Progressive Multifocal Leukoencephalopathy

July 31, 2007

Margo Smith, M.D.Department of Medicine

Washington Hospital Center

Case 5

• A 43 y o man with AIDS presents with a 4 week history of ataxia, progressive R hand weakness, and tremor. On exam he is ataxic and weak on the R when compared to his L side. He is afebrile, CD4 of 56/mm3 and a serum toxoplasma antibody was negative on his first visit to you and he does take TMP-SMX. You order a MRI and it shows a 2x4-cm lesion in the L cerebellar hemisphere on the T2-weighted images. There is no enhancement with gadolinium and no mass effect noted

Case 5

• The most likely diagnosis is?– A. Toxoplasmosis– B. Primary CNS lymphoma– C. Progressive multifocal

leukoencephalopathy (PML)– D. Pyogenic brain abscess

Case 5

• The most likely diagnosis is?– A. Toxoplasmosis– B. Primary CNS lymphoma– C. Progressive multifocal

leukoencephalopathy (PML)– D. Pyogenic brain abscess

Progressive Multifocal Leukoencephalopathy

• Basics– JC virus, papovavirus (DNA)– 1958 first report– Cytolytic to oligodendrocytes – 5-HT2

receptor– Demylinating disease of brain– Optic nerve and spinal cord oligodendrocytes

not affected

Progressive Multifocal Leukoencephalopathy

– Asymmetric involvement • Brainstem – more common in AIDS• cerebellum• cerebral – 10:1 non-AIDS

– Progresses to death rapidly

PML

• Basics– Immunocompromised

• AIDS• Leukemia

– Symptoms• Cognitive, personality, motor weakness• Seizures

PML• Epidemiology

– BK and SV40 related– ? Upper respiratory acquisition– Antibody prevalence increases with age– Latent virus reticuloendothelial system– No proof of CNS latency– 2 strains

• Kidney• Brain

PML • HIV/AIDS

– 2-5%

– Viral DNA in ~ 55% peripheral lymphocytes

– AIDS defining illness

– CD4 < 100

– Dx• MRI – nonenhancing, no shift• CSF-PCR ~ 80% sensitive 90% specific

PML

HIV/AIDS– Treatment

• Highly active antiviral therapy• small studies• ~ 50% respond• ~ 50% progress• Immune reconstitution – BAD NEWS

PML• PML without HIV

– T-cell immunodeficincy • Lymphoproliferative disorders• Chronic granulomatous diseases• Solid organ transplantation• Monoclonal antibody Rx

– MS/Crohn’s Rx natalizumab 1:1000

• Hematologic malignancy prevalence ~ 0.07%

– M:F = 3:2– Pk age 60s

PML• Survival

– AIDS weeks – months– Non-AIDS months – one year

• Treatment Non-AIDS– Case reports

• Interleukin-2• Cytarabine• Cidofovir• 5-HT2 serotonin antagonizer – anti-depressant

– Mitazapine = Remeron™

Dilemma

Can one predict who is at risk to develop PML?

Progressive Multifocal Leukoencephalopathy

• No pre-morbid serologic testing available

• No pre-morbid CNS screen available

• No pre-morbid imaging available

• Not clear if there is an at risk subgroup– ~1/3 of healthy urine + JCV-DNA – Urine +JCV-DNA found more frequently

immune suppressed– +JCV DNA mononuclear cells poor predictor

Progressive Multifocal Leukoencephalopathy

• More questions and no clear answers– Does prior immune suppression increase risk?– If so, does the length of time increase risk?– Is there a role in monitoring antigen specific CD-8

cells?– Is a risk of 1:1000 reasonable?