Overview

Tolosa-Hunt syndrome (THS), also known as painful ophthalmoplegia, recurrent ophthalmoplegia, or ophthalmoplegia syndrome, is a condition in which the patient suffers from a severe headache in the unilateral periorbital region of the head, including pain during eye movement, thus restricting the movement. The National Organisation for Rare Disorders (NORD) characterised THS as a rare disorder. The International Headache Society (IHS) included THS in its headache classification as the most painful cranial neuropathy. A Spanish neurosurgeon, Dr. Eduardo Tolosa, described THS for the first time in 1954, followed by the reporting of similar cases by Hunt et al. in 1961, and so named as “Tolosa-Hunt Syndrome” by Simth and Taxdal for the first time in 1966. THS was considered an unclear clinical unit, for which numerous studies have been made around the world, with the increase in several cases.¹ Recurrent ophthalmoplegia is described by granulomatous inflammation of the cavernous sinus (CS) region,² including the additional area such as the pain behind the eyeball, typically known as retrobulbar pain that may or may not lead to ophthalmoplegia for several days.

Pathophysiology of tolosa-hunt syndrome 

Tolosa-Hunt syndrome involves inflammation and paresis of the third, fourth, and sixth cranial nerves (CNs), including the first and rarely the second division of the trigeminal nerve,³ as the neurological involvement. The oculosympathetic fibres and the optic nerves may also be involved occasionally.⁴ 

There isn’t any report related to the systemic inflammation of the THS; there is a little association of the inflammation occurring within the cavernous sinus region and the intracranial nerves. THS does not have any clear autoimmune cause; it has been associated with other inflammatory autoimmune and systemic disorders such as sarcoidosis, systemic lupus erythematosus, and Wegener’s granulomatosis and also with the presenting complaint of these diseases. THS has no connection with infectious agents such as viruses, bacteria, fungi, etc.⁵ 

Relationship of THS to other cranial neuropathies

Cavernous sinus syndrome

Cavernous sinus syndrome involves the generalised involvement of cranial nerves within the walls of the Cavernous sinus (CS), namely the internal carotid artery, trigeminal nerves, ocular motor nerves, and sympathetic fibres. There is a chance that many other diseases to occur due to the presence of paranasal sinuses along with CS due to their proximity. The diseases may include: 

• Fungal infections generally spread to adjoining paranasal sinuses
• Aneurysm is the internal carotid artery disorder
• Malignancies, including the nasopharyngeal carcinomas⁶

CSS is related to large mortality and morbidity. The reason behind mortality is the occurrence of primary disease entities such as fungal infections and, in the worst cases, malignancies. However, the morbidity is due to the organs involved in the disease performing different vital functions, such as mastication (chewing of food) and vision of the eye. It is difficult to determine the exact underlying cause of CSS because of its distinctive features, that is, its association with different disease processes and their diverse nature, which affect CS, partly due to the fact that biopsies are not possible in that area. Therefore, the majority of the time, treatment is experimental.⁷

Meningioma 

Meningioma has a greater difference in appearance as compared to THS because meningioma is characterised by a brain tumour that grows within the meninges, which are the protective layers of the brain. At the same time, THS is a condition of inflammation within the brain-specific region that is the cavernous sinus, which affects the eyes, causing paralysis of the eye muscles. The neuroimaging diagnosis through magnetic resonance imaging (MRI) of THS appears to be the inflammation of the CS region; in contrast, the meningiomas are distinct masses found on brain imaging.⁸ The problem in eye movement (ophthalmoplegia) appears in both THS and meningioma, but the difference is in the location of THS, which is the unilateral periorbital region, while the symptoms of meningioma appear as per the location of the tumour and include headaches, seizures, and neurological defects.⁹

Cluster headaches

The international classification of headache disorder in its third beta revision in 2013 classified cluster headache (CH) as its own disorder, representing migraine along with restlessness/agitation and autonomic features like runny nose, swelling of the eyelid, and facial flushing, unlike THS, which is associated with a single episode of prolonged pain and involvement of cranial nerves affecting eye muscle movement.¹⁰

