Clinical manifestations

Orbital syndromes

Orbital syndromes include orbital apex syndrome, superior orbital fissure syndrome, and cavernous sinus syndrome. These conditions overlap anatomically and clinicopathologically (Table 1) and, thus, are considered with anterior skull base syndromes, even though the cavernous sinus and the orbital apex have pathology that originates outside the skull per se.

Table 1. Signs and Symptoms of Orbital Syndromes

Orbital apex syndrome. Orbital apex syndrome results from pathology of the bony orbital apex; it typically presents with loss of vision and internal and external ophthalmoplegia, which may be painful.

The most common initial manifestations of orbital apex syndrome are visual loss and ophthalmoplegia (CNs III, IV, VI). Visual loss is due to optic nerve involvement; optic disc edema or subsequent optic atrophy may develop within weeks to months. Pupillary abnormalities can include a relative afferent pupillary defect (CN II), mydriasis (CN III), and loss of pupillary reflex on the involved side (CNs II and III). Other manifestations include periorbital or facial pain, proptosis with or without orbital congestion, chemosis or conjunctival injection, ptosis (CN III), absence of corneal sensations and the corneal reflex (CN V1), and hypoesthesia of the forehead (CN V1).

Example case of orbital apex syndrome (03). An 83-year-old woman presented with a history of recent syncope, a sudden-onset right-sided temporal headache, diplopia, and vision loss. Examination revealed right-sided ptosis, miosis, a relative afferent pupillary defect, vision loss, and ophthalmoplegia. CT showed sphenoid sinus opacification, an eroded lateral sinus wall, pterygoid (Vidian) canal, with disease extension to the posterior ethmoid air cells, orbital apex, medial orbital wall, and pterygopalatine fossa. MRI could not be performed.

She was diagnosed with orbital apex syndrome (Jacod syndrome), Horner syndrome, and pterygopalatine fossa infection due to acute invasive fungal sinusitis developed from a sphenoid sinus fungal ball. She was treated with antimicrobial therapy and transnasal endoscopic surgery twice to decompress the orbital apex, drain the abscess, and obtain specimens for analysis. She was treated with intravenous voriconazole based on radiological, clinical, and intraoperative findings from the first surgery. Cefotaxime and metronidazole were added to the voriconazole after her second surgery.

Her right-sided ptosis, visual loss, ophthalmoplegia, and headache fully resolved. No immune or comorbid diseases were identified, and microbiological and histopathological analyses from surgically obtained specimens identified no bacteria or fungi. A serum galactomannan value was within the normal range (galactomannan is a polysaccharide antigen that exists primarily in the cell walls of Aspergillus species).

Superior orbital fissure syndrome. Superior orbital fissure syndrome may involve any of the structures coursing through the superior orbital fissure anterior to the orbital apex, including CN III, IV, V1, and VI and the ophthalmic veins (30). Although superior orbital fissure syndrome may manifest with dysfunction of multiple ocular motor cranial neuropathies, it is dysfunction of the optic nerve that differentiates orbital apex syndrome from superior orbital fissure syndrome.

Cavernous sinus syndrome. Cavernous sinus syndrome was first described by French neurologist Charles Foix in 1922 (11). It is now clear that the so-called cavernous sinus syndrome is a grab-bag that encompasses a variety of disorders with differing pathologies and variably overlapping clinical manifestations, essentially any disease process involving the cavernous sinus. Cavernous sinus syndrome may present with multiple cranial neuropathies (involving CN III, IV, VI, V1, and V2). Although the optic nerve does not pass through the cavernous sinus, vision may be impaired from the secondary effects on venous drainage of the orbit.

Cavernous sinus syndrome is often used as a working diagnosis for signs and symptoms related to the four cranial nerves passing through the cavernous sinus (III, IV, V1, and VI). Among 68 cases with involvement of one or more of these nerves, as the number of involved cranial nerves increased from one to four, 18%, 44%, 56%, and 78%, respectively, had lesions in the cavernous sinus (35).

Example case of cavernous sinus syndrome due to localized granulomatosis with polyangiitis (Wegener granulomatosis) (44). A 32-year-old woman presented with epistaxis, nasal congestion, recurrent bilateral otitis media, and progressive hearing loss requiring hearing aids. She subsequently developed a left peripheral facial palsy. CT scan showed a left nasopharyngeal mass and inflammatory changes in the middle ear and mastoid air cells. Nasolaryngoscopy revealed inflammation and ulceration of the left nasal turbinate, nasal septum, and posterior pharyngeal wall. She had never used cocaine.

Biopsies of the right and left nasopharynx, left middle meatus, and nasal septum revealed florid acute and chronic inflammation with mucosal ulceration and extensive necrosis of stroma and cartilage. The inflammatory infiltrate consisted of neutrophils, lymphocytes, and plasma cells, with zones of histiocytes representing granulomata and large numbers of multinucleated giant cells but few eosinophils. Although histological assessment of vasculitis was difficult due to the extensive necrosis and marked tissue inflammation, necrotizing vasculitis of small vessels was evident. There was no evidence of malignancy, and stains for fungi and mycobacteria were negative.

