Abstract
Background and Objectives
Autoimmune encephalitis is a rare disease associated with considerable morbidity in the acute phase of the disease. Nationwide cohort studies investigating long-term cognitive outcomes are rare. Furthermore, although bedside cognitive assessments are frequently used in clinical practice to evaluate patients with AE, there is currently no consensus on the optimal test for this purpose. Using the unique Danish centralized antibody testing setup, we identified an unselected, nationwide AE cohort. We then performed a comprehensive evaluation of long-term cognitive outcomes.
Methods
All adult patients with seropositive AE diagnosed in Denmark from 2009 to 2022 were identified and invited to participate in the study. Participants underwent neuropsychological testing and bedside cognitive testing (Montreal Cognitive Assessment [MoCA], Mini-Mental State Examination [MMSE], Addenbrooke’s Cognitive Examination [ACE], and Frontal Assessment Battery [FAB]). Fatigue, depression, anxiety, life satisfaction, and quality of life were assessed using questionnaires.
Results
We included 86 of 108 eligible patients. The median time from symptom onset to participation was 77 months (interquartile range 35/125). All patients with anti-N-methyl-D-Aspartate receptor (NMDAR) encephalitis (NMDARE) (n = 33) and 86% of patients with limbic encephalitis (n = 37) obtained modified Rankin Scale (mRS) 0–2 at the time of testing, while 45% of patients with NMDARE and 43% of limbic encephalitis had multidomain cognitive deficits on formal neuropsychological testing. Memory, visuoconstruction, and executive function were the most affected cognitive domains. Postencephalitic dementia was present in 15% of the cohort, affecting primarily patients with limbic encephalitis, and was associated with higher mRS at peak disease, older age at disease onset, and relapsing disease. The MoCA had the strongest correlation with mean neuropsychological z-score and had the highest sensitivity and specificity for detecting cognitive impairment among patients with NMDARE and limbic encephalitis, when compared with the other bedside cognitive screening tools. There was a high prevalence of fatigue (38% NMDARE and 29% limbic encephalitis), and overall life satisfaction correlated strongly with both fatigue and depression scores in both groups.
Discussion
Long-term cognitive impairment and fatigue were prevalent in AE, despite good functional outcomes as measured by the mRS. The MoCA correlated well with neuropsychological performance and could be the bedside test of choice if a neuropsychologist is not readily available.
Introduction
Several recent studies have sought to evaluate the long-term consequences of autoimmune encephalitis (AE). Many have shown favorable outcomes when using the modified Rankin Scale (mRS).1-6 Despite this, it has been demonstrated that patients with AE are afflicted by lingering cognitive sequelae, and multiple studies have found high rates of fatigue, psychiatric symptoms, sleep dysfunction, and reduced quality of life (QoL).2,5,7-10 The importance of analyzing long-term data on outcomes in this disease was recently reinforced,2 and longitudinal studies have shown improvement in outcome measures over time.11-13 A German study showed cognitive improvement in an anti-N-methyl-D-Aspartate receptor (NMDAR) encephalitis (NMDARE) cohort over time, but two-thirds still had moderate or severe cognitive deficits after 5 years,11 while a large nationwide Dutch NMDARE study found cognitive impairment in a third of patients.7 In a UK-based cohort of 60 patients with anti-LGI1–mediated limbic encephalitis with a median follow-up of 41 months, 32% were cognitively impaired, as measured by Addenbrooke's Cognitive Examination (ACE).5
Gathering large real-life, unselected AE cohorts that represent the true spectrum of outcome is a challenge because of the rarity and phenotypic heterogeneity of AE. This is however possible in Denmark because of its unique centralized antibody testing. This enables registration of all seropositive individuals and reduces the risk of selection bias.
Using such data, we aimed to provide a detailed cross-sectional characterization of the long-term impact of AE on cognition, QoL, fatigue, and mood. Furthermore, we evaluated the correlation between neuropsychological assessment and common bedside cognitive tests.
Methods
Patient Inclusion Criteria
The Danish Autoimmune Encephalitis registry is a nationwide registry that contains all patients with seropositive AE with neuronal surface antibodies (NSAbs), anti-GAD65, and anti-Glial fibrillary acidic protein (GFAP) diagnosed in Denmark since 2009.14 NSAbs were detected using commercial, fixed cell-based assays (CBAs) (Euroimmun, Lübeck, Germany) and tissue-based assays (TBAs) (Euroimmun), while NSAbs not included in the commercial kit and anti-GFAP antibodies were detected on TBAs with subsequent testing on in-house CBAs at Euroimmun. Anti-GAD65 antibodies were detected using TBAs in combination with line immunoassay (LIA) or CBAs. Early in the study period, anti-GAD65 was detected using radioimmunoassay. Where applicable, patients included in the database fulfilled the diagnostic criteria for AE.15
We included patients with AE who were (1) diagnosed between 2009 and 2022, (2) residing in the Danish Commonwealth, and (3) 18 years or older at the time of inclusion. To ensure that patients were at least in the postacute phase, we included patients diagnosed from 2009 to 2022. All patients were recruited and examined between September 2023 and December 2024. Patients underwent a neuropsychological assessment and bedside cognitive testing. Fatigue, QoL, sleep, anxiety, and depression were assessed using questionnaires. The study adhered to the STROBE checklist for cross-sectional studies.
Neuropsychological Assessment
Neuropsychological assessments were performed by a certified neuropsychologist. Seven cognitive domains were assessed: (1) attention/speed, (2) visuoconstruction, (3) short-term/working memory, (4) verbal episodic memory, (5) visual episodic memory, (6) executive function, and (7) language. The battery of tests was selected based on previous studies on cognitive testing in AE while accounting for availability of validated Danish versions of tests and appropriate normative material.11,16 Each test was assigned to one cognitive domain. See eTable 1.
