Diagnosis and Treatment of AE
B cell-based Therapies
Treatment Strategies of AE
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. 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 types of treatment in the protocol.
Immunotherapy treatment is the combination of treatments that include first-line therapies: steroids, IVIG, plasma exchange (plasmapheresis) and second -line therapies: Rituxamab (Rituxan) and cyclophosphamide (Cytoxan), 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.
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 outcomes. 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.
IVIG offers an important advantage of being unlikely to make infectious encephalitis worse. Plasmapheresis is also unlikely to significantly worsen infectious encephalitis. These two treatments 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 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 wises 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. Some patients, an estimate of 35-42% have persistent deficits, especially in the domains of memory and cognition. Autoimmune encephalitis may relapse, so follow-up care is important.
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.
Special Thanks to Autoimmune Encephalitis Alliance who sponsored the symposium from which this video was taken
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 and Inebilizumab.
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, 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.