What is Paraneoplastic Encephalomyelitis?

Paraneoplastic encephalomyelitis (PEM) is part of a group of conditions called paraneoplastic neurological syndromes that usually occur in people with cancer. These conditions are triggered by the immune system’s reaction to cancer, creating antibodies which often end up attacking the brain or spinal cord, causing inflammation.

To diagnose paraneoplastic neurological syndromes, doctors typically look for three things:

An onset of specific neurological symptoms linked to PEM, and cancer is discovered within five years of these symptoms showing up.
A situation where neurological symptoms get better after cancer treatment, without immune-based treatments being used.
Neurological symptoms that don’t fall into the known categories, but are still related to cancer, and cancer is diagnosed within five years of these symptoms starting.

In the case of PEM, the immune system activates a specific type of white blood cell called a B-cell and produces antibodies that aid in identifying disease variants. These antibodies were originally thought to be completely separate from autoimmune diseases. Now, they are categorized into three types:

Antibodies which react with similar proteins in the cancer and the nervous system. These antibodies could be related to diseases like limbic encephalitis, rapidly progressive sensory polyneuropathy, among others. The understanding of these antibodies’ function is still evolving. However, researchers believe that they play a part in aiding immune cells in attacking cancer cells and other similar cells leading to additional damage that might cause paraneoplastic syndromes.
Antibodies which target identical parts in the nervous system cells and can cause certain conditions. These have been linked to diseases such as encephalomyelitis and stiff person syndrome, among others. Transferring these antibodies from patients to experimental animals can reproduce the symptoms of the disease.
Antibodies that target the outer part of the cells and directly affect the nervous system. They are often recognized as the first sign of cancer. Conditions such as paraneoplastic myasthenia gravis, Lambert Eaton syndrome, encephalomyelitis, etc., result from these types of antibodies. Recognizing how these conditions pertains to both paraneoplastic and autoimmune diseases not related to cancer, helps doctors identify and treat these disorders.

It’s important to understand that there are situations where traditional paraneoplastic disorders overlap with autoimmune encephalitis related to the antibodies against certain neuron proteins, which are usually most common in autoimmune disease not related to cancer. It’s especially important to note in cases of individuals on cancer chemotherapy with proteins called checkpoint inhibitors. These treatments often have higher chances of causing unwanted immune responses resulting in paraneoplastic syndromes. Understanding which antibodies are important in the formation of immune diseases and which paraneoplastic antibodies won’t respond to immune therapy helps guide doctors while making treatment decisions.

What Causes Paraneoplastic Encephalomyelitis?

Paraneoplastic encephalomyelitis, as suggested by its name, is linked with the existence of cancer. It is particularly common in individuals with small cell lung cancer. It also frequently occurs in individuals dealing with breast cancer, testicular cancer, gynecological cancers, and Hodgkin’s lymphoma.

There’s also a type of medication called “immune checkpoint inhibitors” that is thought to increase the risk of getting paraneoplastic neurological syndromes. This happens more often with certain drugs like pembrolizumab, nivolumab, and cemiplimab.

Risk Factors and Frequency for Paraneoplastic Encephalomyelitis

Paraneoplastic syndromes are conditions that are linked to cancer, but we aren’t exactly sure how often they occur. Some older studies and research that only looked at classic immune markers suggest that paraneoplastic diseases show up in about 1 in 10,000 cancer cases (0.01%). When it comes to paraneoplastic neurological syndromes, they are reported at a rate of 0.86 per 100,000 with a presence in 4.37 out of every 100,000 cases. But in some specialized centers where patients’ cases are reviewed in depth, they’ve found the rate of these syndromes to be much higher, around 0.25% of cases. So, as science advances and we get better at spotting the immune reactions to cancer, we might start to see more reported cases of these paraneoplastic conditions.

One specific instance of this is Paraneoplastic Encephalomyelitis (PEM), which accounts for 10% of all Encephalomyelitis cases. In 75% of these cases, the patient also has a type of lung cancer called small cell lung cancer.

Signs and Symptoms of Paraneoplastic Encephalomyelitis

Paraneoplastic encephalomyelitis (PEM) is a condition wherein tumors trigger a reaction in the nervous system. This reaction can manifest as various neurological symptoms, usually appearing weeks or months before the tumor is detected. This is the case for about 80% of PEM instances. The onset and progression of symptoms are typically rapid rather than gradual.

