ABSTRACT
Objective
There is a lack of studies on seizure outcomes associated with ofatumumab therapy in patients for relapsing anti‐N‐methyl‐D‐aspartate (NMDA) receptor encephalitis. We aimed to evaluate long‐term seizure outcomes of ofatumumab therapy for relapsing anti‐NMDA receptor encephalitis.
Methods
This is a prospective cohort study, Compared patients with relapsing anti‐NMDA receptor encephalitis who had received at least 1 ofatumumab dose and a control cohort of non‐ofatumumab‐treated patients, continuous follow‐up for 24 months. The primary outcome was the seizure outcomes (including both seizure reduction and seizure freedom; seizure reduction is defined as a reduction in seizure frequency to 50% or more of the baseline level, seizure freedom is defined as having no seizures) at the follow‐up. The secondary outcomes included modified Rankin Scale (mRS) scores and Clinical Assessment Scale in Autoimmune Encephalitis (CASE) scores over the 24‐month follow‐up.
Results
We enrolled 93 patients with relapsing anti‐NMDA receptor encephalitis. A total of 76 patients met the requirements after the inclusion and exclusion criteria. The 38 patients received ofatumumab therapy, and the other 38 patients received non‐ofatumumab therapy. Follow‐up after 6 months, the ofatumumab therapy group demonstrated favorable seizure outcomes (63.16% vs. 36.84%, p < 0.05). Follow‐up after 12 months, this improvement of seizure outcomes was more pronounced (78.95% vs. 60.53%, p < 0.05). Follow‐up after 24 months, this difference between the two groups widened further (94.74% vs. 78.95%, p < 0.05), compared with the non‐ofatumumab therapy group. Follow‐up after 6 months, the ofatumumab group demonstrated a faster mRS scores (2.85 ± 0.65 vs. 3.75 ± 0.55, p < 0.05) and CASE scores (11.80 ± 1.65 vs. 13.75 ± 1.55, p < 0.05). Follow‐up after 12 months, the ofatumumab group demonstrated a faster mRS scores (1.68 ± 0.45 vs. 2.39 ± 0.35, p < 0.05) and CASE scores (6.75 ± 1.45 vs. 9.39 ± 1.35 p < 0.05). Follow‐up after 24 months, the ofatumumab group demonstrated a faster mRS scores (1.25 ± 0.35 vs. 1.68 ± 0.45, p < 0.05) and CASE scores (4.25 ± 0.75 vs. 6.68 ± 1.35, p < 0.05). And no serious adverse events associated with ofatumumab treatment were reported. Furthermore, Multivariate logistic regression analysis identified that early initiation of ofatumumab therapy, psychiatric symptoms, and abnormal brain MRI findings may be associated with seizure outcomes.
Conclusions
Ofatumumab showed substantial improvement in long‐term seizure outcomes in patients with relapsing anti‐NMDA receptor encephalitis, particularly those presenting with seizures as a predominant clinical feature.
Keywords: ofatumumab therapy, relapsing anti‐NMDA receptor encephalitis, seizure outcomes
1. Introduction
Anti‐N‐methyl‐D‐aspartate (NMDA) receptor encephalitis comprises a group of non‐infectious immune‐mediated inflammatory disorders of the brain parenchyma often involving the cortical or deep grey matter with or without involvement of the white matter, meninges or the spinal cord. With the majority of patients presenting primary clinical characteristics such as seizures, psychiatric symptoms, and cognitive impairment. Both domestic and international studies have reported associations with teratomas [1, 2]. Studies have revealed that approximately 70%–80% of patients with anti‐NMDA receptor encephalitis experience seizures or status epilepticus (SE) during the initial disease phase, with some cases presenting with seizures as the primary clinical manifestation. A higher prevalence of such epileptic presentations was observed in pediatric anti‐NMDA receptor encephalitis patients [1, 3, 4]. Immunotherapy can improve functional outcomes in patients with anti‐NMDA receptor encephalitis, with high‐dose corticosteroids, intravenous immunoglobulin (IVIg), or plasma exchange (PE) being widely recognized as first‐line immunotherapeutic options [3]. However, the majority of patients with anti‐NMDA receptor encephalitis are prone to relapse following first‐line immunotherapy [5, 6]. Ofatumumab can be employed in disease‐modifying therapies for autoimmune encephalitis (AE). It is clinically recommended as a second‐line immunotherapy for patients with anti‐NMDA receptor encephalitis who have failed first‐line therapy or have relapsed [7]. However, whether ofatumumab therapy can improve seizure outcomes and associated factors in patients with relapsing anti‐NMDA receptor encephalitis remains unknown. We enrolled patients with relapsing anti‐NMDA receptor encephalitis with seizures as the core clinical presentation. Our study was designed to evaluate long‐term seizure outcomes and associated factors of relapsing anti‐NMDA receptor encephalitis with ofatumumab therapy.