Serum calcium and angiotensin-converting enzyme levels were normal. Anti-neutrophil cytoplasmic antibody (ANCA) testing was positive by immunofluorescence with a cytoplasmic staining pattern. Anti-proteinase-3 antibodies measured by enzyme-linked immunosorbent assay (ELISA) were mildly elevated (5.8; normal range is less than 2). Anti-myeloperoxidase antibodies were not detected.

Based on the clinicopathological findings, she was diagnosed with localized granulomatosis with polyangiitis (formerly known as Wegener granulomatosis). Additional studies revealed no evidence of other systemic features. She was treated with methotrexate 25 mg weekly and prednisolone 60 mg daily. The prednisolone was gradually weaned to 10 mg daily over a 6-month period, but she deteriorated as the steroid dose was reduced; she developed headaches, nausea, diplopia, dysphonia, and progressive dysphagia to both solids and liquids, resulting in a more than 40-pound weight loss.

Approximately 1 year after her initial presentation, examination revealed left ptosis, a dilated and unreactive left pupil, left external ophthalmoparesis consistent with palsies of cranial nerves III, IV, and VI, a left peripheral facial palsy, wasting of the right sternocleidomastoid, and deviation of the tongue to the right on tongue protrusion. Laryngoscopy revealed a right-sided vocal cord palsy. Blood tests showed mild elevation of the inflammatory markers (ESR 34 mm/hour; CRP 26 mg/L). Renal function was normal. Repeat ANCA testing revealed cytoplasmic pattern ANCA staining, but antibodies to anti-proteinase-3 and myeloperoxidase were negative.

Contrast-enhanced CT of her head and neck demonstrated predominantly dural-based enhancing soft tissue abnormality affecting the central skull base. Chronic inflammatory tissue eroded the floor of the sella turcica and involved both cavernous sinuses, the pituitary parenchyma, the pituitary stalk, the hypothalamus, the orbital apices, the petrous temporal bones encasing the carotid canals, and the extra-cranial infratemporal fossae, including the pterygopalatine fossae. Radiological features of right Collet-Sicard syndrome (palsy of cranial nerves IX-XII) were present. Both internal carotid arteries were occluded in their skull base carotid canal segments, with the anterior circulation sustained through collateral vessels. Additional abnormalities involved the sinonasal region, middle ear, and mastoid bilaterally. Her pituitary hormone profile showed elevated prolactin and reduced thyroid-stimulating hormone with normal free thyroxine. On further inquiry, she reported a 1-year history of amenorrhea.

She was treated with rituximab, azathioprine, and intravenous followed by oral corticosteroids and was subsequently discharged after her CRP dropped to 6 mg/L. She was evaluated emergently 10 days later with a considerably worsened clinical picture with marked dysphagia, dilated and sluggishly reactive pupils, a new right-sided ptosis, and a new right-sided sixth nerve palsy. Swallowing evaluation revealed aspiration and an ineffective cough reflex. She was fed through a nasogastric tube. The safety of her airway was assessed because of concern that she was at high risk of life-threatening airway obstruction if her vocal cord palsy became bilateral. Her CRP had risen to 33 mg/L. Cranial MRI confirmed and expanded the prior CT findings.

She was treated with three pulses of intravenous methylprednisolone (500 mg) with rapid improvement in her diplopia and normalization of the CRP. The right pupillary abnormality improved, but the left pupil remained dilated. Subsequently, azathioprine was stopped, her oral prednisolone dose was increased, and she was treated with a series of intravenous cyclophosphamide infusions. Because her swallowing remained compromised, a percutaneous gastrostomy tube was inserted.

Her admission was complicated by hypernatremia (serum sodium 157 mmol/L), and she required 4 to 5 L of fluid per day to maintain her sodium level in the normal range. She had two episodes of syncope due to postural hypotension. Her fluid balance chart revealed polyuria. Blood glucose and calcium were normal. Repeat dedicated pituitary MRI showed pathological enhancement and diffuse thickening of the pituitary. She was diagnosed with cranial diabetes insipidus and treated with desmopressin, with normalization of her serum sodium.

She showed marked clinical improvement after six pulses of cyclophosphamide. Her diplopia had resolved, and her eye movements returned to normal. She was able to eat and drink normally. Her right-sided third nerve palsy entirely resolved, but her left pupil remained dilated and sluggishly reactive to light, and a mild left peripheral facial weakness persisted. Cranial MRI showed marked regression of the skull base inflammatory changes. She was switched to maintenance therapy with azathioprine, and the prednisolone dose was slowly weaned to 5 mg daily. She remained clinically well on this treatment for 20 months following completion of cyclophosphamide with no progression of cranial disease on MRI, but she then had a relapse with nasal blockage and epistaxis, requiring a tapering course of prednisolone.

Cavernous internal carotid artery aneurysms. Cavernous internal carotid artery aneurysms (ie, aneurysms of the internal carotid artery within the cavernous sinus) are most common in the elderly and are thought to be primarily degenerative, but they may occur with trauma or infections (ie, mycotic aneurysms).

Carotid-cavernous fistulas. The most commonly used classification of carotid-cavernous fistulas, the Barrow classification, is primarily anatomic (02) (Table 2). Type A, direct carotid-cavernous fistula, is the most common type. An alternative classification is based on venous drainage (54) (Table 3).

