Tolosa-Hunt Syndrome is a painful neuropathy that causes the compression of the cranial nerves that control the eyes, causing intense pain and restricted movement. This occurs due to inflammation of the cavernous sinus and/or superior orbital fissure. Inflammation and subsequent swelling of this area cause the nerves to be compressed. Current therapies involve reducing this inflammation through the use of corticosteroids. In this article, we will explore the pathophysiology of Tolosa-Hunt syndrome.

What is tolosa-hunt syndrome

Tolosa-Hunt Syndrome (THS) is a rare disorder, classified as a painful neuropathy, involving painful headaches localised behind the eyes, often debilitating. It also presents with restricted eye movements (palsy or paralysis), and visual complaints are common after pain. The pain and restricted movement primarily only affect one eye, but in 5% of cases, it does affect both eyes.

THS was characterised in 1954 and 1961 by Dr Tolosa and Dr Hunt, respectively. Since then, it has been estimated that there is 1 case per 1,000,000 people each year. Current remedies focus on pain relief, an easy way to improve the quality of life. Diagnosis, however, is a difficult process, with up to 40% of patients having a false diagnosis.

The pain is described as sharp, shooting, stabbing pain that is usually intense and severe. The pain is found behind the eyes but can stretch to other areas of the frontal and temporal lobes. For THS, the pain tends to relapse over time, consistently causing the same pain regularly every few months or years.

Additionally, in THS, the nerves involved in eye movement are affected, restricting eye movement. There are 3 nerves involved in eye movement, all of which can be targeted, with varying likelihoods: the oculomotor nerve (~80%), the abducens nerve (~70%), and the trochlear nerve (~29%). Other nerves are also involved, such as the ocular portion of the trigeminal nerve (~30%), the sympathetic and parasympathetic functions, which can cause pupil control disturbance.

Issues with Tolosa-Hunt Syndrome can last up to 8 weeks if not resolved, reducing quality of life and functionality due to pain.

It is also known as:

• Painful ophthalmoplegia
• Recurrent ophthalmoplegia
• Ophthalmoplegia syndrome

It is caused by non-specific inflammation behind the eye, in the cavernous sinus and/or superior orbital fissure. The root cause of the inflammation remains unknown, with theories pointing to immune-mediated responses leading to nerve compression. Potential causes of inflammation include tumours, aneurysms, or traumatic head injuries, but these are not always the case or necessary for inflammation. THS has not been associated with any infectious causes.

Pathophysiology

Tolosa and Hunt both agree that the pathophysiology of THS is described as “non-specific, chronic inflammation of the septa and wall of the cavernous sinus with the proliferation of fibroblasts and infiltration with lymphocytes and plasma cells.”  Hunt adds, “Such inflammatory changes in tight connective tissue may exert pressure upon the penetrating nerves.”

What this means is that the inflammation that occurs in the cavernous sinus walls and the septa areas, located behind the eye, results in 4 events:

• An increase in the number of granulomatous fibroblasts
• An increase in the white blood cells and blood plasma is recruited to the site
• An increased number of cytokines

The above events are designed to assist with rebuilding and repairing damaged tissues. This is particularly vital in the brain, where damage can cause lasting effects. These events may occur during inflammation and not as a result of it; in fact, leukocytes (a type of white blood cell) actually may cause inflammation as a protective measure, although in this case, it has possibly malfunctioned.

Increased pressure on the penetrating nerves, causing nerve compression

Due to the increased inflammation and cellular events, there is an increase in pressure, which, along with the inflammation, can cause the pain present in THS. Additionally, it can cause pressure to be exerted on the nerves within the inflamed connective tissue. This leads to issues with eye motor functionality, as the nerves are now not able to respond properly to the desired signals.

The compressed nerves pass through the cavernous sinus and superior orbital fissure, causing painful sensations along with palsy or paralysis of the motor functions of that nerve.

Histopathological examination also shows that cells present in the inflamed area have multiple nuclei and are enlarged.

