Orbital apex syndrome (OAS) is a syndrome characterized by multiple cranial nerve palsies (CN III, IV, V1, VI) accompanied by optic nerve (CN II) involvement due to a lesion at the posterior apex of the orbit. It is also known as Jacod syndrome.
The orbital apex is the craniofacial junction where the four orbital walls converge, anatomically containing two important passages.
The optic canal transmits the optic nerve (sheathed in meninges) and the ophthalmic artery to the cranial fossa. The superior orbital fissure is approximately 22 mm long, formed between the greater and lesser wings of the sphenoid bone, and is divided into superior, middle, and inferior parts by the common tendinous ring (Annulus of Zinn). The superior part contains the lacrimal nerve (V1), frontal nerve (V1), trochlear nerve (IV), and superior ophthalmic vein; the middle part contains the nasociliary nerve (V1), abducens nerve (VI), and superior and inferior branches of the oculomotor nerve (III); the inferior part contains the inferior ophthalmic vein. Because numerous nerves and blood vessels are concentrated in this narrow space, lesions at the orbital apex can cause extensive cranial nerve deficits. The inferior orbital fissure transmits the second branch of the trigeminal nerve (V2: maxillary nerve) and the inferior ophthalmic vein, communicating with the pterygopalatine fossa.
Total ophthalmoplegia combined with sensory loss in the first division of the trigeminal nerve is defined as “superior orbital fissure syndrome/cavernous sinus syndrome,” and when optic nerve involvement is added, it is distinguished as “orbital apex syndrome.”
Although a rare syndrome, ocular involvement occurs in 58% of patients with granulomatosis with polyangiitis (GPA) 3), and a review of fungal OAS (73 cases) highlighted a mean diagnostic delay of 7.4 weeks as a problem 1).
The key distinguishing feature is the presence or absence of optic nerve involvement. Superior orbital fissure syndrome presents with palsies of CN III, IV, V1, and VI but spares the optic nerve. Orbital apex syndrome adds optic nerve involvement, resulting in a relative afferent pupillary defect (RAPD).
In a representative case, OAS from herpes zoster ophthalmicus (HZO) showed counting fingers vision, APD positive, fixed dilated pupil, and total ophthalmoplegia, while OAS from GPA showed visual acuity 20/250, RAPD 1+, total ophthalmoplegia, color vision 0/11, and corneal infiltration2,3).
The etiology is broadly classified into five categories.
Inflammatory
GPA (Granulomatosis with Polyangiitis): C-ANCA and PR3 antibody positive. Responds well to steroid pulse therapy.
Other inflammatory diseases: Sarcoidosis, Tolosa-Hunt syndrome, orbital inflammatory pseudotumor, IgG4-related orbital myositis, thyroid eye disease, giant cell arteritis, etc.
Idiopathic orbital inflammation: Treatment is initiated with prednisolone 0.25–1.0 mg/kg/day.
Infectious
Fungal: Aspergillus is the most common (78% of fungal OAS). In patients with diabetes or immunodeficiency, be alert for mucormycosis.
Bacterial: Often results from direct spread from sinusitis. Risk increases in patients with diabetes.
Viral: Herpes zoster virus (VZV) is the main cause. It appears approximately 10–14 days after the onset of HZO.
Neoplastic and Other
Neoplastic: Direct invasion of head and neck tumors, metastatic lesions, hematologic malignancies, and sinonasal carcinoma. SMARCB1-deficient sinonasal carcinoma is particularly aggressive.
Vascular: Carotid-cavernous fistula (CCF), cavernous sinus thrombosis, carotid-cavernous aneurysm.
Traumatic/Iatrogenic: Complications after nasal/sinus surgery or orbital surgery. Radiation necrosis (after cumulative high-dose irradiation).
Aspergillosis is the most common pathogen of fungal OAS (78% of 73 cases1)), and in warm climates, Aspergillus flavus accounts for 64%1). Although traditionally considered a disease of immunocompromised individuals, its incidence is increasing in immunocompetent patients1). A mean delay of 7.4 weeks until diagnosis is a problem1).
Mucormycosis has diabetes (especially DKA) as the greatest risk factor. It is highly angioinvasive and causes tissue necrosis, often leading to a fatal course. Mortality reaches 25–60%5).
Diabetes, especially in a state of ketoacidosis (DKA), is the greatest risk factor for mucormycosis and bacterial OAS. The acidic environment and high blood sugar promote the growth of Mucor fungi, causing tissue necrosis through vascular invasion.
Because the underlying diseases range from those with a good prognosis to those affecting life expectancy, diagnosis must be rapid and careful. First, a detailed medical history is taken, and the presence of eye pain and the speed of symptom progression are evaluated. If there is sudden onset with severe eye pain or headache, highly urgent diseases such as aneurysm or pituitary apoplexy should be considered in the differential diagnosis.