Bedside Cognitive Testing
For bedside cognitive testing, we used Montreal Cognitive Assessment (MoCA), Mini-Mental State Examination (MMSE), Addenbrooke's Cognitive Examination (ACE), and frontal assessment battery (FAB). The tests were performed in one sitting, and duplicate tasks were removed. The following cutoff values were used: MoCA (education-adjusted) <26, MMSE <24, ACE <86, and FAB <13.
Self-Reported Outcomes
Anxiety and depression were assessed using the Hospital Anxiety and Depression Scale.17 Fatigue was quantified using the Fatigue Scale for Motor and Cognitive Function (FSMC) and the Modified Fatigue Impact Scale (MFIS), both of which are validated in Danish and used in AE research.5,18-20 Excessive sleepiness was assessed using the Epworth Sleepiness Scale (ESS).21
To assess QoL, the European Quality of Life Scale (EQ-5D-5L) and Short Form-36 (SF-36) version 1 were used. For EQ-5D-5L, an index score was produced and compared with normative data from the Danish population.22,23 For SF-36, mental and physical summary scores were generated and compared with Norwegian normative data because no Danish data are available.24 Life satisfaction was assessed with Life Satisfaction Questionnaire 11 (LISAT-11).
Data Collection and Statistical Analysis
Data were collected in REDCap and analyzed using STATA/SE 18.0 provided by the Open Explorative Patient Network (OPEN) at Odense University Hospital.
Differences in parametric continuous variables were analyzed using independent samples t tests, whereas differences in nonparametric variables were assessed using the Wilcoxon rank-sum test. Differences between groups in categorical variables were tested using the Fisher exact test. Pair-wise correlations were performed between various outcome measures.
Neuropsychological tests were z-standardized to normative material. A cognitive domain was considered abnormal if 2 or more tests yielded a z-score below −1.34 or if at least 1 test yielded a score below −2. The cutoffs were based on the recommendations for labeling neuropsychological test results from the American Academy of Clinical Neuropsychology.25
Patients were categorized by severity of cognitive affection as having (1) no cognitive deficits, (2) single-domain deficits, or (3) multidomain deficits. In this study, verbal episodic memory and visual episodic memory were treated as a single domain.
Mean z-scores were calculated for each cognitive domain, and the mean of these scores was used as a crude global measure for overall neuropsychological performance.
Univariate linear regressions were performed between the mean neuropsychological z-score and bedside cognitive testing scores. Multivariable linear regressions were performed between mean neuropsychological z-score and age at disease onset in years, time from symptom onset to treatment, mRS at peak disease, CASE score at peak disease, and whether patients had relapsing disease. Patients with postencephalitic dementia were defined as patients with multidomain deficits who reported having problems with activities of daily living because of cognitive problems. A multivariable logistic regression was performed to determine the odds ratio (OR) of postencephalitic dementia with the same independent variables as the multivariable linear regressions. Only patients with time to treatment below 1,000 days were included in the multivariable regression analyses, and robust standard errors were applied. To illustrate the impact of choice of analysis on cognitive testing results, a second analysis method was applied to the cognitive data. In the second method, the mean z-scores were generated for each domain, and domains with a z-score below −1.5 were considered abnormal. Holm-Bonferroni correction was applied when performing multiple comparisons and pairwise correlations. Missing data were handled using available case analysis.
Standard Protocol Approvals, Registrations, and Patient Consents
The study was approved by the Regional Ethics Committee of Southern Denmark (S-20220102) and the Region of Southern Denmark and was listed in the internal record (21/29546) under Article 30 of the EU General Data Protection Regulation.
Data Availability
Data will not be publicly available.
Results
Participants
From September 2023 to December 2024, 86 of 108 (80%) eligible patients were included in the study. Eight did not respond to the invitation, and 13 did not wish to participate. One patient was found to be in disease relapse after inclusion and was subsequently excluded (Figure 1).
Figure 1. Inclusion Flow Diagram.
Overall, patients who were not included in the study had similar age and sex distribution as those included, and the proportion of patients with NMDARE and limbic encephalitis was comparable in the 2 groups. There were several differences in markers of disease severity: nonincluded patients had higher peak disease CASE and mRS, a larger proportion was admitted to the ICU or had an underlying cancer, and 29% (20/69) had died within the first year after diagnosis (eTable 2).
Participants were divided into the following groups: (1) NMDARE (n = 33), which included all patients with non–post–herpes simplex encephalitis (post-HSE) NMDARE, (2) post-HSE NMDARE (n = 7), (3) limbic encephalitis (n = 37), and (4) miscellaneous encephalitis (n = 9). Patients with post-HSE NMDAR encephalitis were analyzed separately because additional HSE-derived brain lesions could bias the cognitive test data.
Patients were classified as limbic encephalitis if they had (1) a clinical limbic encephalitis phenotype and (2) an antibody associated with limbic encephalitis (3) with or without brain imaging with limbic involvement (eMethods). This group was predominantly made up of patients with anti-LGI1 encephalitis (n = 22), followed by encephalitis mediated by anti-CASPR2 (n = 6), anti-LGI1 + anti-CASPR2 (n = 1), anti-GAD65 (n = 4), anti-AMPAR (n = 3), and anti-GABAB (n = 1).
