Neuro-Ophthalmic Manifestations of Progressive Multifocal Leukoencephalopathy (PML)
Progressive Multifocal Leukoencephalopathy (PML) is a demyelinating disorder of the central nervous system caused by the John Cunningham virus (JCV), a polyomavirus present in 50 – 70% of the population. Despite the relatively high prevalence of the carrier rate of the virus, PML often requires states of immune system downregulation for activation. In addition to its effect on the nervous system, ocular manifestations of the disease can help identify the condition. The most common neuro-ophthalmic findings of PML are homonymous hemianopsia and cortical blindness, nystagmus, and diplopia with cranial nerve palsies.
The JCV (named for a patient, John Cunningham) is in the Polyomavirus family, a family of DNA viruses. JCV has a non-enveloped icosahedral capsid, with double-stranded, circular DNA.
PML is a rare disorder in the general population, with a prevalence of 0.22 and incidence of 0.11 per 100,000 people. The likelihood of developing the condition increases significantly during states of immune deficiency (e.g., HIV especially with CD4+ T-lymphocyte counts below 200 cells/µL). Underlying autoimmune conditions (e.g., rheumatoid arthritis and systemic lupus erythematous) have an incidence of PML of 0.4 and 4.0 per 100,000 people and drug induced immunosuppression (e.g., rituximab and natalizumab) may also produce PML. Table 1 below demonstrates a list of conditions that predispose to PML.
Table 1: Risk factors for PML
|Underlying predisposing factor to PML||Specific Examples|
Oligodendrocyte involvement by JCV causes demyelination, the primary radiologic finding of PML. Oligodendrocyte destruction causes a large number of demyelinating areas to conglomerate prior to macrophage-mediated phagocytosis of the break-down products, leading to impaired neural transmission.
JCV normally infects individuals at an early age. It is suspected that the initial mechanism of spread is close interpersonal contact or fomite spread. The tonsils are presumed to be site of latency of the initial exposure of the virus, either through direct contact or spread through immune cells. Some studies have demonstrated the gastrointestinal tract as another source of primary infection site.
Infection with JCV in an immunocompetent host rarely causes disease, but a dormant viral population will often persist. During this state, the JCV DNA is detectable, but the protein level (an indicator of active transcription) is not detectable. Prior to reactivation, JCV is believed to be housed in the kidney, lymphoid tissue, and peripheral blood leukocytes. Studies have also demonstrated the presence of JC Virus DNA in oligodendrocytes and astrocytes, suggesting that the brain might be an additional site of latency.
The life cycle of the JC Virus is characterized by the following twelve step process:
- Adsorption of virus to cell surface receptors
- Entry by Clathrin-Mediated endocytosis
- Uncoating of virions and nuclear transport
- Transcription of early coding region
- Translation to produce early regulatory proteins, LT-Ag, Smt-Ag and T’ proteins
- Import of LT-Ag into nucleus to initiate viral DNA replication and late gene activation
- Replication of viral genome
- Transcription of viral late genome
- Translation of viral late transcript to produce agnoprotein and Capsids
- Nuclear import of capsid proteins
- Assembly of viral progeny in nucleus
- Release of virions from infected cells
The etiology of reactivation of JCV is related to the presence of immunosuppression, either infective, inflammatory, or medication related. The strongest association of JCV reactivation is HIV-1 infection. It is believed that the tat regulatory protein, which normally stimulates HIV-1 transcription by binding to the TAR hairpin in the hnRNA, can also stimulate the replication of JCV DNA. Experimental evidence suggests that oligodendrocytes, which house latent JCV DNA, strongly imbibe the Tat protein.
Definitive Diagnosis: Biopsy Results (All three must be present)
- Bizarre Astrocytes
- Oligodendrocytes containing nuclear inclusion bodies
PLUS JCV DNA or protein
Probable Diagnosis (Both Required)
- Positive JCV-specific PCR in CSF
- Typical clinical and MRI findings
Possible Diagnosis (Both Required)
- Typical clinical and MRI findings without detection of JCV DNA in CSF
- No better alternative diagnosis
PML can cause nystagmus, diplopia, and homonymous hemianopia and these signs typically will present in conjunction with neurological symptoms discussed below
The neurological symptoms of PML depend on the region of the brain impacted by the virus, causing a wide range of possible symptoms. Among the most common symptoms, cognitive and behavioral changes occur at the highest rate, with nearly a third of all PML patients presenting with such changes. Other common symptoms include motor weakness, gait abnormalities, speech and language disturbances, and ataxia.
