Efficacy and safety of different oral prednisone tapering course in adult anti-NMDAR encephalitis: A multicenter prospective cohort study

doi:10.21203/rs.3.rs-4113710/v1

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Research Article

Efficacy and safety of different oral prednisone tapering course in adult anti-NMDAR encephalitis: A multicenter prospective cohort study

https://doi.org/10.21203/rs.3.rs-4113710/v1

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Background

In adult N-methyl-D-aspartate receptor (NMDAR) encephalitis, corticosteroids are commonly used as first-line treatment. However, the optimal oral prednisone tapering (OPT) following intravenous methylprednisolone pulse therapy remains unclear. We aim to compare the efficacy and safety of different OPT course in NMDAR encephalitis.

Methods

The CHASE study, a multicenter, prospective, observational cohort study, enrolled patients diagnosed with autoimmune encephalitis from October 2011 to March 2023. Patients were divided into three groups based on the duration of oral prednisone tapering: ≤3 months (Group ≤ 3 mo), 3–6 months (Group 3–6 mo), and > 6 months (Group>6 mo). Kaplan-Meier plots were generated for time-to-event endpoints, including the first relapse within 2 years and total recovery within 2 years, with sensitivity analyses and subgroup analyses conducted to assess estimate robustness.

Results

Among 666 screened patients, 171 (median [IQR] age was 27 [21.0-36.5] years, 55.0% were female) met selection criteria. The proportion of responders at 3 months was higher in Group ≤ 3 mo (OR, 9.404 [95% CI 2.741 to 32.257]) and Group 3–6 mo (OR, 5.360 [95% CI 1.477–19.453]) than in Group > 6 mo. Clinical Assessment Scale for Autoimmune Encephalitis (CASE) scores at 12 months after treatment were higher in Group >6 mo than in Group ≤ 3 mo and Group 3–6 mo (2.5 [IQR: 1.0–4.0] vs. 1 [IQR: 0.0–2.0] vs 1 [IQR: 0.0–2.0]). However, after propensity score matching, these differences disappeared. Weight gain was more frequent in the Group > 6 months than in Group ≤ 3 months (80.0% [95% CI 61.6–98.4%] vs. 33.3% [95% CI 14.1–52.6%]). No significant differences were found in modified Rankin Scale (mRS) scores, relapse rates within 2 years, full recovery within 2 years, time to recovery, impact of residual symptoms, or CASE score changes.

Conclusions

Extending oral prednisone beyond 3 months did not significantly improve outcomes but increased the risk of adverse events, particularly weight gain. This recommends evaluating the possibility of shortening the duration of oral prednisone after a thorough patient assessment.

Trial Registration:

The trial was registered on Cinese Clinical Trial Registry (ChiCTR1800019762).

NMDAR encephalitis

oral prednisone

relapse

outcomes

Anti-N-methyl-D-aspartate receptor (Anti-NMDAR) encephalitis, an autoimmune neurological disorder marked by antibodies against the GluN1 subunit of NMDAR, presents with varied neurological symptoms [1], often associated with teratomas [2]. Corticosteroids, the primary first-line treatment, function through various mechanisms, including lymphocyte activation and pro-inflammatory cytokine suppression [3].

Despite corticosteroid efficacy, the optimal oral prednisone tapering (OPT) course following intravenous methylprednisolone (IVMP) for NMDAR encephalitis remains unclear. Neurologists commonly administer oral prednisone following IVMP, gradually reducing the dosage over months based on clinical experience. The diversity in OPT across autoimmune diseases highlights the lack of consensus. For instance, in multiple sclerosis (MS), the optimal OPT course post IVMP lacks consensus, with some studies suggesting limited benefits compared to IVMP alone [4–7]. In contrast, for neuromyelitis optica spectrum disorders (NMOSD), a 2 to 6-month low-dose oral prednisone is advocated for relapse prevention [8], while chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) suggests a gradual 6 to 8-month reduction [9]. In myasthenia gravis (MG), a rapid prednisone tapering regimen is recommended in combination with azathioprine [10]. However, prolonged prednisone use poses risks such as hypertension, diabetes, osteoporosis, Cushing's syndrome, and increased infection susceptibility [4, 5, 11, 12].

To fill this gap, our large-scale multicenter prospective study assesses various OPT courses in adult NMDAR encephalitis, comparing their efficacy and safety. Additionally, propensity score analysis addresses baseline confounding factors.

Study Design and Participants

The CHASE (China Autoimmune Encephalitis Outcome Study, which was registered on the Chinese Clinical Trial Registry [registration number ChiCTR1800019762] and was previously named as the "ONE-WC study" [13–15]) study is a prospective, observational, multicenter cohort study of 666 identified autoimmune encephalitis. Patients continuously enrolled at three large comprehensive hospitals in western China from October 2011 to March 2023. Inclusion and exclusion criteria for CHASE study were detailed in Additional file 1: Supplemental Method. Additional exclusion criteria of this study were as follows: (1) Patients aged < 18 years. (2) Patients who did not receive IVMP or had contraindications to corticosteroids at the initial onset of the disease. (3) Patients who, due to severe adverse reactions, discontinued IVMP therapy or were not switched to oral prednisone after IVMP. (4) Patients who received intravenous immunoglobulin (IVIG) or plasma exchange (PE) within one month before receiving IVMP. (5) Follow-up period of less than 6 months. (6) Immunosuppressants were administered after relapse during the observation period. (6) Patients with positive serum and/or CSF laboratory tests for another autoimmune encephalitis antibody, including Leucine-rich glioma-inactivated 1 (LGI1), Gamma-Amino butyric acid B Receptor Ab (GABA-B-R), Contactin-associated protein-like 2 (Caspr2), α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor Ab (AMPAR), Gamma-Amino butyric acid A Receptor Ab (GABA-A-R), Neuronal voltage-gated potassium channel Ab (VGKC), Dipeptidyl-peptidase-like protein 6 Ab (DPPX), Metabotropic glutamate receptor 1 Ab (mGluR1), Metabotropic glutamate receptor 5 Ab (mGluR5), IgLON5 Ab, Glial fibrillary acidic protein Ab (GFAP), Aquaporin 4 water channel (Astrocyte) Ab (AQP4), Glutamic acid decarboxylase 65 Ab (GAD65) and myelin oligodendrocyte glycoprotein (MOG). (7) Patients with more than two positive antibodies.

