## 2 Case Presentation  
Here, we report the case of a 37-year-old woman affected by relapsing remitting MS (RRMS) with disease onset at 28 years with left RBON and pyramidal involvement as detected by prevalent tendon reflexes at the right limbs and the ipsilateral Barre's sign. The latter was investigated with magnetic resonance imaging (MRI) demonstrating several periventricular and bilateral T2-weighted lesions and enhanced lesions of the subcortical white matter of the left frontal lobe. Consequently, in accordance with the dissemination in time and space criteria of the current revised McDonald guidelines [18], we posed diagnosis of RRMS. During ten years of first line therapy based on thrice weekly treatments of sub-cutaneous beta-interferon (beta-IFN), no relapse occurred, and her neurological conditions were stable with a low grade of disability, expressed at the 1.5 rank of the expanded disability status scale (EDSS). However, in the summer of 2018, the patient experienced a disabling relapse with an increase of one point of EDSS, despite administration of megadoses of intravenous (i.v.) 6-methyl prednisolone (6-MP) (1 g/die for five days). Specifically, her sphincter score worsened from 1 to 2, resulting in EDSS 2.5. Therefore, we decided to switch from the beta-IFN therapy to the orally administrated 0.5 mg/die Fingolimod. After treatment, the baseline MRI demonstrated a low brain lesion load without spinal cord involvement, with two new T2-weighted lesions in the right frontal lobe. Follow-up visits every three months evidenced a favorable clinical outcome during the treatment and the annual MRI was also stable. The routine laboratory assessment was regular with a lymphocytes count ranging from 1200 to 860/\(\mu\)L and annual MRI scans of the brain and spinal cord were performed on a 1.5- T Philips MR apparatus (180 mT/m) (Achieva, Philips Medical Systems, Best, The Netherlands), in accordance with international guidelines [19]. According the standard protocol, the acquisition sequence types were SE T1-TSE T1 MT-BRAIN VIEW FLAIR 3-D; acquisition time 2.170-3.070-4.140; field of view 230 3183 mm AX-250 3250 FLAIR SAG-180-200 3180 mm COR MT; orientation: TRA-COR-TRA; alignment: TRA-COR-TRA; and voxel size: 0.89/0.88/4-0.56/0.56/4-0.31/0.31/0.6, respectively. Repetition time (TR) was 450-614-4800; echo time (TE) was 15-12-307; and inversion time (TI) was -/-/1660. The flip angle was 69\({}^{\circ}\)-90\({}^{\circ}\)-/, and the NEX was 1-2-2. The SENSE parallel imaging method and contrast enhancement (Gadovist single dose, 10 min post administration) were used. In July 2019, when the Fingolimod was ongoing for about one year, the patient had a brutal relapse starting with leg weakness that was treated initially by a total of 5 g of i.v. 6-MP. At the end of this treatment period, the EDSS 7.0 revealed severe lower-extremity weakness, with leg spasticity and ataxia, so we admitted her at the neurological department of the \"F. Ferrari\" Casarano Hospital. Here, after the MRI assessment, the patient underwent another brief treatment cycle of 3 g i.v. 6-MP without clinical improvement and we founded that the relapse was sustained by new T2-weighted-cervical lesions, situated on C2-C3, and T5 levels (Figure 1A). These lesions did not evidence any contrast enhancement due to the 6-MP cycle performed at home before hospital admission. These lesions, partially confluent and not exceeding three metamers in length, were not associated with timefactive cervical shape and fulfilled the radiological criteria for MS lesions, as expected. No new brain lesions were detected and a total intracranial volume (TIV) of 1328.8 mL was calculated using Siena software. Thus, the diagnosis of steroid-refractory relapsed MS on Fingolimod treatment was posed, DFPP therapy was indicated, and FTY was discontinued. In Figure 1C it could be also glimpsed two subcortical hyperintense left frontal areas, resulting from enhancing lesions at the disease onset.