The nervous system can be affected by PEM in multiple ways, examples include:

Specific cell-type involvement like Cerebellar Purkinje cells
Specific area involvement such as Limbic encephalitis
Multi-level involvement such as Encephalomyelitis

Widespread neural dysfunction occurs in paraneoplastic encephalomyelitis, impacting at least two or more regions like the temporal lobes, limbic areas, brainstem, cerebellum, spinal cord, dorsal root ganglia, and the autonomic nervous system. Specific conditions include Paraneoplastic Limbic Encephalitis which affects cognitive abilities and mood, and Paraneoplastic Brainstem Encephalitis which affects motor functions like speaking and swallowing. Few patients might also develop Paraneoplastic Cerebellar Degeneration leading to difficulties in movement, or Myelitis resulting in loss of sensory and motor functions.

Doctors can identify the regions of the Central Nervous System (CNS) involved by asking patients about their medical history and conducting a detailed neurological examination. Insight into a patient’s cognitive function can be obtained by conducting cognitive tests during the initial neurological exam.

Testing for Paraneoplastic Encephalomyelitis

When dealing with the diagnosis of paraneoplastic neurological syndromes (PNS), antibody tests can be crucial. These tests can take place before, during, or years after the diagnosis of a neurological condition. To get accurate results, both serum (blood) and cerebrospinal fluid (CSF – the fluid around your brain and spinal cord) should undergo testing. The CSF test is especially useful in identifying the precise antibody related to PNS because the serum may contain multiple antibodies that aren’t directly related to the condition.

You can expect doctors to run these tests for antibodies: Hu, Ri, Yo, Tr, Ma, CRMP5, and amphiphysin. However, different antibodies might be related to the same syndrome, and one antibody may be linked with different conditions. Sometimes, many antibodies may be found in the same patient with conditions like small cell lung cancer (SCLC) or thymoma.

High counts of PNS antibodies in your body have been correlated with the diagnosis as well as the level of advancement in the tumor. Your CSF test might also reveal a mild increase in white blood cell count (mild pleocytosis), a slightly elevated protein level, an increased level of the antibody IgG, and the presence of oligoclonal bands (a sign of inflammation in the central nervous system). Additionally, cytology (the study of cells) could be performed on CSF samples to exclude meningeal metastasis of cancer, which occurs when cancer spreads to the covering layers (meninges) of the brain and spinal cord.

Your doctor might order an electroencephalogram (EEG), a test that measures electrical activity in your brain. It can show nonspecific findings like generalized slowing, but also irregular brain wave patterns related to paraneoplastic syndromes. In addition, the EEG can be useful in ruling out undetected seizures or nonconvulsive status epilepticus, a condition that occurs more frequently in patients with PNS.

Magnetic Resonance Imaging (MRI) might be used for diagnosis. It can exclude things like stroke or metastatic disease and helps provide a clearer picture of the extent of conditions like limbic encephalitis (inflammation in certain brain regions). Detailed brain and spinal cord MRI might also reveal conditions like optic neuritis (inflammation in the optic nerve) or longitudinally extensive transverse myelitis (a particular type of inflammation in the spinal cord).

Since finding the tumor is important for treatment, whole-body scans using radioactive tracers (PET scans – Positron Emission Tomography) can reveal any hidden cancers. If the first scan doesn’t turn up anything, repeat cancer screenings in the following months can still be beneficial. Sometimes, the tumor may never be identified. In such cases, it’s assumed that the immune system eradicated the cancer cells on its own.

Treatment Options for Paraneoplastic Encephalomyelitis

When damage to the brain or nervous system starts to occur, it often happens quite quickly. As such, it’s really important to start treatment right away, instead of waiting to conduct tests to check for antibodies.

If a tumor is discovered, doctors will try to remove it completely and as soon as possible. This is because the tumor might be producing harmful substances that can continue to damage neighboring brain cells.

In some cases, where the damage to the brain and nervous system is caused by the patient’s own immune cells, treatment can be quite tricky. For instance, treatments like IVIG and plasmapheresis, which are designed to target antibodies, may not be very effective because they can’t adequately target the overactive immune cells responsible for the damage. In these cases, different medicines that are able to target and reduce the activity of these immune cells, such as cyclophosphamide, rituximab, steroids, mycophenolate mofetil, or tacrolimus, may be used. However, they may only help a little in certain cases.

