Tolosa-Hunt Syndrome

Key Points at a Glance

1. What is Tolosa-Hunt Syndrome?

Tolosa-Hunt syndrome (THS) is a painful ophthalmoplegia caused by idiopathic granulomatous inflammation of the cavernous sinus, superior orbital fissure, or orbital apex.

History

1954 Tolosa: First report of granulomatous inflammation of the cavernous sinus on autopsy.
1961 Hunt: Reported 6 cases and described steroid responsiveness as a feature.
1966 Smith & Taxdal: First named “Tolosa-Hunt syndrome”. ⁶⁾
2004: The International Headache Society (IHS) first included it in disease classification. Currently listed in ICHD-3.

Epidemiology

Annual incidence: approximately 1 case per million people.
Peak age: 30–60 years.
Sex: slightly more common in women.
Laterality: usually unilateral. Rarely bilateral.

ICHD-3 Diagnostic Criteria

Defined as meeting the following criteria A–D.

A: Unilateral orbital or periorbital headache.
B: MRI or biopsy confirms granulomatous inflammation of the cavernous sinus, superior orbital fissure, or orbit, and ipsilateral palsy of one or more of cranial nerves III, IV, or VI.
C: Headache is ipsilateral to the granuloma and precedes or occurs simultaneously with the ophthalmoplegia within 2 weeks.
D: Not better accounted for by another ICHD-3 diagnosis.

Q How rare is Tolosa-Hunt syndrome?

The annual incidence is about 1 per million, making it a very rare disease, and it is recognized as a rare disease by NORD. The typical age of onset is 30–60 years, with a slight female predominance.

2. Main symptoms and clinical findings

Subjective symptoms

Retro-orbital pain: Unilateral, sharp, persistent pain with a “boring” quality. It may radiate to the retro-orbital, temporal, or frontal regions. ²⁾
Pain precedes ophthalmoplegia: Pain may precede eye muscle paralysis by up to 30 days. ²⁾
Diplopia: Occurs with ophthalmoplegia, worsening with distance vision.
Others: Rarely accompanied by blurred vision, photophobia, or nausea.

Clinical findings

The oculomotor nerve (CN III) is most commonly affected (about 80%), followed by the abducens nerve (CN VI, about 70%). ²⁾

CN III (Oculomotor nerve)

Frequency: Most common (about 80%).

Findings: Ptosis, “down and out” eye position, diplopia. Pupillary abnormalities may occur if parasympathetic fibers are involved.

CN IV (Trochlear nerve)

Frequency: Less common than CN III.

Findings: The main symptom is vertical diplopia. It is often involved together with CN III.

CN VI (Abducens Nerve)

Frequency: Approximately 70%.

Findings: Horizontal diplopia and esotropia due to impaired abduction on the affected side. The abducens nerve is the only nerve not protected within the dural wall of the cavernous sinus, making it susceptible even in isolated palsy.

CN V1 (Ophthalmic Nerve)

Frequency: Relatively common.

Findings: Loss of sensation or hypoesthesia in the forehead. Pain or sensory abnormalities in the first division of the trigeminal nerve suggest anterior cavernous sinus or superior orbital fissure lesions. In posterior cavernous sinus lesions, all branches of the trigeminal nerve may be affected.

Proptosis and conjunctival chemosis: May be observed due to spread of inflammation.
RAPD: If optic nerve involvement is present, it indicates an orbital apex lesion, and the presence or absence of RAPD (relative afferent pupillary defect) is an important finding.
Horner syndrome: Occurs due to involvement of internal carotid artery sympathetic fibers.
Frozen globe: Rarely presents as complete unilateral total ophthalmoplegia.
Recurrence: Recurrence occurs in 30–40% of cases, often on the same side. Different cranial nerves may be affected upon recurrence. ³⁾

Q If eye pain and diplopia occur simultaneously, should Tolosa-Hunt syndrome be suspected?

The combination of unilateral retro-orbital pain and ophthalmoplegia is characteristic of THS. However, THS is a diagnosis of exclusion, and tumors, infections, vascular lesions, etc., must be ruled out first. Since recurrence occurs in 30–40% of cases, careful follow-up is required even after response to steroids.

