Progressive Multifocal Leukoencephalopathy

I. What every physician needs to know.

Progressive Multifocal Leukoencephalopathy (PML) is an opportunistic infection of the central nervous system that causes demylenation of the nerves through destruction of oligodendrocytes by the JC virus (JCV). JCV is a double-stranded DNA polyomavirus acquired by asymptomatic infection in childhood. After initial infection, the virus remains latent within the kidneys, lymphreticular tissues, and the brain. Because of its pathology, PML is considered a reactivation infection. The virus is present worldwide, and 50-80% of adults remain seropositive for JC antibodies.

II. Diagnostic Confirmation: Are you sure your patient has Progressive Multifocal Leukoencephalopathy?

A. History Part I: Pattern Recognition:

As the name suggests, the signs and symptoms of PML are often multifocal and nonspecific. Patients with PML often present with progressive neurological deficits over a period of days to weeks. The differential diagnosis of PML should be considered in any immunocompromised patient presenting with impairment of consciousness, dysphagia, apraxia, gait disturbance, aphasia, visual deficits, and/or motor deficits. The most common presenting symptom is limb weakness in 52% of cases. Disorders of speech and/or visual deficits comprise 30% of complaints, limb incoordination comprise 20% of complaints, and 10% of patients present with sensory symptoms.

B. History Part 2: Prevalence:

Nearly 85% of PML cases occur in patients with HIV/AIDS, with 5-10% of all HIV infected patients developing PML. Patients with HIV-negative status and lymphoid malignancies, including Hodgkin’s Disease, non-Hodgkin’s lymphoma, and B chronic lymphatic leukemia represent 4.5% of cases. Organ transplantation and immunosuppression as seen in systemic lupus erythematosus, sarcoidosis, and rheumatoid arthritis, are rarely associated with development of PML.

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Literature reveals that patients with multiple sclerosis and Crohn’s disease treated for more than one year with the monoclonal antibody natalizumab have a risk of developing PML at the rate of 1.35 cases per 1000. In addition, belimumab, rituximab, and mycophenolate mofetil have been linked to cases of PML. The most common immunosuppressive drugs associated with development of PML include corticosteroids (40%) and chemotherapy (16%). In 2014, Calabrese et al. published a risk classification of immunosuppressive therapies commonly used in the treatment of rheumatologic diseases Table I

High Risk Low Risk Very Low Risk
Natalizumab: 1/10,000-1/100 Rituximab: 8 reports of PML with off-label use Anti-TNF therapies: 3 cases in ~3 million patients
Efalizumab: 1/166 in patients treated for >3 years Cyclophosphamide: 2 reports/18,000
Azathioprine: multiple cases
Mycophenolate mofetil: multiple cases
Methotrexate: multiple cases

C. History Part 3: Competing diagnoses that can mimic Progressive Multifocal Leukoencephalopathy.

Because of the multifocal and nonspecific symptoms of PML, the differential diagnosis remains broad. Neurologic symptoms may be consistent with stroke, bacterial or viral meningitis, neoplasm including gliomatosis or lymphoma, or Creutzfeldt-Jakob disease. One must also consider HIV-related opportunistic infections including HSV or VZV, crypotcoccus, cytomagalovirus, neurosyphilis, toxoplasma abscess, tuberculosis meningitis, or HIV dementia. Because of the relationship to those with rheumatologic disease, cerebral vasculitis should also be considered.

In PML, patients are often afebrile and alert without meningeal signs or headache, which makes the presence of bacterial meningitis, HSV, VZV, and tuberculosis less likely. Onset of PML symptoms may progress over days to weeks making stroke lower in the differential. If myoclonus or rigidity is present, these signs may be more consistent with Creutzfeldt-Jakob disease.

D. Physical Examination Findings.

A complete history and physical examination should include the timeline of symptoms and the presence of HIV disease, treatment for rheumatoid disorders, malignancies, or transplant history. Clinicians should pay special attention to cranial nerve deficits, visual field defects, weakness, or presence of gait abnormalities.

