What is Progressive Multifocal Leukoencephalopathy?
Progressive multifocal leukoencephalopathy (PML) is a condition that affects the brain, caused by the JC virus. PML damages the protective coating of the nerves in the brain, a process called demyelinating. Although it generally stays inactive in most people, it can become very harmful in people with weakened immune systems. This includes people with AIDS, those who have had organ or bone marrow transplants, people with cancer, and those with long-term inflammatory conditions. It can also occur in patients taking anti-HIV drugs since these drugs can make the immune system stronger, leading to PML. In these cases, PML is known as PML- IRIS. A specific type of drug used to treat multiple sclerosis, called natalizumab, can also cause PML. Therefore, it’s important for doctors to consider PML when patients with these risk factors show signs of neurological issues.
What Causes Progressive Multifocal Leukoencephalopathy?
The JC virus is a type of virus that most commonly stays hidden without causing any problems in people with a strong immune system. However, in people with weaker immune systems, the virus can become active due to certain gene changes, causing disease.
A condition known as Progressive Multifocal Leukoencephalopathy (PML) can happen when your immune system starts to get better, often known as immune reconstitution syndrome. This is often seen in AIDS patients who are on antiretroviral therapy – drugs used to slow down the progress of AIDS. These patients may notice changes in their thinking or physical coordination, and might have certain spots appear in brain scans. Such symptoms can appear anywhere between 1 week to 26 months after starting the therapy. Doctors will usually suspect PML in such cases.
PML can also occur after using certain drugs, like natalizumab, rituximab, efalizumab, and eculizumab; these are medicines typically used to treat immune system conditions such as multiple sclerosis, Crohn’s disease, psoriasis, and lupus. Doctors should, therefore, be on the lookout for any sudden changes in brain function in patients on these drugs. Natalizumab, in particular, should only be used by itself in treating multiple sclerosis because combining it with other immune-suppressing drugs can increase the risk of getting PML. The more frequently natalizumab is taken, the greater the likelihood of PML occurring.
Risk Factors and Frequency for Progressive Multifocal Leukoencephalopathy
Progressive multifocal leukoencephalopathy (PML) mostly happens when a dormant virus, known as JC virus, reactivates within the body. PML normally shows symptoms in patients with a severely weakened immune system. This includes patients with HIV-AIDS, especially those with a CD4 count below 200, people who have received organ transplants, those with blood cancers, and now includes some who have been treated with specific drugs like natalizumab, a type of monoclonal antibody. Interestingly, instead of decreasing, the occurrence of PML has actually been seen to increase after starting antiretroviral therapy, a type of treatment for HIV. This is thought to be due to the restoration of the immune system following this therapy, which can also worsen existing cases of PML.
Signs and Symptoms of Progressive Multifocal Leukoencephalopathy
If a patient with a weakened immune system starts showing new neurological symptoms, it’s important to consider a condition called Progressive Multifocal Leukoencephalopathy (PML) as a possible cause. These patients might display changes in their mental state or other abnormal neurological signs that need to be investigated.
For people who have AIDS, the level of immune system suppression could give clues about the underlying cause of the new neurological symptoms. The severity of this suppression can be measured by looking at the CD4 cell count. PML is usually considered as a possible cause when the CD4 count falls below 200. However, it’s worth noting that PML can also occur when the CD4 count is above 200.
- Neurological symptoms are linked to the area of the brain where the white matter is damaged
- PML symptoms develop gradually and can vary widely, including difficulties with thinking, balance and coordination issues, muscle weakness on one side of the body, partial blindness, and problems with speech. These symptoms depend on the affected brain area.
- Commonly affected areas include the white matter beneath the brain’s outer layer (the cortex), the area around the brain’s fluid-filled spaces, and the nerves that connect the brain to the cerebellum.
- In most cases, PML doesn’t affect the optic nerves and the spinal cord.
