Maryam Saleemi

Progressive Multifocal Leukoencephalopathy (PML) is a rare infectious disease caused by the John Cunningham virus (JC Virus)[1] . The JC virus is a polyomavirus that only affects humans[2] . Therefore, research on JC viral pathogenesis is limited due to the lack of an animal model [2]. Approximately 35–80% of healthy adults have JC viral antibodies because at some point in their life they were infected with the JC virus; however, it normally remains in its latent form[3] . In most cases only those with compromised immune systems go on to develop an infection [3]. PML has emerged as a major complication in patients with severe immunodeficiency such as HIV [3]. It is estimated that approximately 2-5% of patients with AIDS develop PML [3]. More recently, cases of PML have emerged in organ and stem cell transplant recipients as well as those undergoing immuno-modulatory drug treatment therapies[4] . The JC virus results in damage to the myelin protecting the nerves specifically in the white matter of the brain [3]. Since the white matter of the brain is targeted, symptoms consist of a variety of cognitive deficits [3]. To this day there is no treatment for PML; however, several potential therapies and treatments are currently being investigated.

1. Cause: John Cunningham Virus (JCV)

In 1971, the John Cunningham Virus was first isolated from the cerebrospinal fluid of a patient diagnosed with Hodgkin’s disease, who later on also developed Progressive Multifocal Leukoencephalopathy (PML) [1]. The virus was named after this very patient John Cunningham, from whom it was isolated [1]. The JC virus is a neurotropic virus with narrow host specificity and only infects humans[5]. The JC virus has a high prevalence rate within the human population; over 70% of people acquire JC viral anti-bodies and approximately 40% of the population display viral shedding as tested in their urine[5] . JC viral infection normally tends to take place during early childhood; however, this archetype remains asymptomatic taking sanctuary in the kidneys and B. lymphocytes throughout later years [5]. The JC virus belongs to the Polyomaviridae family of viruses and is closely related to four other polyomaviruses: BKV, WUV, KIV, and MCV. The degree of homology (69-75%) between the JC viral genome and that of the simian virus 40 and BK virus confirms the close evolutionary relationship of these three polyoma viruses [5]. Theses viruses biologically differ with respect to the extent of divergence pertaining to the promoter-enhancer sequences [5]. The JC virus has a closed, circular genome containing double stranded DNA[6] . It consists of 5,130 nucleotide pairs and the amino acid sequence can be divided into six regions that code for non-structural proteins: the large tumor antigen (LT), small tumor antigen (sT), the late capsid viral protein coding regions (VP1, VP2, VP3) and the agnoprotein [6]. In humans the JC virus binds to an N’ linked glycoprotein containing α-2, 6-linked sialic acid, which can be found in a variety of human cell tissue types[7] .

2. Transmission

There is limited information regarding the transmission of the JC virus since there are no obvious symptoms associated with the initial viral infection. Originally it was believed that JC viral transmission had a respiratory or a prophryngeal basis, this was primarily based on JCV positive tests confirming the presence of the virus in tonsillar tissue[8] . But more recent studies involving HIV-positive patients have not been able to support these previous findings and suggest that initial infection of the virus archetype may have an oral mode of transmission [9]. Upon further testing JC viral particles were able to live in sewage at 20◦C, and remain stable for over 72 days [9]. This further supports that contaminated food and water could be mediums for JC viral transmission, through an oral route[9] .