E. What diagnostic tests should be performed?

1. What laboratory studies (if any) should be ordered to help establish the diagnosis? How should the results be interpreted?

A CD4+ count should be obtained in patients with HIV, as the presence of PML is more likely when CD4+ count is less than 100 cells per µL. Lumbar puncture should be obtained for cerebral spinal fluid sample. Analysis of CSF often reveals only mild pleocytosis (<20 cells per µL), slightly elevated protein (<100 mg/dL), and normal glucose levels. Studies suggest that CSF PCR for JCV has a sensitivity of 95% and specificity of 90-99%.

2. What imaging studies (if any) should be ordered to help establish the diagnosis? How should the results be interpreted?

Stereotactic brain biopsy is the only way to make a definitive diagnosis of PML. As this is often an unavailable resource, magnetic resonance imaging (MRI) can be used in conjunction with physical and laboratory findings to make the diagnosis of PML. An MRI enhanced with gadolinium is more sensitive than computed tomography (CT) when diagnosing PML. Imaging with MRI may reveal solitary or multiple focal lesions, nonenhancing areas of focal low density without mass effect or surrounding edema, or multiple regions of high T2 and an absence of T1 signal intensity. Lesion borders are ill-defined and irregularly shaped, confined to white matter tracts, and spare the cortex.

F. Over-utilized or “wasted” diagnostic tests associated with this diagnosis.

Because up to 80% of adults are seropositive for JC virus antibodies, serum testing for antibodies is of low yield.

III. Default Management.

A. Immediate management.

There is no current treatment for JCV infection. Management of PML should begin with improving immune function and providing supportive care for symptoms. Treatment of HIV infected patients includes initiation of antiretroviral therapy (ART) to boost immune function. For patients currently treated with ART, regimens should be changed to promote improved viral suppression. For HIV- negative patients, exogenous immunosupression should be discontinued if possible. In HIV-negative patients with malignancy, chemotherapy may provide some relief of symptoms. Patients treated with monoclonal antibody therapy may undergo plasma exchange to rapidly reduce levels of natalizumab in the blood.

B. Physical Examination Tips to Guide Management.

The clinician should monitor for changes in neurologic status as initiation of ART therapy may lead to a temporary worsening of disease secondary to immune reconstitution inflammatory syndrome (see pitfalls below).

C. Laboratory Tests to Monitor Response To, and Adjustments in, Management.

Success of therapy should be monitored through use of HIV viral loads and CD4+ counts in the HIV positive patient. World Health Organization 2010 guidelines suggest following viral load every 6 months to assess response to ART therapy. A CD4+ count of 200 cells per µL and an initial PC virus load in CSF of less than 100 copies/µL have been shown to be associated with prolonged survival. In HIV-negative patients, one may see improvement in neurological function indicating response to treatment. µ

D. Long-term management.

Prognosis in PML is poor. Long term management will include monitoring response to ART therapy and providing supportive care consisting of assistance with activities of daily living, safety from further neurological harm or brain injury, nutrition support, and possible increased supervision secondary to cognitive decline.

E. Common Pitfalls and Side-Effects of Management.

PML symptoms may worsen despite improved immune function secondary to Immune Reconstitution Inflammatory Syndrome (PML-IRIS). PML-IRIS is a large inflammatory response secondary to infiltration of macrophages and CD8+ lymphocytes into PML lesions after immune function improves with ART initiation. PML-IRIS is observed in as many as 18% of HIV patients treated with ART therapy. This syndrome can develop anywhere from 1 week to 26 months after initiation of ART therapy. Some cases may be mild and resolve spontaneously, while others can lead to significant morbidity. Inflammation can be severe, causing mass effects and even brain herniation.

Patients more prone to developing PML-IRIS include those who are ART naive, have CD4+ counts less than 50 cells per µL, have a rapid increase in immune response as indicated by a decrease in HIV viral load after initiation of ART therapy, or have additional active opportunistic infections at onset of ART therapy. This condition may be seen as an inflammatory response on MRI with presence of gadolinium enhancing lesions.

