Progressive Multifocal Leukoencephalopathy
Progressive Multifocal Leukoencephalopathy
National Organization for Rare Disorders, Inc.
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Progressive multifocal leukoencephalopathy (PML) (1) is a neurological disorder characterized by destruction of cells that produce the myelin, an oily substance that helps protect nerve cells in the brain and spinal cord, also known as central nervous system (CNS) white matter. It is caused by a virus called JC virus (JCV), named after the initials of the patient in whom it was first discovered. The virus is widespread, found in up to 85% of the general adult population. It remains inactive in healthy individuals and causes disease only when the immune system has been severely weakened, such as in people with HIV/AIDS, or hematological malignancies, and in organ transplant recipients who receive immunosuppressant medications to avoid rejection of the transplanted organ. Altogether, PML occurs in approximately one in 200,000 people.
The term "progressive" in PML means that the disease continues to get worse and often leads to serious brain damage. The term "multifocal" means that JCV causes disease in multiple parts of the brain. However, it is possible for an individual with PML to have only one brain lesion instead of several lesions. The term "leukoencephalopathy" means that the disease affects mainly the white matter of the brain or myelin, although there are some rare cases in which the gray matter neurons are also involved.
Symptoms of PML vary from case to case because lesions may occur anywhere in the central nervous system. Most patients present with subacute neurological damage, which may include some degree of mental impairment, and a variety of other symptoms such as vision loss, speech disturbances, facial drooping, weakness, problems with coordination, gait and sensory loss. In addition, approximately 20% of PML patients can present with seizures during the course of their disease.
The disease course of PML used to be considered invariably progressive, with most non-HIV-related cases leading to a fatal outcome within months after the diagnosis. However, it is now known that there are a small number of HIV-positive patients who, having developed PML, will experience disease stabilization and prolonged survival. (2)
CD4+ and CD8+ T lymphocytes are types of immune cells that are of major importance to the health of the immune system. They help to mediate the immune response against many infectious organisms. In a patient with an active HIV infection, the levels of these lymphocytes are greatly decreased. However, antiretroviral medications, which are now a standard part of HIV treatment, have enabled the crucial CD4 and CD8 lymphocytes to rise to within normal levels.
Before the availability of medications used to fight HIV (antiretrovirals), only 10% of HIV-positive patients with PML lived for more than a year. With the advent of highly active antiretroviral therapy (HAART), one-year survival has increased to 50% on average.(3) HAART therapy increases the crucial lymphocyte levels, thus enabling the immune system, under certain circumstances, to fight off the JC virus. However, among these patients, those who are able to mount a strong immune response mediated by T lymphocytes which are directed specifically against JCV have a better outcome. Those patients have a one year survival of 73% compared to 46% for those who do not have T cells capable of recognizing JCV.
Because formation of new white matter by CNS cells (remyelination) does not occur in affected areas, 80% of PML survivors do not experience much regression of their symptoms. They may be left with permanent neurological dysfunction, similar to patients who have suffered a stroke. Nevertheless, PML patients may have extended survival up to 15 years and beyond if the initial cause of immunosuppression is under control, for example in HIV-infected patients treated by HAART or in cancer patients successfully treated with chemotherapy. In these patients, the disease is not active anymore and they have burnt-out PML.
The JC virus usually enters the bloodstream during childhood. It can be found via blood tests in healthy children with no symptoms of PML. Because the virus is also frequently found in the urine of healthy individuals, it is possible that the initial infection may occur through urine-oral contamination.
After primary infection, the virus remains inactive in the kidneys and lymphoid organs. Indeed, JCV can be found in the urine samples of approximately 30% of people, regardless of their immune status.(4) JCV also has been detected in the bone marrow samples, including patients with PML, HIV, leukemia, and bone marrow transplant recipients, but also in bone marrow of some HIV-negative patients without immunosuppression (5). Other studies have suggested that JCV is also latent in the normal digestive system, tonsils and there is growing evidence that JCV can also remain latent in the brain (6).
The exact mechanisms that lead to JCV activation and the development of PML have not been entirely elucidated, but as explained above, most cases occur in the setting of profound cellular immune dysfunction. Studies of the type of blood cells that carries JCV have shown an association with B lymphocytes blood cells that mainly produce antibodies as well as other types of leukocytes including T lymphocytes, monocytes, polymorphonuclear leukocytes, and cell-free plasma(7).
Despite the possible participation of the blood cells in transporting the JC virus throughout the body, the virus is rarely detected in routine blood tests of healthy individuals. While it is believed that PML is usually caused by activation of a dormant JC virus, it may also occur as a new infection in adults who have become severely immune-compromised.
In the advent of the human immunodeficiency virus (HIV) epidemic, PML was soon recognized as a major opportunistic infection of acquired immunodeficiency syndrome (AIDS) occurring in up to 5% of patients (8). Based on a study of 61 cases of PML from 1996 to 2003, it is believed that approximately 80% of PML patients have AIDS, 13% have hematological malignancies, 5% are transplant recipients, and 2% have chronic inflammatory disease (9).
