The treatment of patients should be multidisciplinary and involve neurologists, as well as Neuroimmunologists, oncologists, rheumatologists, and psychiatrists. Autoimmune Encephalitis is treated with immunotherapy. Immunotherapy slows down the over-excited immune system. By slowing down the immune system it slows down the process the immune system is engaging in, which is creating the foreign antibodies that are attacking healthy brain cells. Suppressing the immune system attempts to stop the attack that is occurring.
There is no uniform standard immunotherapy. Initially, high dose steroids are used to slow down the immune system and bring down the inflammation in the brain in a broad way. Many patients experience the return of mental clarity after their initial 3-5 days of one gram IV Solumedrol. However, treatment for autoimmune encephalitis is a marathon and not a sprint as treatment is on-going and usually involves several combinations of treatment in the protocol.
Treatment should begin swiftly. Immunotherapy treatment is the combination of treatments that include first-line therapies: steroids, IVIG, plasma exchange (plasmapheresis), and resection of any underlying tumor are of primary importance. Second-line therapies: Rituxamab (Rituxan) and cyclophosphamide (Cytoxan). Those who remain refractory to first and second line treatment have benefited from Third-line/experimental treatments: IL6 blockade (tocilizumab) or plasma cell-specific therapy (proteasome inhibitors) or bortezomib, a treatment that depletes plasma cells. This is followed in many cases by steroid-sparing agents such as Cellcept or Azathioprine in the long-term. The fact that patients who receive second-line immunotherapies have fewer relapses, is leading many physicians to use rituximab initially as a first-line treatment.
Clinical improvement, an improvement of MRI, and EEG findings may be used to assess the success of treatment. Blood (serum) and cerebral spinal fluid (CSF) antibody titres should also be seen to decrease with adequate treatment response.
If the clinician suspects autoimmune encephalitis, treatment is often given without delay based on clinical observations of symptoms, a history of how the disease developed, and the results of medical evaluations and tests performed. Prompt treatment and escalation of treatment in patients who remain ill, is associated with better long term recovery. Experts in the field do NOT wait for antibody testing to come back. This process can take up to 10 days and time is of the essence. Since a negative antibody test does not rule out autoimmune encephalitis, the clinician treats without delay.
In the case, of ‘probable’ or ‘possible’ autoimmune encephalitis being suspected, treatments may include steroids and/or IVIG. High-dose methylprednisolone therapy can regulate T lymphocyte function and reduce inflammatory responses.
IVIG offers an important advantage of being unlikely to make an infectious encephalitis worse. IVIG is a blood product perpared from the serum of more than 1,000 donors that contains a broad range of antibodies. Some of these antibodies target a patient’s autoantibodies and neutralize them, along with other pro-inflammatory aspects of the immune system. IVIG can inhibit humoral and cellular immunity and regulate immune responses through a variety of mechanisms.
Plasmapheresis is also unlikely to significantly worsen infectious encephalitis. Plasmapheresis (also called PLEX) “cleans” the blood of autoantibodies by replacing the liquid plasma portion of a patient’s blood with that of a donor thereby impoving the disease. Plasmapheresis also changes T and B cells in favorable ways. A more refined form of PLEX called immunoadsorption has also been used to treat AE, and selectively removes antibodies from the blood, instead of all the other components that are also in the plasma. However, both PLEX and immunoadsorption only remove antibodies from the blood, not from the brain; although decreasing antibodies in the blood can lead to a decrease in the brain. These two treatments, IVIG and plasmapheresis, modulate the immune system and do not suppress the immune system.
Since infectious encephalitis mimics autoimmune encephalitis at the beginning, these treatments will not put the patient at risk of having an infection worsen should the outcome of further testing confirm the culprit to be an infection and not autoimmune encephalitis. Additionally, clinicians may initially treat with antibiotics if it is unclear which type of encephalitis is occurring, infectious or autoimmune. The reason for this is antibiotics will not harm the patient if it is confirmed to be autoimmune encephalitis and since infectious encephalitis presents just like AE and has a 25% mortality rate, it is the wiser course of action in many cases. No response to antibiotics helps direct the clinician to move forward with the treatment protocol for autoimmune encephalitis. Clinicians need to also consider that treatment with steroids, rituximab, or cyclophosphamide could complicate tumor diagnosis in the case of tumors like lymphoma.
If a cell-surface/synaptic antibody disorder is diagnosed, (remember those are the extracellular antibodies which are exposed on the OUTSIDE of the brain cell it is attacking). Initial immunotherapy treatments may include IVIG, plasmapheresis, and/or steroids. Immunotherapy is mostly targeting the B cell response which is why positive outcomes are seen in these more commonly occurring antibodies in autoimmune encephalitis.
