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CASE REPORT
Year : 2017  |  Volume : 65  |  Issue : 5  |  Page : 1061-1064

Progressive multifocal leukoencephalopathy in a 44-year old male with idiopathic CD4+ T-lymphocytopenia treated with mirtazapine and mefloquine


1 Department of Pathology, All India Institute of Medical Sciences, New Delhi, India
2 Department of Neurology, All India Institute of Medical Sciences, New Delhi, India

Date of Web Publication6-Sep-2017

Correspondence Address:
Vaishali Suri
Department of Pathology, All India Institute of Medical Sciences, Ansari Nagar, New Delhi - 110 029
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/neuroindia.NI_535_16

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 » Abstract 

Progressive multifocal leukoencephalopathy (PML) is an opportunistic viral infection of the central nervous system caused by the reactivation of John Cunningham virus (JCV) in immunocompromised patients, most commonly in human immunodeficiency virus (HIV) infection, and less commonly in those receiving various immunosuppressive regimens. Prognosis of untreated PML is grave and the mainstay of treatment is the reversal of immunosuppression, usually by institution of antiretroviral drugs in HIV patients and cessation of immunosuppressive therapies in others. PML is increasingly being reported in those with minimal or occult immunosuppression. A small fraction of these patients meet the criteria for idiopathic CD4+ T-lymphocytopenia (ICL) after exclusion of all secondary causes of lymphocytopenia, including HIV. A 44-year-old previously healthy male presented with clinical and radiological features suggestive of PML. Cerebrospinal fluid samples were repeatedly negative for JCV. Immunohistochemistry on brain biopsy eventually confirmed PML. Despite extensive work-up, the only abnormality detected was an unexplained and persistently low absolute CD4+ T-lymphocyte count. Based on the limited available literature on the treatment of non-HIV PML, he was treated with a combination of mirtazapine and mefloquine with clinical improvement. Non-HIV PML remains relatively uncommon, and PML as a presenting feature of ICL is rare. It is important to document and follow these patients to be able to assess the relative risks associated with various causes and formulate effective therapeutic strategies.


Keywords: Brain biopsy, CD4+ T-lymphocytopenia, idiopathic, mefloquine, mirtazapine, non-HIV progressive multifocal leukoencephalopathy
Key Messages:
Progressive multifocal leukoencephalopathy can occur in patients with minimal or occult immunosuppression. The cerebrospinal fluid polymerase chain reaction may be negative in progressive multifocal leukoencephalopathy necessitating a biopsy. Idiopathic CD4+ T-lymphocytopenia presenting with progressive multifocal leukoencephalopathy is rare and represents a therapeutic challenge. Cytokine therapies to improve CD4 counts are being tried with favorable responses. The antiviral agents, mirtazapine and mefloquine, produced clinical improvement in our case.


How to cite this article:
Nambirajan A, Suri V, Kataria V, Sharma MC, Goyal V. Progressive multifocal leukoencephalopathy in a 44-year old male with idiopathic CD4+ T-lymphocytopenia treated with mirtazapine and mefloquine. Neurol India 2017;65:1061-4

How to cite this URL:
Nambirajan A, Suri V, Kataria V, Sharma MC, Goyal V. Progressive multifocal leukoencephalopathy in a 44-year old male with idiopathic CD4+ T-lymphocytopenia treated with mirtazapine and mefloquine. Neurol India [serial online] 2017 [cited 2020 May 29];65:1061-4. Available from: http://www.neurologyindia.com/text.asp?2017/65/5/1061/214055


Progressive multifocal leukoencephalopathy (PML) is a viral infection of the central nervous system (CNS) caused by a neurotropic human polyomavirus, John Cunningham virus (JCV).[1] Primary infection by JCV is commonly acquired in childhood and is usually asymptomatic with the virus remaining latent.[1] Immunosuppression, classically occurring in the setting of human immunodeficiency virus (HIV) infection, reactivates the virus, resulting in brain invasion, destruction of oligodendrocytes, and a debilitating demyelinating illness.[1] The generally accepted notion that severe immunodepression is an absolute prerequisite for the development of PML has been questioned recently, with increasing number of cases being reported in patients with minimal or occult immunosuppression.[2] It is being recognized that subtle or transient failures in cell-mediated immunity may be sufficient to reactivate the virus.[2] As reversal of immunosuppression remains the cornerstone of therapy in PML, the effective treatment of patients, who lack obvious immunosuppressive predisposition, is a therapeutic challenge; we present our experience with one such rare scenario.


