Unveiling the Shadow: Unraveling the Cause of Blindness

A 71-year-old Black woman with a medical history of type 2 diabetes mellitus, hypertension, and asthma was admitted with complaints of painful bilateral vision loss. She reported right-sided vision loss for four months and left-sided vision loss since a week before admission. Additionally, she presented with fatigue and unintentional weight loss, having lost 50 pounds over seven months. Four months before admission, the patient experienced acute right-sided vision loss. Although she reported a history of headaches, she did not exhibit jaw claudication, scalp tenderness, or muscle stiffness and pain. There was no joint pain or swelling reported, nor did she have a fever, photosensitive rashes, alopecia, mucosal ulcers, chest pain, dyspnea, cough, abdominal pain, numbness, or dry eyes/dry mouth. She was initially prescribed prednisone 60 mg daily by an ophthalmologist because of a suspicion of giant cell arteritis (GCA). A left-sided temporal artery biopsy was unremarkable. Despite this, she continued prednisone treatment for suspected biopsy-negative GCA; it was discontinued shortly after when no improvement was observed. A week before admission, she developed bilateral, progressive proptosis followed by acute vision loss in her left eye, leading to hospitalization. The patient had been experiencing right-sided hearing loss for some time. A magnetic resonance imaging (MRI) of the brain performed a year before admission revealed a right-sided vestibular schwannoma, for which she underwent a gamma knife procedure. A follow-up MRI six months later showed no change in the right vestibular schwannoma, and the patient continued to experience right-sided hearing loss. The patient's medical history includes type 2 diabetes mellitus, hypertension, and asthma. The patient's social and family history is unremarkable. The patient reported experiencing painful bilateral vision loss along with unintentional weight loss. The review of systems yielded negative findings otherwise. On physical examination, the patient presented with a blood pressure reading of 105/60 mm Hg, a heart rate of 91 beats per minute, a respiratory rate of 17 per minute, a temperature of 36.3°C, and oxygen saturation of 98% on room air. Her body mass index was 23.56. Bilateral visual acuity indicated no light perception. Intraocular pressure was measured at 10 mm Hg in the right eye and 12 mm Hg in the left eye, within the normal range (10–20 mm Hg). Bilateral visual field assessments revealed total superior temporal, inferior temporal, superior nasal, and inferior nasal deficiencies, suggesting ophthalmoplegia. There was bilateral diffuse periorbital edema, more pronounced on the left side, and bilateral optic atrophy observed through fundus photography. Lung auscultation revealed clear breath sounds without wheezing, rhonchi, or rales. Cardiovascular examination showed normal S1 and S2 heart sounds without murmurs, rubs, or gallops. The skin appeared warm and dry, with no signs of erythema or rash. The abdomen was nondistended, and normal bowel sounds were present. Radial pulses and dorsalis pedis pulses were 2+ bilaterally. The patient displayed a normal range of motion with the ability to fully move all limbs and joints without any limitations. She was alert and oriented to person, place, and time, with no deficits in cranial nerve function, sensory perception, or coordination. Mood, thought content, and judgment were all within normal limits. A complete blood count revealed a hemoglobin level of 10.5 g/dL (reference range 10.9–14.3 g/dL), a white blood cell count of 13.06 K/μL (reference range 3.9–12.7 K/μL) with an eosinophil count of 0.4% (reference range 0%–8%), and an elevated platelet count of 543 K/μL (reference range 150–450 K/μL). Thyroid function, indicated by thyroid-stimulating hormone at 1.1 μIU/mL (0.4–4 μIU/mL), falls within the normal range. Renal function markers, including creatinine at 0.64 mg/dL (reference range 0.5–1.4 mg/dL) and a glomerular filtration rate above 60 mL/min, suggest normal kidney function. Inflammatory markers show significant elevation, with an erythrocyte sedimentation rate of 75 mm/hr (reference range 0–20 mm/hr) and a C-reactive protein level of 1.03 mg/dL (reference range 0–0.9 mg/dL). Complement levels demonstrate normal C3 at 145 