A series of 58 HIV-negative cases diagnosed with PML seen at the Mayo clinic between 1957 and 2005 indicates that 55% have hematological malignancies, 15% have chronic inflammatory diseases, 9% have sarcoidosis, 7% are transplant recipients, 7% have other conditions (cirrhosis, pulmonary fibrosis), and 7% have no detectable predisposing illness except for age between 66 and 80 years.
Among patients with lymphoproliferative disorders, such as chronic lymphocytic leukemia, it has been found that those treated with certain medications that interfere with life cycles of blood cells (i.e. fludarabine) might be at increased risk for developing PML. Studies have shown a 3% incidence of PML in patients receiving these types of medications (10). In addition, rare cases of PML have been diagnosed in HIV-negative patients with other types of drug-induced or idiopathic CD4 and CD8 T cell suppression, as well as in patients with no obvious source of immunosuppression (11).
In February, 2005, two biotechnology companies, Biogen Idec and Elan, voluntarily withdrew a promising new drug for treatment of relapsing/remitting multiple sclerosis and Crohn's disease. The drug is called Tysabri. This drug was taken off the market after the discovery of two people with MS who developed PML after taking Tysabri.(12)
However, after a review of the data by an independent adjudication committee, the "Peripheral and Central Nervous System Drug Advisory Committee of the US Food and Drug Administration", Tysabri was allowed back on the market. It has become available again as of August 2006, for MS patients "who have not responded adequately to, or cannot tolerate, other treatments for MS." It is supplied through a restricted distribution. As of February 2013, there have been than 231 cases of Tysabri-associated PML in MS patients in the world, and the risk of PML in this population is 5/1000 after 24 months. However, if patients are JCV seropositive and have received immunosuppressant medications prior to Tysabri, the risk of PML goes up to 1/90 after 24 months of continuous therapy. (13)
Inflammatory Progressive Multifocal Leukoencephalopathy:
Although antiretroviral medications may help recover from PML, new onset or clinical worsening of PML has been described shortly after initiation of HAART in HIV-infected people. This occurs in the setting of a recovery of the immune system marked by an increase in CD4 +T-cell count and a decrease in HIV plasma viral load, the amount of HIV in human serum. This paradoxical development of PML is usually associated with an inflammatory reaction in brain lesions and it has been called "immune reconstitution inflammatory syndrome" (IRIS)(14). Despite transient worsening, the outcome is usually favorable, and resolution of the inflammatory phase results in clinical improvement, with subsequent imaging studies showing only the classic residual atrophy, loss of brain tissue secondary to previous infection. Nevertheless, fatal cases of PML/IRIS have been described. Magnetic resonance spectroscopy (MRS) allows to study the metabolism of the brain and has proven helpful in diagnosing PML/IRIS (15)
JC Virus Meningitis
One well-documented case of meningitis, or inflammation of the membranes that surround the brain, occurred in an adult patient with long-standing systemic lupus erythematosus (SLE). JCV was the only pathogen found in the cerebrospinal fluid (CSF), a liquid surrounding the brain. No other causes were isolated.
Demyelination of the central nervous system leading to PML is not the only CNS disease caused by the JC virus. Although dysfunction of the cerebellum (a portion of the brain located toward the back of the brain) is frequently found in PML, recent studies have found that problems with coordination, along with cerebellar atrophy, can occur in HIV-infected patients who do not have PML lesions in the cerebellum. Areas of cell loss have been observed in the internal cell layer of the cerebellum. This novel syndrome has been named JCV granule cell neuronopathy (JCV GCN) (16, 17). Recent studies suggest that granule cell neurons within the cerebellum can become infected with a variant of the JC virus(18). Finally, another novel syndrome associated with JCV has been characterized, caused by infection of pyramidal neurons of the cortical gray matter of the brain itself. This was named JCV encephalopathy (JCVE) and it is caused by a different JCV variant(19, 20).
The brain MRI is the first step in diagnosing PML. The brain biopsy is a secondary approach if the MRI is not conclusive. Cerebrospinal fluid, collected via a spinal tap, is also a dependable way to diagnose PML. Due to the expanded population of individuals at risk for PML, early diagnosis has become of critical importance.
There is no specific treatment for JCV. In HIV-positive patients with PML, optimization of HAART is the best therapeutic option, and in HIV-negative patients, removal or decrease of any potential source of immunosuppression is recommended. Because PML has a high mortality rate, numerous drugs have been tried empirically.
Clinical trials related to PML are being conducted at Beth Israel Deaconess Medical Center in Boston. For information, contact:
Igor J. Koralnik, MD
Professor of Neurology
Harvard Medical School/Beth Israel Deaconess Medical Center
330 Brookline Avenue, E/CLS-1005
Boston, MA 02215
Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov. All studies receiving U.S. Government funding, and some supported by private industry, are posted on this government web site.
For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:
Toll free: (800) 411-1222
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For information about clinical trials conducted in Europe, contact:
1.Gheuens S, Wuthrich C, Koralnik IJ. Progressive Multifocal Leukoencephalopathy: Why Gray and White Matter. Annu Rev Pathol 2012;24;8:189-215.
