Tumefactive demyelinating lesions can resemble glial tumors in terms of MRI characteristics. Tumefactive Multiple Sclerosis (TMS) is a rare variant of Multiple Sclerosis (MS) marked by large demyelinating lesions that can be indistinguishable from Central Nervous System neoplasms, particularly Gliomas and CNS lymphomas.

This is a case of a 40-year-old male with no significant past medical history, referred to the Neurology service due to new-onset daily headaches described as pressure-like pain localized to the right hemicranium, rated 9/10 in intensity, and accompanied by blurry vision.

An MRI of the brain, conducted with and without Gadolinium, revealed a well-defined, homogeneously enhancing lesion at the upper convexity of the right frontal lobe, accompanied by significant parenchymal edema and a midline shift of approximately 0.6 cm. The differential diagnosis included Tumefactive Multiple Sclerosis vs cortical-based enhancing mass.

A lumbar puncture was performed, which was negative for oligoclonal bands. The patient was referred to Neurosurgery, and stereotactic biopsy showed a polymorphous lymphoid population with numerous CD68 positive macrophages, suggestive of a reactive/inflammatory process, likely demyelinating.

The patient was diagnosed with Tumefactive Multiple Sclerosis and initiated on Natalizumab therapy, receiving infusions for six months. However, follow-up neuroimaging revealed an increase in the original mass size and the appearance of two additional well-defined, hyperintense lesions on T2/FLAIR sequences. After re-evaluation, an exploratory biopsy was conducted, and final pathology confirmed a diagnosis of Astrocytoma Grade 4.

This case underscores the importance of repeated neuroimaging and reassessment of differential diagnoses when a patient’s condition does not progress as expected following treatment. The emergence of new lesions or changes in existing ones should prompt re-evaluation to avoid potential misdiagnoses, highlighting the critical distinction between demyelinating processes and neoplastic conditions in clinical practice.