The criteria to differentiate CH from THS are the occurrence of severe to very severe pain in the unilateral orbital, supraorbital, and/or temporal regions of the brain, which lasts for 15 minutes to 3 hours when untreated. The frequency of the attack is every other day or once a week, with the symptoms active for half of the duration of the attack. CH lacks the involvement of cranial nerves and the appearance of inflammation, unlike THS.⁸ 

Multiple sclerosis (MS)

The relationship of Multiple Sclerosis (MS) with THS is the similarity that they both are neurological conditions associated with inflammation, but the cause and presentation of MS are not the same as those of THS. MS is a chronic, long-lasting autoimmune disease of the central nervous system (CNS). As it is considered an autoimmune disorder, this condition is the body’s attack against itself. The complexity of this autoimmune response ranges from mild to severe. In severe cases, the patient may lose the ability to speak properly, see, write in good handwriting, and walk properly, and may face difficulty performing different daily routine tasks as the communication between the brain and different parts of the body gets disrupted. The myelin sheath of the nerve fibre, which is composed of protein and fats, is attacked by the body’s immune system, causing the loss of myelin and forming a scar on the nerve tissue called a plaque, or lesion. This led to the misinterpretation of the electrical signals to and from the brain. The repetitive attack results in the condition known as relapsing-remitting MS. 

The cause of MS is known, such as:

• Autoimmune disorder
• Environmental factors
• Infectious agents, such as viruses
• Genetic factors

Unlike THS, MS can affect any part of the CNS, but THS is only associated with the cavernous sinus region and is frequently responsive to steroid treatment, while MS has multiple treatment options, like medicines and equipment such as canes, braces, or walkers. Rehabilitation activities, which may help patients get back to normal daily functions and make the right decisions related to work, help them get back to normal function.¹¹

Diabetic cranial neuropathy

Cranial neuropathy is a complication in diabetic patients and is termed diabetic cranial neuropathy. In this condition, the damage to cranial nerves occurs due to a high blood glucose level, typically in older patients with poorly controlled diabetes. Diabetic cranial neuropathy is extremely rare, which leads to poor diagnosis, as this could only be diagnosed if the patient presents with painful ophthalmoplegia and simultaneous multiple cranial neuropathies.¹² The concomitant occurrence of THS and diabetic cranial neuropathy can be treated with the use of prednisolone 60 mg daily, with the dose tapered off during the eighth week of treatment, along with a proper regimen of antidiabetic medications and insulin therapy, leading to decreased and controlled symptoms of THS, including headache, periorbital pain, and hyperglycemia.¹³

Giant cell arteritis (GCA)

The relationship between giant cell arteritis (GCA) and THS is the uniform appearance of inflammation around the eye and head in both cases, but they differ in their causes and presentation. GCA is a systemic inflammatory disease, affecting the medium and large arteries in the head of particularly older adults with an age greater than 50 years. GCA exhibits varied clinical expressions in both cranial and extracranial locations, particularly involving the cranial branches of a carotid artery, leading to headache and vision problems,¹⁴ while in comparison, THS is typically associated with the cavernous sinus region of the brain. The large arteries in GCA include those supplying blood to the temporal region (the region with the hairline), leading to symptoms like headache, particularly in the temples, jaw pain while chewing, tenderness of the scalp, vision problems like double or blurry vision, and even temporary vision loss. The appearance of fatigue and fever may also occur, with loss of appetite and muscle aches in the upper arms, shoulders, and lower body parts such as hips, upper thighs, lower back, and buttocks.¹⁵ The diagnosis for GCA is through physical examination, like checking the head for scalp tenderness or swelling of the temporal areas.¹⁵ The examination tests include the temporal artery if GCA is suspected. Other imaging tests that help to find changes that are consistent with the disease, such as swelling and inflammation in the large arteries, include an ultrasound of the temporal region, positron emission tomography (PET), magnetic resonance imaging (MRI) scan, or computed tomography (CT) test.¹⁶

Summary

In contrast to different neuropathological problems, it has been noted that the importance of recognising THS has increased manyfold. For that purpose, Smith and Taxdal in 1966 introduced the eponym THS for defining the trait of unilateral orbital pain, additional cranial nerve (CN) palsies, and the symptoms associated with corticosteroid treatment. THS if response to the corticosteroid treatment acts as an alternate marker for confirming the diagnosis of THS, and the early diagnosis is more important to prevent the exacerbation of disease.