Anti-LGI1 Antibody-Associated Encephalitis Misdiagnosed as Schizophrenia: A Case Report

Abstract

Anti-leucine-rich glioma-inactivated 1 (LGI1) antibody-associated encephalitis is a rare but clinically significant form of autoimmune encephalitis, predominantly affecting middle-aged men. Its heterogeneous clinical presentation often leads to misdiagnosis, commonly as other neurological or psychiatric disorders. This report details the case of a 46-year-old male who initially presented with depressive symptoms, personality changes, and visual hallucinations. Over time, his condition progressed to include memory impairment, disorganized behavior, and seizures. Initially misdiagnosed with schizophrenia, the correct diagnosis of LGI1 antibody-associated encephalitis was eventually established through positive serum and cerebrospinal fluid (CSF) tests for LGI1 antibodies. Neuroimaging findings revealed characteristic bilateral temporal lobe lesions. The patient demonstrated marked improvement following treatment with methylprednisolone and intravenous immunoglobulin, ultimately achieving significant recovery. This case highlights the critical importance of comprehensive antibody testing and neuroimaging in patients presenting with nonspecific psychiatric and neurological symptoms to prevent misdiagnosis and delays in appropriate treatment. The article also reviews the pathogenesis, clinical manifestations, diagnostic approaches, and therapeutic strategies for LGI1 antibody-associated encephalitis, aiming to enhance clinical awareness and optimize patient outcomes.

Introduction

Autoimmune encephalitis represents a group of inflammatory brain diseases triggered by the immune system’s aberrant attack on neural tissues. Among these, anti-leucine-rich glioma-inactivated 1 (LGI1) antibody-associated encephalitis is the second most prevalent subtype, following anti-N-methyl-d-aspartate receptor (NMDAR) encephalitis.¹ This condition predominantly affects middle-aged individuals, with a marked male predominance. The pathogenesis is linked to disruptions in voltage-gated potassium channel complexes, with lesions primarily located in the hippocampus, amygdala, and temporal cortex of the limbic system. Clinically, the presentation is heterogeneous, often involving an acute or subacute onset of memory impairment, psychiatric disturbances, seizures, as well as characteristic faciobrachial dystonic seizures (FBDS), and hyponatremia.² These diverse symptoms frequently lead to misdiagnoses, such as viral encephalitis, psychiatric disorders, or even stroke, which in turn contribute to delayed treatment and increased morbidity and mortality. This report presents a detailed case of LGI1 antibody-positive autoimmune encephalitis, with a focus on the clinical manifestations, diagnostic journey, and therapeutic response. The aim is to enhance clinicians’ recognition and management of this disease, thereby reducing the risk of misdiagnosis and inappropriate treatment.

Case Presentation

A 46-year-old male patient presented with a depressive mood, dizziness, and chest tightness in January 2023, following a family conflict. Initial investigations, including brain magnetic resonance imaging (MRI) and electrocardiogram (ECG) conducted at a local hospital, revealed no abnormalities. By April 2023, the patient exhibited marked personality changes, characterized by irritability and frequent interpersonal conflicts. In May 2023, his condition further deteriorated, manifesting as disorganized behavior (eg, searching for deceased parents, competing for food, and repetitive eating), visual hallucinations, memory decline, and a loss of daily living skills. On July 3, 2024, the patient experienced his first episode of unconsciousness and convulsions, which resolved spontaneously after approximately 1 h. Two days later, on July 5, 2024, he presented with a stupor, slowed speech and actions, and restlessness, accompanied by daily episodes of unconsciousness and convulsions. The patient was admitted to another hospital on July 7, 2024, where he was diagnosed with “possible schizophrenia” and treated with fluphenazine, fluoxetine, and clonazepam, though the specific dosages were not documented. The treatment, however, was ineffective, and the patient’s condition worsened, with inappropriate responses to questions, disorganized speech, hand-wringing, and nonsensical speech. On July 10, 2024, the patient was admitted to our hospital for further evaluation.

The patient had no significant medical history, and his personal and family history were unremarkable. Upon admission, a mental status examination revealed altered consciousness, disorientation to time, place, and person, prominent visual hallucinations, and disorganized speech and behavior, which precluded in-depth communication. The physical examination was notable for uncooperative behavior, though vital signs were stable. Neurological examination demonstrated bilaterally equal and round pupils (approximately 2 mm in diameter), absence of nystagmus, involuntary facial muscle movements, muscle strength graded at V in all limbs, normal muscle tone, symmetrical deep tendon reflexes, a questionable positive Babinski sign on the right side, choreiform movements in all limbs, and neck stiffness with questionable resistance (with the chin 2 fingers away from the sternum). Laboratory investigations revealed hyponatremia and hypokalemia. Brain MRI demonstrated fluid-attenuated inversion recovery (FLAIR) hyperintensities in the bilateral temporal lobes, right insula, and frontal-parietal cortex (figure 1). Routine blood tests, urinalysis, thyroid function tests, sex hormone levels, coagulation profile, ECG, and electroencephalogram were all within normal limits. Given the clinical picture, a lumbar puncture was performed after consultation with the patient’s family to rule out encephalitis. Although cerebrospinal fluid (CSF) analysis was unremarkable, both serum and CSF were positive for LGI1 antibodies (1:100 titer), while other autoimmune encephalitis antibodies were negative.

Fig. 1.

Cranial MRI imaging shows FLAIR hyperintensities in the bilateral temporal lobes (A), right insular cortex (B), and frontoparietal cortex (C).

