Cavernous Sinus Syndrome

Key Points at a Glance

Key Points of This Disease

• Cavernous sinus syndrome (CSS) is a syndrome combining ophthalmoplegia (CN III, IV, VI), facial sensory loss (CN V1/V2), and Horner syndrome.
• The most common symptom is diplopia (90.4%), followed by unilateral headache (70.4%) and ptosis (68.4%).
• 63% of cases are caused by tumors (pituitary adenoma and meningioma are typical), followed by vascular causes (20%) and granulomatous inflammation (13%).
• If accompanied by fever, tachycardia, or altered mental status, emergently suspect septic cavernous sinus thrombosis (CST).
• The key to diagnosis is contrast-enhanced MRI, which evaluates the nature, location, and extent of the lesion.
• Since treatment varies greatly by cause, early identification of the cause is essential.
• In septic CST, adding anticoagulation to antibiotics significantly improves mortality and morbidity.

1. What is Cavernous Sinus Syndrome?

Cavernous sinus syndrome (CSS) is a condition resulting from pathological changes in the cavernous sinus, combining ophthalmoplegia (CN III, IV, VI), autonomic dysfunction (Horner syndrome), and sensory loss in the first (V1) or second (V2) division of the trigeminal nerve.

(1) Total ophthalmoplegia + (2) sensory loss/irritative symptoms in the first division of the trigeminal nerve is called “superior orbital fissure syndrome/cavernous sinus syndrome,” and when (3) optic nerve involvement is added, it is distinguished as “orbital apex syndrome.” When abducens nerve palsy is accompanied by ipsilateral Horner syndrome, it strongly suggests a lesion within the cavernous sinus.

In a prospective study of 73 patients by Bhatkar et al. (2017), the frequencies of clinical features of CSS were reported as diplopia 90.4%, unilateral headache 70.4%, ptosis 68.4%, facial numbness 56.2%, and proptosis 31.5%²⁾. The frequencies of affected cranial nerves were CN VI 82.1%, CN III 78.1%, CN IV 68.4%, and CN V 46.5%, with the abducens nerve being the most vulnerable²⁾.

In an analysis of 126 cases by Fernández et al. (2007), the causes of CSS were reported as tumors 63%, vascular 20%, and granulomatous inflammation 13%²⁾. Cavernous sinus thrombosis (CST) accounts for 1-4% of all cerebral venous and sinus thrombosis, with an estimated annual incidence of about 1/100,000⁴⁾.

Syndrome	Affected site	Main features
Cavernous sinus syndrome	Cavernous sinus	Total ophthalmoplegia + V1/V2 sensory loss, conjunctival injection, proptosis
Superior orbital fissure syndrome	Superior orbital fissure	Total ophthalmoplegia + V1 sensory loss, optic nerve spared
Orbital apex syndrome	Orbital apex	Above + optic nerve involvement (RAPD positive)

Q How do cavernous sinus syndrome and orbital apex syndrome differ?

A

CSS primarily involves total ophthalmoplegia and sensory loss in the V1 distribution of the trigeminal nerve. Orbital apex syndrome adds optic nerve involvement to this, and the presence or absence of a relative afferent pupillary defect (RAPD) is key to differentiation.

2. Main symptoms and clinical findings

Subjective Symptoms

• Diplopia: Most common symptom (90.4%). Since abducens nerve palsy is most frequent, horizontal diplopia is typical²⁾.
• Unilateral headache: Present in 70.4%. Often occurs in the periorbital, frontal, or temporal region²⁾.
• Ptosis: 68.4%. Due to oculomotor nerve (CN III) palsy²⁾.
• Facial numbness or pain: Occurs in the trigeminal nerve V1 (forehead, cornea) or V2 (cheek, upper lip) area (56.2%)²⁾.
• Visual loss: Appears when transitioning to orbital apex syndrome with optic nerve involvement.
• Systemic symptoms suggestive of infectious CST: Fever, tachycardia, hypotension, chills, nuchal rigidity, altered mental status. If these occur, urgent management is required.

