Case Presentation: 63-year-old male with chronic lymphocytic leukemia (CLL) presented to the emergency department with altered mentation and difficulty ambulating for one month. He was undergoing treatment in a prospective randomized phase II trial of acalabrutinib followed by obinutuzumab or venetoclax and was currently on acalabrutinib 100 mg twice daily. The initial workup included a CT head that was unremarkable, white blood cell count (WBC) with 17.68 k/mcl, renal and liver function within normal limits. MRI brain without contrast showed diffuse bilateral white matter changes. Neurology was consulted and recommended MRI brain with contrast, which did not show abnormal enhancement. The patient was screened for Vitamin B6, B1, and B12, which were within normal limits. Due to the non-specific findings, oncology was consulted. Oncology recommended to hold acalabrutinib and to rule out infectious etiology. CT chest abdomen pelvis with IV contrast obtained by oncology was less concerning for Richter transformation with interval improvement in lymphadenopathy. Infectious Disease was consulted, a lumbar puncture was obtained. This showed cerebral spinal fluid (CSF) WBC of 153/µL, with 99% lymphocytes. CSF was negative for West Nile virus, JC virus, cryptococcal antigen, and an arbovirus panel. Fungal and bacterial CSF cultures were negative with a negative reflex PCR. A metagenomic next generation sequencing test resulted in negative DNA, RNA, bacterial, parasitic, and fungal pathogenic organisms. CSF Flow cytometry demonstrated monoclonal B cells expressing CD5, consistent with CLL involvement of CSF. After discussion with the patient’s primary hematologist, the patient was then transferred to their institution for further management. A repeat LP was performed which was deemed confirmatory for CLL central nervous system (CNS) involvement with total nucleated cells of 430/µL and negative repeat CSF infectious labs. Acalabrutinib was restarted at 200 mg twice daily with dexamethasone. Five days later, venteoclax was initiated at a rapid escalation to 400 mg daily. The patient ultimately improved, was discharged, and seen in follow up by his hematologist with resolution of his neurological symptoms.

Discussion: Despite CLL being the most common leukemia in western countries, CNS involvement has a reported incidence ranging from 0.4-2% (1). MRI brain is relatively nonspecific in detection of CLL within the CNS. The gold standard of diagnosis is CSF cytology analysis (2). In patients with a history of CLL, or on active treatment, who present with non-specific neurologic symptoms and imaging findings, CNS dissemination of CLL should be on the differential. Given CNS involvement is relatively underdiagnosed; further research regarding risk factors as well as standardized treatment guidelines are needed. Emerging data suggests that high risk cytogenic including del (17p), TP53, and NOTCH1 mutation have been associated with potential for CNS dissemination (8). Commonly used treatments include high dose methotrexate or cytarabine, intrathecal therapy, BTK inhibitors that cross blood brain barrier, and localized radiation (8,9).

Conclusions: This case highlights a rare manifestation of CLL, the importance of early diagnosis, and the need for standardized treatment therapies for CNS CLL. Our patient’s extensive multidisciplinary approach with negative infectious workup led to an early diagnosis and initiation of treatment likely leading to a positive outcome.