Patients with multiple sclerosis on immunomodulating agents are at higher risk of JCV reactivation and PML but also are at risk of having further multiple sclerosis flares. The following table contains some features which may be used to help distinguish an MS flare from PML:
|Flare of RRMS||PML|
|Patient Symptoms (Note these are just suggestive features and not absolute)||Optic Nerve Dysfunction
Pyramidal Tract Dysfunction
|Altered Mental Status
|Location of MRI lesions||Periventricular, pericallosal||Subcortical|
|Individual lesions will grow with time||Less likely||Yes|
|Size||Usually smaller||Usually larger|
|Clinical Course||Full or partial recovery expected||Recovery less likely|
Routine monitoring on immunosuppressive medications: In patients who are immunosuppressed on medications known to cause PML (see list above), routine bloods studies prior to commencing the medication and every 6 months could be performed for JCV DNA. Risk benefit should be considered if the patient is JCV positive as to whether the drug should be continued.
If PML is suspected: High viral load of JCV DNA in the cerebrospinal fluid and supporting clinical or imaging findings in an immunosuppressed patient is typically adequate to make the diagnosis of PML.
If there is uncertainty (most commonly occurs because infectious brain lesions can also cause similar symptoms and atypical MRI appearances), a brain biopsy can be considered. Previous studies have demonstrated the following findings on biopsy:
- Reactive Astrocytosis
- Perivascular lymphocytic cuffing
- Myelin-breakdown products
The imaging study of choice in suspected PML is cranial magnetic resonance imaging (MRI). Typical MRI findings include areas of multifocal demyelination throughout the white matter with a preference for the frontal or parieto-occipital regions. Lesions demonstrate areas of hypointensity on T1 and areas of hyperintensity on T2 and fluid-attenuated inversion recovery (FLAIR).
The treatment for PML is currently supportive and there is no proven specific JCV therapy. For patients with HIV, infectious diseases should be consulted regarding timely administration of combination Antiretroviral Therapy (cART) to help reactivate the immune system. For patients on immunosuppressants, immediate cessation of therapy is generally advised.
The risk of immune reconstitution syndrome should be considered if there is a paradoxical clinical decline after commencing cART or ceasing immunosuppressants. This condition involves hyperactivity of the immune system to the large antigenic burden. This condition is known as PML- Immune Reconstitution Inflammatory Syndrome (PML-IRIS), and should be treated with corticosteroid therapy, due to high morbidity from excess immune reactions.
As of current studies, the diagnosis of PML is associated with a poor prognosis. HIV+ patients who develop PML have a survival rate of 52%, while patients who do not have HIV have a survival rate of 58%. Higher CD4+ counts are associated with higher survival outcomes. While the current standard of care is supportive care, laboratory studies have demonstrated some potential drug treatments that may be beneficial. JCV cell entry inhibitors, retrograde transport inhibitors, and DNA replication inhibitors have all shown some clinical benefit in patients with PML. Further clinical trials are still pending. Early identification where possible and management of the underlying condition are the best options available for lowering patient morbidity and mortality risk from this condition.
- ↑ 1.0 1.1 1.2 1.3 1.4 1.5 1.6 1.7 1.8 Bohra, C., Sokol, L., & Dalia, S. (2017). Progressive Multifocal Leukoencephalopathy and Monoclonal Antibodies: A Review. Cancer control : journal of the Moffitt Cancer Center, 24(4), 1073274817729901. https://doi.org/10.1177/1073274817729901
- ↑ 2.0 2.1 Wein, F., Francis, G.S., Gans, M.S., Connolly, W.E., & Burnier, M.N. (1998). Neuro-Ophthalmic findings in progressive multifocal leukoencephalopathy. Canadian Journal of Ophthalmology, 33(5), 270-5. Referenced from https://www.ncbi.nlm.nih.gov/pubmed/9740956.
