Autoimmune encephalitis (AE) is a severe neurological inflammatory disorder characterized by acute or subacute onset of seizures, cognitive impairment, psychiatric symptoms, and altered consciousness. It often presents as new-onset refractory status epilepticus (NORSE), a challenging neurological emergency defined by prolonged seizures that persist despite adequate administration of first- and second-line antiepileptic drugs [1,2]. Patients with AE, particularly those with NORSE, frequently require intensive care, including anesthetic therapy, prolonged immobilization, and immunotherapy, placing them at a heightened risk of complications such as venous thromboembolism [3].

Enoxaparin, a low-molecular-weight heparin, is widely used in clinical practice for thromboprophylaxis and venous thromboembolism because of its predictable anticoagulant profile, ease of administration, and relatively lower risk of heparin-induced thrombocytopenia compared with unfractionated heparin. Major bleeding events associated with enoxaparin administration occur in approximately 0.5% to 3.6% of treated patients, indicating its relative safety [4,5]. This report presents a rare case of fatal retroperitoneal hemorrhage following standard prophylactic enoxaparin dosing in a patient diagnosed with AE presenting with NORSE. No previous cases of fatal hemorrhage associated with enoxaparin use have been reported in patients with AE in South Korea, underscoring the significance and novelty of this adverse event.

This study was approved by the Institutional Review Board/Ethics Committee of Kyungpook National University Chilgok Hospital (approval No. 2025-04-009). Written informed consent was obtained from the patient's legal guardian for the publication of this report including all clinical images.

A 61-year-old female with underlying diabetes mellitus, dyslipidemia, and asthma, but no prior seizure history, was admitted to a local medical center with fever and headache. Five days after hospitalization, the patient developed confusion, disorientation, and seizures. Magnetic resonance imaging (MRI) raised the suspicion of right middle cerebral artery infarction, prompting her transfer to a regional tertiary hospital. Despite 22 days of anesthetic therapy with midazolam, recurrent seizures persisted, necessitating transfer to our institution.

Upon transfer, the patient exhibited a stuporous mentality. Bilateral upper and lower limb muscle strength were assessed as Medical Research Council grade 2. Brainstem signs, including pupillary light and oculocephalic reflexes, were intact. Neck stiffness was absent and Babinski’s sign was negative. Initial laboratory results at the previous hospital showed a serum white blood cell count of 10,490/μL and a C-reactive protein level of 0.33 mg/dL. Cerebrospinal fluid (CSF) analysis revealed a white blood cell count of 5/μL, protein level of 44.0 mg/dL, glucose level of 89 mg/dL (serum glucose level of 127 mg/dL), and adenosine deaminase level of 1.3 U/L. Brain MRI revealed diffuse subcortical hyperintensities in both cerebral hemispheres.

At our hospital, brain MRI revealed diffuse gyral swelling in the right hemisphere and worsening of the diffuse subcortical and cortical hyperintensities in both frontal areas (Figure 1). Repeat CSF analysis showed a white blood cell count of 2/μL, protein level of 63.0 mg/dL, glucose level of 179 mg/dL (serum glucose of 295 mg/dL), and adenosine deaminase level <2 U/L. Panel results of CSF viral markers, polymerase chain reaction for Mycobacterium tuberculosis, and meningitis were negative. Paraneoplastic and AE antibody panels were performed in both the CSF and serum. The paraneoplastic antibody panel included anti-Hu, anti-Ri, anti-YO, anti-PNMA2, anti-amphiphysin, anti-CV2, anti-titin, anti-recoverin, and anti-SOX1 antibodies, while the autoimmune panel included anti-synaptic antibodies. All results were negative.

Despite continuous midazolam infusion and the use of maximum doses of antiepileptic drugs, including levetiracetam (3,000 mg/day), valproic acid (3,000 mg/day), and lacosamide (400 mg/day), the patient exhibited recurrent seizures characterized by eye blinking and facial twitching. Interictal discharge revealed abundant 1.5 to 2 Hz lateralized rhythmic delta activity over the left hemisphere (Figure 2). The patient was diagnosed with NORSE and AE and was immediately treated with intravenous methylprednisolone (1 g/day) and immunoglobulin (0.4g/kg/day) for 5 consecutive days. Concurrently, rituximab therapy was initiated at a dose of 375 mg/m² per week. Following immunotherapy, the patient’s consciousness improved markedly, with spontaneous eye opening and visual tracking with both eyes, and no seizure recurrence was observed after discontinuation of midazolam.