Testing for Progressive Multifocal Leukoencephalopathy
To figure out why the JC virus has become active again, doctors usually recommend routine blood counts and HIV PCR testing. This is because the virus tends to reactivate when a patient’s immune system isn’t working well.
When patients with weakened immune systems, such as those with AIDS, show abnormal neurological symptoms, the first step in evaluating them is typically to use radiological imaging. This could involve using a CT scan or MRI with a contrast dye to help see if there is any inflammation or swelling in the brain.
PML, or Progressive Multifocal Leukoencephalopathy, shows up as lighter, blended-together areas on a CT scan, with no signs of swelling or brain herniation. On an MRI scan, these areas show up as ‘quiet’ spots on T1 weighted images. When an MRI with contrast is done, the spots show up as ‘noisy’ or bright on T2 weighted images. These bright spots are typically found under the cortex (subcortical), near the brain’s ventricles (periventricular), or just in the cerebellum.
In a condition called PML-IRIS, where the immune system reacts strongly after starting antiretroviral therapy, or after lowering immunosuppressive therapy, these reactions can cause inflammation. In these cases, an MRI with contrast will show swelling, brightness, and a mass effect.
Likewise, in patients who develop PML after being treated with a drug called natalizumab, the MRI scan might show similar findings.
Diagnosis of PML is confirmed by isolating JCV DNA from the cerebrospinal fluid (CSF) using a technique known as PCR. Sometimes, in PML-IRIS, the PCR test may not show any JCV DNA in the CSF. This could be because the patient’s immune system is now functioning well enough to keep the virus from replicating to levels detectable on a viral test.
Treatment Options for Progressive Multifocal Leukoencephalopathy
Currently, we have not yet found a complete cure for progressive multifocal leukoencephalopathy (PML), a disease that damages the brain and spinal cord’s white matter. While several drugs such as cidofovir, cytarabine, and mefloquine have been explored for treatment, they haven’t proven significantly effective in clinically managing PML.
Treatment these days is usually focused on enhancing the body’s adaptive immune response. This means finding ways to help the body’s own immune system fight the infection. The ways to do this can vary widely based on each patient’s specific situation.
For HIV patients with PML, the rapid introduction of Highly Active Antiretroviral Therapy (HAART) is usually recommended. In patients who have had a transplant, doctors might need to limit the use of multiple immunosuppressive therapies, which are drugs that reduce the body’s immune response, as they also have to consider the risks of the body rejecting the graft. In cases of PML caused by using the drug natalizumab, the advice is often to stop this therapy and switch to plasma exchange therapy as a treatment approach.
Enhancing the adaptive immune response using dendritic cell vaccines has also been explored in some studies. These are cells from your immune system that have been modified with JC virus antigens (the virus that causes PML), which can trigger a significant immune response and have shown prolonged survival in some PML patients. However, these studies were only conducted on a small number of patients, so further research is needed before this approach can become a standard treatment option.
In terms of treating PML IRIS, a condition where the body’s immune system responds too vigorously causing damage to its own tissues, improvement has been seen when patients stop antiretroviral therapy. Some studies have shown that treatment with steroids can have a positive outcome. However, stopping antiretroviral therapy may increase the viral load (the amount of virus in the body), and lead to resistance to antiretroviral drugs. Since PML IRIS can result in severe health risks, including brain herniation (when brain tissue moves into areas where it shouldn’t), glucocorticoids, a type of steroid, may be used to counter the damage caused by this overactive immune response.
What else can Progressive Multifocal Leukoencephalopathy be?
When a patient who has a weakened immune system shows signs of abnormal brain function, doctors consider several possibilities. These include toxoplasma encephalitis, primary CNS lymphoma, PML, HIV encephalopathy, and CMV encephalitis.
PML can present similar symptoms to toxoplasma and primary CNS lymphoma, such as changes in the senses, movement, or vision. To distinguish between these conditions, doctors use imaging techniques. Unlike others, PML is often asymmetrical and clearly defined without enhancing when a contrast dye is used.
