Autoimmune Neurology—Recent Advances in Disease Identification and Treatment
Autoimmune neurologic diseases are more common than traditionally believed. The recognition of antibodies associated with these conditions has grown significantly over recent years, leading to improvements in diagnosis and treatment.
Dr. Steven Vernino, Professor and Vice Chair for Academic Affairs, University of Texas, Southwestern Medical Center, reviews the current understanding of these diseases and recent developments in the field. He makes the case for heightened awareness of these conditions to enable timely diagnosis and early treatment when possible.
Defining the field
“Traditionally, neuroimmunology has been synonymous with multiple sclerosis (MS),” notes Dr. Vernino. “We’ve recognized more and more over the past 20 years that neuroimmunology extends beyond MS to other diseases. One group of disorders, the autoimmune neurologic diseases, are defined by an identifiable immune response targeting a specific site or antigen in the nervous system. These can be further divided into peripheral and central diseases, and those that are associated with cancer (paraneoplastic neurological disorders) and those that are non-paraneoplastic.
“Autoimmune neuromuscular diseases include the best characterized autoimmune neurologic disorder, myasthenia gravis (MG). MG is caused by antibodies targeting the muscle acetylcholine receptor or other neuromuscular junction proteins like muscle-specific kinase (MUSK). These antibodies cause malfunction of the communication between nerve and muscle leading to muscular weakness and fatigue. MG is the prototypic autoimmune neurologic disease, since the antibody targeting the acetylcholine receptor was identified back in the 1970s.
“Other autoimmune neuromuscular diseases include Lambert-Eaton myasthenic syndrome (which is also a disorder of transmission at the neuromuscular junction), neuromyotonia (or Isaacs syndrome, where antibodies target regulatory proteins on the nerves, causing excessive muscle activity), and autoimmune autonomic ganglionopathy (AAG) (antibodies target a receptor on the autonomic nerves, resulting in autonomic failure).
“An area that has generated much interest in the in last 10 to 15 years concerns the autoimmune encephalopathies,” continues Dr. Vernino. “It’s been long recognized that certain viruses can attack the brain and cause limbic encephalitis, which is a disease characterized by seizures, behavioral changes, and memory loss. It is now known that many patients who present with these same symptoms are not suffering from a virus, but rather from an autoimmune attack on their brain. The first of these conditions recognized around 50 years ago was a disorder called paraneoplastic limbic encephalitis, which was seen in lung cancer patients. Patients with small-cell lung cancer experienced a change of behavior and seizures. Ultimately, it was found that these patients had autoantibodies that targeted nuclear proteins in both neurons and in the cancer cells.
“Paraneoplastic limbic encephalitis is actually quite rare, but more recently we’ve recognized that more common autoimmune encephalitides are associated with different antibodies and may occur in patients who don’t have cancer.1 This includes NMDA receptor antibody encephalitis and the autoimmune encephalitides associated with antibodies against proteins associated with voltage-gated potassium channels (LGI1 and CASPR2).2-4 In addition to these recognized autoimmune encephalopathies, we also encounter patients with similar symptoms who get better with immunotherapy such as steroids, but where no specific antibody has been found.
“This is an area of rapid growth because an increasing number of antibodies have been found to be associated with autoimmune encephalitis, such as antibodies specific for DPPX (a potassium channel protein), glycine-receptor or AMPA-receptor, each of which present differently. It’s important to recognize these conditions because they’re potentially treatable. An autoimmune cause needs to be recognized and treated before permanent damage to the nervous system develops.
“There are also a number of autoimmune disorders that target the cerebellum causing autoimmune ataxia. These can be associated with various antibodies and can occur in the setting of cancer or without cancer.”
Another condition of interest in the world of autoimmune neurology is neuromyelitis optica or NMO. “For many years, NMO was thought to be a peculiar variant of MS but now we recognize it is really an autoimmune neurologic condition, where antibodies target the aquaporin4 water channels in the brain,” says Dr. Vernino. “This causes characteristic spinal cord lesions and optic neuritis, which is treatable with drugs used for antibody-mediated disorders but typically not responsive to drugs used for MS. Thus, it is important to make the distinction between MS neuroimmunology and autoimmune neurology.
In the past there has been a challenge in identifying autoimmune neurologic disorders, partly due to a lack of awareness and partly due to limited diagnostic options. “Awareness of the field is improving,” says Dr. Vernino, “but sometimes patients with these diseases still go for years without being diagnosed.”
Availability of testing has improved in a number of ways. With the advent of MRI, clinicians now have the ability to look at the brain structure and see signs of inflammation, which isn’t visible on CT. A significant development has been the identification of antibodies associated with these conditions. “When I entered this field in the mid-90s, only a handful of antibodies were recognized as related to these conditions— the anti-Hu and anti-Yo antibodies,” notes Dr. Vernino. “We thought these disorders were quite rare because these antibodies were not found that often. But over time, particularly in the past several years, there’s been an explosion of discovery of various neurological autoantibodies. Many antibody tests are now commercially available, allowing us to test for the biomarkers that are strongly associated with these autoimmune neurologic diseases.