3. Causes and Risk Factors

Underlying Cause

It is an idiopathic, sterile granulomatous inflammation in the cavernous sinus, superior orbital fissure, and orbital apex. Histopathology shows infiltration of fibroblasts, lymphocytes, plasma cells, and non-caseating granulomas (sometimes with giant cells), classified as non-specific granulomatous inflammation.

IgG4-related disease: Some THS cases may be a type of IgG4-related orbital disease.
Sarcoidosis and autoimmune vasculitis: Can present with similar granulomatous inflammation.
SLE: There are reports of THS presenting as the initial symptom of SLE (positive for ANA, anti-dsDNA, anti-Sm antibodies). ⁶⁾
Granulomatosis with polyangiitis (GPA): There are case reports of C-ANCA-PR3 positive GPA patients presenting with THS-like symptoms. ⁵⁾

Post-COVID-19 vaccination: Reported with mRNA, adenovirus vector, and inactivated vaccines. Multiple cases have been reported with onset 5–35 days after vaccination. ⁴⁾¹⁾
Post-COVID-19 infection: A case has been reported with onset 14 days after infection. ⁷⁾

In typical THS, infectious or neoplastic causes are not identified, but recent viral infection may be a risk factor.

4. Diagnosis and Testing Methods

THS is a diagnosis of exclusion, combining clinical findings, imaging, blood tests, and exclusion of other diseases.

Imaging Diagnosis

MRI/MRA is the first choice. It provides more detailed information about the cavernous sinus and orbital apex than CT.

MRI findings: Abnormal tissue with isointensity to gray matter on T1-weighted images and iso- to hypointensity on T2-weighted images. It shows homogeneous enhancement with gadolinium. ⁸⁾²⁾ Enlargement of the cavernous sinus and convex changes of the dural margin may be observed. ⁸⁾
Imaging conditions: Coronal and axial sections with fat suppression or STIR conditions. Gadolinium contrast is very useful for differentiating inflammation from tumors. High-resolution 3D MRI (e.g., CISS method) improves visualization of cranial nerves and cavernous sinus lesions.
Frequency of normal MRI: Normal MRI has been reported in 18–57% of cases; a negative image does not exclude the clinical diagnosis. ⁸⁾
Confirmation of treatment response: MRI changes before and after steroid therapy can confirm treatment efficacy, but imaging resolution may take several months. ⁸⁾
When MRI/MRA is unavailable: Contrast-enhanced CTA can be used as an alternative.

Blood Tests

Basic items: ESR, CRP, ANA, ANCA, ACE, IgG4, syphilis serology (RPR/FTA-ABS).
Additional items: CBC, blood glucose, anti-dsDNA antibody, RF, thyroid function, HbA1c, Lyme disease panel, serum protein electrophoresis.
Reference: Peripheral blood, ESR, CRP, antinuclear antibody, C-ANCA, P-ANCA, ACE, β-D-glucan are also useful.

Other Tests

Cerebrospinal fluid examination: Performed to check initial pressure and evaluate infection or oligoclonal bands. In recurrent cases, mild elevation of CSF protein may be observed. ³⁾
Biopsy: Allows direct confirmation of granulomatous inflammation. Although the procedure is difficult and invasive, it is important for definitive diagnosis and exclusion of malignancy. ⁸⁾

Differential Diagnosis

The following major differential diagnoses must be excluded.

Category	Major diseases	Steroid response
Inflammatory/Autoimmune	Sarcoidosis, granulomatosis with polyangiitis, IgG4-related disease	Variable
Tumor	Meningioma, lymphoma, metastatic cancer	None/Minimal
Infection	Cavernous sinus thrombosis, fungal infection, tuberculosis	None/Worsening
Vascular	Carotid-cavernous fistula, internal carotid artery aneurysm, cerebral aneurysm	None
Endocrine/Metabolic	Diabetic CN III palsy	None
Neurologic/Demyelinating	Multiple sclerosis, neuromyelitis optica, ADEM, neuro-Behçet disease, Wernicke encephalopathy	None
Brainstem/Vascular	Brainstem vascular disorder	None
Other	Ophthalmoplegic migraine, orbital pseudotumor	Variable

The Tensilon test and ice test are useful for differentiating from myasthenia gravis, and the presence or absence of diurnal variation is an important clue. Note that steroid responsiveness supports THS but does not confirm it. Also note that malignant lymphoma can be temporarily suppressed by steroids.