The “miscellaneous encephalitis” group consisted of other, rarer AE antibodies and phenotypes: anti-GFAP–associated encephalomyelitis (n = 4) and meningoencephalitis (n = 1), anti-GABAA+anti-GAD65–-associated cortical encephalitis (n = 1), anti-DPPX with progressive encephalomyelitis with rigidity and myoclonus (n = 1), anti-IgLON5 (n = 1), and anti-GAD65–mediated encephalitis of uncertain type (n = 1). Participant demographics are presented in Table 1.
Table 1.
Participant Characteristics at Study Participation and at Disease Onset by Group
| NMDAR encephalitis | Post-HSE NMDAR encephalitis | Limbic encephalitis | Miscellaneous encephalitis | |
| N = 33 | N = 7 | N = 37 | N = 9 | |
| At study participation | ||||
| Age, median (range) | 31 (18–80) | 60 (22–78) | 74 (18–90) | 58 (27–73) |
| Female, % | 64 (21/33) | 29 (2/7) | 27 (10/37) | 22 (2/9) |
| Months from symptom onset to study participation, median (IQR) | 77 (38–117) | 55 (44–74) | 114 (63–133) | 30 (13–42) |
| Education, ISCED classification, median (IQR) | 3 (3–5) | 3 (3–6) | 3 (3–6) | 3 (2.5–4.5) |
| Current occupation, % | ||||
| Employed/education | 55 (18/33) | 29 (2/7) | 11 (4/37) | 33 (3/9) |
| Unemployed | 12 (4/33) | 0 (0/7) | 5 (2/37) | 11 (1/9) |
| Disability pension/part time | 18 (6/33) | 43 (3/7) | 22 (8/37) | 11 (1/9) |
| Age related retirement | 15 (5/33) | 29 (2/7) | 62 (23/37) | 44 (4/9) |
| Current ability to work/study affected by disease | 33 (11/33) | 29 (2/7) | 27 (10/37) | 44 (4/9) |
| Subjective cognitive complaints | 67 (22/33) | 86 (6/7) | 70 (26/37) | 78 (7/9) |
| Current use of anticonvulsants | 9 (3/33) | 43 (3/7) | 49 (18/37) | 22 (2/9) |
| Current use of antipsychotics | 0 (0/33) | 29 (2/7) | 0 (0/37) | 0 (0/9) |
| Current use of antidepressants | 6 (2/33) | 29 (2/7) | 19 (7/37) | 0 (0/9) |
| Current use of immunomodulators | 12 (4/33) | 0 (0/7) | 16 (6/37) | 22 (2/9) |
| Cannot drive currently because of disease | 0 (0/33) | 29 (2/7) | 19 (7/37) | 11 (1/9) |
| Not legally competent | 0 (0/33) | 14 (1/7) | 3 (1/37) | 0 (0/9) |
| At diagnosis | ||||
| Age at diagnosis, median (range) | 23 (11–77) | 54 (19–73) | 66 (9–83) | 57 (24–71) |
| Estimated mRS score, median (range) | 4 (3–5) | 4 (3–5) | 3 (1–5) | 3 (2–5) |
| Estimated CASE score, median (range) | 8 (5–15) | 6 (1–16) | 4 (1–17) | 4 (1–12) |
| CSF pleocytosis, median (IQR) (patients with pleocytosis) | 53 (105) ((29/33)) | 30 (28) ((7/7)) | 8 (19) ((7/37)) | 120 (575) ((7/9)) |
| MRI brain, %abnormal | 39 (13/33) | 100 (7/7) | 59 (22/37) | 67 (6/9) |
| PET brain, %abnormal | 73 (11/15) | . (0/0) | 94 (16/17) | 50 (1/2) |
| MRI and/or PET brain, %abnormal | 55 (18/33) | 100 (7/7) | 68 (25/37) | 67 (6/9) |
| EEG, %abnormal | 97 (29/30) | 71 (5/7) | 76 (28/37) | 44 (4/9) |
| Days from symptom onset to treatment, median (IQR) | 24 (34) | 11 (31) | 96 (211) | 37.5 (208) |
| First line treatment, % | 97 (32/33) | 86 (6/7) | 95 (35/37) | 89 (8/9) |
| Second line treatment, % | 42 (14/33) | 14 (1/7) | 14 (5/37) | 56 (5/9) |
| Maintenance treatment, % | 76 (25/33) | 57 (4/7) | 86 (32/37) | 78 (7/9) |
| Relapse, % | 18 (6/33) | 0 (0/7) | 24 (9/37) | 0 (0/9) |
| Underlying malignancy/tumor, % | 12 (4/33) | 0 (0/7) | 11 (4/37) | 11 (1/9) |
Abbreviations: CASE = Clinical Assessment Scale for Autoimmune Encephalitis; ISCED = International Standard Classification of Education; mRS = modified Rankin Score; IQR = interquartile range.
LGI1 vs Non–LGI1-Mediated Limbic Encephalitis
When comparing outcomes between patients with anti-LGI1 and non–LGI1-mediated limbic encephalitis, we found no significant differences (eTable 3). We therefore chose to group patients with limbic encephalitis across antibody specificities.
Neuropsychological Assessment
On formal testing, the prevalence of cognitive deficits was high, with multidomain impairment in 45% of patients with non–post-HSE NMDARE and 43% of patients with limbic encephalitis and single-domain impairment in 33% of NMDARE and 46% of limbic encephalitis. Fifteen percent of patients with AE without prior HSE (12/79) had postencephalitic dementia. Patients with dementia were older, had longer time to treatment, and were all male. Most patients with dementia were survivors of limbic encephalitis (67%). The difference in sex distribution remained statistically significant after correction for multiple comparisons (eTable 4).