2. Materials and Methods
2.1. Study Design and Participants
This study has included consecutive patients with relapsing anti‐NMDA receptor encephalitis who visited or were hospitalized at Affiliated Aerospace Hospital of Zunyi Medical University between October 2015 and September 2024. The study protocol was approved by the Ethics Review Committee of Affiliated Aerospace Hospital of Zunyi Medical University (Clinical trial number: not applicable). This study was approved by the institutional review boards of all actively recruiting centers and performed according to the Declaration of Helsinki. All enrolled patients or their next of kin gave written informed consent before enrollment in the study.
Relapsing anti‐NMDA receptor encephalitis was defined using the following criteria: (1) Defined diagnosis of anti‐NMDA receptor encephalitis; (2) These patients relapsed after receiving standardized first‐line immunotherapy; (3) Exclusion of additional potential causes of neurological deterioration and confirmation of sustained CSF anti‐NMDA receptor antibody positivity during relapses. The “Chinese Consensus on Diagnosis and Treatment of Autoimmune Encephalitis” in 2022 defined recurrent AE as the recurrence of symptoms or aggravation of symptoms (mRS score increased by 1 point or more) after the symptoms have improved or stabilized for more than 2 months [8]. Our study also aligns with the definition of relapse in the 2021 consensus paper by Nosadini et al. [9].
Inclusion and Exclusion Criteria (Figure 1): (1) The patients (age ≥ 18 years) with relapsing anti‐NMDA receptor adult encephalitis; (2) All patients presenting with seizures as the primary clinical features, concomitant with other clinical symptoms; (3) All relapsing anti‐NMDA receptor adult encephalitis patients were administered standardized antiepileptic drug regimens (including monotherapy and combination therapy), whose seizures remained uncontrolled; (4) Exclusion not receiving standard first‐line immunotherapy; (5) Exclusion not meeting the inclusion criteria; (6) Exclusion cases refused to participate in this study.
FIGURE 1.
Flowchart of study population.
2.2. Antibody Determination, Data Collection
Comprehensive clinical data were collected from attending physicians or referring clinicians. For each patient, demographic and clinical characteristics were recorded—including sex, age, clinical presentation, autoantibody profile, brain MRI, EEG, CSF laboratory test results, and presence of comorbid tumors. Clinical information was collected at each follow‐up visit in the form of a clinical report. Neurological status was blinded‐assessed by 2 experienced neurologists via face‐to‐face interviews and at regular interval follow‐up visits after admission (Months 6, 12, and 24). For patients treated with ofatumumab, we monitored B‐cell depletion through the percentage of CD19‐positive B‐cells in peripheral blood samples.
The guidelines and new epilepsy classification of the International League Against Epilepsy (ILAE) were used to define epileptic seizures. Epileptic seizures with an immune etiology were defined as at least 2 seizures, not provoked by other factors, occurring more than 24 h apart resulting directly from an immune disorder, and with evidence of autoimmune‐mediated CNS inflammation [10]. Drug‐resistant epileptic seizures were defined as failure to achieve seizure freedom, despite treatment with 2 tolerated, adequately dosed AEDs [11]. SE is characterized by either prolonged seizure containing more than 5 min or recurrent seizures without full recovery of consciousness between episodes.
Neural autoantibody screening was performed with the earliest available serum and CSF in all patients. NMDA receptor antibody testing was performed using cell‐based assay and confirmed by indirect immunofluorescence (commercial test kit panels Euroimmun, Lübeck). NMDAR abs detected in serum by CBA confirmed by IHC (in the absence of confirmatory IHC in serum, only CBA serum titers of > 1:500 were considered specific) and/or CSF positive. CSF pleocytosis was defined as a leukocyte count > 5/mm3, and elevated CSF protein was defined as a protein level exceeding 0.45 mg/dL. Tumor screening was performed via contrast‐enhanced computed tomography (CT) scans of the chest or abdomen. Only tumors definitively diagnosed after confirmation of anti‐NMDA receptor encephalitis were included in this study.