Abdominal computed tomography revealed a 3.5-cm cystic lesion with suspicious wall thickening in the right adnexal region, suggesting a possible teratoma (Figure 3). After a single infusion of rituximab, while preparing for surgical intervention, computed tomography angiography revealed deep vein thrombosis (DVT) in both common femoral veins and the right superficial femoral vein. There was no evidence of pulmonary thromboembolism, and enoxaparin therapy was initiated at a dose of 1 mg/kg twice daily (Figure 4). At that time, the patient’s laboratory results showed a D-dimer level of 2.32 μg/mL, an international normalized ratio of 1.02, and a platelet count of 118,000 /µL. On day 3 of enoxaparin treatment, the patient suddenly developed hypovolemic shock, and computed tomography revealed a massive retroperitoneal hemorrhage (Figure 5). Emergency abdominal arterial angiography failed to identify the source of bleeding. Despite intensive management with daily transfusions of red blood cells and platelets (apheresis platelets, fresh frozen plasma, and filtered platelets) as well as vasopressor support, the patient’s condition progressively worsened, leading to acute kidney injury that required dialysis and hepatic failure. She received intensive care in the intensive care unit (ICU) for one month; however, multiorgan failure persisted. The patient died following the family’s decision to withdraw life-sustaining treatment.

This case represents the first reported instance of a fatal adverse event following enoxaparin administration in a patient with AE presenting with NORSE. There has only been one previously reported case of fatal hemorrhage associated with enoxaparin use in South Korea [6]. Enoxaparin is widely used to prevent and treat DVT and pulmonary embolism and exhibits a more predictable anticoagulant effect and a lower risk of heparin-induced thrombocytopenia than unfractionated heparin. However, major bleeding complications have been reported in approximately 0.5% to 3.6% of patients, particularly in those with underlying risk factors [4,5].

A previous case in South Korea was reported by Oh et al. [6] and involved a 74-year-old woman with rheumatic heart disease and atrial fibrillation who experienced a spontaneous and fatal retroperitoneal hemorrhage during enoxaparin therapy. The hemorrhage occurred after 5 days of anticoagulation, and despite aggressive resuscitation, the patient succumbed following abrupt hemodynamic collapse, abdominal pain, and a rapid decline in hemoglobin, underscoring the rare but devastating risk of retroperitoneal bleeding associated with low-molecular-weight heparin. Similarly, in our patient, retroperitoneal hemorrhage developed shortly after the initiation of therapeutic enoxaparin. This event occurred in the context of prolonged immobilization, systemic inflammation related to AE, and concurrent immunotherapy—factors that may have promoted vascular fragility and exacerbated the prothrombotic–prohemorrhagic imbalance. Worldwide, although rare, several case reports have described retroperitoneal bleeding or hematoma following enoxaparin administration, underscoring the importance of careful monitoring [7,8].

Patients with AE, particularly those with anti-N-methyl-ᴅ-aspartate receptor (NMDAR) encephalitis, are at an increased risk of DVT because of factors such as catatonia, prolonged immobilization, ICU admission, and use of immunotherapies such as corticosteroids and intravenous immunoglobulin (IVIG). Catatonia, a common manifestation of anti-NMDAR encephalitis, is associated with complications due to prolonged immobility, including venous thromboembolism. Studies have shown that a significant proportion of patients with AE require ICU care, with one series reporting that 70% of such patients had critical care needs during their initial hospital stay [9]. The administration of immunotherapies, such as corticosteroids and IVIG, further contributes to the prothrombotic state in such patients. Corticosteroids are known to increase coagulation factors, impair fibrinolysis, and induce endothelial dysfunction, which can predispose patients to venous thromboembolism [10]. Likewise, IVIG has been associated with increased blood viscosity and enhanced platelet activation, elevating thrombotic risk [11].

Nearly 40% to 50% of female patients with anti-NMDAR encephalitis have an associated ovarian teratoma, often necessitating surgical intervention [12]. Tumors, primarily ovarian teratomas, have been identified as triggers for anti-NMDAR encephalitis, and their removal is considered an important treatment strategy. Considering the need for perioperative thromboprophylaxis and therapeutic anticoagulation in such cases, enoxaparin is frequently administered. However, as demonstrated in this case, standard therapeutic enoxaparin dosing can lead to life-threatening hemorrhagic complications. Therefore, clinicians should remain vigilant for signs of internal bleeding and weigh the benefits of therapeutic anticoagulation against potential bleeding risks, particularly in patients with AE, who might experience complex and evolving clinical courses.

This case underscores the rare but potentially fatal risk of hemorrhagic complications associated with enoxaparin use in patients with AE, particularly those presenting with NORSE. Given their complex clinical status, including prolonged immobilization, intensive immunotherapy, and potential surgical interventions, careful risk-benefit assessment and close monitoring of bleeding are essential when initiating anticoagulation therapy.