The most commonly affected cognitive domains among patients with NMDARE were visual episodic memory (44%), visuoconstruction (41%), verbal episodic memory (36%), and short-term/working memory (33%). In comparison, the most affected domains in limbic encephalitis were verbal episodic memory (64%), visual episodic memory (56%), and executive function (33%) The least affected cognitive domains in both groups were attention/speed (NMDARE 13% and limbic encephalitis 12%) and language (NMDARE 6% and limbic encephalitis 11%).
Visual and verbal memory impairments were present at higher absolute levels in limbic encephalitis compared with NMDARE, and a larger proportion of patients with limbic encephalitis also had abnormal delayed visual and verbal recognition (42% and 44%, respectively) compared with NMDARE (12% and 18%). This finding indicates impairment of long-term memory consolidation (Figure 2). Although the prevalence of verbal memory domain deficits and verbal and visual recognition was significantly higher in patients with limbic encephalitis compared with patients with NMDARE, these findings did not survive correction for multiple comparisons (eTable 5). For a graphical presentation of test-level deficits at different cutoff values, see eFigure 1.
Figure 2. Deficits at the Test and Domain Levels.
(A) Spider plot showing percentage of patients with test results below z-score −1.34 in each neuropsychological test. The dashed line represents patients with NMDAR encephalitis, and the solid line represents patients with limbic encephalitis. (B) Bar chart showing percentage of patients with domain deficits by group.
In patients with NMDARE with multidomain impairments, 47% (7/15) did not report any subjective cognitive impairment, while the same was true for 25% (4/16) in limbic encephalitis. By contrast, 100% (7/7) of the patients with NMDARE without any cognitive impairment on formal testing reported subjective cognitive difficulties, compared with 25% (1/4) in limbic encephalitis.
There were no significant associations with worse neuropsychological z-score in the NMDARE group. For patients with limbic encephalitis, higher mRS at nadir was associated with lower neuropsychological z-score (−0.5, 95% CI −0.8 to −0.1; p = 0.016).
Factors associated with developing postencephalitic dementia were higher mRS at peak disease (OR 23.0 95% CI 5.1–104.2 p < 0.001), older age at onset (OR 1.08 95% CI 1.03–1.13 p = 0.001), and one or more disease relapses (OR 22.2 95% CI 2.9–170.5 p = 0.003).
Time from symptom onset to treatment initiation did not significantly predict cognitive outcomes in any analyses. For scatter plots of time to treatment and mean neuropsychological z-score, see eFigure 2.
Using the second analysis method reduced the prevalence of cognitive impairment. When means of cognitive domain z-scores were calculated and considered abnormal below mean z-score −1.5, the prevalence of cohort-wide, multidomain deficits was reduced from 43% to 25% and the proportion of patients with no cognitive deficits more than doubled from 19% to 44% (eTable 6).
Bedside Cognitive Testing
When correlated with neuropsychological performance, MoCA performed well in the NMDARE (R2 = 0.61; p < 0.001) group, whereas the correlation was less strong in limbic encephalitis (R2 = 0.44; p < 0.001). The MMSE and ACE showed comparable correlation (R2 = 0.49 and R2 = 0.43; p < 0.001) with MoCA in limbic encephalitis but did poorly in NMDARE (R2 = 0.37 and R2 = 0.40; p < 0.001). The FAB performed poorly in both groups (Figure 3).
Figure 3. Univariate Regressions Between Total Scores of MoCA, MMSE, ACE, and FAB and the Mean Z-Score of the Neuropsychological Assessment for NMDARE and Limbic Encephalitis.
*p < 0.05. Univariate correlations between bedside cognitive testing and mean neuropsychological z-score. The red dashed line represents the standard cutoff for each test: MoCA <26, MMSE <24, ACE <86, and FAB <13. The percentage of abnormal tests represents the proportion of patients who scored lower than the cutoff value. ACE = Addenbrooke's Cognitive Examination; FAB = frontal assessment battery; MMSE = Mini-Mental State Examination; MoCA = montreal cognitive assessment.
Although none of the tests were very efficient at detecting NMDARE patients with single or multidomain deficits, the MoCA performed the best (sensitivity 56% and specificity 100%). In limbic encephalitis, the MoCA outperformed the other tests and was more specific than in NMDARE (sensitivity 81% and specificity 75%). In NMDARE, multiple cognitive domains correlated with MoCA (verbal episodic memory, visuoconstruction, working memory, and language) compared with MMSE where only verbal memory correlated significantly. Both MoCA and MMSE correlated with attention and language in limbic encephalitis (eFigure 3).
For a table of sensitivities and specificities for the detection of cognitive impairment with bedside cognitive testing, see eTable 7.
Fatigue, Sleep, Anxiety, Depression, and QoL
Fatigue was present in 38% of patients with NMDARE and 29% of patients with limbic encephalitis as measured by the MFIS, while excessive daytime sleepiness was less frequent (NMDARE 18% and LGI1 12%) (Table 2). The prevalence of anxiety was 23% in NMDARE and 12% in limbic encephalitis, while levels of depression were similar (13% vs 15%) (Table 2). The EQ-5D-5L index score for both groups was comparable with the background population after z-standardization, with 3% of patients with NMDARE and 6% of patients with limbic encephalitis below 2 standard deviations from the mean.
Table 2.
