Refractory, Intensive Care-Dependent NMDAR encephalitis

Background

N-methyl-D-aspartate receptor encephalitis (NMDARE) is an autoimmune disease in which patient’s immune systems generate antibodies against the NMDAR protein expressed in the brain, resulting in severe neuropsychiatric symptoms.

Since NMDARE was first identified in 2007, research has been devoted to understanding the different subgroups of the disease and establishing treatment protocols. Therapeutic approaches aim to decrease the inflammatory autoimmune processes that cause NMDARE. Though first-line therapies, including steroids and intravenous immunoglobulins, may offer some relief, patients tend to require second-line treatments, such as immunosuppressants, to achieve recovery. Establishing effective treatment protocols is of the utmost importance given the often sudden and dramatic onset of the disease, with admission to the intensive care unit (ICU) admission necessary for approximately 65-75% of patients.

A study published in Neurology Neuroimmunology and Neuroinflammation earlier this year characterised a subgroup of patients that the authors refer to as refractory, intensive care-dependent NMDARE (RI-NMDARE). The RI-NMDARE subgroup specifically includes patients whose symptoms are not alleviated by first- and second-line treatments and who require extended stays (>90 days) in the ICU. Given the severity of disease and often difficult-to-treat complications of RI-NMDARE, gaining clearer insight into the clinical and biomarker features of this subgroup could help to improve patient outcomes.

Identifying Clinical Features and Biomarkers in RI-NMDARE

To better characterise RI-NMDARE, researchers examined the cases of 379 patients with NMDARE at the French Reference Center for Autoimmune Encephalitis in Lyon, France who were admitted to the ICU between 2005 and 2023. 26 RI-NMDARE patients were identified, with a median age of 24 years. 92% were women, and non-White ethnicities accounted for a larger percentage of RI-NMDARE patients (14/25, 56%) compared to the larger cohort (55/156, 35%). The study noted a distinct clinical profile in RI-NMDARE, characterised by a more frequent display of severe symptoms – seizures, dysautonomia, and hyperkinetic movement disorders – compared to non-RI-NMDARE patients. Furthermore, patients in this subgroup exhibited a more fulminant, or sudden, disease presentation, as reflected by a faster average admission to the ICU (7 days after onset) compared to other patients (14 days).

In addition to these clinical hallmarks, certain biomarkers also distinguished this subgroup. Most notably, RI-NMDARE patients exhibited elevated white blood cell counts and anti-NMDAR antibody levels in cerebrospinal fluid (CSF). These features indicate a higher level of inflammation in subgroup patients, perhaps accounting for the more severe clinical profile. Also elevated in the RI-NMDARE population were serum neurofilament (Nfl) levels. While the exact significance of higher Nfl levels remains unclear, the authors suggest that this may result from greater neuronal damage. Finally, extreme delta brush (EDB), a feature of electroencephalograms (EEGs) associated with NMDARE treatment resistance and worse, was also more frequently noted in RI-NMDARE.

Overall, these findings present a clearer picture of the RI-NMDARE patient profile, allowing us to better understand what characterises this particularly severe form of the disease.

Significance of RI-NMDARE for Patients

While NMDARE has been the focus of ground-breaking research in the field of neuroimmunology since its identification nearly two decades ago, the high variability in patient response to treatment and disease outcome warrants further investigation. Researchers in this study presented the distinct clinical and biomarker features the define refractory, intensive care-dependent NMDARE (RI-NMDARE). Given the higher mortality in this subgroup, identifying RI-NMDARE as soon as possible is critically important.

This research has direct consequences for a clinical setting, as identification of RI-NMDARE could enable physicians to identify which patients may benefit from more aggressive, third-line therapies earlier on in the progression of disease. In all, this study provides critical insight into a high-risk subgroup of NMDARE that paves the way for more effective treatment and greater recovery.

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To read the full paper, click here.

To read our factsheet on NMDAR-antibody encephalitis, click here.