There are no evidence-based guidelines of the prevention or treatment of PML-IRIS. Anecdotal evidence suggests that use of corticosteroids for severe inflammation may be beneficial. Although corticosteroids have been used in the treatment of severe inflammation, trials are lacking.

IV. Management with Co-Morbidities.

A. Renal Insufficiency.

Patients with renal insufficiency should have baseline creatinine clearance checked before initiation of ART therapy, especially when starting zidovudine (AZT) and tenofovir disproxil fumarate (TDF). Concomitant use of nephrotoxic drugs should be avoided. TDF doses can be altered to current creatinine clearance. CrCl >50 ml/min= 300 mg once daily. CrCl 30-49 ml/min = 300 mg once every 48 hours. CrCl 10-29 ml/min or hemodialysis= 300 mg once every 72-96 hours.

B. Liver Insufficiency.

Serologies for hepatitis B virus (HBV) and hepatitis C virus (HCV), as well as liver function tests should be recorded before onset of ART. ART therapy with nevirapine (NVP), and darunavir (DRV) can elevate hepatic enzymes. In addition, ART should be used with caution when combined with rifabutin for patients requiring treatment for tuberculosis (TB) or Mycobacterium avium complex (MAC) prophylaxis, as these combinations can also cause elevation of hepatic enzymes. ART regimens should be selected for concomitant activity against HBV.

C. Systolic and Diastolic Heart Failure.

No change in standard management.

D. Coronary Artery Disease or Peripheral Vascular Disease.

Patients with known coronary artery disease should have a baseline fasting lipid panel prior to ART initiation with DRV and ritonavir (RTV), as these drugs can elevate lipid levels.

E. Diabetes or other Endocrine issues.

Careful monitoring of glucose levels should be continued in patients with diabetes, as DRV and RTV can cause hyperglycemia.

F. Malignancy.

No change in standard management.

G. Immunosuppression (HIV, chronic steroids, etc).

No change in standard management.

H. Primary Lung Disease (COPD, Asthma, ILD).

No change in standard management.

I. Gastrointestinal or Nutrition Issues.

No change in standard management.

J. Hematologic or Coagulation Issues.

Patients with baseline anemia should be monitored when treating with AZT or rifabutin in patients receiving treatment for TB or MAC prophylaxis, as these drugs can cause neutropenia and leukopenia.

K. Dementia or Psychiatric Illness/Treatment.

No change in standard management.

V. Transitions of Care.

A. Sign-out considerations While Hospitalized.


B. Anticipated Length of Stay.

Length of stay in patients with PML varies depending on time to diagnosis, underlying comorbidities, previous diagnosis of HIV, and neurological status. If the patient has stable neurological status and ART therapy can be initiated, patients may be discharged home after diagnosis. If patients have underlying disease that needs treatment, such as tuberculosis or leukemia, discharge may be delayed until appropriate treatment is arranged. For patients who have significant neurological decline, discharge may be delayed until additional support or hospice is available.

C. When is the Patient Ready for Discharge.

The patient with PML is ready for discharge when vital signs remain stable, a safe environment has been established at home, and education has been provided to the patient and caregivers.

D. Arranging for Clinic Follow-up.

1. When should clinic follow up be arranged and with whom?

In the HIV positive patient, follow up appointment with an infectious disease clinic should be obtained within 1 week. This timeline is ideal to initiate or to continue monitoring of ART therapy. In the patient with rheumatologic disease, an appointment with a rheumatologist should be obtained within one week. Treatment of leukemia or other hematologic malignancies should be discussed with an oncologist.

2. What tests should be conducted prior to discharge to enable best clinic first visit?

If possible, baseline CD4+ counts, HIV viral load, hepatitis serologies, CBC, fasting lipid panel, and creatinine clearance should be obtained in patients with HIV undergoing initiation of ART therapy.

