What is Tolosa-Hunt Syndrome?

Tolosa-Hunt syndrome is a severe headache caused due to inflammation in the area around and behind the eyes, usually disappearing without treatment after approximately 8 weeks.¹ It affects 1 in a million people a year, offering no bias in terms of sex or race. On average, those around 41 years old are affected, although rarely patients as young as 8 have been affected.^1,2 This sharp, shooting pain presents on only 1 side of the head in 95% of cases, sometimes extending from behind/ around the eyes to the front or side of the head (peri/retroorbital to frontal and temporal lobes of the brain).¹ 

Systemic inflammation isn’t typically seen, so white blood cell counts won’t be elevated, but lymphocytes and plasma cells can invade the area behind the eyes (cavernous sinus and/ or superior orbital fissure).¹ Although there is no known cause for this inflammation, it can recur every few months (on the same side, on the opposite side or both sides of the head)¹. Although symptoms typically improve within 2-3 days of steroidal treatment (sometimes with immunosuppressants), there are no indications whether this treatment can help prevent recurrence.¹

The recurrence of these painful headaches can irritate the cranial nerves in the area, namely the 3rd (oculomotor), 4th (trochlear), 6th (abducens) and upper branch of the 5th (trigeminal) cranial nerves. Because of this, these nerves can cease to function properly, causing temporary or permanent paralysis of their corresponding body parts. 

Due to the rarity of this disease, severe, long-lasting, one-sided headaches with shooting pain in the general eye area coupled with palsy (paralysis/ extreme weakness) of at least one of the corresponding body parts will ordinarily prompt a referral to a neurologist. The palsy may develop at the same time as the headache, or up to 2 weeks afterwards.

Figure 1: Left ocular palsy due to Tolosa-Hunt syndrome (ophthalmoplegia). 9 images show the patient looking in various directions, demonstrating the right eye moving correctly, with the left eye experiencing some paralysis.²

Blood tests can help rule out other causes, as well as cerebrospinal fluid tests. These symptoms, along with imaging scans of the brain, can help provide a diagnosis. Biopsy of the tissue is ordinarily avoided because of the complex nature and high risk of further injury due to the neurosurgery involved.¹

Cranial nerve control

Due to the specific action of each cranial nerve, the approximate area of a lesion/ dural thickening from Tolosa-Hunt syndrome can be isolated from the cranial nerves affected. This can also be used to inform the location affected due to other pathologies such as brain tumours, aneurysms or infections. 

Oculomotor nerve (cranial nerve 3): This controls 4 of the 6 muscles involved in rotating your eyeball. This can move your eye up, down, in towards the nose and up into the outer corner of your skull. It also helped constrict the pupil in response to light being flashed in your eye. It helps open your eyelid, and it helps your sight focus on nearby objects. 

Trochlear nerve (cranial nerve 4): This helps move your eye outwards. It helps your eye look down, and moves the top of your eye towards your nose. 

Trigeminal nerve (ophthalmic branch) - (top branch of cranial nerve 5): This allows you to feel things in your eyelid, scalp, forehead, cornea and conjunctiva. It also provides sensation to your nose and sinuses, but doesn’t cause movement in any of these body parts.

Abducens nerve (cranial nerve 6): controls movement of your eye outwards from the centre of your face, controlling only 1 of the 6 eye muscles. 

Damage to any of these can be symptomatic of Tolosa-Hunt syndrome, along with a host of other neurological symptoms, which can prompt further inquiry.

Other causes

Other causes of these symptoms could include brain aneurysms, tumours or other types of trauma. Bloods, brain scans and cerebrospinal fluid tests can also help rule out.^1,2 

• Anisocoria
• CNS Whipple Disease
• Diabetic Neuropathy
• Mycobacterium tuberculosis
• Lyme Disease
• Contiguous sinusitis
• Migraine Headache
• Neurosarcoidosis
• Sarcoidosis
• Wegener's granulomatosis
• Pediatric Craniopharyngioma
• Polyarteritis Nodosa
• Primary CNS Lymphoma
• Primary Malignant Skull Tumours
• Systemic Lupus Erythematosus
• Tuberculous Meningitis
• Varicella Zoster
• Carotid-cavernous fistula
• Herpes Zoster virus
• Periostitis
• Carotid-cavernous thrombosis
• Pituitary adenoma
• Meningioma
• Craniopharyngioma
• Chordoma
• Diabetic ophthalmoplegia
• Eosinophilic granuloma
• Orbital pseudotumor
• Ophthalmoplegic migraine
• Nasopharyngeal tumour metastasis
• Squamous cell carcinoma metastasis
• Lymphoma metastasis
• Multiple myeloma metastasis
• Carcinomatous metastases
• Giant cell arteritis
• Treponema pallidum infection
• Mucormycosis infection
• Actinomycosis infection

Figure 2: Magnetic resonance imaging (MRI) of a patient with Tolosa-Hunt syndrome. White arrows point to thickening of the dura in a fashion typical of Tolosa-Hunt syndrome.³ 

Surgical intervention

In some cases, no thickening or lesions may be seen with MRI around the eyes, brain or cavernous sinus. If the condition is responsive to steroids, e.g. hydrocortisone, and there is a positive skin tuberculosis test (Mantoux test) and there is tuberculosis within the body (positive QuantiFERON test), exploratory surgery may be required for definite diagnosis, especially due to the debilitating nature of this condition. This is especially important if positron emission tomography (PET) scans fail to show any abnormality, too, even with fluorodeoxyglucose. 

