Wednesday, April 12, 2023

Progressive Multifocal Leuko Encephalopathy:

Dr.Roopchand PSSenior Resident Academic

Dept. of Neurology

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.

• 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.

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.

• 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.

• 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.

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).

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.

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.

• 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.

• 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.

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.

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

• 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.

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.

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

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.

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.

• 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.

• 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.

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.

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.

• 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.

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.

THANK YOU