Progressive Multifocal Leukoencephalopathy (PML) is a demyelinating disease of the central nervous system caused by the JC polyomavirus that occurs almost exclusively in immunosuppressed individuals. It presents with focal neurological deficits and MRI shows multifocal white matter lesions. There is no effective treatment, but starting antiretroviral therapy for HIV-infected patients can improve outcomes.

1. Progressive Multifocal Leuko
Encephalopathy:
Dr.Roopchand PS
Senior Resident Academic
Dept. of Neurology
Monday, August 18, 2014

2. Introduction:
• Demyelinating disease of the CNS
• Due to infection of oligodendrocytes by a
human papovavirus.
• Occurs almost exclusively in
immunosuppressed individuals.
– AIDS, hematological and lymphoreticular
malignancies, autoimmune rheumatological
diseases, or those undergoing organ
transplantation.

3. • HIV infection accounts for almost 85% of the
total cases.
• Prevalance in HIV infected : 4-5%
• One of the AIDS defining illness in HIV infected
patients.
• Occurs usually when CD4 count <200
microliter.
• Can also occur when immunity improves with
HAART.

4. Pathophysiology:
• Caused by reactivation of the endemic JC
papovavirus.
• About 90% of healthy individuals have serum
antibodies to this virus.
• Enter the body via the respiratory or oral
route.
• Becomes latent in the kidneys,
lymphoreticular tissues, tonsil.

5. • Asymptomatic viremia can occur.
• Virus may be shed in urine.
• Infection sets in when cell mediated immunity
is impaired.
• Viral particles are shown to be carried to the
CNS via B-lymphocytes in the setting of
systemic dissemination.
• HIV gene products, such as Tat, may be able to
transactivate the JC viral promoter directly.

6. • Infects the oligodentrocytes and cause
demyelination.
• Abortive infection of astrocytes can occur.
– take bizarre appearance
• Granule neuron cells of cerebellum can get
infected.
• Infects other cells from a central nidus in a
circumferential manner.

7. Epidemiology:
• The incidence of PML is low in India and
Africa, possibly due to diagnostic challenges
and differences in JC virus isolates.
• Third most common cause of encephalopathy
in HIV-infected patients. (Italian NeuroAIDS
study 2000-2002).

8. Prognosis:
• Approximately 95% of patients died within 4-6
months after diagnosis in the pre HAART era.
• 8% spontaneously recovered.
• With HAART more than 60% survive for about
2 years.
• CD4+ T-cell counts less than 100/μL at baseline
are associated with a higher mortality rate.

9. Clinical Presentation:
• Insidious onset and steady progression of
focal symptoms.
– behavioral, speech, cognitive, motor and visual
impairment.
• PML evolves over several weeks.
• More rapid progression than ADC.
• Occipital sub cortical white matter
involvement can result in cortical blindness.

10. • Brain stem involvement is more in PML
associated with AIDS.
• Seizure is seen in 18%.
• PML associated with immune reconstitution
may be seen weeks to months after HAART.
• Gait abnormalities in 65% and cognitive
impairment in up to 30% of patients at
presentation.

11. • Conjugate gaze abnormalities are common –
up to 30%.
• Aphasia, hemiparesis, ataxia, cortical
blindness, limb apraxia, brainstem symptoms
and, less frequently, head tremor are seen.
• May progress to quadriparesis and coma.

12. Neuroimaging:
• CT:
– Asymmetric focal zones of low attenuation
involving the peri-ventricular and sub-cortical
white matter.
– more symmetrical hypo-attenuation seen in HIV
encephalopathy.

13. MRI:
• Multifocal, asymmetric peri-ventricular and sub-cortical
involvement.
• There is little or no mass effect .
• The U-fibers are commonly involved.
• T1 - involved regions are usually hypo-intense
• T2 - involved regions are hyper-intense
• T1 C+ (Gd) - typically there is no enhancement(however if
present it may be associated with improved survival)
• MR spectroscopy - according to one study spectra of PML
lesions were characterised by significantly reduced NAA,
lactate presence, and by significantly increased Cho and
lipids compared with control group values

16. • Can resemble lymphoma, toxoplasmosis, or
HIV encephalitis.
• The absence of a mass effect or displacement
of normal structures is more consistent with
PML than these other disorders.
• Deep grey matter is usually spared in PML.
• Rarely PML can present with mass effect.

17. Lumbar Puncture:
• Routine CSF studies may be normal.
• JC virus CSF culture is negative.
• CSF PCR for DNA particles highly specific (92-
99%) and sensitive (74-93%).
• Brain biopsy : sensitivity of 74-92% and a
specificity of 92-100%.
• Oligodendrocytes at the gray-white junction
are the most common sites of infection.

18. sliced fixed brain shows multiple isolated or confluent gray demyelinative foci.

19. Microscopically, multiple demyelinative foci are detected. The microscopic
hallmark of the disease is intranuclear basophilic or eosinophilic inclusions
within the swollen nuclei of oligodendrocytes, often at the periphery of
lesions. Large, occasionally multinucleated astrocytes with prominent
processes are another characteristic feature.

20. Management:
• All treatments are experimental in PML.
• Two recommendations are:
– Starting antiretroviral therapy immediately in
patients with PML who are not on therapy.
– Optimizing the antiretroviral regimen for virologic
suppression in patients who are receiving
antiretroviral therapy but who remain HIV-viremic
because of antiretroviral resistance.

21. • The use of drugs that block the serotonergic
5HT2a receptor.
– olanzapine,ziprasidone, mirtazapine,
cyproheptadine, risperidone .
• Mefloquine : noted to reduce viral replication.
• Intensive treatment with 4 classes of
antiretroviral drugs, including enfuvirtide has
shown to improve survival.

22. • Cytosine arabinoside at 2 mg/kg/day for 5
days showed 30% response rate in one study
with patients (non-AIDS–related PML ).
• In AIDS related PML – not useful.
• PREVENTION:
– the only effective way to prevent disease is to
prevent progression of HIV-related
immunosuppression with ART.

23. Monitoring:
• Quantitation of CSF JCV DNA may prove useful
as an index to follow for assessing treatment
response.
• Clinically stable/improving:
– Rpt MRI @ 6 to 8 wks after ART initiation.
– screen for radiographic signs of progression or of
immune response.
• If pt worsens before that, a repeat MRI is
indicated earlier.

24. PML-Immune Reconstitution
Inflammatory Syndrome:
• Reported to occur within the first weeks to
months after initiating ART.
• Clinically and radiographically different from
classical PML.
– lesions with contrast enhancement, edema and mass
effect, and a more rapid clinical course.
• 3- to 5 day course of IV methylprednisolone
dosed at 1 g per day, followed by an oral
prednisone taper, dosed according to clinical
response.

25. • Carefully monitor the clinical status.
• Contrast-enhanced MRI at 2 to 6 weeks may
be helpful in documenting resolution of
inflammation and edema and to obtain a new
baseline.

26. Treatment failure:
• Continued clinical worsening and continued
detection of CSF JCV without substantial
decrease within 3 months.
• Failing ART regimens should be changed based
on standard guidelines for use of ART.
• PML continues to worsen despite suppressive
anti-HIV treatment
– Above mentioned unproven therapies can be
used.