Overview 

Tolosa-Hunt syndrome (THS) is a rare neurological disease of the eyes, it is categorised as an ophthalmoplegia syndrome. THS affects eye movement, causing pain and restriction. This results in the primary pain characteristics: unilateral (one side of the eye) and periorbital headaches in the surrounding tissue of the eyes. 

The syndrome affects everyone and is equally common in both men and women. The typical age it develops at is 41 years old, but there have been rare cases of THS in children under the age of 10.¹ 

The early diagnosis of Tolosa-Hunt syndrome is important as it can imitate other serious neurological diseases and when it is identified it can be treated with corticosteroids preventing anything worse from arising.² 

Pathophysiology behind pain in Tolosa-Hunt syndrome 

Tolosa-Hunt syndrome’s cause is still unknown but it is speculated to develop by non-specific granulomatous inflammation; thickening in the region of the cavernous sinus and the superior orbital fissure,⁴ along with the rapid growth of fibroblasts, and lymphocytes and plasma cells invading the walls.¹ The cavernous sinus is a venous network made up of cranial nerves III, IV, VI and the superior division of the fifth cranial nerve, when inflammation arises it applies pressure on the nerves leading to periorbital pain.³  

Anatomy of the cranial nerves 

There are twelve pairs of cranial nerves that are found in the brain and these nerves control sensory and motor functions of the head and neck. 

• Olfactory nerve (CN I)
• Optic nerve (CN II)
• Oculomotor nerve (CN III)
• Trochlear nerve (CN IV)
• Trigeminal nerve (CN V)
• Abducens nerve (CN VI)
• Facial nerve (CN VII)
• Vestibulocochlear nerve (CN VIII) 
• Glossopharyngeal nerve (CN IX)
• Vagus nerve (CN X)
• Accessory nerve or spinal accessory nerve (CN XI)
• Hypoglossal nerve (CN XII)

There are some nerves that pass through the cavernous sinus and superior orbital fissure regions which are structures impacted by Tolosa-Hunt syndrome. The cranial nerves include the oculomotor nerve (CN III) which alters the width of pupils and opens and moves the eye, the trochlear nerve (CN IV) which allows the eyes to look down in the direction of the nose and away and the abducens nerve (CN VI) which makes the eyes move left to right. The trigeminal nerve which transmits sensations to the eyes is also found through the cavernous sinus.¹

Characteristics of pain

Location of pain 

• Unilateral headache: The pain in Tolosa-Hunt syndrome always remains on one side of the head¹ 
• Periorbital and retro-orbital: Pain usually originates in the periorbital region but can sometimes occur in the retro-orbital region, extending towards frontal and temporal areas⁵ 

Description of pain 

• Sharp, shooting, and stabbing: knife-stab like pain and pressure in the eye⁶
• Severe, boring, and intense:⁵ boring pain around the orbital region⁶ 

Duration of pain 

• If left alone without being treated the orbital pain lasts around these areas for around 8 weeks, which can lead to nausea and vomiting
• 2 weeks of ocular dysfunction due to pain occurring in the ipsilateral palsies of the third, fourth, and sixth cranial nerves⁵

Response of pain to treatment 

• THS Pain responds very fast to treatment as pain can be relieved after 48 hours when treated with large doses of systemic corticosteroids
• Treatment with systemic corticosteroids improves cranial nerve dysfunction and decreases abnormal tissue volume
• Even so, there’s a possibility that after treating it with corticosteroids recurring attacks and spontaneous remission may reappear after months or years. This would require the diagnosis of lymphoma and sarcoidosis through a biopsy⁵

Signs and symptoms of Tolosa-Hunt syndrome

Ophthalmoplegia (restricted eye movements)

Ophthalmoplegia appears from the granulomatous inflammation of the cranial nerves inside the cavernous sinus, this paralyses the ocular motor nerves responsible for coordinating eye movements.⁷

Ptosis (drooping of the upper eyelids) 

The damaged third cranial nerve struggles to support the upper eyelids and movement of the muscles is restricted which leads to ptosis.⁸

Diplopia (double vision) 

Followed by Ptosis, diplopia occurs when the eyes see overlapping images, resulting from the misalignment of the eyes because of the damage to the third, fourth or sixth cranial nerves. There are two types of diplopia which can either be monocular where it only happens when one eye is open or binocular when both eyes are shut.⁹

Proptosis (protruding of the eye) 

Proptosis refers to abnormal swelling and protrusion of the eye, this is caused by the inflammation of the cranial nerves. 

