Related Autoimmune Neurological Diseases

Encephalitis is a heterogeneous group of disorders including both infectious encephalitis and Autoimmune Encephalitis (AE). Encephalitis is a common neurological disease and a major public health concern in the United States with more than 20,000 hospitalizations per year and a fatal outcome in 5.8 percent.  It is estimated that over 50 percent of patients remain without a clear diagnosis and etiology (or cause) despite an extensive work up. However, recent research shows that autoimmune encephalitis is not as uncommon as previously thought. One study, found an incident rate (from 1995-2015) of autoimmune encephalitis was 0.8 per 100,000 people (1).

Particularly in younger patients, less than the age of 30 years old, autoimmune encephalitis is found more frequently than viral encephalitis (2). Forms of autoimmune encephalitis include paraneoplastic disorders, classically associated with cancer, and other antibody-mediated diseases associated with cell-surface antibodies that may or may not be associated with cancer.

The diagnosis of autoimmune encephalitis is based on the overall clinical picture and looking various parts of the diagnostic work up. Sometimes a clear antibody is found, but many times an antibody is not found. As our understanding of autoimmune encephalitis grows, we will likely continue to discover new antibodies since these auto-antibodies continue to be discovered at a very rapid pace. Additionally, there are limitations to antibody testing and not all the antibodies we recognize to cause autoimmune encephalitis are commercially available for testing yet.

The discovery of new neural autoantibodies has revealed that these conditions are much more common than previously appreciated and often times patients are misdiagnosed or remain undiagnosed. As the increased awareness of autoimmune neurological disease continues to increase, it is likely more patients will be diagnosed and will require appropriate treatment.

The two most common antibody-mediate autoimmune encephalitides are NMDA receptor encephalitis and LGI1 autoimmune encephalitis which are detailed here:

NMDA receptor encephalitis

What is NMDA receptor encephalitis? 

Anti-NMDA receptor encephalitis was first described in 2007 as a syndrome of memory problems and confusion, psychiatric symptoms, seizures, hallucinations and movement disorders in four young women with ovarian teratomas (3). Since that time, there have been many causes reported in children, as well as, young to middle age adults including men and women without an underlying tumor. This syndrome is often diagnosed based on the presentation of rapid onset of abnormal or psychiatric behavior, speech dysfunction, seizures, abnormal movements, decreased level of consciousness and/or autonomic dysfunction. Diagnostic testing often includes a lumbar puncture, brain imaging (MRI), and electroencephalogram (EEG). Patients often have evidence of inflammation in their CSF and the diagnosis is confirmed when patients are found to have a positive NMDA receptor antibody in the CSF.

What are the symptoms?

Anti-NMDA receptor encephalitis patients may have a flu-like illness before the onset of psychosis, hallucinations, memory problems and many times seizure and abnormal movements.  Untreated, patients can eventually develop respiratory failure and coma. Overall patients typically respond well to immunotherapy and should be treated rapidly. Sometimes, depending on severity, it can take a longtime to slowly recover.

What are the treatment options?

Immunosuppressive therapies used in the treatment of anti-NMDA receptor encephalitis. First-line therapies include intravenous steroids, intravenous immunoglobulin (IVIg), or plasma exchange. Second-line therapies often include off use label of rituximab and/or cyclophosphamide.

Rapid diagnosis and early treatment is essential in the treatment of autoimmune neurological disease, particularly in the setting of cell-surface antibody-mediated encephalitis such as NMDA receptor encephalitis. Treatment approaches are largely based on expert opinion and retrospective studies currently, as there is a strong need for future research with prospective trials (4). There are no randomized, prospective clinical trials in the treatment of anti-NMDA receptor autoimmune encephalitis currently.

LGI1 autoimmune encephalitis

What is LGI1 autoimmune encephalitis?

LGI1 autoimmune encephalitis is a rare antibody-mediated autoimmune encephalitis (5). It is likely to be the second most common form of antibody-mediated autoimmune encephalitis after NMDA receptor encephalitis. It often causes a limbic encephalitis which is an inflammatory process of the limbic system and temporal lobe of the brain which is a vital part involved in forming memories and emotions.  Individuals with this condition have severe short-term memory problems and often seizures with characteristic changes of inflammation in the temporal lobes seen on the brain MRI. Some individuals develop a distinct seizure pattern called faciobrachial dystonic seizures either before or at the onset of the limbic encephalitis and can provide a clue to the diagnosis.

What are the treatment options?

Similar to Anti-NMDA receptor encephalitis, immunosuppressive therapies used in the treatment of LGI autoimmune encephalitis.  There are no randomized, prospective clinical trials in the treatment of LGI autoimmune encephalitis.

