Progressive multifocal leukoencephalopathy
Encyclopedia
Progressive multifocal leukoencephalopathy (PML), also known as progressive multifocal leukoencephalitis, is a rare and usually fatal viral
disease that is characterized by progressive damage (-pathy) or inflammation
of the white matter
(leuko-) of the brain
(-encephalo-) at multiple locations (multifocal).
It occurs almost exclusively in people with severe immune deficiency, such as transplant patients on immunosuppressive medications, patients receiving certain kinds of chemotherapy, patients receiving natalizumab
(Tysabri) for multiple sclerosis, psoriasis patients on long-term efalizumab
(Raptiva) or AIDS
patients.
It is caused by a virus, the JC virus
, which is normally present and kept under control by the immune system. Immunosuppressive drugs prevent the immune system from controlling the virus.
called the JC virus
(JCV), after the initials of the patient from whose tissue the virus was first successfully cultured. Recent publications indicate 39% to 58% of the general population are seropositive for antibodies to JCV, indicating current or previous infection with virus. The virus can cause persistent asymptomatic infection in approximately one third of the adult population, based on viral shedding into the urine from the site of asymptomatic infection in the kidney. The virus causes disease only when the immune system has been severely weakened.
Prior to the advent of effective antiretroviral therapy, as many as 5 percent of people with AIDS eventually developed PML. It is unclear why PML occurs more frequently in AIDS than in other immunosuppressive conditions; some research suggests that the effects of HIV on brain tissue, or on JCV itself, make JCV more likely to become active in the brain and increase its damaging inflammatory effects.
, belatacept
, rituximab
, natalizumab
, infliximab
chemotherapy
, corticosteroids, and various transplant drugs such as tacrolimus
.
, in which the myelin
sheath covering the axon
s of nerve cells is gradually destroyed, impairing the transmission of nerve impulses. It affects the sub-cortical white matter, particularly that of the parietal and occipital lobes. PML destroys oligodendrocyte
s and produces intranuclear inclusions. PML is similar to another demyelinating disease, multiple sclerosis
, but progresses much more quickly.
.
in cerebrospinal fluid
or in a brain biopsy
specimen. Characteristic evidence of the damage caused by PML in the brain can also be detected on MRI
images which classically show multifocal non-enhancing lesions without mass effect. The most common area of involvement is the cortical white matter, but the brainstem and cerebellum may also be involved.
improves; some AIDS patients with PML have been able to survive for several years, with the advent of highly active antiretroviral therapy
(HAART).
AIDS patients who start HAART after being diagnosed with PML tend to have a slightly longer survival time than patients who were already on HAART and then develop PML. A rare complication of effective HAART is immune reconstitution inflammatory syndrome
(IRIS), in which increased immune system activity actually increases the damage caused by the infection; although IRIS is often manageable with other types of drugs, it is extremely dangerous if it occurs in PML.
Other antiviral agents that have been studied as possible treatments for PML include cidofovir
and interleukin-2, but this research is still preliminary.
Cytarabine (also known as ARA-C), a chemotherapy drug used to treat certain cancers, has been prescribed on an experimental basis for a small number of non-AIDS PML patients. It is reported to have stabilized the neurological condition of a minority of these patients. One patient regained some cognitive function lost as a result of PML.
In June 2010, the first case report appeared of a PML patient being successfully treated with mefloquine
. Mefloquine is an antimalarial drug that can also act against the JC virus. Administration of mefloquine seemed to eliminate the virus from the patient's body and prevented further neurological deterioration.
Virus
A virus is a small infectious agent that can replicate only inside the living cells of organisms. Viruses infect all types of organisms, from animals and plants to bacteria and archaea...
disease that is characterized by progressive damage (-pathy) or inflammation
Inflammation
Inflammation is part of the complex biological response of vascular tissues to harmful stimuli, such as pathogens, damaged cells, or irritants. Inflammation is a protective attempt by the organism to remove the injurious stimuli and to initiate the healing process...
of the white matter
White matter
White matter is one of the two components of the central nervous system and consists mostly of myelinated axons. White matter tissue of the freshly cut brain appears pinkish white to the naked eye because myelin is composed largely of lipid tissue veined with capillaries. Its white color is due to...
