Brief review of pathogenesis and clinical features of Progressive multifocal leukoencephalopathy, PML.

1. Progressive Multifocal
Leukoencephalopathy
A rare but often fatal disease caused by the reactivation of the JC virus.
Daniel Vela-Duarte, MD
PGY-3. Department of Neurology
Loyola University Medical Center
January, 2014

2. Introduction,
History

First described as a
neuropathological entity in
1958

Suspected viral infection based
on the pathologic appearance
of the inclusion-bearing
oligodendrocytes.

in 1971, a brain from a patient
with PML was cultured. The
virus was isolated, named JC
virus (James Cunningham)

Before the HIV epidemic, it was
a disease mainly seen in
individuals with hematological
malignancies, organ transplant
recipients and chronic
inflammatory disorders.

Suspected viral infection based
on the pathologic appearance
of the inclusion-bearing
oligodendrocytes.

3. Introduction

From 9675 cases of PML, 82% with HIV, 8% with
hematological cancers, 3% with solid organ cancers and
0.44% with rheumatologic diseases.

Inmumodulators

Natalizumab for multiple sclerosis and Crohn’s disease

Rituximab for lupus,

Efalizumab for psoriasis.

4. Prevalence of JC Virus

Using whole JC virions, seroprevalence of 60% was detected
individuals aged 20–29 years in the USA.

By use of a haemagglutination inhibition assay based on viruslike particles containing the JC virus, VP1 major capsid
proteins, Knowles and colleagues, reported a seroprevalence
of up to 50% in individuals aged 60–69 years in England and
Wales.

The use of recombinant VP1 protein and quantitative enzyme
immunoassay could detect IgG antibodies in up to 86% of
healthy individuals in Germany.

5. 
The virus is acquired in
childhood or young adulthood
and becomes latent in
lymphocytes, spleen, kidney,
bone marrow, and other
lymphoid tissue.

It also may establish latency in
the brain. With
immunosuppression, JC virus
replicates in oligodendrocytes;
kills them, causing
demyelination; and
nonproductively infects
astrocytes, causing bizarre
histologic changes.

6. Clinical presentation

Infection of oligodendrocytes and
astrocytes, therefore deficits are
associated with demyelination in
the brain.

Unifocal syndrome of cerebral or
brainstem dysfunction
Generally, subacute presentation


No involvement of the optic nerve
and spinal cord.

7. Clinical manifestations






Motor system involvement causes corticospinal tract
findings
Cortical sensory loss
Ataxic cerebellar deficits
Focal visual field defects
Cortical deficits: Aphasia, visual-spatial disorientation
could occur with subcortical lesions
Patients with more immunopreserved status may have a
slower clinical course, mimicking brain tumors such as
CNS lymphoma or glioma

8. 
Progressive Multifocal
Leukoencephalopathy Patients
at Mayo Clinic: Non-AIDS
PML−Associated Diseases
(n=58)

9. Brain MRI findings

10. 
T2-weighted FLAIR brain MRI
Bifrontal PML lesions including
involvement of the corpus
callosum mimicking glioma or
lymphoma.


T2-weighted FLAIR brain MRI
Left cerebellar and pontine
PML lesion.
T2-weighted FLAIR brain
MRI. Right frontal large PML
lesion with tiny left frontal
lesions.

11. Brain MRI scan of progressive
multifocal leukoencephalopathy
(PML). All are T2-weighted fluidattenuated inversion recovery
images except D, which is a T1
postgadolinium image.


B. Multifocal right-greater-than-left
subcortical frontal PML lesions.

© 2013 American Academy of Neurology
A. Single superficial subcortical left
frontal PML lesion.
C, D. Symmetric bioccipital PML
lesions that show trace
enhancement after gadolinium.

12. A 47-year old HIV infected man with
jerking of his right hand
Teaching NeuroImages
Neurology
Resident and Fellow Section
January 7, 2014 82:e8
© 2013 American Academy of Neurology

13. Case
A 47- year old with longstanding HIV infection
presented with with 3-week history of clumsiness
and shaking of his right hand. Clinical examination
revealed a slow, irregular distal tremor of the right
upper limb present at rest and posture (Video)
Katchanov et al.

14. © 2013 American Academy of Neurology

15. 
The imaging of his brain
revealed a demyelinating lesion
affecting the right middle
cerebellar peduncle and
adjacent cerebellar white matter

The CSF PCR for JC-virus was
strongly positive establishing
the diagnosis of progressive
multifocal leukoencephalopathy
(PML).

Holmes tremor is a rare
manifestation of PML.

16. Diagnostic tests

Detection of JCV DNA in CSF -by PCR amplification- is required for a definite dx of
PML.

The PCR technique is, however, less sensitive in patients with HIV receiving HAART.

When JCV DNA is not detected in the CSF, PML can be confirmed by a stereotactic
brain biopsy

JCV DNA in the biopsy sample by in situ hybridization is required for diagnosis of PML.

Histological features include:

focal areas of demyelination,

enlarged oligodendrocytes containing intranuclear inclusions,

Large 'bizarre-looking' astrocytes,

Llipid-laden macrophages

17. Neuropathology
Gross and microscopic appearance of PML lesions affecting the superficial
subcortical gray-white matter junction in the cerebral hemisphere.

A. Coronal section of fixed
PML brain. The subcortical
white matter is undermined
by multifocal punctate
coalescent demyelinating
lesions (black arrows).

B. Luxol fast blue stain
shows a microscopic
demyelinated lesion
(between opposing black
arrows) in the white matter
immediately subcortical.

18. Management



Goal: restoration of immune function.
Immunosuppressant or immunomodulatory therapy
should be stopped if possible.
Questionable treatment (Poor effectiveness, lack of
trials)


Cytosine arabinoside 2 mg/kg/d for 5 days, single
course
Cidofovir 5 mg/kg once weekly for 2 weeks, then every 2
weeks for 2 months

19. Treatment
options

20. Clinical pearls

What factors confer an increased risk of developing PML
in a patient taking natalizumab?

Positive status with respect to anti-JC virus antibodies

Increased duration of natalizumab treatment

Prior use of immunosuppressants, alone or in combination, were
associated with discrete levels of PML risk in patients with multiple
sclerosis.

The risk of PML increased with increasing duration of treatment, with the
greatest increase in risk occurring after 2 years of therapy (25 to 48
N Engl J Med. 2012 May 17;366(20). Risk of natalizumab-associated progressive multifocal leukoencephalopathy.
months).

21. PML-IRIS.
(Immune reconstitution inflammatory syndrome)

Inflammatory reaction after initiation of cART or after cessation
of immunosuppressive therapy in HIV-negative patients. (nonAIDS PML patients)

This immune reconstitution is inferred by an increase in Tlymphocyte counts

Acute and usually transient clinical worsening not consistent
with the expected course of previously or newly diagnosed
PML.

MRI: Gadolinium-enhancing lesions, edema of previous PML
lesions with possible mass effect

22. Tan, Koralnik, The Lancet Neurology, Volume 9, Issue 4, April 2010, Pages 425-437