Reported are two cases of patients with central nervous system systemic lupus erythematosus (SLE) with clinical features of a myelopathy confirmed by magnetic resonance imaging (MRI). In one case, further evaluation including Single Photon Emission Computerized Tomography (SPECT) and neuropsychological testing, indicated higher cortical deficits which improved after treatment with monthly pulse intravenous cyclophosphamide. Subsequent cessation of cyclophosphamide was associated with further progression of the neurological disease in this patient.