Research Update: Immune-Mediated Myelopathies
By Hannah Kelly In a recent issue of Continuum, the American Academy of Neurology’s review journal for clinicians, Dr. Michael Levy discusses how to best diagnose and treat immune-mediated myelopathies. Immune-mediated myelopathies happen when the immune system attacks the spinal cord. The spinal cord sends messages from the brain to the rest of the body to help us move, feel things, and control activities such as heart rate, breathing, and digestion. Inflammation occurs when the immune system treats specific parts of the body as foreign or like a germ it needs to fight off. Inflammation of the spinal cord can damage the protective layer around the nerves of the spinal cord called myelin. The inflammation can also damage the nerves directly. This interferes with messages getting to and from different parts of the body. Dr. Levy’s article reviews common causes of immune-mediated myelopathies and emphasizes the importance of using data from bloodwork, imaging, and spinal fluid analyses to determine the cause of the myelopathy. After finding the cause, doctors then follow the appropriate treatment guidelines based on research studies. According to the article, there are several important clues that may suggest a diagnosis of an immune-mediated myelopathy. These include an attack that happens over hours to days (although this is not always the case), a personal or family history of autoimmune disease, a history of cancer, or recent triggers such as infections or vaccines that may activate the immune system. Other clues include finding a large amount of inflammatory cells in the spinal fluid, seeing certain findings on imaging, and/or from detecting certain antibodies in the blood. Results from these tests help clinicians narrow down the diagnosis. This blog post will break down the causes of immune-mediated myelopathies that are mentioned in the review article. Multiple Sclerosis (MS) MS attacks on the spinal cord usually present as numbness or a heavy feeling in one leg occurring over the course of one week. MRI typically shows small lesions in the white matter tracts of the spinal cord. The white matter tracts are made up of myelinated nerves sending signals up and down the spinal cord. Spinal fluid analysis shows oligoclonal bands in most cases. Oligoclonal bands are proteins called immunoglobulins (or antibodies), and their presence suggests inflammation in the brain and spinal cord. Severe MS attacks on the spinal cord are generally treated with steroids while more mild attacks are observed without treatment. Those with spinal cord attacks are usually treated with long-term therapies that change the immune system in a way to prevent further attacks. Neuromyelitis Optica Spectrum Disorder (NMOSD) In NMOSD, attacks on the spinal cord are severe, and most of those diagnosed do not fully recover. Those with NMOSD present with severe weakness or even paralysis of the arms or legs, difficulty feeling things, and/or loss of control of bowel or bladder function. The attacks typically progress over four to 28 hours. MRI shows long lesions that often involve both sides of the spinal cord. Individuals with NMOSD will almost always test positive for the AQP-4 antibody. Spinal fluid analysis is not usually needed but will show over 50 inflammatory cells. All NMOSD attacks must be treated, and earlier treatment leads to better outcomes. Acute attacks are usually treated with steroids. Plasma exchange is often added, especially in those with limited improvement after steroids. Plasma exchange is a process that involves the removal and return of some of the person’s blood in order to remove harmful antibodies, including those against AQP-4. All of those with NMOSD should use medication to prevent future attacks or decrease the severity of future attacks. Three therapies are approved by the FDA to treat NMOSD–eculizumab, satralizumab, and inebilizumab. These therapies all change the immune system in a way that helps prevent NMOSD attacks. Myelin Oligodendrocyte Glycoprotein Antibody Disease (MOGAD) A spinal cord attack may be the first event in MOGAD. Those with MOGAD tend to present with difficulty emptying the bladder, leg weakness, and difficulty feeling things in the lower abdomen and legs. The location of the attack in the spinal cord varies, and the attacks can be mild, moderate, or severe. On MRI, lesions can be either long or short. Those diagnosed typically recover well, and old lesions may not be seen on MRIs done after recovery. In the spinal fluid, oligoclonal bands are rare; over 50 inflammatory cells can be seen. A high enough level of the MOG antibody in the blood confirms the diagnosis. Individuals whose MOG antibody level decreases and becomes undetectable have a lower risk of a repeated attack. Acute MOGAD attacks are treated with steroids and a long steroid taper. Some may receive IVIG during an attack. IVIG is an intravenous infusion of antibodies taken from thousands of