Neuro‐Ophthalmic‐Onset Non‐Thrombotic Primary Antiphospholipid Antibody Syndrome: Case Report

A 43-year-old woman presented to our department with fever, impaired vision, and headache. The patient initially developed a high fever (peak temperature 38.7°C), accompanied by chills, but no respiratory symptoms such as cough or sputum production. A chest CT scan revealed evidence of a pulmonary infection. Although the fever was successfully controlled with antibiotic treatment at a local hospital, she subsequently experienced acute-onset visual loss in the left eye (light perception only, snellen equivalent 0/20), accompanied by a persistent headache. This prompted an emergency referral to our institution. Physical examination: vital signs: Stable. Ophthalmological examination: significant reduction in visual acuity in the left eye. Neurological examination: positive right Babinski sign. The initial workup revealed leukocytosis (WBC: 10.26 × 109/L), neutrophilia (7.65 × 109/L; 74.5%), a normal platelet count (323 × 109/L) and unremarkable results from routine tests, including biochemical tests, coagulation tests, PCT, ESR and CRP. Immunological profiling showed antiphospholipid antibodies positivity, with elevated anticardiolipin IgM (28.6 MPLU/mL) and anti-β2-glycoprotein I antibodies (155.4 AU/mL; IgM isotype: 141.4 AU/mL), alongside negative IgG and IgA isotypes for both antigens, while ANAs and other autoantibodies were negative. An ophthalmological evaluation revealed absent visual evoked potentials bilaterally, despite normal ocular angiography. Brain MRI scan (Figure 1) revealed left temporo-insular swelling, enhancement of the optic chiasm, and multiple medullary and cerebral ischaemic demyelinating lesions with ventriculomegaly. SWI imaging showed a nodular hypointensity in the right parietal lobe (suggestive of a vascular abnormality or old microbleed), as well as bilateral frontal subcortical hypointensities (possibly arachnoid granulations). However, MRA imaging showed no vascular anomalies. Lumbar puncture revealed normal CSF pressure, mild mononuclear pleocytosis (18 × 106/L), and negative microbiological studies. Autoimmune encephalitis antibody testing was negative; these findings warrant consideration of atypical neuroinflammatory disorders or antibody-negative autoimmune encephalopathy. On Day 2, the patient developed involuntary limb movements, a choreiform gait, and progressive deterioration of vision in the right eye; ophthalmological examination confirmed a best-corrected visual acuity (BCVA) of 0.3 (Snellen equivalent ~20/60). Given these neurological manifestations, coupled with persistently positive antiphospholipid antibodies, we diagnosed antiphospholipid syndrome involving the central nervous system. Initial immunotherapy comprised intravenous methylprednisolone (1 g daily) and immunoglobulin (20 g daily) pulse therapy, with concurrent dual antithrombotic therapy (aspirin plus rivaroxaban), and addition of low dose rituximab (200 mg every 2 weeks for 2 weeks) for immunomodulatory therapy [1]. At the four-month follow-up, the patient had made a full visual recovery. BCVA improved to 1.0 (Snellen equivalent 20/20) in the left eye and 0.5 (Snellen equivalent ~20/40) in the right eye, and the fever and headache had resolved. Repeat MRI (Figure 1) demonstrated progressive lesion regression, while serial antibody titres showed declining but still high levels. Maintenance therapy was transitioned to mycophenolate mofetil, alongside continued anticoagulation therapy. APS is an autoimmune disorder characterized by thrombosis and/or pregnancy morbidity, which must be accompanied by persistently positive antiphospholipid antibodies (aPL) [2]. Neurological manifestations (e.g., stroke, epilepsy and cognitive impairment) are relatively common in APS. However, isolated visual impairment due to APS-related optic neuropathy or central nervous system (CNS) involvement as the initial presentation is rare. Diagnosing APS in this patient was particularly challenging due to the absence of a typical thrombotic or obstetric history. Following multidisciplinary consultations with specialists in neurology, ophthalmology and radiology, we carefully evaluated the case. The temporal and occipital lobe lesions were consistent with ischaemic changes, while the right parietal lobe findings suggested old microhaemorrhages, indicating possible cerebral microangiopathy. The following conditions should be excluded: (1) Neuromyelitis optica spectrum disorder (NMOSD)—while absence of spinal cord involvement and negative AQP4 antibody; (2) multiple sclerosis (MS)—the patient absence of temporal dissemination and typical MRI findings; and (3) autoimmune encephalitis—the patient's cerebrospinal fluid (CSF) antibody panel was entirely negative, and the clinical presentation lacked characteristic features (e.g., psychiatric symptoms or seizures). Current research has identified a broad range of non-thrombotic clinical manifestations associated with antiphospholipid antibodies (aPLs). These include cutaneous manifestations such as livedo reticularis and superficial thrombophlebitis; haematological manifestations such as thrombocytopenia and haemolytic anaemia; cardiac manifestations; neurological manifestations such as chorea, cognitive dysfunction and transverse myelitis; and renal manifestations such as aPL-associated nephropathy. While these diverse presentations are distinct from classic vascular thrombotic events, they are increasingly recognised as part of the APS spectrum. It is thought that they arise through alternative pathogenic mechanisms, including direct antibody-mediated endothelial activation, complement pathway dysregulation and tissue-specific inflammatory responses [3]. CNS manifestations constitute one of the most prominent features of APS, encompassing arterial and/or venous thrombotic events, as well as various non-thrombotic neuropsychiatric syndromes. Although the prothrombotic effects of antiphospholipid antibodies (aPLs) are well-established, their relationship with non-stroke neuropsychiatric manifestations (NPMs) remains unclear. Neuroimaging in these patients typically reveals a combination of ischaemic and inflammatory white matter changes, suggesting a complex pathophysiology involving microvascular thrombosis and direct, antibody-mediated neuroinflammation [4]. Reino et al. [5] documented a seminal case involving a middle-aged woman who presented with acute bilateral visual loss. Diagnostic evaluation revealed impaired visual conduction pathways, despite normal retinal architecture. Subsequent immunological testing demonstrated antiphospholipid antibody (aPL) positivity. This case established primary APS as the definitive diagnosis, complete visual recovery was achieved through anticoagulation therapy. A retrospective case series [6] of 23 patients with catastrophic antiphospholipid syndrome (CAPS) and visual impairment revealed that 64% had primary APS, while the remaining 36% were secondary to SLE. The main causes of vision loss were retinal vascular occlusion (73%), choroidopathy (36%), and ischaemic optic neuropathy (9%). Ischemic optic neuropathy was categorised as either anterior ischemic optic neuropathy (AION), which is caused by ischemia at the optic nerve head (optic disc) and typically presents with optic disc oedema, or posterior ischemic optic neuropathy (PION), which results from impaired blood supply to the retrobulbar, intracanalicular, or intracranial optic nerve segments and is characterised by vision loss without optic disc swelling. Our patient exhibited intracranial ischaemic lesions with optic chiasm enhancement, normal optical coherence tomography results, delayed visual evoked potentials and unremarkable fundus angiography—findings suggestive of PION. This case highlights APS heterogeneity, emphasizing multidisciplinary evaluation, antibody testing, and imaging in atypical presentations. Further research is needed to elucidate aPL-mediated CNS injury mechanisms and standardize non-thrombotic APS treatment. Huiyang Liu: article writing. Zheng Cui: data collection. Dongmei Bao: data collection. Yongfu Wang: data collection and organization. The authors declare no conflicts of interest. The data that support the findings of this study are available from the corresponding author upon reasonable request.