . 1d ) and few detected cd1a cells , cd30 cells , cd10 cells and cd20 cells .
neuroradiological images on admission and 3 weeks after steroid therapy and pathological findings from brain biopsy .
representative t1-weighted imaging with gadolinium enhancement ( top row ) and corresponding t2-weighted imaging ( bottom row ) on cervical mri demonstrate changes of mri features after steroid therapy .
the images performed on admission show punctate and nodular enhancing lesions in the bilateral pons , the basal ganglia , the midbrain , the pontine brachium , and extensively in cerebral white matter , with a perivascular enhancement pattern ( a1 , a2 ) .
a decrease in the number and extent of pathology is observed on a cervical mri scan after steroid treatment ( b1 , b2 ) . in pathology findings from the parietal lobe specimen , hematoxylin and eosin staining showed lymphocytic inflammatory infiltration with perivascular and parenchymal cells ( c ;    100 ) .
the lymphocytic infiltrates were mainly composed of cd3 t lymphocytes ( d ;  100 ) .
proliferation rate , detected by ki67 antigen immunohistochemistry , was about 10% ( e ;  100 ) .
( 15  mg daily ) was initiated , the patient responded well with gradually improved symptoms within a week from starting treatment , despite mild persistent mental abnormality and dysphagia .
csf analysis results also showed a decrease of the cytology ( white blood cells : 47/mm , 99% lymphocytes ) .
the pontine lesions in mri decreased in numbers and extent 3 weeks from starting treatment ( fig .
four weeks later , the dexamethasone was tapered by 5  mg every 5 days until discontinuance . oral prednisolone (
30  mg daily ) was therefore initiated , ultimately maintained at 5  mg daily after sequential tapering . during the 5 months of steroids therapy ,
the patient was admitted with 7 months history of mental disorder , 20 days history of gait and limb ataxia , dysphagia , and cough . the mri images and histopathological features , along with the favorable clinical and radiological responses to corticosteroids led us to consider the diagnosis of clippers .
however , the specialty in our patient should be noted : ( i ) this patient has a history of mediastinal hodgkin 's lymphoma ( lymphocyte predominance type ) , and after treated with abvd ( adriamycin , bleomycin , vinblastine , dacarbazine ) , he obtained complete remission and remained free of relapse for 11 years ; ( ii ) this is the first study reporting a clippers patient with an elevated load of ebv - dna in the csf ; ( iii ) this patient 's mri showed lesions of broad areas of cerebral white matter .
although recurrence of hodgkin 's lymphoma in the brain is rarely reported , we did consider the possibility of newly emerged cns lymphoma occurring after treatment for hodgkin 's lymphoma because of the immunosuppression .
however , findings in brain biopsy showed no evidence of cns lymphoma since the ki67 labeling index , which is strictly associated with cell proliferation , was 10% .
in addition , the patient did not suffer from suspicious fever or body weight loss . nor was lymphadenopathy found .
thus , we intended to diagnose the patient with clippers for now . still , it remains to be elucidated whether clippers is associated with cns lymphoma .
some of the reported patients initially diagnosed with clippers finally progressed to cns lymphoma despite receiving timely treatment in literatures .
these patients responded well to steroids therapy at first and gained symptoms improvement with decreased lesions .
however , long - term follow - up revealed worsened symptoms and re - emerged lesions in mri , consequently leading to a second brain biopsy which gave the confirmed diagnosis of cns lymphoma
. therefore , a long - term follow - up is necessary , aiming at monitoring the possible changes of symptoms or mri features to confirm whether there is coexisting or subsequent development of cns lymphoma . at the same time
, a second biopsy is recommended if it is necessary , especially when worsening of clinical or radiological presentation appears in spite of proper immunosuppressive treatment , or when the immunosuppressive therapy is refractory .
previous investigators proposed that clippers might be an autoimmune disorder due to the clinical response to immunosuppressive therapies , and the inflammatory infiltration around perivascular regions , where the possible targeted autoantigen is located .