Table 2. Barrow Classification of Carotid-Cavernous Fistulas

Table 3. Thomas Classification of Carotid-Cavernous Fistulas Based on Venous Drainage

Direct carotid-cavernous fistulas typically have an abrupt and dramatic onset, whereas indirect carotid-cavernous fistulas (ie, connections between meningeal branches of either the internal carotid artery, the external carotid artery, or both with the cavernous sinus) are associated with a gradual onset and chronic course. The earliest clinical features involve the orbit due to venous congestion resulting from impeded venous drainage through the superior and inferior ophthalmic veins into the cavernous sinus.

The classic diagnostic triad of direct carotid-cavernous fistulas is pulsatile exophthalmos, orbital bruit, and chemosis (swelling of the eye surface membranes, including the conjunctiva and eyelids), but symptoms of carotid-cavernous fistulas may include ocular redness, diplopia, orbital or retro-orbital pain, headache, pulsatile tinnitus, and vision loss. Symptoms are usually ipsilateral to the fistula but can be bilateral. Signs of direct or indirect carotid-cavernous fistulas may include proptosis, pulsatile exophthalmos, an ocular bruit (objective tinnitus), eyelid edema, ptosis, conjunctival hyperemia (resulting from arterialization of conjunctival and episcleral veins, producing tortuous "corkscrew" blood vessels that converge at the limbus), elevated intraocular pressure, pupillary abnormalities, ophthalmoparesis or ophthalmoplegia (involving combinations of CN III, IV, and VI innervated muscles), Horner syndrome, papilledema, dilated retinal veins, central retinal vein occlusion, ischemic optic neuropathy, and ipsilateral facial hypesthesia (in the distribution of V1 and V2) (05; 02; 04; 33; 38; 39; 07; 60; 08).

Unlike direct high-flow carotid-cavernous fistulas, indirect low-flow carotid-cavernous fistulas may be asymptomatic or may present insidiously. The most common presentation is conjunctival injection, which is often misinterpreted initially as conjunctivitis. Some indirect carotid-cavernous fistulas may have sufficiently increased arterial flow into the cavernous sinus, resulting in venous congestion and retrograde drainage into the orbital veins. Findings then start to resemble those of direct carotid-cavernous fistulas with arterialization of the conjunctival veins, chemosis, orbital or retro-orbital headache, proptosis, orbital bruit, elevated intraocular pressure, diplopia, and decreased vision; however, the classic triad seen in direct carotid-cavernous fistulas is uncommon with indirect carotid-cavernous fistulas.

Example case with a carotid-cavernous fistula (53). A 70-year-old woman with a history of primary angle closure glaucoma presented with right eye pain and redness, accompanied by 4 mm of proptosis, resistance to retropulsion, tortuous corkscrew blood vessels of her conjunctiva, and an orbital bruit on that side. Cerebral angiography showed a small indirect Barrow Type D carotid-cavernous fistula on the right. Transarterial embolization was planned, but repeat cerebral angiography before the procedure demonstrated spontaneous partial closure of the fistula, so the procedure was aborted. A month later, her vision was getting worse, and she had developed choroidal detachments of that eye. She declined further testing or endovascular treatment at that time. After another month, her choroidal detachments and angle closure had worsened further. She eventually agreed to surgical intervention, but repeat cerebral angiography then showed thrombosis of the carotid-cavernous fistula, so no intervention was warranted. An examination 2 months later showed complete resolution of the choroidal detachments and open angles of both eyes.

Cavernous sinus thrombosis. Cavernous sinus thrombosis is a rare, life-threatening disorder that can complicate craniofacial infections, especially in conjunction with a thrombophilic disorder, although noninfectious cases also uncommonly occur. Craniofacial infections that may cause cavernous sinus thrombosis include sinusitis (especially sphenoid and ethmoid sinusitis), orbital cellulitis, pharyngitis, otitis media, mastoiditis, and dental infections. Thrombophilic disorders that may contribute to the development of cavernous sinus thrombosis include factor V Leiden mutation, prothrombin G20210A mutation, antithrombin III deficiency, protein C or S deficiency, sickle cell disease, and antiphospholipid antibody syndrome. Other risk factors may include facial trauma (particularly with open facial wounds or penetrating injuries), dental extractions or procedures, maxillofacial surgery, oral contraceptives, pregnancy, puerperium, hormone replacement therapy, steroids, uncontrolled diabetes, cancer and chemotherapy, hyperhomocysteinemia, heparin-induced thrombocytopenia, severe dehydration, nephrotic syndrome, and obesity.

Cavernous sinus thrombosis typically presents with fever, headache, periorbital swelling, and ophthalmoplegia.

Cavernous sinus thrombosis is initiated by the embolization of infectious organisms to the cavernous sinus; in turn, the development of the thrombosis hinders clearance of the infection from the cavernous sinus. The lack of valves in the dural sinus system allows infection and thrombosis to propagate in the dural system. In addition, infection and thrombus can spread from one side to the other via the intercavernous sinuses, channels anterior and posterior to the sella that directly connect the right and left cavernous sinuses.