(leuko-) of the brain
Human brain
The human brain has the same general structure as the brains of other mammals, but is over three times larger than the brain of a typical mammal with an equivalent body size. Estimates for the number of neurons in the human brain range from 80 to 120 billion...
(-encephalo-) at multiple locations (multifocal).
It occurs almost exclusively in people with severe immune deficiency, such as transplant patients on immunosuppressive medications, patients receiving certain kinds of chemotherapy, patients receiving natalizumab
Natalizumab
Natalizumab is a humanized monoclonal antibody against the cellular adhesion molecule α4-integrin. Natalizumab is used in the treatment of multiple sclerosis and Crohn's disease. It is co-marketed by Biogen Idec and Élan as Tysabri, and was previously named Antegren. Natalizumab is administered by...
(Tysabri) for multiple sclerosis, psoriasis patients on long-term efalizumab
Efalizumab
Efalizumab is a formerly available medication designed to treat autoimmune diseases, origianally marketed to treat psoriasis. As implied by the suffix -zumab, it is a recombinant humanized monoclonal antibody administered once weekly by subcutaneous injection...
(Raptiva) or AIDS
AIDS
Acquired immune deficiency syndrome or acquired immunodeficiency syndrome is a disease of the human immune system caused by the human immunodeficiency virus...
patients.
It is caused by a virus, the JC virus
JC virus
The JC virus or John Cunningham virus is a type of human polyomavirus and is genetically similar to BK virus and SV40. It was discovered in 1971 and named using the two initials of a patient with progressive multifocal leukoencephalopathy...
, which is normally present and kept under control by the immune system. Immunosuppressive drugs prevent the immune system from controlling the virus.
Cause
The cause of PML is a type of polyomavirusPolyomavirus
Polyomavirus is the sole genus of viruses within the family Polyomaviridæ. Murine polyomavirus was the first polyomavirus discovered by Ludwik Gross in 1953. Subsequently, many polyomaviruses have been found to infect birds and mammals...
called the JC virus
JC virus
The JC virus or John Cunningham virus is a type of human polyomavirus and is genetically similar to BK virus and SV40. It was discovered in 1971 and named using the two initials of a patient with progressive multifocal leukoencephalopathy...
(JCV), after the initials of the patient from whose tissue the virus was first successfully cultured. Recent publications indicate 39% to 58% of the general population are seropositive for antibodies to JCV, indicating current or previous infection with virus. The virus can cause persistent asymptomatic infection in approximately one third of the adult population, based on viral shedding into the urine from the site of asymptomatic infection in the kidney. The virus causes disease only when the immune system has been severely weakened.
Prior to the advent of effective antiretroviral therapy, as many as 5 percent of people with AIDS eventually developed PML. It is unclear why PML occurs more frequently in AIDS than in other immunosuppressive conditions; some research suggests that the effects of HIV on brain tissue, or on JCV itself, make JCV more likely to become active in the brain and increase its damaging inflammatory effects.
Contributing causes
There are case reports of PML being caused by pharmacological agents, although there is some speculation this could be due in part to the existing impaired immune response or 'drug combination therapies' rather than individual drugs. These include efalizumabEfalizumab
Efalizumab is a formerly available medication designed to treat autoimmune diseases, origianally marketed to treat psoriasis. As implied by the suffix -zumab, it is a recombinant humanized monoclonal antibody administered once weekly by subcutaneous injection...
, belatacept
Belatacept
Belatacept is a fusion protein composed of the Fc fragment of a human IgG1 immunoglobulin linked to the extracellular domain of CTLA-4, which is a molecule crucial for T-cell costimulation, selectively blocking the process of T-cell activation...
