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|Year : 2020 | Volume
| Issue : 2 | Page : 478-480
A Case of High Grade Glioma Following Treatment of Relapsing-Remitting Multiple Sclerosis with Fingolimod
Mehmet Fatih Erbay1, Ozden Kamisli2
1 Department of Radiology, Inonu University, Malatya, Turkey
2 Department of Neurology, School of Medicine, Inonu University, Malatya, Turkey
|Date of Web Publication||15-May-2020|
Department of Neurology, School of Medicine, Inonu University, Malatya
Source of Support: None, Conflict of Interest: None
Multiple sclerosis is a major cause of neurological disability, especially in young adults. There have been several case reports of an increased risk of cancer after long-term treatment for multiple sclerosis. Fingolimod is an immunomodulating agent used in the treatment of relapsing-remitting multiple sclerosis. The side effects commonly associated with fingolimod are cardiac side effects, macular edema, and elevated liver enzyme levels. Increased risks of infection and cancer have also been reported. High grade glioma is an aggressive primary brain tumor. There has been one case report of high grade glioma during fingolimod treatment. Here, we report the case of a 58-year-old woman diagnosed with glioblastoma multiforme after one year of fingolimod treatment for multiple sclerosis.
Keywords: Fingolimod, high grade glioma, multiple sclerosisKey Message: The most common side effects associated with fingolimod during the MS treatment; are bradycardia, atrioventricular block, hypertension,macular edema, and elevated liver enzyme levels. There have been case reports of cancers in fingolimod-treated patients. As the use of disease-modifying therapies increases worldwide, heightened clinical suspicion, and early recognition of these serious adverse events remain crucial.
|How to cite this article:|
Erbay MF, Kamisli O. A Case of High Grade Glioma Following Treatment of Relapsing-Remitting Multiple Sclerosis with Fingolimod. Neurol India 2020;68:478-80
Multiple sclerosis (MS) is a chronic demyelinating inflammatory disease of the central nervous system (CNS). Disease-modifying therapies have become the standard for treating MS since the 1990s. Fingolimod (FTY720) is a disease-modifying drug used to treat relapsing-remitting multiple sclerosis (RRMS) as a first- or second-line therapy. Fingolimod modulates lymphocyte sphingosine-1-phosphate (S1P) receptors., Upon binding to a receptor on the surface of a lymphocyte, it induces degradation of the receptor, inhibits lymphocyte egress from the lymph node, and decreases the number of autoaggressive lymphocytes invading the CNS.
There have been several reports on the incidence of cancer in MS. A recent study demonstrated that MS patients have a decreased overall cancer risk, but an increased risk for brain tumors. Although brain tumors such as astrocytomas, oligodendrogliomas, meningiomas, glioblastomas, and spinal cord ependymomas have been described in MS patients,, no systematic study has examined the incidence of brain tumors in MS patients. It is still debated whether the rare concurrence of MS and glioblastoma is a coincidence or a result of MS treatment.
Here, we report a 58-year-old woman with RRMS treated with fingolimod who developed high grade glioma (HGG) in the right parietal lobe.
| » Case|| |
A 58-year-old woman was diagnosed with RRMS in 2008. The initial sign of MS was left optic neuritis in 2008. Brain magnetic resonance imaging (MRI) showed periventricular white matter T2 hyperintensities in the frontoparietal regions bilaterally, and contrast-enhanced orbital MRI revealed enhancement of the left optic nerve. She was treated with 1 g methylprednisolone intravenously for three days. After three years with no substantial symptoms, she developed mild left hemiparesis in 2011 and 2012. She began treatment with interferon beta 1b in 2012. After she was admitted to our clinic with complaints that included reduced walking distance and urinary incontinence, her treatment was switched to fingolimod in May 2017. She had been treated with fingolimod 0.5 mg per day for one year before presenting with mental deterioration and seizures in May 2018. When she was admitted to the emergency department, she was disoriented as to place, time, and person. She had tetraparesis and could not walk without assistance. Her white blood cell count was normal at 5,300/μL but showed lymphopenia with 600/μL. Other biochemical and hormone tests were normal. Brain MRI showed a new 4 × 2.5 cm lesion in the parietal deep white matter of the right hemisphere that showed a mass effect and was not seen on previous MRIs. After intravenous gadolinium administration, heterogeneous irregular enhancement was seen in the lesion periphery, and there were two smaller, nodular, contrast-enhancing foci in the perilesional region that were thought to be satellite malignant foci. On diffusion-weighted imaging (DWI), the entire lesion showed restricted diffusion with low ADC values [Figure 1] and [Figure 2]. Although a mass-like appearance and enhancement pattern due to a tumefactive demyelinating lesion (TDL) was unlikely considering the previous diagnosis of RRMS, dynamic susceptibility (DSC) perfusion MR was performed in order to exclude the possibility. Because the patient did not tolerate the imaging procedures, in order to avoid prolonging the procedure, magnetic resonance spectroscopy (MRS) was not performed. On DSC perfusion MR, the relative cerebral blood volume (rCBV) map revealed marked hyperperfusion of the lesion compared with the contralateral white matter regions [Figure 3]a. In our case, Diffusion tensor imaging (DTI) slices revealed a hyperintense rim at the lesion periphery and no central hyperintense focus on the Fractional Anisotropy (FA) map. Furthermore, we found low FA values, ranging from 0.11 to 0.14 [Figure 3]b. Based on both the enhancement pattern on conventional MRI and the hyperperfusion in the rCBV map on DSC perfusion and DTI findings, we diagnosed a HGG rather than tumefactive demyelinating lesions (TDL).
