Tissue-based assay-confirmed,antibody-negative autoimmune encephalitis responsive to low-dose rituximab in an elderly patient

Abstract

Antibody-negative Autoimmune encephalitis (AE) presents a diagnostic challenge, requiring a high index of clinical suspicion and comprehensive evaluation. We report a 66-year-old man presenting with a seizure accompanied by progressive cognitive decline over several days. Despite the presence of hallmark symptoms and suggestive imaging, the patient was initially misdiagnosed, delaying timely immunotherapy. The diagnosis of antibody-negative AE was made based on clinical criteria, including consistent serological and cerebrospinal fluid (CSF) analyses (negative for known autoimmune and paraneoplastic antibodies), alongside a positive tissue-based assay (TBA), cranial MRI findings, and peripheral blood B-cell profiling. The patient responded well to immunotherapy with a low-dose sequential rituximab regimen, demonstrating clinical improvement and halting disease progression. This case highlights the importance of adhering to diagnostic criteria for AE and integrating TBA into the diagnostic workflow for antibody-negative AE.

Keywords

Alzheimer's disease antibody-negative autoimmune encephalitis immunotherapy low-dose rituximab tissue-based assay

Introduction

Autoimmune encephalitis (AE) encompasses a diverse group of immune-mediated inflammatory disorders affecting the central nervous system. These disorders are characterized by the production of antibodies by immune cells that target self-antigens located on neuronal surfaces, synapses, and within nerve cells.^1,2 The identification of specific autoantibodies is pivotal for accurate diagnosis. However, approximately one-third of patients presents with antibody-negative AE, exhibiting clinical features akin to those with antibody-positive AE, yet lacking detectable autoantibodies.^3,4 In 2016, Graus et al.¹ established diagnostic criteria for antibody-negative but probable AE, which include rapid progression of symptoms, exclusion of well-defined AE syndromes, absence of definitive autoantibodies, and fulfillment of additional criteria such as magnetic resonance imaging (MRI) abnormalities or cerebrospinal fluid (CSF) changes. Recent insights by Dalmau et al.⁵ in 2023 suggest that these criteria may be adapted in cases with prolonged symptoms, isolated seizures, or isolated psychiatric manifestations.

The laboratory hallmark of AE is the presence of Immunoglobulin G (IgG) autoantibodies against neural antigens,^6,7 detected through various methods including western blot, neuronal cell culture, and indirect immunofluorescence (IIF)—such as the transfected cell-based assay (CBA) and tissue-based assay (TBA) employing murine brain sections, these detections are performed in serum and/or CSF^8,9 based on the specific AE subtype, and for some subtypes, CSF detection is mandatory. For patients negative for cell surface antibodies, immunostaining with CBA or TBA is particularly valuable, as positive results strongly indicate an immune-mediated process potentially responsive to immunotherapy. This diagnostic approach is especially critical in older patients, where delayed or missed diagnoses can result in irreversible neurological damage. Early initiation of immunotherapy is strongly associated with improved outcomes in AE, highlighting the critical role of timely and accurate diagnosis.¹⁰ This case highlights the clinical value of TBA in diagnosing antibody-negative AE and demonstrates the efficacy of low-dose rituximab in an elderly patient with this condition.

Case report

Clinical presentation and history

A 66-year-old male was admitted to our hospital in June 2024, presenting with progressive cognitive decline. His symptoms began three years earlier with an episode of impaired consciousness following an emotionally stressful event, which was diagnosed as epileptic seizure despite no prior history of epilepsy. This diagnosis was based on clinical presentation and electroencephalogram (EEG) findings, which showed epileptiform discharges. There were no indications of a dissociative genesis related to the emotional stress. Initial treatment at a local hospital with antiepileptic medication successfully prevented further seizures. However, the patient experienced a rapid deterioration in cognitive function over several days after the initial seizure.

