It is a neurological disorder characterized by the destruction of the cells that produce myelin.
Myelin is an oily substance that helps protect nerve cells in the brain and spinal cord, also known as the white matter of the central nervous system (CNS).
Progressive multifocal leukoencephalopathy (PML) is caused by a virus called JC virus (JCV), named after the patient’s initials in whom it was first discovered. The virus is widespread and is 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 hematologic malignancies and in organ transplant recipients receiving immunosuppressive medications to prevent rejection of the transplanted organ.
In total, PML occurs in about one in every 200,000 people. Each year, an estimated 4,000 people develop PML in the United States and Europe.
The term “progressive” in PML means that the disease worsens and often leads to severe brain damage. The word “multifocal” means that JCV causes disease in multiple brain parts.
However, a person with PML can have only one brain injury rather than multiple injuries. The term “leukoencephalopathy” means that the disease mainly affects the brain’s white matter or myelin, although there are some rare cases in which the gray matter neurons are also involved.
The term “multifocal” means that JCV causes disease in multiple parts of the brain. However, it is possible for a person with PML to have only one brain injury rather than various injuries.
Signs and symptoms of leukoencephalopathy
The symptoms of PML vary from case to case because lesions can occur anywhere in the central nervous system.
Most patients present with subacute neurological damage, which can include some degree of mental impairment and various other symptoms such as vision loss, speech disturbances, drooping of the face, weakness, coordination problems, gait, and sensory loss.
Additionally, approximately one-third of PML patients may experience seizures during their illness.
The disease course of PML used to be considered invariably progressive, with most non-HIV-related cases leading to a fatal outcome in the months after diagnosis.
However, it is now known that a small number of HIV-positive patients who have developed PML, will experience stabilization of the disease and prolonged survival.
CD4 + and CD8 + T lymphocytes are types of immune cells that are of great importance to the immune system’s health. They help mediate the immune response against many infectious organisms.
In a patient with an active HIV infection, the levels of these lymphocytes are significantly decreased. However, antiretroviral drugs, which are now a standard part of HIV treatment, have allowed CD4 and CD8 cells to cross over to normal levels.
Before the availability of drugs used to fight HIV (antiretrovirals), only 10% of HIV-positive PML patients lived for more than a year.
With the advent of highly active antiretroviral therapy (HAART), one-year survival increased to an average of 50%.
HAART therapy increases the levels of crucial lymphocytes, allowing the immune system, in certain circumstances, to fight the JC virus. However, those who can develop a robust immune response mediated by T lymphocytes that specifically target JCV have a better outcome among these patients.
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 new white matter formation by CNS cells (remyelination) does not occur in affected areas, 80% of PML survivors do not experience much regression of their symptoms.
They can be left with permanent neurological dysfunction, similar to stroke patients.
However, PML patients can have prolonged survival of up to 15 years if the initial cause of the immunosuppression is under control, for example, in HIV-infected patients treated with HAART or in cancer patients successfully treated with chemotherapy. The disease is no longer active in these patients, and they have burned PML.
Causes of leukoencephalopathy
The JC virus generally enters the bloodstream during childhood. It can be found through blood tests in healthy children without PML symptoms. Because the virus is also frequently found in the urine of healthy individuals, it is possible that the initial infection could occur through contamination of urine and urine.
After primary infection, the virus remains inactive in the kidneys and lymphoid organs. JCV can be found in the urine samples of approximately 30% of people, regardless of their immune status.
JCV was also detected in bone marrow samples, including patients with PML, HIV, leukemia, and bone marrow transplantation. Receptors, but also in the bone marrow of some HIV-negative patients without immunosuppression.
Other studies have suggested that JCV is also latent in the regular digestive system and the tonsils, and there is growing evidence that JCV may also remain latent in the brain.
The exact mechanisms that lead to JCV activation and PML development have not been fully elucidated. Still, as explained above, most cases occur in the context of profound cellular immune dysfunction.
Studies of the type of blood cells that carry JCV have shown an association with B lymphocytes, blood cells that produce antibodies primarily, and other types of leukocytes, including T lymphocytes, monocytes, polymorphonuclear cells, and cell-free plasma.
Despite the possible involvement of blood cells in transporting the JC virus throughout the body, the virus is rarely detected in routine blood tests in healthy people.
While PML is generally believed to be caused by activating an inactive JC virus, it can also occur as a new infection in adults who have become severely compromised with immunity.
In the advent of the human immunodeficiency virus (HIV) epidemic, PML was early recognized as a significant opportunistic infection of the acquired immunodeficiency syndrome (AIDS) in up to 5% of patients.