3. Predisposing Risk Factors

3.1 Drug Therapies

Natalizumab, rituximab and efalizumab are three popular immunomodulatory drugs on the market that have been attributed to the development of PML. Natalizumab is an immunomodulatory monoclonal antibody used as a second-stage treatment for Multiple Sclerosis (MS) patients[10] . It is used to prevent relapses and prevent further debilitation in MS patients [10]. Natalizumab was remarketed in June of 2006 after its use was suspended in 2004, to further investigate complications that arose from its use[11] . Currently, it is only prescribed as a monotherapy and patients that are prescribed natalizumab are carefully monitored through a program called TOUCH™ [12] . Rithuximab is an intravenous drug used primarily for the treatment of non-Hodgkin’s lymphoma, which is a rare cancer of the lymph nodes, as well as a common treatment of rheumatoid arthritis; an inflammatory disease of the joints[13] . Efalizumab is monoclonal antibody primarily used to treat patients with plaque psoriasis, which is a cutaneous condition[14] . In June of 2009, efalizumab was taken of the market globally, due to health concerns with regards to patients being at a high risk for developing PML[15] . Both natalizumab and efalizumab bind α-integrin molecules on the surface of T and B cells, blocking their entry into brain, gut, and skin tissue[16] . Preventing the entry of T cells from passing through the blood-brain barrier decreases immune surveillance; therefore, stopping an immune response from taking place, against the JC viral particles [16]. Rituximab binds to the CD20 surface molecule on the B cells, depleting them from the peripheral circulation via complement-mediated cytolysis[17] . Once the immune surveillance is decreased, the widely present JC virus is able to travel to the brain and infect oligodendrocyes, which support its replication[18] .

3.2 Immunodeficiency

There has been a significantly higher incidence of PML reported in patients who are also infected with the human immunodeficiency virus (HIV) [19]. Studies estimate that 5-10% HIV-1 infected patients also develop PML[19] . The underlying cause for this can be attributed to the up-regulation of adhesion molecules in the brain epithelium that occurs as a result of being infected with HIV[20] . Another factor contributing to the development of PML in HIV-infected individuals is the potential for the HIV tat protein to trans-activate the latent JC virus[21] .

4. Symptoms

PML is a rapidly progressing disease and the impairments that accompany it also progress quickly[22] . PML symptoms are similar to those of other HIV-related conditions that affect the brain, such as: toxoplasmosis, cryptococcal meningitis, HIV leukoencephalopathy, and lymphoma of the central nervous system [22].

Patients affected with PML present various neurological deficits that develop over the course of the illness . Initial symptoms can vary between patients because the initial sites of lesion in the brain can vary[23] .The most common symptoms include weakness in the arms and legs, as well as a variety of cognitive defects [23]. Other common symptoms include: motor dysfunction, sensory dysfunctions and implications involving speech [23]. A characteristic symptom includes alien hand, which presents in later stages of the disease [24]. Alien hand syndrome (AHS) is a rare condition resulting in involuntary movements of a limb, normally an arm [24]. The patient feels as though an external force is controlling the activity of the arm[24] .

5. Pathophysiology

It has long been suspected that JC virus is carried into the (central nervous system) CNS. However, it is still not understood as to how the exactly the JC virus travels into the CNS. One prevailing hypothesis is centered on B cells and considers them to be the cells of importance because the JC virus is present in the B cells in bone marrow, and since it has been detected in the B cells in the blood of immunosuppressed patients [25]. However, JC viral infection of the B cells in areas of the brain affected by PML has not yet been directly demonstrated[25] . An alternative hypothesis considers T-cells to play the most important role in the spread of the infection because in the majority of patients who develop PML the implicated immune function seems to be the major cause for developing PML [16].

Another controversy concerning PML pathogenesis relates to the question of when the JC virus enters the nervous system. The first hypothesis is that JC viral reactivation occurs in organs outside the nervous system, in lymphoreticular cells, or in the kidney and is disseminated at the time of immune suppression via the bloodstream to the nervous system, leading to the infection of oligodendrocytes.[26] . Another hypothesis postulates that when the primary JCV infection occurs in childhood or adolescence, latency is established not only in lymphoreticular cells and kidney cells but also in brain tissue [27]. Then, in the case of immune suppression, the virus is activated from its latent state[27] .
Once the JC virus disseminates into the CNS it infects oligodendrocyes via the serotonergic 5HT2a receptor[28] . Upon entering the nucleus of oligodendrocytes the virus takes advantage of its cellular machinery and undergoes replication, and further upon exporting of viral particles oligodendrotic apoptosis ensues resulting in cell death [18]. In some patients diagnosed with PML analysis of JC viral DNA isolated from their brain has revealed mutations in the JC virus capsid protein (VP1), which is a cell attachment protein and these mutations seem to have acquired overtime in patients with more sever cases of PML[29] .

