IS THERE A CURE FOR AUTOIMMUNE ENCEPHALITIS?
While there is no known cure for autoimmune encephalitis, this question needs clarification. For that, we reached out to Dr. Josep Dalmau who identified the first antibody in AE, along with many other antibodies, and is a world-renown expert. Here is his explanation.
“Autoimmune encephalitides are not one but many diseases. Many patients with these diseases are cured and never have any relapses or need further treatments. As with many other diseases, some patients are cured with one type of treatment or combination of treatments, and other patients are cured with other treatments or combinations.
The fact that a disease is cured does not necessarily mean that all patients need to be treated with the same drug or “magic bullet”, it depends on the patient and the disease. These concepts apply even for cancer; there are many patients with cancer that are cured. Not all receive the same treatment. The treatment varies with the type of cancer, and even with a specific type of cancer, not all patients are treated similarly. This example applies to many different diseases.
The question can be formulated as: Are there patients with autoimmune encephalitis that are eventually cured? Answer: Yes.”
Autoimmune Encephalitis can have a single phase. Instances of spontaneous recovery without immunotherapy or tumor removal, when present, have been reported. However, this is not typical. A patient enters recovery when the disease is no longer present. Patinets and family should have an expectation of a two year period of treatment to reach the point where it is determined that the disease is no longer present. Recovery from Autoimmune Encephalitis is not without the patient experiencing abnormality following the disease or permanent deficits resulting in an acquired brain injury (ABI) because of the disease. Deficits the patient experiences in cognitive domains at the beginning of their recovery may slowly improve even years following the end of treatment. Nevertheless, it is not uncommon for a patient to need several months of convalescence with intensive rehabilitation. Rehabilitation plays an important role in re-learning and re-training the brain from an acquired brain injury. (See: Rehabilitation cognitive exercises). Persistent cognitive impairment observed in long-term follow-up suggests irreversible neuronal death.
A longitudinal study for cognitive outcome has now been produced with 43 anti-NMDAr patients. All patients had cognitive deficits about 2 years after disease onset, mainly affecting memory and executive function. After 4 years, moderate or severe cognitive deficits persisted in 2/3 of patients despite good functional neurological outcome. Impaired cognitive outcome was predicted by delayed treatment and higher disease severity. However, continued improvement of cognitive function was observed for several years after disease onset in some patients. AE has a 7% mortality rate. AE-related deaths during the acute stage or follow up after discharge from the hospital have also been noted. Even if patients survive without immunotherapy, they may suffer a slower recovery requiring prolonged hospitalization.
Treatment for AE is a marathon, not a sprint. In practice, most patients are treated with glucocorticoids, intravenous immune globulin, or plasma exchange, and if there is no clinical response, rituximab and cyclophosphamide are used. Rituximab is usually effective in cases resistant to treatment. Rituxan appears to reduce the risk of a clinical relapse, which accounts for its increasing use as an initial treatment. Those who remain refractory to this treatment have benefited from IL6 blockade (tocilizumab) or plasma cell-specific therapy (proteasome inhibitors).
The speed of recovery, degree of residual deficit, and frequency of relapse vary according to the type of autoimmune encephalitis. AE is a family of syndromes, (group of diseases). Therefore it is important to understand that the experience of patients with one autoimmune encephalitis syndrome might differ from that of patients with different syndromes. A 2017 study concluded that patients with autoimmune encephalitis frequently suffer from persistent impairment in neurologic disability, neurocognitive symptoms, and adaptive function. Many of these impairments are not captured adequately by the Modified Rankin Scale.
Clinicians use caution when extrapolating findings from anti-NMDAR encephalitis to other forms of autoimmune encephalitis because each type (syndrome) of AE reacts a bit differently.
Cognitive deficits are frequent and severe long-term sequelae following NMDAR encephalitis. These deficits show a slow and incomplete recovery and persist beyond recovery of other neuropsychiatric symptoms of the disease. Rapid diagnosis and treatment at disease onset as well as for continued and customized cognitive rehabilitation to improve the long-term outcome is of vital importance. Anti-NMDAr recovery is often protracted with long hospital admissions. One remarkable feature of NMDAR encephalitis is the prolonged recovery, with progressive improvements in cognitive domains noted for years following the end of treatment. Another study showed that patients with anti-LGI1 encephalitis, the second most common type of AE, had a more rapid response to treatment but that only 70% had substantial recovery at 24 months. In LGI1 encephalitis, structural damage to the hippocampus often leads to permanent cognitive deficits. These persisting deficits can, however, be prevented by early immunotherapy after the first epileptic seizures.
The rapid increase in the number of syndromes and autoantibodies identified since the first antibody was identified in 2007 suggests that other autoimmune encephalitides have yet to be discovered. Antibody titers correlate imperfectly with the course of the disease and may remain detectable (albeit at a low titer) after clinical recovery.