2.3. First‐Line and Second‐Line Immunotherapy
The choice of immunotherapy is determined by the preferences of the treating physician and the acceptance of the treatment by the patient or their family. First‐line immunotherapy was defined as the administration of high‐dose corticosteroids (1000 mg ivgtt for 5 days), intravenous immunoglobulin (IVIG, 0.4 g/kg ivgtt for 5 days), or plasma exchange (PE,40 mL/kg/time for 5 days), either as monotherapy or in combination, and all patients received continuous oral hormone (methylprednisolone) maintenance treatment after first‐line immunotherapy. Failure of first‐line immunotherapy was defined as the mRS scores remaining at 2 or higher and/or no sustained improvement of the most prominent symptom, assessed by 2 experienced neurologists after 4 weeks from the treatment initiation. In addition, the patients with relapsing anti‐NMDA receptor encephalitis are still receiving standard first‐line immunotherapy. Following relapse, 38 patients received ofatumumab treatment (20 mg on Days 1, 7, and 14, followed by a monthly dose of 20 mg). The other 38 patients in the received immunotherapy inclusion and exclusion criteria except for ofatumumab treatment were included as a control group. The occurrence of relapses during follow‐up was based on the overall clinical impression of the treating physician. Functional status was assessed using the mRS scores and CASE scores at the peak of disease and then throughout the disease course.
2.4. Outcome Measures
All patients with relapsing anti‐NMDA receptor encephalitis received second‐line immunotherapy (ofatumumab or non‐ofatumumab) and were followed continuously for 24 months, with seizure frequency assessed at 6, 12 and 24 months, including seizure reduction, seizure freedom, and no change. Primary outcome was the seizure outcomes (including both seizure reduction and seizure freedom) in relapsing anti‐NMDA receptor encephalitis; seizure reduction is defined as a reduction in seizure frequency to 50% or more of the baseline level, seizure freedom is defined as having no seizures. Ssecondary outcomes included modified Rankin Scale (mRS) scores and Clinical Assessment Scale in Autoimmune Encephalitis (CASE) scores and treatment related adverse events following immunotherapy administration. Multivariate logistic regression models were used to assess factors associated with seizure outcomes.
2.5. Statistics
Continuous variables in this study were presented as mean ± standard deviation (SD), while categorical variables were expressed as frequency and percentage. For continuous data with normal distribution, the student t‐test was applied, while the Mann–Whitney U‐test was used for non‐normal distribution data. Categorical data were analyzed using the Chi‐square test or Fisher's exact test. Multivariate logistic regression models were used to assess the correlation between independent and outcome variables. All statistical analyses were performed with SPSS 27.0 software (IBM, USA), and visualizations were generated using GraphPad Prism 8.0 (GraphPad Software, USA). Two‐tailed tests were adopted for hypothesis testing, with the significance level set at α = 0.05.
3. Results
3.1. Clinical Features and Demographics
We enrolled 76 patients with relapsing anti‐NMDA receptor encephalitis. Among them, 38 patients received ofatumumab treatment, and 38 patients in the control group received non‐ofatumumab treatment. Baseline data show the detailed clinical characteristics of the ofatumumab group and non‐ofatumumab group. We observed no statistical differences in clinical characterization, including demographics, symptoms, disease severity, and auxiliary examination results between the two groups (Table 1).
TABLE 1.
Intergroup comparisons of demographics and clinical profiles.
| Variables | Ofatumumab group (n = 38) | Non‐ofatumumab group (n = 38) | p |
|---|---|---|---|
| Female; n (%) | 24 (63.16) | 26 (68.42) | 0.647 |
| Age; (mean ± SD) | 43.60 ± 13.84 | 45.71 ± 4.94 | 0.373 |
| Symptoms; n (%) | |||
| Decreased consciousness | 11 (28.95) | 14 (36.84) | 0.471 |
| Psychiatric symptoms | 15 (39.48) | 18 (47.37) | 0.489 |
| Cognitive impairment | 9 (23.68) | 11 (28.95) | 0.602 |
| Brain‐stem symptoms | 9 (23.68) | 12 (31.58) | 0.439 |
| Cerebellar symptoms | 5 (13.16) | 7 (18.42) | 0.536 |
| Types of seizures; n (%) | |||
| FS− | 10 (26.32) | 11 (28.95) | 0.796 |
| FS+ | 16 (42.11) | 17 (44.74) | 0.815 |
| GTCS | 7 (18.42) | 4 (10.53) | 0.326 |
| SE | 5 (13.16) | 6 (15.79) | 0.747 |
| mRS score at onset; median (IQR) | 5 (4–5) | 5 (3–5) | 0.866 |
| CASE score at onset; median (IQR) | 15 (8–21) | 17 (9–20) | 0.918 |
| Brain MRI; n (%) | |||
| Normal | 5 (13.16) | 7 (18.42) | 0.527 |
| T2/FLAIR hyperintensity | 33 (86.84) | 31 (81.57) | |
| ECG n (%) | |||
| Spiking abnormalities of EEG | 12 (31.57) | 9 (23.68) | 0.434 |
| Slowing abnormalities of EEG | 26 (68.43) | 29 (76.32) | |
| CSF abnormalities; n (%) | |||
| CSF WBC > 5/mm3 | 31 (81.58) | 29 (76.32) | 0.979 |
| CSF protein > 0.45 mg/dL | 30 (78.95) | 31 (81.58) | |
| NMDAR‐antibody postive; n (%) | 38 (100.00) | 38 (100.00) | 1.000 |
| Tumor presence; n (%) | 2 (5.26) | 3 (7.89) | 1.000 |
Abbreviations: CSF, cerebrospinal fluid; ECG, electroencephalogram; FS−, focal seizure without impairment of consciousness; FS+, focal seizure with impairment of consciousness; GTCS, generalized tonic–clonic seizure; IQR, interquartile range; MRI, magnetic resonance imaging; nMDAR, n ‐methyl‐D‐aspartate receptor; SE, status epilepticus.
