Peter Awad, Mark Awad, John Awad

Learning Points

• Tolosa-Hunt syndrome is a rare but important cause of painful ophthalmoplegia
• It should be considered in patients presenting with unilateral retroorbital pain associated with cranial nerve palsies affecting ocular motility.
• The condition remains a diagnosis of exclusion and requires careful investigation to exclude vascular, neoplastic, infectious and inflammatory causes
• MRI with contrast is the imaging modality of choice and may demonstrate inflammatory changes within the cavernous sinus or superior orbital fissure
• A rapid response to corticosteroid therapy is characteristic and often leads to dramatic improvement in pain within days
• Recurrence is common, and long-term follow-up is advisable

Background

Tolosa-Hunt syndrome (THS) is a rare idiopathic granulomatous inflammatory disorder affecting the cavernous sinus, superior orbital fissure or orbital apex (1,2). It classically presents with unilateral periorbital pain associated with ipsilateral ophthalmoplegia due to involvement of the third, fourth and/or sixth cranial nerves (2,3). The estimated incidence is approximately one in a million per year, and the condition can occur at any age and affects males and females equally (3).

The diagnosis of THS remains challenging because its presenting symptoms overlap with several potentially life-threatening conditions, including cavernous sinus thrombosis, intracerebral aneurysm, neoplasia, giant cell arteritis and inflammatory disorders such as sarcoidosis and granulomatosis with polyangiitis (2,4). Consequently, THS remains a diagnosis of exclusion and requires careful investigation to rule out the broad differential diagnosis of painful ophthalmoplegia (2).

A characteristic feature of THS is its dramatic response to corticosteroid therapy, with pain often improving within 24-72 hours and cranial nerve palsies resolving over subsequent weeks (3,5). In this article, we describe a typical presentation of Tolosa-Hunt syndrome and discuss the diagnostic challenges associated with this rare condition.

Case Presentation

A 58-year-old gentleman presented to the emergency department with a five-day history of severe left-sided retroorbital pain associated with double vision and partial ptosis of his left upper eyelid. He denied any history of trauma, headache, fever, jaw claudication, scalp tenderness or constitutional symptoms. His past medical history included hypertension and hypercholesterolaemia.

On examination, best corrected visual acuity was 6/6 in both eyes. Pupillary responses were normal and there was no relative afferent pupillary defect. The left eye demonstrated partial ptosis and restricted ocular movements in all directions, but eye movements were particularly restricted in abduction and elevation. The patient reported horizontal diplopia worse of lateral gaze. There was reduced sensation over the left forehead and upper eyelid in the distribution of the ophthalmic division of the trigeminal nerve (V1). Fundoscopy was unremarkable and there was no evidence of optic disc swelling.

Routine bloods demonstrated a normal full blood count, renal function and liver function tests. Inflammatory markers were mildly elevated with a C-reactive protein of 18mg/L and erythrocyte sedimentation rate of 34m/hr.

Given the presentation of painful ophthalmoplegia, an urgent CT angiogram of the head was performed; this showed no evidence of aneurysm or cavernous sinus thrombosis. MRI of the brain and orbits with contrast demonstrated abnormal enhancing soft tissue within the left cavernous sinus extending towards the superior orbital fissure (4,6). There was no evidence of intracranial mass, orbital tumour, demyelination or acute infarction.

Further investigations, including antinuclear antibodies, antineutrophil cytoplasmic antibodies, angiotensin-converting enzyme levels, serum immunoglobulin G4 levels and an infectious screen, were unremarkable.

Following multidisciplinary discussion with neurology and ophthalmology a diagnosis of Tolosa-Hunt syndrome was made based on the clinical presentation, imaging findings and exclusion of alternative causes according to the International Classification of Headache Disorders (2).

The patient was commenced on intravenous methylprednisolone followed by a tapering course of oral prednisolone. Within 48 hours, he reported significant improvement in orbital pain. At six-week follow-up, the ptosis and ophthalmoplegia had markedly improved with only minimal residual diplopia on extreme lateral gaze.

Discussion

Tolosa Hunt syndrome is characterised by painful ophthalmoplegia resulting from non-specific granulomatous inflammation of the cavernous sinus, superior orbital fissure or orbital apex (1,2). The International Classification of Headache Disorders (ICHD-3) diagnostic criteria require unilateral orbital or periorbital pain associated with paresis of one or more of the third, fourth and/or sixth cranial nerves, with evidence of granulomatous inflammation on MRI or biopsy and exclusion of alternative diagnoses (2).

Patients typically present with severe retro-orbital pain preceding the onset of cranial nerve palsies by several days (3,5). The oculomotor nerve is most commonly involved, followed by the abducens and trochlear nerves (5). Involvement of the ophthalmic division of the trigeminal nerve may result in sensory disturbance over the forehead and upper eyelid, as seen in our case. 

The differential diagnosis of painful ophthalmoplegia is broad and includes:

1. Posterior communicating artery aneurysm
2. Cavernous sinus thrombosis
3. Intracranial neoplasm and metastatic disease
4. Pituitary apoplexy
5. Sarcoidosis
6. Granulomatosis with polyangiitis
7. Giant cell arteritis
8. Diabetic cranial neuropathy
9. Orbital inflammatory disease
10. Infectious meningitis

MRI with gadolinium contrast remains the investigation of choice and commonly demonstrates enlargement and enhancement of the cavernous sinus or superior orbital fissure (4,6). However, imaging findings are not entirely specific and can occasionally be normal, particularly early in the disease process (6).

A hallmark of THS is its dramatic response to corticosteroid treatment. Pain frequently improves within 24 to 72 hours of commencing therapy, and this rapid response may support the diagnosis (3,5). Nevertheless, steroid responsiveness is not pathognomonic and should not replace thorough investigation for alternative causes.

Recurrence occurs in up to half of patients and may develop months or years following the initial presentation (5). Consequently, long-term follow-up is recommended to monitor for recurrent symptoms and ensure an alternative diagnosis does not subsequently become apparent.

References

1. HUNT, W. E., MEAGHER, J. N., LEFEVER, H. E., & ZEMAN, W. (1961). Painful opthalmoplegia. Its relation to indolent inflammation of the carvernous sinus. Neurology, 11, 56–62. https://doi.org/10.1212/wnl.11.1.56
2. Headache Classification Committee of the International Headache Society (IHS) The International Classification of Headache Disorders, 3rd edition. (2018). Cephalalgia : an international journal of headache, 38(1), 1–211. https://doi.org/10.1177/0333102417738202
3. Kline, L. B., & Hoyt, W. F. (2001). The Tolosa-Hunt syndrome. Journal of neurology, neurosurgery, and psychiatry, 71(5), 577–582. https://doi.org/10.1136/jnnp.71.5.577
4. Cakirer S. (2003). MRI findings in Tolosa-Hunt syndrome before and after systemic corticosteroid therapy. European journal of radiology, 45(2), 83–90. https://doi.org/10.1016/s0720-048x(02)00012-8
5. Kim, H., & Oh, S. Y. (2021). The clinical features and outcomes of Tolosa-Hunt syndrome. BMC ophthalmology, 21(1), 237. https://doi.org/10.1186/s12886-021-02007-0
6. Smith, J. L., & Taxdal, D. S. (1966). Painful ophthalmoplegia. The Tolosa-Hunt syndrome. American journal of ophthalmology, 61(6), 1466–1472.