Functional, Cognitive, and Self-Reported Outcomes by Group
| NMDAR encephalitis (n = 33) | Post-HSE NMDAR (n = 7) | Limbic encephalitis (n = 37) | Miscellaneous encephalitis (n = 9) | |
| Functional outcomes | ||||
| mRS, median (range) | 0 (0–2) | 2 (0–3) | 2 (0–4) | 2 (0–4) |
| mRS 0–2, % | 100 (33/33) | 86 (6/7) | 86 (32/37) | 67 (6/9) |
| Cognitive outcomes, % | ||||
| No cognitive deficits | 21 (7/33) | 14 (1/7) | 11 (4/37) | 33 (3/9) |
| Single-domain deficits | 33 (11/33) | 29 (2/7) | 46 (17/37) | 22 (2/9) |
| Multidomain deficits | 45 (15/33) | 57 (4/7) | 43 (16/37) | 44 (4/9) |
| Postencephalitic dementia | 6 (2/33) | 14 (1/7) | 22 (8/37) | 22 (2/9) |
| Psychiatric outcomes, % | ||||
| HADS anxiety | 23 (7/30) | 50 (3/6) | 12 (4/34) | 25 (2/8) |
| HADS depression | 13 (4/30) | 33 (2/6) | 15 (5/34) | 12 (1/8) |
| Fatigue and sleepiness, % | ||||
| MFIS, excessive fatigue | 38 (11/29) | 33 (2/6) | 29 (10/34) | 50 (4/8) |
| FSMC, excessive fatigue | 13 (4/31) | 33 (2/6) | 15 (5/34) | 50 (4/8) |
| ESS, excessive daytime sleepiness | 18 (5/28) | 33 (2/6) | 12 (4/33) | 25 (2/8) |
| Quality of life | ||||
| EQ-5D-5L, index z-score, median (IQR), % | 0.25 (−0.11/0.62) (31/33) | −0.30 (−0.47/0.62) (6/7) | 0.06 (−0.38/0.61) (35/37) | 0.03 (−0.55/0.41) (8/9) |
| EQ-5D-5L, index z-score < −2, % | 3 | 0 | 6 | 0 |
| EQ-5D-5L, VAS, median (IQR), (nonmissing/total) | 90.00 (75.00/95.00) (30/33) | 73.50 (70.00/90.00) (6/7) | 80.00 (60.00/90.00) (33/37) | 72.50 (62.50/82.50) (8/9) |
| SF-36, physical functioning, median (IQR), (nonmissing/total) | 0.47 (−0.38/0.50) (31/33) | −0.05 (−0.68/0.63) (6/7) | 0.63 (0.16/1.06) (35/37) | 0.19 (−0.58/0.36) (8/9) |
| SF-36, mental wellbeing, median (IQR), (nonmissing/total) | 0.26 (−0.20/0.67) (31/33) | −0.75 (−1.77/0.63) (6/7) | 0.35 (−0.40/0.79) (35/37) | 0.18 (−0.96/0.58) (8/9) |
| SF-36, role limitations(physical), median (IQR), (nonmissing/total) | 0.44 (−0.47/0.48) (31/33) | −0.32 (−1.77/0.57) (6/7) | 0.44 (−0.66/0.98) (35/37) | 0.02 (−1.56/0.61) (8/9) |
| SF-36, role limitations(emotional), median (IQR), (nonmissing/total) | 0.43 (−0.77/0.46) (31/33) | 0.07 (−0.61/0.45) (6/7) | 0.44 (−1.10/0.69) (34/37) | 0.38 (−1.82/0.46) (7/9) |
| SF-36, energy/vitality, median (IQR), (nonmissing/total) | 0.16 (−0.45/0.94) (30/33) | −0.61 (−1.52/0.91) (6/7) | 0.34 (−0.47/1.02) (35/37) | −0.02 (−0.78/0.60) (8/9) |
| SF-36, social functioning, median (IQR), (nonmissing/total) | 0.62 (−0.78/0.64) (31/33) | −0.08 (−1.02/0.62) (6/7) | 0.65 (0.20/0.70) (34/37) | −0.04 (−1.59/0.62) (8/9) |
| SF-36, bodily pain, median (IQR), (nonmissing/total) | 0.82 (−0.05/0.94) (31/33) | 0.93 (0.19/1.18) (6/7) | 1.00 (0.24/1.16) (34/37) | −0.22 (−0.73/−0.00) (8/9) |
| SF-36, general health perception, median (IQR), (nonmissing/total | −0.23 (−1.22/0.73) (31/33) | −0.63 (−1.15/0.40) (6/7) | −0.02 (−0.87/0.51) (35/37) | −0.43 (−1.13/0.05) (8/9) |
| SF-36, physical summary z-score, median (IQR) (nonmissing/total) | 0.22 (−0.71/0.53) (30/33) | 0.62 (−0.07/1.47) (6/7) | 1.11 (0.20/1.61) (34/37) | −0.12 (−0.97/0.71) (7/9) |
| SF-36, physical summary z-score <−2, (nonmissing/total) | 13 | 0 | 0 | 0 |
| SF-36, mental summary z-score, median (IQR) (nonmissing/total) | 0.15 (−0.20/0.72) (30/33) | −0.46 (−0.87/0.35) (6/7) | −0.21 (−0.87/0.34) (34/37) | −0.15 (−2.93/0.03) (7/9) |
| SF-36, mental summary z-score <−2, (nonmissing/total) | 10 | 0 | 6 | 29 |
| LISAT-11, life as a whole, % dissatisfied | 26 (8/31) | 50 (3/6) | 26 (9/35) | 62 (5/8) |
| LISAT-11, vocational situation, % dissatisfied | 27 (8/30) | 50 (3/6) | 29 (9/31) | 71 (5/7) |
| LISAT-11, financial situation, % dissatisfied | 48 (15/31) | 17 (1/6) | 21 (7/34) | 62 (5/8) |
| LISAT-11, leisure situation, % dissatisfied | 35 (11/31) | 60 (3/5) | 31 (11/35) | 62 (5/8) |
| LISAT-11, contact with friends/acquaintances, % dissatisfied | 32 (10/31) | 50 (3/6) | 34 (12/35) | 50 (4/8) |
| LISAT-11, sexual life, % dissatisfied | 52 (16/31) | 100 (6/6) | 58 (19/33) | 100 (8/8) |
| LISAT-11, self-care % dissatisfied | 6 (2/31) | 0 (0/6) | 11 (4/35) | 12 (1/8) |
| LISAT-11, family life, % dissatisfied | 10 (3/31) | 0 (0/6) | 11 (4/35) | 38 (3/8) |
| LISAT-11, relationship, % dissatisfied | 37 (10/27) | 50 (2/4) | 17 (5/30) | 29 (2/7) |
| LISAT-11, physical health, % dissatisfied | 32 (10/31) | 50 (3/6) | 46 (16/35) | 50 (4/8) |
| LISAT-11, psychological health, % dissatisfied | 35 (11/31) | 50 (3/6) | 37 (13/35) | 50 (4/8) |
Abbreviations: CASE = Clinical Assessment Scale for Autoimmune Encephalitis; EQ-5D-5L = European Quality of Life Scale; ESS = Epworth Sleepiness Scale; FSMC = Fatigue Scale for Motor and Cognitive Function; HADS = Hospital Anxiety and Depression Scale; LISAT-11 = Life Satisfaction Questionnaire 11; MFIS = Modified Fatigue Impact Scale; mRS = modified Rankin Score; SF-36 = Short Form 36.