Test selection and interpretation
“Having a diagnostic test does not eliminate the need for clinical judgment,” cautions Dr. Vernino. “Clinicians first need to select the patients and antibodies to test for according to the clinical syndrome, so there does need to be a certain understanding of what the antibodies mean. A simple formulation grouping antibodies based on their target can be helpful in this regard.
“It’s generally accepted there are two broad categories of these antibodies. One consists of antibodies that target intracellular antigens in the nucleus or cytoplasm of neurons and the other group of antibodies target cell membrane antigens, which could be ion channels, receptors or related proteins. These two groups of antibodies are interpreted quite differently. Those that target intracellular neuronal antigens are often associated with cancer, and the neurological damage is often very difficult to treat. Those that target cell membrane antigens are more common, less likely to be associated with cancer, and more responsive to treatment. Antibodies against cell membrane antigens also have to be interpreted more cautiously since the specificity of these antibody tests is not 100%.
“There is also a third category of antibodies, often tested for in the context of autoimmune neurological disorders, which must be interpreted with caution. One of these is the GAD65 antibody, which targets a cytoplasmic enzyme. This antibody is associated with a range of different diseases including autoimmune neurological disorders such as stiff person syndrome or epilepsy, but it can be found in other conditions including diabetes and is also found in a small number of normal subjects.”
Although there have been no double-blind placebo-controlled trials to determine treatment efficacy for the autoimmune neurologic conditions there is a growing body of evidence to support therapeutic approaches.1, 3-5 “Most experts in the field believe these conditions are autoimmune diseases,” says Dr. Vernino. “There’s good animal model evidence for some of these disorders demonstrating that the autoantibodies or cells of the immune system are responsible for the neurological problems. So treatment that targets the immune system should be effective. There have certainly been a large number of case reports and case series that have indicated the benefits of immunotherapy.1, 3-5
“Most of us believe that early treatment is more effective because over time there will be some degree of permanent neurological injury. Also, treatment has to be targeted based on what we know about the pathophysiology. In the paraneoplastic conditions associated with neuronal nuclear and cytoplasmic antibodies, we believe the main effector of neurologic damage is a cell- mediated cytotoxic response—a cellular attack on neurons—which unfortunately often leads to permanent neurological injury. So, we have to be aggressive with those patients. If they have cancer, the cancer needs to be found and treated. And then we would often use strong immunosuppressant therapies.
“Antibodies targeting cell membrane antigens may cause functional effects rather than actual neurological permanent damage. So, the main approach with these is to remove the relevant antibodies. Treatment like plasmapheresis, anti-CD20 therapy or intravenous immunoglobulin therapy is favored in those conditions. Some retrospective case series have shown these treatments are effective and that patients treated have a positive outcome; in some cases they can return to near normal functioning if the disease is identified early and effective treatment is started. There is certainly a need in the field for proper class I evidence of treatment benefits, and some of us are working on that, but there is general agreement that these patients have a treatable condition and that there are a variety of therapeutic tools we believe can be effective in the appropriate cases.”
A call to action
“The autoimmune neurologic diseases are not rare and we should have a clinical suspicion about them,” summarizes Dr. Vernino. “They should be part of the differential diagnosis for anyone that develops a rapid onset, meaning within weeks, of neurological deficits, particularly if they fit one of the classic modes of limbic encephalitis, neuromuscular junction problem or cerebellar ataxia.
“We now can use antibody testing as a powerful diagnostic tool, Antibody tests can be used to help clarify the diagnosis, but we still have to interpret those antibody results based on clinical correlation. It is important to get it right because some patients with these diseases will respond to treatment.”
1. Vernino S, O’Neill BP, Marks RS, O’Fallon JR, Kimmel DW. Immunomodulatory treatment trial for paraneoplastic neurological disorders. Neuro Oncol.2004;6: 55–62
2. Irani SR, Alexander S, Waters P. Antibodies to Kv1 potassium channel-complex proteins leucine-rich, glioma inactivated 1 protein and contactin-associated protein-2 in limbic encephalitis, Morvan’s syndrome and acquired neuromyotonia. Brain. 2010;133: 2734–2748
3. Titulaer MJ, McCracken L, Gabilondo I et al.Treatment and prognostic factors for long-term outcome in patients with anti-NMDA receptor encephalitis: an observational cohort study. Lancet Neurol.2013;12:157-65.
4. Vincent A, Buckley C, Schott JM et al. Potassium channel antibody-associated encephalopathy: a potentially immunotherapy-responsive form of limbic encephalitis.Brain.2004;127:701-12
5. Thieben MJ, Lennon VA, Boeve BF, Aksamit AJ, Keegan M, Vernino S. Potentially Reversible Autoimmune Limbic Encephalitis With Neuronal Potassium Channel Antibody. Neurology.2004;62:1177-1182
Steven Vernino, M.D. Ph.D.
Professor and Vice Chair for Academic Affairs
Department of Neurology & Neurotherapeutics
University of Texas, Southwestern Medical Center
Released on Thursday, August 17, 2017