All patients with relapsing anti‐NMDA receptor encephalitis received standardized first‐line immunotherapy. The first‐line regimens, selected based on the prescribing physician's clinical preference, included combinations of corticosteroids with IVIG or PE. No statistically significant differences were observed in the selection of first‐line regimens (Table 2). Following first‐line immunotherapy, the observation group received ofatumumab treatment, while the control group received non‐ofatumumab treatment, the decision to initiate additional cycles of treatment is based on a clinical assessment of disease activity. Neither the timing of second‐line immunotherapy initiation nor the maintenance duration showed statistically variations. However, Among patients who relapsed after immunotherapy, the again relapsed with seizure rate of the observation group was lower than that of the control group, and the difference was statistically significant. (p = 0.036, Table 2). The mRS scores and CASE scores of patients in both groups showed continuous improvement during the follow‐up. We found that among patients who failed first‐line immunotherapy, those who received ofatumumab treatment showed a greater trend of improvement with lower mRS scores at 6 (2.85 ± 0.65 vs. 3.75 ± 0.55, p = 0.027), 12 (1.68 ± 0.45 vs. 2.39 ± 0.35, p = 0.04) and 24 (1.25 ± 0.35 vs. 1.68 ± 0.45, p = 0.043) months and lower CASE scores at 6 (11.80 ± 1.65 vs. 13.75 ± 1.55, p = 0.034), 12 (6.75 ± 1.45 vs. 9.39 ± 1.35, p = 0.037), and 24 (4.25 ± 0.75 vs. 6.68 ± 1.35, p = 0.02) months of follow‐up compared with patients who did not receive ofatumumab (Figure 2A,B).
TABLE 2.
Intergroup comparisons of immunotherapy profiles.
| Variables | Ofatumumab group (n = 38) | Non‐ofatumumab group (n = 38) | p |
|---|---|---|---|
| First‐line immunotherapy; n (%) | |||
| Methylprednisolone+IVIG | 10 (26.32) | 15 (39.48) | 0.228 |
| Methylprednisolone+PE | 28 (73.68) | 23 (60.52) | |
| Time from disease onset to first‐line immunotherapy, days; median (IQR) | 13 (6–22) | 14 (7–25) | 0.887 |
| Total cycles of first‐line immunotherapy; (mean ± SD) | 1.7 ± 0.8 | 1.8 ± 0.6 | 0.912 |
| Time from disease onset to first‐line immunotherapy, days; median (IQR) | 11 (6–22) | 15 (10–25) | 0.058 |
| Delayed first‐line immunotherapy; n (%) | 9 (23.68) | 10 (26.32) | 0.912 |
| Total cycles of first‐line immunotherapy; (mean ± SD) | 1.7 ± 0.8 | 1.8 ± 0.9 | 0.843 |
| Second‐line immunotherapy; n (%) | |||
| Firet time second‐line treatment (days); median (IQR) | 38 (22–142) | 29 (20–132) | 0.609 |
| Time to immunotherapy initiation | |||
| ≤ 1 months | 24 (63.16) | 26 (68.42) | 0.629 |
| Over 1 months | 14 (36.84) | 12 (31.58) | |
| Duration of immunotherapy | |||
| ≤ 12 months | 20 (52.64) | 21 (55.26) | 0.819 |
| Over 12 months | 18 (47.36) | 17 (44.74) | |
| Average relapse time of immunotherapy days; median (IQR) | 78 (45–122) | 69 (40–108) | 0.763 |
| Relapse after ofatumumab/s‐line immunotherapy; n (%) | 1 (2.63) | 8 (21.05) | 0.036 |
Note: IQR, interquartile range; IVIG, intravenous immunoglobulin; PE, plasma exchange.