The response to immune therapy is generally good, particularly if the more effective treatments are used promptly. However, powerful immune suppression may be needed for weeks or months in difficult cases and treatment may take many months to reach its full effects. The speed of recovery, degree of residual deficit, and frequency of relapse vary according to the type of autoimmune encephalitis and level of severity. The length a patient may be treated for AE can range from many months/less than a year of treatment after diagnosis to many years of treatment until recovery is reached. It is estimated that some AE patients are left with a 35-42% amount of persistent deficits, especially in the domains of memory and cognition. Autoimmune encephalitis may relapse, so follow-up care is important.
Treatment of autoimmune encephalitis is currently based on expert opinion and experience. Randomized controlled trials are needed to establish best practice and standards of care for these conditions.
Many forms of autoimmune encephalitis are paraneoplastic, and each of these conveys a distinct risk profile for various tumors. Tumor screening and, if necessary, tumor removal is essential to proper management of treatment.
When a patient begins treatment
They patient and their family have an expectation that they will see a straight line of improvement, when the current reality is topsy-turvy (left image). The image to the right, is a an honest visual of what recovery from autoimmune encephalitis looks like and explains what the patient and family should expect. There are going to be big ups and downs. Especially on a day to day basis with AE. What the doctor and patient are looking for, is improvement that is trending in the right direction. We are not talking about day to day or month to month, but rather over the course of months and years. Is the patient moving toward the ultimate goal? Little ups and downs are okay, but is the patient steadily improving? Understanding this as what the patient can expect as a baseline, helps set the stage of what success looks like moving forward.
Why Does Recovery Move So Slowly?
The human brain is, by design, not primed for quick recovery post brain injury from AE. The process of regrowth is complicated by the fact that the old pathways don’t exist. So, the body first grows axons and tries to form synaptic connections which may be shooting in the wrong direction. Then the immune system goes to work to give those a trim to shape them so that there is a more organized connection. You will see a lot of symptoms that may seem like a regression as a result of this; when they are really just the natural process of the order being reestablished in the brain that is working hard to recover. Creating a new way of functioning takes a ton of energy physically, which is why you see fatigue, irritability, flooding, seizures, headaches, etc. In the end, the new pathways might still be less efficient than the old ways of doing things, again contributing to fatigue and a much less efficient working process, at least at the early stages of recovery.
Dr. Justin Abbatemarco of the Cleveland Clinic provides an outstanding overview of Treatment for Autoimmune Encephalitis.
AE Awareness Month 2021.
As of 2016, experts in the field of autoimmune encephalitis did not yet have any really good immunotherapy treatments for patients with intracellular antibodies. Researchers know that conventional therapies are not effective.
Help is on the horizon as researchers work to identify effective treatments. Some very preliminary small studies in immunology are looking at medications like the immune suppressant, Tacrolimus. Tacrolimus has been used in other types of neurological syndromes and is being explored for patients with intracellular antibodies in paraneoplastic autoimmune encephalitis. Tacrolimus is a potent inhibitor of lymphocyte proliferation that is commonly used to suppress the immune system for transplant patients to prevent rejection. Tocilizumab is showing some promise in research as a good treatment strategy for treating AE refractory to conventional immunotherapies and rituximab.
Intracellular antibodies (those that are INSIDE the cell and involve aggressive T-cell responses targeting the neuronal brain cells) are mostly mediated by cytotoxic CD8+ T cells that cause functional and structural neuronal damage and this is why there is a likelihood that a response to immunotherapy is not seen in these patients.
At this time, plasmaphereses, Rituxamab (Rituxan) and the chemotherapy drug, Cyclophosphamide (Cytoxan) is used to treat various types of paraneoplastic autoimmune encephaladies.
New Treatments for Refractory Cases:
As research continues to unfold, alternative treatments for cases that have been resistant to the prior mentioned immunotherapies have come to the forefront. More prominently: Bortezomib, Tocilizumab, Ofatumumab, Obinutuzumab and Tofacitinib. In October 2020, Enspryng, was approved by the FDA for the treatment of neuromyelitis optica spectrum disorder (NMOSD), which involves antibodies against the aquaporin 4 (AQP4) protein and can co-exist with anti-NMDAr AE.
Clinical trials are currently testing the effectiveness of intrathecal injections of methotrexate and glucocorticoids as an attempt to block the intrathecal synthesis of anti-NMDAR antibodies. So far, this treatment showed promise by improving the symptoms of patients and reducing CSF antibody titers.
Early Treatment and Outcomes:
The speed of recovery, degree of residual deficit, and frequency of relapse vary according to the type of autoimmune encephalitis. The case that early treatment provides the best outcomes for long term recovery, has been made in several studies. A small case series reported that 4 of 5 children treated with combinations of first-line immunotherapy within 6 days of symptom onset recovered fully with no relapses. The strongest evidence in favor of early treatment comes from the largest observational cohort published, Clinical experience and laboratory investigations in patients with anti-NMDAR encephalitis.