At the local hospital, the patient with acute onset was misdiagnosed as having acute cerebral infarction. However, subsequent neuroimaging including cranial computed tomography (CT) and MRI, demonstrated no evidence of cerebral infarction. The patient was prescribed aspirin (antiplatelet aggregation) and atorvastatin (lipid lowering and plaque stabilization), but his cognitive function continued to decline. He exhibited temporal and spatial disorientation, frequent short-term memory loss, and signs of impatience. No antipsychotic medications were prescribed for his impatience. As his condition worsened, he became increasingly dependent on family support for daily activities. A lumbar puncture performed at the local hospital tested CSF for autoimmune antibodies, which returned negative results. However, no TBA was conducted, leading to the premature exclusion of AE. As cognitive dysfunction progressed, the patient was later misdiagnosed with Alzheimer's disease (AD). This diagnosis was based on clinical examination and neuropsychological testing, which revealed deficits in memory, executive function, and visuospatial abilities. However, no specific CSF biomarkers for AD (e.g., amyloid-β (Aβ), tau proteins) were evaluated. Treatments with donepezil (enhanced cholinergic neurotransmission by inhibiting acetylcholinesterase) and memantine (modulates glutamatergic signaling via NMDA receptor antagonism) were initiated but failed to yield significant improvement in cognitive function. Given the severity of his condition and the increasing burden of care, the patient's family sought a comprehensive evaluation and treatment at our facility.

Past medical history and clinical examination

The patient had a medical history significant for well-controlled type 2 diabetes and arterial hypertension, managed with regular pharmacotherapy. The patient's family denies that the patient has any other neurologic disorder and there is no similar cognitive impairment in the family. Upon admission, a comprehensive neurological examination was conducted, revealing prominent high-level cortical dysfunction, specific deficits included significant impairment in memory retrieval, calculation ability, temporal and spatial orientation, and executive function. Importantly, the patient did not exhibit any motor deficits such as bradykinesia, gait instability, or signs of autonomic dysfunction, including urinary incontinence. Based on these findings, differential diagnosis considered included immune-mediated disorders such as AE, neurodegenerative diseases such as AD, and other conditions such as idiopathic normal pressure hydrocephalus (iNPH) and vascular cognitive impairment.

Diagnostic evaluation and findings

Comprehensive laboratory evaluations, including blood, urine, and fecal analyses, as well as assessments of blood glucose, liver, kidney, and thyroid function, homocysteine, and infectious disease markers (HIV, syphilis, hepatitis), returned normal results (Table 1). Tumor marker screenings were also unremarkable. Imaging studies, including chest CT and cardiac and abdominal ultrasounds, revealed no abnormalities. Cranial MRI revealed no overt inflammatory lesions or acute infarctions, but it did demonstrate significant cerebral cortical mild atrophy (using the Global Cortical Atrophy rating scale, 1 point) and bilateral hippocampal atrophy (using the Medial Temporal Lobe Atrophy visual rating scale, 2 points for left hippocampus and 1 point for right hippocampus) (Figure 1). Additionally, magnetic resonance angiography (MRA) excluded vascular stenosis. Retrospective evaluation of previous imaging from the local hospital also failed to reveal evidence of infarction despite the earlier misdiagnosis of cerebral infarction.

Figure 1.

The patient's cranial MRI and MRA in hospital. (A-F) MRI reveals prominent cortical and bilateral hippocampal atrophy across multiple sequences; (A) Axial T1-weighted; (B) Axial T2-weighted; (C) Axial FLAIR; (D) Diffusion-weighted imaging (DWI); (E) Coronal T1-weighted; (F) Sagittal T1-weighted. (G) MRA shows no significant stenosis in intracranial vessels; (H) Susceptibility-weighted imaging (SWI) shows absence of cerebral microbleeds.

Table 1.

Patient clinical characteristics and diagnostic findings.

Category	Admission	Follow-Up			Reference/Notes
Category	Admission	1 month	3 months	1 year
Characteristics
Age (y)	66	−	−	−
sex	male	−	−	−
vital signs
blood pressure (BP, mmHg)	132/81	129/78	125/76	134/80	<140/90
heart rate (HR, bpm）	71	70	68	69	60–100
Temp (T, °C)	36.4	36.7	36.5	36.5	36.0–37.0
Laboratory variables
Hemoglobin (g/L)	133	−	−	−
fasting glucose (mmol/L)	5.71	−	−	−
liver function	normal	−	−	−
kidney function	normal	−	−	−
thyroid function	normal	−	−	−
homocysteine (μmol/L)	12.46	−	−	−
infectious disease markers (HIV, syphilis, hepatitis)	normal	−	−	−
CSF Aβ₄₂ (pg/mL)	1202	−	−	−	No support for AD diagnostics
CSF Aβ₄₂/Aβ₄₀ (pg/mL)	0.091	−	−	−
CSF T-Tau (pg/mL)	260	−	−	−
CSF P-Tau 181 (pg/mL)	44.72	−	−	−
blood B cell (CD19+/CD20+)	11.37%/11.38%	0.07%/0.09%	−	0.16%/0.16%
score of Symptoms
MMSE	3	6	−	11	30
ADL	45	70	75	75	100
NPI-12	19	13	6	6	144

