Progressive multifocal leukoencephalopathy (PML) is a demyelinating disease which results from the reactivation of John Cunningham virus (JC virus) infecting oligodendrocytes in patients with compromised immune systems. It is considered the most common clinical manifestation of John Cunningham virus (JC) virus infection in the brain 7, and is seen in three clinical contexts:
- PML due to immunocompromised state
- PML-s-IRIS: simultaneous development of Immune Reconstitution Inflammatory Syndrome (IRIS) and PML due to immune reconstitution
- PML-d-IRIS: immune reconstitution worsens pre-existing PML
Progressive multifocal leukoencephalopathy is strongly associated with immunosuppressed states, particularly AIDS, but also can occur in patients with bone marrow or solid organ transplants, leukaemia, solid organ malignancies, inflammatory diseases and isolated CD4 lymphocytopenia 4,17. The incidence in the non-HIV settings is thought to be increasing. Primary PML developing in an immunocompetent patient is very rare.
In AIDS, it typically develops in patients with CD4 counts of 50-100 cells/μL and is found in approximately 5% of autopsies of patients who died from AIDS 2.
More recently it has also been associated with natalizumab (TysabriTM), an IgG monoclonal antibody used in the treatment of relapsing-remitting multiple sclerosis 5.
In addition to being seen in immunocompromised patients, it is also seen in patients whose immune function is recovering, and PML is one of the classic conditions encountered in immune reconstitution inflammatory syndrome (IRIS) 16.
Patients with PML present with various neurological symptoms. It typically spares the optic nerve and the spinal cord. The most frequently encountered symptoms include:
- altered mental status
- motor deficits
- limb and gait ataxia
- visual symptoms (diplopia and hemianopia)
- seizure (as PML can also involve the grey matter in late stage)
The final diagnosis is established with brain biopsy (specificity: 100%, sensitivity: 65-95%).
PML lesions are secondary to progressive demyelination due to John Cunningham (JC) virus (usually reactivation) which infects oligodendrocytes. In PML seen in HIV/AIDS, reactivation is typically seen when CD4 cell count drops below 100/μL 17.
Lesions tend to have a confluent, bilateral but asymmetrical supratentorial white matter and thalamic involvement 7. However, basal ganglia, brain stem and cerebellum also can be involved. Subcortical frontal and parietooccipital regions are common locations. However, isolated posterior fossa involvement has also been reported 15. While the condition invariably involves white matter, subcortical U-fibers and in late stages of disease grey matter involvement is also seen 6.
Histology reveals demyelinating plaques involving the white matter and subcortical U-fibers. Other findings include infected oligodendrocytes with enlarged amphophilic nuclei located at the periphery of the lesions, macrophages containing phagocytosed cellular debris and myelin, and reactive gliosis with enlarged astrocytes 13.
Asymmetric focal zones of low attenuation involving the periventricular and subcortical white matter. This is in contradistinction to more symmetrical hypo-attenuations seen in HIV encephalopathy.
Typically seen as multifocal, asymmetric periventricular and subcortical involvement. There is little, or no mass effect or enhancement 10 and the subcortical U-fibers are commonly involved with a predilection for the parietooccipital regions 17. Corpus callosum may be involved 17.
- T1: involved regions are usually hypointense
- T2: involved regions are hyperintense
T1 C+ (Gd)
- typically there is no enhancement 10
- enhancement can be seen in PML-IRIS, AIDS with HAART, and in patients on natalizumab 16,17
- when enhancement is present, it may be associated with improved survival 3,17
- MR spectroscopy: according to one study, spectra of PML lesions were characterised by significantly reduced NAA, lactate presence, and by significantly increased choline and lipids compared with control group values 8
- ADC/DWI: peripheral patchy diffusion restriction particularly at the leading edge 14
- elevated at the leading edge of lesions
- most commonly seen in progressive non-IRIS PML 18
Treatment and prognosis
Prognosis is generally poor with an inexorable neurologic decline leading to coma and death occurring in the majority of patients with PML 9. If untreated, PML is usually fatal within one year, often within 2 to 6 months 17. Treatment with highly active antiretroviral therapy (HAART) may prolong survival, although in some instances this leads to PML-IRIS. High-dose glucocorticoid therapy is recommended for patients with PML-IRIS. Some reports also state some benefit with cytarabine or mirtazapine, the latter especially in natalizumab-associated PML.