Twenty-six percent were dissatisfied with life as a whole, as measured by the LISAT-11, among both patients with NMDARE and limbic encephalitis. Both groups were most often satisfied with the dimensions of self-care and family life. Patients with NMDARE were least often satisfied with their sexual life and their financial situation, while patients with limbic encephalitis were the least satisfied with sexual life and physical health. For an overview of QoL scores, see Table 2.
Post-Herpetic NMDARE vs Noninfectious NMDARE
Participants with post-HSE NMDARE (n = 7) had higher CASE scores than noninfectious NMDARE (n = 33). Similarly, the proportion of multidomain impairment was higher in the post-HSE group (57% vs 45%). The most frequently affected cognitive domains were visual episodic memory (83%), visuoconstruction (50%), verbal episodic memory (33%), and short-term/working memory (29%).
Fatigue measured by the MFIS was comparable in the 2 groups; however, the FSMC and ESS were abnormal in a third of the post-HSE group compared with 13% and 18% of noninfectious NMDARE. Moreover, anxiety (50% vs 23%) and depression (33% vs 13%) were twice as prevalent in the post-HSE group.
Half of the post-HSE patients were dissatisfied with life as a whole compared with 26% in noninfectious NMDARE (Table 2). After correction for multiple comparisons, there were no statistically significant differences between the 2 groups.
Correlation of Outcome Measures
In patients with NMDARE, fatigue and depression scores were strongly correlated with overall life satisfaction (r = 0.7; p = 0.002 and r = 0.8; p < 0.001). These correlations, while less strong, were also observed in patients with limbic encephalitis (r = 0.5; p = 0.048 and r = 0.6; p = 0.002) with an additional correlation between life satisfaction and anxiety in this group (r = 0.5; p = 0.032).
In both groups, there was a strong correlation between depression and fatigue scores (NMDARE r = 0.7, p = 0.002; limbic encephalitis r = 0.7, p < 0.001) and a moderately strong correlation between CASE and mRS score at peak disease (NMDARE r = 0.6, p = 0.002; limbic encephalitis r = 0.6, p = 0.001). Cognition did not correlate directly with any of the outcome measures, in either group. Furthermore, there were no significant correlations between peak disease mRS or CASE score with any other outcomes. Correlations are presented in Figure 4.
Figure 4. Correlation Matrix of Outcomes for NMDARE and Limbic Encephalitis.
Pair-wise correlation matrix. Significant correlation coefficients marked with * (<0.05). Correlations were corrected for multiple comparisons with Holm-Bonferroni. Neuropsychology: Mean of all cognitive domain z-scores, Satisfaction: Mean of all LISAT11 dimension scores, Fatigue: Modified Fatigue Impact Scale score, Anxiety: Hospital Anxiety and Depression Scale (HADS) anxiety score, Depression: HADS depression score, mRS_nadir: modified Rankin Scale score at peak disease, and CASE_nadir: Clinical Assessment Scale in Autoimmune Encephalitis (CASE) score at peak disease. mRS = modified Rankin Score.
Discussion
In this nationwide cross-sectional study of a large, unselected cohort of patients with AE, we found that despite generally favorable functional outcomes on the mRS, cognitive deficits persisted for years after disease onset and treatment. Overall QoL scores were comparable with normative data, but fatigue was highly prevalent, and both fatigue and depressive symptoms correlated with overall life satisfaction. When comparing bedside cognitive screening tools with formal neuropsychological testing, the MoCA demonstrated the strongest correlation and outperformed MMSE, ACE, and FAB. Using established clinical cutoff values, MoCA outperformed the other bedside cognitive tools for both correlation with mean neuropsychological z-score and sensitivity and specificity of detecting cognitive impairment. Thus, MoCA should be the preferred bedside screening tool for long-term follow-up in patients with AE in the postacute phase. However, the sensitivity of MoCA in patients with NMDARE was low (56%), indicating that cognitive deficits in NMDARE can be subtle and not adequately captured by the bedside screening tools. Furthermore, correlations between domains and bedside testing indicate that memory deficits, which are prevalent among patients with limbic encephalitis, may not be tested sufficiently in either of the included bedside screening tools. These findings emphasize the continued importance of comprehensive neuropsychological testing in AE.