Participants were prespecified to be divided into three groups based on their OPT course: OPT course ≤ 3 months (Group ≤ 3 mo), OPT course 3–6 months (Group 3–6 mo), and OPT course >6 months (Group>6 mo).

Approval for this study was provided by the Research Ethics Committee of the Medical School of Sichuan University. Informed consent was obtained from all enrolled patients and their caregivers, following the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) reporting guideline.

Procedures

Data collection involved reviewing electronic medical records for all identified NMDAR encephalitis patients and prospectively collecting data in a structured format (Additional file 1: Supplemental Method). Regular face-to-face follow-up was conducted with patients, involving the assessment of both modified Rankin Scale (mRS) scores and Clinical Assessment Scale for Autoimmune Encephalitis (CASE) scores. Additionally, adverse events were evaluated, and blood samples were collected to detect adverse events following prednisone usage.

The mRS score assessed patients' conditions on a scale of 0 to 6[16] (mRS score details in Additional file 1: Supplemental Method). Adverse events were evaluated through a structured interview using a specific questionnaire (Additional file 2: Table S1). The questionnaire was divided into two parts: Part A requested basic sociodemographic details, OPT course, adverse event severity, adverse event duration (completely recovered after discontinuation of prednisone; persisted), and the impact of residual symptoms on activities of daily living (not at all; a little; somewhat; very much; severely). Adverse events were assessed, documented, and classified by the treating clinical physician according to the Common Terminology Criteria for Adverse Events (CTCAE v.5.0) [17]. Part B inquired about the presence of 29 symptoms that were identified in the literature as common adverse events associated with oral prednisone [4, 5, 11].

Determination of antibodies and clinical examinations

Serum and CSF antibody tests were conducted within one week of disease onset. Antibodies against neuronal surface antibodies (NSAbs) were determined using commercial cell-based assays (CBAs) [18]. Detailed information on the antibody detection methods is provided in Additional file 1: Supplemental Method.

NMDAR antibody titers in serum and CSF were classified as strong positive (titer of 1:100 and above), positive (1:32), weak positive (1:10), and negative. Patients were grouped into the low titer group (titers < 1:32 and negative in CSF) or the high titer group (titers ≥ 1:32 in CSF) [19]. Intracranial pressure was assessed using a CSF pressure gauge, with pressure > 180 mmH₂O considered elevated. Integrated CSF analyses included total cell count, total protein content, and albumin in both CSF and serum. Abnormally increased cell counts were defined as total white cell counts > 5/ml and CSF protein levels > 500 mg/L.

MRI data were collected within one week of disease onset and at various time points throughout the disease course by an experienced technician. MRI information was reported by local radiologists according to the local MRI protocols and reporting standards. The MRI studies were conducted using a 3.0 T Siemens-Trio Erlangen MRI machine from Germany, equipped with a 12-channel coil. Routine MRI scans included axial T2-weighted images (T2WI), T1-weighted images (T1WI), and fluid-attenuated inversion recovery images (FLAIR). Contrast-enhanced studies were performed using intravenous gadopentetate dimeglumine. A comprehensive tumor examination was conducted, including CT scans of the chest and abdomen, a pelvic CT scan, positron emission tomography (PET), or transvaginal ultrasound.

Outcomes and definitions

The primary outcomes included the mRS scores, the degree of change in mRS scores (ΔmRS), and the proportion of individuals with at least a one-point improvement in mRS score at 1, 3, 6, 12, 18, 24 months and the last follow up after the initial treatment.

The secondary outcomes included the proportion of relapse-free patients within 2 years, the proportion of patients who fully recovered from onset within 2 years, the time to total recovery within 2 years, the impact of residual symptoms on activities of daily living, CASE scores, the degree of change in CASE scores (ΔCASE) at 1, 3, 6, 12, 18, 24 months, as well as during last follow-up after the initial treatment, and adverse events. Clinical relapse was defined as the emergence of new-onset symptoms or worsening of symptoms after initial improvement or stabilization, with a duration of at least 2 months [20]. The diagnosis of relapse was consistently established by experienced neurologists based on clinical evidence of active encephalitis and laboratory findings.

Total recovery was defined as an mRS score decreasing from the baseline score to 0. Responders were defined as a decrease of ≥ 1 point in the mRS score after initial treatment, while non-responders were defined as having no improvement in the mRS score after initial treatment [15]. Favorable outcome was defined as an mRS score ≤ 2 at the last follow-up, and poor outcome was defined as an mRS score > 2 at the last follow-up [21]. Delayed treatment was defined as the initiation of treatment more than 30 days after disease onset [22].

Statistical analysis

Data were entered into an Excel spreadsheet and analyzed using SPSS IBM 26.0. Figures were created with GraphPad Prism 9, R (version 4.2.1, R Programming). To assess the distribution of the variables, we performed the Kolmogorov–Smirnov test. Normally distributed data were presented as mean (± standard deviation), while non-normally distributed data were expressed as median (interquartile range, IQR). Categorical variables were analyzed using the chi-square test or Fisher's exact test. For continuous variables in the three groups, we utilized one-way analysis of variance (ANOVA) and the Kruskal-Wallis test. To account for multiple comparisons, we applied the Bonferroni’s method. To adjust for confounding factors, we employed multiple linear regression models and logistic regression models.

We generated Kaplan-Meier plots for both time-to-event endpoints, including the time to the first new relapse within 2 years and the time to total recovery within 2 years. If participants did not experience the event, their time to the event was censored at the date of their last visit. For participants who achieved complete remission within a follow-up period of less than two years, they were considered to have reached the endpoint. Relapse was evaluated in pairwise-censored groups. Hazard ratios (HR) with 95% confidence intervals (CI) were calculated using the Cox model. We tested the null hypothesis of no difference between cohorts using log-rank tests, with Group ≤ 3 months as the reference category. The proportionality assumption was assessed using the Schoenfeld global test.

To compare mRS scores and CASE scores during the follow-up period, we conducted a repeated measures analysis of variance to evaluate the effect of time, group, and the interaction between time and OPT groups.