FIGURE 2.
Outcomes in patients with relapsing anti‐NMDA receptor encephalitis. Comparison of the trend in mRS score (A) and CASE score (B) improvement during the 24‐month follow‐up between the ofatumumab group and non‐ofatumumab group among patients with relapsing anti‐NMDA receptor encephalitis, respectively.
3.2. Seizure Outcomes
We enrolled 76 patients with relapsing anti‐NMDA receptor encephalitis. Among them, 38 patients received ofatumumab treatment, and 38 patients received non‐ofatumumab treatment, and were followed continuously for 24 months, with seizure frequency assessed at 6, 12 and 24 months. After a 6‐month follow‐up, patients in the ofatumumab group had seizure reduction, showing a statistically significant difference compared to the non‐ofatumumab group (63.16% vs. 36.84%, p = 0.031, Table 3 Figure 3A). After a 12‐month follow‐up, patients in the ofatumumab group had seizure reduction, showing a statistically significant difference compared to the non‐ofatumumab group (78.95% vs. 60.53%, p = 0.043, Table 3 Figure 3A). After a 24‐month follow‐up, patients in the ofatumumab group had seizure reduction, showing a statistically significant difference compared to the non‐ofatumumab group (94.74% vs. 71.05%, p = 0.007, Table 3 Figure 3A). After a 6‐month follow‐up, patients in the ofatumumab group had seizure freedom, showing no statistically significant difference compared to the non‐ofatumumab group (26.32% vs. 15.79%, p = 0.263, Table 3 Figure 3B). After a 12‐month follow‐up, patients in the ofatumumab group had seizure freedom, showing a statistically significant difference compared to the non‐ofatumumab group (52.63% vs. 34.21%, p = 0.047, Table 3 Figure 3B). After a 24‐month follow‐up, patients in the ofatumumab group had seizure freedom, showing a statistically significant difference compared to the non‐ofatumumab group (78.95% vs. 47.37%, p = 0.003, Table 3 Figure 3B). After a 6‐month follow‐up, patients in the ofatumumab group had no change, showing a statistically significant difference compared to the non‐ofatumumab group (36.84% vs. 63.16%, p = 0.031, Table 3). After a 12‐month follow‐up, patients in the ofatumumab group had no change, showing no statistically significant difference compared to the non‐ofatumumab group (21.05% vs. 39.47%, p = 0.081, Table 3). After a 24‐month follow‐up, patients in the ofatumumab group had no change, showing a statistically significant difference compared to the non‐ofatumumab group (5.26% vs. 28.95%, p = 0.004, Table 3).
TABLE 3.
The frequency of seizures and seizure outcomes during follow‐up in patients.
| Variables | Ofatumumab group (n = 38) | Non‐ofatumumab group (n = 38) | p |
|---|---|---|---|
| Seizure reduction n (%) | |||
| 6 months | 24 (63.16) | 14 (36.84) | 0.031 |
| 12 months | 30 (78.95) | 23 (60.53) | 0.043 |
| 24 months | 36 (94.74) | 27 (71.05) | 0.007 |
| Seizure freedom n (%) | |||
| 6 months | 10 (26.32) | 6 (15.79) | 0.263 |
| 12 months | 20 (52.63) | 13 (34.21) | 0.047 |
| 24 months | 30 (78.95) | 18 (47.37) | 0.003 |
| No change n (%) | |||
| 6 months | 14 (36.84) | 24 (63.16) | 0.031 |
| 12 months | 8 (21.05) | 15 (39.47) | 0.081 |
| 24 months | 2 (5.26) | 11 (28.95) | 0.004 |
| Seizure outcomes n (%) | |||
| 6 months | 24 (63.16) | 14 (36.84) | 0.031 |
| 12 months | 30 (78.95) | 23 (60.53) | 0.043 |
| 24 months | 36 (94.74) | 27 (71.05) | 0.007 |
Note: Seizure reduction is defined as a reduction in seizure frequency to 50% or more of the baseline level. Seizure freedom is defined as having no seizures. No change is defined as no change in seizure frequency. Seizure outcomes include both seizure reduction and seizure freedom.
FIGURE 3.
The frequency of seizures during patient follow‐up. Comparison of the trend in seizure reduction (A) seizure freedom (B), and seizure outcomes (C) improvement during the 24‐month follow‐up between the ofatumumab group and the non‐ofatumumab group among patients with relapsing anti‐NMDA receptor encephalitis, respectively.