Cavernous sinus thrombosis impedes drainage from the facial vein and superior and inferior ophthalmic veins, causing facial and periorbital edema, ptosis, proptosis, chemosis, pain with eye muscle movement, papilledema, retinal venous distention, loss of vision, and cranial polyneuropathy.

Presenting symptoms often develop subacutely over days and include fever, headache, periorbital swelling and pain, photophobia, diplopia, and loss of vision. Symptoms start in one eye and typically progress to the opposite side. The clinical presentation is often marked by spiking fevers (the so-called "picket fence" fever pattern, due to the periodic release of septic emboli), tachycardia, and hypotension, often accompanied by ocular manifestations, cranial polyneuropathy, and altered mentation. Ocular findings include periorbital edema (initially unilateral but typically bilateral), lid erythema, chemosis, ptosis, proptosis (due to impaired venous drainage of the orbit), restricted or painful eye movement, and, less commonly, photophobia, pulsating conjunctiva, a sluggish or nonreactive pupillary reflex, papilledema, retinal hemorrhages, and decreased visual acuity or blindness. Local compression and inflammation of cranial nerves passing through the cavernous sinus may lead to combinations of partial or complete cranial neuropathies including (1) external ophthalmoplegia from compression of CNs III, IV, and V; (2) internal ophthalmoplegia (nonreactive pupil) or Horner syndrome from involvement of autonomic fibers; and (3) facial numbness, paresthesia, or pain with loss of the corneal reflex from compression of V1 and V2. Abducens palsy is the most common early cranial nerve finding because CN VI is the most vulnerable as it passes through the central portion of the cavernous sinus, whereas CNs III, IV, V1, and V2 pass along the wall of the cavernous sinus; however, most cases progress rapidly to complete external ophthalmoplegia. Seizures or strokes (eg, hemiparesis) are rare.

Tolosa-Hunt syndrome. Tolosa-Hunt syndrome, also known as painful ophthalmoplegia and recurrent ophthalmoplegia, or ophthalmoplegia syndrome, is a syndrome of severe, unilateral periorbital headaches associated with painful and restricted eye movements and nonspecific granulomatous inflammation involving the cavernous sinus, superior orbital fissure, or orbit. It is really a diagnosis of exclusion.

Tolosa-Hunt syndrome was defined as a syndrome based on 12 case reports in the 1950s and 1960s. In 1954, Spanish neurologist and neurosurgeon Eduardo Tolosa i Colomer (1900-1981) reported a patient with left orbital pain, ipsilateral progressive visual loss, total left ophthalmoplegia, and reduced sensation over the first division of the trigeminal nerve (55). Cerebral angiography disclosed narrowing of the intracavernous left internal carotid artery. Surgical exploration of the left parasellar region was unremarkable, but the patient died 3 days later. Autopsy findings were significant for granulomatous inflammation of the affected carotid artery and cavernous sinus.

In 1961, American neurologist and neurosurgeon William E Hunt (1921-1999) and colleagues (John Meager, Harry LeFever, and Wolfgang Zeman) reported six cases of unilateral painful ophthalmoplegia “of somewhat obscure aetiology” that tested negative with angiography and lumbar puncture and rapidly resolved with steroids (23). In one patient, surgical exploration of the parasellar region identified no abnormality. In addition, Hunt and coworkers reported that systemic corticosteroids produced prompt, dramatic improvement of signs and symptoms in two patients. Following Tolosa, the authors tentatively attributed the painful ophthalmoplegia to an inflammatory lesion in the cavernous sinus. Hunt himself continued discussions of this syndrome into the late 1980s (20; 21; 22).

In 1966, American neuro-ophthalmologist J. Lawton Smith (1929-2011) and neurosurgeon David Samuel Rasmussen Taxdal (1926-2010) reported five additional cases, coined the eponym “Tolosa-Hunt syndrome,” and emphasized the response to high-dose corticosteroids as a differentiating feature of these cases (50).

Example case of Tolosa-Hunt syndrome (37). A 19-year-old woman was admitted with a 4-day history of left orbital pain and a 2-day history of painful ophthalmoplegia of the left eye. Examination disclosed normal visual acuity, normal ocular fundus bilaterally, left ptosis, left exotropia, external ophthalmoparesis involving all of the extraocular muscles (CNs III, IV, and VI), and hypoesthesia in the distribution of V1 and V2.

Laboratory tests showed normal complete blood cell count, glucose, renal function studies, thyroid function studies, D-dimer, and negative ELISA for HIV. ANA was positive in a homogenous pattern 1:40; anti-dsDNA, 15.1 U/ml (0-9.6); c-ANCA, positive 1:40 and x-ANCA, 1:20. CSF analysis showed only two mononuclear cells/uL and normal glucose (51 mg/dl) and protein (15 mg/dl) concentrations; PCR in CSF for tuberculosis and CSF cultures were negative. CT scan of the brain and paranasal sinuses and MRI and MRA of the brain were normal.

She was diagnosed with Tolosa-Hunt syndrome and was started on methylprednisolone 1 gm intravenously daily for 3 days, at which time there was a significant improvement in left periorbital pain, ptosis, and ipsilateral ophthalmoplegia.