In that study, 53% had clinical improvement within 4 weeks, and 81% had substantial recovery (i.e., mild or no residual symptoms) at 24 months. Approximately 50% of patients respond to first line immunotherapies (intravenous immunoglobulins (IVIG), steroids, or plasma exchange) and the other 50% require second line therapies, such as rituximab or a combination of rituximab and cyclophosphamide. Relapses occur in 12–20% of cases (12% during the first 24 months of the disease), often presenting as fragments of the syndrome (perhaps due to prompt diagnosis), and respond to immunotherapy. Patients who do not respond to treatment, or who have relapses, should be reassessed for the presence of an underlying contralateral (opposite side) or recurrent teratoma with anti-NMDAr and tumor search in other variants where this may occur.
In the July 2016 study, Anti-LGI1-associated cognitive impairment: Presentation and long-term outcome, Drs. Dalmau and Graus were surprised to discover in their study of the most common Limbic encephalitis, at follow up after 2 years shows patients had a more rapid response but that only 70% had substantial recovery. 35% of patients were fully recovered but not able to return to their previous jobs or function as they had previously due to lasting brain injury. Of the patients who received treatment within 3 months 27% relapsed. Relapse usually occurs when immunotherapies are tapered early. The final outcome for those with LGI1 antibodies is far from optimal. Improvement occurs but they acknowledge that there is a lot more that needs to done to get better improvement for these patients.
The associated syndromes often respond to immunotherapy, resulting in substantial or complete recovery particularly if the more effective treatments are used promptly. However, treatment may take many months to reach its full effects, and some patients have persistent deficits, especially in the domains of memory and cognition.
The frequency of clinical relapse in the encephalitides associated with antibodies against NMDAR, AMPAR, LGI1, CASPR2, or DPPX ranges from 12 to 35%. Relapses often occur when immunotherapy is reduced or discontinued. Relapses may occur due to a recurrence of the associated tumor or identifying a tumor that was missed in the initial evaluation. Immunotherapy and treatment of the tumor usually result in improvement.
Prior to these disorders being identified, and taking into account the severity and duration of symptoms, the clinical recovery of similar patients was not expected. Unaware of how the disorders worked and that they could respond to a treatment, they were thought to be untreatable and the disease was allowed to progress. These patients eventually died of status epilepticus or coma. The discovery of the first antibody, NMDAr, and subsequent antibodies since, has changed the concepts about supportive therapy today in cases that would have been considered futile in the past.
Modified Ranking Scale:
Most studies have used the modified Rankin Scale (mRS) to measure outcome. The is a commonly used scale for measuring the degree of disability or dependence in the daily activities of people who have suffered an illness that caused neurological disability. The Dalmau and Lancaster co-hort study of 577 patients, demonstrated that early treatment, the lack of need for intensive care admission, and maximum mRS score of ≤ 3 were independently associated with good outcome. In that study, about half the patients who received first-line immunotherapy improved within 4 weeks of treatment, and 97 % of these patients went on to have a good outcome (mRS 0–2) at 24 months of follow-up.
Even in those patients classified as having good outcome in Autoimmune Encephalitis, (mRS 0–2), incomplete recovery with deficits in executive function and memory are common and are more severe in those with delayed treatment. This would suggest that the initial part of the illness may be critical in terms of neuronal damage and long-term disability which is why it is so important to be aware of this syndrome during its earlier psychiatric presentation. As it progresses into the the later neurologic stages, the potential for a long term deficit increases.
In addition, the associated syndromes often respond to immunotherapy, resulting in substantial or complete recovery in 70–80% of the patients. Physicians should be aware that isolated psychiatric symptoms can last for months before neurological symptoms and should remain hopeful for a good prognosis because continuous immunotherapy can achieve a favorable outcome despite delayed diagnosis. Owing to the severity and duration of symptoms, before these disorders were known the clinical recovery of similar patients was not expected, thus changing our concepts about supportive therapy today in cases that would have been considered futile in the past.
The Modified Rankin Scale is widely used in neurology and clinical trials as a predictor of “good” or “bad” outcomes. It does have some severe limitations. It looks at ‘big picture ideas’, are patients able to return home? Can they resume some of their activities? Do they need assistance walking or nursing care assistance? What is missing in the scale are cognitive deficits, fatigue, and psychiatric symptoms. So the scale used to determine if a patient as a “good” or “bad” outcome, don’t encompass the day to day troubles that patients can experience. Therefore, there are big limitations researchers have when describing AE outcomes in publications and potential therapies.
Neurology started looking at this and in 2019 the Clinical Assessment Scale in Autoimmune Encephalitis (CASE) Score was developed. This does a better job of holistically describing what patients can truly experience with autoimmune encephalitis. The more comprehensive CASE scale consists of 9 items (seizure, memory dysfunction, psychiatric symptoms, consciousness, language problems, dyskinesia/dystonia, gait instability and ataxia, brainstem dysfunction, and weakness). Each item is assigned a value of up to 3 points. The total score could therefore range from 0 to 27 points. It is not perfect, but clinicians are starting to understand In the graph pictured, patients go from high scores to lower scores showing their improvement. It is important to highlight the time frame involved, which shows the true marathon involved with autoimmune encephalitis of 450 to over 700 days for this kind of recovery.