Biopsy in this case can help differentiate between tuberculosis and Tolosa-Hunt Syndrome. Due to the rarity of surgical intervention in these cases, there are very few surgical approaches documented. The suspected lesion can be accessed from the eye socket or the side of the head (frontotemporal approach), depending on the positioning relative to the optic nerve. 

One of the most recent cases described is as follows:

Positioning and initial approach

• Perform a left frontotemporal craniotomy. This provides access to the cavernous sinus through the lateral skull base
• Resection of the sphenoid ridge and base of the temporal bone should be done to allow adequate exposure of the lateral wall of the cavernous sinus
• No zygomatic or orbitozygomatic osteotomy is required for this approach

Dissection of the meningo-orbital band

• Identify and carefully cut the meningo-orbital band to facilitate elevation of the dura propria from the lateral wall of the cavernous sinus. The dura may be tightly adhered to the inner layer of the sinus, so be prepared for more extensive dissection

Elevating the dura propria

• Once the meningo-orbital band is severed, attempt to elevate the dura propria from the cavernous sinus wall. In some cases, the dura may be thick and tightly adherent, requiring sharp dissection with microscissors to separate the dura propria from the inner layer of the cavernous sinus

Exposure of the trigeminal nerve and ganglion

• Carefully identify and expose the trigeminal nerve (V1, V2) and trigeminal ganglion. These structures are important landmarks for identifying the entry point into the cavernous sinus
• Surgeons can enter the cavernous sinus anterolaterally, between the V1 and V2 branches of the trigeminal nerve (the anterolateral triangle). This is a commonly chosen approach due to its relative safety and adequate access for obtaining a biopsy sample
  

Biopsy entry points

• Anterolateral Triangle: The space between V1 and V2 allows for easier access to the cavernous sinus. This approach is typically preferred for a safe biopsy
• Far Lateral Triangle: Entry between V2 and V3 is an alternative, but it’s more difficult to navigate and offers a narrower working space. While this area is less likely to injure the abducens nerve, it may not allow for easy specimen retrieval
• Parkinson Triangle: This approach involves entry between the trochlear nerve and V1. However, this may require more temporal lobe retraction, and additional dissection could increase bleeding risks

Enlarging the superior orbital fissure

• If necessary, enlarge the superior orbital fissure to improve access to the cavernous sinus and facilitate biopsy collection. The bony lateral wall of the fissure should be carefully thinned to avoid damage to surrounding structures.
  

Identification of abnormal tissue

• Carefully inspect the area between V1 and V2 for abnormal tissue that may replace the cavernous sinus structures. This tissue may appear whitish, elastic, and hard, and could be indicative of the pathological changes associated with Tolosa-Hunt syndrome

Specimen collection

• Once the abnormal tissue is identified, use microscissors to sharply resect several pieces of the tissue for biopsy. Handle the tissue with care to avoid damage to the surrounding neural structures

4 other surgical cases for biopsy have been described, but their presentation differed. ^5,6,7,8 Two of these involved an aneurysm that also affected multiple cranial nerves, and thus the surgical approach differed. ^7,8 Nerve and vascular injury is possible, so after ensuring the dura has been closed, these patients are carefully followed post-operatively to ensure there are no complications. ⁵ 

Figure 3: Hematoxylin-stained biopsy results confirming Tolosa-Hunt syndrome. Thick, fibrous tissue with cellular degeneration and inflammatory cell infiltration (x100 magnification)4. Epithelioid and Langhan cells are absent from the sample (x200 magnification).⁴

Summary

Tolosa-Hunt syndrome is a recurring, long-lasting headache occurring in and around the eye for unknown reasons. Steroidal treatment and immunosuppressants can ordinarily treat this condition within 1-2 weeks, though without treatment, it often resolves within 8 weeks. However, in some very rare cases, surgical biopsy is required for diagnosis, especially when brain imaging is clear and other comorbidities are present. Surgical intervention can occur by accessing the region from the eye socket or from the side of the head, depending on where the suspected abnormality is present. Nerve and vascular injury are possible in these cases, which is why surgical intervention is often avoided.