5. Standard Treatment

First-line: Corticosteroids

Prednisolone 50–60 mg/day is administered for the first 3 days. Orbital pain often improves dramatically. Since early dose reduction can cause relapse, taper carefully.

Pain improvement: Usually within 24–72 hours after starting treatment.
Tapering period: Gradual tapering over 3–4 months is common.
Severe cases: Methylprednisolone 500–1000 mg/day intravenously for 3–5 days, followed by oral prednisolone tapering. ³⁾²⁾
Recovery of eye movement: Slower than pain relief, may take weeks to months.

Second-line: Immunosuppressants (refractory/recurrent)

For refractory or recurrent THS, the following drugs are options.

Drug	Dosage guide
Azathioprine	2 mg/kg/day
Methotrexate	7.5–25 mg/week
Mycophenolate mofetil	1–2 g/day
Infliximab	3–5 mg/kg/dose
Cyclosporine	2–5 mg/kg/day
Radiation therapy	30–60 Gy

In cases with recurrent episodes, combination therapy with azathioprine and low-dose steroids has been reported to successfully suppress recurrence. ³⁾ Rituximab is also an option for steroid-resistant cases.

Follow-up

Post-treatment MRI should confirm resolution of the lesion. Since recurrence occurs in 30–40% of cases, long-term follow-up is necessary.

Q How quickly does steroid treatment take effect?

Pain usually improves markedly within 24–72 hours after starting steroids. On the other hand, recovery of eye movement is often delayed and may take weeks to months. Since early dose reduction can lead to relapse, gradual tapering over 3–4 months is common.

6. Pathophysiology and detailed pathogenesis

Nature of inflammation and histopathology

The condition is essentially idiopathic sterile granulomatous inflammation in the cavernous sinus, superior orbital fissure, and orbital apex. Histologically, infiltration of fibroblasts, lymphocytes, and plasma cells, non-caseating granulomas (sometimes with giant cells), and dural thickening are observed. ²⁾

Anatomical Background

Nerve arrangement within the cavernous sinus: The oculomotor nerve (CN III) runs in the uppermost lateral wall, followed sequentially below by the trochlear nerve (CN IV), trigeminal nerve (CN V), and abducens nerve (CN VI). The abducens nerve is the only nerve not protected within the dural wall, making it prone to isolated palsy.
Lesion localization: Typically confined to the area from the posterior cavernous sinus to the superior orbital fissure. If optic neuropathy is also present, it suggests an orbital apex lesion.

Anatomical Classification of Cavernous Sinus Lesions

Lesion Site	Affected Nerves	Characteristic Symptoms
Superior orbital fissure to anterior cavernous sinus	CN III, IV, VI, V1	Painful external ophthalmoplegia, pain and sensory abnormalities in the first division of the trigeminal nerve
Middle to posterior cavernous sinus	CN III, IV, VI, V1, V2, V3	All trigeminal nerve branches affected
Posterior cavernous sinus (with optic neuropathy)	Above + optic nerve	Corresponds to orbital apex syndrome, positive RAPD

Pain or sensory abnormalities limited to the first division of the trigeminal nerve suggest lesions in the anterior cavernous sinus or superior orbital fissure, while involvement of the second division or beyond indicates lesions in the middle to posterior cavernous sinus.

Mechanism of nerve damage

Granulomatous inflammation directly involves cranial nerves III, IV, V1, and VI, causing external compression leading to ophthalmoplegia and pain. When sympathetic nerve fibers of the internal carotid artery are involved, Horner syndrome appears, and involvement of parasympathetic fibers of CN III leads to pupillary abnormalities.

Some cases of THS may represent a form of IgG4-related orbital disease. In such cases, elevated serum IgG4 levels and infiltration of IgG4-positive plasma cells into tissues are characteristic.