Example of a false-positive case meeting the criteria for Tolosa-Hunt syndrome (40). A 38-year-old man presented with horizontal diplopia, divergent strabismus, left ptosis, left frontal and upper face numbness (territory of V1 and V2), and an intense, persistent headache predominantly in the left temporal and periorbital regions with a stabbing or throbbing character. The headache did not improve with common analgesics and nonsteroidal anti-inflammatory agents. There was no nausea, vomiting, phonophobia, or photophobia. Examination disclosed a complete third nerve palsy, sixth nerve palsy, and analgesia and thermanalgesia in the territories of V1 and V2 on the left side. There was no papilledema. A diagnosis of cavernous sinus syndrome was made, and he was started on prednisone 60 mg/day, with significant improvement in his headache intensity, resolution of ptosis, improvement in adduction and elevation, and partial improvement in abduction of the left eye.

Brain MRI revealed an asymmetry of the cavernous sinuses, with the left larger than the right. There were also four noncalcified enhancing meningeal lesions in the upper convexity adjacent to the left and right frontal lobes, the left cerebellopontine angle, and the left posterior temporal region. A biopsy of the meningeal lesion in the frontal convexity showed histiocytic proliferation. Immunohistochemistry was negative for CD1a and ALK-1 and was positive for S100, CD68 (KP1 clone), and EMA (E29 clone), consistent with Rosai-Dorfman disease. Whole-body CT revealed no other masses or lymphadenopathy, indicating isolated CNS Rosai-Dorfman disease.

The patient was treated with intravenous methylprednisolone (1 g/kg daily for 5 days) with significant improvement of his cavernous sinus syndrome. Maintenance treatment after tapering consisted of prednisone 10 mg/day. Follow-up brain MRI showed a decrease in the size of meningeal lesions and a decrease in cavernous sinus asymmetry. He is now asymptomatic.

This patient fulfilled ICHD-3 criteria for Tolosa-Hunt syndrome but was found instead to have Rosai-Dorfman disease (or “sinus histiocytosis with massive lymphadenopathy”), a rare disorder characterized by an abundance of histiocytes in involved tissue (48). Although Rosai-Dorfman disease typically manifests as painless lymphadenopathy, orbital disease also occurs, sometimes without lymph node involvement.

Prognosis and complications

Cavernous internal carotid artery aneurysms. Most cavernous internal carotid artery aneurysms are asymptomatic and do not require treatment, but when symptomatic, they typically present with indolent ophthalmoplegia and pain (52). Because cavernous internal carotid artery aneurysms are contained within the dura of the cavernous sinus, subarachnoid hemorrhage is rare with these aneurysms; instead, rupture of cavernous internal carotid artery aneurysms (either spontaneously or from trauma) typically results in a direct (high-flow) carotid-cavernous fistula, although massive and life-threatening epistaxis (eg, with erosion into the sphenoid sinus) and subarachnoid hemorrhage (eg, rupture through the dural wall of the cavernous sinus) are unlikely though possible outcomes.

Carotid-cavernous fistulas. Successful angiographic fistula closure can be achieved in more than 90% of cases.

Cavernous sinus thrombosis. Despite treatment with antibiotics and anticoagulation, there is a high risk of long-term sequelae (eg, impaired vision, ophthalmoparesis, and stroke).

Tolosa-Hunt syndrome. The prognosis of Tolosa-Hunt syndrome is good if that is indeed the correct diagnosis. Great care and ongoing monitoring are needed for at least 2 years after a presumptive diagnosis of Tolosa-Hunt syndrome.

Biological basis

In addition to the bony structures, the complex anatomy of this area includes cranial nerves I-VI; dural sinuses, including the cavernous sinus; and a portion of the internal carotid artery and the circle of Willis (42). The complex interrelationships of these structures are best visualized with 3D digital virtual models of the skull, brain, cranial nerves, and vasculature derived using specialized neuroimaging and modeling techniques (42).

Orbits and orbital apices

The orbit. Contents of the orbit include the eye and optic nerve; annular fibrous tissue that is continuous with the skull base dura and serves as the supporting framework for the origin of extraocular muscles; the extraocular muscles and their corresponding nerves; the short ciliary nerves that provide autonomic control to the ciliary muscle, iris, and cornea; the levator of the eyelid and its innervation; sensory branches of the two divisions of the trigeminal nerve; and supporting blood vessels (29).

There are typically six extraocular muscles: the superior, inferior, medial, and lateral recti muscles and the superior and inferior oblique muscles. However, some individuals have accessory rectus muscles (14). Accessory rectus muscles are muscular “bands” or “slips” originating from the common tendinous ring (annulus of Zinn); they are innervated by the inferior branch of the oculomotor nerve and insert in rectus muscles (14).

Orbital apex. The orbital apex is the posterior part of the orbit where the orbital walls converge in the region of the optic canal and the superior orbital fissure. The optic canal transmits the optic nerve (surrounded by a meningeal sheath) and the ophthalmic artery (46).

