Infectious Diseases

JC polyomaviruses: Progressive Multifocal Leukoencephalopathy (Clinical Condition)

OVERVIEW: What every practitioner needs to know

Are you sure your patient has disease PML? What should you expect to find?

  • Neurological symptoms are usually subacute, including dysarthria, paralysis, sensory deficits, cognitive dysfunction, and coordination problems. Up to 18% of PML patients can also present with seizures.

  • PML is a disease mainly of the brain and rarely of the spinal cord. Therefore, physical findings are restricted to the nervous system. PML can affect myelinated regions of the brain, including both cortical and subcortical regions. Patients generally present with new onset subacute neurological abnormalities, including, but not limited to, aphasia, gait abnormalities, parethesias, and paralysis. Abnormalities can be detected by neurological exam.

  • Radiographic images of the brain show multiple areas of demyelination that are usually non-enhancing (see Figure 1).

Figure 1

MRI image of the brain of a PML patient displaying white matter demyelination.

How did the patient develop PML? What was the primary source from which the infection spread?

  • PML is due to the reactivation of JC virus, a human polyomavirus, which causes a lytic infection of the oligodendrocytes in the brain. The asymptomatic JC virus primary infection occurs most likely as a result of urine-oral transmission in childhood. In the healthy adult population, JC virus serology prevalence rises with age and can reach as high as 86%. JC virus can be latent in kidneys, bone marrow, and lymphoid organs of healthy individuals, and viral shedding can be detected in the urine of one-third asymptomatic healthy individuals.

  • Reactivation of JC virus occurs with immunosuppression. A recent study of United States inpatient diagnoses codes showed 82% of PML patients were HIV positive, 8.4% had a hematologic cancer, 2.8% had a solid organ cancer, and 0.44% had a rheumatologic disease.

Which individuals are at greater risk of developing the disease PML?

  • A thorough history needs explored to include risks of acquiring HIV, including sexual practices and needle sharing habits. If the patient is at a high risk for acquiring HIV, then an HIV antibody test should be obtained, and, if positive, a CD4 cell count is important.

    • For patients with hematological cancers or a history of treatment with chemotherapy, CD4 cell counts should be obtained.

    • For patients with autoimmune diseases, such as rheumatoid arthritis, history should include immunosuppressive treatments used.

    • For patients with multiple sclerosis or Crohn's disease, it would be important to know if the patient was treated with the monoclonal antibody, natalizumab.

    • For patients without obvious immunosuppression, the history should focus on undiagnosed cancers, immunodeficiencies, and chronic infections, such as hepatitis C.

  • Immunosuppression is due to:

    • HIV

    • Hematologic cancer

    • Solid organ cancer

    • Rheumatologic disease

    • Treatment with monoclonal antibodies (particularly those targeting α-integrins)

    • Primary immune deficiency

    • Organ and bone marrow transplantation

Beware: there are other diseases that can mimic disease PML:

  • For patients with HIV, HIV encephalopathy and primary central nervous system (CNS) lymphoma mimic PML.

  • For patients without HIV, stroke and brain tumor mimic PML.

What laboratory studies should you order and what should you expect to find?

Results consistent with the diagnosis

  • CSF: PCR detection of JC virus

  • CSF: mild pleocytosis

  • CSF: normal glucose

  • Peripheral white blood cell (WBC) with differential in the normal to low range

  • Lymphocyte differentiation: CD4 and CD8 absolute counts and percentages showing lower or aberrant T-cell subsets

Results that confirm the diagnosis

  • Brain biopsy showing demyelination and immunnohistochemical staining positive for JC virus protein or in situ hybridization positive for JC virus DNA is the gold standard for diagnosis of PML.

  • Cerebrospinal fluid (CSF) with positive polymerase chain reaction (PCR) detection of JC virus along with clinical features and consistent radiographic images can also confirm PML.

Histological appearance of JC virus infected brain

  • JCV infection of oligodendrocytes results in total destruction of these cells.

  • Demyelinating lesions

  • Presence of astrocytes with ingested debris; these cells are enlarged and have bizarre features.

What imaging studies will be helpful in making or excluding the diagnosis of PML?

  • MRI with gadolinium $$$$

  • CT scan with contrast $$$

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What consult service or services would be helpful for making the diagnosis and assisting with treatment?

If you decide the patient has PML, what therapies should you initiate?

  • Infectious Diseases and Neurology would be helpful for making the diagnosis and assisting with treatment.

  • There are no available antiviral therapies for PML. Several medications with initial encouraging results in a small number of patients all fail to show survival benefit when tested in randomized control studies. Often, these were retrospective studies with limited numbers of patients.

