Article In Brief
An analysis of case reports across many different studies of anti-NMDA receptor encephalitis showed the lack of any treatment in the first 30 days was associated with poorer outcome, while the best outcomes were seen with apheresis alone, or corticosteroids plus IVIg, or all three first line therapies early in the disease course.
While NMDA receptor encephalitis (NMDARE) is the most common autoimmune encephalitis, it is rare enough that clinical trials have been challenging to mount; indeed, there have been no prospective trials in the disorder. In their absence, evidence for the best treatment strategy has come mainly from reports of individual cases and small series, and reviews by experts.
Now, in a study published September 20 in JAMA Neurology, researchers have brought together all the reported cases in the literature—1550 patients from 652 reports—since the 2007 discovery of NMDARE, analyzing the range of treatments and the factors associated with outcomes and relapse rates.
“The overriding message from this herculean undertaking,” said study leader Ming Lim, MD, PhD, “is that we need to recognize this condition early, and begin treatment right away. Treating it early and escalating as quickly as possible gives you a better outcome.” Dr. Lim is a reader in pediatric neurology at King's College London and a consultant pediatric neurologist at the Children's Neurosciences Centre of Evelina London Children's Hospital.
Of the 1550 patients described in the literature, three-quarters were female. Patients ranged in age from 0 to 85 years, with about half 18 years or younger at onset. One quarter had a tumor, primarily of the ovaries, a well-recognized cause of NMDARE. Half the patients required admission to the intensive care unit, and at initial presentation, over half had a Modified Rankin Scale (MRS) score of 5, indicating severe disability, and another quarter had a score of 4.
Despite the grave condition of most patients, only half (365 of 728 reported) received immunotherapy within 30 days of symptom onset. This lag, Dr. Lim said, was likely related to the delay in diagnosis.
“In many health care settings getting the diagnosis and the antibody test is difficult, and I think people are reluctant to start treatment early without it,” he added.
The lack of rapid diagnosis and treatment was nonetheless surprising, he said, and the proportion of patients receiving early treatment was no greater than in a 2013 “landmark” paper by Josep Dalmau, MD, PhD, and colleagues which described treatment and outcomes for 577 patients.
Initial treatment was corticosteroids, used in 91 percent of patients, followed by intravenous immunoglobulin (IVIg) in 66 percent, and therapeutic apheresis in 34 percent—all so-called first-line treatments, Dr. Lim said.
Second-line treatments, including rituximab, were used in 32 percent of patients, the majority of whom began second-line treatment between 30 and 60 days after symptom onset.
Long-term follow-up data was available for more than one thousand patients. Good outcomes, defined by MRS scores of 0 to 2, were achieved in 71 percent of patients, while 225 “survived with poor outcome,” Dr. Lim said, with MRS scores of 3 to 5. Six percent of patients died.
Thirteen percent of patients experienced at least one relapse; the median number of relapses was 2. Relapses occurred despite modest improvements on the MRS.
The team, including joint first authors Margherita Nosadini, MD, PhD, and Michael Eyre, MD, created a bootstrapped logistic regression model to determine factors associated with outcome and relapse. They found that the worst outcomes were associated with either older age (65 years or older) or very young age (2 years of younger) at disease onset; admission to the ICU; and an “extreme delta brush pattern” on EEG, which Dr. Lim explained was evocative of an extremely early pattern in brain development, with more mature networks switched off. “It is a marker of how sick the brain is in an adult” with NMDARE, he said.
Lack of any treatment in the first 30 days was associated with poorer outcome, while the best outcomes were seen with apheresis alone, or corticosteroids plus IVIg, or all three first line therapies early in the disease course. “The best predictor of good outcome is stopping the symptoms as quickly as possible,” Dr. Lim said.
When the team looked at relapse risk, the picture that emerged was complex and in some ways at odds with that for outcome. While adolescents had overall better outcomes, they had twice the risk of relapse as other age groups. Similarly, use of IVIg for six months or more was associated with a poorer outcome, but reduced the risk of relapse. Use of rituximab reduced the risk of relapse, and its use increased over time. Meanwhile, the risk of relapse fell over time, from 22 percent in 2008 to 11% in 2017 and after.
“Relapse is due is to chronic inflammation biology, and we don't really understand it,” Dr. Lim said. “For some people, once they have a bit of inflammation, it triggers chronic inflammation, which increases the risk of relapse.” Long-term treatment may be able to switch off that process, he added.
“When a patient is more severely affected, we tend to treat with more treatments, including second-line treatments like rituximab,” Dr. Lim said. “What the data show is that that really doesn't change your outcome very much, but it changes your relapse risk.”
Complicating the analysis was that, over the time of past decade, rituximab has been used more often and earlier. “The key point is that if it is given early because the disease is very severe, it changes the outcome for the better, versus if it is given later, after first-line treatments.”
Several caveats must be kept in mind, Dr. Lim noted. First, the possibility of publication bias after the initial description of NMDARE, toward more unusual or refractory cases, can't be ruled out, and there is still an important role for expert opinion and clinical judgment about the individual patient when weighing treatment and prognosis. Second, current outcome measures are relatively crude, and don't encompass the full range of symptoms and effects of the disorder, especially cognitive ones.
He and others have observed that cognitive symptoms respond well to rituximab, but this is not captured in most of the reports in the literature, he said. And third, “We are putting all our eggs in the immune treatment basket, but there is only so much that immune therapy can do. We still need to get the brain better, but we don't yet know how to do that.”
“The authors did a great analysis, and while the main message is not new, it is very important: We need to treat these patients early,” commented Luigi Zuliani, MD, PhD, of the department of neurology at Ospedale San Bortolo in Vicenza, Italy. Another important message, he said, “is that early treatment with rituximab to destroy the cells that are producing the antibodies” is warranted. B cell-targeting agents that can cross the blood-brain barrier may be even more effective, he suggested.
“This paper provides updates for what has been accomplished in the last nine years,” since publication of the largest case series in 2013, said Gregory S. Day, MD, assistant professor of neurology and vice chair of research at Mayo Clinic College of Medicine in Jacksonville, FL. Dr. Day agreed that better outcome measures are a critical unmet need in NMDARE, including those that track cognitive, quality-of-life, and non-motor functional changes.
“The big driver in the fall in relapse rate is probably the approach to treatment. We are diagnosing patients earlier and treating them more aggressively,” he said. Early use of induction therapy with high-efficacy immunosuppressants may be a key to further improvement in outcomes, a hypothesis that is set to be tested in the first randomized trial in NMDARE, he added.
The first prospective trial in NMDARE is set to begin enrollment in early 2022. Dr. Day is co-project principal investigator of the ExTINGUISH trial, which plans to enroll 120 patients in the first randomized clinical trial in NMDARE, which will test the efficacy of the B-cell targeting agent inebilizumab as an adjunct to first-line therapies in patients with moderate-to-severe disease. More details are available at ClinicalTrials.gov identifier: NCT04372615—https://bit.ly/2X59pxO
Dr. Ming currently serves on the advisory board and steering committee for Octapharma (which makes IVIG). Dr. Day in the co-project principal investigator on the ExTINGUISH Trial, and is supported via NINDS/NIH for this study. Dr. Zuliani had no disclosures.