The most common cognitive deficits affected verbal and visual episodic memory, visuoconstruction, executive function, and short-term/working memory. Visual and verbal episodic memory deficits were more common and severe in limbic encephalitis, while visuoconstruction and short-term/working memory deficits were more common in NMDARE. Of interest, we found high levels of impaired figure copying with relatively normal block pattern test results, particularly in patients with NMDARE (Figure 2). A nationwide study on long-term outcomes in patients with NMDARE from the Netherlands found impairments of one or more cognitive domains in a third of patients.7 As in our cohort, a large proportion of patients (25%) were affected on the figure copying test, whereas only 5% showed impairment of the other visuoconstructive test performed. This mismatch in both cohorts indicates that some of the impairment attributed to visuoconstructive deficits may be caused by impairment of other cognitive domains, for example, the executive function required for planning and executing a complex drawing.
Previous cognitive studies in LGI1-mediated limbic encephalitis have found impairments similar to those found in our limbic encephalitis group.5-7,26,27 Prior cohorts of NMDARE have also shown a cognitive profile largely consistent with our findings,7,11,12,28 although impairment of visuoconstruction was more prevalent in our cohort than previous studies. However, there is marked heterogeneity among previous studies in the choice of cognitive tests and in the operational definition of impairment, which represents an inherent challenge in studies of cognitive outcomes and limits cross-study comparability.2 Indeed, applying 2 different analysis methods to our data substantially changed the estimated impairment rates (eTable 6). Averaging performance across tests within a cognitive domain may mask clinically meaningful deficits because impaired performance on one task can be compensated for by preserved performance on another. For example, impaired performance on a delayed recall task may be attenuated at the domain level if other measures of episodic memory are preserved, even if the patient experiences clinically relevant memory difficulties. On the other hand, although our approach is more sensitive to cognitive deficits, it may also carry a risk of overestimating the prevalence of cognitive impairment. When investigating outcomes in rare diseases such as AE, comparability across studies is important for subsequent pooling of results. The field may therefore benefit from a standardized neuropsychological test battery and harmonized, prespecified analytical approaches.16
We found no correlation between QoL and cognition, indicating some degree of anosognosia among patients with AE. This is further suggested by the large proportion of patients with cognitive deficits on formal testing, reporting no cognitive difficulties. Indeed, this phenomenon was also reported in a recently published cohort of 50 patients with NMDARE, where only 50% of patients correctly evaluated their cognitive performance, a third of patients with memory impairment on neuropsychological testing rated their memory as normal, and 15% reported impairment but had normal test results.10 Anosognosia is well described in patients with Alzheimer disease, where reduced awareness of cognitive deficits is associated with more severe cognitive impairment.29-31
We found that 15% of patients with AE could be classified as postencephalitic dementia and that higher mRS at peak disease, older age at onset, and disease relapse were predictors for developing postencephalitic dementia. This finding suggests that more aggressive treatment might reduce the long-term risk of dementia. It could also be that disease relapse itself is a marker of disease severity.
We found no difference in overall QoL in our AE cohort when compared with national averages, a finding consistent with several previous studies examining long-term QoL in different types of AE.32-35 Perhaps, decreased disease awareness and memory deficits contribute to masking the impact of disease on life. We did not find that time to treatment was correlated with QoL, mirroring the findings of a previous study.8
A 2024 study of NMDARE found a high prevalence of fatigue (63%), depression (36%), and anxiety (54%).10 Similarly, a 2021 study evaluating fatigue and depression in a large cohort of mixed AE patient phenotypes found substantial rates of fatigue (60%) and depression (30%).19 By contrast, our cohort showed lower overall frequencies of both fatigue (35%) and depression (14%). It is important to note that the 2021 study used a lower cutoff value for overall fatigue (MFIS >29) compared with our study (MFIS >37), with our cutoff based on a previous study in a cohort of Danish patients with multiple sclerosis.18 When applying the lower cutoff to our data, the prevalence of overall fatigue increases from 35% to 45%. Furthermore, the 2021 study had a mean time from symptom onset to participation of 4 months, indicating that fatigue and depression could be more prevalent in the postacute phase and improve with time in some patients.
Another study from 2025 investigated long-term QoL and disability in patients with anti-CASPR2 antibody–mediated disease. They found that worse long-term patient QoL was predicted by the presence of fatigue and neuropathic pain but not mRS.36
Our findings together with those of previous studies highlight the need for nuanced and bespoke outcome measures for patients with AE that extend beyond the scope of the mRS and monitor the disease sequelae that are important for long-term disability and QoL. The first LGI1-specific outcome rating scale has already been developed (LGI1-ANTibody encephalitis outcome RatiNg (LANTERN scale)),37 and more are under development.
When comparing patients with post-HSE NMDARE with patients with NMDARE, we found higher levels of multidomain deficits, daytime sleepiness, depression, anxiety, and life dissatisfaction (Table 2). These findings most likely reflect the much more extensive brain damage associated with HSE, predominantly involving the medial temporal lobes, frequently extending into the inferior and lateral temporal cortex and insular cortex, causing severe memory impairment and, in some cases, complete amnesia.38 The post-HSE group was small (n = 7), and the median follow-up time was shorter (55 months) compared with the NMDARE group (77 months). In addition, one of the post-HSE patients was too cognitively impaired to complete any of the questionnaires. These factors could contribute to the observed differences in clinical and patient-reported outcomes.