  • In HIV-positive PML patients, we recommend immune reconstitution with combined antiretroviral therapy. The improvement in the resulting cellular immune response can often control JC virus replication and halt the progression of PML. One-year survival of HIV-positive patients with PML is 50%. However, immune reconstitution inflammatory syndrome (IRIS) is a risk in PML treatment.

  • In HIV-negative patients, it is often difficult to effect immune reconstitution. If possible, such as in transplant recipients, a reduction of immunosuppression can rejuvenate the adaptive immune system and control JC virus replication. However, a decrease in immunosuppression can also lead to increased risk of graft versus host disease.

  • In patients with multiple sclerosis or Crohn's disease receiving natalizumab treatment, plasma exchange can be considered to remove natalizumab. However, the patient needs closely monitored for any signs of IRIS after the exchange. If this occurs, they may then need treated with corticosteroids to dampen the destructive inflammation.

  • Future treatments of PML may involve use of immunotherapies, such as dendritic cell vaccines currently being researched.

PML IRIS

  • The rapid restoration of immune response can result in over exuberant inflammatory reactions resulting in severe destructive changes that can be fatal. PML IRIS is seen in up to 23% of HIV positive patients. The rate of PML IRIS in HIV-negative patients has yet to be determined.

  • In HIV-positive patients, PML IRIS is usually associated with the start of treatment for HIV. The onset of IRIS can be anywhere from 1 week to several months after the start of HIV treatment. Patients present with worsening or new onset of neurological symptoms. PML IRIS lesions can be associated with brain edema with risk of herniation.

  • MRI with gadolinium show enhancement in or near the previous PML demyelinated regions. CSF JC virus PCR can be undetectable because of cellular control of JC virus replication. Histologically, an influx of CD8+ cells can be seen near the PML lesions.

  • Treatment with corticosteroid is controversial. Although steroids are absolutely needed to stop impending herniation, the use may alter HIV replication in HIV-positive patients and perhaps alter efficacy of primary disease treatment in HIV-negative patients who have cancer or autoimmune disease. Developing PML IRIS does not improve PML associated survival.

Treatments tested with minimal efficacy

  • Cidofovir is an antiviral that benefited HIV-positive PML patients in initial observational studies. However, a combined analysis of one prospective study with small number of patients, along with five cohort studies that did not show survival benefits or decrease in disability in HIV-positive patients on treatment for HIV.

  • Cytarabine is a chemotherapy agent that showed good results in HIV-negative PML patients but failed to show significant benefits when tested in a randomized controlled study in HIV-positive PML patients. Furthermore, when used intrathecally, cytarabine was also not beneficial in HIV-negative PML patients.

  • Mirtazapine is a serotonin receptor blocker that has been used by clinicians after the demonstration of JC virus entry into cell cultures via the serotonin receptor 5-HT2a. There are published case reports of beneficial results. True efficacy remains to be determined.

  • Mefloquine is an antimalaria medication that blocked JC virus replication in cell culture. This drug was studied in a multi-center international prospective trial and did not show efficacy.

2. Other key therapeutic modalities.

  • Because PML is a demyelinating disease, the affected area will dictate symptoms. Supportive care is usually required, depending on the types of disability. The restoration of the immune system can result in an over reactive inflammatory syndrome termed IRIS. Corticosteroids may be necessary to dampen this response.

  • Since JC virus-specific cellular immune response can control viral replication and is associated with improved PML prognosis, therapy to try to restore the cellular immune response is important in the treatment of PML.

What complications could arise as a consequence of PML?

What should you tell the family about the patient's prognosis?

  • One-third of PML patients recover and have no significant disabilities, but the remaining patients may be left with a wide range of disabilities including paralysis and dysarthria.

  • Patients may die from PML.

  • For HIV-positive patients, the 1-year survival rate is 50%. Starting combined antiretroviral therapy increases the chances of survival. Furthermore, having a detectable cellular immune response to JC virus within 3 months of the diagnosis of PML can increase the 1-year survival to 73%. However, the neurological abnormalities present at diagnosis can be life-long.

  • For HIV-negative patients, the prognosis is worse, and the 1-year survival rate is less than 50%. If immune reconstitution occurs with either chemotherapy or a decrease in immunosuppressive medications, then the chances for survival are better.

Add what-if scenarios here:

  • What if the CSF PCR is negative for JC virus?

    • Even with a negative CSF PCR for JC virus, patients with typical clinical signs and symptoms and radiographic images can be given a diagnosis of "possible PML" when all other causes have been ruled out.

    • A negative CSF PCR for JC virus is often seen in patients presenting with PML-associated IRIS. The inflammatory reaction results in an influx of lymphocytes into the infected region and destruction of JC virus.