, rituximab
Rituximab
Rituximab, sold under the trade names Rituxan and MabThera, is a chimeric monoclonal antibody against the protein CD20, which is primarily found on the surface of B cells...
, natalizumab
Natalizumab
Natalizumab is a humanized monoclonal antibody against the cellular adhesion molecule α4-integrin. Natalizumab is used in the treatment of multiple sclerosis and Crohn's disease. It is co-marketed by Biogen Idec and Élan as Tysabri, and was previously named Antegren. Natalizumab is administered by...
, infliximab
Infliximab
Infliximab is a monoclonal antibody against tumour necrosis factor alpha . It is used to treat autoimmune diseases. Remicade is marketed by Janssen Biotech, Inc...
chemotherapy
Chemotherapy
Chemotherapy is the treatment of cancer with an antineoplastic drug or with a combination of such drugs into a standardized treatment regimen....
, corticosteroids, and various transplant drugs such as tacrolimus
Tacrolimus
Tacrolimus is an immunosuppressive drug that is mainly used after allogeneic organ transplant to reduce the activity of the patient's immune system and so lower the risk of organ rejection...
.
Disease process/Pathogenesis
PML is a demyelinating diseaseDemyelinating disease
A demyelinating disease is any disease of the nervous system in which the myelin sheath of neurons is damaged. This impairs the conduction of signals in the affected nerves, causing impairment in sensation, movement, cognition, or other functions depending on which nerves are involved.The term...
, in which the myelin
Myelin
Myelin is a dielectric material that forms a layer, the myelin sheath, usually around only the axon of a neuron. It is essential for the proper functioning of the nervous system. Myelin is an outgrowth of a type of glial cell. The production of the myelin sheath is called myelination...
sheath covering the axon
Axon
An axon is a long, slender projection of a nerve cell, or neuron, that conducts electrical impulses away from the neuron's cell body or soma....
s of nerve cells is gradually destroyed, impairing the transmission of nerve impulses. It affects the sub-cortical white matter, particularly that of the parietal and occipital lobes. PML destroys oligodendrocyte
Oligodendrocyte
Oligodendrocytes , or oligodendroglia , are a type of brain cell. They are a variety of neuroglia. Their main function is the insulation of axons in the central nervous system of some vertebrates...
s and produces intranuclear inclusions. PML is similar to another demyelinating disease, multiple sclerosis
Multiple sclerosis
Multiple sclerosis is an inflammatory disease in which the fatty myelin sheaths around the axons of the brain and spinal cord are damaged, leading to demyelination and scarring as well as a broad spectrum of signs and symptoms...
, but progresses much more quickly.
Symptoms
Symptoms include weakness or paralysis, vision loss, impaired speech, and cognitive deterioration. In addition, the lesions affecting the parietal and occipital lobes can lead to a phenomenon known as Alien hand syndromeAlien hand syndrome
Alien hand syndrome is a neurological disorder in which the afflicted person's hand appears to take on a mind of its own...
.
Diagnosis
PML is diagnosed by testing for JC virus DNADNA
Deoxyribonucleic acid is a nucleic acid that contains the genetic instructions used in the development and functioning of all known living organisms . The DNA segments that carry this genetic information are called genes, but other DNA sequences have structural purposes, or are involved in...
in cerebrospinal fluid
Cerebrospinal fluid
Cerebrospinal fluid , Liquor cerebrospinalis, is a clear, colorless, bodily fluid, that occupies the subarachnoid space and the ventricular system around and inside the brain and spinal cord...
or in a brain biopsy
Biopsy
A biopsy is a medical test involving sampling of cells or tissues for examination. It is the medical removal of tissue from a living subject to determine the presence or extent of a disease. The tissue is generally examined under a microscope by a pathologist, and can also be analyzed chemically...
specimen. Characteristic evidence of the damage caused by PML in the brain can also be detected on MRI
Magnetic resonance imaging
Magnetic resonance imaging , nuclear magnetic resonance imaging , or magnetic resonance tomography is a medical imaging technique used in radiology to visualize detailed internal structures...
images which classically show multifocal non-enhancing lesions without mass effect. The most common area of involvement is the cortical white matter, but the brainstem and cerebellum may also be involved.