After a 6‐month follow‐up, patients in the ofatumumab group showed significant improvement in seizure outcomes, with a statistically significant difference compared to the non‐ofatumumab group (63.16% vs. 36.84%, p = 0.031, Table 3). After a 12‐month follow‐up, patients in the ofatumumab group showed significant improvement in seizure outcomes, with a statistically significant difference compared to the non‐ofatumumab group (78.95% vs. 60.53%, p = 0.043, Table 3). After a 24‐month follow‐up, patients in the ofatumumab group showed significant improvement in seizure outcomes, with a statistically significant difference compared to the non‐ofatumumab group (94.74% vs. 78.95%, p = 0.007, Table 3).
To investigate the correlation between seizure outcomes and follow‐up duration, we performed a comparative analysis of seizure outcomes across different follow‐up periods. The results revealed that the ofatumumab group showed statistically significant differences in seizure outcomes between the 6‐month and 12‐month follow‐ups (p = 0.014, Figure 3C), between the 6‐month and 24‐month follow‐ups (p < 0.001, Figure 3C), and between the 12‐month and 24‐month follow‐ups (p = 0.041, Figure 3C). The non‐ofatumumab group showed statistically significant differences in seizure outcomes between the 6‐month and 12‐month follow‐ups (p = 0.003, Figure 3C), and between the 6‐month and 24‐month follow‐ups (p < 0.001, Figure 3C). There was no statistically significant difference in seizure outcomes between the 12‐month and 24‐month follow‐ups (p = 0.134, Figure 3C).
Our study demonstrated that relapsing anti‐NMDA receptor encephalitis patients treated with ofatumumab exhibited progressively better seizure improvement with extended follow‐up duration. Previous studies have reported seizure improvement rates of only 50% within the initial 6 months, which may be attributed to the long recovery period of anti‐NMDA receptor encephalitis and insufficient follow‐up time [12, 13]. In contrast, our findings reveal favorable seizure outcomes, suggesting a potential association between extended follow‐up and early initiation of ofatumumab therapy. In addition, all patients underwent continuous follow‐up for 24 months. In our study, there was 1 relapse in the ofatumumab group, a relapse with seizure rate of 2.63%. There were 8 relapses in the non‐ofatumumab group, a relapse with seizure rate of 21.05%. The ofatumumab group showed a statistically significant decrease in the relapse rate compared with the non‐ofatumumab group (p = 0.036, Table 2).
Additionally, we performed a logistic regression analysis to assess the association between seizure outcomes and a range of potential predictive variables, including demographic factors such as sex and age, as well as detailed clinical characteristics, laboratory parameters, and neuroimaging findings, in a cohort of patients diagnosed with relapsing anti‐NMDA receptor encephalitis. This statistical approach allowed us to identify independent predictors of seizure reduction or freedom during the 24‐month follow‐up period. The multivariate logistic regression results revealed that the presence of psychiatric symptoms at disease onset was strongly associated with poorer seizure outcomes. Specifically, patients presenting with psychiatric manifestations had significantly higher odds of unfavorable seizure control, with an odds ratio (OR) of 19.5 (95% confidence interval [CI]: 4.157–91.462, p < 0.001), indicating a robust and statistically significant association (Table 4). Similarly, abnormal findings on brain magnetic resonance imaging (MRI), such as cortical or subcortical hyperintensities on T2‐weighted or fluid‐attenuated inversion recovery (FLAIR) sequences, were also identified as a significant predictor. Patients with such radiological abnormalities exhibited a notably increased risk of persistent seizures, with an OR of 6.125 (95% CI: 1.181–31.768, p = 0.031), suggesting that structural brain involvement may reflect more severe neurological dysfunction. Furthermore, the timing of immunotherapy initiation emerged as a critical factor influencing clinical outcomes. Our analysis demonstrated that early initiation of ofatumumab treatment was independently associated with more favorable seizure outcomes. This protective effect was statistically significant, with an OR of 0.257 (95% CI: 0.072–0.923, p = 0.037), indicating that timely intervention may reduce the likelihood of ongoing seizure activity by modulating the underlying autoimmune process before irreversible neuronal damage occurs. These findings collectively highlight the importance of early diagnosis, prompt immunotherapeutic intervention, and comprehensive assessment of clinical and radiological features in managing patients with relapsing anti‐NMDA receptor encephalitis.
TABLE 4.
