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September 9, 2018 | Tabitha Andrews Orth

One of the most frequently asked questions we hear from our ‘AE Family’ is: What treatment gave you the best result?  It’s a sound question.  When our lives are flipped upside down, run over, tossed down the rabbit hole and we are hit by the train known as autoimmune encephalitis, all we want to know is: How do I get well? How do I reach recovery? You’re thinking, (to cite an example), ‘I want the best treatment there is.  My loved one was perfectly healthy and out of the blue went into psychosis, started having seizures, lost my memory, became cognitively impaired, had trouble talking, slipped into catatonia and entered coma.  They came close to losing their life in the blink of an eye.  So, I want to know the treatment that will put them into recovery and get their life back!’  

The situation, however, is that there are many forms of autoimmune encephalitis and they are divided into several groups of diseases.  Most forms of autoimmune encephalitis respond to immune therapies, although powerful immune suppression for months or years may be needed in difficult cases and may take many months to reach their full effects.  Treatment usually involves removal of the immunologic trigger, such as a tumor when applicable, followed by escalating immune therapies.  Early tumor treatment is particularly important in achieving a positive outcome.  For the Neurologist, the process of caring for AE patients requires patience and repeated evaluations to determine the proper degree of immune therapy needed at any given time.

The aim of this article is to lead you to a stronger understanding of why treatments vary from case to case, so you can become a stronger advocate/self-advocate in your own AE journey back to health.  By gaining a greater understanding of Autoimmune Encephalitis, it will become clearer to you why asking the question: “What treatment gave you the best result?” won’t provide you with the answer you are seeking.  We all wish it was as simple as taking a poll of AE patients and going with the treatment that seemed to be the most common response. Wouldn’t it be nice if it were as straightforward and uncomplicated as that?  Unfortunately, there is no ‘one size fits all’ answer to treatment. No simple absolutes. No magic bullets for everyone receiving this diagnosis. 

It is important to understand that treatment recommendations are based largely on retrospective co-hort studies and expert opinion, since few clinical trials have been conducted.  It is for this reason that IAES has set a standard that doctors placed on the IAES Doctor’s List need to have met to be placed on the list. IAES requires that physicians need to have either published on autoimmune encephalitis, presented at a conference as an expert in the field or demonstrated expertise that confirms their knowledge since that knowledge is paramount to ensure that a patient with autoimmune encephalitis receive the most accurate and aggressive treatment plan that will lead them to the best possible outcome. Since treatment recommendations are based largely on retrospective co-hort studies and expert opinion, and treating a patient with AE is complex, choosing who you hire to oversee your care is the most important decision you will make.

Different Forms of Autoimmune Encephalitis-  

The antibodies that have been identified in autoimmune encephalitis, act differently and have distinct symptoms and syndromes associated with each of them. Some have cancer associations. This means that many of these forms of autoimmune encephalitis have treatments in the protocol that have been specifically identified through research and case studies that can affect and hopefully arrest that form of the disease.

Here are some examples to illustrate the point. If you have the LGI1 antibody, the LGI1-associated disease spectrum spans from patients with only faciobrachial dystonic seizures (FBDS) to patients with severe encephalopathies, and less persistent aggressive treatment is often appropriate; plasmapheresis (PLEX) or IVIg with oral steroids is successful in many patients, although some require second-line therapies.

If you have the AMPAR antibody, first-line treatment (steroids or IVIg) and, when appropriate tumor removal, often lead to a complete or partial remission of the symptoms.  

Anti-NMDAr encephalitis requires tumor removal if present which brings some patients into recovery. However, since anti-NMDAr encephalitis is characterized by long-lasting antibodies (Abs) in patients and often a prolonged disease that can relapse-remit, a relatively aggressive treatment approach with extensive use of immunosuppressive drugs such as rituximab and cyclophosphamide for several months, may be justified alone or in combination with other anti-NMDAr patients. (1).

Are you beginning to understand why asking this basic question: “What treatment gave you the best result?“ is not going to garnish helpful information to your specific situation?  We want to help you understand AE with a good enough grasp of the basics in hand that your doctor’s appointments leave you with a better understanding of the reasoning behind treatment decisions and confidence in your treating physician. Because we at IAES believe “Education is Power”, conscientiously reporting your history and symptoms accurately will help to guide the physician in treatment plan decisions for your best outcome.