|Figure 1: Diffuse hypointensity of the lesion (arrow) on ADC map showing restricted diffusion (a). Peripheral irregular enhancement of the lesion (b) and satellite enhancing foci in adjacent slices shown with arrows on T1 contrast enhanced images (c and d)|
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|Figure 3: (a) rCBV map of a DSC perfusion study showing increased perfusion in the right parietal lesion (rCBV: 4,76). (b) Hyperintense rim of the lesion on the FA map (arrows) and no central hyperintense focus (not all slices are shown|
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Mass excision and duraplasty were performed with a right parieto-occipital craniotomy. Histopathologically, the specimen showed hypercellular glial features, with anaplasia, mitotic activity, and possibly necrosis with focal palisade fragments. The findings were consistent with HGG. Radiation therapy was subsequently initiated. The patient died ten months after the diagnosis of HGG.
| » Discussion|| |
In our patient, the onset of disease was typical for relapsing–remitting MS, and she responded to the treatment with a decreased relapse rate, but then her symptoms and signs worsened. MRI showed an atypical lesion for MS. Instead of the classical MS-fulfilling MRI criteria, some MS patients have atypical MRI findings. Demyelinating lesions larger than 2 cm are called tumefactive demyelinating lesions (TDLs). TDLs may mimic glial tumors, lymphomas, or abscesses on imaging studies and may pose diagnostic difficulty in patients with MS.,
Conventional MRI techniques are sometimes insufficient to distinguish TDLs from tumors. Additional techniques may help to make the true diagnosis, including DWI, MRS, and perfusion imaging studies., DSC perfusion is a useful MRI technique for differentiating TDLs from high-grade gliomas. High-grade gliomas have high rCBV values, representing increased perfusion in non-necrotic portions of the lesion. The T2 shine-through effect, which is characterized by high signals on both DWI and ADC, represents vasogenic edema and is the most common DWI pattern of MS lesions. Diffusion tensor imaging (DTI) may also assist with diagnosis. Some authors have defined several features of high-grade gliomas on DTI using visual inspection and quantitative analysis, such as a hyperintense rim sign on the fractional anisotropy (FA) map, lower (FA) values in the periphery of the lesion than in TDLs, and the absence of a hyperintense focus on the FA map in the center of the lesion. In our case, DTI slices revealed a hyperintense rim in the periphery of the lesion and no central hyperintense focus on the FA map.
The most common side effects associated with fingolimod are bradycardia, atrioventricular block, hypertension, macular edema, and elevated liver enzyme levels. Multifocal leukoencephalopathy, varicella zoster infection, herpes encephalitis, and Listeria monocytogenes meningitis have also been reported as possibly related to the immunosuppressive effects of fingolimod., There have been case reports of cancers in fingolimod-treated patients involving the lungs, brain, and hematopoietic and lymphatic systems. However, most of these cancers are skin cancers, such as basocellular carcinoma and malignant melanoma.
To our knowledge, there has been only one reported case of glioblastoma following treatment with fingolimod for RRMS. The present case is the second case of high-grade glioma reported to occur during fingolimod treatment.
The treatment of HGGs is limited, and the prognosis remains poor. It is difficult to make an association between fingolimod use and HGG development, but immunosuppression may be a possible cause. However, it is important to differentiate tumors from TDLs. As the use of disease-modifying therapies increases worldwide, heightened clinical suspicion, and early recognition of these serious adverse events remain crucial.
Declaration of patient consent
The authors certify that they have obtained all appropriate patient consent forms. In the form, the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2], [Figure 3]