CSF: cerebrospinal fluid; MMSE: Mini-Mental State Examination; ADL: Activity of Daily Living; NPI-12: Neuropsychiatric Inventory 12.

A lumbar puncture indicated normal CSF pressure, cell count, and biochemical profile, with negative results for antacid and ink stains. Cognitive biomarker analysis revealed a mildly elevated Aβ₄₂ level of 1202 pg/ml and a decreased Aβ_42/40 ratio of 0.091, and tau protein (both total Tau and phosphorylated Tau) levels were in the normal range (Table 1). According to the China Aging and Neurodegenerative Initiative (CANDI) study, an Aβ_42/40 ratio below 0.0642 is indicative of AD¹¹; thus, this patient's biomarker profile does not support an AD diagnosis.

Further serological and CSF analyses for antibodies associated with AE, including NMDAR, AMPAR1, AMPAR2, LGI1, CASPR2, GABABR, DPPX, IgLON5, GlyRα1, GABAARα1, GABAARβ3, mGluR1, mGluR5, D2R, Neurexin-3α, GAD65, KLHL11, and gAChR, as well as paraneoplastic antibodies (Hu, Yo, Ri, CV2, Ma1, Ma2, Amphiphysin, SOX1, Tr, Zic4, PKCγ, Recoverin, Titin), were negative. However, the CSF TBA conducted on mouse whole-brain sections revealed weakly positive signals primarily within neuronal cells of various brain regions, including the Purkinje cell layer in the cerebellum. Validation of these findings with serum TBA demonstrated targeted positive signals predominantly in the hippocampal molecular layer, neuronal dendrites, and the Purkinje cell layer (Figure 2). For serum samples, we used a 1:10 dilution in phosphate-buffered saline for all TBA assays, and for CSF samples, we used undiluted (neat) CSF for all TBA assays.¹² All TBA interpretations were independently evaluated by two qualified technologists blinded to clinical data, with three replicate tests performed.

Figure 2.

TBA staining of patient-derived cerebrospinal fluid (CSF) and serum on murine brain tissue.

EEG monitoring over 24 h identified slightly increased abnormal waveforms, including sharp and sharp-slow complex waves, in the right prefrontal and temporal leads during wakefulness and light sleep (Figure 3). Peripheral blood analysis showed CD19+/CD20 + lymphocyte counts of 11.37% and 11.38%, respectively, increased lymphocyte counts indicate active immune system engagement. Upon admission, cognitive assessments revealed a Mini-Mental State Examination (MMSE) score of 3, an Activity of Daily Living (ADL) score of 45, and a Neuropsychiatric Inventory 12 (NPI-12) score of 19 for the patient (Table 1).

Figure 3.

Electroencephalogram (EEG) detection. (A, B) EEG recordings during wakefulness and light sleep show a slight increase in abnormal waveforms in the right frontal and temporal leads, including sharp waves and sharp-slow wave complexes.

Treatment and follow-up

The diagnosis of antibody-negative AE was confirmed following a comprehensive analysis of the patient's ancillary tests, including serological and CSF evaluations, which were negative for autoimmune and paraneoplastic antibodies. However, TBA results were positive, supporting the diagnosis. The patient was initially treated with intravenous immunoglobulin (IVIG) at a dosage of 0.4 g/kg daily for five days. Following this, a regimen of low-dose rituximab was employed, with 100 mg administered weekly for three consecutive weeks.^13–15 This dose was chosen to minimize the risk of adverse effects and immunosuppression, considering the patient's age and comorbidities.