Clinical Findings (Findings Confirmed by Physician Examination)

Findings by cranial nerve involvement

• CN III palsy: Impaired elevation, depression, and adduction of the ipsilateral eye; ptosis; pupillary dilation.
• CN IV palsy: Impaired abduction and depression of the ipsilateral eye. Vertical diplopia occurs.
• CN VI palsy: Impaired abduction of the ipsilateral eye. Most commonly affected (82.1%)²⁾.
• CN V1/V2 sensory loss: Decreased corneal sensation, asymmetry of forehead and cheek sensation.
• Horner syndrome: Miosis, mild ptosis, anhidrosis. Due to damage to postganglionic sympathetic fibers along the internal carotid artery.
• Proptosis and conjunctival chemosis: Caused by impaired venous return due to increased cavernous sinus pressure.

Differences in findings depending on lesion location

Anterior / superior orbital fissure lesions

Pain and sensory abnormalities in the CN V1 area: Symptoms mainly in the forehead and periorbital region.

Ophthalmoplegia (CN III, IV, VI): All nerves passing through the superior orbital fissure are affected.

Horner syndrome: Damage to postganglionic sympathetic fibers causes miosis and ptosis.

Middle to posterior cavernous sinus lesions

Sensory abnormalities in CN V1 ± V2 areas: As the lesion extends posteriorly, the V2 area (cheek, upper lip) is also affected.

In posterior lesions, all of V1, V2, and V3 are affected: May be accompanied by lesions of the optic chiasm, optic tract, or brainstem.

Characteristic finding of CST: Rapid spread of symptoms to the contralateral side (usually within 24–48 hours) ¹⁰⁾.

Disease-specific findings

• Three main signs of carotid-cavernous fistula (CCF): Pulsatile proptosis, bruit, conjunctival injection and edema (“Medusa head” appearance).
• Tolosa-Hunt syndrome: Characterized by painful ophthalmoplegia. Pain markedly improves within 1–2 days with steroid therapy.
• CST secondary to sphenoid sinusitis or pharyngitis: Abducens nerve palsy is important as an initial symptom. Congestive symptoms appear later.
• Infectious CST: May be complicated by venous stasis retinopathy or central retinal vein occlusion.

Q What symptoms should raise suspicion for cavernous sinus thrombosis (CST)?

A

When ocular muscle palsy, ptosis, proptosis are accompanied by systemic signs of infection such as fever, tachycardia, chills, nuchal rigidity, and altered mental status, CST should be urgently suspected. Rapid spread to the contralateral side (within 24–48 hours) is also an important clue ¹⁰⁾.

3. Causes and Risk Factors

The causes of CSS are diverse. Representative classifications are shown below.

Cause Category	Main Diseases/Conditions	Frequency (Fernández et al., 2007)
Neoplastic	Pituitary adenoma, meningioma, chordoma, schwannoma, metastasis, lymphoma, nasopharyngeal carcinoma	63%2)
Vascular	Carotid-cavernous fistula (direct/dural type), ICA aneurysm, cavernous sinus thrombosis	20%2)
Granulomatous Inflammation	Tolosa-Hunt syndrome, sarcoidosis, Wegener’s granulomatosis, hypertrophic pachymeningitis	13%2)
Infectious	Fungal sinusitis (Mucor, Aspergillus), herpes zoster, septic CST	—
Traumatic	Skull base fracture, post-surgery	—

Neoplastic (63%, most common)

Pituitary adenoma and meningioma are representative. Lymphoma accounts for about 2.3% of CSS causes ²⁾. Pituitary adenoma can cause acute CSS due to apoplexy (pituitary apoplexy). The prevalence of pituitary apoplexy is reported as 6.2 cases per 100,000 people ¹⁾.

Vascular (20%)

• Direct carotid-cavernous fistula: The main trunk of the ICA directly penetrates the cavernous sinus. Mostly traumatic.
• Dural carotid-cavernous fistula (dural CCF): Shunt via dural perforating branches. In addition to congenital AVM, hypertension and diabetes are triggers.
• IC-PC aneurysm: Internal carotid-posterior communicating artery bifurcation aneurysm compresses structures within the cavernous sinus.

