tumefactive demyelinating lesions ( tdls ) are a rare inflammatory demyelinating disease of the central nervous system ( cns ) that can mimic the clinical and radiological features of intracranial neoplasms ( 1 ) . therefore , brain biopsy is often needed for an accurate diagnosis , particularly if tdls occur in patients without a pre - existing diagnosis of demyelinating disease , such as multiple sclerosis ( ms ) or neuromyelitis optica spectrum disorder ( nmosd ) . although tdls are generally considered a single event , previous studies have indicated that the majority of patients with tdls ultimately develop definite relapsing - remitting multiple sclerosis ( rrms ; 2 , 3 ) . the management of tumefactive demyelinating disease is a challenge , as standardized guidelines do not exist . we herein report a patient with relapsing - remitting tumefactive ms characterized by recurrent large demyelinating lesions that successfully responded to natalizumab treatment . a 57-year - old woman with a 1-month history of slowly progressive left - sided hemiparesis visited another hospital in november 2013 . brain magnetic resonance imaging ( mri ) showed a well circumscribed rounded mass lesion in her right frontal lobe accompanied by mild perilesional edema ( figure a - d ) . given the possibility of a brain tumor , she was transferred to the neurosurgical department of our hospital , and brain biopsy was performed . histology revealed a loss of myelinated fibers with relative axonal preservation , lipid - laden macrophages , bizarre astrocytes , and perivascular lymphocytic inflammatory infiltration ( figure q - t ) as well as occasional creutzfeldt cells , findings compatible with tumefactive demyelination . a - c : axial and coronal t2-weighted magnetic resonance imaging ( mri ) images , and axial fluid - attenuated inversion recovery ( flair ) mri image obtained at the clinical onset reveal a high - intensity tumefactive lesion with mild perilesional edema in the right frontal lobe . d : axial post - contrast t1-weighted mri image obtained at clinical onset shows open ring enhancement . e - g : axial t2 weighted and coronal flair mri images obtained on her first admission ( 2.5 months after the clinical onset ) show enlargement of the pre - existing tumefactive lesion and a new hyper - intense lesion in the left basal ganglia . h : magnetic resonance spectroscopy ( mrs ) performed on her first admission shows an abnormal elevation of the glutamate / glutamine ( glx ) peaks , a decreased n - acetylaspartate ( naa ) level , and elevation of the choline ( cho ) , lipid , and lactate levels . i - l : axial and coronal flair mri images obtained on her second admission ( 9 months after the clinical onset ) reveal multiple new tumefactive lesions in the right frontal and temporal lobe . m , n : axial and coronal flair mri images obtained 2 weeks after her second admission show new lesions in the right frontal lobe . o , p : axial t2-weighted and coronal flair mri images obtained on her third admission ( 13 months after the clinical onset ) reveal a new high - intensity tumefactive lesion in the left temporal lobe . q - t : brain biopsy of the tumefactive lesion revealed the characteristic features of active inflammatory demyelination consisting of perivascular lymphocytic infiltration ( q ; hematoxylin and eosin staining ) , gliosis of reactive astrocytes ( q ) , myelin loss ( r ; kluver - barrera ) , relative axonal preservation ( s ; neurofilament ) and macrophage infiltration ( t ; cd68 ) . . the patient 's neurological status did not deteriorate until january 2014 , when she began to suffer from progressive gait disturbance and rapid cognitive deterioration , and so she entered our department . a neurological examination uncovered left - sided paresthesia and motor weakness , and her mini mental state examination ( mmse ) score was 14/30 . a repeat mri demonstrated an increase in the size of the pre - existing lesion ( figure e and f ) and one new lesion in the left basal ganglia ( figure g ) . magnetic resonance spectroscopy ( mrs ) showed an abnormal elevation of the glutamate / glutamine ( glx ) peaks , a decreased n - acetylaspartate ( naa ) level , and elevated levels of choline ( cho ) , lipids , and lactate ( figure h ) . a cerebrospinal fluid ( csf ) analysis showed a protein concentration of 62 mg / dl and a myelin basic protein ( mbp ) level of 712 pg / ml . her glucose level was normal , and oligoclonal bands were negative . a diagnosis of tumefactive demyelinating disease was confirmed , and 3 courses of intravenous methylprednisolone pulse ( ivmp ) therapy ( 1,000 mg / day for 3 days ) were started , followed by maintenance therapy with oral prednisolone ( psl ; 30 mg / day ) . thereafter , the patient 's serum collected on admission was reported as being negative for anti - aquaporin-4 ( aqp4 ) antibody as assessed by an enzyme - linked immunosorbent assay . furthermore , her mental activity had gradually decreased , and she had become apathetic . the psl dose at that time was 5 mg / day . brain mri showed multiple new lesions involving both cortical gray and white matter in the right frontal and temporal lobes ; however , the pre - existing lesion in the left basal ganglia had decreased in size ( figure a csf sample showed elevated mbp ( 615 pg / ml ) and was negative for cultures , cytology , and viruses , including jc polyomavirus , based on the results of polymerase chain reactions . as 3 courses of ivmp therapy did not ameliorate the disease progression ( her mmse score decreased to 7/30 ) and follow - up mri revealed another new