healthy people. These extra antibodies overwhelm the immune system in a way that prevents it from attacking healthy proteins such as MOG. While there are no FDA-approved treatments to prevent MOG antibody disease attacks, those diagnosed often receive IVIG every four weeks or take pills to suppress the immune system, such as azathioprine or mycophenolate mofetil. Two new treatments that change the immune system in a way to prevent future attacks are currently being tested in clinical trials. Other Antibody-Associated Autoimmune Diseases In rare cases, immune-mediated myelopathies are caused by antibodies besides AQP-4 or MOG. The most common is GFAP encephalomyelitis. In this condition, the immune system attacks GFAP, a protein found on astrocytes, which are important cells in the nervous system. This causes inflammation in the brain and spinal cord, and those diagnosed can have persistent symptoms. Steroids and sometimes plasma exchange are used in treatment. Seronegative Relapsing Inflammatory Myelitis This condition occurs in those who have repeated attacks on the spinal cord but who do not test positive for any antibodies in the blood (seronegative). In individuals who have had two attacks and remain seronegative, treatment is recommended to prevent a third attack. Some of these individuals have presentations that look similar to NMOSD and therefore use treatments used for NMOSD. Others more closely resemble individuals with MOGAD and tend to use therapies for MOGAD. Monophasic Idiopathic Inflammatory Myelitis Individuals with this disorder have had only one attack on the spinal cord (monophasic), and a cause for the attack has not been found (idiopathic). MRI findings vary, but lesions are usually short. A high number of inflammatory cells is seen in the spinal fluid. Steroids are the standard treatment, but plasma exchange is sometimes added if the response to steroids is poor. Treatment helps to improve recovery and decrease any decline in neurologic function. Those diagnosed typically have an incomplete recovery. Neurosarcoidosis Sarcoidosis is a disease in which inflammation occurs in the lungs, liver, skin, lymph nodes, and/or other organs. When it occurs in the nervous system, it is called neurosarcoidosis. In the spine, neurosarcoidosis attacks occur over weeks to months. Those diagnosed often have weakness in the arms or legs and difficulty feeling things. Almost all cases occur in people who have sarcoidosis in other parts of the body, especially the lungs. MRI will show lesions that attach to the outer coverings of the spinal cord, look bumpy, and may have the appearance of a trident. These lesions remain visible and bright on MRI for at least six weeks, which is not generally seen in other causes of inflammatory spinal cord attacks. PET scans can be helpful in making a diagnosis by showing a spinal cord lesion that is very active. If a very active lesion is found, a spine biopsy may be pursued. The best way to confirm a neurosarcoidosis diagnosis is to biopsy a lesion and see clumps of abnormal tissue and immune cells called granulomas. Sometimes, imaging of the chest and abdomen is done to look for sarcoidosis elsewhere in the body. An easier location to perform a biopsy (rather than the spine) may be found with this approach. Spinal fluid analysis is also helpful in the diagnosis because some people will have a low level of sugar (in addition to a high amount of inflammatory cells), which is unique to this cause of inflammatory myelopathy. Attacks are almost always treated. Steroids are often used and may need to be given for a period of months to years. Other treatments such as methotrexate or mycophenolate may be used to decrease the amount of steroids needed. Another medication called infliximab blocks a certain immune cell and is helpful in those who do not respond to steroids. Paraneoplastic Disease Paraneoplastic diseases are a group of rare disorders that happen when the immune system reacts to a cancer in the body. Several cancers, especially lung cancer, are associated with immune-mediated myelopathies. This should be suspected in individuals older than 55, those with known cancer, or those who present with symptoms occurring over a longer time period. MRI may show findings such as long lesions that follow along the white matter tracts of the spinal cord. Other cases may show signs of necrosis, or cell death, on imaging. These individuals often test positive for certain antibodies in the blood. Treatment is aimed at treating the underlying cancer. While MS is the most common cause of an immune-mediated myelopathy, AQP-4 and MOG antibodies should be tested in everyone who has a first inflammatory attack on the spinal cord. In addition to testing antibodies, collecting data from imaging, spinal fluid analyses, and even biopsies help clinicians determine the diagnosis. Finding the correct diagnosis is important because the different causes of immune-mediated myelopathies have different treatments.