Autoimmune Epilepsy

What is Autoimmune Epilepsy? 

Autoimmune epilepsy can be caused by the same class of antibodies seen in encephalitis, however seizures predominate the clinical presentation. Often seizures come on rapidly and are severe and refractory to standard anti-seizure medications (6) (7).

What are the treatment options?

Treatment approaches are similar to autoimmune encephalitis with the use of immune therapies.  First-line therapies include intravenous steroids, intravenous immunoglobulin (IVIg), or plasma exchange. Second-line therapies often include off use label of rituximab, mycophenolate mofetil, or azathioprine. Again, there are no randomized, prospective clinical trials in the treatment of autoimmune epilepsy.

 

Encephalitis

Encephalitis is a heterogeneous group of disorders including both infectious encephalitis and Autoimmune Encephalitis (AE). Encephalitis is a common neurological disease and a major public health concern in the United States with more than 20,000 hospitalizations per year and a fatal outcome in 5.8 percent.  It is estimated that over 50 percent of patients remain without a clear diagnosis and etiology (or cause) despite an extensive work up. However, recent research shows that autoimmune encephalitis is not as uncommon as previously thought. One study, found an incident rate (from 1995-2015) of autoimmune encephalitis was 0.8 per 100,000 people (1).

Particularly in younger patients, less than the age of 30 years old, autoimmune encephalitis is found more frequently than viral encephalitis (2). Forms of autoimmune encephalitis include paraneoplastic disorders, classically associated with cancer, and other antibody-mediated diseases associated with cell-surface antibodies that may or may not be associated with cancer.

The diagnosis of autoimmune encephalitis is based on the overall clinical picture and looking various parts of the diagnostic work up. Sometimes a clear antibody is found, but many times an antibody is not found. As our understanding of autoimmune encephalitis grows, we will likely continue to discover new antibodies since these auto-antibodies continue to be discovered at a very rapid pace. Additionally, there are limitations to antibody testing and not all the antibodies we recognize to cause autoimmune encephalitis are commercially available for testing yet.

The discovery of new neural autoantibodies has revealed that these conditions are much more common than previously appreciated and often times patients are misdiagnosed or remain undiagnosed. As the increased awareness of autoimmune neurological disease continues to increase, it is likely more patients will be diagnosed and will require appropriate treatment.

(Pictured: Brain MRI showing a limbic encephalitis from LGI1 autoimmune encephalitis.)

The two most common antibody-mediate autoimmune encephalitides are NMDA receptor encephalitis and LGI1 autoimmune encephalitis which are detailed here:

NMDA receptor encephalitis

What is NMDA receptor encephalitis? 

Anti-NMDA receptor encephalitis was first described in 2007 as a syndrome of memory problems and confusion, psychiatric symptoms, seizures, hallucinations and movement disorders in four young women with ovarian teratomas (3). Since that time, there have been many causes reported in children, as well as, young to middle age adults including men and women without an underlying tumor. This syndrome is often diagnosed based on the presentation of rapid onset of abnormal or psychiatric behavior, speech dysfunction, seizures, abnormal movements, decreased level of consciousness and/or autonomic dysfunction. Diagnostic testing often includes a lumbar puncture, brain imaging (MRI), and electroencephalogram (EEG). Patients often have evidence of inflammation in their CSF and the diagnosis is confirmed when patients are found to have a positive NMDA receptor antibody in the CSF.

(Pictured: Image for NMDAR encephalitis, from: Piquet AL, Linnoila J. Surface Antibody-Mediated Autoimmune Encephalitis . In: Neurorheumatology. Cho TA, Bhattacharyya S, Helfgott S, editors. New York: Springer Publishing Company; 2019. Imaging Courtesy of Otto Rapalino, MD.)

What are the symptoms?

Anti-NMDA receptor encephalitis patients may have a flu-like illness before the onset of psychosis, hallucinations, memory problems and many times seizure and abnormal movements.  Untreated, patients can eventually develop respiratory failure and coma. Overall patients typically respond well to immunotherapy and should be treated rapidly. Sometimes, depending on severity, it can take a longtime to slowly recover.

What are the treatment options?

Immunosuppressive therapies used in the treatment of anti-NMDA receptor encephalitis. First-line therapies include intravenous steroids, intravenous immunoglobulin (IVIg), or plasma exchange. Second-line therapies often include off use label of rituximab and/or cyclophosphamide.

(Pictured: Picture of positive NMDA-R antibody test in cerebrospinal fluid.)