Infectious/Septic CST

Retrograde infection from facial or sinus infections is the main mechanism. Thrombus spreads through facial veins that lack valves. Infections from the “danger triangle of the face” (area bounded by the corners of the mouth and the root of the nose) are common ⁴⁾. Staphylococcus aureus accounts for about 67% of causative bacteria ⁴⁾.

COVID-19 infection has been reported to cause CST through a hypercoagulable state (ACE2 receptor-mediated endotheliitis, IL-6 elevation, protein S deficiency, etc.) in multiple reports ^6)9)10).

Risk factors for fungal CSS

• Severe diabetes (including diabetic ketoacidosis)
• Long-term steroid use
• Use of immunosuppressive drugs
• Hematologic malignancies

Prevention and daily care

Facial infections such as sinusitis and dental infections should be treated appropriately before they become severe. Especially if toothache or sinusitis is accompanied by fever and eye symptoms (double vision, drooping eyelid), seek medical attention promptly. For individuals with conditions that weaken the immune system (such as diabetes), thorough management of infections can help prevent cavernous sinus syndrome.

Q What is the most common cause of cavernous sinus syndrome?

A

Tumors account for 63%, with pituitary adenoma and meningioma being representative. Next, vascular causes (CCF or aneurysm) account for 20%, and granulomatous inflammation (such as Tolosa-Hunt syndrome) accounts for 13% ²⁾.

4. Diagnosis and examination methods

Approach to clinical diagnosis

A detailed medical history is the starting point for diagnosis. Focus on the following points.

• Onset pattern: Sudden onset with severe eye pain/headache → suspect aneurysm or pituitary apoplexy as an emergency.
• Presence of eye pain: Painful ophthalmoplegia suggests Tolosa-Hunt syndrome, CST, or aneurysm.
• Systemic symptoms: Presence of fever or chills (to differentiate infectious CST).
• Neurological examination: Asymmetry of corneal and forehead sensation (checking V1 impairment), relative afferent pupillary defect (RAPD; assessment of optic nerve involvement).

Imaging studies

Imaging modality	Main indications/features
Contrast-enhanced MRI	Optimal for evaluating tumors, inflammation, and CST. Combine T1/T2, fat suppression, and gadolinium contrast.
MRV (magnetic resonance venography)	Useful for confirming and assessing the extent of CST.
CT/CTV	Evaluation of trauma, bone destruction, and vascular lesions. Confirmation of CST.
MRA (SPGR method)	Most useful for detecting IC-PC aneurysms.
DSA (digital subtraction angiography)	Essential for definitive diagnosis of carotid-cavernous fistula. Perform four-vessel angiography of bilateral ICA and ECA.
CTA	Useful for serial follow-up of infectious aneurysms5).

Blood and Cerebrospinal Fluid Tests

• General inflammatory markers: CBC, blood culture (mandatory if infectious CST is suspected), ESR, CRP.
• Autoimmune screening: ANA, c-ANCA, p-ANCA, etc.
• Infection-related tests: β-D-glucan (to differentiate fungal infection), serum ACE (if sarcoidosis is suspected).
• Cerebrospinal fluid examination: Consider performing in cases of cavernous sinus or skull base lesions.
• Biopsy: Consider before steroid administration if infection cannot be ruled out. This is because malignant lymphoma and fungal infections may temporarily improve with steroids but recur during dose reduction, leading to a worse prognosis.

Differential Diagnosis

• Orbital cellulitis: Proptosis, eyelid swelling, fever. The pattern of extraocular movement limitation differs.
• Superior ophthalmic vein thrombosis: Orbital venous congestion due to thrombosis of the superior ophthalmic vein.
• Orbital apex syndrome: CSS plus optic neuropathy (positive RAPD).
• Myasthenia gravis: Fatigable ptosis and extraocular movement limitation. Differentiate with ice test (sensitivity 80–92%) and Tensilon test.
• Tolosa-Hunt syndrome: Pain improvement with steroids (within 1–2 days) is a key differentiating feature, but can only be safely performed after excluding infection and tumor.

5. Standard Treatment

Treatment of CSS varies greatly depending on the cause. Identifying the cause is the most important step in treatment selection.

