Acute isolated neurological syndromes, such as optic neuropathy or transverse myelopathy, may cause diagnostic problems since they can be the first presentations of a number of diseases such as multiple sclerosis (MS) and collageneous tissue disorders. In the present study, particular systemic lupus erythematosus (SLE) and primary Sjogren syndrome (pSS) patients, who were followed up with the initial diagnosis of possible MS with no evidence of collagen tissue disorders for several years, are described. Five patients with the final diagnosis of SLE and five pSS patients are evaluated with their neurologic, systemic and radiologic findings.Over several years, all developed some systemic symptoms like arthritis, arthralgia, headache, dry mouth and eyes unexpected in MS. During the regular and close follow-up laboratory evaluations of vasculitic markers revealed positivity, leading to the final definite diagnosis of SLE or pSS. Patients with atypical neurological presentation of MS, a relapsing remitting clinical profile, or lack of response to the regular MS treatment should be evaluated for the presence of a connective tissue disease. Various laboratory tests, such as cerebrospinal fluid findings, autoantibodies profile, markers, cranial and spinal magnetic resonance imaging, can be helpful for the differential diagnosis. Lack of response to the regular multiple sclerosis treatment, even increasing rate of relapses can force the clinician for the differential diagnosis. In particular cases an accurate diagnosis can only be made after close follow-up.