To ensure the robustness of our findings, we conducted several sensitivity analyses: (1) Exclusion of patients who received more than two rounds of OPT, followed by a repeated analysis. (2) Comparison of the long-term mRS scores of responders and non-responders at 1 month after the initial treatment. (3) Employment of a competitive risk model for the two-year relapse risk, considering death as a competing event. (4) Propensity score matching using the R TriMatch package to minimize differences among the three OPT course [23, 24]. More details are presented in Additional file 1: Supplemental Method.

We conducted subgroup analyses on pre-specified baseline factors using Cox models, testing the interaction between OPT course and these factors regarding the primary outcome rate. Subgroups were stratified by age (≤ 35, > 35 years), sex (male, female), CSF antibody titer (low titer, high titer), and tumor status (concurrent, non-concurrent).

Statistical significance was defined as two-sided p-values < 0.05.

Data availability

All raw data that are presented or mentioned in the paper are available from the corresponding author on request.

Demographic and Clinical Characteristics

Out of 666 participants, 171 with NMDAR encephalitis met inclusion and exclusion criteria (Fig. 1). The median follow-up duration was 47 months (median [IQR], 30.0–67.0 months). After propensity score matching, 51 participants were included. The clinical features after propensity score are shown in Additional file 2: Table S2.

Detailed patient demographic and clinical characteristics are presented in Table 1. The total cumulated dose of prednisone in Group > 6 mo and Group 3–6 mo was higher than in Group ≤ 3 mo (6310 [5092.5–8125.0] mg, 3935 [3850.0-6300.0] mg vs. 1470 [1050.0-2100.0] mg, P_corr < 0.05). Notably, the proportion of patients presenting with consciousness disturbance was higher in Group > 6 mo than in Group 3–6 mo (57.7% [95% CI 36.8–78.6%] vs. 27.7% [95% CI 10.11–45.2%], P_corr < 0.05). The proportion of patients with high CSF antibody titers was greater in Group > 6 mo than in Group ≤ 3 mo (76.9% [95% CI 63.0%, 87.9%] vs. 69.4% [95% CI 59.3–79.5%], P_corr < 0.05).