Neoplastic

Surgery + radiation therapy: The approach differs depending on the histopathological type.

Meningioma, chordoma: Tumor resection plus postoperative radiation therapy is standard.

Pituitary adenoma: Transsphenoidal resection. Hormone replacement therapy for adrenal insufficiency is performed concurrently ¹⁾.

Vascular (CCF)

Referral to neurosurgery is the rule.

Low-flow shunts: Observation (spontaneous closure in <50%).

High-flow shunts or symptomatic: Endovascular surgery (balloon or coil embolization to close the fistula). Direct carotid-cavernous fistulas rarely close spontaneously after 3 weeks. For ocular complications such as elevated intraocular pressure, symptomatic treatment with antihypertensive agents is given.

Infectious (CST)

Start broad-spectrum intravenous antibiotics immediately.

Antibiotic selection: MRSA coverage + third-generation cephalosporin + metronidazole. In immunocompromised patients, consider antifungal agents ⁴⁾.

Duration of antibiotics: 3–4 weeks or longer, or at least 2 weeks after clinical improvement ⁴⁾.

Anticoagulation: Addition of unfractionated heparin (UFH) reduces mortality from 40% to 14% and morbidity from 61% to 31% ⁴⁾. The European Federation of Neurological Societies recommends 3 months of anticoagulation ⁴⁾.

ENT consultation: To evaluate drainage of the primary infection source (sinuses, teeth).

Inflammatory (Tolosa-Hunt syndrome)

Systemic glucocorticoid therapy is effective. Pain improves markedly within 1–2 days of administration, followed by improvement of ocular motor deficits. However, infectious causes (especially fungal and tuberculous) and malignant lymphoma must be thoroughly excluded before starting steroids. Fungal infections and malignant lymphoma may be temporarily suppressed by steroids, but there is a risk of rapid recurrence and worsening of prognosis during dose reduction.

Infectious Intracranial Aneurysm (ICIA)

In addition to 4–6 weeks of antibiotic therapy, endovascular treatments such as coil embolization, flow diverter stenting, and balloon occlusion are combined. In a literature review of 22 cases by Shen et al. (2024), the clinical remission rate in the endovascular treatment group was 93% (13/14 cases)⁵⁾.

Selection of Anticoagulant Agents

The new oral anticoagulants (NOACs) dabigatran and rivaroxaban have been reported to have similar efficacy and safety to warfarin for cerebral venous thrombosis⁷⁾, and may be useful options for long-term outpatient management.

Management of Residual Ocular Motor Dysfunction

If abducens nerve palsy persists after treatment of the underlying cause, for mild to moderate cases, lateral rectus shortening and medial rectus recession are selected; for severe palsy, vertical rectus transposition is chosen.

Precautions in Treatment

• Steroid administration is dangerous when infectious causes have not been ruled out. Fungal infections, lymphoma, and tuberculosis may temporarily improve with steroids but will relapse.
• In septic CST, visual impairment (blindness rate 8–15%) and cranial nerve deficits (persisting in about half of cases) have worse prognosis the later treatment is initiated⁴⁾.
• CST due to dental infection has delayed presentation as a poor prognostic factor⁷⁾, and visual impairment may become permanent.
• The complication rate associated with flow diverter use is 17.0% (neurological morbidity 4.5%), and indications should be carefully considered³⁾.

Prognosis

• Tolosa-Hunt syndrome: Steroid responsiveness is good, but recurrence may occur.
• Infectious (e.g., fungal sinusitis): Can be fatal without early diagnosis and treatment. Fungal sinusitis requires surgical debridement combined with antifungal agents.
• Neoplastic: Depends on the nature of the primary lesion and treatment response.
• CCF: Endovascular treatment often leads to symptom improvement.
• Septic CST: Mortality decreases to 14% with anticoagulation, but cranial nerve deficits persist in about half of patients⁴⁾.

Q Should anticoagulation be used for septic CST?

A

Addition of unfractionated heparin anticoagulation significantly reduced mortality from 40% to 14% and morbidity from 61% to 31%⁴⁾. Anticoagulation is recommended unless there are strong contraindications (e.g., active bleeding). The European Federation of Neurological Societies recommends continuation for 3 months.

