Progressive multifocal leukoencephalopathy as the presenting feature in a patient with occult low-count monoclonal B-cell lymphocytosis

Abstract

Introduction:

Low Count Monoclonal B-Cell Lymphocytosis (LC-MBL) is a relatively poorly understood entity which has been suggested to be very common in asymptomatic adults and possibly related to infectious complications despite not progressing to CLL.

Methods:

We describe the first case of Progressive Multifocal Leukoencephalopathy (PML) presenting in a 72-year-old man with LC-MBL but no other immunocompromising conditions.

Results:

A diagnosis of PML was confirmed with classic MRI findings in association with a high CSF John Cunningham polyomavirus (JCV) viral load (4.09′ 10⁵ copies/mL). An extensive search for underlying immunocompromising conditions only demonstrated LC-MBL representing approximately 4% of total leukocytes (0.2′ 10⁹/L).

Discussion:

This is the first report of PML in association with LC-MBL. Careful review of peripheral blood flow cytometry results is necessary to identify this disorder. Further study of the epidemiology and infectious complications of LC-MBL are warranted.

Case Report

A 72-year-old left-handed man initially presented to an ambulatory clinic in London, Ontario, with a 2-week history of left-sided clumsiness, word-finding difficulties, slurring of speech, and a sudden onset right temporo-occipital headache. His medical history was notable for ischemic stroke in 2015 secondary to carotid artery atherosclerosis manifesting as left-sided weakness which completely resolved, carotid endarterectomy, hypertension, dyslipidemia, and bladder cancer managed surgically with no evidence of residual disease. He had no history of known immunodeficiency. Home medications included atorvastatin, citalopram, and aspirin. He had a 20-pack-year smoking history but quit 30 years prior. CT head and neck angiogram showed a 2 × 3.2 cm right temporoparietal white matter hypodensity. He subsequently had an MRI of the brain (Figure 1), with diffusion trace hyperintensity in the right hemisphere (frontal, thalamus, temporo-occipital, parietal subcortical) but no diffusion restriction, mostly nonenhancing with no significant local mass effect or findings to suggest parenchymal metastases. The differential diagnosis included progressive multifocal leukoencephalopathy (PML) versus acute disseminated encephalomyelitis (ADEM).

Figure 1:

MRI imaging (A) T1, (B) T2-Flair, and (C) diffuse-weighted imaging modalities. Findings demonstrate T1 hypointensity in the deep right temporoparietal white matter, with no mass effect nor enhancement, and involvement of sub-cortical U fibers. The red arrows show punctate low T1 signal lesions surrounding the main lesion, a pathognomonic sign of PML. Trace hyperintensities with no diffusion restriction are seen surrounding the main lesion.

He was seen in follow-up 2 months later with worsening left-sided weakness requiring a wheelchair for ambulation, dysarthria, headaches, as well as new vision changes, dysphagia, fatigue, 10-lb weight loss, and left-sided numbness. He was admitted to hospital to accelerate investigations. On exam he had right gaze preference, homonymous hemianopia, lack of fluency, spasticity in the left arm, 0/5 strength in the left upper extremity, weakness in the left lower extremity, hyporeflexia in bilateral upper extremities, reduced pinprick sensation in the left arm, missing vibration sense in the left leg, and neglect on the left leg. There was no lymphadenopathy, normal chest, cardiac and abdominal exam with no hepatomegaly or splenomegaly.