6. Diagnosis

6.1 CSF: PCR analysis

Cerebrospinal fluid (CSF) samples taken from individuals are analyzed by the polymerase chain reaction (PCR) technique to detect for the presence of the JC virus[30] . This method of detection is preferred due to its non-invasive nature and is more sensitive than some of the other methods of detection [30]. In most cases two specific JC viral DNA target sequences are used for detection, one is a sequence specific for the JC virus capsid protein (VP1) and the other is a sequence specific for the large T antigen [31]. The reintroduction of natalizumab in 2006 was done under the TOUCH™ program, which carefully monitors patients taking natalizumab and under their program guidelines copies of JC viral DNA are frequently tested for using PCR analysis, if a notable increase is detected, natalizumab is discontinued[31] .

Figure 1. MRI showing lesions involving the temporal/occipital lobes and corpus callosum. Adapted from “Fatal Progressive Multifocal Leukoencephalopathy: Still a Problem in the Era of Highly Active Antiretroviral Therapy,” by Joanna Cole, MD; David M. Aboulafia, MD. (2009). AIDS Reader. 13(3): 263-281.
6.2 Imaging

A very plausible diagnosis can be made based on magnetic resonance imaging (MRI)[32] . MRI scans can reveal characteristic brain lesions in the white matter of the brain that are attributed to PML [32]. Images obtained usually reveal asymmetric cortical damage in the frontal and right temporal-parietal subcortical regions in the cerebral hemispheres [32].

external image insert_table.gif

6.3 Brain Biopsy

In most cases in order to establish a definite diagnosis of PML, a brain biopsy is usually done [33]. Another reason to carry out a histo-pathological examination serves to rule out other pathologies that present with similar physical manifestations, some of which include: HIV leukoencephalopathy, cerebral toxoplasmosis, malignant lymphoma or brain tumours[33] .

Stereotactic brain biopsy is a procedure used to locate a specific region of the brain from which you would like obtain tissue from. A stereotactic brain biopsy makes use of a 3-D system that helps to coordinate and precisely locate a region of the brain using MRI/CT/PET imaging technology[34] . Using the (x.y, z) coordinates that are generated, and upon applying local anesthesia, a hole is drilled into the skull so that a needle can be inserted to extract a tissue sample[35]
Evidence of PML from a brain biopsy is indicative of demyelination, damaged oligodendroglia which appears to have enlarged nuclei and smudgy chromatin, abnormal astrocytes, and enlarged basophilic glial cell nuclei[35] . Further examination may also reveal the presence of excess macrophages to be present in white matter[36] .

Figure 2. Brain Biopsy showing viral inclusion bodies in oligodendrocytes. Adapted from “Fatal Progressive Multifocal Leukoencephalopathy: Still a Problem in the Era of Highly Active Antiretroviral Therapy,” by Joanna Cole, MD; David M. Aboulafia, MD. (2009). AIDS Reader. 13(3): 263-281.

7. Potential Therapies and Current Research

Most cases of PML are fatal and currently there is no treatment for PML; however, more recent medical reports have noted longer survival rates [22]. To date, the introduction of highly active antiretroviral therapies (HAART) have contributed to the steady decline in the mortality rates as well as much lower incidences of PML in HIV-infected patients [22].