Often, treatment gets delayed and by the time it starts, a lot of irreversible damage to the brain cells or nervous system has already occurred. For this reason, doctors may recommend that brain imaging tests be repeated after 3 to 6 months of treatment. If the imaging shows that the disease has continued to progress despite treatment, then it may be necessary to stop immunotherapy.

Further, some symptoms such as seizures can be managed with anti-epileptic drugs, and muscle stiffness and spasms can be controlled with muscle relaxants like baclofen, tizanidine, and benzodiazepines.

If there are reasons to believe that the symptoms are being caused by immune checkpoint inhibitors, these should be stopped promptly.

When doctors investigate a case of paraneoplastic disease (diseases that occur with cancer), they will usually consider the possibility of other health conditions that might be causing the patient’s symptoms. These can be grouped into several categories:

Infectious diseases, which could come from viruses, bacteria, spirochetes, fungi, tuberculosis, or Creutzfeldt–Jakob disease
Toxic or metabolic disorders that stem from drug use, chemotherapy, radiotherapy, exposure to harmful levels of carbon monoxide, Wernicke’s encephalopathy, or neuroleptic malignant syndrome
Vascular abnormalities like posterior reversible encephalopathy syndrome, angiitis (blood vessel inflammation) in the central nervous system, Behcet’s disease or Susac’s syndrome
Neoplastic disorders (cancerous diseases), such as leptomeningeal or epidural metastasis, glioma, or central nervous system lymphoma
Demyelinating or Inflammatory conditions like multiple sclerosis, neurosarcoidosis, neuromyelitis optica, acute disseminated encephalomyelitis, and Bickerstaff encephalitis
Neurodegenerative diseases such as Alzheimer’s disease, frontotemporal dementia, vascular dementia, or dementia with Lewy bodies
Psychiatric conditions like schizophrenia or bipolar disorder
Inherited or metabolic disorders, such as mitochondrial encephalopathies or Hashimoto’s encephalitis

The exact cause can only be identified through a detailed examination of the patient’s health history and current health status.

What to expect with Paraneoplastic Encephalomyelitis

For most people diagnosed with a set of conditions called paraneoplastic syndromes, the outcomes aren’t always good. However, younger male patients with testicular cancer and anti-Ma-2 antibodies (proteins that the body mistakenly produces against its own cells) tend to fare better. For children suffering from a condition called ‘anti-Hu encephalomyelitis’, treatments are usually less effective.

Yet, the story isn’t all bad. Many patients can see improved results if we target the harmful antibodies causing these syndromes, and if the cancer that triggers the syndrome is promptly removed.

Several factors can lead to less favorable outcomes in the neurological aspect of these syndromes. These include delaying immunotherapy (a treatment that helps your body’s immune system fight illnesses), needing mechanical assistance to breathe, inflammation within certain parts of the body’s nervous system, and needing a tracheostomy (a surgery to enable breathing directly through the neck).

The major causes of death for these patients include issues with the brain or autonomic nervous system (which controls functions like heart rate and breathing), severe pneumonia, failure of multiple organs, and uncontrollable seizures.

In some cases, patients may develop a second paraneoplastic syndrome even after they’ve stabilized from the first one. This might mean the initial cancer has come back, or a second cancer has appeared.

In the case of a brain inflammation called ‘limbic encephalitis,’ which can be a side effect of certain cancer treatments, the situation is usually better. If the medication causing it is stopped and steroid treatment is quickly started, most patients tend to respond well.

Possible Complications When Diagnosed with Paraneoplastic Encephalomyelitis

The main reasons people need intensive care unit (ICU) treatment often include things like:

A change in mental state that requires breathing support via a tube (intubation)
Serious and/or continuous seizures (status epilepticus/refractory status epilepticus)
Excessive and uncontrollable body movements
Difficulty in breathing or lung failure (respiratory failure)
Problems with the body’s automatic functions, like heart rate or digestion (autonomic dysfunction)
Increased pressure inside the skull (increased intracranial pressure)

Preventing Paraneoplastic Encephalomyelitis

People who have been diagnosed with cancer or are currently being treated with a type of drug called immune checkpoint inhibitors should immediately consult a doctor if they experience any changes in their nervous system. Neurological symptoms could include headaches, numbness, or problems with vision, hearing, or balance. It’s crucial to treat these symptoms as early as possible to avoid any complications.