6. Pathophysiology and Detailed Mechanisms

Anatomy of the Cavernous Sinus

The cavernous sinus is a dural venous sinus located on both sides of the sella turcica of the sphenoid bone, and the left and right sides communicate. It is bordered laterally by the temporal bone, inferiorly by the sphenoid bone (adjacent to the sphenoid sinus), with the pituitary gland inside the sella turcica and the optic chiasm located superiorly in the midline.

Venous Drainage

• Inflow: Superior and inferior ophthalmic veins (anteriorly), superficial middle cerebral vein, deep cerebral veins via the sphenoparietal sinus, and inferior cerebral veins.
• Outflow: Pterygoid venous plexus (inferiorly), superior and inferior petrosal sinuses (posteriorly) → internal jugular vein.
• No valves: Blood can flow in both antegrade and retrograde directions, allowing thrombus to propagate retrograde from facial infections.

Intrasinus Neural and Vascular Arrangement

• Internal carotid artery (ICA): Passes through the sinus (most medial).
• CN III, IV, V1, V2: Fixed in the lateral wall.
• CN VI: Lies freely inferolateral to the ICA (medial to other CNs). It is not fixed and thus susceptible to compression, with the highest frequency of involvement (82.1%)²⁾.
• Postganglionic third-order sympathetic fibers: Run along the ICA and CN VI, then transition to V1. Damage to this pathway results in Horner syndrome.

Pathophysiology by Condition

Compression mechanism (tumor, hematoma)

Because the cavernous sinus is a fixed space surrounded by bone, space-occupying lesions within the sinus compress internal structures, leading to ophthalmoplegia and facial sensory changes. CN VI is more freely positioned than other cranial nerves, so it is affected first even by minor pressure changes.

Mechanism of infectious CST formation

The absence of valves in the facial veins leads to venous stasis within the sinus during severe infection, followed by thrombus formation. The formed thrombus causes local inflammation and can also lead to emboli to the brain (stroke, encephalitis, meningitis).

Mechanism of infectious aneurysm (ICIA) formation

Infection from adjacent tissues causes septic thrombophlebitis of the cavernous sinus, leading to inflammatory cell infiltration of the internal carotid artery wall (adventitia → media → intima). Weakening of the arterial wall results in aneurysm formation⁵⁾.

COVID-19-related coagulopathy

SARS-CoV-2 causes endotheliitis via ACE2 receptors, triggering a cascade of inflammatory response (activation of IL-6 and VEGF), vasoconstriction, and hypercoagulability, leading to CST⁶⁾⁹⁾. Protein S and C deficiency may contribute to thrombus formation⁹⁾.

Intraocular branches of the oculomotor nerve and partial palsy

The oculomotor nerve passes through the cavernous sinus and superior orbital fissure, then divides into a superior branch (superior rectus, levator palpebrae superioris) and an inferior branch (inferior rectus, inferior oblique, medial rectus, and intraocular muscles). Partial palsy of only the superior or inferior branch suggests a lesion in the posterior orbit.

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7. Latest Research and Future Perspectives (Preliminary Reports)

For patients: Please read this section.

The following content is currently at the research stage or in clinical trials and is not standard treatment available at general hospitals. It is reference information for experts regarding future medical developments.

Accumulation of Reports on COVID-19 and Vaccine-Related CST

Multiple cases of CST after COVID-19 infection and vaccination have been reported, and they are being recognized as new triggers.

Raj et al. (2021) reported a 37-year-old man who developed CST → central retinal artery occlusion → optic atrophy (no light perception in the left eye) after severe COVID-19 pneumonia ⁶⁾. D-dimer >10,000 ng/mL and IL-6 560 pg/mL indicated markedly elevated coagulation and inflammatory markers.

Nusanti et al. (2022) reported a 50-year-old woman who developed bilateral CST 16 days after CoronaVac vaccination ⁹⁾. She had underlying deficiencies in coagulation regulatory factors (protein S 37%, protein C 61.9%). With methylprednisolone and anticoagulation therapy, her left eye recovered to 20/20, but no light perception remained in the right eye.