A newer target for treatment has been the use of nucleotide analogs to inhibit JC viral replication. Cytarabine is one such analog; however, it still does not show remarkable clinical improvements or consistent results[37]. It is also associated with aversive effects such as: nausea, fever, and bone marrow toxicity[37] .After establishing the relationship between JC viral binding to serotonin 5-HT2a receptors, attention was then directed towards considering clinically approved antipsychotic drugs possessing serotonin 5-HT 2a receptor antagonist activity as potential treatments [28,38]. Risperidone is one such anti-psychotic drug that showed to have positive results in a patient who had developed PML, however; further testing is yet to be done in order o establish it as being effective[38] .
Research on the JC virus is continuously growing. Many aspects concerning its pathogenesis are still debated among researches and remain unclear. Understanding these key pieces will be crucial for bringing forth more effective treatment.

  1. ^ Padgett, B. L. et al. (1971). Cultivation of papova-like virus from human brain with progressive multifocal leukoencephalopathy. Lancet, 7712(1): 1257-1260.
  2. ^ Egli, A. et al. (2009). Prevalence of polyomavirus BK and JC infection and replication in 400 healthy blood donors. The Journal of Infectious Diseases, 199: 837–846.
  3. ^ Berger, J.R., & Major, E.O. (1999). Progressive multifocal leukoencephalopathy. Seminars in Neurology, 19(1): 193–200.
  4. ^ Mateen, F. J. et al. (2011). Progressive multifocal leukoencephalopathy in transplant recipients. Annals of Neurology, 70(2): 305–322.
  5. ^ Knowles, W. A. (2006). Discovery and epidemiology of the human polyomaviruses BK virus (BKV) and JC virus (JCV). Adv. Exp. Med. Biol. 577:19-45.
  6. ^ Frisque, R.J., Bream, G.L., & Cannella, M.T. (1984). Human polyomavirus JC virus genome. Journal of Virology, 51(2): 458-469.
  7. ^ Eash, S., et al. (2004). Differential Distribution of the JC Virus Receptor-Type Sialic Acid in Normal Human Tissues. The American Journal of Pathology. 164(2): 419-428.
  8. ^ Monaco, M.C. et al. (1996). JC virus infection of hematopoietic progeni- tor cells, primary B lymphocytes, and tonsillar stromal cells: implications for viral latency.Journal of Virology 70: 7004–7012.
  9. ^ Bofill-Mas, S. & Girones, R. (2003). Role of the environment in the transmission of JC virus.Journal of Neurovirology. 9(1): 54–58.
  10. ^ Ransohoff, R.M. (2007). Natalizumab for multiple sclerosis N. Engl. J. Med. 356: 2622-2629.
  11. ^ U.S Food and Drug Administration (FDA). Information on Natalizumab (marketed as Tysabri). 2012. Web. 29. Mar. 2012.
  12. ^ Stuve, O., et al. (2006) Immune surveillance in multiple sclerosis patients treated with natalizumab. Ann Neurol. 59(1): 743-747.
  13. ^ Carson, K. K., et al. (2009). Progressive multifocal leukoencephalopathy following rituximab therapy in HIV negative patients: a report of 57 cases from the Research on Adverse Drug Event and Reports (RADAR) project. Blood.113(20):4834-2840.
  14. ^ Lebwohl M., et al. (2003). A novel targeted T-cell modulator, efalizumab, for plaque psoriasis. N Engl J Med. 349:2002-2011
  15. ^ U.S Food and Drug Administration (FDA). Raptiva (Efalizumab). 2009. Web. 29. Mar. 2012.
  16. ^ Polman, C.H., et al. (2006). A randomized, placebo-controlled trial of natalizumab for relapsing multiple sclerosis. N Engl J Med. 354:899.
  17. ^ McLaughlin, P., et al. (1998). Rituximab chimeric anti-CD20 monoclonal antibody therapy for relapsed indolent lymphoma: half of patients respond to a four-dose treatment program Journal of Clinical Oncology.16(8): 2825.