Rapid diagnosis and early treatment is essential in the treatment of autoimmune neurological disease, particularly in the setting of cell-surface antibody-mediated encephalitis such as NMDA receptor encephalitis. Treatment approaches are largely based on expert opinion and retrospective studies currently, as there is a strong need for future research with prospective trials (4). There are no randomized, prospective clinical trials in the treatment of anti-NMDA receptor autoimmune encephalitis currently.

LGI1 autoimmune encephalitis

What is LGI1 autoimmune encephalitis?

LGI1 autoimmune encephalitis is a rare antibody-mediated autoimmune encephalitis (5). It is likely to be the second most common form of antibody-mediated autoimmune encephalitis after NMDA receptor encephalitis. It often causes a limbic encephalitis which is an inflammatory process of the limbic system and temporal lobe of the brain which is a vital part involved in forming memories and emotions.  Individuals with this condition have severe short-term memory problems and often seizures with characteristic changes of inflammation in the temporal lobes seen on the brain MRI. Some individuals develop a distinct seizure pattern called faciobrachial dystonic seizures either before or at the onset of the limbic encephalitis and can provide a clue to the diagnosis.

What are the treatment options?

Similar to Anti-NMDA receptor encephalitis, immunosuppressive therapies used in the treatment of LGI autoimmune encephalitis.  There are no randomized, prospective clinical trials in the treatment of LGI autoimmune encephalitis.

Autoimmune Epilepsy

What is Autoimmune Epilepsy? 

Autoimmune epilepsy can be caused by the same class of antibodies seen in encephalitis, however seizures predominate the clinical presentation. Often seizures come on rapidly and are severe and refractory to standard anti-seizure medications (6) (7).

What are the treatment options?

Treatment approaches are similar to autoimmune encephalitis with the use of immune therapies.  First-line therapies include intravenous steroids, intravenous immunoglobulin (IVIg), or plasma exchange. Second-line therapies often include off use label of rituximab, mycophenolate mofetil, or azathioprine. Again, there are no randomized, prospective clinical trials in the treatment of autoimmune epilepsy.

 

Brain MR showing a limbic encephalitis from LGI1 autoimmune encephalitis

Related Autoimmune Neurological Diseases

Autoimmune Neurology is a rapidly evolving field in Neurology. Autoimmune diseases that target the central nervous system involve a variety of diseases that are distinctly different from multiple sclerosis (MS). An example of an antibody-mediated neurological disease is Neuromyelitis Optica Spectrum Disorder (NMOSD); once thought to be a form of multiple MS, NMOSD has now been defined as a distinct clinical–pathological disorder, although the initial clinical presentation and neurological symptoms may mimic MS. Additionally, newer recognized autoantibody-mediated neurological diseases include autoimmune encephalitis such as NMDA receptor encephalitis, among others.

The MS Center's Dr. Amanda Piquet and Dr. Enrique Alvarez recently collaborated as Editors for the book Neuroimmunology: Multiple Sclerosis, Autoimmune Neurology and Related Diseases, published by Springer International Publishing. You can learn more about this book by clicking here.

Some risk factors for developing autoimmune neurological diseases include:  coexisting autoimmune disease, such as thyroid disease, type 1 diabetes, lupus, or other rheumatologic disease; family history of autoimmune disease; and cancer association and factors such as smoking that put you at risk for cancers.  However, sometimes patients do not have any of these risk factors.The two most common antibody-mediate autoimmune encephalitides are NMDA receptor encephalitis and LGI1 autoimmune encephalitis which are detailed here:

Please read on for more information on Autoimmune Neurological Diseases, which we've grouped into these three main categories:

  • Encephalitis
    • Including NMDA Receptor Encephalitis, LGI1 Autoimmune Encephalitis and Autoimmune Epilepsy
  • Autoimmune Demyelinating Syndromes
    • Including Neuromyelitis Optica (NMOSD) and MOG Antibody Disease (MOGAD)
  • Other Autoimmune Neurological Diseases
    • Including Stiff Person Syndrome, Autoimmune/Paraneoplastic Cerebellar Ataxia, Transverse Myelitis, Neurosarcoidosis, Central nervous system (CNS) Vasculitis, and Neuro-rheumatological disorders


 

 

 

Piquet Amanda cudocsDr. Amanda Piquet
Rocky Mountain MS Center
Dr. Piquet specializes in Autoimmune Neurological Diseases related to multiple sclerosis, and has produced numerous papers on various subjects in this field.  Click here to see Dr. Piquet’s complete bibliography of contributions at the National Library of Medicine.

Dr. Piquet, along with the MS Center's Dr. Enrique Alvarez, collaborated as Editors for the book Neuroimmunology: Multiple Sclerosis, Autoimmune Neurology and Related Diseases, published by Springer International Publishing. You can learn more about this book by clicking here.

