Background

Tolosa-Hunt syndrome is a unilateral and severe periorbital headache accompanied by painful and limited movement of the eyes. It is estimated that around one case per million per year is the incidence rate of Tolosa-Hunt syndrome, and in these cases, there is no specificity for race or geographical differences. This is a rare condition with the onset age of forty-one years. There is no difference in predisposition of males and females, and around 5% of affected cases showed bilateral involvement. This condition is characterised by intense pain, often described as sharp, shooting, stabbing, or burning. The pain is usually felt around the eye but can also extend behind it and into the forehead. In most cases, the pain is the first symptom and may appear up to a month before any eye movement problems develop. The pattern of Tolosa-Hunt syndrome is typically relapsing-remitting, with episodes occurring every few months or years.¹

Aetiology and pathophysiology of Tolosa-Hunt syndrome

The cause of Tolosa-Hunt syndrome is idiopathic, which indicates inflammation in the region of the cavernous sinus or superior orbital fissure.²

Potential causes of Tolosa-Hunt syndrome 

• Tumor
• Traumatic injury
• Aneurysm
• Autoimmune conditions¹

Pathophysiology of Tolosa-Hunt syndrome 

The pathophysiology of Tolosa-Hunt syndrome is still unclear, but it is found that chronic, non-specific inflammation in the cavernous sinus affects its walls and septa, leading to the proliferation of fibroblasts and the accumulation of immune cells such as lymphocytes and plasma cells. Because this inflammation occurs in dense connective tissue, it can put pressure on nearby nerves, potentially causing symptoms. The presence of granulomatous material, including specialised immune cells like epithelioid and giant cells, further contributes to the condition, though necrosis is uncommon. Additionally, the dura mater within the cavernous sinus tends to thicken as part of the inflammatory process. Cranial nerves III, IV, VI and the superior division of the V cranial nerve contribute to the pathology of Tolosa-Hunt syndrome.¹

Clinical manifestations of Tolosa-Hunt syndrome

• Constant pain behind the eyes
• Reduced eye movement
• Ptosis
• Double vision
• Large pupil
• Facial numbness³

Tolosa-Hunt syndrome usually doesn’t affect other parts of the nervous system or the body. However, some individuals will experience symptoms such as nausea and vomiting due to intense pain. These will improve as the pain gets reduced and long-term fatigue is noted in some cases. If this is left untreated, the condition might persist for up to 8 weeks but typically improves itself. Fortunately, lasting neurological problems are uncommon.

Diagnostic criteria of Tolosa-Hunt syndrome

Generally, diagnosis of Tolosa-Hunt syndrome is based on clinical signs and symptoms, neuroimaging(MRI- demonstrates cavernous sinus thickening as a result of aberrant soft tissue; Convexity of the cavernous sinus's lateral wall and extension into the orbital apex) and the patient's responsiveness to steroids. Although it lacks sensitivity, high-resolution computed tomography (HRCT) can also reveal soft tissue alterations. Other supportive evidence for diagnosis includes Laboratory investigations and cerebrospinal fluid investigations. These supportive investigations help to rule out various causes of ophthalmoplegia. Tissue biopsy is not usually considered for diagnosis as there is a high risk and difficulties in performing this test.¹

Laboratory investigations include complete blood count (CBC), HbA1c, comprehensive metabolic panel, C-reactive protein(CRP), erythrocyte sedimentation rate(ESR), antinuclear antibody (ANA), anti-ds DNA antibody, Serum Protein Electrophoresis, Anti-nuclear Cytoplasmic Antibody, Anti-sm Antibody, Lyme Panel and Fluorescent Treponemal Antibody Test. 

Cerebrospinal fluid investigations include protein, cell count, glucose, cytology, angiotensin converting enzyme, culture and gram stain, syphilis and Lyme serology. In patients with Tolosa-Hunt syndrome, blood and CSF tests should be normal. Another diagnosis should be taken into consideration if abnormalities are discovered.¹

International Headache Society (IHS) diagnostic criteria for Tolosa-Hunt syndrome

This IHS diagnosis has four criteria to diagnose Tolosa-Hunt syndrome:

1. One-sided headache

2. Fulfilling both of the following criteria

• Biopsy or MRI showing granulomatous inflammation of the cavernous sinus, superior orbital fissure or orbit
• Weakness or limited movement in the eye muscles due to partial paralysis of one or more cranial nerves (IIIrd, IVth, or VIth) on the same side of the head

3. Causation is supported if both of the following conditions are met:

• The headache began within two weeks before or at the same time as the weakness or paralysis of the IIIrd, IVth, and/or VIth cranial nerves
• The headache is mainly felt around the brow and eye on the same side

4. Additionally, there is no better explanation for the symptoms based on other causes of headache⁴

Autoimmune conditions associated with Tolosa-Hunt syndrome

Systemic lupus erythematosus (SLE) is considered a chronic autoimmune condition that affects multiple organs with different severities. This condition causes inflammation and tissue damage as a result of autoantibody production. In around 1 to 10% of patients, there is neuro-ophthalmic damage, which is very rare. These neuro-ophthalmic involvements in SLE can lead to symptoms such as cranial nerve palsy, optic neuritis, papilledema, retinal vasculitis, ischemic optic neuropathy and vascular occlusive disease, which affects the eye. Early diagnosis and management is very crucial to prevent visual impairment. Tolosa-Hunt syndrome is a very rare complication of SLE. In SLE, the immune system generates antibodies that attack the body's own tissues, causing extensive inflammation and damage. The detection of high antinuclear antibodies (ANA) titres with a speckled pattern in this patient suggests ongoing autoimmune activity and reinforces the possibility that Tolosa-Hunt syndrome could, in some cases, manifest as an extra-pulmonary complication of SLE.⁵

Management of Tolosa-Hunt syndrome

As first-line treatment, steroids are used. There are currently no established guidelines for the optimal dosage, course of treatment, or mode of administration for Tolosa-Hunt syndrome. In certain situations, symptoms could go away without intervention. Although steroid treatment is quite good at reducing orbital pain, there isn't much proof that it hastens the healing process for cranial nerve palsies. Typically, a high-dose glucocorticoid regimen is started for a few days and then tapered gradually over weeks to months, depending on how well symptoms resolve. MRIs and other follow-up imaging can be useful, although they frequently come a few weeks after clinical recovery.

To reduce the negative effects of long-term steroid use or to achieve long-term disease control, a small percentage of patients may need immunosuppressive therapy with other medicines. Azathioprine, methotrexate, mycophenolate mofetil, cyclosporine, and infliximab have all been used as second-line therapies. Radiotherapy has occasionally been described as a first-line treatment when steroids are contraindicated or as a second-line alternative for recurring flare-ups that result in steroid dependence. Before starting second-line treatment, these patients usually have a biopsy-confirmed diagnosis of Tolosa-Hunt syndrome.¹

Summary 

As Tolosa-Hunt syndrome is a rare condition causing damage to the eyes, early diagnosis is very crucial to avoid further complications of the disease. Studies should be conducted to rule out the exact cause of this disease. Differential diagnosis can be considered if the symptoms of this condition may align with other autoimmune diseases like systemic lupus erythematosus. Educating patients and family members about this condition is very necessary for better patient outcomes