- ↑ 3.0 3.1 3.2 3.3 White M.K., Sariyer I.K., & Gordon J. Diagnostic assays for polyomavirus JC and progressive multifocal leukoencephalopathy. (2016). Rev Med Virol, 26(2):102‐114. doi:10.1002/rmv.1866
- ↑ 4.0 4.1 4.2 Kartau M, Verkkoniemi-Ahola A, & Paetau A. (2019). The Incidence and Predisposing Factors of John Cunningham Virus-Induced Progressive Multifocal Leukoencephalopathy in Southern Finland: A Population-Based Study. Open Forum Infect Dis. 6(2). doi:10.1093/ofid/ofz024
- ↑ 5.0 5.1 5.2 5.3 5.4 5.5 Bharat, A., Xie, F., Baddley, J. W., Beukelman, T., Chen, L., Calabrese, L., Delzell, E., Grijalva, C. G., Patkar, N. M., Saag, K., Winthrop, K. L., & Curtis, J. R. (2012). Incidence and risk factors for progressive multifocal leukoencephalopathy among patients with selected rheumatic diseases. Arthritis care & research, 64(4), 612–615. https://doi.org/10.1002/acr.21564
- ↑ 6.0 6.1 6.2 6.3 6.4 6.5 6.6 6.7 White, M.K., & Khalili K. (2011) Pathogenesis of Progressive Multifocal Leukoencephalopathy—Revisited, The Journal of Infectious Diseases. 203( 5): 578–586. Retrieved from: https://doi.org/10.1093/infdis/jiq097
- ↑ Saribas A.S., Ozdemir A., Lam C., & Safak M. (2010) JC Virus-induced Progressive Multifocal Leukoencephalopathy. Future Virol, 5(3):313‐323. doi:10.2217/fvl.10.12
- ↑ 8.0 8.1 8.2 Das AT, Harwig A, Berkhout B. (2011). The HIV-1 Tat protein has a versatile role in activating viral transcription. J Virol. 85(18):9506‐9516. doi:10.1128/JVI.00650-11
- ↑ Tada H, Rappaport J, Lashgari M, Amini S, Wong-Staal F, & Khalili K. (1990). Trans-activation of the JC virus late promoter by the tat protein of type 1 human immunodeficiency virus in glial cells. Proc Natl Acad Sci U S A. 87(9):3479‐3483. doi:10.1073/pnas.87.9.3479
- ↑ 10.0 10.1 10.2 10.3 10.4 Tavazzi E., White M.K., & Khalili K. (2012). Progressive multifocal leukoencephalopathy: clinical and molecular aspects. Rev Med Virol, 22(1):18‐32. doi:10.1002/rmv.710
- ↑ 11.0 11.1 Boster, A., Hreha, S., & Berger, J. (2009). Progressive Multifocal Leukoencephalopathy and Relapse-Remitting Multiple Sclerosis. Arch Neurology, 66(5): 593-599. doi:10.1001/archneurol.2009.31
- ↑ Lee, S. Y., Ko, H. C., Kim, S. I., Lee, Y. S., & Son, B. C. (2019). Progressive Multifocal Leukoencephalopathy Diagnosed by Brain Biopsy, not by the DNA Test for JC Virus. Asian journal of neurosurgery, 14(1), 240–244.
- ↑ Adang, L., & Berger, J. (2015). Progressive Multifocal Leukoencephalopathy. F1000Research, 4, F1000 Faculty Rev-1424.
- ↑ 14.0 14.1 14.2 14.3 14.4 14.5 14.6 14.7 14.8 Pavlovic D, Patera A.C, Nyberg F, Gerber M, & Liu M. (2015). Progressive multifocal leukoencephalopathy: current treatment options and future perspectives. Ther Adv Neurol Disord, 8(6):255‐273. doi:10.1177/1756285615602832
- ↑ 15.0 15.1 Marzocchetti A, Tompkins T., & Clifford D.B. (2009). Determinants of survival in progressive multifocal leukoencephalopathy. Neurology. 73(19):1551‐1558. doi:10.1212/WNL.0b013e3181c0d4a1