Based on a study of 61 cases of PML. From 1996 to 2003, approximately 80% of PML patients were believed to have AIDS, 13% had hematologic malignancies, 5% were transplant recipients, and 2% had the chronic inflammatory disease.
A series of 58 HIV-negative cases diagnosed with PML observed between 1957 and 2005 indicates that 55% have hematological malignancies, 15% have chronic inflammatory diseases, and 9% have sarcoidosis.
7% are transplant recipients, 7% have other conditions (cirrhosis, pulmonary fibrosis), and 7% have no detectable predisposing disease, except for the age between 66 and 80 years.
Among patients with lymphoproliferative disorders, such as chronic lymphocytic leukemia, it has been found that patients treated with certain medications that interfere with the life cycles of blood cells (i.e., fludarabine) may have an increased risk of developing PML.
Studies have shown a 3% incidence of PML in patients receiving this type of medication.
In addition, rare cases of PML have been diagnosed in HIV-negative patients with other types of drug-induced or drug-induced CD4 and CD8 T-cell suppression. As well as in patients without an obvious source of immunosuppression.
In February 2005, two biotech companies, Biogen Idec and Elan, voluntarily recalled a promising new drug to treat relapsing / remitting multiple sclerosis and Crohn’s disease. The drug is called Tysabri.
This drug was withdrawn from the market after discovering two people with MS who developed PML after taking Tysabri.
However, after a review of the data by an independent adjudication committee, the “Central and Peripheral Nervous System Drug Advisory Committee of the US Food and Drug Administration,” Tysabri was able to return to the market.
It has been available again as of August 2006 for MS patients “who have not responded adequately or cannot tolerate other MS treatments.” Supplied through restricted distribution.
As of June 2015, there have been 563 cases of Tysabri-associated PML in MS patients worldwide, and the risk of PML in this population is 6/1000 after 24 months.
However, if patients are JCV seropositive and have received immunosuppressive medications before Tysabri, the risk of PML increases to 1/90 after 24 months of continuous therapy.
Inflammatory Progressive Multifocal Leukoencephalopathy
Although antiretroviral drugs can help recovery 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 context of recovery of the immune system marked by an increase in the CD4 + T cell count and a decrease in the plasma viral load of HIV, the amount of HIV in human serum.
This paradoxical development of PML is often associated with an inflammatory reaction in brain lesions and has been termed “immune reconstitution inflammatory syndrome” (IRIS).
Despite the transient worsening, the result is usually favorable. The resolution of the inflammatory phase results in clinical improvement, with subsequent imaging studies showing only classic residual atrophy and loss of brain tissue secondary to a previous infection.
However, fatal cases of PML / IRIS have been described. Magnetic resonance spectroscopy (MRS) allows the study of brain metabolism and has proven helpful in diagnosing PML / IRIS.
JC virus granule cell neuropathy (JCV GCN)
Central nervous system demyelination 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 towards the back of the brain) is frequently found in PML, recent studies have found that coordination problems, along with atrophy of the cerebellum, can occur in patients infected with it. HIV that does not have PML lesions in the cerebellum.
Areas of cell loss have been observed in the inner cell layer of the cerebellum. This new syndrome has been called JCV granule cell neuronopathy (JCV GCN). A specific mutation of the JC virus is necessary for the infection of granule cell neurons in the cerebellum.
More recently, the GCN of JCV was also described in two multiple sclerosis patients treated with Tysabri.
JC virus encephalopathy (JCVE)
Another novel syndrome associated with JCV has been characterized, different from PML and GCN of JCV, caused by infection of the pyramidal neurons of the brain’s cortical gray matter.
This syndrome is associated with subacute and global cognitive dysfunction, and brain lesions can be seen on MRI in the cerebral cortex of the cerebral hemispheres. This condition is called JCV encephalopathy (JCVE), caused by a different JCV variant.
Meningitis by JC virus (JCVM)
The JC virus has also been shown to infect the membranes surrounding the brain, causing meningitis in a previously healthy person with headaches and accumulation of cerebrospinal fluid in the brain (hydrocephalus).
No other causes were isolated in this patient, but direct infection by JC virus of choroid plexus cells, which produces CSF in the brain, was documented.
Diagnosis of leukoencephalopathy
Brain MRI is the first step in diagnosing PML. Brain biopsy is a secondary approach if MRI is inconclusive.
Cerebrospinal fluid, collected through a lumbar puncture, is also a reliable way to diagnose PML. Due to the expanding population of individuals at risk for PML, early diagnosis has become critically important.
There is no specific treatment for JCV. In HIV-positive PML patients, HAART optimization is the best therapeutic option, and in HIV-negative patients, elimination or reduction of any potential source of immunosuppression is recommended.