 » Case History Top


A 44-year old man presented with insidious onset of impaired vision in the form of repeated collisions with wall on the left side of body, followed soon by behavioural changes in the form of irritability, inappropriate laughter, and aggressiveness. Within 2 weeks, he developed weakness of the left lower and upper limbs that gradually progressed to paralysis. His verbal output was reduced and he developed left facial paresis. He also had difficulty in reading, writing, and was completely mute within the next 4 weeks. There was no history of fever, headache, seizures, bladder, or bowel involvement. On examination, he was conscious with simple comprehension preserved. He was, however, aphasic and exhibited left-sided neglect. His left upper and lower limbs were spastic with reduced power. The left plantar reflex was extensor. His family and personal history were noncontributory. The magnetic resonance imaging showed T2/fluid-attenuated inversion recovery (FLAIR) asymmetric, nonenhancing hyperintensities in bilateral parieto-occipital lobes, suggestive of an atypical demyelinating lesion, and a possibility of PML was suggested [Figure 1]. His routine investigations revealed normal biochemical parameters and hemogram. Urine examination showed the presence of budding yeast forms. He was nonreactive for HIV-1 and HIV-2 tested by both enzyme-linked immunosorbent assay and Western blot (on three occasions) and HBsAg. Cerebrospinal fluid (CSF) examination was negative for infectious organisms and polymerase chain reaction (PCR) for JCV performed twice was negative. An image-guided brain biopsy showed demyelination, reactive astrogliosis, and enlarged oligodendrocytes with intranuclear viral inclusions that were immunopositive for p53 and SV40, findings that were diagnostic of PML [Figure 2]. Following this, he was investigated thoroughly for a cause of immunosuppression. CSF HIV antibodies, acid-fast bacilli staining, geneXpert for Mycobacterium tuberculosis, and venereal disease research laboratory tests were negative. The only abnormalities detected were low absolute CD4 levels of 176/cu.mm, and mediastinal lymphadenopathy seen on whole body positron emission tomography (PET) imaging, raising the suspicion for the underlying presence of sarcoidosis. Serum angiotensin converting enzyme levels were, however, normal at 31.9 microgram/litre (normal: 8–52 microgram/litre), and aspirate from mediastinal lymph nodes did not show any granulomas, thus excluding sarcoidosis. His serum IgG levels (945 mg/dL) and CD8+ T lymphocyte count (655/cu.mm) were within normal limits. A repeat CD4+ T lymphocyte count performed after 2 months was 243/cu.mm, leading to a diagnosis of idiopathic CD4+ T lymphocytopenia (ICL). The patient was started on cotrimoxazole (960 mg BD), mefloquine (250 mg/week), and mirtazapine (15 mg/day). At the last follow-up 11 months after the onset of complaints, the patient showed improvement. He was walking with a stick and could speak and comprehend.
Figure 1: Axial T2-weighted (a) and fluid-attenuated inversion recovery (b and c) magnetic resonance images show hyperintense lesions involving bilateral parieto-occipital subcortical and deep white matter (right > left), contiguous along the splenium of the corpus callosum. These lesions show no enhancement with contrast (d)

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Figure 2: Brain biopsy comprising of white matter fragments showing rarefaction and infiltration by foamy histiocytes (a, hematoxylin and eosin, ×200), perivascular lymphocytic infiltrate (b, hematoxylin and eosin, ×200), reactive astrocytes (c, hematoxylin and eosin, ×400), and oligodendroglial cells with nuclear enlargement and basophilic viral inclusions (d, hematoxylin and eosin, ×400). Inset in d shows immunopositivity for SV-40 antigen in oligodendrocytes with viral inclusions (immunohistochemistry, ×200)

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 » Discussion Top


An extremely rare disease in the pre-acquired immunodeficiency syndrome (AIDS) era, the occurrence of PML increased 50-fold after the HIV pandemic, with an incidence rate of 3–5% in HIV patients with AIDS.[1] Although, its frequency decreased following the advent of highly active antiretroviral therapy (HAART), it is still significantly common in HIV patients. At present, approximately 79% of PML patients have underlying AIDS, 13% have hematological malignancies, 5% are organ transplant recipients, and 3% have autoimmune diseases treated with immunosuppressive or immunomodulatory medications.[3],[4] Cellular immune response, mediated by CD4+ and CD8+ T lymphocytes, plays a crucial role in the containment of JCV. It is becoming increasingly evident that transient or discrete failure in cellular immunity might be enough to promote JCV reactivation.[2] Non-HIV PML is being reported in patients with untreated systemic lupus erythematosus, tuberculosis, sarcoidosis, chronic kidney disease, cirrhosis, and even normal pregnancy.[2] The common denominator in most of these conditions is depressed cellular immunity, and CD4+ T-lymphocytopenia.[2] Despite extensive investigations, we were unable to find a predisposing cause for the low CD4 counts in our patient, leading to its categorization as ICL.