mg/dL (reference range 50–180 mg/dL) and C4 at 35 mg/dL (reference range 11–44 mg/dL), and angiotensin-converting enzyme is within the normal range at 16 U/L (reference range16–85 U/L). Autoimmune markers reveal a negative antinuclear antibody titer (<1:80), perinuclear antineutrophil cytoplasmic antibody (P-ANCA) at <1:20, and cytoplasmic antineutrophil cytoplasmic antibody (C-ANCA) at <1:20. Glomerular basement antibody is negative. The patient's immunoglobulin levels revealed IgG1 at 246 mg/dL (reference range 382–929 mg/dL), IgG2 at 214 mg/dL (reference range 242–700 mg/dL), IgG3 at 18 mg/dL (22–176 mg/dL), and IgG4 at 81 mg/dL (4–86 mg/dL). Urinalysis shows negative results for proteins, glucose, ketones, occult blood, red blood cells, nitrite, and leukocytes. Flow cytometry results exhibit normal immunophenotyping without a monotypic B cell population or increased blasts, suggesting no evidence of hematological malignancies. Lumbar puncture findings include normal cerebrospinal fluid glucose at 70 mg/dL (reference range 40–70 mg/dL), elevated protein at 58 mg/dL (reference range 15–40 mg/dL), and an absence of white blood cells (reference range 0–5/cu mm). Tests for neuromyelitis optica and myelin oligodendrocyte glycoprotein antibodies are negative, and the IgG index is 0.75 (reference <0.85), indicating no evidence of central nervous system inflammation. The MRI of the orbit and brain depicted extensive areas of enhancement involving the posterior aspect of the intra- and extraconal space, extraocular muscles, orbital apices, infratemporal fossae, pterygopalatine fossae, and retro maxillary fat. Bilateral enlargement of the medial and superior rectus muscles was observed, along with pachymeningeal enhancement along the base of the frontal lobes and the falx. Pansinusitis was evident, and intrinsic and perineural contrast enhancement of the intraorbital optic nerves suggested bilateral optic neuritis/perineuritis, with evolving ischemic changes in the left optic nerve (Figure 1A). A vestibular schwannoma in the right internal auditory canal remained unchanged (Figure 1B). The computed tomography (CT) of the sinuses confirmed soft-tissue density and mass-like attenuation in various orbital and maxillofacial locations. A pan CT scan showed no evidence of ground-glass opacities or mediastinal or hilar lymphadenopathy in the lungs, but it detected a solid noncalcified pleural-based nodule measuring 17 mm in the left apical region, along with a 1.5 cm solid-appearing hypodense lesion in the right kidney interpolar region (Figures 2 and 3). The patient was initiated on a treatment regimen of isavuconazonium, micafungin, vancomycin, and meropenem because of a suspicion of infectious etiology while concurrently maintaining a low dose of oral prednisone. Continuous application of frequent lubrication and ointments in the eyes was also maintained. Subsequently, after a day of starting antibiotics, the patient underwent right endoscopic sinus surgery, septoplasty, right external ethmoidectomy, and right orbital decompression. Pathological examination of sinus mucosa, bone, right orbital fat, right periorbital fascia, and aerobic, anaerobic, fungal, and acid-fast bacilli cultures were conducted. However, all cultures yielded negative results. Pathological findings indicated mucosal inflammation with arterial wall fibrinoid damage and giant cells suggestive of granulomatosis with polyangiitis (GPA) (Figure 4). A CT-guided biopsy of the lung nodule further revealed acute granulomatous vasculitis, supporting a systemic vasculitis process. Despite three doses of pulse steroids and cyclophosphamide, the patient did not show significant improvement. Subsequently, she was started on oral prednisone (60 mg) with sulfamethoxazole and trimethoprim for Pneumocystis jiroveci prophylaxis and rituximab every 6 months. Prednisone was gradually tapered off, and rituximab treatment was continued; despite this, after a six-month follow-up, vision remained unchanged, although orbital swelling had improved. Active surveillance for the mass in the right kidney is continued because it has remained stable in size. The lung mass has reduced to 9 mm and is currently under follow-up by the pulmonology department. A 71-year-old Black woman presented with a history of painful right-sided vision loss four months ago, followed by left-sided vision loss a week before admission, along with symptoms of fatigue and unintended weight loss. Orbital and brain MRI revealed pansinusitis and bilateral optic neuritis. A pan CT scan identified a 17-mm solid nodule in the left apical region and a 1.5-cm solid lesion in the right kidney. Laboratory results indicated normal complements, IgG4, urinalysis, and negative antibodies, including C-ANCA and P-ANCA. The patient was initially treated with antibiotics and a low dose of oral prednisone. Further, biopsy results of sinus tissues and lung nodule confirmed GPA. Despite receiving three doses of pulse steroids and cyclophosphamide, the patient did not exhibit significant improvement. Subsequently, she was prescribed oral prednisone (60 mg) and rituximab every six months. Although orbital swelling showed improvement, her vision remained unchanged. GPA is a rare autoimmune vasculitis characterized by inflammation of small- to medium-sized blood vessels. The disease predominantly affects the upper and lower respiratory tract and kidneys but can involve virtually any organ system. There are several differential diagnoses to consider for orbital involvement in GPA (Table 1). The patient meets five points for GPA according to the 2022 American College of Rheumatology/EULAR classification criteria, fulfilling required features like pulmonary nodule, granulomatous inflammation, and sinus inflammation for diagnosis, while microscopic polyangiitis (MPA) and eosinophilic granulomatosis with polyangiitis (EGPA) scored 0 points.1 Granulomatous inflammation and the presence of granulomas helped exclude MPA, while the lack of eosinophilic infiltration and a normal eosinophil count indicated the absence of EGPA. Orbital sarcoidosis and necrotizing sarcoid granulomatosis can also present with proptosis, periorbital swelling, ocular pain, and visual disturbances due to direct infiltration by sarcoid tissue. The absence of noncaseating granulomas or classic necrosis pattern favors GPA in this case. IgG4-related disease is another important differential diagnosis that can present with periorbital swelling and proptosis. However, in this case, the biopsy did not show the characteristic features of a dense lymphoplasmacytic infiltrate, focal storiform fibrosis, or obliterative phlebitis. Additionally, the criteria for elevated serum IgG4 levels (>135 mg/dL), more than 10 IgG4+ plasma cells per high-power field, and an IgG4+/IgG+ cell ratio >40% on immunohistochemistry were not met. Inflammatory disorders like idiopathic orbital inflammation, including variants like the apical form of Tolosa-Hunt syndrome and a sclerosing form featuring chronic progressive fibrosis, pose another set of considerations. Ocular infections that resemble GPA often stem from fungal pathogens such as histoplasmosis, blastomycosis, and coccidioidomycosis, as well as from mycobacterial and bacterial agents like streptococcus. However, these were ruled out due to negative results from stains, cultures, and biopsy findings. Neoplastic conditions such as orbital lymphomas, head and neck squamous cell carcinomas, nasopharyngeal carcinoma, metastases, and schwannomas can mimic GPA, but biopsy ruled them out. Endocrine-related conditions, specifically thyroid ophthalmopathy, can manifest with orbital symptoms akin to those seen in GPA. GPA features the presence of serum proteinase 3 (PR3)- or myeloperoxidase (MPO)-ANCA, which serves as a crucial serological marker. Studies emphasize the diagnostic importance of PR3-ANCA testing, demonstrating a sensitivity and specificity of 79.8% to 86.6% and 96.8% to 98.3%, respectively.2 The ANCA titer may also serve as an indicator of disease activity or relapse after treatment, though its role in managing ANCA-associated vasculitis is still under investigation. In the context of GPA, approximately 82% to 94% of patients display positive ANCA.3 PR3-ANCA is the predominant subtype in 65% to 75% of cases, whereas 20% to 30% of patients with clinical GPA present with alternative ANCA.4 Although most cases of ANCA-associated vasculitis (AAV) are identified by positive ANCA titers, there exists a less common subset of patients with ANCA-negative AAV. It is essential to recognize that a negative ANCA assay does not definitively rule out GPA, because at least 10% of patients are ANCA-negative.5 