lesion in the left frontal lobe ( figure m and n ) , plasma exchange ( plex ) therapy was subsequently initiated , resulting in improvements in her mental and cognitive dysfunction . she became able to walk unassisted , and her mmse recovered from 7/30 to 17/30 following completion of the seventh plex cycle . another brain mri disclosed an additional lesion in the left temporal lobe ( figure o and p ) , leading to the discontinuation of ifn-1a therapy . three additional courses of ivmp and 7 cycles of plex improved her symptoms partially . at this time her clinical condition did not respond to this natalizumab therapy , but follow - up mri revealed a reduction in the size of the left temporal lesion . she became stable with neither clinical relapse nor new mri lesions throughout the following 16 months of clinical follow - up . our patient presented with pathologically confirmed tdl and recurrently developed multiple cortical and subcortical lesions , despite short - term positive responses to ivmp and plex . the radiological characteristics of tdls are lesions a diameter larger than 2 cm , located mainly in white matter , with varying degrees of mass effect or perilesional edema and often complete or incomplete ring enhancement ( 2 ) . the initial lesions in the present case had these mri characteristics consistent with a diagnosis of tdls . however , the recurrent lesions were large , intracranial ones exceeding 2 cm in size , although these lesions did not resemble brain tumors . mrs of the tdls may cause a decrease in the naa / creatine ( cr ) ratio and an increase in the cho / cr ratio , but this is also a common finding in gliomas ( 4 ) . a few previous reports have indicated that an abnormal elevation of the glx peaks appears to favor tdls ( 5,6 ) , a finding which was in accordance with our results . recurrence of a tumefactive lesion itself is infrequent in patients who present with a tumefactive lesion . stated that only 16.7% of patients developed new lesions exceeding 2 cm in diameter , with a median follow - up of 38 months after the first attack with tdl ( 3 ) . in addition , jeong et al . reported that only 16.1% of 31 patients with initially diagnosed tdl developed new lesions exceeding 2 cm in diameter over a median follow - up period of about 38 months ( 7 ) . our patient had a third large demyelinating attack during the first year of follow - up . our case met the 2010 mcdonald criteria for ms ( 8) , as there were two or more attacks disseminated in time and space with clinical evidence of two or more lesions . however , a diagnosis of ms appeared unlikely , as there were several discrepancies between the present case and typical ms cases , including the superficial gray matter involvement , the presence of recurrent large demyelinating lesions , the absence of small ovoid lesions typical of ms , the lack of oligoclonal bands in the csf , and the unresponsiveness to ifn-1a therapy , which has been demonstrated to have beneficial effects in rrms patients . anti - aqp4 antibody was not found , but the presence of anti - myelin oligodendrocyte glycoprotein ( mog ) antibody has not yet been investigated in our case . given that autoantibodies against mog are reportedly found in patients with acute disseminated encephalomyelitis , ms , and aqp4-seronegative nmosd ( 9 ) , further analysis and longer follow - up will be required for a definitive clinical diagnosis of ms . hardy et al . proposed an algorithm for the acute management using ivmp and/or plex followed by disease modification with ifn or glatiramer acetate ( ga ; 1 ) . as tdls have also been reported as a first clinical event in patients with nmosd ( 10,11 ) , we decided to continue the maintenance therapy with oral psl after pulse therapy . however , the possibility of nmosd was excluded based on the diagnostic criteria ( 12 ) and serologic test findings for aqp4 antibody , and so oral psl was tapered . six months later , when the psl dose had been reduced to 5 mg / day during tapering , the patient relapsed severely . we commenced ifn-1a treatment to prevent the attacks as disease modification therapy ( dmt ) , but she experienced another event 1 month after the start of ifn-1a . at present , second - line dmts , such as fingolimod and natalizumab , are available in japan . given the increasing evidence of an association between tdls and fingolimod treatment ( 13 - 15 ) and the fact that natalizumab has been recommended for the treatment of rrms in patients with not only insufficient response to ifn/ga but also aggressive ms ( 16 ) , we decided to initiate natalizumab therapy , regardless of the lack of seropositivity for jc polyomavirus . in our case , treatment with natalizumab effectively suppressed disease activity . although the clinical outcomes have only been reported in a few cases , natalizumab seems to be effective in treating patients with relapsing - remitting tdls ( 17 - 19 ) . the findings in our present case further suggest that natalizumab may also be used to prevent new events as an immunomodulatory treatment for tumefactive demyelination with relapsing episodes . in conclusion , we presented a case of rapidly evolving severe relapsing - remitting tumefactive ms , where the patient showed no evidence of disease activity after the initiation of natalizumab treatment . the management of tumefactive demyelinating disease can be a challenge , as tdls are pathologically heterogeneous . when a diagnosis of relapsing ms is supported , we should consider natalizumab therapy as soon as possible for patients presenting with recurrent large demyelinating lesions .