Table 1

Characterization of the Patient Cohort
	Patients, No. (%)
	Total (n = 171)	Group ≤ 3 mo (n = 98)	Group 3–6 mo (n = 47)	Group >6 mo (n = 26)	P value
Demographic data
Sex (female)	94 (55.0)	59 (60.2)	23 (48.9)	12 (48.9)	0.274
Age at onset, median (IQR), years	27 (21.0-36.5)	27.5 (22.0-38.8)	26 (20.5–32.5)	28 (18.0-36.2)	0.379
Length of hospital stay, median (IQR), days	20 (14.0–28.0)	19.5 (14.0–28.0)	19 (12.5–27.0)	21 (16.2–35.5)	0.358
Initial symptoms
Fever	58 (33.9)	31 (31.6)	16 (34.0)	11 (42.3)	0.593
Headache	60 (35.1)	31 (31.6)	16 (34.0)	13 (50)	0.215
dizziness	8 (4.7)	6 (6.1)	2 (4.3)	0 (0)	0.416
Ataxia	7 (4.1)	7 (7.1)	0 (0)	0 (0)	0.066
Limb weakness	4 (2.3)	3 (3.1)	0 (0)	1 (3.8)	0.474
Limb numbness	12 (7)	8 (8.2)	3 (6.4)	1 (3.8)	0.731
Cognitive impairment	40 (23.4)	21 (21.4)	8 (17)	11 (42.3)	0.051
Disturbance of consciousness	65 (38)	37 (37.8)	13 (27.7) ^a	15 (57.7)	0.040
Speech disturbance	19 (11.1)	13 (13.3)	5 (10.6)	1 (3.8)	0.394
Dyskinesias and movement disorders	8 (4.7)	8 (8.2)	0 (0)	0 (0)	0.044
Sleep disorders	31 (18.1)	21 (21.4)	7 (14.9)	3 (11.5)	0.404
Seizures	115 (67.3)	59 (60.2)	35 (74.5)	21 (80.8)	0.065
Focal onset	22 (12.9)	12 (12.2)	9 (19.1)	1 (3.8)	0.167
Generalized onset	103 (60.2)	54 (55.1)	29 (61.7)	20 (76.9)	0.126
Status epilepticus	32 (18.7)	16 (16.3)	7 (14.9)	9 (34.6)	0.077
Psychosis	125 (73.1)	75 (76.5)	33 (70.2)	17 (65.4)	0.455
Mania	46 (26.9)	26 (26.5)	12 (25.5)	8 (30.8)	0.883
Depression	29 (17)	16 (16.3)	9 (19.1)	4 (15.4)	0.890
Hallucinations	42 (24.6)	28 (28.6)	8 (17)	6 (23.1)	0.313
Paranoia	16 (9.4)	8 (8.2)	4 (8.5)	4 (15.4)	0.517
Autonomic dysfunction	46 (26.9)	26 (26.5)	14 (29.8)	6 (23.1)	0.819
Central hypoventilation	24 (14.0)	11 (11.2)	6 (12.8)	7 (26.9)	0.117
ICU admission	21 (12.3)	11 (11.2)	5 (10.6)	5 (19.2)	0.500
ICU length of stay, median (IQR), days	27 (21.0–47.0)	25 (20.0-46.5)	47 (30.0–62.0)	27 (21.0–37.0)	0.252
Complications	68 (39.8)	42 (42.9)	18 (38.3)	8 (30.8)	0.519
Tumor	19 (11.1)	13 (13.3)	5 (10.6)	1 (3.8)	0.394
NMDAR antibody titer
Low titer	59 (34.5)	30 (30.6) ^a	23 (48.9)	6 (23.1)	0.039
High titer	112 (65.5)	68 (69.4) ^a	24 (51.1)	20 (76.9)	0.039
Auxiliary examinations
MRI, abnormality	66 (38.6)	38 (38.8)	18 (38.3)	10 (38.5)	0.998
EEG, abnormality	158 (92.4)	92 (93.9)	42 (89.4)	24 (92.3)	0.630
CSF, abnormality	93 (54.4)	58 (59.2)	22 (46.8)	13 (50.0)	0.333
Pleocytosis	82 (48.0)	52 (53.1)	20 (42.6)	10 (38.5)	0.285
Increase protein concentration	39 (22.8)	22 (22.4)	8 (17.0)	9 (34.6)	0.228
Increase ICP	30 (17.5)	14 (14.3)	8 (17.0)	8 (30.8)	0.144
IVMP Dose/duration (days)
1000 mg/day*5 days	154 (90.1)	85 (86.7)	45 (95.7)	24 (92.3)	0.217
500 mg/day*5 days	17 (9.9)	13 (13.3)	2 (4.3)	2 (7.7)	0.217
Cumulated dose of prednisone at 3 months, mg, median (IQR)	3220 (2660.0-3990.0)	1470 (1050.0-2100.0)	3185 (2660.0-4200.0) ^b	3240 (2642.0-3900.0) ^b	<0.001
Cumulated dose of prednisone at 6 months, mg, median (IQR)	4410 (3875.0-6300)	-	3935 (3850.0-6300.0)	4730 (4147.0-6300.0)	0.199
Total cumulated dose of prednisone, mg, median (IQR)	2660 (1470.0-4410.0)	1470 (1050.0-2100.0)	3935 (3850.0-6300.0) ^b	6310 (5092.5–8125.0) ^b	<0.001
Number of IVMP at first episode, median (IQR)	1 (1.0–1.0)	1 (1.0–1.0)	1 (1.0–1.0)	1 (1.0–1.0)	0.557
Combination therapy	152 (88.9)	89 (90.8)	42 (89.4)	21 (80.8)	0.321
Number or OPT, median (IQR)	1 (1.0–1.0)	1 (1.0–1.0)	1 (1.0–1.0)	1 (1.0–1.0)	0.875
Time from onset to the beginning of IVMP, days, median (IQR)	23 (12.5–35.5)	22 (12.0-34.8)	24 (15.0-34.5)	23.5 (10.0-39.8)	0.774
Delayed treatment	57 (33.3)	31 (31.6)	15 (31.9)	11 (42.3)	0.573
Acute phase combination therapy	152 (88.9)	89 (90.8)	42 (89.4)	21 (80.0)	0.321
Immunosuppressant type
CTX	20 (80.0)	12 (85.7)	5 (83.3)	3 (60.0)	0.532
OFA	2 (8.0)	1 (7.1)	0 (0.0)	1 (20.0)
Tacrolimus	3 (12.0)	1 (7.1)	1 (16.7)	1 (20.0)
Follow-up time, months, median (IQR)	47 (30.0–67.0)	47 (43.0-55.7)	46 (39.7–53.7)	36.5 (33.6–53.4)	0.517
mRS scores at baseline, median (IQR)	4 (3.0–5.0)	4 (3.0–5.0)	4 (3.0–5.0)	4 (3.0–5.0)	0.891
mRS scores at last FU, median (IQR)	0 (0.0–1.0)	0 (0.0–1.0)	0 (0.0–1.0)	0 (0.0–1.0)	0.868
CASE scores at baseline, median (IQR)	9 (5.0–20.0)	8 (5.0–19.0)	10 (4.5–18.0)	12 (4.8–22.0)	0.759
CASE scores at last FU, median (IQR)	0.0 (0.0–0.0)	0.0 (0.0–0.0)	0.0 (0.0–0.0)	0.0 (0.0–0.0)	0.380
Outcome
Favorable outcome	154 (90.1)	87 (88.8)	43 (91.5)	24 (92.3)	0.805
Poor outcome	17 (9.9)	11 (11.2)	4 (8.5)	2 (7.7)	0.805
Death	9 (5.3)	8 (8.2)	1 (2.1)	0 (0)	0.134
Impact of residual symptoms on ADL
Not at all	113 (70.2)	66 (74.2)	31 (67.4)	16 (61.5)	0.448
A little	22 (13.7)	11 (12.4)	8 (17.4)	3 (11.5)
Somewhat	13 (8.1)	3 (3.4)	4 (8.7)	6 (23.1)
Very much	11 (6.8)	8 (9.0)	3 (6.5)	0 (0)
Severely	2 (1.2)	1 (1.1)	0 (0)	1 (3.8)
Responder’ number at 1 month	84 (49.1)	52 (53.1)	23 (48.9)	9 (34.6)	0.247
Responder’ number at 3 months	130 (76.0)	81 (82.7) ^a	36 (76.6)	13 (50.0)	0.002
Responder’ number at 6 months	122 (73.5)	69 (73.4)	36 (78.3)	17 (65.4)	0.490
Responder’ number at 12 months	135 (86.0)	74 (85.1)	40 (88.9)	21 (84.0)	0.814
Responder’ number at 18 months	132 (91.7)	71 (89.9)	40 (93.0)	21 (95.5)	0.768
Responder’ number at 24 months	129 (94.2)	71 (94.7)	38 (95.0)	20 (90.9)	0.776
Relapse within 2 years	39 (22.8)	25 (25.5)	11 (23.4)	3 (11.5)	0.318
Number of relapses within 2 years, median (IQR)	0 (0.0–0.0)	0 (0.0-0.8)	0 (0.0–0.0)	0 (0.0–0.0)	0.289
Relapse during OPT	16 (9.4)	9 (9.2)	5 (10.6)	2 (7.7)	0.914
Time to first relapse during OPT, months, median (IQR)	3.5 (2.0-6.3)	2 (1.2–2.9)	6 (5.0–7.0) ^b	9.5 (8.3–10.8) ^b	0.004
Time to first relapse within 2 years, months, median (IQR)	6.5 (3.3–20.0)	5 (3.0-21.8)	11 (4.8–15.5)	5.5 (1.8–16.8)	0.636
Total recovery from onset within 2 years	92 (53.8)	52 (53.1)	29 (61.7)	11 (42.3)	0.275
Time to total recovery from onset within 2 years, months, median (IQR)	12 (6.0–24.0)	12 (6.0–24.0)	12 (6.0–24.0)	18 (12.0–24.0)	0.437
a compared with Group >6 months
b compared with Group ≤ 3 months
Abbreviation: ΔmRS: mRS change from baseline; ADL: activities of daily living; FU: follow-up; ICU: intensive care unit; IQR: interquartile range; OPT: oral prednisone tapering; Group ≤ 3 mo: oral prednisone tapering course ≤ 3 months; Group 3–6 mo: oral prednisone tapering course for 3–6 months; Group >6 mo: oral prednisone tapering course for >6 months.
NA: not available

During the 24-month follow-up period, the distribution of mRS scores and initial treatment regimens for the three groups are shown in Fig. 2. No statistically differences were observed in acute phase treatment regimens among the three groups (P > 0.05; Fig. 2e-f). The median time from onset to the initiation of IVMP was 23 days (12.5–35.5). Among the patients, 24 (14.0%) underwent 2 rounds of OPT, 8 (4.7%) had 3 rounds, and 2 (1.2%) underwent 4 rounds.