Superior orbital fissure. The superior orbital fissure, located lateral to the optic canal, can be divided into superior, middle, and inferior portions by the annulus of Zinn or annular tendon, the common tendinous ring that serves as the origin of the four recti muscles. The annulus of Zinn is named for German physician, anatomist, and botanist Johann Gottfried Zinn (1727-1759), who described this structure in 1755 (61; 62). The contents of the optic canal and the middle portion of the superior orbital fissure pass through the annulus of Zinn (29).

The superior portion of the superior orbital fissure transmits the trochlear nerve, the lacrimal and frontal nerves (branches of V1), the superior branch of the ophthalmic vein, and the recurrent meningeal artery; these pass outside of the annulus of Zinn. The middle portion of the superior orbital fissure transmits the superior and inferior branches of the oculomotor nerve, the abducens nerve, and the nasociliary nerve (branch of V1). The inferior portion of the superior orbital fissure transmits the inferior branch of the ophthalmic vein, which passes outside of the annulus of Zinn.

Inferior orbital fissure. Below the superior orbital fissure is the inferior orbital fissure, which transmits branches of the inferior ophthalmic vein, the infraorbital nerve and artery, and the zygomatic nerve. These structures pass outside of the annulus of Zinn.

Branches of the trigeminal nerve in the orbit. The ophthalmic (V1), maxillary (V2), and mandibular (V3) branches of the trigeminal nerve leave the skull through different foramina: the superior orbital fissure for V1, the foramen rotundum for V2, and the foramen ovale for V3. Of the trigeminal nerve branches, only branches of V1 are part of the orbital apex, entering through the superior orbital fissure. Branches of V2 (the infraorbital and zygomatic nerves) enter the orbit through the inferior orbital fissure, between the lateral wall and floor of the orbit.

Cavernous sinuses

The cavernous sinuses are a pair of complex, blood-filled spaces about 1 cm wide and 2 cm long, located on either side of the sphenoid bone and pituitary fossa, extending from the superior orbital fissure to the petrous part of the temporal bone (15). They are divided into smaller cavities by fibrous septa. The inferior and lateral walls, as well as the roof, are extensions of the dura mater. They receive blood from the superior and anterior ophthalmic veins, superficial middle cerebral vein, and sphenoparietal sinus; they drain through the facial vein, transverse sinus, and internal jugular vein. They contain the internal carotid artery, several cranial nerves or branches of cranial nerves (III, IV, V1, V2, and VI), and sympathetic fibers that form a plexus accompanying the internal carotid artery; these cranial nerves pass along the lateral wall of the cavernous sinus except for the abducens nerve, which passes through the central portion of the cavernous sinus (57; 31).

Autonomic pathways and the intrinsic muscles of the eye

The intrinsic muscles of the eye that control the shape of the lens and the size of the pupil are controlled by sympathetic innervation passing through the superior cervical ganglion and the carotid plexus, and parasympathetic innervation derived from the Edinger-Westphal nucleus in the midbrain passing through the third cranial nerve.

Ciliary muscle. The ciliary muscle is an intrinsic smooth muscle of the eye formed as a ring of smooth muscle that (1) changes the shape of the lens to control accommodation (ie, for viewing objects at varying distances) and (2) regulates the flow of aqueous humor into Schlemm's canal.

Iris sphincter and dilator muscles. The pupil size is controlled by the iris sphincter (sphincter pupillae) and iris dilator (dilator pupillae) muscles. The iris sphincter muscle is a smooth muscle that encircles the pupil; stimulation by the parasympathetic nervous system causes the pupil to constrict. In contrast, the iris dilator muscle is a smooth muscle oriented radially in the iris; stimulation by the sympathetic nervous system causes the pupil to enlarge.

The sphincter muscle is controlled by parasympathetic postganglionic fibers. The parasympathetic preganglionic fibers originate in the Edinger-Westphal nucleus in the midbrain and travel along the oculomotor nerve (CN III) before terminating in nicotinic cholinergic synapses on neurons in the ciliary ganglion. Postganglionic parasympathetic fibers from the ciliary ganglion then enter the eye through the short ciliary nerves to supply the sphincter muscle.

The dilator muscle is innervated by postganglionic sympathetic nerves arising from the superior cervical ganglion. These postganglionic fibers travel in a plexus with the internal carotid artery through the carotid canal and then the cavernous sinus. From there, they can travel with the ophthalmic artery in the optic canal or on the nasociliary branch of the ophthalmic nerve through the superior orbital fissure to ultimately reach the dilator muscle via the long ciliary nerves (47; Parkinson and Johnston 1978). Alternatively, they may also pass through the ciliary ganglion and travel in short ciliary nerves to reach the dilator muscle.