Let’s take an overview together; a bit of a ‘mini lesson’ about autoimmune encephalitis that will give you a better understanding of the disease process and treatment decisions.

In 2005 Dr. Josep Dalmau had his first case of autoimmune encephalitis. His research was published in 2007. anti-NMDAr had been identified and antibody-mediated Autoimmune encephalitis was ‘put on the map’. Since that time, approximately 2 dozen antibodies (cell surface or synaptic proteins) have been identified as well as 2 intracellular antibodies (that are usually non-paraneoplastic). It is thought that many more antibodies are yet to be identified. Some researchers think it could be 100+. Each new discovery brings us closer to understanding the disease and the symptoms that occur that are unique to each antibody, how they affect us and the best treatment to combat each.

The memes below are a lay person’s picture that I hope will help to explain the antibodies. To see how each antibody affects us, go to Antibodies in Autoimmune Encephalitis page of our website and review the antibody charts there. Pictured are the 16 most common extracellular antibodies.  They are known as cell surface antibodies or synaptic proteins.  They bind to the outside of the cell which is why they are called ‘extracellular’. Because they are exposed out in the open, immunotherapy treatments can target them easily and arrest the progression of the disease. Antibodies in red are the most common in this category: anti-NMDAr, LGI1, CASPR2, AMPAR, GABA aR, GABA bR, and DPPX.

These cell surface or synaptic antibodies, known as EXTRACELLULR antibodies, do not aggressively kill healthy brain cells (neurons) as paraneoplastic antibodies do and the effects on the synaptic function in brain neurons can be reversed with relatively little neuronal death with early and aggressive treatments. Some patients have had reversal of symptoms with significantly delayed treatment as well. Research has shown that best outcomes result when early and aggressive treatment is received. 

These two antibodies, GAD65 and amphiphysin are INTRACELLULAR synaptic antibodies. Intracellular antibodies seep INSIDE the brain cell they are attacking. Synaptic antibodies (also called proteins) transfer information from one cell to another cell. The transfer of information can be from nerve to nerve or muscle to muscle. Most often they are non-paraneoplastic but do have a cancer association. Immunotherapies have limited responses with these antibodies because they are ‘inside’ the cell they are attacking making them harder to affect. Researchers share that not everything is known about the GAD65 antibody and postulate that when the synapse fires and sends its information from one cell to another there is a momentary exposure of GAD65 to the outside which provides an opportunity for the immunotherapy treatment to make an affect.

The rarest antibodies in AE are the paraneoplastic antibodies. They are even more rare in children. These intracellular antibodies (inside the cell) are associated with a systemic cancer. They are T-cell mediated and do not respond well to immunotherapies. A tumor search is repeated approximately every 3-6 months. Rituxan is used in case a co-existing extracellular B-cell mediated antibody is co-existing. (Yes. You can have more than one antibody in autoimmune encephalitis).  Plasmapheresis and cyclophosphamide (Cytoxan) are used to affect the inside of the cell.  Cellcept (mycophenolate mofetil) and Imuran (azathioprine) may also be used as they affect both B and T cells. Research for better treatments is on-going. You can read about some of the more prominent treatments for refractory (non-responsive) cases such as Bortezomib, Tocilizumb, Ofatumumab and Inebilizumab on the Diagnosis and Treatment page of our website.  

Now that you have a ‘lay person’s’ image of what the antibodies do. Take a close look at these scientifically based illustrations to further solidify your understanding. On the left you see what the cell surface antibody does. See how it attaches itself (blue upside-down Y) to the OUTSIDE of the healthy brain cell (neuron)? The attacking antibody is exposed to the OUTSIDE. So, immunotherapy treatment can affect it easily.

Now, look at the right image. See how the attacking antibody (pictured as yellow circles) has seeped INSIDE the cell? This is why these antibodies are very hard to treat and don’t respond well to immunotherapy. Cyclophosphamide is often used because other treatments don’t have the same effect as they do with the types of antibodies on the left (which are the most common ones).