The patient underwent a thorough infectious and inflammatory workup. He had a pan-CT that was negative for primary or metastatic malignancy or lymphadenopathy. He had a lumbar puncture and CSF studies which showed an elevated nucleated cells 50 × 10⁶/L, 90% lymphocyte, 10% monocyte, erythrocyte count of 0, total protein 408, and glucose value of 3.7. CSF fluid culture, fungal cultures, cryptococcal antigen, RPR, PCR for HSV, VZV, EBV, CMV, were all negative. CSF protein electrophoresis, oligoclonal band, and cytology were also negative. CSF flow cytometry showed lymphocytes represented 90% of total leukocyte count consisting of T cells expressing either helper or suppressor immunophenotype, too few B cells to assess light chain expression. CSF PCR for John Cunningham polyomavirus (JCV) was positive with 4.09 × 10⁵ copies/mL. His blood work including serum HIV Ag/Ab screen, Syphillis EIA test, Lyme IgG/IgM EIA, Bartonella Ab, Q-fever, Hep B Surface Ab, Hep C Ab, HLTV1, HTLV2, ANA, Anti dsDNA, Anti MPO, Anti PR3, Anti Glomerular Basement Membrane, Rheumatoid Factor S, anti-MOG IgG, serum immunoglobulins, serum protein electrophoresis, serum free light chains were all normal except for a weakly positive ANA (1:80 titer) and slightly elevated free Ig kappa chains (20.7 mg/L, normal range 3.3–19.4).

Peripheral blood flow cytometry showed 17% lymphocytes and a low count monoclonal B-cell lymphocytosis representing approximately 4% of total leukocytes (0.2 × 10⁹/L), positive for CD19, CD5, dim CD20, CD 200 expressing dim kappa light chains and negative for CD10. The remainder of the lymphocytes consisted of T cells expressing either helper or suppressor immunophenotype and polyclonal B cells. Repeat MRI of the head showed no interval progression of T1 hypointensity in the deep right temporoparietal white matter a month after initial MRI.

Given the clinical picture, imaging and CSF findings, the patient was diagnosed with PML. The patient chose to pursue a comfort-based approach and thus declined mirtazapine and brain biopsy as they were not within goals of care and would not reverse the patient’s disability. Palliative care was involved and managed his symptoms including headaches and restlessness. The patient was repatriated to a hospital closer to family where his neurological deficits plateaued for 2 months until he was discharged to long-term care, 6 months from his initial symptom onset.

Discussion

PML is a serious CNS infection that is caused by JCV. Primary infection often occurs in childhood, with antibodies present in 86% of adults (1). While JCV normally exists as an asymptomatic or latent infection in immunocompetent hosts, impairment of cellular immunity can lead to reactivation of JCV and PML (1). Reactivation of JCV and crossing of the blood brain barrier is thought to result in PML. PML can be diagnosed via demonstration of JCV by PCR in CSF along with clinical and imaging manifestations consistent with diagnosis, with no alternative possibilities (2). Detection of JCV DNA from CSF PCR has a sensitivity of 74%–92% and a specificity of 92%–100% in immunocompromised hosts (3). A moderately to strongly positive CSF JCV PCR, quantified as ≥2.82 log copies/mL is strongly suggestive of PML, with a sensitivity of 86% and specificity of 99% (4). Our patient had a CSF JCV PCR quantification of 4.09 × 10⁵ copies/mL, which is well above the cut off of a moderately positive value. Definitive diagnosis of PML is based on brain biopsy findings showing demyelination, bizarre astrocytes, and enlarged oligodendroglial nuclei, along with established findings of JCV (2). While a brain biopsy remains the gold standard for diagnosis with a specificity of 100%, it is more invasive. Conventional treatment for PML involves reversing underlying immunosuppression (1).

PML usually presents in the setting of immunodeficiency such as AIDS, organ transplantation, hematological malignancies, autoimmune conditions, such as systemic lupus erythematosus, and in patients treated with monoclonal antibodies for MS. It has been estimated that the occurrence of PML in AIDS patients can range from 3% to 5% of patients (2). PML is also a documented complication of fludarabine or rituximab treatment in chronic lymphocytic leukemia (CLL) patients. There have only been five case reports of PML occurring in CLL patients who have not undergone treatment (5–9). In addition, there have been 21 reported cases in the literature of JCV PML occurring in individuals with minimal or occult immunodeficiency (10).

