DOI: https://doi.org/10.21203/rs.3.rs-2579449/v1
Background: Progressive multifocal leukoencephalopathy (PML) is an opportunistic viral demyelinating infectious disease of the central nervous system (CNS) which is rare & fetal. There is various clinical presenting symptoms for the disease.
Case presentation: This paper presents a clinical case of PML in a patient with B-CLL in remission, previously treated with Chlorambucil that complicated later in disease course with Covid-19 and mucormycosis.
Conclusion: like many other viruses, the more relevant immune-competent cells in host defense against JCV, appear to be T cells. This issue is recently also suggested in Covid 19 patients which a dissociation between severity and seroconversion has been reported. The case reported due to its rarity and multiple challenges in its diagnosis and treatment.
Progressive multifocal leukoencephalopathy (PML) is an opportunistic viral demyelinating infectious disease of the central nervous system (CNS) which is rare & fetal, initially described in 1958 in patients with lymphoproliferative and myeloproliferative diseases [1, 2]. PML, at first named with respect to its pathological characteristics as a white matter progressive demyelinating multifocal disease, which can now be thought of as the classical form of this disease.
The causative agent of the disease is the John Cunningham polyomavirus (JCV) reactivation, which almost always occurs in the context of a major suppression of cell-mediated immunity. JCV is a dsDNA ubiquitous human pathogen which the main routs of its transmission are both inhalation and ingestion of contaminated water causing primary infection that is presumably asymptomatic; thereafter the second phase would be a variable long period of latent infection in the body, most recognized in the kidneys, bone marrow, spleen and B lymphocytes. The third or final stage is reactivation and homogenous dissemination of virus into the CNS when cellular immunity is impaired. Of note, cellular immunity suppression is a potent risk factor for PML occurrence rather than humoral immunity impairment [3]. In the brain, where astrocytes and oligodendrocytes support JCV replication, the virus makes a lytic destruction and demyelination.
High prevalence (about 86%) JCV antibody has found in adults after an initial asymptomatic exposure to JCV in childhood [4]. Reactivation of JCV occurs in immunocompromised patients with HIV/HTLV1 and hematologic malignancies, organ transplantation, or individuals being treated with immunosuppressive or immunomodulatory therapies (e.g. monoclonal antibodies such as natalizumab).
There are few population based studies of PML epidemiology; most reports have looked at incidence in specific populations of patients at risk (eg, autoimmune disorders, HIV infection, malignancy, organ transplantation…). Malignancy is the most common predisposing condition among PML cases [5].
There is various clinical presenting symptoms for the disease: usually it begins with focal or multifocal neurological deficits that progress in a sub-acute course leading to serious disabilities or even death. Sometimes acute onset of symptoms may represent other neurological diagnosis like stroke. Previous studies has shown higher cerebral rather than brain stem involvement at a ratio of 10:1. [6]. There are few case reports of completely asymptomatic course of the disease in the literature [7]. In brain MRI imaging of these patients multifocal and mostly asymmetric lesions are seen in periventricular and subcortical regions which some of them may have minimal mass effect or enhancement.
As over time more data about the disease and its predisposing underlying factors has discovered, its diagnosis and management have changed to some extent. Underlying immunosuppression state is the main factor determining the prognosis, treatment course and immune reconstruction inflammatory syndrome (PML-IRIS) occurrence possibility.
Early detection of PML especially in asymptomatic phase is associated with a more acceptable outcome and survival rate; although the disease is devastating anyway with a significant risk of long term mortality & morbidity. There is no confirmed therapy for PML at the time of reporting this case, and the treatment is mainly consists of supportive care.
Here we are reporting a clinical case of PML in a patient with B-CLL in remission, previously treated with Chlorambucil that complicated later in disease course with Covid-19 and mucormycosis. Just few cases of PML following Chlorambucil treatment has described in the literature. Another challenging issue in our patient was his early manifestations just after Covid-19 vaccination making its diagnosis more difficult.
The patient was a 68-year-old-man admitted to our tertiary hospital with complaints of progressive drowsiness and confusion from 2 months before. He had a history of B-CLL (previously confirmed by PBS, flow-cytometry, bone marrow aspiration/biopsy & IHC with a low risk prognostic group; due to deletion of 13q14) which had diagnosed about 10 years before (following a common cold and routine check-up). After B-CLL diagnosis (2011) he was on follow-up every 3–6 months when treatment with Chlorambucil begun on 2015 (20-day periods every year until 2020 when the cytotoxic drug was stopped due to good resultant response & Covid-19 pandemic). He had also a documented history of basal cell carcinoma diagnosed in a facial papule which was resected with normal margin 2 years before without any local recurrence. No any other chemotherapy or radiotherapy was done for the patient.
