generally , fingolimod administration is simply discontinued when fingolimod - associated macular edema ( me ) appears , and the majority of cases are said to recover spontaneously . however , to the best of our knowledge , this is the 1st report regarding improvement of me without discontinuation of fingolimod administration . she was started on treatment with fingolimod to prevent recurrence , after which she developed me that was probably due to fingolimod . the patient expressed a strong fear of recurrence if fingolimod was discontinued , so we continued fingolimod therapy and followed up the patient frequently . we believe that the continuation of fingolimod therapy with strict follow - up examination is one option for treatment , though strategies for managing rapid deterioration of me should be borne in mind . fingolimod - associated macular edema ( fame ) is well known as an adverse drug reaction ( adr ) during fingolimod therapy for multiple sclerosis ( ms ) , although its incidence is low . generally , fingolimod is simply discontinued when fame appears , and the majority of fame cases improve without the concomitant use of other drugs . here , we report a case of ms in which the ophthalmologist and patient strongly desired continuation of fingolimod despite the appearance of macular edema ( me ) soon after starting fingolimod therapy , and the me improved with no other concomitant treatment . she was being treated with oral amlodipine besylate and sitagliptin phosphate hydrate for hypertension , and steroid - induced diabetes mellitus . her lifestyle history revealed no history of smoking or alcohol consumption . in terms of the history of the present illness , the patient became aware of a mild weakness in the right lower limb around 1991 ( aged 42 years ) , which was left untreated . the symptoms worsened ( details unknown ) in 1994 ( aged 46 years ) . the patient was then examined at hospital a and diagnosed with ms . thereafter , the symptoms ( details unknown ) followed a remitting and relapsing course , but around 2009 ( aged 61 years ) , motor paralysis of the right lower limb developed and she was admitted to hospital b. the patient was administered steroid pulse therapy for relapsing - remitting ms ( rrms ) at this hospital and was discharged walking with a cane . since that time , the patient had been treated with oral prednisolone and self - administered interferon -1b injections , but noticed that the symptoms persisted and followed the same remitting and relapsing course . her activities of daily living decreased to the point that she required a wheelchair , and commuting to hospital became difficult , so the patient was referred to a new doctor at the outpatients department at hospital c. when the patient was referred , she was noted to have hyperglycemia due to long - term oral prednisolone intake , so the dose was gradually reduced until prednisolone was discontinued , and interferon -1b injections were also discontinued . on june 17 , 2014 , the patient was referred to our hospital for the introduction of fingolimod therapy to prevent relapse in rrms . at the time of admission , the blood pressure was 143/84  mm  hg , the pulse rate was 78  beats / minute and regular , and the body temperature was 36.2  c . the general internal medical examination revealed no abnormalities , while the positive neurological findings included the already - known isolated right lower limb paralysis , hyperreflexia in the right upper limb , a disorder of deep sensation affecting the lower limbs bilaterally , and an autonomic nervous system disorder . cerebrospinal fluid testing revealed a cell count of 1  monocyte/l ( normal range < 5 ) , protein level of 57  mg / dl ( normal range 1050 ) , igg index of 0.7 ( normal range < 0.7 ) , myelin basic protein levels of < 31.3  pg / ml ( normal range < 102 ) , and positive oligoclonal igg bands . the electrocardiogram showed that the patient was in sinus rhythm with a pulse rate of 75  beats / minute , with no ischemic changes . the cardiothoracic ratio on the chest x - ray was 47.0% , with no abnormalities observed in the lung fields . bilateral paraventricular and juxtacortical focal demyelination on cranial double inversion recovery and t2-weighted magnetic resonance imaging ( mri ) , t1 black hole on t1-weighted mri , and spinal cord demyelination on cervical t2-weighted mri at high cervical levels were observed . 1 ) . the patient was given a definitive diagnosis of rrms after the tests were performed during admission , and was started on oral fingolimod at a dose of 0.5  mg per day on june 27 , 2014 ( day 11 of the hospital stay ) . she experienced no issues after introduction , such as bradycardia , and was discharged home on day 13 . since her discharge , 1.5 years have elapsed to date , and during that time , no clinical ms recurrence has been observed . bilateral paraventricular (  ) and juxtacortical (  ) focal demyelination on cranial double inversion recovery and t2-weighted mri , t1 black hole (  ) on t1-weighted mri , and spinal cord (  ) demyelination on cervical t2-weighted mri at high cervical levels were observed . ant  =  anterior , dir  =  double inversion recovery , flair  =  fluid attenuated inversion recovery , mri  =  magnetic resonance imaging , rt  =  right , t1wi  =  t1-weighted image , t2wi  =  t2-weighted image . meanwhile , we noted the appearance of me in the left eye from the middle of july , which was approximately 2 weeks since the start of fingolimod therapy , while following up the findings in the fundus using optical coherence tomography ( oct ) . thereafter , until around march 2015 , the me observed in the left eye gradually worsened and took on a cystoid appearance . however , the patient herself did not complain of decreased visual acuity and there was no worsening of the hba1c on the blood test results , and it was difficult for the ophthalmology department to differentiate between fame and diabetic macular edema ( dme ) . the patient also strongly desired continuation of treatment as she considered prevention of clinical relapse to be paramount , so the oral fingolimod therapy was continued . thereafter , she received fingolimod without interruption , and the me in the left eye disappeared spontaneously approximately 1 year after introduction without the use of concomitant drugs , such as corticosteroids , or laser therapy ( fig . approximately 8 months thereafter , we noted gradual cystoid deterioration of the me , but the patient did not complain of decreased visual acuity and there was no worsening of hba1c levels , so oral fingolimod was continued . the me disappeared spontaneously after approximately 1 year after introduction of fingolimod therapy without the use of any concomitant drugs . cyl  =  cylindrical , d  =  diopter , lv  =  left vision , me  =  macular edema . fingolimod has been approved for use for  the prevention of both ms recurrence and progression of somatic injuries  in japan since 2011 . adrs include bradyarrhythmia when therapy is initiated , decreased peripheral blood lymphocyte counts , infection , and liver dysfunction in addition to me . among these adrs , me has a low incidence at 0% to 1.6% , and 3 to 4 months commonly elapse from the time of fingolimod introduction to the appearance of me , though there have also been reports of onset from 1 to 2 weeks up to 2 years after starting treatment . in addition , it occurs more readily in patients with diabetic retinopathy , uveitis , retinal vascular occlusion , and age - related macular degeneration as an underlying disease . me disappears after fingolimod is discontinued in the majority of patients who experience me , so early detection is important for the treatment . for this reason , periodic ophthalmology tests such as visual acuity tests , examinations of intraocular pressure and fundus , slit lamp microscopy , and oct are recorded at 1 , 3 , and 6 months after starting treatment with fingolimod , and then every 6 months thereafter . there have also been reports of patients who required concomitant administration of intraocular triamcinolone injections when improvement did not occur after discontinuing fingolimod , but to the best of our knowledge , there have been no reports of remission occurring after fingolimod was continued in the absence of concomitant treatment . in the present case , we started frequent ophthalmological examinations early , because she had well - controlled , steroid - induced impaired glucose tolerance before fingolimod therapy was introduced . this allowed us to detect the appearance of me after the short period of 2 weeks after fingolimod introduction , and we considered discontinuing fingolimod therapy . however , we discussed this with both the ophthalmologist and the patient herself , and it was not possible to conclusively state that the me was caused by fingolimod , so we decided to continue without changing the treatment and scheduled strict follow - up examinations . as a result , we noted spontaneous improvement of the me approximately 1 year later without the use of concomitant drugs and reported this case for its clinical significance . the details regarding the mechanism of fame are unknown , but similar to dme , vascular permeability increases in a fingolimod - dependent fashion and is mediated by s1p1 receptors . this causes a breakdown of the blood - retinal barrier and extravasation occurs . as previously mentioned , discontinuation of oral fingolimod therapy is considered appropriate for stopping this extravasation , but it may become necessary to consider reintroduction of fingolimod therapy when 2 or more weeks have elapsed , and apprehension regarding the possibility of bradyarrhythmia at the time of introduction and recurrence of ms when oral intake is discontinued must be considered . we were unable to make a definitive diagnosis regarding whether me was due to fame or dme in the present case . during the 1st year of treatment , the hba1c was well - controlled , there were originally no diabetic findings , such as fundal hemorrhage , cotton - wool spots or macroaneurysms , and the patient presented with cystoid me , and the ocular changes were unilateral . we considered this condition to be fame , but we could not state this definitively as the interval until fame onset was short , at approximately 2 weeks after fingolimod introduction . although worsening of me was observed when examined using oct from the time fingolimod was started until approximately 8 months later , the patient did not complain of decreased visual acuity and wanted to continue treatment with fingolimod . after 1 year had elapsed , we noted that the me was disappearing and that the me had improved without the need for concomitant therapy , such as triamcinolone intraocular injections , laser therapy , or vascular endothelial growth factor antibody therapy . based on the above , although the contemporary belief is that fingolimod should be discontinued immediately after the appearance of me , we believe it is necessary to acknowledge cases like the present case , in which administration of fingolimod was continued . our patient has not required treatment for me , experienced no recurrence of ms , and is under frequent ophthalmology follow - up , but the clinical course did take some time . the accumulation of further cases will be required . we observed gradually worsening me for 8 months on oct from approximately 2 weeks after starting fingolimod therapy , but the patient did not complain of decreased visual acuity and we observed spontaneous disappearance of me after approximately 1 year . although the general belief is that fingolimod should be discontinued immediately after the appearance of me , the present case showed that spontaneous improvement could be observed despite continuation of fingolimod therapy , though improvement does take some time . we believe that the continuation of fingolimod therapy with strict follow - up examination is one option for the treatment , though strategies for managing rapid deterioration of me should be borne in mind the patient or their next of kin gave written informed consent for publication of this report .
abstractintroduction : generally , fingolimod administration is simply discontinued when fingolimod - associated macular edema ( me ) appears , and the majority of cases are said to recover spontaneously . 
 however , to the best of our knowledge , 
 this is the 1st report regarding improvement of me without discontinuation of fingolimod administration.case presentation : the patient was a 66-year - old woman with relapsing - remitting multiple sclerosis . 
 she was started on treatment with fingolimod to prevent recurrence , after which she developed me that was probably due to fingolimod . 
 the patient expressed a strong fear of recurrence if fingolimod was discontinued , so we continued fingolimod therapy and followed up the patient frequently . 
 the me improved after approximately 1 year without any need for concomitant treatment.conclusion:we believe that the continuation of fingolimod therapy with strict follow - up examination is one option for treatment , though strategies for managing rapid deterioration of me should be borne in mind .