 

Autoimmune Demyelinating Syndromes

Neuromyelitis optica Spectrum Disorder (NMOSD)

What is NMOSD?

Neuromyelitis Optic (NMO) was once thought to be a form of multiple sclerosis (MS). NMO has now been defined as a distinct clinical–pathological disorder, although the initial clinical presentation often mimics MS (1). In 2004, Neuromyelitis Opticia (or NMO) was defined by the finding of a positive aquaporin-4 antibody (AQP4-IgG), also known at the NMO antibody. Before the discovery of this antibody, neurologists speculated about whether or not NMO and MS were the same or different disease. It is very clear now however that NMO is a distinct clinical–pathological disorder, although the initial clinical presentation may mimic MS. It is very important to differentiate between these two diseases because they have different treatments.

What are the treatment options?
There are now three new FDA-approved therapies for NMOSD since 2019, including Soliris (eculizumab), Uplizna (inebilizumab-cdon), and Enspryng (satralizumab-mwge).  When a patient presents acutely, steroids are commonly used to treat urgently and if the attack is severe often plasma exchange (PLEX) is added. The use of these acute therapies is similar to approaches used in multiple sclerosis.  To avoid future attacks or relapses, just like multiple sclerosis, chronic disease modifying therapies are used, although these longer-term disease-modifying treatments are different.

MOG Antibody Disease (MOGAD)

What is MOG Antibody Disease (MOGAD)?

MOG Antibody Disease (MOGAD) has a similar presentation to NMOSD and includes recurrent optic neuritis and spinal cord lesions (2) (3).  Importantly, it also includes the presence of anti-MOG antibody found in the blood. The full clinical spectrum of MOGAD continues to described in the literature, as the ability to accurately and widely test for this antibody did not occur until 2017. Clinical syndromes seen with MOGAD include: optic neuritis (inflammation of the optic nerve), encephalitis (inflammation of the brain), myelitis (inflammation of the spinal cord), and ADEM (acute disseminated encephalomyelitis; a syndrome often seen in children).

What are the treatment options?

We continue to learn more about this disease and the best treatment approaches. MOG antibody testing became commercially available in 2017. It is apparent however, that traditional MS disease-modifying agents appear to be ineffective.  Often similar treatment approaches to NMOSD are used, however we do not yet know whether B cell therapies are truly the best treatment approach or not. A retrospective study published in 2020 of 121 MOGAD patients treated with rituximab showed a reduction in relapse rates by 37%. Another large retrospective, multicenter study suggested that maintenance IVIg therapy might be helpful to reduce recurrent attacks. Prospective controlled studies are needed.

Other Autoimmune Neurological Diseases

Stiff Person Syndrome

What is Stiff Person Syndrome?

Stiff person syndrome (SPS) is a rare neurological disorder characterized by fluctuating muscle rigidity in the trunk and limbs and a heightened sensitivity to stimuli such as noise, touch, and emotional distress, which can set off muscle spasms (1).

This syndrome was first described as “stiff man syndrome” in 1956 by Moersch and Woltman at the Mayo clinic in the setting of being first identified in a 49 year old man with progressive stiffness in his neck, back and episodic painful muscle spasm and difficult walking. We now know that this syndrome affects both men and woman hence the terminology was changed to Stiff Person syndrome. This disease is rare and it is considered a one-in-a-million diagnosis with an estimate of it occurring in 1-2 per million people, although this is likely an underestimation based on the under-recognition of less severe or atypical presentations. Until recently in 2020, there was also limitation on the commercial availability of antibody testing with glycine receptor antibodies.

Diagnosis of SPS is made based on a combination of patient’s presenting symptoms, neurological examination, antibody testing, and electromyography (EMG). Antibodies that have been associated with SPS include GAD65, glycine receptor antibodies (2), amphiphysin, and DPPX.

What are the treatment options?

Treatment includes symptomatic treatment with antispasmodic agents and immunomodulatory therapy. Immunotherapy is often used given the presumed antibody-mediated disease mechanism, however large, randomized control trials are lacking. Intravenous immunoglobulin (IVIg) is most widely used as first-line therapy and there are small trials that have been shown to provide benefit with improved ambulation, decreased falls and increased ability to perform functions of daily living (3). Rituximab, while still used commonly as second-line therapy failed to demonstrate a statistically significant difference in only a small group of 24 patients (4).

Autoimmune/Paraneoplastic Cerebellar Ataxia

What is Autoimmune/Paraneoplastic Cerebellar Ataxia?