2.Lima MA, Bernal-Cano F, Clifford DB, Gandhi RT, Koralnik IJ. Clinical outcome of long-term survivors of progressive multifocal leukoencephalopathy. J Neurol Neurosurg Psychiatry 2010;81:1288-91.
3.Marzocchetti A, Tompkins T, Clifford DB, Gandhi RT, Kesari S, Berger JR, Simpson DM, Prosperi M, De Luca A, Koralnik IJ. Determinants of survival in progressive multifocal leukoencephalopathy. Neurology 2009; 73:1551-8.
4.Koralnik IJ, Boden D, Mai VX, Lord CI, Letvin NL. JC virus DNA load in patients with and without progressive multifocal leukoencephalopathy. Neurology 1999; 52:253-60.
5.Tan CS, Dezube BJ, Bhargava P, Autissier P, Wuthrich C, Miller J, Koralnik IJ. Detection of JC virus DNA and proteins in the bone marrow of HIV-positive and HIV-negative patients: implications for viral latency and neurotropic transformation. J Infect Dis 2009;199:881-8.
6.Tan CS, Ellis LC, Wuthrich C, Ngo L, Broge TA, Jr., Saint-Aubyn J, Miller JS, Koralnik IJ. JC virus latency in the brain and extraneural organs of patients with and without progressive multifocal leukoencephalopathy. J Virol 2010;84:9200-9.
7.Atwood WJ, Amemiya K, Traub R, Harms J, Major EO. Interaction of the human polyomavirus, JCV, with human B-lymphocytes. Virology 1992;190: 716-23.
8.Berger JR, Kaszovitz B, Post MJ, Dickinson G. Progressive multifocal leukoencephalopathy associated with human immunodeficiency virus infection. A review of the literature with a report of sixteen cases. Ann Intern Med 1987;107:78-87.
9.Koralnik IJ, Schellingerhout D, Frosch MP. Case records of the Massachusetts General Hospital. Weekly clinicopathological exercises. Case 14-2004. A 66-year-old man with progressive neurologic deficits. N Engl J Med 2004;350:1882-93.
10.Garcia-Suarez J, de Miguel D, Krsnik I, Banas H, Arribas I, Burgaleta C. Changes in the natural history of progressive multifocal leukoencephalopathy in HIV-negative lymphoproliferative disorders: impact of novel therapies. Am J Hematol 2005;80:271-81.
11.Gheuens S, Pierone G, Peeters P, Koralnik IJ. Progressive multifocal leukoencephalopathy in individuals with minimal or occult immunosuppression. J Neurol Neurosurg Psychiatry 2010;81: 247-54.
12.Berger JR, Koralnik IJ. Progressive multifocal leukoencephalopathy and natalizumab--unforeseen consequences. N Engl J Med 2005;353:414-6.
13.Bloomgren G, Richman S, Hotermans C, Subramanyam M, Goelz S, Natarajan A, Lee S, Plavina T, Scanlon JV, Sandrock A, Bozic C. Risk of natalizumab-associated progressive multifocal leukoencephalopathy. N Engl J Med 2012;366:1870-80.
14.Tan K, Roda R, Ostrow L, McArthur J, Nath A. PML-IRIS in patients with HIV infection. Clinical manifestations and treatment with steroids. Neurology 2009;28;72(17):1458-64.
15.Gheuens S, Ngo L, Wang X, Alsop DC, Lenkinski RE, Koralnik IJ. Metabolic profile of PML lesions in patients with and without IRIS: An observational study. Neurology 2012;79:1041-8.
16.Du Pasquier RA, Corey S, Margolin DH, Williams K, Pfister LA, De Girolami U, Mac Key JJ, Wuthrich C, Joseph JT, Koralnik IJ. Productive infection of cerebellar granule cell neurons by JC virus in an HIV+ individual. Neurology 2003;61:775-82.
17.Koralnik IJ, Wuthrich C, Dang X, Rottnek M, Gurtman A, Simpson D, Morgello S. JC virus granule cell neuronopathy: A novel clinical syndrome distinct from progressive multifocal leukoencephalopathy. Ann Neurol 2005;57:576-80.
18.Dang X, Vidal JE, Oliveira AC, Simpson DM, Morgello S, Hecht JH, Ngo LH, Koralnik IJ. JC virus granule cell neuronopathy is associated with VP1 C terminus mutants. J Gen Virol 2012;93:175-83.
19.Wuthrich C, Dang X, Westmoreland S, McKay J, Maheshwari A, Anderson MP, Ropper AH, Viscidi RP, Koralnik IJ. Fulminant JC virus encephalopathy with productive infection of cortical pyramidal neurons. Ann Neurol 2009;65:742-8.
20.Dang X, Wuthrich C, Gordon J, Sawa H, Koralnik IJ. JC virus encephalopathy is associated with a novel agnoprotein-deletion JCV variant. PLoS ONE 7(4) 2012;e35793.
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Last Updated: 3/19/2013
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