Based on the clinical presentation, imaging findings, and positive LGI1 antibody results in both serum and CSF, a diagnosis of LGI1 antibody-associated encephalitis was established. The patient was subsequently transferred to the neurology department and treated with intravenous methylprednisolone (500 mg/day for 5 days, followed by a taper to 250 mg/day for 5 days, 120 mg/day for 3 days, and 60 mg/day for 3 days) and oral prednisone (30 mg/day, with a 5 mg taper every 2 weeks until discontinuation). Intravenous immunoglobulin (IVIG) was also administered at 0.4 g/kg/day for 5 days. Following treatment, the patient exhibited significant clinical improvement, with stabilization of mood, resolution of psychotic symptoms, and restoration of memory function. He was discharged in good condition and has remained symptom-free during follow-up.

Discussion

Anti-LGI1 antibody-associated encephalitis was first reported in 2010 by Lai et al., who identified LGI1 as the pathogenic antibody responsible for this condition.¹ It accounts for approximately 30% of limbic encephalitis cases, making it the second most common form of autoimmune encephalitis after anti-NMDA receptor encephalitis. LGI1, a protein secreted by neurons, forms trans-synaptic complexes with pre- and postsynaptic proteins such as a disintegrin and metalloproteinase domain-containing protein 11 (ADAM11), ADAM22, and ADAM23, playing a crucial role in regulating neuronal excitability.^3,4

This condition predominantly affects middle-aged men and is more prevalent in males. The clinical presentation is highly variable, with seizures and memory impairment being the most frequent symptoms. Other manifestations include psychiatric symptoms, sleep disturbances, autonomic dysfunction, and speech disorders.² Seizures are observed in approximately 90% of patients, with FBDS being a hallmark feature, occurring in about 66.7% of cases. FBDS is characterized by brief, frequent dystonic movements affecting 1 side of the face and upper limb.⁵ Memory impairment often presents as progressive short-term memory loss, which can lead to misdiagnosis as Alzheimer’s disease or other cognitive disorders. Psychiatric symptoms, including mood instability, behavioral abnormalities, and visual or auditory hallucinations, are linked to the involvement of the medial temporal lobe, hippocampus, and amygdala.⁶ Additionally, hyponatremia is a common feature, occurring in approximately 65% of patients, usually due to inappropriate antidiuretic hormone secretion induced by LGI1 antibodies acting on the hypothalamus and kidneys. Hyponatremia is often considered a prodromal symptom.⁵

The diagnosis of LGI1 antibody-associated encephalitis requires a thorough evaluation of clinical symptoms, imaging findings, and laboratory results. Neuroimaging, particularly MRI, typically reveals unilateral or bilateral medial temporal lobe abnormalities, with involvement of the amygdala and hippocampus. In some cases, amygdala hypertrophy or basal ganglia abnormalities may be observed, with FLAIR sequences being particularly sensitive.⁷ The imaging characteristics in this case are consistent with those reported in the literature, reinforcing the diagnostic accuracy. The detection of LGI1 antibodies in both serum and CSF is the gold standard for diagnosing this condition. In this case, the presence of LGI1 antibodies, combined with the clinical and imaging findings, confirmed the diagnosis of LGI1 antibody-associated encephalitis. This case underscores the importance of considering antibody testing in patients with nonspecific psychiatric and neurological symptoms.

It is important to note that this patient was initially misdiagnosed with schizophrenia due to prominent psychiatric symptoms, a scenario not uncommon in cases of LGI1 antibody-associated encephalitis. Reports in the literature indicate that a significant proportion of patients are initially misdiagnosed with psychiatric or other neurological disorders.⁸ Contributing factors to misdiagnosis include a lack of awareness among clinicians about this condition and the nonspecific nature of its early symptoms, which complicate the diagnostic process. To reduce the risk of misdiagnosis, clinicians should increase their understanding of LGI1 antibody-associated encephalitis and maintain a high index of suspicion when encountering atypical psychiatric and neurological presentations.

Immunotherapy is the first-line treatment during the acute phase of LGI1 antibody-associated encephalitis, and most patients respond well. Studies have shown that after 2 weeks of first-line treatment, approximately 80% of patients experience a reduction in seizures and an improvement in cognitive impairment.⁵ Current treatment options include intravenous corticosteroids, immunoglobulins, or plasma exchange. If there is no significant clinical or imaging improvement after 2–4 weeks of first-line treatment, second-line immunosuppressive agents with rapid and sustained effects can be considered to improve outcomes.⁹ In this case, the patient showed significant improvement following treatment with methylprednisolone and IVIG, which aligns with findings from previous research. In terms of prognosis, studies indicate that approximately 80% of patients have a favorable outcome after 2 years of follow-up, although the relapse rate is around 35%.^5,10 Some patients may have residual symptoms such as spatial disorientation, insomnia, or occasional seizures, and a minority may require long-term use of immunomodulators and antiepileptic drugs. The mortality rate for LGI1 antibody-associated encephalitis ranges from 6% to 19%.^5,10

Conclusion

The complex and nonspecific clinical manifestations of LGI1 antibody-associated encephalitis pose significant diagnostic challenges for clinicians. This case highlights the critical importance of timely recognition and accurate diagnosis, particularly the role of early antibody testing and neuroimaging in confirming the diagnosis and optimizing treatment strategies. Future research should focus on elucidating the pathogenesis and optimizing treatment protocols for this disease to improve long-term patient outcomes.

Funding

The authors report no sources of funding.