Multivariate logistic regression analysis of the seizure outcomes.
| Variables | OR | 95% CI | p |
|---|---|---|---|
| Six | 2 | 0.520–7.691 | 0.313 |
| Age | 1.5 | 0.384–5.86 | 0.560 |
| Decreased consciousness | 0.6 | 0.174–2.073 | 0.419 |
| Psychiatric symptoms | 19.5 | 4.157–91.462 | 0.000 |
| Cognitive impairment | 3.286 | 0.900–11.992 | 0.072 |
| Brain‐stem symptoms | 0.459 | 0.132–1.591 | 0.219 |
| Cerebellar symptoms | 1.458 | 0.422–5.042 | 0.551 |
| MRI | 6.125 | 1.181–31.768 | 0.031 |
| ECG | 3.429 | 0.898–13.091 | 0.071 |
| CSF | 2.13 | 0.387–11.734 | 0.385 |
| NMDAR‐antibody | 0.247 | 0.047–1.294 | 0.098 |
| Tumor | 0.778 | 0.116–5.211 | 0.796 |
| Time of first ofatumumab therapy | 0.257 | 0.072–0.923 | 0.037 |
| Total time of immunotherapy | 1.036 | 0.295–3.637 | 0.956 |
Note: Bold values are statistically significant difference.
3.3. Adverse Events
All adverse events were grade one or two (mild to moderate) in severity [14]: The ofatumumab treatment group had one patient experienced injection‐related reactions (including pain, fever). No serious adverse effects were observed during ofatumumab treatment. The non‐ofatumumab treatment group had five patients who reported adverse side effects. Two patients presented with nausea and vomiting, two patients with hair loss, and one patient with hematuria. After symptomatic hemostatic treatment, they improved. No serious adverse effects were observed during non‐ofatumumab treatment.
4. Discussion
This study describes an enrolled study conducted at a tertiary hospital in Zunyi, Guizhou, China. Our findings demonstrate that ofatumumab therapy significantly improves seizure outcomes in patients with relapsing anti‐NMDA receptor encephalitis. At the 6‐month follow‐up, the seizure improvement rate reached 63.16%, increasing to 78.95% at 12 months and further rising to 94.74% at 24 months. Our study highlights that early initiation of ofatumumab therapy significantly improves seizure outcomes and functional outcomes of patients with relapsing anti‐NMDA receptor encephalitis. Furthermore, multivariate logistic regression analysis revealed that early initiation of ofatumumab treatment, psychiatric symptoms, and abnormal brain MRI may be associated with seizure outcomes.
It is well‐established that most patients with anti‐NMDA receptor encephalitis respond favorably to first‐line immunotherapy, yet exhibit high relapse rates [3, 5], Prospective studies have demonstrated that second‐line immunotherapy significantly improves functional prognosis in patients with AE [15, 16]. Previous studies have demonstrated that rituximab (RTX) therapy improves overall outcomes in AE, with favorable outcomes achieved in more than 80% of patients with anti‐NMDA receptor encephalitis. However, the relapse rate is as high as 20% [13, 17]. However, its clinical applications may be limited, such as severe allergic reactions, production of anti‐drug antibodies, and elevated susceptibility to infection.
Ofatumumab is a fully human anti‐CD20 monoclonal antibody that, in contrast to the epitopes recognized by RTX, exerts its effect by binding to two distinct epitopes, thereby inducing complement‐mediated CD20 + B‐cell lysis and antibody‐dependent cell‐mediated cytotoxicity for effective elimination of pathogenic B cells. A fully human design significantly reduces the likelihood of treatment failure by avoiding the risk of developing anti‐drug antibodies, and injection‐related systemic reactions are fewer than those associated with the infusion. In addition, drug administration is convenient and can be performed by the patients themselves [18, 19, 20]. Several case reports have documented its use in patients with AE [21, 22, 23, 24]; however, large‐scale comparative studies are still relatively limited.
During extended follow‐up, our study found that ofatumumab therapy significantly improvement in seizure outcomes compared to conventional second‐line immunotherapy. While conventional second‐line immunotherapy demonstrated favorable seizure outcomes, comparative analyses revealed consistent superiority of ofatumumab therapy over non‐ofatumumab therapy, both in intra‐group trends and in inter‐group comparisons. Furthermore, in our study, the 76 patients who all received second‐line immunotherapy, 38 patients who received ofatumumab, and 38 patients who received non‐ofatumumab therapy and were followed continuously for 24 months. There were 1 relapses in the ofatumumab group, a relapse with seizure rate of 2.63%. There were 8 relapses in the non‐ofatumumab group, a relapse with seizure rate of 21.05%. The ofatumumab group has a lower recurrence rate, compared to the non‐ofatumumab group. Neither of the two groups of patients had serious adverse events after immunotherapy.