Treatment
There is no known cure. In some cases, the disease slows or stops if the patient's immune systemImmune system
An immune system is a system of biological structures and processes within an organism that protects against disease by identifying and killing pathogens and tumor cells. It detects a wide variety of agents, from viruses to parasitic worms, and needs to distinguish them from the organism's own...
improves; some AIDS patients with PML have been able to survive for several years, with the advent of highly active antiretroviral therapy
Antiretroviral drug
Antiretroviral drugs are medications for the treatment of infection by retroviruses, primarily HIV. When several such drugs, typically three or four, are taken in combination, the approach is known as Highly Active Antiretroviral Therapy, or HAART...
(HAART).
AIDS patients who start HAART after being diagnosed with PML tend to have a slightly longer survival time than patients who were already on HAART and then develop PML. A rare complication of effective HAART is immune reconstitution inflammatory syndrome
Immune reconstitution inflammatory syndrome
Immune reconstitution inflammatory syndrome is a condition seen in some cases of AIDS or immunosuppression, in which the immune system begins to recover, but then responds to a previously acquired opportunistic infection with an overwhelming inflammatory response that paradoxically makes the...
(IRIS), in which increased immune system activity actually increases the damage caused by the infection; although IRIS is often manageable with other types of drugs, it is extremely dangerous if it occurs in PML.
Other antiviral agents that have been studied as possible treatments for PML include cidofovir
Cidofovir
Cidofovir is an injectable antiviral medication for the treatment of cytomegalovirus retinitis in patients with AIDS. It suppresses CMV replication by selective inhibition of viral DNA polymerase and therefore prevention of viral replication and transcription...
and interleukin-2, but this research is still preliminary.
Cytarabine (also known as ARA-C), a chemotherapy drug used to treat certain cancers, has been prescribed on an experimental basis for a small number of non-AIDS PML patients. It is reported to have stabilized the neurological condition of a minority of these patients. One patient regained some cognitive function lost as a result of PML.
In June 2010, the first case report appeared of a PML patient being successfully treated with mefloquine
Mefloquine
Mefloquine hydrochloride is an orally administered medication used in the prevention and treatment of malaria. Mefloquine was developed in the 1970s at the United States Department of Defense's Walter Reed Army Institute of Research as a synthetic analogue of quinine...
. Mefloquine is an antimalarial drug that can also act against the JC virus. Administration of mefloquine seemed to eliminate the virus from the patient's body and prevented further neurological deterioration.
See also
- LeukoencephalopathyLeukoencephalopathyThe term Leukoencephalopathy is a broad term for leukodystrophy-like diseases . It is applied to all brain white matter diseases, whether their molecular cause is known or not...
- Leukoencephalopathy with vanishing white matterLeukoencephalopathy with vanishing white matterLeukoencephalopathy with vanishing white matter is an autosomal recessive neurological disease. The cause of the disease are mutations in any of the 5 genes encoding subunits of the translation initiation factor EIF-2B: EIF2B1, EIF2B2, EIF2B3, EIF2B4, or EIF2B5...
- Toxic leukoencephalopathyToxic leukoencephalopathyToxic leukoencephalopathy or toxic spongiform leukoencephalopathy is a condition that is characterized by progressive damage , of the white matter of the brain due to ingested toxins ....
External links
- Overview at NIH
- Overview at Cleveland ClinicCleveland ClinicThe Cleveland Clinic is a multispecialty academic medical center located in Cleveland, Ohio, United States. The Cleveland Clinic is currently regarded as one of the top 4 hospitals in the United States as rated by U.S. News & World Report...
- PML Disease Support Website