Frequently asked questions

The prognosis for Paraneoplastic Encephalomyelitis (PEM) is generally not good, as outcomes for most people diagnosed with paraneoplastic syndromes are unfavorable. However, younger male patients with testicular cancer and anti-Ma-2 antibodies tend to have better outcomes. Prompt removal of the cancer that triggers the syndrome and targeting the harmful antibodies causing the syndrome can lead to improved results.

Paraneoplastic Encephalomyelitis can be triggered by tumors in the body, which then cause a reaction in the nervous system.

Signs and symptoms of Paraneoplastic Encephalomyelitis (PEM) include: - Neurological symptoms that manifest before the tumor is detected, usually appearing weeks or months earlier. - Rapid onset and progression of symptoms, rather than a gradual onset. - Specific cell-type involvement, such as Cerebellar Purkinje cells. - Specific area involvement, such as Limbic encephalitis. - Multi-level involvement, such as Encephalomyelitis. - Widespread neural dysfunction impacting at least two or more regions of the nervous system, including the temporal lobes, limbic areas, brainstem, cerebellum, spinal cord, dorsal root ganglia, and the autonomic nervous system. - Paraneoplastic Limbic Encephalitis, which affects cognitive abilities and mood. - Paraneoplastic Brainstem Encephalitis, which affects motor functions like speaking and swallowing. - Paraneoplastic Cerebellar Degeneration, leading to difficulties in movement. - Myelitis, resulting in the loss of sensory and motor functions. Doctors can identify the regions of the Central Nervous System (CNS) involved by asking patients about their medical history and conducting a detailed neurological examination. Additionally, cognitive tests can be conducted during the initial neurological exam to gain insight into a patient's cognitive function.

To properly diagnose Paraneoplastic Encephalomyelitis, the following tests may be needed: - Antibody tests for Hu, Ri, Yo, Tr, Ma, CRMP5, and amphiphysin - CSF (cerebrospinal fluid) testing to identify the precise antibody related to PNS - Electroencephalogram (EEG) to measure electrical activity in the brain and rule out seizures or nonconvulsive status epilepticus - Magnetic Resonance Imaging (MRI) to exclude other conditions and provide a clearer picture of inflammation in the brain and spinal cord - Whole-body scans using PET (Positron Emission Tomography) to reveal any hidden cancers - Repeat brain imaging tests after 3 to 6 months of treatment to assess disease progression - Cytology on CSF samples to exclude meningeal metastasis of cancer - Additional tests may be ordered based on individual symptoms and clinical presentation.

Infectious diseases, toxic or metabolic disorders, vascular abnormalities, neoplastic disorders, demyelinating or inflammatory conditions, neurodegenerative diseases, psychiatric conditions, and inherited or metabolic disorders.

The side effects when treating Paraneoplastic Encephalomyelitis can include the following: - Delayed treatment leading to irreversible damage to the brain cells or nervous system - Ineffectiveness of treatments like IVIG and plasmapheresis in targeting overactive immune cells responsible for the damage - Possible use of medicines like cyclophosphamide, rituximab, steroids, mycophenolate mofetil, or tacrolimus to reduce the activity of immune cells, but with limited effectiveness in certain cases - Need for repeated brain imaging tests after 3 to 6 months of treatment to assess disease progression - Management of symptoms such as seizures with anti-epileptic drugs - Control of muscle stiffness and spasms with muscle relaxants like baclofen, tizanidine, and benzodiazepines - Prompt discontinuation of immune checkpoint inhibitors if they are causing symptoms - Possible need for intensive care unit (ICU) treatment for severe symptoms, including breathing support, serious seizures, uncontrollable body movements, respiratory failure, autonomic dysfunction, and increased intracranial pressure.

A neurologist.

Paraneoplastic Encephalomyelitis is reported at a rate of 0.86 per 100,000 cases.

Paraneoplastic Encephalomyelitis can be treated with various medications that target and reduce the activity of the immune cells responsible for the damage, such as cyclophosphamide, rituximab, steroids, mycophenolate mofetil, or tacrolimus. However, these medications may only provide limited help in certain cases. Additionally, symptoms such as seizures can be managed with anti-epileptic drugs, and muscle stiffness and spasms can be controlled with muscle relaxants like baclofen, tizanidine, and benzodiazepines. If the symptoms are being caused by immune checkpoint inhibitors, these should be stopped promptly.

Paraneoplastic encephalomyelitis (PEM) is a condition that occurs in people with cancer, where the immune system's reaction to cancer triggers the production of antibodies that attack the brain or spinal cord, causing inflammation.

Brain Cancer Inflammation Spine