Overexpression of sphingosine-1-phosphate receptors on reactive astrocytes drives neuropathology of multiple sclerosis rebound after fingolimod discontinuation

We present the neuropathological description of an autoptic case of fatal rebound of disease activity after fingolimod discontinuation in a multiple sclerosis patient. MRI prior to the fatal outcome showed several large tumefactive demyelinating lesions. These lesions were characterized by prominent astrocytic gliosis, with a remarkable preponderance of large hypertrophic reactive astrocytes showing intense expression of sphingosine-1-phosphate receptor 1. Prominent astrocytic gliosis was also diffusely observed in the normal-appearing white matter. Dysregulated sphingosine-1-phosphate signaling on astrocytes following fingolimod withdrawal might represent a possible contributing mechanism to disease rebound and might account for the unusual radiological and neuropathological features observed in the present case.