To evaluate optic neuropathy, in addition to visual acuity and visual field tests, the central flicker value (CFF) and the presence of a relative afferent pupillary defect (RAPD) are checked. If the pupil is dilated due to oculomotor nerve palsy, RAPD is assessed using the consensual light reflex of the fellow eye. For trigeminal nerve evaluation, differences in corneal sensation and forehead sensation between the two sides are checked.
This is performed when lesions are found in the cavernous sinus or skull base.
The main differentiating points of OAS, superior orbital fissure syndrome (SOFS), and cavernous sinus syndrome (CSS) are shown.
| Feature | OAS | SOFS | CSS |
|---|---|---|---|
| Optic neuropathy | Present | Absent | Absent |
| V1/V2 | V1 only | V1 only | V1+V2 |
| Horner syndrome | None | None | Present |
In differentiating from meningitis, the presence or absence of systemic symptoms (fever, nuchal rigidity) and findings of leptomeningeal enhancement and bilateral involvement on MRI are key distinguishing points 4).
Broad differential diagnoses include brainstem disorders (Wernicke encephalopathy, brainstem vascular disorders, brainstem tumors), demyelinating diseases (multiple sclerosis, neuromyelitis optica, ADEM), systemic diseases (neuro-Behçet disease, sarcoidosis, lymphoma), neuromuscular junction disorders (myasthenia gravis), and metabolic diseases (diabetic neuropathy).
Systemic steroid administration is the mainstay of treatment.
Surgical resection, radiotherapy, and chemotherapy are selected based on the etiology. For SMARCB1-deficient sinonasal carcinoma, long-term survival has been reported with cisplatin plus radiation for 9 weeks followed by endoscopic tumor debulking 9).
The first-line drug differs depending on the pathogen. For aspergillosis, voriconazole 200 mg twice daily is first-line, combined with debridement via FESS. For mucormycosis, amphotericin B and emergency surgical debridement are essential, along with correction of underlying conditions such as diabetic ketoacidosis.
A literature review (20 cases) showed recovery of eye movement in 76.5% (mean 4.4 months), partial visual improvement in 60%, and complete recovery in only 26.7%2). Delayed treatment tends to result in poor prognosis, and antiviral therapy is recommended to start within 72 hours of onset.
The orbital apex is an anatomical “bottleneck” at the posterior orbit, where numerous nerves and blood vessels converge through the optic canal and superior orbital fissure. Since the orbit and intracranial cavity communicate via the optic canal, superior orbital fissure, and inferior orbital fissure, direct extension of infection or tumors from the paranasal sinuses (especially the ethmoid and sphenoid sinuses) is anatomically facilitated.
Inflammatory mechanism: In GPA, neutrophil infiltration of the vessel wall and granuloma formation occur, damaging local nerves and blood vessels.
Infectious mechanism (fungal): Mucormycosis is highly angioinvasive, leading to tissue infarction and necrosis due to vascular endothelial damage5). An acidic environment (pH 7.3–6.8) and iron overload promote the growth of Mucorales5).
Infectious mechanism (viral): VZV spreads to CN III, IV, and VI via the communicating branches of the first division of the trigeminal nerve7). In addition to direct nerve damage, immune-mediated tissue injury, inflammatory edema causing nerve compression, and ischemia are also involved in a complex manner2).
Neoplastic mechanism: Paranasal sinus tumors directly infiltrate the orbital apex with bone destruction, compressing nerves.
Radiation necrosis: In addition to local coagulative necrosis due to vascular endothelial damage, demyelination occurs due to oligodendrocyte damage8). The optic nerve is highly radiosensitive because it is myelinated by oligodendrocytes, making it particularly vulnerable8).
Pathogen Identification by Next-Generation Sequencing (NGS): There is a first report identifying Pseudomonas aeruginosa by 16S rRNA PCR in cell-free serum and paraffin-embedded tissue in culture-negative cases6). NGS may contribute to improved accuracy in difficult-to-diagnose cases, including idiopathic cranial pachymeningitis (HCP).
Prognosis and Treatment Optimization of HZO-OAS: A review of 20 cases reported outcomes of 76.5% ocular motility recovery and 26.7% complete visual recovery2). Delayed treatment initiation is associated with poor prognosis, and quantitative evaluation of vaccine preventive effects is a future challenge.
Invasive Fungal Sinus Infection in Immunocompetent Individuals: Traditionally considered a disease of immunocompromised patients, its incidence in immunocompetent individuals is increasing1). A review by Rupa et al. (147 papers) showed a predilection in warm-climate regions of Africa, India, and Saudi Arabia1), and elucidation of geographic and climatic factors is needed.
Diagnosis and treatment of radiation necrosis: Noninvasive differentiation using MR perfusion and FDG-PET has been attempted, but the efficacy of bevacizumab plus steroids has been reported to be limited8).
SMARCB1-deficient sinonasal carcinoma: This is a rare but aggressive tumor. In an analysis of 39 cases by Agaimy et al., 56% died with a median survival of 15 months9). Long-term survival cases with multimodal therapy (chemoradiotherapy plus surgery) are accumulating.