3. What tests should be ordered as an outpatient prior to, or on the day of, the clinic visit?


E. Placement Considerations.

Patients with significant neurological decline or functional disability may need placement in a skilled nursing facility, nursing home, or hospice. For patients who are HIV positive, PPD may be placed on admission to assess for presence of tuberculosis. An alternative to conventional skin testing is the QuantiFERON®-TB Gold Test (QFT-G). QFT-G testing is indicated for diagnosing active or latent infection with tuberculosis. When using the QFT-G for diagnosis, patient history and physical findings should be considered when interpreting test results. Physical and occupational therapy consults are essential for evaluation of functional ability and support needs. This should be done within 24 hours of admission for PML.

F. Prognosis and Patient Counseling.

In HIV-negative patients, death usually occurs within 3-6 months from onset of neurological symptoms. In HIV-positive patients treated with appropriate ART therapy, survival at one year remains low at 50%. Discussion regarding advanced directives, patient’s wishes, and supportive services should be initiated. If starting ART therapy, the patient and family must be educated on a strict medication regimen and given information regarding drugs and side effects.

VI. Patient Safety and Quality Measures.

A. Core Indicator Standards and Documentation.

The World Health Organization recommends that all asymptomatic HIV patients be started on ART when CD4+ count is 350 cells per µL or less. Those patients with severe or advanced clinical disease should begin ART regardless of CD4+ count.

B. Appropriate Prophylaxis and Other Measures to Prevent Readmission.

Fall precautions should be initiated in patients with gait disturbance, weakness, and visual loss. The Centers for Disease Control and Prevention recommend yearly influenza vaccination, as well as scheduled vaccinations for pneumococcus, hepatitis B, tetanus, diphtheria, and pertussis for all patients with HIV.

VII. What's the evidence?

Cei, M, Mumoli, N, Ferrito, G, Scazzeri, F. “Progressive multifocal leukoencephalopathy”. Southern Medical Journal. vol. 103. 2010. pp. 1074-1075.

Aksamit, AJ. “Progressive multifocal leukoencephalopathy”. Current Treatment Options in Neurology. vol. 10. 2008. pp. 178-185.

Weissert, R. “Progressive multifocal leukoencephalopathy”. Journal of Neuroimmunology. vol. 30. 2008. pp. 90-98.

Weber, T. “Progressive multifocal leukoencephalopathy”. Neurologic Clinics. vol. 26. 2008. pp. 833-853.

“Antiretroviral therapy for HIV infection in adults and adolescents”. Recommendations for a public health approach. 2010.

Ciricillo, SF, Rosenblum, ML. “Use of CT and MR imaging to distinguish intracranial lesions and to define the need for biopsy in AIDS patients”. J Neurosurg. vol. 73. 1990. pp. 720-724.

Moret, H, Guichard, M, Matheron, S, Katlama. “Virological diagnosis of progressive multifocal leukoencephalopathy: Detection of JC virus DNA in cerebrospinal fluid and brain tissue of AIDS patients”. Journal of Clinical Microbiology. vol. 31. 1993. pp. 3310-3313.

Tan, K, Roda, R, Ostrow, L. “PML-IRIS in patients with HIV infection: Clinical manifestations and treatment with steroids”. Neurology. vol. 72. 2009. pp. 1459-1464.

Warnatz, K, Peter, HH, Schumacher, M, Wiese, L, Prasse, A, Petschner, F. “Infectious CNS disease as a differential diagnosis in systemic rheumatic diseases: three case reports and a review of the literature”. Ann Rheum Dis. vol. 62. 2003. pp. 50-57.

Antinori, A, Ammassari, A, DeLuca, A. “Diagnosis of AIDS-related focal brain lesions: A decision-making analysis based on clinical and neuroradiologic characteristics combined with polymerase chain reaction assays in CSF”. Neurology. vol. 48. 1997. pp. 687-694.

Calabrese, LH, Molloy, E, Berger, J. “Sorting out the risks in progressive multifocal leukoencephalopathy”. Nat Rev Rheumatol. vol. 11. 2015. pp. 119-123.

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