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

Discussion

We report an adult patient with progressive cognitive decline and neurological dysfunction secondary to a diagnosis of PML. This occurred after B-cell-depleting therapy with ofatumumab in an attempt to treat his underlying CLL.

A tug of war has occurred in recent years between those who believe B-cells partake in both humoral and cellular immunity and those who dispute the role of B-cells in the latter. One can find evidence in the literature to support both arguments: for example, mice studies indicate that B-cell depletion impairs CD4+ T-cell memory and cytokine production, thus reducing protection against viruses,[9] whilst others would argue the opposite, showing that cytotoxic T-cell memory is maintained even in B-cell-deficient mice subjected to lymphocytic choriomeningitis virus.[10] Nevertheless, studies that refute a role for B-cells in cellular immune responses have typically been published around the turn of the millennium, whereas they are now dwarfed in number by those supporting a role for B-cells in both types of immune response. Given the weight of evidence to support a modulatory role for B-cells in CD4 and CD8 T-cell responses, it is hard to ignore the association. Indeed, in a perversion of their intended action, B-cell depleting therapies have provided the milieu for researchers to shed light on the multi-mechanistic role that B-cells have in immune responses.

The existence of distinct B-cell populations within the subsets 'effector' (memory) and 'regulatory', and the ability of both types to modulate T-cell activity through antigen-presentation, cytokine release and co-stimulation, have long been known. Several studies have demonstrated a role for antigen-presenting B cells in the proliferation and differentiation of T-cells.[11–13] Furthermore, co-stimulatory B-cell surface molecules have their own role to play in T-cell responses; for example, a study demonstrated that in mouse bone marrow chimeras with CD80/86 knockout B-cells (but with other APCs retaining these CD markers), resistance to the induction of proteoglycan-induced arthritis was present. This suggested that CD80/86 upregulation on B-cells was a prerequisite for autoreactive T-cell activation and induction of arthritis; interestingly, proteoglycan-specific autoantibody titres were comparable in CD80/86 wild-type and knockout populations, thus offering more credence to the antibody-independent action of B-cells in cellular immunity.[14] The dichotomy between 'effector' and 'regulatory' B-cell is most apparent when related to their profile of cytokine production. Two effector subgroups, Be1 and Be2, produce cytokines linked to Th1 and Th2 responses respectively and are known to enhance T-cell-mediated immune responses. Conversely, B regulatory cells (the term Bregs was first coined by Mizoguchi and Bhan in 2002) also exist that produce an IL-10 predominant cytokine profile with T regulatory-cell (Treg) action, ultimately suppressing the T-cell response and creating a more tolerogenic immune environment.

Relevant to this particular case is the occurrence of PML in populations receiving B-cell-depleting therapy for lymphoproliferative disorders. The incidence of haematologic B-cell malignancies continues to rise in the Western world, but the advent of B-cell-depleting monoclonal antibody (mAb) therapy in the 1980s revolutionised treatment.[15] Identification of B-cell-restricted CD19 and CD20 antigens ushered in development of targeted mAb therapy, thereby leading to multi-mechanistic elimination of malignant B-cells.[16] Commonly used agents include rituximab, alemtuzumab and ofatumumab; the latter binds to a more proximal membrane epitope leading to improved complement-dependent cytotoxicity, with the potential caveat of increased susceptibility to the complications of B-cell depletion. As discussed, to say that decreased humoral activity explained the action of B-cell-depleting therapy would be an oversimplification; indeed, reviews and longitudinal case studies suggest a minimal role for specific antibody response as a regulatory factor in JCV infection.[17,18] This supports suggestions that the role of B-cells in PML is multi-faceted, independent of antibody secretion and related to altered cell-mediated immunity; for example, B-cell-deficient IgM knockout mice lose their normal CD4 and CD8 response to a lymphocytic choriomeningitis virus (LCMV) variant, whilst non-IgM secretory B-cell-replete mice retained this function.[19,20] Moving back toward the concept of Bregs, rituximab (an anti-CD20 monoclonal antibody) has repeatedly been shown to enrich the Breg pool, whilst depleting the Be1 levels and thus shifting the ratio of T- and B-cells in favour of the regulatory (Breg/Treg) phenotype.[21] Prior to B-cell-depleting therapy, the memory effector B- and T-cell activity predominates, and Be1/Th1 amplification loops are closely involved (when dysregulated) in the development of autoimmune disease.[22] This is where rituximab (and other B-cell depleting mAbs) come in—curtailing T-cell effector activity and depleting malignant B-cell clones in autoimmune and lymphoproliferative disease respectively. Nevertheless, where there is push, there is pull; shifting the immune environment to one of 'tolerance' and regulatory B- and T-cell activity removes the protection against JCV that the effector presence provided. One is left with the dilemma of how to retain the role of B-cells in JCV control—Th1-type cytokine release and propagation of Th1/CD8 activity—when treatment of these conditions necessitates B-cell depletion and leads to repopulation of the B-cell pool with naïve IL-10/35-producing Bregs.

