First Long-Term Study ID’s Recovery Time for Brain Disorder

Recovery from anti–N-methyl-D-aspartate receptor (anti-NMDAR) encephalitis can take 3 years or longer, with lingering memory, language and emotional problems, results of a new study suggest. 

After a 3-year recovery period for young adults with the condition, 34% had continued impairment and 65% scored below average in one or more areas of cognition, with memory and language being most affected. 

The greatest improvement in neurocognitive symptoms occurs in the first 6 months of treatment, lead investigator Maarten Titulaer, MD, PhD, co-director of the Erasmus Medical Center for Neuroinflammatory Disorders of the Central Nervous System in Rotterdam, the Netherlands, told Medscape Medical News. 

“Despite improvement after immunotherapy with respect to the severity of this disease, 30% of patients will not return to work and another 15%-20% will return at a lower level,” he added.

The findings were published online on November 20 in Neurology. 

Rare, Often Misdiagnosed, Disorder

First identified in 2006, anti-NMDAR encephalitis is a rare disorder, affecting 1 in 1.5 million people, and primarily strikes young adults. 

Initial symptoms — headache, fatigue, and fever — can progress to confusion, memory loss, movement issues, behavioral changes, disordered thinking, hallucinations, seizures, and loss of consciousness. Often misdiagnosed as schizophrenia or bipolar disorder, the condition is linked to ovarian tumors or prior brain inflammation from herpes simplex virus, though the cause is usually unknown. Treatment typically involves immunotherapy.

Prior research has shown that self-reported difficulties with attention and concentration have been linked to 25%-33% of patients with anti-NMDAR encephalitis not returning to work or school. 

However, the recovery timeline remains unclear because there have been no large-scale studies examining cognitive improvement over time. To investigate, the researchers looked at potential factors that may contribute to persistent cognitive deficits as well as those that might promote cognitive recovery.

The study included 92 participants (mean age, 29 years; 77% female) from a larger national anti-NMDAR encephalitis cohort whose cerebrospinal fluid and blood samples were tested at Erasmus Medical Center. 

Patients were diagnosed with the condition in the Netherlands before July 2023, were at least 16 years old, and were functionally independent as measured by a modified Rankin Scale score ≤ 2. 

Participants with a preceding herpes simplex virus encephalitis (HSVE) were included in the study (n = 11), but these data were analyzed separately because research has shown HSVE is associated with notable memory impairment and inferior language performance.

Every 6 months for 5 years, participants completed a battery of cognitive tests, including the Rey Auditory Verbal Learning Test, the Rey-Osterrieth Complex Figure Test, the Boston Naming Test, the Judgement of Line Orientation, the Brixton Spatial Anticipation Test, Trail Making Tests, the Letter Digit Substitution Test, and the Wechsler Adult Intelligence Scale-IV digit span test. 

Cognitive Problems Linger

Cognitive scores showed improvement over time, with more rapid gains occurring within the first 6 months, followed by a slower increase up to the 3-year mark (P = .022). 

Of the 44 participants followed beyond 36 months, 34% had continued impairment (P = .25) and language (P = .23) being most affected. 

Participants assessed beyond 36 months also continued to report problems with emotional well-being, social functioning, energy levels, and quality of life. 

In addition, 30% did not return to school or work and 18% needed special accommodation in order to return. Participants who returned to school or work were more likely to have better scores on well-being and processing speed.

Notably, participants with a preceding HSVE scored significantly lower than those without the prior diagnosis in domains of memory (P = .028) and language (P = .012).

Titulaer said that despite the diversity of problems seen in the participants, early rehabilitation efforts are helpful. 

“This is important as the initial months can sometimes be complicated by psychiatric and iatrogenic challenges such as sedative medication and behavioral issues,” Titulaer said, adding, “[T]he complexity of different domains affected also merits a broad strategy aiming to educate and train both the patient and the family.”

Need for Better Biomarkers

Commenting for Medscape Medical News, Jonathan D. Santoro, MD, director of the Neuroimmunology and Demyelinating Disorders Program at Children’s Hospital Los Angeles, said that one of the biggest challenges with the disorder is determining who will fully recover and who won’t.

“We treat patients aggressively with the idea that early management can change these outcomes, but sometimes we still have refractory disease,” he said.

He added that as better biomarkers are developed in the blood and cerebrospinal fluid of patients with anti-NMDAR encephalitis, physicians will be better able to predict recovery trajectories. 

The study’s limitations include a selection bias tending toward less severely affected participants in the acute phase and the difficulty of conducting cognitive assessments in the acute phase of the illness. 

The study was funded by Dioraphte and the AEA Community Seed Grant. Titulaer reports receiving funds from Amgen, UCB, Dioraphte, Guidepoint Global LLC, CSL Behring, and Euroimmun. Santoro reports being a consultant for UCB, TG Pharmaceuticals, and Cylce Pharma on non–NMDAR-related topics.