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A rational approach to PML for the clinician

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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.


 

References

Our remarkable progress in understanding progressive multifocal leukoencephalopathy (PML) since its discovery more than 50 years ago has evolved in three stages, concurrent with the changing epidemiology of PML: the pre–human immunodeficiency virus (HIV) era; the HIV era, with highly active antiretroviral therapy (HAART) bringing further change; and the biologic therapy era.

Before the appearance of HIV, PML developed mostly in patients who had lymphoma, other malignancies, and rare forms of immunosuppression. The development of HIV changed the nature of PML, with more than 75% of cases now reported in HIV-infected patients. Within the HIV population, the epidemiology and prognosis of PML have undergone additional changes since the late 1990s. The introduction of HAART transformed PML from an almost uniformly fatal and inexorably progressive disease to one in which long-term survival is expected, particularly in the setting of robust immune reconstitution.1

The third and most recent stage in the evolution of PML and our understanding of it has coincided with the introduction and use of increasingly potent immunosuppressive regimens and novel biologic immunologic therapies that target various aspects of the integrated immune response. These agents are being applied not only in the field of autoimmune and autoinflammatory disease but also in transplantation and oncology.

Collectively, vulnerable populations (ie, patients with lymphoreticular malignancies and autoinflammatory diseases) are now being subjected to therapies that singly or in combination have unknown effects on the immune system. As a byproduct, practitioners who were only vaguely aware of PML in the past now must consider PML in their differential diagnosis, develop a rational plan for evaluating such patients, and recognize when referral to a specialist is indicated. Recent descriptions of atypical forms of PML2,3 add to the challenge for clinicians, as do reports of cases of PML in patients with minimal immunosuppression, in the absence of immunosuppressive therapy, and in patients who appear to have “normal” immune systems but in fact have diseases such as sarcoidosis.4 Rare cases are also being reported in patients with advanced liver disease.4

This article offers recommendations for enhanced awareness of PML, suggestions for improved evaluation of predisposed patients, and a summary of currently accepted treatment strategies.

WHEN TO SUSPECT PML

Consideration of PML in the differential diagnosis is based on the patient’s vulnerability and the signs and symptoms of the disease. In an otherwise immunologically healthy individual, PML rarely accounts for focal neurologic deficits. Clinicians should therefore focus their suspicions on individuals who are predisposed to PML (Table 1). Predisposed individuals are not always obvious; for example, HIV-positive individuals who have not been diagnosed with HIV infection may present with PML as the heralding manifestation of their disease.

Patients being treated with immunosuppressive biologic agents represent a significant group that is predisposed to PML. At one time, focal neurologic deficits were required to consider the possibility of PML, but cognitive/behavioral abnormalities rather than focal neurologic findings are often the presenting sign in individuals treated with immune-modulating biologic agents. This phenomenon is most strikingly observed in recipients of natalizumab. Any central nervous system (CNS) dysfunction in a patient taking an immunosuppressive biologic agent should arouse suspicion for PML.

Peripheral neuropathy is not caused by PML but can coexist with it. Accordingly, in patients with rheumatologic disease who are receiving immune modifiers, neuromuscular symptoms in the absence of brain abnormalities on magnetic resonance imaging (MRI) argue against consideration of PML but do not rule it out—especially in patients with connective tissue diseases.

Systemic lupus erythematosus (SLE) represents a special challenge for several reasons. First, SLE appears to be a predisposing factor among other connective tissue diseases.5 In addition, SLE is associated with a variety of CNS complications, including a spectrum of focal and diffuse signs and symptoms that can mimic PML and lead to underdiagnosis.

Underrecognition is a risk in the HIV population as well, where cognitive impairment is common. Irrespective of immune or virologic status, 57% of HIV patients demonstrate impairment on neuropsychiatric testing. Often, mild to moderate cognitive impairment in HIV is attributed to HIV encephalopathy with no further workup, resulting in a missed or late diagnosis of PML.

IMAGING CONSIDERATIONS

In the rheumatologic disease population, especially those with SLE, and the HIV population, neuroimaging is indicated in any patient who presents with cognitive impairment. Typical radiographic characteristics of PML on MRI are subcortical white matter hyperintense areas on T2-weighted images and fluid-attenuated inversion recovery. T1-weighted images will reveal hypointense lesions that usually do not enhance, but may do so in fewer than 10% of patients with PML. Typically, no mass effect is seen.

In addition to rare faint gadolinium enhancement of lesions, other lesion characteristics may depart from the classic picture—for example, white matter and gray matter involvement, and monofocal instead of multifocal lesions. In HIV-positive patients, MRI can demonstrate diffuse cerebellar atrophy and subtle white matter abnormalities within the cerebellum.

Unfortunately, nonspecific white matter lesions occur in HIV infection as well as connective tissue diseases, compromising diagnostic specificity of a single imaging study. Nevertheless, progression of clinical signs and symptoms and progressive MRI changes should prompt a more vigorous diagnostic evaluation for PML. Alternatively, a normal MRI in a patient in whom PML is suspected has strong negative predictive value. In either situation, baseline neuroimaging is not recommended.

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