Dr. Sergio Muñiz-Castrillo is a Stanford University Scholar and specialist in autoimmune encephalitis and paraneoplastic neurological syndromes. He provides an excellent overview of the prognostic indicators and cognitive and functional outcomes in AE patients. Relapse rates are also reviewed.
Dr. Tworek of the Cleveland Clinic provides an overview of the unique needs and opportunities to provide support and therapeutic services to those diagnosed with autoimmune encephalitis. She is working toward expanding behavioral medicine services to the AE patient population to include inpatient hospitalizations, outpatient follow up, and caregiver support.
Relapse of encephalitis was defined as the new onset or worsening of symptoms occurring after at least two months of improvement or stabilization. Patients without a tumor had a higher frequency of relapses than those with a tumor. If a tumor is found, removal is important because it expedites improvement and decreases relapses.
The frequency of clinical relapse, as stated in a 2018 review by Dr. Josep Dalmau and Dr. Francesc Graus, reported in the encephalitides associated with antibodies against NMDAR, AMPAR, LGI1, CASPR2, or DPPX ranges from 12 to 35%. The relapse rate in NMDAR encephalitis is reported to be 12–25 %, and relapses may occur in cases of anti-LGI1 or anti-NMDAR encephalitis months to several years after the initial episode. Relapses often occur when immunotherapy is reduced or discontinued. Relapses may herald recurrence of the associated tumor or a tumor that was missed in the initial episode. Immunotherapy and treatment of the tumor, if it was missed initially, usually result in improvement.
Relapses in NMDAR Ab encephalitis are often less severe and may be mono- or pauci-symptomatic. In children, atypical presentations such as cerebellar ataxia or brainstem signs have been described. The majority of relapses occur in patients who do not have a tumor associated with NMDAR antibody encephalitis, those who received no or limited treatment for the initial episode, and those not exposed to second-line agents. Second-line immunotherapy also appears to prevent further relapses in those with a multi-lapse disease course. At present, there is no clinical or paraclinical predictive marker for relapses. Although alterations in CSF antibody titers relate well to clinical changes, it is impractical and perhaps unsafe to conduct CSF analysis for predictive purposes in well patients. Changes in serum antibody titers were not well correlated with relapses. The effects of long-term immunosuppression with oral agents such as azathioprine or CellCept (mycophenolate mofetil) on relapse rate is currently unknown.
Following antibody titers in the management of patients has several limitations and rarely helps guide therapy, which should be based on clinical ﬁndings as titers are not reliable markers of disease severity, but they can sometimes predict relapses and support the use of prolonged immunotherapy for prevention.
To prevent relapses and maximize the response to acute phase therapy, maintenance immunotherapy should be instituted especially if early relapses during steroid taper occur. Commonly used drugs in this phase include oral corticosteroids, IVIG, and steroid-sparing agents such as mycophenolate mofetil, azathioprine, and rituximab. There are no guidelines regarding treatment duration; maintenance therapy is typically continuing for 3 years after stability is achieved. It is important to remember that the prolonged use of immunosuppressive medications increases the risk of lymphoproliferative disorders, and they have also been associated with progressive multifocal leukoencephalopathy.
The NEOS Score, published in December 2018, accurately predicts 1-year functional status in patients with anti-NMDAR encephalitis. This score could help estimate the clinical course following diagnosis and may aid in identifying patients who could benefit from novel therapies.
The prognosis in individual cases varies depending on the target antigen of the autoantibody, the presence or absence of associated tumors, the patient’s age, and the severity of the disease. Two independent predictors of a good outcome included the lower severity of symptoms assessed and no need for ICU support. For all types of autoimmune encephalitides, prompt immunotherapy has been associated with a favorable outcome; spontaneous clinical improvement is infrequent. Most studies have used the modified Rankin Scale (mRS) to measure the outcome. This 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 Titulaer and Dalmau cohort study of 577 patients, demonstrated that early treatment, the lack of need for intensive care admission, and a maximum mRS score of ≤ 3 were independently associated with good neurological outcomes. This study did not address lasting cognitive deficits. About half the patients who received first-line immunotherapy improved within 4 weeks of treatment, and 97 % of these patients went on to have good neurological outcomes (mRS 0–2) at 24 months of follow-up. These findings, which excluded measuring cognitive outcomes, were reported throughout the research until the end of 2019.
Even in those patients classified as having a good neurological outcome in Autoimmune Encephalitis, (mRS 0–2), cognitive recovery was incomplete with deficits in executive function and memory common and 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 autoimmune encephalitis as a culprit during the disease’s earlier psychiatric presentation. As AE progresses into the later neurologic stages, the potential for a long-term deficit increases.
Patients and Physicians should remain hopeful for a good prognosis as continuous immunotherapy can achieve a favorable outcome despite a delayed diagnosis.
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.
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 gain a better understanding.
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.