So he was relatively good until August, 2021 when he presented with fever, imbalance and restlessness 4 days after the second dose of Sinopharm vaccine. Over the next three days his fever decreased but within 2 months, the patient gradually developed memory impairment (like leaving equipment & difficulty in finding directions while driving), restlessness as well as behavioral & personality changes. In late September, urinary & stool incontinency added to the symptoms & he admitted for primary evaluation in another center; there empirical treatment and evaluation for meningo-encephalitis initiated. At the time of admission in our tertiary center, the patient was drowsy answering the questions with short sentences and confused especially in multi-step tasks. In Mini Mental State Exam (MMSE) his score was about 17 points (mostly impaired in recall and calculation parts). He wasn’t febrile and general examination revealed only massive splenomegaly without any obvious meningismus or lymphadenopathy. In neurological examination cranial nerves were intact, and no hemiparesis or hemi sensory loss detected while he had an unsteady gait. Plantar reflexes were both downward. Brain CT scan performed which showed multiple areas of hypo-densities without mass effect. On brain MRI, relatively large areas of intensity alteration and gliosis were seen at sub cortical white matter of both parieto-occypital lobes. Similar changes at left hemisphere of cerebellum as well as in the midbrain were seen (showed in Fig. 1). At DWI sequences the lesions showed peripheral restriction without significant enhancement in post contrast evaluation. In brain MRS, showed in Fig. 2, mild decrease in NAA & also in choline in abnormal area was seen. Choline/Cr ratio was up to 0.8 there for possibility of neoplastic lesion (primary or secondary) could be exclude & possibility of PML should be considered.
Laboratory tests showed an abnormal CBC in the form of severe leukocytosis with anemia and thrombocytopenia (WBC: 36000 (95% lymphocytes), (Hb: 10.9; MCV: 88.5) (Plt: 91000)). Liver, renal and thyroid function tests, serum electrolytes and CRP all reported within normal limits. Encephalitis panel, vasculitis markers & also viral markers including HIV tests and Covid-19 PCR were negative. Serum serology was negative for brucella and toxoplasmosis IgM.
A lumbar puncture showed normal cell count, protein (0.28 mg/dL) and glucose. There were no abnormal cells on direct smear and fungul evaluation. CSF cytology was acellular and in CSF flow cytometry, no evidence of CNS involvement by CLL found. CSF polymerase chain reaction was negative for HSV 1 & 2, HIV, TB, Cryptococcus and toxoplasma. Finally John Cunningham polyomavirus virus (JCV) PCR, the causative agent of PML, reported positive in serum and also in CSF which clarified the diagnosis.
Unfortunately during hospitalization the patient gradually worsened so we concerned about Covid-19 involvement, proven later with second chest CT scan and Covid PCR (showed in Fig. 3). Under conservative and supportive treatment he also showed early signs of rhinosinositis leading to another ENT evaluation which nasal direct fungal smear showed septate hyphae, indicated the involvement of mucormycosis as the patient was predisposed to it due to underlying immunosuppression, diabetes mellitus and recently poor control blood glucose. Despite all efforts for supportive treatment, the patient eventually died with multi-organ failure after 3 months of his first symptoms.
Multiple overlapping risks factors and underlying conditions are involved in PML occurrence, including background diseases such as hematologic malignancies, AIDS and immunosuppressive agents [8]. Hematologic malignancies, including Hodgkin and Non-Hodgkin lymphoma, Waldenstrom macroglobulinemia, myeloma and CLL are the most commonly seen malignancies associated with PML, as well as in conditions such as hematopoietic stem cell transplantation (HSCT) [9]. As mentioned, the main predisposing factor in our case was CLL. Impairment of CD4 differentiation into Th1 cells and decreased CD8 T cell cytotoxicity are the result of significant alterations of T lymphocyte gene expression seen in CLL patients. [9]. This immune system impairment also may leads to several opportunistic infections such as fungal infections. Mucormycosis (black fungus) as a rare life threatening fungal infection occurs in immunocompromised patients just like in our case. So in our case despite the large number of WBCs, functional impairment of these cells made a serious immunosuppression caused PML and the same pathophysiology led to the occurrence of Mucormycosis.
This case of PML was complicated leading to an inevitable death. Regarding to underlying low grade CLL previously treated only with Chlorambucil and presenting symptoms shortly after Covid-19 vaccination we had also a diagnostic challenge to exclude infiltration of CLL which could mimic PML and even post vaccination inflammation phenomenon like ADEM. Another remarkable feature is that Covid vaccination may act as a trigger for presenting PML in this patient as the disease can be asymptomatic or subclinical before diagnosis which is the basis of screening protocols for MS patients receiving Natalizumab. According to evidences diagnostic delay in PML cases is not uncommon as frequent misdiagnose of it.
Based on literature, anti-JCV seropositivity of virtually all patients with PML related to Natalizumab therapy and positive correlation of antibody titers with disease incidence rates [10], altogether demonstrate the ineffectiveness of the humoral immune response to prevent reactivation of JCV. Thus T cells are seemingly the principle immune cells in defense against JCV. Therefore like many other viruses, the more relevant immune-competent cells in host defense against JCV, appear to be T cells. This issue is recently also suggested in Covid 19 patients which a dissociation between severity and seroconversion has been reported [11].
Ethics approval and consent to participate
The authors have no ethical conflicts to disclose. The patient’s legal guardian has given written informed consent to publish this case report and any accompanying images.
Consent for publication
The authors have no ethical conflicts to disclose. The patient’s legal guardian has given written informed consent to publish this case report and any accompanying images.
Conflict of Interest Statement
The authors have no conflicts of interest to declare.
Availability of Data and Materials
The datasets generated and/or analyzed during the current study are not publicly available due the nature of the study but are available from the corresponding author on reasonable request.
Competing interests
None declared.
Funding
The authors received no financial support for the search, authorship or publication of this manuscript.
Author Contributions
All persons listed as authors in the manuscript have made substantial contributions. All authors contributed to the conception and design or analyzing and interpreting data, drafting the article or revising it critically for important intellectual content. All authors approved the final version to be published.
Acknowledgements:
We would like to express our special thanks of gratitude to our attending physicians as well as our principal who gave us this opportunity to do this project, which also helped us to know about so many new things. We are really thankful to them.