Conditions like PML, CMV encephalitis, and HIV encephalopathy also don’t enhance with contrast dye, so they need to be differentiated from each other. HIV encephalopathy, for instance, usually involves cognitive problems and doesn’t involve the same kind of local neurological issues that PML does. Furthermore, brain imaging for HIV encephalopathy typically shows symmetrical, undefined lesions.
CMV encephalitis is another condition to consider. Although it presents symptoms similar to PML and also doesn’t enhance with contrast dye on a brain image, the presentation on brain imaging is different. In CMV encephalitis, the MRI shows small nodules scattered across various parts of the brain.
Lastly, distinguishing a recurrence of multiple sclerosis from PML can be challenging as they both involve the loss of myelin, a substance that protects nerve fibers. Both conditions can present overlapping signs and symptoms. However, imaging can be useful for telling the two apart. PML lesions tend to be larger, more intense, and singular while multiple sclerosis lesions are typically numerous and less intense.
What to expect with Progressive Multifocal Leukoencephalopathy
PML, or Progressive Multifocal Leukoencephalopathy, is a severe and often fatal disease. Right now, the main goal of treatment is to increase the patient’s chance of survival. There are several factors that can boost survival chances, such as a lower amount of the JC virus (identified through a type of test called a PCR CSF sample), a higher number of certain white blood cells known as CD4, and noticeable changes on medical imaging that uses a special dye (contrast enhancement).
For patients with AIDS, starting antiretroviral therapy (medical treatment that slows down the progression of the disease) can help improve their chances of surviving. Evidence shows that if the body can adapt and mount a strong response to the virus (which can be recognized by the presence of special immune cells, the PML-specific CTL lymphocytes, in the blood), this can also promote longer survival.
Within the transplant recipient group, the patients who had hematopoietic (or blood) stem cell transplantations tend to have lower mortality rates and a higher survival chance compared to those who received a solid organ transplantation.
Regarding patients who develop PML due to treatment with the drug natalizumab, certain factors were associated with better survival rates. These include being younger, having a lower JC viral load, less neurological dysfunction prior to starting the therapy, and presence of an area of increased intensity seen on contrast imaging.
In patients who develop a worsened form of PML, known as PML-IRIS, after starting antiretroviral therapy, the use of steroids (medicine that reduces inflammation) and positive results on contrast-enhancing MRI (a detailed medical imaging technique) have been associated with better survival outcomes.
Possible Complications When Diagnosed with Progressive Multifocal Leukoencephalopathy
PML, short for Progressive Multifocal Leukoencephalopathy, is a serious, continually worsening disease that causes damage to the protective layer of the brain’s nerve fibers. Unfortunately, this disease is typically fatal. Current treatments aim to extend survival time rather than curing the disease. The damage that PML causes to the brain is irreversible since the body cannot repair the lost protective layer around nerve fibers. Over time, people with PML may experience other problems primarily related to brain function. These can include loss of cognitive abilities, sensory issues, problems with movement, and coordination difficulties.
List of Long Term Complications from PML:
- Cognitive Impairment (Issues with thinking and understanding)
- Sensory Deficits (Difficulty with senses such as touch, taste, smell, etc.)
- Motor Deficits (Problems with movement)
- Disturbances in Coordination (Trouble with body movements)
Preventing Progressive Multifocal Leukoencephalopathy
Patients and their family members who know they have a weakened immune system should be informed about the dangers of a brain infection called PML. This is especially true for people living with AIDS. They should be encouraged to consistently take their antiretroviral therapy, which is medication to suppress the HIV virus and stop the progression of the disease. If there are any problems with following this medicine plan, it’s necessary to discuss this with their primary care doctor.
Should there be any unusual changes in thinking abilities, muscle or sensory function, walking, and sight, it’s very important to notify their medical professionals immediately. These symptoms, combined with a history of a weakened immune system, could be significant.