Strengths of our study include that it represents a nationwide cohort including all patients with AE ever identified in Denmark, with an inclusion rate among eligible patients of 80%. Although one previous nationwide AE outcomes study exists,7 this is the first nationwide study to include and compare multiple subtypes of AE. Examining both patients with NMDARE and limbic encephalitis using the same cognitive test battery allows for direct comparison, which is a major strength of this study. Furthermore, this is one of the most comprehensive outcome studies performed in AE, assessing a broad range of clinical, cognitive, and patient-reported long-term outcomes. Our study allowed us to compare the utility of bedside cognitive screening tools with formal neuropsychological assessment in AE.
Limitations include the cross-sectional nature of the study, which precludes the assessment of temporal trends in cognition or self-reported outcomes on an individual level. In addition, there were no healthy controls in the study, which makes interpretation of some of the self-reported outcomes less clear. Although most eligible patients were included in the study, some patients had died and nonincluded patients had significantly higher markers of disease severity leading to potential selection bias.
We found no significant differences in outcomes between LGI1 and non–LGI1-mediated limbic encephalitis. However, it is possible that grouping patients with limbic encephalitis together across antibodies could be obfuscating distinct features of long-term outcomes specific to the different antibodies.
The order in which bedside cognitive testing was performed was not randomized per patient. This could lead to systematic bias in performance between testing tools because of patient fatigue.
Previous studies have demonstrated improvement in neuropsychological performance among patients with NMDAR over time,7,11 with the Dutch NMDAR cohort finding that patients improved until 3 years after diagnosis and the German NMDARE cohort reporting individual patients with continued recovery even 6–7 years after disease onset. In our cohort, a fifth of patients with NMDARE and limbic encephalitis had follow-up time of less than 3 years, which may contribute to the prevalence of cognitive deficits in both groups. However, there were no significant differences in mean neuropsychological z-score between those with more or less than 3 years of follow-up in either group.
Although time to treatment was included in the analyses, detailed information on treatment type, treatment duration, and number of treatments was not available; therefore, this study cannot draw firm conclusions regarding the effect of treatment on long-term cognitive outcome.
Although most patients with AE obtain a favorable functional outcome, cognitive deficits are prevalent, even many years after the disease. Nevertheless, as demonstrated in this study, neuropsychological testing results can change dramatically depending on how the data are analyzed. This is important to consider when conducting or reading neuropsychological studies.
Although there were no significant predictors for cognitive outcome in patients with NMDARE, higher mRS at peak disease was associated with worse cognitive outcome in patients with limbic encephalitis.
The prevalence of postencephalitic dementia in patients with AE without prior neuroinfection in our cohort was 15%. Most of these patients had limbic encephalitis and were exclusively men. Higher mRS at peak disease, older age at disease onset, and one or more relapses were associated with an increased risk of developing postencephalitic dementia. Fatigue was present in approximately a third of patients, and there were robust correlations of fatigue and depression with overall life satisfaction.
MoCA correlated well with neuropsychological testing and had the highest sensitivity and specificity in both NMDARE and limbic encephalitis and may serve as a cognitive screening tool, particularly when access to a neuropsychologist is limited. On the other hand, some patients exhibit cognitive deficits that could go undetected by the MoCA, and a large proportion of patients are not aware of their impairment. This makes comprehensive neuropsychological testing an essential tool in patient assessment and rehabilitation, especially in those of working age, to guide appropriate rehabilitation and support.
Glossary
- ACE
Addenbrooke's Cognitive Examination
- AE
autoimmune encephalitis
- CBA
cell-based assays
- EQ-5D-5L
European Quality of Life Scale
- ESS
Epworth Sleepiness Scalesleepiness scale
- FAB
frontal assessment battery
- FSMC
Fatigue Scale for Motor and Cognitive Function
- LISAT-11
Life Satisfaction Questionnaire 11
- MFIS
Modified Fatigue Impact Scale
- MMSE
Mini-Mental State Examination
- MoCA
montreal cognitive assessment
- mRS
modified Rankin Scale
- NSAbs
neuronal surface antibodies
- OR
odds ratio
- QoL
quality of life
- SF-36
Short -Form-36
- TBA
tissue-based assay
Author Contributions
T.A. Gaist: drafting/revision of the manuscript for content, including medical writing for content; major role in the acquisition of data; study concept or design; analysis or interpretation of data. L.R. Lodahl: drafting/revision of the manuscript for content, including medical writing for content; major role in the acquisition of data; analysis or interpretation of data. H.A. Thorup: drafting/revision of the manuscript for content, including medical writing for content; major role in the acquisition of data. M.S. Nissen: drafting/revision of the manuscript for content, including medical writing for content; study concept or design. K. Hansen: major role in the acquisition of data. T. Harbo: drafting/revision of the manuscript for content, including medical writing for content; major role in the acquisition of data. S. Rekers: drafting/revision of the manuscript for content, including medical writing for content; analysis or interpretation of data. C. Finke: drafting/revision of the manuscript for content, including medical writing for content; analysis or interpretation of data. M. Blaabjerg: drafting/revision of the manuscript for content, including medical writing for content; study concept or design; analysis or interpretation of data.
Study Funding
This research is supported by the Novo Nordisk Foundation (NNF22OC0080327).
Disclosure
The authors report no relevant disclosures. Go to Neurology.org/NN for full disclosures.
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Associated Data
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Data Availability Statement
Data will not be publicly available.