Residual Fatigue and Cognitive Deficits in Patients After Leucine-Rich Glioma-Inactivated 1 Antibody Encephalitis

Leucine-rich glioma-inactivated 1 antibody encephalitis (LGI1-Ab-E) typically affects older men who present with prominent amnesia and frequent seizures^1-3 and often shows a marked short-term improvement with immunotherapies.⁴ In particular, seizure cessation occurs within just a few weeks. However, only traditional cognitive domains have been investigated as longer-term outcomes, with improvements in cognition described as “not good enough.”⁵ Here, motivated by patient feedback and our clinical observations, we aimed to quantify the residual deficits observed after LGI1-Ab-E across several functional domains.

Participants were recruited to this cross-sectional study from previous cohorts,⁴ author clinics, or via the Encephalitis Society and assessed by neurologist interview and a battery of tests measuring:

1. Cognition: Addenbrooke’s Cognitive Examination (ACE), Mini-Mental State Examination (MMSE), and Frontal Assessment Battery (FAB)

2. Affective symptoms: Hospital Anxiety and Depression Scale (HADS)

3. Clinician-rated disability: modified Rankin Scale (mRS) and the Clinical Assessment Scale in Autoimmune Encephalitis (CASE)

4. Fatigue: Fatigue Scale for Motor and Cognitive Function (FSMC) and Modified Fatigue Impact Scale (MFIS).

All patients gave written informed consent (Research Ethics Committee approval 16/YH/0013).

Clinical data were gathered from 60 patients with LGI1-Ab-E, assessed at a median of 41 months (range, 4-179 months) after symptom onset (Table). From peak illness to post illness, a marked fall in disability was noted using both the CASE (median [SD] score of 6 [3.4] to 2 [1.7]) and mRS (median [SD] score of 3 [1.1] to 2 [1.1]; Figure, A; both P < .001), with 81% (n = 48 of 59) showing a “good” functional outcome (mRS ≤2). However, only 4 of 27 (15%) of those in employment at diagnosis returned to their premorbid role (Table). The median age of those medically retired or transitioning to a less demanding role was 56 years (range, 46-70 years), representing a reduction of 10 years’ fully productive working life in the United Kingdom. Consistent with this vocational effect, more detailed clinical testing captured widespread deficits.

By comparison with age-appropriate cutoffs derived from manuals or publications, 63% of the LGI1-Ab-E cohort (n = 38 of 60) were impaired on at least 1 of cognition, mood, and fatigue (Figure, B). Cognitive testing revealed total ACE was impaired in 32% (n = 18 of 56; score <88 of 100); 16% (n = 9 of 56) attained scores less than that of healthy elderly individuals in memory, fluency, and visuospatial capabilities, whereas attention (9% impaired [n = 5 of 56]) and language abilities (5% impaired [n = 3 of 56]) were relatively spared. Of affective features, both depression (HADS-D >7) and anxiety (HADS-A >7) were present in 19% (n = 11 of 58) and 33% (n = 19 of 58), respectively. However, overall fatigue was the most common long-term deficit, detected in 52% with the FSMC (n = 16 of 31), rated as severe in 56% of these patients (n = 9 of 16) (Figure, B).

The interrelationships between these deficits revealed the strongest correlations between fatigue and both anxiety and depression (ρ = 0.78 and ρ = 0.77, respectively; P < .001, after Holm-Bonferroni multiple comparison corrections; Figure, C and D). In addition, extent of fatigue correlated with both the greater disability (from mRS) and poorer cognition by ACE (Figure, D).

Although mRS represents the most widely used outcome measure in studies of autoimmune encephalopathies, the data here indicate that despite a “good” mRS, several long-term residual deficits remain: across domains of cognition, mood, and fatigue, with a significant effect on employment status. Our cohort’s mean mRS was comparable with other LGI1-Ab-E studies,^2-4 suggesting this traditional outcome measure captures only limited long-term morbidity in multiple studies. Fatigue was the most commonly impaired domain in our cohort, a novel finding in LGI1-Ab-E. This observation is closely reflected by the many patients in our clinic who volunteer fatigue as a major residual symptom. Also, it parallels findings in pediatric N-methyl-d-aspartate receptor antibody encephalitis, where fatigue is associated with quality of life.⁶

Overall, we continue to advocate early immunotherapy to achieve optimal clinical outcomes in patients with LGI1-Ab-E. Future studies can now also ask whether this approach mitigates the appearance of fatigue, in addition to amelioration of the other expanded long-term cognitive deficits highlighted within our study.

Corresponding Author: Sarosh R. Irani, DPhil, Oxford Autoimmune Neurology Group, Department of Clinical Neurology, University of Oxford, John Radcliffe Hospital, Level 3, West Wing, Oxford, Oxfordshire OX3 9DS, England (sarosh.irani@ndcn.ox.ac.uk).

Accepted for Publication: February 5, 2021.

Published Online: March 29, 2021. doi:10.1001/jamaneurol.2021.0477

Open Access: This is an open access article distributed under the terms of the CC-BY License. © 2021 Binks SNM et al. JAMA Neurology.

Author Contributions: Dr Irani had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. These authors contributed equally to the manuscript: Drs Binks and Veldsman. Joint senior authors: Drs Husain and Irani.

Concept and design: Binks, Veldsman, Easton, Okai, Irani.

Acquisition, analysis, or interpretation of data: Binks, Veldsman, Leite, Okai, Husain, Irani.

Drafting of the manuscript: Binks, Veldsman, Easton, Okai, Irani.

Critical revision of the manuscript for important intellectual content: All authors.

Statistical analysis: Binks, Veldsman, Okai, Irani.

Obtained funding: Binks, Husain, Irani.

Administrative, technical, or material support: Easton, Irani.

Supervision: Leite, Okai, Husain, Irani.

Conflict of Interest Disclosures: Dr Binks reported grants from Wellcome Trust and grants from the National Institute for Health Research during the conduct of the study; in addition, Dr Binks had a patent for PCT/GB2019/051257 pending University of Oxford. Dr Husain reported personal fees from Otsuka Consulting, Biogen, Excemed, and Lilly outside the submitted work. Dr Irani reported grants and personal fees from UCB Pharma and grants from CSL outside the submitted work; in addition, Dr Irani had a patent for LGI1/Caspr2 antibody detection with royalties paid from euroImmun AG and a patent for antibody diagnostics issued. No other disclosures were reported.

Funding/Support: Dr Irani is supported by the Wellcome Trust (104079/Z/14/Z), BMA Research Grants–Vera Down grant (2013), Margaret Temple (2017), Epilepsy Research UK (P1201), the Fulbright UK-US commission (MS Society research award), and by the NIHR Oxford Biomedical Research Centre. Dr Husain is supported by the Wellcome Trust (206330/Z/17/Z) and the National Institute for Health Research Oxford Biomedical Research Centre during the conduct of the study. Dr Binks has received salary support from the National Institute for Health Research and is currently supported by the Wellcome Trust. his research was funded in whole, or in part, by the Wellcome Trust (104079/Z/14/Z).

Role of the Funder/Sponsor: The funding sources had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

Disclaimer: The views expressed are those of the author(s) and not necessarily those of the National Health Service, the National Institute for Health Research, or the Department of Health).