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A rational approach to PML for the clinician

November 1, 2011|Cleveland Clinic Journal of Medicine
Leonard Calabrese, DO
Author and Disclosure Information

Leonard Calabrese, DO
Professor of Medicine, Cleveland Clinic Lerner College of Medicine of Case Western Reserve University;R.J. Fasenmyer Chair of Clinical Immunology, Department of Rheumatic and Immunologic Diseases, Orthopaedic & Rheumatologic Institute, Cleveland Clinic, Cleveland, OH

Correspondence: Leonard Calabrese, DO, R.J. Fasenmyer Chair of Clinical Immunology, Department of Rheumatologic and Immunologic Disease, Cleveland Clinic, 9500 Euclid Ave., A50, Cleveland, OH 44195; calabrl@ccf.org

Dr. Calabrese reported consulting relationships with Abbott Laboratories, Amgen Inc., Centocor, Elan Corporation, Genentech, Roche, and Wyeth; and teaching and speaking relationships with Abbott Laboratories, Amgen Inc., Centocor, and Genentech.

This article was developed from an audio transcript of Dr. Calabrese’s presentation at a roundtable convened at Cleveland Clinic on January 31, 2011. The transcript was edited by the Cleveland Clinic Journal of Medicine staff for clarity and conciseness, and was then reviewed, revised, and approved by Dr. Calabrese.

ABSTRACTThe first step in the management of progressive multifocal leukoencephalopathy (PML) is awareness of the disease. Patients vulnerable to PML are those with immunosuppression, either through their disease or use of immune-modulating therapy. In patients susceptible to PML who exhibit focal neurologic signs and symptoms, brain magnetic resonance imaging can detect the telltale PML brain lesions—subcortical white matter hyperintense areas on T2-weighted images and fluid-attenuated inversion recovery sequences and hypointensity on T1-weighted images, typically without enhancement. Demonstration of JC virus DNA by ultrasensitive polymerase chain reaction in cerebrospinal fluid is diagnostic for PML. Immune restoration whenever possible is the cornerstone of treatment. Highly active antiretroviral therapy has dramatically improved the prognosis for patients infected with human immunodeficiency virus. Alternatively, restoration of immunity is frequently attended by the immune reconstitution inflammatory syndrome which can be clinically devastating or even fatal. In the case of natalizumab-associated PML, withdrawal of therapy and prompt institution of plasmapheresis to desaturate target receptors provides the best chance for long-term survival.

DIAGNOSIS AND REFERRAL

A neurology consult is advised when a patient has a predisposing condition for PML or suspicious neurologic signs or symptoms, whether focal or diffuse, and in whom an MRI demonstrates white matter changes.

Evaluation for JC virus DNA

When the neurology consult has been scheduled, and before the actual visit to the neurologist, a cerebrospinal fluid (CSF) sample should be obtained and evaluated for JC virus (JCV) DNA using a highly sensitive polymerase chain reaction (PCR) assay. Lumbar puncture in the setting of possible PML is critical to exclude the presence of other opportunistic infections.

The importance of using ultrasensitive PCR assays for diagnosing PML cannot be overstated, as falsely negative CSF PCR has been observed for JCV DNA despite high levels of JCV DNA in spinal fluid when utilizing less sensitive assays. The most sensitive commercial assays can detect as few as 50 copies of JCV DNA per mL of CSF fluid.

The risk of PML imparted by biologic agents other than natalizumab and nonbiologic immunosuppressive agents has been difficult to quantify, but no immune-modifying drug or combination of drugs appears entirely free of risk. Any patient who has had significant or prolonged immunosuppression should be considered vulnerable, and any patient with suspicion of PML based on unexplained neurologic symptoms warrants CSF examination for JCV DNA.

Brain biopsy

In patients with progressive clinical and MRI findings that suggest PML, but whose CSF PCR for JCV DNA is repeatedly negative, a brain biopsy is appropriate regardless of background immunosuppression. In the patient with rheumatologic disease, for example, suspicion of PML should be heightened if there is neurologic deterioration in the face of escalating antiinflammatory or immunosuppressive therapy for immune-driven inflammatory disease. Diagnostic urgency is particularly warranted in those disorders where the possibility for immune reconstitution is highest (ie, those receiving immunosuppressive regimens).

PML MANAGEMENT DEPENDS ON CLINICAL SETTING

Management of PML starts with risk stratification to identify those patients most prone to developing PML based on their immune status; the presence of autoimmune disease; the subtype of disease (in the case of SLE); and the nature, intensity, and duration of their immunosuppression. If a high-risk patient develops signs and symptoms of PML, the diagnosis should be anticipated and serious consideration given to withholding immunosuppressive therapies while the patient is being worked up.

When PML is diagnosed, whether by demonstration of JCV in CSF or documented by brain biopsy in a patient with a suggestive clinical picture, the appropriate management depends on the clinical setting (Table 2). In the HIV-infected patient who is not receiving antiviral therapy, initiation of HAART is the core of treatment. For natalizumab-treated patients, the standard approach is to discontinue natalizumab, institute plasmapheresis to accelerate clearance of therapeutic levels of natalizumab and increase the number and function of leukocytes entering the CNS, and monitor for immune reconstitution.

Accelerating immune reconstitution

Once a diagnosis of PML is confirmed, immune reconstitution should be accelerated whenever possible. This can include temporary or permanent withdrawal of immunosuppressive therapy and initiation of plasmapheresis. Evidence supports continuing plasma exchange until natalizumab serum drug levels decline to less than 1 μg/mL to achieve desaturation of the alpha-4 integrin receptor.6 Typically, desaturation of the targeted integrin receptor occurs after five plasmapheresis sessions.

Immune reconstitution may also precipitate a syndrome known as the immune reconstitution inflammatory syndrome (IRIS), characterized by enlargement and contrast enhancement of PML lesions, appearance of new brain lesions, and worsening of neurologic deficits. The infiltration of the brain with inflammatory multinucleated cells and lymphocytes following abrupt immune reconstitution requires treatment. Opinion suggests that judicious use of corticosteroids may control the immune response in the brain in patients with PML-IRIS,7,8 although further studies are needed.

Involving the patient in treatment decisions

Because risk tolerance varies considerably among individuals, patients should be informed of the risks of PML on the basis of their disease and the agents used to treat it. They should also be given information about the effects of individual treatments on the course of their disease, and they should be encouraged to participate in the selection of therapy.

SUMMARY

The approach to PML in the biologic era starts with an increased awareness of the disease followed by recognition of vulnerable populations and factors that contribute to the development of PML, such as biologic and nonbiologic immunosuppressive therapy. Optimal management includes a low threshold for investigating neurologic signs and symptoms and new-onset signs and symptoms in vulnerable populations, the use of MRI to detect typical PML brain lesions and other atypical brain features (ie, cerebellar atrophy), lumbar puncture and spinal CSF analysis to detect JCV DNA, and timely neurologic consultation for further evaluation. Much still needs to be learned about PML and the risks imparted by background diseases and individual drugs used in rheumatologic, neurologic, and oncologic disease.

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