  18. ^ Burns, R., et al. (2002). Progressive multifocal leukoencephalopathy and apoptosis of infected oligodendrocytes in the central nervous system of patients with and without AIDS. Arch Neurol. 59:1930–1936.
  19. ^ Cinque P., et al. (2009). Progressive multifocal leukoencephalopathy in HIV-1 infection. Lancet. 9(10): 625-636.
  20. ^ Peitito, C. K., et al. (1986). Neuropathology of acquired immunodeficiency syndrome (AIDS): an autopsy review J. Neuropathol. Exp. Neurol. 45:635.
  21. ^ Tada, H., et al (1990). Trans- activation of the JC virus late promoter by the tat protein of the type 1 human immunodeficiency virus in glial cells. Proceedings of the National Academy Sciences of the USA 87: 3479-3483.
  22. ^ Engsig, F.N., et al. (2009). Incidence, clinical presentation, and outcome of progressive multifocal leukoencephalopathy in HIV-infected patients during the highly active antiretroviral therapy era: a nationwide cohort study. Journal of Infectious Diseases. 199:77-83.
  23. ^ Berger, J.R. (2007). Handbook of Clinical Neurology: Progressive multifocal leukoencephalopathy. 85: 169-183.
  24. ^ Ay, H., et al. (1998) Sensory alien hand syndrome: case report and review of the literature. J Neurol Neurosurg Psychiatry. 65:366–369.
  25. ^ Monaco, M.C., et al. (1996). JC virus infection of hematopoietic progenitor cells, primary B lymphocytes, and tonsillar stromal cells: implications for viral latency. J Virol. 70:7004–701.
  26. ^ Chesters P.M., et al. (1983). Persistence of DNA sequences of BK virus and JC virus in normal human tissues and in diseased tissues. Journal of Infectious Diseases. 147: 676-684.
  27. ^ Lipton R.B., et al. (1988) Progressive multifocal Leukoencephalopathy of the posterior fossa in an AIDS patient: clinical, radio- graphic and evoked potential findings. Eur. Neuro. 128 :258-261.
  28. ^ Elphick G.F., et al. (2004). The human polyomavirus, JCV, uses serotonin receptors to infect cells. Science. 306(5700): 1380-1383.
  29. ^ Sunyaev, S.R. et al. (2009). Adaptive mutations in the JC virus protein capsid are associated with progressive multifocal leukoencephalopathy (PML). PLoS Genet. 5, e1000368.
  30. ^ White, F.A., et al. (1992). JC virus DNA is present in many human brain samples from patients without progressive multifocal leukoencephalopathy. J Virol. 66:5726–5734.
  31. ^ Sadiq, S.A., et. al, (2010). JCV detection in multiple sclerosis patients treated with natalizumab. Journal of Neurology. 257: 954-958.<ref/>.
  32. ^ Oguz, B., et al. (2003). A case of progressive multifocal leukoencephalopathy (PML): diffusion-weighted MRI imaging findings. Neuroanatomy. 2: 9-12.
  33. ^ Zhang, M., et al. (2010). Prolonged Stability of Progressive Multifocal Leukoencephalopathy in a Patient With Chronic Lymphocytic Leukemia. American Society of Clinical Oncology.28(28):e503-e506.
  34. ^ Pirottte, B. et al. ( 1995). Use of Positron Emission Tomography (PET) in Stereotactic Conditions for Brain Biopsy. Acta Neurochirurgica.134 (1-2):79-82.
  35. ^ Berger, J.R. (2011). The Clinical Features of PML. Cleaveland Clinic Journal of Medicine. 78(2):S8-S12.
  36. ^ Hall, W. A. et al. (1998). The safety and efficacy of stereotactic bipsy for intracacranial lesions. Cancer. 82(9): 1749-1755.
  37. ^ Hou, J., et al. (1998). The efficacy of nucleoside analogs against JC virus multiplication in a persistently infected human fetal brain cell line. J Neurovirol. 4(4):45.
  38. ^ Focosi, D., et al. (2010). Progressive Multifocal Leukoencephalopathy: What’s New? Progress in Clinical Neuroscience.16(3): 308-323.