Tolosa-Hunt syndrome differential diagnosis

There are many possible conditions warranting differential diagnosis.¹ 

• Benign skull tumours 
• Brain Mets
• Cavernous sinus syndromes
• Cerebral aneurysm 
• Cerebral venous thrombosis 
• CNS Whipple Disease
• Diabetic Neuropathy
• Epidural Hematoma
• Lyme Disease
• Meningioma
• Migraine Headache
• Neurosarcoidosis
• Pediatric Craniopharyngioma
• Polyarteritis Nodosa
• Primary CNS Lymphoma
• Primary Malignant Skull Tumours
• Systemic Lupus Erythematosus
• Tuberculous Meningitis
• Varicella Zoster

Diagnostic approach 

It is important to note that a diagnosis of Tolosa-Hunt syndrome can only be made by exclusion because there are no definitive tests available, so the possible disorders listed in differential diagnosis must be acknowledged and excluded before diagnosing for THS. Diagnosis is typically carried out using high-resolution CT and MRI techniques. These techniques are important for looking at the cavernous sinus and superior orbital fissure. 

However, there can be limitations with using MRI as it lacks specificity. For instance, some diagnostic features of Tolosa-Hunt syndrome can also be found in other disorders such as sarcoidosis, lymphoma, and meningioma. Also, the reduction in size of the original imaging abnormalities does support THS but doesn’t have diagnostic potential. It is suggested that MRI is repeated after treatment with corticosteroids. 

High-resolution CT is less sensitive than MRI and has the ability to detect changes in the soft tissue of the cavernous sinus and the superior orbital fissure. High resolution CT can be used together with MRI to find calcification and changes in the bones. 

There are other techniques used to diagnose specific features of Tolosa-Hunt syndrome such as using cerebral angiography to detect abnormalities in the intracavernous carotid artery. A neurosurgical biopsy is another technique that is rarely carried out as it is recommended for patients who have progressive neurological impairments, no response to corticosteroids and neuroimaging examinations show abnormalities linked with THS.⁵ 

Diagnostic criteria of Tolosa-Hunt syndrome

• Persistent pain in the ophthalmic division of the trigeminal nerve
• Dysmotility and pupillary defects caused by damage to the third, fourth and sixth cranial nerves 
• Acute or subacute symptoms as a response to corticosteroids
• Inflammation within the cavernous sinus⁵ 

Summary 

Tolosa-Hunt syndrome is a rare neurological condition that is characterised by unilateral and periorbital headaches and severe ophthalmoplegia. It results in intense pressure in the cranial nerves and idiopathic granulomatous inflammation in the cavernous sinus and superior orbital fissure. Correct diagnosis and successful treatment relies on understanding its specific pain characteristics. 

The pain related with Tolosa-Hunt syndrome is usually described as intense boring and sharp. If treatment isn’t received immediately, the pain can last for weeks and even months. Treatment with corticosteroids significantly reduces Tolosa-Hunt syndrome pain and relieves symptoms as it does not respond well to other usual treatments for headaches. 

Patients experience symptoms such as ptosis (drooping of eyelids), diplopia (double vision), and ophthalmoplegia due to damage to the cranial nerves. Inflammation of the cavernous sinus can cause some proptosis (protrusion of the eye). These symptoms allow Tolosa-Hunt syndrome to be easily distinguished from other disorders such as migraine headaches. 

Diagnosis of Tolosa-Hunt syndrome is quite complex as diagnosis happens by exclusion of other conditions such as cerebral venous thrombosis or primary malignant skull tumours which are stated as part of differential diagnosis. The main diagnostic approach is the combination of MRI with High-resolution CT scans to find inflammation in the cavernous sinus. There are specific diagnostic criteria to make the process easier to link to Tolosa-Hunt syndrome such as acute or subacute symptoms in response to treatment with corticosteroids. 

Overall, these pain characteristics must be recognised early to prevent recurrent attacks and prolonged pain. For Tolosa-Hunt syndrome to be diagnosed and managed effectively, it is important to raise awareness about the pain characteristics that emerge from it to more doctors and individuals.