7. Latest research and future perspectives (research-stage reports)

COVID-19 vaccine and THS

Ang et al. (2023) reported 14 or more cases of post-vaccination orbital inflammation (including THS). Onset was recorded 9 hours to 42 days (median around 5 to 35 days) after vaccination with Pfizer/BioNTech, Moderna, CoronaVac, or Janssen vaccines. It has been suggested that degradation of mRNA molecules may trigger inflammation, and patients with a history of orbital inflammation may have a higher risk of recurrence. THS is also listed as an adverse event of special interest (AESI) in VAERS (Vaccine Adverse Event Reporting System). ¹⁾⁴⁾

THS after COVID-19 infection and severe complications

Gogu et al. (2022) reported a 45-year-old man who developed THS two weeks after contracting COVID-19 on day 9 post-vaccination. He subsequently died from ischemic stroke and hemorrhagic encephalitis. This suggests a possible dual mechanism involving immune abnormalities and infection. ⁷⁾

THS as the initial symptom of SLE

Nilofar et al. (2024) reported a 54-year-old woman diagnosed with SLE presenting with THS as the initial symptom. She was positive for ANA 4+, anti-dsDNA, and anti-Sm antibodies, and maintenance therapy was performed with hydroxychloroquine plus mycophenolate mofetil. ⁶⁾

THS-like symptoms in patients with granulomatosis with polyangiitis

Mohebbi et al. (2024) reported a 40-year-old woman with C-ANCA-PR3-positive granulomatosis with polyangiitis who presented with THS-like symptoms. She was treated with steroid pulse therapy plus rituximab. ⁵⁾

Azathioprine for recurrent THS

Thu et al. (2021) reported a case of a 48-year-old woman with poor response to low-dose steroids and three recurrences, in whom the addition of azathioprine 2 mg/kg/day successfully suppressed recurrence. ³⁾

Advances in imaging technology and future prospects

High-resolution MRI (3T): Improved sensitivity for detecting subtle cavernous sinus inflammation.
Molecular imaging (PET-CT): Useful for excluding systemic inflammatory diseases and expected to contribute to improved diagnostic accuracy.

Q Is there an association between COVID-19 vaccines and Tolosa-Hunt syndrome?

Onset of THS has been reported with multiple vaccine types (mRNA, adenovirus vector, inactivated), with onset ranging from 9 hours to 42 days after vaccination. However, a causal relationship has not been established at this time. THS is listed as a special interest adverse event in VAERS, and monitoring continues. ¹⁾⁴⁾

8. References

Ang T, Tong JY, Patel S, Khong JJ, Selva D. Orbital inflammation following COVID-19 vaccination: A case series and literature review. Int Ophthalmol. 2023;43:3391-3401.
Kasarabada H, Singh D, Iyenger S, Praveena K. Tolosa Hunt syndrome: A rare cause of headache. Med J Armed Forces India. 2024;80:S272-S274.
Thu PW, Chen YM, Liu WM. Recurrent Tolosa-Hunt syndrome. Tzu Chi Med J. 2021;33(3):314-316.
Chuang TY, Burda K, Teklemariam E, Athar K. Tolosa-Hunt Syndrome Presenting After COVID-19 Vaccination. Cureus. 2021;13(7):e16791. doi:10.7759/cureus.16791. PMID:34513398; PMCID:PMC8405240.
Mohebbi M, Nafssi S, Alikhani M. A New Case of Granulomatosis with Polyangiitis Presented with Tolosa-Hunt Syndrome Manifestations. Case Rep Rheumatol. 2024;2024:5552402.
Nilofar F, Mohanasundaram K, Kumar M, Gnanadeepan T. Tolosa-Hunt Syndrome as the Initial Presentation of Systemic Lupus Erythematosus. Cureus. 2024;16(6):e61692.
Gogu AE, Motoc AG, Docu Axelerad A, Stroe AZ, Gogu AA, Jianu DC. Tolosa-Hunt Syndrome and Hemorrhagic Encephalitis Presenting in a Patient after COVID-19 Vaccination Followed by COVID-19 Infection. Brain Sci. 2022;12:902.
Ramirez JA, Ramirez Marquez E, Torres G, Muns Aponte C, Labat EJ. Tolosa Hunt Syndrome: MRI Findings. Cureus. 2023;15(10):e46635.
Ammari W, Kammoun A, Zaghdoudi A, Berriche O, Younes S, Messaoud R. A Case of Painful Diplopia after COVID-19 Vaccination: Could It Be Tolosa-Hunt Syndrome? Korean J Fam Med. 2023;44:240-243.

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