Orbital apex syndrome

The causes of orbital apex syndrome include endocrine, infectious, inflammatory or immunologic, neoplastic, and traumatic pathologies. The primary endocrine disorder associated with orbital apex syndrome is thyroid orbitopathy in Grave disease. Inflammatory and immunologic causes include sarcoidosis, systemic lupus erythematosus, Churg-Strauss syndrome, granulomatosis with polyangiitis (formerly called Wegener granulomatosis), giant cell arteritis, orbital inflammatory pseudotumor, and IgG4 related orbital myositis. Infectious etiologies are most often due to invasive fungal sinusitis (aspergillosis or mucormycosis) or bacterial orbital cellulitis (34) but may result from aggressive bacterial sinusitis without cellulitis (27; 32; 10). Neoplastic etiologies include head and neck tumors with extension into the orbital apex (eg, nasopharyngeal carcinoma, primary orbital adenoid cystic carcinoma), neural tumors (eg, neurofibroma, meningioma, glioma, ciliary neurinoma, schwannoma), hematologic malignancies (eg, leukemia and non-Hodgkin lymphoma), and various metastases (eg, lung, breast, and renal cell carcinomas, as well as melanoma). Orbital apex syndrome from traumatic injury typically results from displaced bony fragments but may also result from shearing forces to the anatomic structures of the superior orbital fissure or optic nerve (19). Iatrogenic causes include sinonasal surgery and orbital or facial surgery.

Superior orbital fissure syndrome

Many inflammatory etiologies require treatment of the primary process and systemic immunomodulatory agents. With thyroid orbitopathy, decompressive surgery and radiation therapy (to alleviate inflammation causing compression of the optic nerve) may be necessary to preserve vision. Infectious causes are treated with appropriate broad-spectrum anti-microbial therapy. Surgical intervention via a direct or endoscopic approach may be necessary in cases of orbital or subperiosteal abscess. Management of neoplastic etiologies may include surgical resection, radiation therapy, or chemotherapy, depending on the specific type of cancer. Traumatic orbital compartment syndrome may require corticosteroids and decompressive surgery to alleviate cranial nerve dysfunction, including visual loss (06).

Cavernous sinus syndrome

Pathologies of the cavernous sinus include tumors, vascular disorders, infections (bacterial or fungal most commonly), and inflammatory disorders (eg, Tolosa-Hunt syndrome) (24; 56; 58; 16; 45). Tumors of the cavernous sinus may be primary or metastatic, and they include the following: meningiomas; schwannomas of CN III, IV, V1/V2 (the most common), or VI; hemangiomas; and metastatic disease from lung, breast, or prostate. Vascular pathologies in the cavernous sinus include cavernous internal carotid artery aneurysms, carotid-cavernous fistulas, and cavernous sinus thrombosis. Fungal infections include primarily aspergillosis and mucormycosis.

Venous air emboli may sometimes appear in the cavernous sinus; in the absence of a history of trauma, this is usually iatrogenic following infusions.

Cavernous internal carotid artery aneurysms

Cavernous internal carotid artery aneurysms (ie, aneurysms of the internal carotid artery within the cavernous sinus) are most common in the elderly and are thought to be primarily degenerative, but they may occur with trauma or infections (ie, mycotic aneurysms).

Carotid-cavernous fistulas

Direct carotid-cavernous fistulas often result from existing internal carotid artery aneurysms or trauma. Traumatic causes include head injuries (from minor falls to severe penetrating wounds) and iatrogenic causes, such as complications of endovascular therapy or transphenoidal procedures.

Indirect carotid-cavernous fistulas result from rupture of the dural branches of the carotid artery weakened by genetic conditions or comorbidities (eg, hypertension) or from alterations in pressure (eg, associated with thrombosis).

Cavernous sinus thrombosis

Various infectious organisms can cause cavernous sinus thrombosis, although most are bacterial. Staphylococcus aureus accounts for most cases, with various Streptococcus species accounting for most of the remainder. A wide variety of organisms accounts for the residual cases, and these include aerobic and anaerobic bacteria, fungi (eg, Aspergillosis, Mucormycosis, and Coccidioidomycosis in immunocompromised individuals), parasites (eg, toxoplasmosis, malaria, and trichinosis), and viruses.

Differential diagnosis

Confusing conditions

Cranial neuropathies of the anterior skull base involve CNs I-VI. Cranial polyneuropathies of the anterior skull base are most often paired olfactory or optic neuropathies and various "orbital syndromes" (applying a broad sense of "orbital"). Paired olfactory or optic neuropathies are not considered in this chapter.

Orbital syndromes include the orbital apex syndrome, the superior orbital fissure syndrome, and the cavernous sinus syndrome. These conditions have anatomic and clinicopathologic overlap but can be distinguished somewhat clinically based on anatomical and pathological differences for these areas.

The cavernous sinus and the superior orbital fissure do not include the optic nerve, which is included among the structures of the orbital apex. However, this distinction, although anatomically correct, is not absolute in a pathologic sense because with cavernous sinus thrombosis, for example, the thrombus impedes drainage from the superior and inferior ophthalmic veins, causing papilledema, retinal venous distention, and loss of vision.

Similarly, the cavernous sinus includes sensory branches of the trigeminal nerve in its lateral wall (V1 and V2), but only branches of V1 pass through the superior orbital fissure into the orbital apex. Branches of V2 enter the orbit through the inferior orbital fissure.

Indirect carotid cavernous-carotid fistulas are often initially misdiagnosed as conjunctivitis because the most common presentation of such fistulas is conjunctival injection.

Anatomical characterization of orbital syndromes should employ clinical and neuroradiological methods.

Diagnostic workup

For most cranial polyneuropathies of the anterior skull base, neuroimaging is critical: CT provides the best information on the bony structures; MRI is often best at visualizing the soft structures of the orbit, nasal cavities, sinuses, cranial nerves, and brain parenchyma; and CTA, MRA, MRV, and digital subtraction angiography are needed to assess vascular structures, particularly dural venous sinuses, including the cavernous sinus, and the cavernous internal carotid artery.