  • What if the patient's symptoms worsen after starting combined antiretroviral therapy for HIV?

    • Development of immune response inflammatory syndrome (IRIS) is one of the risks encountered when starting combined antiretroviral therapy in HIV-positive patients with PML. One study showed that up to 23% of HIV-positive PML patients with recent treatment with combined antiretroviral therapy developed IRIS.

    • A repeat MRI of the brain with gadolinium showed enhancement in the existing PML lesions in 44% of the cases studied (see Figure 2).

    • There is no survival difference between PML and PML IRIS patients.

  • What if, after a thorough work-up, there is no obvious source of immunosuppression?

    • Although rare, there were 38 published cases of PML in patients with no apparent immunosuppression. A portion of these patients were eventually diagnosed with idiopathic lymphopenia. Therefore, PML can still be considered in patients without overt immunosuppression at the onset.

Figure 2

Classic PML at diagnosis presenting with multiple demyelinating lesions (left upper) that are non enhancing (left lower), as compared to the same patient with PML IRIS after initiation of HIV treatment, who presented with increased area of demyelination (right upper) and some area with enhancement with Galdolinium (right lower).

How do you contract PML and how frequent is this disease?

  • The prevalence of PML in the general population has been calculated as 4.4 cases per 100,000 individuals.

  • The prevalence of JC virus infection in the general adult population, by measuring JC virus antibody, increases with age and ranges from 39% in the 24-30 years of age group to 65% in the 65-74 years of age group.

  • The incidence of PML in HIV/AIDS patients can be up to 5%.

  • There is no seasonal variation.

PML is caused by reactivation of JC virus. JC virus is a ubiquitous DNA virus that infects up to 86% of the general population via the urine-oral route. Primary infection is asymptomatic, and the virus remains latent in the kidney, bone marrow, tonsillar lymphoid tissue, and brain. Most individuals remain asymptomatic. JC virus can reactivate and is shed in the urine without causing any renal problems. However, JC virus reactivation and replication in the brain occurs in immunosuppressed individuals and results in PML.

  • Humoral immune response to JC virus has been extensively studied because of the worldwide spread of this virus.

  • Hemagglutination assays using JC virons performed in the 1970's documented seropositivity in 60% of individuals 20-29 years of age in the United States.

  • Hemagglutination assays using virus-like particles containing JC virus capsid protein, VP1, showed seropositivity in 50% of individuals 60-69 years of age in the United Kingdom and Wales.

  • More recently, enzyme immunoassays have detected seropositivity of 39% in individuals 24-30 years of age in the United States, 72% in pregnant women 26-31 years of age in Finland, and 68% in blood donors 50-59 years of age in Switzerland.

What pathogens are responsible for this disease?

  • PML is caused by the reactivation of JC virus in the brain.

How does JC virus cause PML?

  • JC virus is a small ubiquitous human DNA polyomavirus that causes asymptomatic primary infection in up to 86% of the general population.

  • Seroprevalence of JC virus increases with age worldwide.

  • JC virus is spread via the urine-oral route.

  • JC virus remains latent in the kidney epithelium cells, in bone marrow hematopoietic cells, in tonsillar lymphocytes, and in the brain.

  • Although JC virus antibodies are detectable in most individuals, these antibodies cannot control JC virus reactivation and replication. Furthermore, the loss of the cellular immune control in an immunosuppressed individual can reactivate JC virus in the brain and result in PML. The importance of the cellular immune response in controlling JC virus is further illustrated by studies showing that PML patients with detectable JC virus specific cellular immune response around the time of PML diagnosis have a better chance of survival.

What other clinical manifestations may help me to diagnose and manage PML?

  • Chronicity of symptom onset (although PML generally presents with subacute neurological abnormalities, PML IRIS can present acutely.)

  • Risk of acquiring HIV and hepatitis C

  • Family history of immune deficiency

  • A thorough neurological exam is essential.

What other additional laboratory findings may be ordered?

  • Assessment of JC virus-specific cellular immune response may help in providing prognosis. This is currently only available in research laboratories.

How can PML be prevented?

  • There are no prophylactic drugs or vaccines for prevention of PML. Treating HIV when appropriate helps reduce the loss of T-cells and decreases the risk of developing PML. For multiple sclerosis patients on natalizumab, ongoing studies try to determine the utility of CSF monitoring of JC virus by PCR.

WHAT'S THE EVIDENCE for specific management and treatment recommendations?

DRG CODES and expected length of stay

  • Length of stay varies depending on the neurological disabilities. Some patients also need inpatient rehabilitation.

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