The diagnosis of PML is contingent on the sum of clinical, radiological, virologic and histopathologic findings. The clinical signs are varied, the most common of which are motor impairment (typically hemiparesis), visual field defects, dysphasia and behavioural changes. MRI is the preferred imaging modality for detecting the changes synonymous with PML: multiple hyperintense (on T2-weighted and FLAIR images; hypointense on T1) white matter lesions within the affected lobes without oedema or mass effect, although a definitive diagnosis is only established by either virologic or histopathologic findings.[23] With well-established, evidence-based consensus guidelines recommending high-frequency MRI brain monitoring in high-risk natalizumab-treated multiple sclerosis patients, cases such as ours raise the question as to whether this practice should be extended to other at-risk groups.[24] Nevertheless, whilst studies in natalizumab-treated patients demonstrate improved survival and morbidity outcomes with early PML diagnosis,[25,26] similar results need to be demonstrated outside this group before sequential MR imaging is recommended more broadly.

For diagnosis, cerebrospinal fluid (CSF) examination for presence of the JCV is advised (ultrasensitive PCR techniques have a sensitivity > 95%), with several authorities accepting positive CSF JCV, clinical and radiological findings as confirmatory of PML.[27] Notably, a potential exists for both false-negative and false-positive CSF JCV DNA results (even with ultrasensitive PCR).[28] In these instances, clinical assessment is paramount; proceeding to brain biopsy in high-suspicion patients with negative CSF tests is appropriate, while low CSF JCV titres in patients lacking clinical and imaging evidence of PML should be followed up with repeat testing and consideration of other pathology. Brain biopsy demonstrating asymmetric foci of demyelination and oligodendroglial cell intranuclear inclusions of JCV is an invasive, but extremely sensitive and specific, diagnostic tool.

As mentioned earlier, the prognosis of the disease is extremely poor. The incidence of PML is likely underestimated on account of its rapid progression and fickle presentation, thereby rendering diagnosis difficult. If confirmed, treatment options remain sparse (JCV is species-specific to humans, thus preventing animal model studies), with timely implementation of combination anti-retroviral treatment (cART) in HIV populations and cessation of immunomodulatory therapy being the only current options offering any survival benefit.[29] Currently, no specific prophylaxis for PML or effective anti-JCV treatment exists, and therefore, outcomes in PML are dependent on an individual's ability to recover immune function.[30] Consequently, the poorest prognosis group is that of haematological malignancy; immune reconstitution is often not achievable in this group because of the innate bone marrow depression associated with the primary disease and long-term immune cell depletion that occurs secondary to treatment.

Moving forwards, the focus should be on prevention, early diagnosis and expanding treatment options. The identification of immunisation options is an ongoing endeavour; passive and active vaccines are at various stages of drug development, but isolated case reports with the use of JCV-directed cytotoxic T lymphocytes (CTLs) show promise.[31] Regular imaging and stratification of high-risk patients using expert-developed algorithms and JC biomarkers (e.g., the JCV antibody index) already play a role in the timely diagnosis of PML in certain patient cohorts and could be used more widely if studies demonstrated evidence in their favour.[32] Pharmacological treatment of established PML with antiviral agents preventing JCV cell entry, retrograde transport and DNA replication is in its infancy and currently is based on theoretical and anecdotal evidence.[30] Furthermore, as alluded to earlier, the understanding of B-cell function in JCV behaviour and PML is still unclear, although many studies suggest a significant role for B-cells in modifying the T-cell-mediated control of JCV infection. Therefore, further endeavours to better classify the relationships that exist between JCV and B-cells is likely to have a significant impact within the field of PML prevention and management.

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