Optimal management guidelines for post-infection and post-vaccination CST have not yet been established.

Application of NOACs to Cerebral Venous Thrombosis

Dabigatran and rivaroxaban have been reported to have similar efficacy and safety to warfarin ⁷⁾, and their convenience for long-term outpatient management is expected to lead to increased use. However, large-scale randomized controlled trials have not yet been conducted.

Flow Diverter Treatment for Carotid-Cavernous Fistula and Aneurysm

Endovascular treatment using flow diverters has been reported to be useful for cavernous sinus ICA aneurysms and carotid-cavernous fistulas.

Reid et al. (2024) reported a case of a 65-year-old woman with a carotid-cavernous fistula and multiple aneurysms who underwent flow diverter placement and coil embolization, and was discharged in stable condition ³⁾. A systematic review reported technical success in all patients, but a complication rate of 17.0% (neurological morbidity 4.5%) ³⁾.

Endovascular Treatment of Infectious ICIA

Evidence for the efficacy of endovascular treatment for infectious cavernous sinus ICA aneurysms (ICIA) is accumulating.

In a literature review of 22 cases by Shen et al. (2024), the clinical remission rate in the endovascular treatment group was 93% (13/14 cases), while only one case in the conservative treatment group showed complete regression ⁵⁾. The overall mortality rate for infectious aneurysms remains high at 18.7–46.0%, making early diagnosis and multidisciplinary treatment essential.

CST Associated with Lemierre Syndrome

CST associated with Lemierre syndrome (infectious thrombophlebitis of the internal jugular vein due to Fusobacterium necrophorum bacteremia) is rare, but reports have increased after COVID-19.

Dai et al. (2022) reported an 18-year-old male who developed Lemierre syndrome → left CST + left ICIA → CSS after COVID-19 ⁸⁾. Left ICA embolization + sacrifice resulted in a good outcome (visual acuity recovered to 20/20, diplopia resolved at 3 months).

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8. References

1. Jamal Y, Camacho Y, Hanft S, et al. A Case of Pituitary Apoplexy and Cavernous Sinus Syndrome during Hemodialysis. Case Reports in Endocrinology. 2023;2023:3183088.

2. Kim TR, Bae KN, Son JH, et al. A Case of Cavernous Sinus Syndrome Due to Extranodal Diffuse Large B-Cell Lymphoma. Ann Dermatol. 2023;35(Suppl 2):S300-303.

3. Reid DM, Chalasani N, Khadka M, et al. Cavernous Sinus Syndrome in a Polio-Afflicted Patient With Multiple Aneurysms. Cureus. 2024;16(5):e60673.

4. Spalitto D. An Atypical Presentation of Bilateral Cavernous Sinus Thrombosis. Cureus. 2024;16(7):e64647.

5. Shen Y, Hu F, Wu L, Nie H. Concomitant rapidly growing aneurysm of intracavernous carotid artery and cavernous sinus thrombosis: Case report and review of the literature. Medicine. 2024;103(30):e39022.

6. Raj A, Kaur N, Kaur N. Cavernous sinus thrombosis with central retinal artery occlusion in COVID-19: A case report and review of literature. Indian J Ophthalmol. 2021;69:1327-1329.

7. Ng EMC, Othman O, Chan LY, Bahari NA. Cavernous Sinus Thrombosis and Blindness Complicating Dental Infection. Cureus. 2022;14(1):e21318.

8. Dai YL, Chen VM, Hedges TR III, Malek A. Lemierre syndrome associated mycotic cavernous sinus thrombosis and carotid aneurysm after COVID-19. Am J Ophthalmol Case Rep. 2022;27:101642.

9. Nusanti S, Putera I, Sidik M, et al. A case of aseptic bilateral cavernous sinus thrombosis following a recent inactivated SARS-CoV-2 vaccination. Taiwan J Ophthalmol. 2022;12:334-338.

10. LoBue SA, Park R, Giovane R, DeLury J, Hodgson N. Bilateral Cavernous Sinus Thrombosis in Presumed COVID-19 Infection. Cureus. 2022;14(11):e31986.