Hypertrophic pachymeningitis

THS has been considered by some to be a type of ‘idiopathic hypertrophic pachymeningitis (HP)’. Specifically, a focal HP targeting the affected areas.

HP is a chronic progressive inflammatory fibrosis that can affect any part of the dura mater in the brain and spine. The causes of HP include trauma, infections, tumours, autoimmune/inflammatory diseases and spontaneous intracranial hypotension.

Many of these causes are shared with theories of potential THS causes. This focal HP theory will lead to the compression of the nerves, typical of THS, but then also compress additional cranial nerves. This suggests a more spread pathology causing a wider area that is painful.

Other neuropathies

Inflammation in other areas of the brain (systemic inflammation) has not been observed in THS, and though the pain may spread, issues with nerve function in other areas have also not been observed.

However, THS has been seen as a result of other systemic and autoimmune diseases, such as systemic lupus erythematosus, sarcoidosis, and Wegener's granulomatosis. These have vastly different pathologies from THS, but THS is still present due to the inflammation described.

Other diagnoses are common with THS, meaning that an accurate diagnosis is important. Conditions may present with similar symptoms, primarily that of painful ophthalmoplegia, but have a variety of causes unrelated to the pathology of THS. A sinus infection may be mistaken, especially if it is a recurring issue, but due to the different pathologies, many different treatments are needed; in this case, antibiotics.

A particular interest of researchers has been the commonalities between THS and IgG4-related disease, where IgG4-positive plasma cells infiltrate the affected tissues, causing fibrosis and inflammation. If present in the cavernous sinus and/or superior orbital fissure, its clinical presentation is the same as THS. IgG4-related disease, in this manner, appears the same as focal HP and THS on an MRI scan, making diagnosis particularly difficult.

This similar presentation can often lead to a misdiagnosis, leading to the wrong treatment, so it is recommended that those with THS also undergo IgG4 immunostaining to confirm any THS suspicions.

Treatment associated with pathophysiology

Corticosteroids

Corticosteroids are used as the first rapid treatment for acute relapse episodes. They help to decrease inflammation, preventing pain and nerve compression. The dosage is dependent on the state of the individual’s condition and their response.

Often, this treatment course can help prevent relapses in 50% of cases and treat relapses in many others. However, extensive or frequent use of corticosteroids can have lasting harmful effects on a person’s health.

Current research is looking into ways to prevent long-term use of corticosteroids in such a way that still prevents inflammation while reducing steroid use. Recent studies by Arthur et al. (2020) found that newly developed substances reduced the recurrence rate from 50% to 20%. While more research is needed to confirm their findings, and also confirm the best way this medication should be administered.

Gamma knife radiosurgery

Patients with new and old therapies have been unresponsive to medications. In these cases, riskier procedures may be the best solution to alleviating symptoms. Gamma knife radiosurgery is one of these methods, using a precise gamma emitter to surgically remove the inflamed portion to alleviate the neurons beside it.

This is also why correct diagnosis is extremely important for THS, so that people administering care know what won't work and, more importantly, what is necessary.

Diagnosis improvements

More research into the diagnostic techniques and criteria looks to more accurately diagnose THS. The misdiagnosis can halt treatment severely. Advancements made in MRI and imaging technology help differentiate the problem further. Improved diagnostic criteria and techniques are used to prevent false diagnoses and promote proper diagnosis of this condition and other possible related conditions.

Summary

Tolosa-Hunt Syndrome is inflammation of the cavernous sinus and/or superior orbital fissure. Inflammation causes the compression of cranial nerves involved in eye movement, causing an intense amount of pain and restricted movement. Although the initial source of the inflammation is not concretely found, there are treatments that are able to provide relief. These treatments involve the use of corticosteroids to reduce inflammation, relieve the nerves and reduce symptoms.

Future directions point to non-steroidal medications that reduce inflammation to prevent long-term steroid use issues and improve the diagnostic process and criteria to better diagnose and treat those who require it. Improvements in diagnosis are of great importance, as many diseases and conditions share symptoms, and diagnostic issues are extremely common. This is of particular importance as they all require different treatments varying from THS.