While studies have demonstrated the efficacy of ofatumumab therapy in reducing relapse rates in anti‐NMDA encephalitis, it is unknown whether ofatumumab therapy improves seizure outcomes in relapsed anti‐NMDA encephalitis cases with a seizure‐dominated clinical presentation. Small‐sample studies have indicated that immunotherapy may reduce seizure frequency in patients with AE [7, 25]. However, fewer than 50% of autoimmune encephalitis patients presenting with new onset seizures or seizure‐dominated clinical manifestations achieved seizure remission during short‐term follow‐up following standard immunotherapy. This limited efficacy is primarily attributed to the poor early response to initial immunotherapy in anti‐NMDA receptor encephalitis patients and the potential requirement of months for neurological recovery [26, 27]. Studies have suggested that autoantibody‐positive patients may exhibit better responses to immunotherapy compared to antibody‐negative individuals, with improved clinical prognoses [27, 28]. In contrast to prior studies, our study enrolled specifically anti‐NMDA receptor antibody‐positive patients, initiated ofatumumab therapy at an earlier stage of disease, and maintained a longer follow‐up duration. These methodological distinctions most likely explain the favorable seizure outcomes observed in our study.
We performed logistic regression analysis on the baseline characteristics of all study participants, including gender, age, clinical characteristics, laboratory data, and auxiliary examination results, to assess their association with seizure outcomes. Given the limited sample size in our study, we performed a stepwise multivariate logistic regression analysis to adjust for potential confounding interactions between variables and to mitigate bias in the outcomes. Multivariate logistic regression analysis revealed that psychiatric symptoms, abnormal brain MRI, and early initiation of ofatumumab therapy were independent predictors of seizure outcomes. Despite the limited sample size, the high homogeneity of our data and minimal confounding factors suggest the relative reliability of our study conclusions. Therefore, we propose that psychiatric symptoms, abnormal brain MRI, and early initiation of ofatumumab therapy were independent predictors of seizure outcomes in patients with relapsing anti‐NMDA receptor encephalitis. Our findings are consistent with previous studies [7].
Our study has several limitations. First, as a single‐center registry study, it is susceptible to selection bias in data collection. Second, the clinical profile lacked a control group of other sub‐AE patients for comparative analysis. Third, all recruited patients are Chinese, with a lower proportion of teratoma‐associated cases, showing demographic and clinical differences from Western NMDAR‐AE cohorts, as mentioned in previous studies [29, 30], which limited the generalizability of the findings. In addition, heterogeneity in the timing of ofatumumab initiation among participants introduces confounding factors, making it challenging to determine whether favorable seizure outcomes are due to ofatumumab therapeutic efficacy or natural disease progression. However, due to the limited number of rare cases such as anti‐NMDA receptor encephalitis in our region and nationally, it has been challenging to collect sufficient cases for a large‐scale controlled study in a single center. We also anticipate further collaborations with other medical institutions. Nevertheless, given the inherent difficulties in conducting randomized controlled trials (RCT) for rare diseases. Therefore, real‐world registry data are particularly valuable, as these datasets provide critical clinical insights and may facilitate the initiation of multicenter, large‐scale RCT.
5. Conclusions
Our study demonstrates that ofatumumab therapy significantly improves seizure outcomes in patients with relapsing anti‐NMDA receptor encephalitis, particularly those presenting with seizures as a predominant clinical feature. Furthermore, the psychiatric symptoms, abnormal brain MRI, and early initiation of therapy may be independent predictors of seizure outcomes. Further studies, with prospective designs and including larger sample sizes and multicenter randomized controlled trials, are warranted to validate these findings.
Author Contributions
Jian Wang treated patients, reviewed literature, designed the study, and drafted the manuscript. Jian Wang, Meng Jiao Li and Ping Kong contributed to the design and implementation of this study. Jian Wang reviewed, read, revised, and approved the final manuscript. All authors have reviewed and approved the final version of the manuscript for publication.
Funding
This study was supported by the Science and Technology plan project of Zunyi City (Zunyi City Science and Technology Cooperation HZ [2024] No. 108).
Ethics Statement
The study involving human participants was reviewed and approved by Affiliated Aerospace Hospital of Zunyi Medical University Research Ethics Committee.
Consent
The participants provided their written informed consent to participate in this study.
Conflicts of Interest
The authors declare no conflicts of interest.
Acknowledgments
The authors are sincerely grateful for the support of the Department of Neurology, Affiliated Aerospace Hospital of Zunyi Medical University.
Funding Statement
This work was funded by the Science and Technology plan project of Zunyi City .
Data Availability Statement
The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Data Availability Statement
The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions.