Pupil-Sparing Third Nerve Palsy and Papilledema Due to Granulomatosis With Polyangiitis

Granulomatosis with polyangiitis (GPA) is a rare antineutrophilic cytoplasmic antibody (ANCA)-associated vasculitis predominantly affecting small vessels. Although almost any organ system can be affected, the upper and lower respiratory tracts and renal system are most commonly involved. Neurological involvement mainly manifests as peripheral neuropathy, which has been reported in up to 67% of patients; cranial nerve involvement is rare with the optic nerve being the most commonly affected (1). Cranial nerve 3 (CN3) palsy in the context of GPA has been reported in isolation in 2 previous case reports (2,3), and no previous publication documented a complete, pupil-sparing CN3 palsy. We report a case of GPA in a patient with chronic sinusitis presenting with a severe, pupil-sparing CN3 palsy and papilledema. CASE REPORT A 44-year-old woman presented to the emergency department with headache and new left ptosis. She had a past medical history of chronic rhinosinusitis and underwent endoscopic sinus surgery and septoplasty 1 and 4 years before presentation and did not take any regular medications. She reported a 4-month history of new headaches and presented to outside emergency departments 4 times. As part of her workup at the outside hospitals, she had computed tomography (CT) of the head that demonstrated opacification of the left maxillary, ethmoid, and frontal sinuses. Two weeks before presentation she was admitted to an outside hospital for worsening acute-on-chronic rhinosinusitis and a seizure and was treated with intravenous antibiotics without improvement. She presented to our emergency department after she developed 5 days of progressively worsening ptosis and 2 days of binocular diplopia. Neuro-ophthalmological examination revealed a visual acuity of 20/25 in each eye, full confrontation visual fields, left complete ptosis with complete limitation of elevation, and minimal depression and adduction (Fig. 1A). Her pupils were equal diameters and reactive to light (Fig. 1B/C). Dilated fundus examination revealed moderate bilateral optic disc edema with optic disc hemorrhages. She underwent CT of the sinuses, which showed bilateral mucosal thickening of the paranasal sinuses. However, the most concerning feature was bony disruption at the cribriform plate bilaterally with suspected intracranial extension (Fig. 2). MRI of the brain with contrast showed extensive bifrontal cerebritis and meningitis with a significant mass effect, transalar herniation, and rightward midline shift, which was all considered to be secondary to the aggressive sinonasal process (Fig. 3). CT of the chest, abdomen, and pelvis demonstrated a lobular heterogeneous mass in the posteromedial right upper lobe, and abnormal enhancing tissue on the upper poles of both kidneys.FIG. 1.: A. External photographs demonstrating a left exoptric and hypotropic eye in primary position with a limitation of elevation, depression, and adduction. Pupils were equal sizes (B), and both pupils were normally reactive to light (C).FIG. 2.: Coronal computed tomography (CT) of the head demonstrating confluent involvement of the upper ethmoid region with associated bony disruption and widening at the level of the cribiform plate (white arrows).FIG. 3.: MRI of the brain with Fluid-attenuated inversion recovery (A) and T1 postgadolinium (B) images demonstrating extensive bifrontal cerebritis and meningitis, greater on the left.Given the acute visual symptoms and the concerning imaging findings, she underwent urgent endoscopic exploration of the sinonasal cavity under general anesthesia because there was a concern for an invasive fungal infection. Multiple biopsies were taken for culture and sensitivity, fungal stains, and samples for pathology. Histopathology revealed inflammation with loosely formed granulomas with areas of necrosis (necrotizing granulomas) and several arteries infiltrated by a mixture of histiocytes and chronic inflammatory cells, showing damage to the muscular wall and elastic layer (Fig. 4). Overall, the histologic pattern was considered to be consistent with granulomatous vasculitis. Stains for fungal and acid-fast organisms were negative. Serum antiproteinase-3 (PR3) ANCA antibodies returned strongly positive >200 RU/mL (negative < 20 RU/mL); she was diagnosed with GPA and was treated with intravenous methylprednisolone 1 g daily for 3 days, followed by oral prednisone and cyclophosphamide. Because there was also light growth on sinus tissue culture of methicillin-sensitive Staphylococcus aureus (MSSA), she was also treated with 2 weeks of intravenous cloxacillin and metronidazole. Her symptoms rapidly improved, and at the 1- and 3-month neuro-ophthalmology follow-ups, she had normal visual function, no ptosis, full extraocular movements, and resolved optic disc edema. Repeat CT chest 4 months after initiation of treatment demonstrated considerable improvement in the lung and renal masses.FIG. 4.: A. H&E high-power slide from an excisional biopsy from the nose demonstrating a loosely formed granuloma with multinucleated giant cells and a small focus of necrosis. B. Movat's elastic trichrome stain from nasal tissue demonstrating an inflamed artery with extensive damage to the elastic layer and muscle wall. The lumen is obliterated and replaced by histiocytes and fibroblasts.DISCUSSION GPA is often a challenging diagnosis to establish because it can manifest in a variety of ways and resemble infectious or neoplastic etiologies (4). Our patient presented with an extensive history of chronic rhinosinusitis—a feature suggestive of an infectious etiology—, but further investigations were not congruent with a possible acute fungal infection. Isolated oculomotor nerve involvement is not typically observed with invasive fungal rhinosinusitis because they commonly involve the orbital apex and cavernous sinus where multiple cranial nerves are present. The combination of all her clinical findings, pathology demonstrating granulomatous inflammation and vasculitis, strongly positive anti-PR3 antibodies, and prompt response to corticosteroids confirmed the diagnosis of GPA. There was also a possibility of a superimposed MSSA sinusitis, and she was concomitantly treated with intravenous antibiotics. TABLE 1. - Summary of case series of patients with granulomatosis with polyangiitis (GPA) and third nerve palsies Author ref (Year Published) Study Type Included Patients # Of Patients With GPA (Total Enrolled) Cranial Nerve Involvement CN3 Palsy Details Regarding CN3 Palsy CN3 Palsy Isolated or With Other Cranial Nerves? Gheita et al (6) (2019) Retrospective case series Consecutive GPA patients 46 (46) 10 (21.7%) 3 All unilateral Isolated Nishino et al (5) (1993) Retrospective case series Consecutive GPA patients 324 (324) 21 (6.5%) 2 NS NS Rothschild et al (7) (2013) Retrospective case series Patients with systemic necrotizing vasculitides 343 (1,286) NS 5 NS NS Durel et al (8) (2019) Retrospective case series ANCA-associated vasculitides patients with an orbital mass 56 (59) NS 12* NS NS de Groot et al (9) (2001) Prospective case series Consecutive GPA patients 128 (128) 6 (4.7%) 2 NS One isolated one with CN 2, 5, and 7 involvement Anderson et al (13) (1975) Literature review Patients with nonhealing granuloma 249 (374) NA 9 NS NS Provenzale et al (14) (1996) Retrospective case series Consecutive GPA patients 15 (15) 2 (13.3%) 1 NS Isolated Kiessling et al (15) (2020) Retrospective case series GPA patients with skull involvement 29 (29) 24 (83%) 4 NS NS Konaté et al (16) (2004) Retrospective case series Consecutive GPA patients 14 (14) 3 (21.4%) 1 NS CN 7 and 8 *Minimum of 12 GPA patients presented with oculomotor palsy – 15 patients overall in the study.CN, cranial nerve; NS, not stated. The combination of clinical symptoms described here is highly atypical for GPA (Table 1). In a study of 324 patients with GPA from the Mayo Clinic, only 2 (0.6%) patients presented with meningitis, 3 (0.9%) had papilledema, and 5 (1.5%) had cerebritis (5). In our review of the literature, we retrieved 5 large case series, including 1,204 combined patients assessing consecutive GPA patients; CN3 palsy was found in 39 (3%) of patients (5–9). No additional details were provided regarding the CN3 palsy severity and pupillary reflex in these series. The 2 previously isolated CN3 palsies reported in the literature were described as partial without details on the pupillary reaction in one case (3), and no details were provided in the other (2). The pupillary light reflex was intact in one additional report of a patient with GPA, a case with partial CN3 palsy and additional cranial nerve involvement, including the first and second branches of the trigeminal nerve (10). This patient also had an enhancing mass in the cavernous sinus, which was unlike our case. Microvascular ischemia is a likely explanation for the CN3 palsy in our patient and resembles the complete, pupil-sparing CN3 palsy seen in patients with vascular risk factors. This has been reported in other vasculitides, such as giant cell arteritis (11). Pupil-sparing is believed to occur due to the fact that the peripherally located pupillary fibers receive more collateral blood supply than the central nerve substance (12). Another possibility is contiguous spread of granulomatous inflammation into the orbit and cavernous sinus, but the isolated involvement of the third cranial nerve argues against this. The papilledema and raised intracranial pressure were likely secondary to the extensive cerebritis, meningitis, and rightward midline shift, which all resolved with corticosteroid treatment. In conclusion, severe pupil-sparing CN3 palsy can be seen in the context of vasculitides, and ANCA-associated vasculitis should be kept in the differential diagnosis, especially in a patient with chronic sinusitis. The presence of papilledema indicates intracranial involvement from a meningeal or cerebral process. STATEMENT OF AUTHORSHIP Category 1: a. Conception and design: A. R. Vosoughi and J. A. Micieli; b. Acquisition of data: A. Vosoughi, C. J. Streutker, S. P. Yang, J. M. Lee, and J. A. Micieli; c. Analysis and interpretation of data: A. R. Vosoughi, C. J. Streutker, S. P. Yang, J. M. Lee, and J. A. Micieli. Category 2: a. Drafting the manuscript: A. R. Vosoughi and J. A. Micieli; b. Revising it for intellectual content: C. J. Streutker, S. P. Yang, and J. M. Lee. Category 3: a. Final approval of the completed manuscript: A. R. Vosoughi, C. J. Streutker, S. P. Yang, J. M. Lee, and J. A. Micieli.

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