ICL is a diagnosis of exclusion and a rare, clinically heterogeneous entity, defined by a documented absolute CD4+ T lymphocyte count <300/cu.mm or <20% of total T cells, on more than one occasion, usually 2 to 3 months apart.[5] The vast majority of patients who meet the criteria for ICL usually come to clinical attention due to an opportunistic infection, most commonly, cryptococcal meningitis.[6] The natural history and outcome of ICL is poorly defined and is based on individual case reports.[6] Although patients by definition are HIV-negative, autoimmune diseases and lymphoreticular malignancies have been reported in 15–20% of these patients.[6]

PML as a presenting manifestation of ICL is rare with approximately 14 cases reported in English literature [Table 1]. All patients were adult males in the 4th to 7th decades of life with a median age at diagnosis of 55 years. Few of them suffered from comorbid conditions such as tuberculosis, Kaposi sarcoma, psoriasis, and syphilis; however, the temporal association of ICL with PML and low CD4-T cell counts is not clear.[2],[8],[12] Although most patients, including ours, presented with the typical clinical and radiological features of PML, diagnosis was delayed owing to the low index of clinical suspicion in the face of apparent immunocompetence.[17]
Table 1: Reported cases of ICL presenting with PML including the current case

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Definitive diagnosis of PML is achieved by examination of CSF or by a brain biopsy. Although highly specific (92–99% specificity rate), the sensitivity of CSF PCR in detecting JCV is low, ranging from 74–93%, and repeated sampling is required.[1] In our patient, CSF samples were repeatedly negative. Brain biopsy is the gold standard of diagnosis, with sensitivity and specificity rates of 65–95% and 100%, respectively.[1] Immunohistochemistry for commercially available polyomavirus specific SV-40 antigen helps in confirming the diagnosis.[1] p53 immunopositivity serves as a surrogate marker, highlighting the accumulation of wild-type p53 in virus infected cells.[19]

In the absence of treatment, PML usually progresses over the period of several weeks to months, culminating in coma and death, usually 3–6 months from the onset of neurological symptoms in up to 50% patients, and even more rapidly in patients with AIDS.[1] The most important therapeutic intervention is to reverse immunosuppression, either by institution of HAART in HIV patients or by cessation of immunosuppressant drugs.[1] Specific antiviral agents being tried include cidofovir and cytosine arabinoside that target viral DNA replication; antidepressant mirtazapine, which inhibits the 5-hydroxytryptamine-2a serotonin receptor for JCV entry; and the antimalarial agent, mefloquine.[14] Among patients with ICL with PML, the two patients who were treated with cidofovir alone had a poor outcome.[9],[12] Mirtazapine monotherapy has been tried in three patients,[2],[17],[18] with clinical improvement in only one of them.[17] Treatment with interleukin-7, with an aim to increase the CD4 counts, has also been tried in two cases of ICL,[16],[18] with one achieving complete long term remission with reversal of CD4 counts[17] and the other achieving partial remission.[14] One patient treated with interferon alpha went on to survive without progression for 5 years.[2] Our patient improved clinically on a dual therapy of mirtazapine and mefloquine, even though his CD4 T-lymphocyte counts remained low. Although those patients who received no specific antiviral therapy succumbed to their illness within months;[12],[15] there are exceptions where the patients have survived for up to 36 months, albeit with considerable morbidity and disability.[8],[11] Nevertheless, controlled clinical trials are required for ascertaining the indications, choice of therapy, and duration of treatment in these patients.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

 
 » References Top

1.
Ferenczy MW, Marshall LJ, Nelson CD, Atwood WJ, Nath A, Khalili K, et al. Molecular biology, epidemiology, and pathogenesis of progressive multifocal leukoencephalopathy, the JC virus-induced demyelinating disease of the human brain. Clin Microbiol Rev 2012;25:471-506.  Back to cited text no. 1
    
2.
Gheuens S, Pierone G, Peeters P, Koralnik IJ. Progressive multifocal leukoencephalopathy in individuals with minimal or occult immunosuppression. J Neurol Neurosurg Psychiatry 2010;81:247-54.  Back to cited text no. 2
    
3.
Koralnik IJ, Schellingerhout D, Frosch MP. Case records of the Massachusetts General Hospital. Weekly clinicopathological exercises. Case 14-2004. A 66-year-old man with progressive neurologic deficits. N Engl J Med 2004;350:1882-93.  Back to cited text no. 3
    