In these patients, the diagnosis often relies on clinicopathologic features rather than ANCA positivity, particularly in those with limited or nonrenal manifestations of AAV.6 ANCA status may change over time, with patients initially testing negative and eventually testing positive, particularly as the disease becomes more generalized. ANCA-negative AAV may involve undetectable ANCA antibodies, either because of a low levels in the blood or their presence solely in tissues. Alternatively, there could be ANCA antibodies with undiscovered specificities, targeting unique antigenic targets or posttranslational modifications. Also, pathological mechanisms unrelated to traditional antibody-mediated pathways, such as cell-mediated immunity or alternative autoantibodies, might contribute to the vascular inflammation observed in this condition. This underscores the complexity of the serological landscape and emphasizes the need for a comprehensive understanding of ANCA-related dynamics in the context of GPA. Regarding clinical manifestations, ocular symptoms may serve as initial indicators of GPA in approximately 15% of patients.7 Proptosis is the most common presentation of orbital GPA, often resulting from contiguous disease in the nasal and paranasal sinuses, illustrating the interconnected nature of manifestations in this vasculitic disorder. Additionally, scleritis is a significant and early presentation of GPA, occurring in roughly 50% of patients. Episcleritis typically follows a milder course and tends to resolve independently, although topical glucocorticoids may expedite symptom relief. Approximately 20% to 50% of patients with orbital manifestations may experience significant visual impairment.8 Treatment for GPA varies depending on disease severity and patient condition, with regimens tailored accordingly. Initial assessment focuses on determining if GPA poses a threat to life or organs, guiding treatment decisions for first occurrences, refractory cases, relapses, or maintenance therapy. Azathioprine has become a prominent medication for managing mild disease, replacing methotrexate, and rituximab is now commonly used as the first-line treatment for severe disease instead of cyclophosphamide. In cases of ocular GPA, rituximab shows promise in inducing remission but requires close monitoring for symptom exacerbation.9 This case presented significant challenges because of the absence of ANCA antibodies, which might have been attributed to any of the previously mentioned reasons. Although the vestibular schwannoma was unrelated to the acute vision loss and systemic symptoms, and the right kidney lesion appeared atypical for GPA because it did not resemble hypodensity from ischemia potentially linked to vasculitis, the presence of these incidentalomas complicated the diagnostic process. The patient was initially suspected to have GCA and was promptly started on steroids. This treatment could have potentially aided in managing GPA and possibly delayed the onset of left eye blindness. However, the steroids were discontinued prematurely because of a lack of vision improvement and other suspected causes. The delayed restart of steroids and the gradual resolution of orbital pseudotumors might have exacerbated the outcome. Such cases necessitated intensive and aggressive measures from the outset. In summary, the interplay between serological markers, dynamic ANCA status, and diverse clinical presentations highlights the complexity of diagnosing and managing GPA, demanding a nuanced and multidisciplinary collaboration in clinical practice. Seronegative granulomatosis with polyangiitis All authors contributed to at least one of the following manuscript preparation roles: conceptualization AND/OR methodology, software, investigation, formal analysis, data curation, visualization, and validation AND drafting or reviewing/editing the final draft. As corresponding author, Dr Sondhi confirms that all authors have provided the final approval of the version to be published, and takes responsibility for the affirmations regarding article submission (eg, not under consideration by another journal), the integrity of the data presented, and the statements regarding compliance with institutional review board/Helsinki Declaration requirements. Disclosure form Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.