Progressive multifocal leukoencephalopathy (PML)
Scott Newsome, D.O., Jeffrey Rumbaugh, M.D., and Anita Venkataramana, M.B., B.S.
- Incidence/prevalence of PML in Africa uncertain; cases only rarely reported.
- Possible biologic reasons to explain rarity of Dx in Africa: different interactions between JC virus and HIV clades B and C or presence of nonvirulent strains of JC virus.
- Dx in Zambia difficult without CSF PCR studies or brain imaging (CT or MRI); largely a Dx of exclusion made after failure of treatment for CNS toxoplasmosis ± CNS TB.
- Prognosis poor but HAART warranted.
Zambia Information Author: David Riedel, M.D.
- Caused by JC virus, a double-stranded DNA polyomavirus. JC virus infection leads to destruction of oligodendrocytes in susceptible individuals.
- JC virus present in >70% of human population and is typically asymptomatic, although it can reactivate and cause PML in immunosuppressed host.
- Virus resides in extraneural reservoirs such as lymphoid tissue, kidney, and bone marrow.
- Primarily affects white matter of brain, but can involve deep gray matter structures and rarely spinal cord.
- Demyelinating disease of CNS. Areas of demyelination are monofocal or multifocal and can occur in any region of brain. Posterior regions of brain and posterior fossa structures (i.e. brainstem and cerebellum) commonly involved. Myelopathy rare.
- Affects pts with immunosuppression due to HIV and other causes. Most pts have advanced AIDS, though can sometimes present with higher CD4 counts. Was associated with poor prognosis before HAART.
- Presenting Sx: subacute onset of focal neurological deficits (classic triad of hemiparesis, visual field deficit, and cognitive dysfunction)
- Other Sx: gait disorders, brainstem signs, sensory and language disturbances. Focal seizures in 10%.
- Higher mortality with CD4 <100.
- Favorable prognostic features: younger age, presenting manifestation of AIDS, CD4 >300, low JC virus DNA load at baseline, contrast-enhancement on MRI, ART-naive, neurologic improvement on ART.
- Though ART is treatment of choice, PML may progress or appear after initiating ART due to IRIS.
- Even with ART, mortality still approximately 50% within first year of Sx onset.
- MRI with and without contrast: subcortical white matter hyperintense areas on T-2 weighted images and fluid attenuated inversion recovery (FLAIR) sequences. T-1 weighted images reveal hypointense lesions that typically do not enhance but can do so in 5-10% of cases. Mass effect and edema can rarely be seen in setting of PML-IRIS.
- Enhancing MRI lesions may occur on ART in context of IRIS.
HIV dementia can be differentiated from PML by its symmetrical appearance and involvement of periventricular and deep white matter areas. Also, U fiber involvement commonly seen in PML and not HIV dementia.
- CSF valuable to exclude other OIs and to obtain CSF JC virus PCR: moderate sensitivity, high specificity. Higher CSF levels of JC virus associated with poorer prognosis.
- Brain Bx: multifocal demyelination, hyperchromatic and enlarged oligodendrocytes; and enlarged bizarre astrocytes. EM: JC virus in oligodendrocytes.
- Most effective therapy is ART, which prolongs survival and decreases neurologic deficits when effective immune reconstitution achieved.
- MRI lesions may get worse after beginning ART because of IRIS. For severe cases of PML-IRIS, steroids have been used with varying success. Further studies needed to specifically evaluate potential role of steroids in PML-IRIS.
- Interferon (IFN) alpha studied in an open-label trial, with delayed progression and slightly prolonged survival; some pts showed marked improvement. MRI showed lesion regression in 4 pts, but did not correlate with clinical remission.
- Topotecan at dose of 0.3 gm/m2/d to maximum dose of 0.6 mg/m2/day showed decreased lesion size and prolonged survival, but small study size. Most frequent side effects were hematologic (anemia, thrombocytopenia, and neutropenia).
- Cytosine arabinoside (ARA-C) administered IV or intrathecally did not affect overall prognosis or neurologic status.
- Cidofovir not effective in treatment of PML; can cause nephrotoxicity and ocular hypotonia.
- 5HT2A receptor antagonists (chlorpromazine, clozapine, mirtazapine) decrease replication of JC virus in vitro; no adequate clinical studies available. Other medications studied include atypical antipsychotics (ziprasidone, olanzapine, risperidone).
- In vitro screening suggests that the antimalarial drug, mefloquine, could be an effective therapy for PML by an unknown mechanism. A randomized, rater-blinded human study is underway to determine mefloquine's usefulness in PML.
|ART ||Most effective therapy for PML when virologic suppression achieved.
||Not effective for treatment of PML.
|Cytosine arabinoside ||Not effective for treatment of PML.
|| Not recommended for treatment of PML.
|| Not recommended for treatment of PML.
|Atypical Antipsychotics ||Preclinical data available. Clinical studies needed.
|5HT2A receptor antagonist (mirtazapine) ||May be beneficial in treating PML; however, clinical studies needed.
|Mefloquine ||May be beneficial in treating PML. Multicenter trial ongoing to assess its effect.
- Reassess MRI 1 mo after beginning therapy to look for improvement or progression.
- Monitor virological serology (i.e. CD4 count and VL) while on ART to assess for immune reconstitution.