Clinical improvements were observed by the end of the first week of treatment, with the patient exhibiting reduced irritability and increased calmness. Following the completion of the rituximab regimen (one month), the patient demonstrated significant improvements in temporal and spatial orientation. Cognitive assessments showed an increase in the MMSE score from 3 to 6, an improvement in the ADL score from 45 to 70, and a reduction in the NPI-12 score from 19 to 13 for the patient. CD19+/CD20+ B-lymphocyte counts were monitored post-treatment and showed a depletion with levels decreasing to 0.07%/0.09% (Table 1), correlating with the therapeutic efficacy of rituximab.^13–15

At the third month post-discharge, the patient underwent a telephone follow-up. The family reported significant cognitive improvement compared to baseline, with the patient now capable of independent daily living with ADL at 75 and NPI-12 at 6. One year later during an outpatient clinic review, the patient's condition remained stable. Repeat peripheral blood tests showed CD19+/CD20+ B-cell counts both at 0.16%, indicating low levels. The ADL score remained at 75 and NPI-12 score at 6 (Table 1). Although residual deficits persisted due to delayed immunotherapy, the family expressed satisfaction with the patient's current status and treatment outcomes. The patient continues maintenance oral therapy with donepezil and memantine, and reinforced recommendations were given for cognitive function training. Rituximab therapy was not continued thereafter, as the clinical improvements observed suggested sufficient disease control after the initial dosing.

Discussion

In this case, the patient experienced acute illness onset, manifested initially by a seizure and followed by persistent cognitive impairment. The delayed diagnosis, due to an initial misdiagnosis, underscores the critical importance of considering autoimmune etiologies in the differential diagnosis of encephalitis-like symptoms, such as seizures, cognitive decline, and behavioral changes, particularly in older patients. Older individuals with AE are often misdiagnosed with AD due to overlapping clinical features, including memory loss and hippocampal atrophy. This case highlights the impact of delayed diagnosis on prognosis, as the patient's cognitive recovery remained incomplete despite immunotherapy.

Significant atrophy in the cerebral cortex and bilateral hippocampus was observed. However, due to the absence of prior cranial imaging, it remains unclear whether this atrophy was present in the early stages of the disease. The ventriculomegaly observed was attributed to cerebral atrophy, as the patient did not exhibit symptoms typical of iNPH, such as gait disorder or urinary incontinence, and a CSF Tap test performed during lumbar puncture did not result in cognitive improvement.

Seizures are a distinguishing feature between AE and AD. While seizures typically occur in the advanced stages of AD,¹⁶ they often present early in AE and may persist throughout the disease course.¹⁷ AE can induce progressive cerebral atrophy through antibody-mediated neuronal injury, involving both direct mechanisms (e.g., antigen-specific neuronal targeting) and indirect pathways, such as microglial/astrocytic activation and neuroinflammatory cascades. This dual-pathway neurotoxicity may accelerate neurodegeneration. Therefore, the diagnostic challenges of AE in elderly patients are significant, as its presentation can mimic AD.¹⁸ It is recommended that specific antibodies in both serum and CSF be tested as early as possible, particularly in cases with red flags such as acute onset of seizures, behavioral changes, or CSF abnormalities inconsistent with typical AD,¹⁹ as early administration of immunotherapy may benefit these individuals. Although a negative result does not rule out AE, especially when other potential causes have been excluded, incorporating TBA is crucial for diagnosing antibody-negative AE. Antibody-negative results may be attributed to low antibody titers, methodological limitations of current assays, or the existence of novel antibodies yet to be identified.^20,21

Studies have demonstrated that TBA offers a distinct advantage in diagnosing probable AE. For example, paired sample analysis shows that serum testing demonstrates greater sensitivity, while CSF exhibits higher specificity.²² However, TBA lacks standardized protocols and requires expert interpretation, which may limit its widespread application.⁸ Combining TBA with CBA is recommended for comprehensive evaluation. Recent studies also suggest that immunohistochemistry on mouse brain sections can enhance the accuracy of neural antibody tests for AE patients.²³