Primary outcome

Compared to baseline, mRS scores at 1, 3, 6, 12, 18, 24 months and the last follow up decreased in all groups (P < 0.001 for all groups at each time point; Additional file 2: Table S3). No statistically significant differences were observed in mRS scores at each time point among the three groups (P > 0.05; Fig. 3a). The median degree of ΔmRS at 3 months after initial treatment in Group ≤ 3 mo was greater than that in Group > 6 mo (1 [IQR: 0.0–1.0] vs. 0 [IQR: 0.0–1.0], P_corr < 0.05; Fig. 3c). However, this association was not significant in adjusted model 2 (β, 0.394 [95% CI 0.157 to 0.631; β, 0.399 [95% CI 0.013–0.784]; P > 0.05; Additional file 2: Table S4). Additionally, no significant difference was found in ΔmRS degree at 1, 6, 12, 18, 24 months and the last follow up (Fig. 3c).

The proportion of responders at 3 months after initial treatment was higher in Group ≤ 3 mo than in Group > 6 mo (82.7% [95% CI 70.7–91.3%] vs. 50.0% [95% CI 47.4–62.6%], P_corr < 0.05; Table 1). In adjusted model 1 and model 2, the proportion of responders at 3 months was higher in Group ≤ 3 mo (OR, 9.404 [95% CI 2.741 to 32.257], P < 0.001) and Group 3–6 mo (OR, 5.360 [95% CI 1.477–19.453], P = 0.011) than in Group > 6 mo (Additional file 2: Table S5). No significant difference was found in the proportion of responders at other time points (P > 0.05).

Second outcome

Among NMDAR encephalitis patients, 39 individuals (22.8%) experienced a relapse within 2 years (Table 1). Of these, 9 patients (23.1%) had two relapses, and 2 patients (5.1%) relapsed three times. The most prevalent symptoms observed in the relapsed patients included psychosis (26/39, 66.7%), seizures (16/39, 41.0%), cognitive impairment (5/39, 12.8%), and speech disturbances (4/39, 10.3%).

During the 2-year follow-up, 16 patients (9.4%) experienced relapses during OPT course, with a median relapse time of 3.5 months. There were no significant differences in 2-year relapse-free survival among the three groups (P log rank = 0.27; Fig. 4a). In the adjusted Cox regression model, the OPT course was not a significant factor for 2-year relapse-free survival (P > 0.05; Additional file 2: Table S6). A total of 92 patients (53.8%) achieved total recovery within two years, with no significant differences among the three groups (P log rank = 0.28; Fig. 3c). Among the 161 patients reporting the impact of residual symptoms on daily activities, 135 (83.9%) indicated that the symptoms had "not at all or a little" effect on activities of daily living, with no significant differences between the groups (P > 0.05).

CASE scores at 12 months after treatment were higher in Group >6 mo than in Group ≤ 3 mo and Group 3–6 mo (2.5 [IQR: 1.0–4.0] vs. 1 [IQR: 0.0–2.0] vs 1 [IQR: 0.0–2.0], P_corr < 0.05; Fig. 5a). In adjusted model 1 and model 2, the results were still significant (Additional file 2: Table S7). The degree of ΔCASE was not significant at each time points (Fig. 3, Fig. 5). The mRS scores and CASE scores exhibited a strong positive correlation (Additional file 3: Figure S1).

Subgroup and Sensitivity analysis

To explore the relationship between risk factors and OPT course, we conducted subgroup analysis. The number of responders at 3 months did not show improvement in Group > 6 mo in each subgroup (Additional file 2: Table S8).

OPT course was a significant factor for CASE at 12 months in patients ≤ 35 years old at disease onset (P < 0.05), in male (P < 0.05), in high CSF titer (P < 0.05), and in patients without tumor (P < 0.05) (Additional file 2: Table S9). Patients in Group > 6 mo did not show improvement in CASE scores at 12 months.

Notably, all tumors were teratomas and were surgically removed during the disease course. Patients with NMDAR encephalitis and tumors (11.5%) experienced no relapses within two years. The 2-year relapse-free survival and total recovery rate were consistent across all subgroups (Additional file 3: Figure S2-S3). No significant interaction with treatment was found for any of the prespecified baseline factors (P > 0.05 for all comparisons). Adjusted analyses were not conducted due to a violation of the proportional hazards assumption.

To address baseline inconsistencies, we implemented propensity score matching. Following matching, no differences were observed in mRS scores, the degree of ΔmRS, CASE scores, the degree of ΔCASE at each time points (Fig. 3, Fig. 5). Notably, there were no significant differences in 2-year relapse-free survival (P log rank = 0.86; Fig. 4b) or 2-year total recovery rate (P log rank = 0.31; Fig. 4c).

Sensitivity analysis consistently indicated that, even after excluding patients who received more than 2 rounds of OPT, the proportion of responders in Group ≤ 3 mo remained higher than in Group > 6 mo in an adjusted model (OR: 8.111 [95% CI 2.184 to 30.122], P = 0.002; data not shown). The mRS scores at 3 months were higher in Group >6 mo than in Group ≤ 3 mo and Group 3–6 mo in an adjusted model (β, -982 [95% CI -1.565 to -0.399; β, -0.705 [95% CI -1.348- -0.063]; P<0.05; data not shown). CASE scores at 12 months were higher in Group >6 mo than in Group ≤ 3 mo and Group 3–6 mo in an adjusted model (β, -2.185 [95% CI -3.795 to -0.576; β, -2.333 [95% CI -4.091- -0.575]; P<0.05; data not shown). Other secondary outcomes did not show significant differences. Additionally, long-term outcomes of responders and non-responders at 1 month after initial treatment revealed no differences in mRS scores and CASE scores at 12 months, 18 months, 24 months, and the last follow-up (P > 0.05; data not shown). In a competing risk model, there was no significant difference in the 2-year relapse risk (P = 0.383) when considering death as a competing risk event (Additional file 3: Figure S4).

Adverse events

A total of 200 adverse events were reported (Table 2). Of the individuals, 68.1% had recovered after withdrawal, and 75% experienced adverse events classified as CTCAE grade 1. The severity and duration of adverse events did not differ significantly before and after propensity score matching (P > 0.05; Table 2). After propensity score matching, weight gain was the most common adverse event, and its incidence was higher in Group > 6 months than in Group ≤ 3 months (80.0% [95% CI 61.6–98.4%] vs. 33.3% [95% CI 14.1–52.6%], P_corr < 0.05; Additional file 2: Table S2). No reports of treatment discontinuation due to severe adverse events during oral prednisone. Three patients reported femoral head necrosis but made a good recovery after surgical treatment. In Group 3–6 mo, two patients exhibited random blood sugar levels that exceeded 27 mmol/L, necessitating urgent intervention and treatment. Additional adverse events are detailed in Table 2.

Table 2

Adverse events of oral prednisone
	Patients, No. (%)
	Total (n = 171)	Group ≤ 3 mo (n = 98)	Group 3–6 mo (n = 47)	Group >6 mo (n = 26)	P value
Adverse events	116 (67.8)	52 (53.1)	41 (87.2) ^a	23 (88.5) ^a	<0.001
Weight gain	96 (56.1)	43 (43.9)	34 (72.3) ^a	19 (73.1) ^a	0.001
Increased appetite	47 (27.5)	26 (26.5)	14 (29.8)	7 (26.9)	0.971
Hyperglycemia	10 (5.8)	3 (3.1)	4 (8.5)	3 (11.5)	0.172
Hypertension	1 (0.6)	0 (0)	1 (2.1)	0 (0)	0.427
Stomach pain	3 (1.8)	0 (0)	1 (2.1) ^a	2 (7.7) ^b	0.022
Rash acneiform	24 (14)	9 (9.2)	9 (19.1)	6 (23.1)	0.096
Hyperhidrosis	2 (1.2)	1 (1.0)	0 (0)	1 (3.8)	0.356
Hirsutism	1 (0.6)	0 (0)	1 (2.1)	0 (0)	0.472
Abnormal liver-function	2 (1.2)	2 (1.2)	1 (1.0)	1 (2.1)	0.673
Palpitations	1 (0.6)	1 (1.0)	0 (0)	0 (0)	1
Fatigue	4 (2.3)	3 (3.1)	1 (2.1)	0 (0)	1
Upper respiratory infection	3 (1.8)	1 (1.0)	1 (2.1)	1 (3.8)	0.390
Oral infection	1 (0.6)	0 (0)	0 (0)	1 (3.8)	0.152
Femoral head necrosis	4 (2.3)	2 (2.0)	1 (2.1)	1 (3.8)	0.792
Menstrual irregularities	4 (2.3)	1 (1.0)	2 (4.3)	1 (3.8)	0.254
Osteoporosis	1 (0.6)	1 (1.0)	0 (0)	0 (0)	1
Insomnia	6 (3.5)	2 (2)	3 (6.4)	1 (3.8)	0.353
Agitation	1 (0.6)	0 (0)	0 (0)	1 (3.8)	0.152
Total	211 cases	95 cases	73 cases	45 cases	NA
Adverse events duration
Recovery	79 (68.1)	37 (71.2)	28 (68.3)	14 (60.9)	0.682
Persistence	37 (31.9)	15 (28.8)	13 (31.7)	9 (39.1)	0.682
Severity of adverse events
CTCAE grade 1	87 (75.0)	39 (75.0)	33 (80.5)	15 (65.2)	0.462
CTCAE grade 2	18 (15.5)	7 (13.5)	5 (12.2)	6 (26.1)
CTCAE grade 3	9 (7.8)	6 (11.5)	1 (2.4)	2 (8.7)
CTCAE grade 4	2 (1.7)	0 (0)	2 (4.9)	0 (0)
CTCAE grade 5	0 (0)	0 (0)	0 (0)	0 (0)
a compared with Group ≤ 3 months
b compared with Group 3–6 months
Abbreviation: CTCAE: Common Terminology Criteria for Adverse-Events; Group ≤ 3 mo: oral prednisone tapering course ≤ 3 months; Group 3–6 mo: oral prednisone tapering course for 3–6 months; Group >6 mo: oral prednisone tapering course for >6 months.
NA: not available

In this prospective observational study, we aimed to investigate the efficacy and safety of different OPT course in adult NMDAR encephalitis. Our study is the first of its kind, providing valuable insights into the optimal treatment duration for this condition. Here, we summarize our main findings: (1) The proportion of responders at 3 months after initial treatment was significantly higher in Group ≤ 3 mo and Group 3–6 mo compared to Group > 6 mo. However, after propensity score matching, no significant improvement in outcomes, including the proportion of responders and the degree of mRS change at different time points, was evident for OPT courses lasting more than 3 months. (2) Over a 2-year follow-up, the three groups showed no significant differences in relapse risk, the proportion of patients who fully recovered from onset, time to total recovery, residual symptom impact on daily life or CASE scores. (3) Group > 6 mo received higher prednisone doses and experienced more adverse events, particularly weight gain. Overall, our study suggests that extending the oral prednisone course beyond 3 months in adult NMDAR encephalitis may not lead to further improvements in clinical outcomes. Moreover, it increases the risk of adverse events, primarily weight gain. These findings contribute to the understanding of treatment strategies for NMDAR encephalitis and have practical implications for optimizing patient care.

The common OPT strategy is to initiate oral prednisone at 1–2 mg/kg/day, often followed by a gradual taper over several weeks to months [25]. However, the optimal treatment duration is uncertain. Our study suggests that extending oral prednisone beyond 3 months may not yield notable improvements in neurological function. We observed no benefits in the number of respondents, changes in mRS scores, mRS scores at various time points, CASE scores, changes in CASE scores, favorable outcomes (mRS ≤ 2), total recovery rate within 2 years, or residual symptom impact on daily life for oral prednisone for over three months. Our findings align with a retrospective pediatric study of 190 children with NMDAR encephalitis, which found no significant differences in recovery rates between long-term and short-term oral prednisone treatments [26]. In a recent report by Li et al., which focused on autoimmune encephalitis, the choice of OPT course, in combination with MMF, did not significantly affect patient outcomes [21]. However, it's worth noting that this study had a small cohort and didn't investigate the benefits of a shorter taper within the initial 3 months.

