Longitudinal Follow-Up of Patients with Anti-NMDA Receptor Encephalitis

By Hai H. Hoang, MD

Assistant Professor of Clinical Neurology, Weill Cornell Medical College

SYNOPSIS: In this retrospective, observational study of 38 patients with autoimmune encephalitis, using standard clinical assessment rating scales, the only predictor of poor outcome was muscle weakness at symptom onset. Most patients had long-term problems with cognitive and mood disorders.

SOURCE: Morgan A, Li Y, Thompson NR, et al. Longitudinal disability, cognitive impairment, and mood symptoms in patients with anti-NMDA receptor encephalitis. Neurology 2024;102:e208019.

There are limited data regarding the factors that influence outcomes in patients with anti-N-methyl-D-aspartate (NMDA) receptor encephalitis (anti-NMDARe), one of the most frequently encountered autoimmune encephalitides. This makes it challenging for neurologists to prognosticate and provide guidance for patients and caretakers on what can be expected after the acute stage of the disease.

A positive autoantibody never confirms a diagnosis, even in a patient with a clinical presentation strongly supporting an autoimmune etiology. After a positive autoantibody result, clinicians must evaluate the source of the positive autoantibody (serum or cerebrospinal fluid [CSF]); if there is an associated titer, how low or high the titer is; whether the autoantibody been associated with the patient’s neurologic syndrome; and whether the autoantibody is specific for an autoimmune encephalitis.

Although autoantibodies can be associated with atypical presentations, in such cases, care should be taken to ensure that no other causes can explain any unusual presentations. Not all autoantibodies are pathogenic for an autoimmune disorder. In the past, anti-voltage-gated potassium channel (VGKC) was thought to be indicative of an autoimmune etiology, but with current advances in molecular biology, we know now that positive autoantibodies to VGKC are not pathologic. Rather, two components of the VGKC complex, leucine-rich glioma-inactivated-1 (LGI-1) and contactin-associated protein-2 (CASPR-2), if positive with VGKC testing, are indicative of an autoimmune etiology. Positive VGKC without positive LGI-1 or CASPR-2 antibodies is a false-positive test result and not indicative of an autoimmune etiology.

The current literature relies on the evaluation of patients with autoimmune encephalitis using the Modified Rankin Scale (mRS), which is validated to characterize morbidity in patients with strokes, a patient population vastly different than patients with anti-NMDARe. The Clinical Assessment Scale in Autoimmune Encephalitis (CASE) was developed to accurately grade this patient population. The Morgan et al study was a retrospective observational study at the Cleveland Clinic that aimed to examine the predictors of short- and long-term outcomes in anti-NMDARe using mRS, CASE, and other cognitive and mood evaluations. Short-term was defined as the time of discharge from initial hospitalization. Long-term outcome was defined as the degree of return to premorbid function at last outpatient follow-up visit. Scoring systems to assess post-acute function included mRS and CASE. Cognitive evaluations were conducted using the Montreal Cognitive Assessment or Mini-Mental State Examination. Depression was evaluated based on Patient Health Questionaire-9, while anxiety was measured using the General Anxiety Disorder-7 questionnaire.

Thirty-eight patients were included in the study. Regarding short-term outcomes, 34 patients had data available. Within this group, both mRS and CASE did not significantly improve from baseline. Regarding long-term outcomes, 31 patients had data that were available. Both mRS and CASE improved during follow-up compared to the time of acute illness, but muscle weakness at the time of symptom onset predicted a higher mRS score during long-term follow up. Psychiatric morbidity, specifically depression, was the main contributor to high CASE scores. Interestingly, lack of clinical improvement within four weeks of immunosuppressant therapy was a predictor of better long-term CASE scores.

COMMENTARY

This study attempts to provide objective data to guide the complex conversations clinicians have with anti-NMDARe patients and their caretakers. Although it is not difficult to place a numerical value on a patient’s current presentation using the mRS or CASE, this study clearly demonstrates that while mRS and CASE generally improved (a comforting result), many patients still did not return to their premorbid function as the result of high burdens of cognitive and psychiatric symptoms. The study highlights how mRS and CASE are not suitable measures for detecting more subtle long-term impairments.

For practicing clinicians, this study reiterates the need to proactively explore cognitive and psychiatric symptoms during follow-up. Patients and caregivers may not identify these issues as pertinent to the visit. Additionally, neurologists need to be more comfortable exploring ways to manage cognitive and psychiatric symptoms using conservative (non-medical) and aggressive (medical) approaches. Deferring these tasks to other subspecialty neurologists or disciplines inevitably will delay their diagnosis and opportunity to treat, and limit improvement in the patient’s quality of life.