Regarding treatment, research indicates no significant difference in the efficacy of immunotherapy between antibody-negative and antibody-positive AE cases.²⁴ First-line treatments, including glucocorticoids, IVIG, or plasma exchange, are recommended, while second-line options, such as rituximab or intravenous cyclophosphamide, are reserved for refractory cases or maintenance therapy.^25–27 Rituximab, a monoclonal antibody targeting CD20+ B cells, has demonstrated efficacy in AE.²⁸ In autoimmune diseases, dysfunctional B cells often have normal circulating counts, unlike the high levels seen in lymphomas, Low-dose rituximab appears effective for completely depleting peripheral CD20+ B cells.¹⁵ Low-dose rituximab (100 mg weekly for three weeks) has been shown to effectively deplete peripheral CD20+ B cells and improve AE prognosis.¹⁴ However, B-cell repopulation occurs over time, necessitating regular monitoring and potential re-administration of rituximab to maintain therapeutic efficacy. There are no established guidelines for when to start second-line treatments like rituximab in AE, but early use is recommended regardless of first-line therapy outcomes. Using rituximab early may lead to a quicker onset of action and help prevent early relapses during the transition from immunosuppression, making it an effective long-term immunosuppressant alternative.¹⁰

This case highlights the critical role of TBA in diagnosing antibody-negative AE, future research should focus on refining TBA methodologies to improve sensitivity and specificity. Additionally, our findings affirm the low-dose rituximab could offer a feasible therapeutic option for antibody-negative AE patients, particularly in scenarios where conventional treatments are ineffective. However, this report has several limitations. First, the patient's response to low-dose rituximab reflects an individualized outcome, limiting its generalizability due to interindividual variability. Larger, multicenter prospective studies are needed to confirm the efficacy and safety of this approach. Second, the lack of early imaging data hinders the determination of whether the observed cerebral atrophy is an early feature or a result of disease progression, restricting insights into disease evolution. Finally, the absence of long-term follow-up data prevents a comprehensive evaluation of the sustained efficacy and safety of low-dose rituximab, particularly in elderly patients.

Conclusion

In conclusion, this case demonstrates the diagnostic utility of TBA in antibody-negative AE and the potential efficacy of low-dose rituximab therapy. While our findings are promising, the individualized treatment response, lack of early imaging data, and absence of long-term follow-up limit their generalizability. Future multicenter studies with larger cohorts and standardized protocols are needed to validate these findings and optimize therapeutic strategies for antibody-negative AE.

Footnotes

Acknowledgements

We thank the patients and relatives for their collaboration.

ORCID iD

Lin Han

Ethical considerations

The studies involving humans were approved by The Ethics Committee of Tangdu Hospital. The study was conducted in accordance with the ethical principles outlined in the World Medical Association's Declaration of Helsinki.

Consent to participate

Written informed consent to participate in this case report was provided by the patient and his immediate family members.

Consent for publication

Written informed consent was obtained from the patient and his immediate family members for publication of this case report and any accompanying images.

Author contribution(s)

Lin Han: Data curation; Formal analysis; Writing – original draft.

Chuan Li: Data curation; Writing-review & editing.

Lin Li: Data curation; Methodology.

Dan Yao: Data curation; Methodology.

Yunfeng Hao: Data curation.

Chao Zhao: Data curation.

Xuan Zhou: Data curation.

Ying Li: Data curation.

Yuting Dang: Data curation.

Rong Zhang: Data curation.

Wenping Zhu: Data curation.

Shuyu Liu: Data curation.

Lan Gao: Data curation.

Ying Du: Formal analysis; Writing – review & editing.

Wei Zhang: Formal analysis; Writing – review & editing.

Funding

The authors disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This work was supported by research grants from the National Natural Science Foundation of China (grant numbers 82271457, 82171406), Shaanxi Province Health Research and Innovation Team for Cognitive Dysfunction Disease (grant number 2023TD-06), Shaanxi Innovative Team for Science and Technology (grant number 2024RS-CXTD-87), Xi’an medical key project for science and technology (grant number 2024JH-YXZD-0047), Tangdu hospital discipline promotion project (grant number 2024JCRH022), Tangdu hospital clinical research project (grant number 2021LCYJ040), Tangdu hospital foundation for social recruitment talent (grant number 2021SHRC011), Tangdu hospital innovation development foundation (grant numbers 2018QYTS010, 2019QYTS002), Clinical research project of AMMU (grant number 2024LC2440).

Declaration of conflicting interests

The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Data availability statement

The data supporting the findings of this study are available within the article and/or the cited publications.

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