Carotid-cavernous fistulas. Diagnosis of direct carotid-cavernous fistulas is usually straightforward, whereas diagnosing indirect carotid-cavernous fistulas is often delayed. Although ocular pneumotonometry (to assess for increased ocular pulse amplitude) or orbital ultrasonography may provide supportive information, the usual first-line diagnostic modalities are CTA and MRA; they will identify most arterial dissections and cavernous internal carotid artery aneurysms causing a carotid-cavernous fistula as well as some of the pathological consequences of such fistulas, including enlargement of the affected cavernous sinus, proptosis, enlargement of the superior and inferior orbital veins, and enlargement of extraocular muscles. Digital subtraction angiography can confirm the diagnosis and identify the precise location of the fistula, the arterial supply, the flow rate, and the venous drainage, all of which are usually necessary for treatment planning (eg, endovascular treatment).

Tolosa-Hunt syndrome. Tolosa-Hunt syndrome is really a diagnosis of exclusion.

Hunt and colleagues proposed the first diagnostic criteria for Tolosa-Hunt syndrome in 1961 (23) (Table 4).

Table 4. The Hunt Criteria for Tolosa-Hunt Syndrome

In 1966, American neuro-ophthalmologist J Lawton Smith (1929-2011) and neurosurgeon David Samuel Rasmussen Taxdal (1926-2010) proposed that the response to steroids could serve as a diagnostic test for the disorder (50): “The administration of large doses of systemic steroids for 48 hours produces a dramatic response in painful ophthalmoplegia, which allows prompt differentiation of these cases.” In other words, Smith and Taxdal suggested that a dramatic reduction in painful ophthalmoplegia with administration of high-dose systemic steroids could serve to confirm the diagnosis (50).

Later criteria were developed by the International Headache Society (Table 5).

Table 5. ICHD-3 Diagnostic Criteria for Tolosa-Hunt Syndrome

Unfortunately, the various International Classification of Headache Disorders (ICHD) criteria for Tolosa-Hunt syndrome over time, including those of ICHD-3 (Table 5), are suboptimal for the accurate diagnosis (12; 17; 41; 40). In a single-institution, retrospective chart review of cases with external ophthalmoplegia, 10 had presenting symptoms concerning for Tolosa-Hunt syndrome (41); five (50%) met ICHD-3 criteria for Tolosa-Hunt syndrome, but two of these (40%) were found to have other diagnoses, whereas two of the five (40%) not meeting ICHD-3 criteria for Tolosa-Hunt syndrome nevertheless had a final diagnosis of Tolosa-Hunt syndrome. Problems with the diagnosis of Tolosa-Hunt syndrome, including failure to diagnose other conditions that need urgent disease-specific management, have led some to question whether Tolosa-Hunt syndrome should be abandoned as a clinical entity (36).

Close follow-up for all patients with symptoms of Tolosa-Hunt syndrome is recommended until a definitive etiology is established (12; 41). Other causative lesions must be excluded by neuroimaging, especially of the region of the cavernous sinus, superior orbital fissure, and orbital apex, and by blood and CSF examinations (12). Note, though, that MRI or CT findings compatible with inflammatory tissue neither exclude nor confirm Tolosa-Hunt syndrome (12). Clinical and radiological follow-up examinations are necessary for at least 2 years, even in patients with negative findings on MRI at onset (12).

Management

Cavernous internal carotid artery aneurysms. Endovascular treatment of cavernous internal carotid artery aneurysms results in a significantly higher rate of pain resolution compared with untreated patients, even after adjusting for initial pain severity, but does not necessarily resolve any resulting diplopia (52). Indications for treatment of cavernous internal carotid artery aneurysms include (1) disabling pain, (2) diplopia or a decline in vision, (3) a carotid-cavernous fistula, (4) erosion of an aneurysm into the sphenoid sinus (which risks life-threatening epistaxis), and (5) extension into the subarachnoid space (49).

Carotid-cavernous fistulas. Direct carotid-cavernous fistulas are usually treated with endovascular repairs to stop the abnormal blood flow, repair the cavernous internal carotid artery, and preserve vision and oculomotor function. Indications for urgent treatment of direct carotid-cavernous fistulas include progressive exophthalmos, visual impairment, progressive ophthalmoparesis, and intractable orbital pain. Successful angiographic closure of the fistula can be achieved in more than 90% of cases.

Cavernous sinus thrombosis. Cavernous sinus thrombosis requires anticoagulation, aggressive broad-spectrum antibiotics, and possibly adjunctive corticosteroid therapy.

Tolosa-Hunt syndrome. Systemic corticosteroids produced prompt, dramatic improvement of signs and symptoms in Tolosa-Hunt syndrome (23). The problem, though, is that Tolosa-Hunt syndrome is a diagnosis of exclusion, and response to steroids does not in itself establish the diagnosis. In fact, steroid responsiveness in cases of presumed Tolosa-Hunt syndrome may delay the diagnosis of other conditions that require urgent disease-specific management.