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- 6. Mark AS, Atlas SW. Progressive multifocal leukoencephalopathy in patients with AIDS: appearance on MR images. Radiology. 1989;173 (2): 517-20. Radiology (abstract) - Pubmed citation
- 7. Bag AK, Curé JK, Chapman PR et-al. JC virus infection of the brain. AJNR Am J Neuroradiol. 2010;31 (9): 1564-76. doi:10.3174/ajnr.A2035 - Pubmed citation
- 8. Iranzo A, Moreno A, Pujol J et-al. Proton magnetic resonance spectroscopy pattern of progressive multifocal leukoencephalopathy in AIDS. J. Neurol. Neurosurg. Psychiatr. 1999;66 (4): 520-3. doi:10.1136/jnnp.66.4.520 - Free text at pubmed - Pubmed citation
- 9. Post MJ, Yiannoutsos C, Simpson D et-al. Progressive multifocal leukoencephalopathy in AIDS: are there any MR findings useful to patient management and predictive of patient survival? AIDS Clinical Trials Group, 243 Team. AJNR Am J Neuroradiol. 20 (10): 1896-906. AJNR Am J Neuroradiol (full text) - Pubmed citation
- 10. Garrels K, Kucharczyk W, Wortzman G et-al. Progressive multifocal leukoencephalopathy: clinical and MR response to treatment. AJNR Am J Neuroradiol. 1996;17 (3): 597-600. AJNR Am J Neuroradiol (abstract) - Pubmed citation
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- 12. Thurnher MM, Post MJ, Rieger A et-al. Initial and follow-up MR imaging findings in AIDS-related progressive multifocal leukoencephalopathy treated with highly active antiretroviral therapy. AJNR Am J Neuroradiol. 2001;22 (5): 977-84. AJNR Am J Neuroradiol (full text) - Pubmed citation
- 13. Vendrely A, Bienvenu B, Gasnault J et-al. Fulminant inflammatory leukoencephalopathy associated with HAART-induced immune restoration in AIDS-related progressive multifocal leukoencephalopathy. Acta Neuropathol. 2005;109 (4): 449-55. doi:10.1007/s00401-005-0983-y - Pubmed citation
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- 15. Gonçalves FG, Lamb L, Del Carpio-O'Donovan R. Progressive multifocal leukoencephalopathy restricted to the posterior fossa in a patient with systemic lupus erythematosus. Braz J Infect Dis. 2012;15 (6): 609-12. Pubmed citation
- 16. Tan K, Roda R, Ostrow L et-al. PML-IRIS in patients with HIV infection: clinical manifestations and treatment with steroids. Neurology. 2009;72 (17): 1458-64. doi:10.1212/01.wnl.0000343510.08643.74 - Free text at pubmed - Pubmed citation
- 17. Sarbu N, Shih RY, Jones RV et-al. White Matter Diseases with Radiologic-Pathologic Correlation. Radiographics. 2016;36 (5): 1426-47. doi:10.1148/rg.2016160031 - Pubmed citation
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Infections of the central nervous system
- classification by aetiology
- eastern equine encephalitis
- enterovirus rhomboencephalitis
- flavivirus encephalitis
herpes virus family
- herpes simplex virus 1 (HSV-1) encephalitis
- herpes simplex virus 2 (HSV-2) encephalitis
- varicella zoster virus (VZV) encephalitis
- Epstein-Barr virus (EBV) encephalitis
- cytomegalovirus (CMV) encephalitis
- human herpesvirus 6 (HHV-6) encephalitis
- HIV CNS manifestations
- HTLV-1-associated myelopathy
- JC virus
- measles encephalitis
- Nipah virus (NiV) encephalitis
- rabies encephalitis
- CNS listeriosis (Listeria monocytogenes)
- CNS nocardiosis (Nocardia spp)
- CNS tuberculosis (Mycobacterium tuberculosis)
- Lyme disease (Borrelia burgdorferi)
- neurosyphilis (Treponema pallidum)
- Rocky Mountain spotted fever (Rickettsia rickettsii)
- cerebral amoebiasis
- cerebral malaria (Plasmodium falciparum)
- cerebral sparganosis (Spirometra mansonoides)
- neurocysticercosis (Taenia solium)
- neurohydatidosis (Echinococcus spp)
- neurotoxoplasmosis (Toxoplasma gondii)
- others or those with possible infectious aetiologies
- classification by location
- meninges and ventricular system
- brain parenchyma, brainstem, and spinal cord
- classification by aetiology