4.
Amend KL, Turnbull B, Foskett N, Napalkov P, Kurth T, Seeger J. Incidence of progressive multifocal leukoencephalopathy in patients without HIV. Neurology 2010;75:1326-32.  Back to cited text no. 4
    
5.
Centers for Disease Control (CDC). Unexplained CD4+ T-lymphocyte depletion in persons without evident HIV infection - United States. MMWR Morb Mortal Wkly Rep 1992;41:541-5.  Back to cited text no. 5
    
6.
Ahmad DS, Esmadi M, Steinmann WC. Idiopathic CD4 lymphocytopenia: Spectrum of opportunistic infections, malignancies, and autoimmune diseases. Avicenna J Med 2013;3:37-47.  Back to cited text no. 6
[PUBMED]  [Full text]  
7.
Chikezie PU, Greenberg AL. Idiopathic CD4+ T lymphocytopenia presenting as progressive multifocal leukoencephalopathy: Case report. Clin Infect Dis 1997;24:526-7.  Back to cited text no. 7
    
8.
Iwase T, Ojika K, Katada E, Mitake S, Nakazawa H, Matsukawa N, et al. An unusual course of progressive multifocal leukoencephalopathy in a patient with idiopathic CD4+ T lymphocytopenia. J Neurol Neurosurg Psychiatry 1998;64:788-91.  Back to cited text no. 8
    
9.
Haider S, Nafziger D, Gutierrez JA, Brar I, Mateo N, Fogle J. Progressive multifocal leukoencephalopathy and idiopathic CD4+ lymphocytopenia: A case report and review of reported cases. Clin Infect Dis 2000;31:E20-2.  Back to cited text no. 9
    
10.
Kokubun N, Ishihara T, Nishibayashi M, Ikeda S, Nagashima K, Hirata K. Progressive multifocal leukoencephalopathy with idiopathic CD4 positive T-lymphocytepenia mimicking a low grade glioma on proton MR spectroscopy. A case report. Rinsho Shinkeigaku 2005;45:663-8.  Back to cited text no. 10
    
11.
Rueger MA, Miletic H, Dorries K, Wyen C, Eggers C, Deckert M, et al. Long-term remission in progressive multifocal leukoencephalopathy caused by idiopathic CD4+ T lymphocytopenia: A case report. Clin Infect Dis 2006;42:e53-6.  Back to cited text no. 11
    
12.
Inhoff O, Doerries K, Doerries R, Scharf J, Groden C, Goerdt S, et al. Disseminated cutaneous Kaposi sarcoma and progressive multifocal leukoencephalopathy in a patient with idiopathic CD4+ T lymphocytopenia. Arch Dermatol 2007;143:673-5.  Back to cited text no. 12
    
13.
Melzi S, Bonfanti P, Carenzi L, Faggion I, Resta M, Resta F, et al. Progressive multifocal leukoencephalopathy in a patient with idiopathic CD4+ cells deficit. Clin Ter 2008;159:325-7.  Back to cited text no. 13
    
14.
Patel A, Patel J, Ikwuagwu J. A case of progressive multifocal leukoencephalopathy and idiopathic CD4+ lymphocytopenia. J Antimicrob Chemother 2010;65:2697-28.  Back to cited text no. 14
    
15.
Puri V, Chaudhry N, Gulati P, Patel N, Tatke M, Sinha S. Progressive multifocal leukoencephalopathy in a patient with idiopathic CD4+ T lymphocytopenia. Neurol India 2010;58:118-21.  Back to cited text no. 15
[PUBMED]  [Full text]  
16.
Moloney F, Fernandez D, Harrington H. Progressive multifocal leucoencephalopathy in a patient with idiopathic CD4+ lymphocytopenia. Ir Med J 2012;105:84-5.  Back to cited text no. 16
    
17.
Delgado-Alvarado M, Sedano MJ, González-Quintanilla V, de Lucas EM, Polo JM, Berciano J. Progressive multifocal leukoencephalopathy and idiopathic CD4 lymphocytopenia. J Neurol Sci 2013;327:75-9.  Back to cited text no. 17
    
18.
Alstadhaug KB, Croughs T, Henriksen S, Leboeuf C, Sereti I, Hirsch HH, et al. Treatment of progressive multifocal leukoencephalopathy with interleukin 7. JAMA Neurol 2014;71:1030-5.  Back to cited text no. 18
    
19.
Yang B, Prayson RA. Expression of Bax, Bcl-2, and P53 in progressive multifocal leukoencephalopathy. Mod Pathol 2000;13:1115-20.  Back to cited text no. 19
    


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