Intravenous methylprednisolone is the guideline-recommended first-line treatment for NMDAR encephalitis [27]. Prednisone tapering regimens vary considerably in clinical practice. Decisions about treatment duration should consider the patient's clinical status, treatment response, tolerance, and safety. Our study shows that neurologists tend to prescribe oral prednisone for over 6 months, especially for patients with consciousness disorders and high CSF antibody titers. Additionally, previous research has indicated that physicians may extend oral prednisone courses based on the presence of MRI abnormalities [21]. Although these factors may be linked to a worse prognosis [28–31], our propensity score-matched analysis didn't find significant differences among the OPT groups. This suggests that clinical decisions to prolong prednisone treatment based solely on these factors may not always be justified, emphasizing the need for evidence-based guidance.

Our study observed variations in treatment responses among male patients, patients without tumors, and patients with high CSF antibody titers. Patients in Group ≤ 3 months showed better short-term responses (more responders at 3 months after initial treatment) and better long-term prognosis (CASE scores at 12 months). Prior research has identified risk factors for outcomes in NMDAR encephalitis, including ovarian teratoma, male gender, and high CSF antibody titers [30, 32, 33]. While patients without ovarian teratoma who received ≤ 3 months of OPT had expectedly better short-term prognosis, it's intriguing that male patients or those with high CSF antibody titers also showed improved short-term outcomes. However, the limited sample size and the absence of propensity matching in our subgroup analysis may introduce baseline confounding factors.

Experts recommend avoiding shorter steroid tapering in autoimmune encephalitis cases with poor initial responses [34]. However, these recommendations lack robust supporting evidence. Our data shows that 49.1% of individuals experienced symptom improvement at 1 month after treatment, with no significant differences in long-term outcomes between patients with good or poor initial responses across the three OPT courses. Notably, due to the limited sample size within each subgroup, propensity score matching was not feasible. Thus, further investigations are warranted to validate these preliminary observations.

Our study found no significant differences in the risk of relapse within a 2-year period among the three OPT groups, regardless of age, sex, CSF antibody titers, or tumor presence. These results emphasize that oral prednisone alone may not be the primary strategy for preventing relapses in NMDAR encephalitis. In our study, 22.8% of participants experiencing relapses within 2 years. Notably, 9.4% of patients relapsed during the course of oral prednisone, suggesting that the risk of relapse persists despite such treatment. The literature on the efficacy of oral prednisone course in preventing relapse is limited. As far as we know, only one retrospective pediatric cohort study has explored the relationship between OPT courses and relapse rates in NMDAR encephalitis [26]. Previous research indicated that corticosteroids exhibit limited specificity in countering antibody-mediated immune responses, rendering them insufficient to mitigate the autoantibody-mediated immune processes [35, 36]. Importantly, combining corticosteroids with second-line immunosuppressive agents may hold promise for reducing relapses [37–39].

Corticosteroids are commonly employed in the treatment of various autoimmune diseases due to their anti-inflammatory and immunosuppressive properties. The optimal duration of corticosteroid tapering, however, varies across different diseases, possibly due to distinct disease mechanisms and corticosteroid involvement in signaling pathways. For example, in MG, an autoimmune disease with antibodies targeting neuromuscular junction proteins, long-term, low-dose corticosteroids are recommended to suppress immune responses [40]. Corticosteroids reduce germinal centers and modulate chemokines and angiogenesis, possibly through acetylation [41]. This is in contrast to CIDP, where long-term corticosteroid use is associated with reductions in the frequencies of total CD4 + T cells, CD4 + memory subsets, and natural killer (NK) cells, contributing to its efficacy [42]. In NMDAR encephalitis, the mechanisms underlying long-term corticosteroid response remain unclear, with a possible interaction between the NMDA receptor system and the glucocorticoid pathway influencing neuronal signaling [43]. Further research is needed to elucidate these mechanisms and guide the development of more targeted and effective treatment regimens.

Long-term corticosteroid use is associated with adverse events [4, 5, 11, 44]. Patients receiving oral prednisone for over 3 months are more likely to experience weight gain and higher cumulative prednisone doses. Reducing the cumulative dose is crucial as complications increase with dose [45]. Another study has similarly reported an increased risk of weight gain in autoimmune encephalitis patients receiving long-term oral prednisone [21]. Notably, obesity can lead to various comorbidities such as hypertension and cardiovascular events [46]. In addition, corticosteroids may induce or exacerbate psychiatric symptoms in NMDAR encephalitis, such as depression, insomnia, agitation, and psychosis [35]. However, our study did not find similar symptoms. In summary, oral prednisone for ≤ 3 months offers a safer alternative when comparable efficacy to longer courses is observed, favoring a shorter OPT course.

However, this study has several limitations. Although we applied the propensity score matching to balance baseline covariates and our study findings were consistent with insensitivity analyses, potential bias caused by unmeasured and unobserved factors cannot be completely ruled out. RCTs with standardized OPT protocols are vital to evaluate benefits and risk. Furthermore, the generalizability of our findings is restricted by the study's exclusive enrollment of Asian participants and the uniform use of prednisone, which may not apply to individuals from diverse racial backgrounds or those treated with different corticosteroids. Additionally, diverse antibody subtypes in autoimmune encephalitis may result in distinct treatment responses, necessitating further research stratified by antibody subtype. Moreover, the impact of symptomatic medications on mRS scores should also be considered. In addition, our prior study and a meta-analysis have established that combination therapy during the acute phase is more effective than monotherapy [14, 27]. Consequently, most patients in this study received combination therapy. Even though we used propensity score matching and excluded patients who received IVIG and PE within one month before prednisone treatment, the potential synergistic effects of PE and IVIG cannot be ruled out entirely. Finally, although we used CASE scores to assess the severity of disability, that lacks evaluations of sleep and neuropsychological assessments such as Pittsburgh Sleep Quality Index, Hamilton Depression Scale (HAMD) and Hamilton Anxiety Scale (HAMA).