however , this hypothesis is incomplete because the specific mechanism is still unclear . in this clippers patient , a great attention should be paid to the early elevated load of ebv - dna in csf as well as the possible history of ebv infection .
several autoimmune diseases , including multiple sclerosis , systemic lupus erythematosus , and sjgren 's syndrome , are associated with ebv infection .
ebv causes autoimmune reaction through molecular mimicry , epitope spreading , and suppression of tlrs .
growing evidence suggests that some of the ebv - encoded latent proteins , such as the ebnas , share linear and functional sequences identity with host proteins such as neuronal protein -synuclein . during acute or persistent reactivating infection
, ebv can produce pro - inflammatory signals which promote anti - viral responses and cause tolerance abandon of immune system with mimicry to -synuclein , leading to the oligomerization of -synuclein . besides the main expression in neurons ,
-synuclein is also expressed in cerebral blood vessels , around where is exactly the place of inflammatory infiltration in clippers .
thus , we propose a possible mechanism that the autoimmune response induced by ebv infection might be one of the possible pathological causes of clippers , contributing to the autoimmune hypothesis .
the high load of ebv dna in the csf but not in the blood suggests that the affected cells are resident to the cns rather than recruited from the periphery .
it is reported that the main target cells of ebv are epithelial cells and b cells .
thus , the elevated ebv dna in csf may be due to the cns ebv reactivation or the activated resident ebv - positive cells in the cns by the local inflammation .
the manifestation of bipolar disorder may be attributable to lesions of broad areas of cerebral white matter , which may also cause seizure - like activity at the early stage of the disease .
although the reported lesions were located predominantly in the pons , brachium pontis , and cerebellum , a recent study showed that diffuse white matter might be involved in clippers as well .
close attention should be paid to the clinical manifestations of lesions in other cerebral regions .
this is the first study reporting a clippers case with an elevated load of ebv - dna in the csf .
our findings indicate that intracranial ebv infection may be associated with the pathogenesis of clippers through autoimmunity .
in addition , as it remains undetermined whether clippers is an independent disease entity or syndrome or a presage of other diseases , long - term follow - up of clippers patients , especially those who have a history of hodgkin 's lymphoma , is highly recommended .
 abstractbackground : chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids ( clippers ) is an inflammatory disorder in the central nervous system ( cns ) with distinct clinical , radiological , and pathological features . 
 the pathophysiology of clippers still remains unclear and the reports are quite few . 
 although the radiological lesions were reported to be located predominantly in the pons , brachium pontis , and cerebellum , other adjacent structures such as the white matter and spinal cord were very recently reported as involved regions in clippers . in this study 
 , we report a case of clippers presenting with intracranial epstein  barr virus ( ebv ) infection and diffuse white matter involvement.case summary : a 37-year - old male was diagnosed with mediastinal hodgkin 's lymphoma ( lymphocyte predominance type ) at the age of 26 , and then obtained complete remission after treatment and remained free of relapse for 11 years . 
 he was admitted with 7 months history of mental disorder , and 20 days history of gait and limb ataxia , dysphagia , and cough . 
 the diagnosis of clippers was established based on the findings of punctate and nodular enhancing lesions in the bilateral pons , the basal ganglia , the mid - brain , the pontine brachium , and diffuse white matter in magnetic resonance imaging ( mri ) , together with cd3 + t - lymphocytic inflammatory infiltration in perivascular and parenchymal area revealed by bilateral parietal lobe brain biopsy . 
 also , our patient exhibited a good response to steroid therapy and remained free of relapse for 5 months . 
 importantly , we found intracranial epstein  
 barr virus infection in this patient.conclusion:clippers might be an autoimmune disorder , and intracranial ebv - infection raises the possibility that ebv - associated autoimmunity is associated with clippers pathogenesis . 
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Introduction
Case report
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