Rapid Cognitive Decline in a Patient With Chronic Lymphocytic Leukaemia

A Case Report

James Forryan; Jun Yong

Disclosures

J Med Case Reports. 2020;14(39) 

In This Article

Background

Progressive multifocal leukoencephalopathy (PML) is a rare but increasingly common demyelinating disease of the central nervous system (CNS) with a particularly poor prognosis, most conspicuously so among patients with haematological malignancy (typically having a 90% mortality rate within 2 months of diagnosis).[1,2]

The aetiologic agent, the JC virus (JCV), was first culture-isolated in 1971 and posthumously named after an early subject with PML, John Cunningham. JCV is of the Polyomavirus genus and is pervasive in healthy human populations, although pertinently, the JCV archetype (found in the urine of approximately 1/3 of adults) is not pathogenic.[3,4] Therefore, whilst the archetypal form of the virus is attributed to the primary infection (usually occurring in childhood), for pathogenicity, the JCV requires explicit conditions. Studies have demonstrated homogeneity of the non-coding regulatory region (RR) in archetypal JCV, whilst the RR seen in isolated JCV prototypes from PML patients differs, with unique (to each individual) repeats of a 98-bp element that shows variation from the norm.[5] Therefore, rearrangement of the RR in the context of immunosuppression, rather than transmission, likely allows activation of the JCV. Furthermore, it is the RR that contains determinants of neurotropism and neurovirulence, giving further credence to its rearranging serving as a catalyst for PML.[6]

The three most common PML populations comprise those with human immunodeficiency virus positive (HIV+) disease, haematological malignancies and relapsing-remitting multiple sclerosis (RRMS) on natalizumab.[7] Indeed, as human immunodeficiency virus (HIV) infection has become more prevalent throughout the world, and with the advent of B-cell-depleting immunomodulatory therapy in malignancy and autoimmune conditions, the prevalence of PML has risen; as an example, a 2018 study from Sweden looking at the incidence of PML per 100,000 found an increase in the average incidence rate from 0.026 (between 1988 and 2010) to 0.11 (between 2011 and 2013).[8]

Here we report a case of PML secondary to B-cell-depleting therapy with ofatumumab. Over the past decade, a new understanding of the role of B-cells in autoimmunity has begun to emerge. Whereas B-cells initially were thought to exert their effects predominately through antibody production, considerable evidence now exists to support their role in modifying T-cell function through cytokine production, co-stimulation and antigen presentation. Therefore, the wielding of B-cell depleting monoclonal antibodies in the treatment of autoimmune pathology and lymphoproliferative disorders should be appreciated for what it is—a double-edged sword with clear benefits of a more tolerable immune environment and suppression of uncontrolled lymphoproliferation—with the unwanted potential for previously suppressed viruses (i.e., JCV) to exploit the softening of immune regulation.

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