Primary Central Nervous System (CNS) lymphoma is a rare, aggressive form of non-Hodgkin’s lymphoma confined to the CNS. Lymphomatosis cerebri, a rare variant, presents with diffuse, non-enhancing infiltrative lesions, often mimicking other neurological disorders and subsequently delaying diagnosis.

A 72-year-old male presented with a year of progressive cognitive decline, weakness, and falls. His symptoms began after receiving a COVID-19 booster. Initial manifestations included lower extremity weakness with atrophy, fine motor issues, and lower extremity paresthesias. Over six months, he developed cognitive impairment and daytime somnolence. Extensive workups, including neuromuscular antibody panels, electromyography, electroencephalogram, and magnetic resonance imaging (MRI) revealed polyclonal positive IgM antibodies against GD1B, histone H3, and MAG, sensorimotor peripheral neuropathy, and diffuse T2 FLAIR signal throughout the bilateral frontotemporal regions and right parietal region with sparing of U fibers without mass effect. Lumbar puncture (LP) showed pleocytosis, elevated protein, positive 14-3-3 with negative RT-QUIC, and positive oligoclonal bands. Infectious, paraneoplastic, and genetic leukoencephalopathy workups were unremarkable. Cytology and JC-Virus testing were not obtained due to lack of sample. Given his positive ganglioside antibodies, IVIG was trialed, but the patient did not respond. 

Months later, he was hospitalized with worsening mentation, inability to stand, and left facial droop. Prednisone was given for suspected Bell’s Palsy, which mildly improved his systemic symptoms. He was referred to our hospital, but his condition worsened and he was brought to our emergency department. Repeat MRI, LP, and serology confirmed previous findings. Stereotactic brain biopsy ultimately revealed Primary CNS B-Cell Lymphoma.