Our case was suspicious for CLL because of the aberrant expression of CD4, given the dim CD20 expression and CD200 co-expression. CLL is a known cause of secondary immunodeficiency. However, the very low number of monoclonal B cells in the peripheral blood (fewer than 5 × 10⁹/L) and the absence of lymphadenopathy rules out CLL and makes the diagnosis low-count MBL (11). Unlike high-count MBL (0.5–5 × 10⁹/L), low-count MBL rarely progresses to CLL (>5 × 10⁹/L) (12).

MBL is a rather common condition in adults and may be associated with increased risk of infection. A large study using the biobank from the Mayo Clinic and Olmstead County Medical Center found that in adults age 40 or above, MBL was quite common, occurring in 119 of 984 (12%) persons screened (13). 106 of these 119 individuals had low-count CLL-like MBL clones (mean age 69 years, 55% male), as did our patient. An association between low-count MBL and hospitalization with infection was observed with the unadjusted hazard ratio (HR) for hospitalization with infection among the 106 Olmsted County residents with LC MBL relative to the 865 Olmsted County residents with normal immunophenotype 2.41 (95% CI 1.39 to 4.19; p = 0.002). After adjusting for age and sex, the HR was 1.65 (95% CI 0.95 to 2.88; p = 0.08). The most frequent sites of infection were urinary tract infection (21 patients; 26%), cellulitis (20 patients; 26%), pneumonia (14 patients; 18%), and blood stream infection (6 patients; 8%).

As noted, PML is most commonly seen in patients with advanced T-cell immunodeficiencies. low-count MBL therefore is surprising as a predisposing factor in PML. However, there is experimental evidence that CLL cells themselves can exert significant immunosuppressive effects (in addition to causing hypogammaglobulinemia—which was not seen in our patient due to the very early stage of presentation). Both effectors of the innate and adaptive immune response exhibit marked dysfunction in CLL (14). Major deregulations have been found in the T lymphocyte compartment of CLL patients, ‘with inhibition of CD8⁺ cytotoxic and CD4⁺ activated effector T cells, replaced by exhausted and more tolerogenic subsets’ (14). Leukemic cells also drive immunosuppression due to their B-regulatory phenotype. There are also signaling cascades ‘triggered by soluble mediators and cell-cell contacts’ which impact immunomodulation in CLL (14).

Although we cannot rule out the possibility that low-count MBL and PML were coincidentally associated, we suggest MBL induced blunting of anti-viral T cell–mediated immunity may be the possible pathogenic mechanisms for the unexplained PML infection in this patient.

Conclusion

To our knowledge this case is the first report of PML in association with low-count MBL, and this increases the importance of further study of this potentially common hematological condition. It is possible that low-count MBL may result in similar immunodeficiencies as CLL, and therefore this warrants further investigation. In addition, PML may be a first presentation of underlying immunodeficient states, however mild they may initially seem. It is therefore important that clinicians are watchful of underlying immunodeficiency in any patient that presents with PML.

Contributors:

Conceptualization, D Santhanam, S Chan, C Nguyen, M Silverman; Writing - original draft & editing, D Santhanam, S Chan, C Nguyen, M Silverman; Writing - review & editing, D Santhanam, S Chan, C Nguyen, J Racosta, A Xenocostas, K Robertson, M Silverman; Investigation, M Silverman; Supervision, M Silverman

Ethics Approval:

Ethics approval was not required for this article.

Informed Consent:

Informed written consent for publication was provided by the patients next of kin.

Registry and the Registration No. of the Study/Trial:

N/A

Data Accessibility:

All data will not be made publicly available. Researchers who require access to the study data can contact the corresponding author for further information.

Funding:

No funding was received for this work.

Disclosures:

The authors have nothing to disclose.

Peer Review:

This manuscript has been peer reviewed.

Animal Studies:

N/A