If the physician suspects autoimmune encephalitis, treatment is often given empirically prior to specific antibody test results. This may include steroids and/or IVIG. If a cell-surface/synaptic antibody disorder is diagnosed, initial treatments may include IVIG, plasmapheresis, and/or steroids.  If a synaptic/cell-surface antibody is detected, and the patient has any significant symptoms, first-line therapy should be given if it has not already been tried. In general, prompt treatment, and escalation of treatment in patients who remain ill, is associated with better outcomes.

Oh, I am hearing you worry. You are reading this and thinking: ‘But I don’t have an identified antibody!’ You’re in good company because a large percentage of us, estimates of around 35-40%, don’t have an identified antibody.  Being a patient with an unidentified antibody is not cause for concern. The history of how the illness appeared tells the expert a great deal. The doctor can identify a great deal about the probable disease course when they compare against how the other forms of AE present.  Doctors treat the AE patient based on the symptoms that are presenting. They consider how the illness came on and developed to guide them and can identify, for example, that it is a limbic encephalitis without knowing what the antibody is. Treatment decisions are not made by considering how high the antibody titers are (antibody concentration level). Titers have limited clinical usefulness for several reasons: they provide little information on disease severity.  Titers in serum do not correlate reliably with disease status, and CSF titers correlate only roughly to the status of the disease.  This is why it is better to focus on the clinical status of the patient and not changes in antibody titer during the early phases of the illness.  Therefore, the treatment plan is based on how the patient is presenting and how they respond to that treatment. I will note here that NMDAR CSF titers may be compared to earlier samples from the patient side by-side in assessing whether symptom worsening represents a true relapse, but this is only rarely helpful.

Treatment protocols have been proposed for anti-NMDAR encephalitis, and these approaches have been applied to other autoimmune encephalitis diseases/forms in the cell-surface/synaptic autoantibody category, which are the most common antibodies in autoimmune encephalitis. (The antibodies listed in the first image above).

Treatment begins with a complete tumor search. If a tumor is detected, tumor therapy (removal of the tumor) and immune therapy may need to be given at the same time and in a coordinated fashion.  It is important that this occurs first because treatment with steroids, rituximab (rituxan) and cyclophosphamide could complicate the diagnosis of a tumor such as the case in tumors like lymphoma.

Experts at UPENN, where the anti-NMDAr antibody was first identified by Dr. Josep Dalmau in a 2007 paper, often uses IV solumedrol (1 gram daily for 3-5 days then a taper over several weeks) and IVIg (0.4 g/kg/day for 5 days). Other experts in the field of autoimmune encephalitis have advocated plasmapheresis instead of IVIg, and so far, there is not convincing evidence of superiority for either approach.

If the patient remains significantly impaired after first-line therapy, second-line treatments are typically used. Some experts might wait 2 weeks or longer to allow first-line therapies time to work, but Dr. Eric Lancaster and Dr. Dalmau’s group at UPENN and Barcelona often proceeds more quickly to second line therapy sooner if patients who are very ill, for instance comatose patients with anti-NMDAR encephalitis.

Second line therapies include rituximab (often 375 mg/m2 weekly for 4 weeks) or cyclophosphamide (750 mg/m2 IV monthly until improvement is noted), or both. Rituximab is a monoclonal antibody targeting CD20, so plasmapheresis generally should not be done after it is administered. Due to its relatively favorable safety profile, rituximab is more often used as monotherapy in children. Treatment strategies are similar in children and adults, but physicians may be more reluctant to use cyclophosphamide with children, relying more on rituximab as a second line treatment.  As with adults, the optimal treatment strategies are not known. Responses to treatment are similar in children and adults, with about half failing first line therapies.

Patients with autoimmune encephalitis may recover, completely or partially, and then experience worsening symptoms.  Autoimmune Encephalitis patients may relapse so follow up care is important. Relapsed patients are usually treated with second-line therapies, possibly after first line therapies. These patients may be treated for longer periods of time with second line therapy, especially rituximab, but the optimal duration of treatment has not been established.

What is the answer to the most frequently asked question:  What Treatment has given you the Best Result?  It depends on the antibody you have or form of autoimmune encephalitis and the severity of the case/how the patient is presenting. 
 

References:  Antibody-Mediated Autoimmune Encephalopathies and Immunotherapies

Matteo Gastaldi,Anaïs, Thouin and Angela Vincent

The Diagnosis and Treatment of Autoimmune Encephalitis Eric Lancaster


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