In conclusion, our study suggests that extending oral prednisone treatment for adult NMDAR encephalitis beyond 3 months may not significantly improve outcomes but could increase the risk of adverse events, particularly weight gain. The findings will contribute to the decision-making process for treatment choices in clinical practice. To enhance treatment effectiveness and safety, we recommend evaluating the possibility of shortening the duration of oral prednisone after a thorough patient assessment.

CASE: Clinical Assessment Scale for Autoimmune Encephalitis; CBAs: cell-based assays; CIDP: chronic inflammatory demyelinating polyradiculoneuropathy; CI: confidence intervals; CTCAE: Common Terminology Criteria for Adverse Events; HAMA: Hamilton Anxiety Scale; HAMD: Hamilton Depression Scale (HAMD); IVMP: intravenous methylprednisolone; IQR: interquartile range; MG: myasthenia gravis; mRS: modified Rankin Scale; MS: multiple sclerosis; NMDAR: N-methyl-D-aspartate receptor (Anti-NMDAR); NK: natural killer; NMOSD: neuromyelitis optica spectrum disorders; NSAbs: neuronal surface antibodies; OPT: oral prednisone tapering

Supplementary Information

Additional file 1. Supplemental methods.

Additional file 2: Table S1-S9. Table S1. Safety assessment questionnaire. Table S2. Patients’ characteristics after propensity score matching. Table S3. Comparison of mRS score before treatment VS after treatment in the 1th, 3th, 6th, 12th, 18th, 24th month after initial treatment. Table S4. Univariate and multivariable linear regression of the degree of mRS score change at 3 months after initial treatment. Table S5. Univariate and multivariable logistic regression of responders at 3 months after initial treatment. Table S6. Univariate and multivariable Cox regression models of relapse within 2 years. Table S7. Univariate and multivariable linear regression of the CASE score at 12 months after initial treatment. Table S8. The number of responders at 3 months after initial treatment in subgroup analysis. Table S9. CASE scores at 12 months after initial treatment in subgroup analysis.

Additional file 3: Figure S1-S4. Figure S1. The correlation analysis between mRS scores and CASE scores. Figure S2. Forest plot of the relapse risk within 2 years for subgroup. Figure S3. Forest plot of the total recovery rate within 2 years for subgroup. Figure S4. Two-year risk of the relapse competitive survival model among the three groups.

Acknowledgements

We thank the patients who have agreed to participate in our study.

Author’s contributions

LC and GL contributed equally to this study and are co-first authors. ZH had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. Study concept and design: LC, GL and ZH. Acquisition, analysis, or interpretation of data: All authors. Drafting of the manuscript: LC, GL and ZH. Critical revision of the manuscript for important intellectual content: all authors. Statistical analysis: LC, GL and ZH. Study supervision: DZ and ZH. All authors reviewed the manuscript. All authors read and approved the final manuscript.

Funding

This study was supported by the National Key R&D Program of China (Grant No. 2022YFC2503800), Clinical Research Incubation Project of West China Hospital of Sichuan University (22HXFH022), the 1.3.5 project for disciplines of excellence and Brain Science project of West China Hospital, Sichuan University (ZYJC21001), West China Nursing Discipline Development Special Fund Project, Sichuan University (HXHL20004), Natural Science Foundation of Sichuan Province（24NSFSC5638), and the China Postdoctoral Science Foundation (GZC20231808).

Availability of data and materials

The data will be shared on a reasonable request to the corresponding author.

Ethics approval and consent to participate

This study was approved by the Research Ethics Committee of the Medical School of Sichuan University (No. 2018–292).

Consent for publication

Not applicable.

Competing interests

The authors declare that they have no competing interests.

Author details

¹ Department of Neurology, West China Hospital of Sichuan University, Chengdu, Sichuan, China

² Department of Neurosurgery, West China Hospital, Sichuan University, Chengdu, Sichuan, China

³ Institute of Brain Science and Brain-inspired Technology of West China Hospital, Sichuan University, Chengdu, Sichuan, China

⁴ Department of Neurology, Chengdu Shangjin Nanfu Hospital, Chengdu, Sichuan, China

⁵ Department of Neurology, West China Tianfu Hospital of Sichuan University, Chengdu, Sichuan, China

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No competing interests reported.

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FigureS1.png
Figure S1. The correlation analysis between mRS scores and CASE scores. The mRS scores and CASE scores exhibited a strong positive correlation.
FigureS2.png
Figure S2. Forest plot of the relapse risk within 2 years for subgroup. Group ＞6 months was defined as a reference category. No significant interactions were observed among the three groups. Relapse-free survival was consistent across all subgroups, including age, sex, CSF antibody titer and tumor. Abbreviation: CSF: cerebrospinal fluid; HR: hazard ratio; Group ≤3 mo: oral prednisone tapering course for ≤3 months; Group 3-6 mo: oral prednisone tapering course for 3-6 months; Group ＞6 mo: oral prednisone tapering course for ＞6 months. a Hazard ratio (HRs) and the associated 95% CIs were calculated using an unadjusted Cox proportional hazards model.
FigureS3.png
Figure S3. Forest plot of the total recovery rate within 2 years for subgroup. Group ＞6 months was defined as a reference category. No significant interactions were observed among the three groups. Total recovery rate was consistent across all subgroups, including age, sex, CSF antibody titer and tumor. Abbreviation: CSF: cerebrospinal fluid; HR: hazard ratio; Group ≤3 mo: oral prednisone tapering course for ≤3 months; Group 3-6 mo: oral prednisone tapering course for 3-6 months; Group ＞6 mo: oral prednisone tapering course for ＞6 months. a Hazard ratio (HRs) and the associated 95% CIs were calculated using an unadjusted Cox proportional hazards model.
FigureS4.png
Figure S4. Two-year risk of the relapse competitive survival model among the three groups. No statistical difference in the risk of relapse and death within two years among the three groups (P = 0.383, P = 0.132). Death is the competing event. Group ≤3 mo: oral prednisone tapering course for ≤3 months; Group 3-6 mo: oral prednisone tapering course for 3-6 months; Group ＞6 mo: oral prednisone tapering course for ＞6 months.

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Efficacy and safety of different oral prednisone tapering course in adult anti-NMDAR encephalitis: A multicenter prospective cohort study

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