Ataxia is described at the lack of muscle control and incoordination of movements often resulting in problems with walking. Paraneoplastic cerebellar ataxia, also known as paraneoplastic cerebellar degeneration, is one of the wide array of paraneoplastic neurological syndromes in which neurological symptoms are indirectly caused by an underlying malignancy, most commonly gynecological, breast, or lung cancer or Hodgkin's lymphoma. This syndrome often presents with progression of neurological symptoms over weeks to months and results in severe disability including the loss of ability to walk, changes in speech, and eye movement abnormalities. More than 20 autoantibodies have been reported in association to autoimmune cerebellar ataxia. The term autoimmune cerebellar ataxia is used when is the underlying antibody is not associated to an underlying cancer, unlike paraneoplastic cerebellar ataxia.

What are the treatment options?

There are no randomized clinical trials in autoimmune or paraneoplastic cerebellar ataxia. Treatment strategies are based on expert opinion and case series. Cancer treatment for patients with paraneoplastic syndromes is critical and the first step in treatment. Immunotherapy maybe used in addition to oncological treatment or in the setting of autoimmune cerebellar ataxia immunotherapy alone is often used to help stabilize or improve neurological symptoms.

Transverse Myelitis

What is Transverse Myelitis?

Transverse myelitis (TM) includes a large group of disorders that leads to inflammation causing injury to the spinal cord with varying degrees of weakness, sensory alterations, and autonomic dysfunction. Autonomic dysfunction affects the part of the nervous system that controls involuntary activity, such as the heart, breathing, the digestive system, and reflexes. Wide ranges of causes include infections (often viral infections), post-infectious process (inflammation triggered by the infection and not direct infection of the spinal cord by the virus), demyelinating disease (such as MS, NMOSD, MOGAD – see above), autoimmune or paraneoplastic myelitis (caused by a particular autoantibody), or other systemic inflammatory disease (such as rheumatological disease or sarcoidosis). Diagnostic work up includes imaging of the spinal cord with MRI, blood work, and a lumbar puncture to evaluate for inflammation, virus, and/or antibodies in the cerebrospinal fluid (CSF).

(Pictured: Image of transverse myelitis, before and after administration of a contrast agent.)

What are the treatment options?

Treatment depends of the cause of the transverse myelitis and can range from antiviral therapy (if due to an infectious process) to immune therapy (if due to an inflammatory process).

Neurosarcoidosis

What is Neurosarcoidosis?

Neurosarcoidosis can occur when the nervous system is involved in sarcoidosis. Rarely, neurosarcoidosis can occur without any other organ involvement of sarcoidosis. It is a chronic disease of the central or peripheral nervous system and can results in many different types of neurological presentations. Symptoms are quite variable and range from cranial neuropathies (similar to a Bell ’s palsy, among others), chronic meningitis, transverse myelitis, and even strokes. Symptoms vary according to where the inflammation is occurring and sometimes it can look similar to multiple sclerosis.

What are the treatment options?

Often high-dose steroids are used as first-line treatment of sarcoidosis. Other longer-term, steroid-sparing treatment options include methotrexate and/or infliximab.

Central nervous system (CNS) Vasculitis

What is CNS Vasculitis?

Vasculitis is a group of related conditions that cause inflammation in the blood vessel walls. Vasculitis can involve the central and peripheral nervous system; therefore, can case many different types of neurological symptoms. Primary Central Nervous System (CNS) vasculitis is a very rare inflammatory disease that is isolated to the brain and/or spinal cord. Symptoms often include headache, cognitive impairment and stroke syndromes. Secondary nervous system vasculitis may occur in the setting of systemic vasculitis, connective tissue disease, infection, or from drug-induced.

What are the treatment options?

Treatment options may vary depending on whether it is a primary or secondary cause of CNS vasculitis, however the majority of the time steroids with our without the addition of cyclophosphamide are often used in the acute phase.

Neuro-rheumatological disorders

Rheumatological disease can vary greatly in presentation and can involve the central, peripheral, and/or autonomic nervous system. Beyond neurological symptoms, often there are systemic clues including constitutional symptoms (weight loss, fevers, generalized unwell feeling), muscle and joint involvement, skin involvement, eye involvement, Raynaud’s phenomenon, dry eyes and mouth, and gastrointestinal involvement. Examples of rheumatological disease include Sjögren’s syndrome, systemic lupus erythematosus, and antiphospholipid syndrome. Other inflammatory, systemic disease that can have neurological involvement include vasculitis, neurosarcoidosis, Behçet disease, Vogt-Koyanagi-Harda Syndrome, among many others.  Treatment will depend on the specific rheumatological or inflammatory disease and often requires specialist care including both rheumatology and neurology.

 

 

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