Tolosa-Hunt Syndrome

Background

Tolosa-Hunt syndrome (THS) is a painful ophthalmoplegia caused by nonspecific inflammation of the cavernous sinus or superior orbital fissure. In 2004, the International Headache Society provided a definition of the diagnostic criteria which included granuloma.^[1] See the image below.

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MRI of a 40-year-old man with severe periorbital pain ocular sinister (OS; ie, left eye), complete oculomotor nerve palsy OS, and partial abducens ner....

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Pathophysiology

Nonspecific inflammation (noncaseating granulomatous or nongranulomatous) within the cavernous sinus or superior orbital fissure is the cause of the constant pain, which characterizes the onset of this disorder. Ophthalmoparesis or disordered eye movements occur when cranial nerves III, IV, and VI are damaged by granulomatous inflammation. Pupillary dysfunction may be present and is related to injury to the sympathetic fibers in the cavernous portion of ICA or parasympathetic fibers that surround the oculomotor nerve. Trigeminal nerve involvement (primarily V1) may cause paresthesias of the forehead. Pathological involvement beyond the cavernous sinus, superior orbital fissure, or apex of the orbit occurs rarely, and the disorder is part of a continuum with idiopathic orbital pseudotumor, with which it shares histopathologic features. Spontaneous remissions can occur; relapses may occur in up to 40% of the patients.

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Epidemiology

Frequency

Tolosa-Hunt syndrome (THS) is uncommon in both the United States and internationally. The disorder is rare during the first 2 decades of life; in people older than 20 years, it appears to have an even distribution. When THS occurs in children, the course of the disorder appears to be similar to that experienced by adults.^[2] THS affects males and females equally. And, as stated, although rare in children it is important to keep this condition in the differential diagnosis.^[32]

Mortality/Morbidity

Tolosa-Hunt syndrome is not a fatal disorder; patients experience unilateral onset of acute orbital pain and ophthalmoparesis, and the disorder may threaten sight if untreated inflammation extends beyond the cavernous sinus to affect the optic nerve.

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History

See the list below:

• Patients present with usually severe retro-orbital or periorbital pain of acute onset. This pain may be described as constant and "boring" in nature.
• Diplopia related to ophthalmoparesis follows the onset of pain (in rare cases, the ophthalmoparesis precedes the pain, sometimes by several days).
• Patients may report visual loss. This is noted if the inflammation extends into the orbit to affect the optic nerve, and it is not a factor in disease limited to the cavernous sinus.
• Paresthesias along the forehead may be described if the first division of the trigeminal nerve is involved.
• Tolosa-Hunt syndrome is most often unilateral, although bilateral cases have been described.
• Tolosa-Hunt syndrome frequently mimics other conditions; a single characteristic that is pathognomonic for this process does not exist. As such, realizing that this is a diagnosis of exclusion becomes even more important. Many of the processes that are found within the differential diagnosis of Tolosa-Hunt syndrome can have significant associated morbidity if not diagnosed and treated appropriately.

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Physical

See the list below:

• Painful ophthalmoparesis or ophthalmoplegia is the hallmark of this syndrome.
• In addition to the optic and trigeminal nerves (V1, rarely V2 distribution), any of the ocular motor nerves may be involved. The oculomotor and abducens nerves are most commonly affected. Evidence of incomplete third nerve palsy with or without pupillary sparing may be present. Conversely, inflammatory involvement of the sympathetic nerves passing through the interior of the cavernous sinus may produce Horner syndrome with miosis. The combination of unilateral oculomotor palsy and Horner syndrome increases the localization specificity for the cavernous sinus.
• Ptosis may be observed related to oculomotor palsy. Lid swelling is more likely to occur with orbital disease rather than inflammation limited to the cavernous sinus. These changes have been misdiagnosed as a complication of sinusitis, as reported by Lachanas et al.^[3]
• Mild proptosis and/or optic disc edema may be noted if the orbit is involved.
• Evidence of trigeminal nerve involvement is suggested by loss of the ipsilateral corneal reflex.
• The International Headache Society criteria for Tolosa-Hunt syndrome^{[4, 5]} include the following:

  • Episode(s) of unilateral orbital pain for an average of 8 weeks if left untreated
  • Associated paresis of the third, forth, or sixth cranial nerves, which may coincide with onset of pain or follow it by a period of up to 2 weeks
  • Pain that is relieved within 72 hours of steroid therapy initiation
  • Exclusion of other conditions by neuroimaging and (not compulsory) angiography

   

  

   

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Causes

The cause of Tolosa-Hunt syndrome is unknown (idiopathic).

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Laboratory Studies

The diagnosis of Tolosa-Hunt syndrome is usually one of exclusion.

CBC count, erythrocyte sedimentation rate (ESR), electrolytes with glucose, thyroid function tests, fluorescent treponemal antibody (FTA), antinuclear antibody (ANA), lupus erythematosus (LE) preparation, antineutrophil cytoplasmic antibody (ANCA), serum protein electrophoresis, Lyme titre, angiotensin-converting enzyme (ACE) level, and HIV titre are helpful in eliminating other processes. This level of evaluation is required to exclude other conditions, which can have significant morbidity associated.

Cell count and differential, protein, glucose, fungal and/or bacterial cultures, Gram stain, cytology, and opening pressure of CSF are helpful in eliminating conditions mimicking Tolosa-Hunt syndrome; a mild (lymphocytic) pleocytosis within the spinal fluid may occur in patients with Tolosa-Hunt syndrome.

Anti-GQ1b antibodies may be helpful in distinguishing early, painless Tolosa-Hunt syndrome from Miller Fisher syndrome.

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Imaging Studies

MRI^[6] of the brain and orbit with and without contrast, magnetic resonance (MR) angiography or digital subtraction angiography (DSA), and CT scan of the brain and orbit with and without contrast may all be useful (see the images below). Inflammatory changes in the cavernous sinus, superior orbital fissure, and/or orbital apex are typically observed on high-resolution contrast-enhanced imaging. In the authors' experience, thin-slice high–magnetic field MRI of the cavernous sinus region, including coronal sections with and without contrast and fat-suppressed cuts of the orbital regions, is the modality of choice. These changes are not specific for Tolosa-Hunt syndrome and may also be present in neoplastic conditions of the cavernous sinus. Enlargement of the optic nerve or external ocular muscles has been described, emphasizing the continuum with idiopathic orbital inflammatory disorders.^[31]

Note that findings on all imaging studies may be normal in some cases of Tolosa-Hunt syndrome.

Narrowing of the internal carotid artery within the cavernous sinus may be identified on angiography. Note that these changes are not specific to Tolosa-Hunt syndrome.

MRI with 3-dimensional constructive interference in steady state (3D CISS) provides an enhanced picture within the cavernous sinus. This type of imaging may assist with future diagnoses of TSH, but it is not yet used routinely.^[7]

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MRI of a 40-year-old man with severe periorbital pain ocular sinister (OS; ie, left eye), complete oculomotor nerve palsy OS, and partial abducens ner....

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Coronal T1-weighted MRI with (below) and without (above) enhancement demonstrates left cavernous sinus fullness consistent with Tolosa-Hunt syndrome (....

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Procedures

Biopsy of the lesion may be required to confirm the diagnosis. The technical difficulty of cavernous sinus region biopsies usually mitigates for a trial of steroids; nonetheless, biopsy may be needed to exclude neoplasm or if symptoms are progressing, atypical, or recurrent.

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Histologic Findings

Biopsy reveals nonspecific granulomatous or nongranulomatous inflammation. This is histologically indistinguishable from the pathology of orbital pseudotumor, and these diseases may exist along a continuum.

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Medical Care

Corticosteroids are the treatment of choice, usually providing significant pain relief within 24-72 hours of therapy initiation. Ophthalmoparesis usually requires weeks to months for resolution; indeed, ophthalmoparesis may not completely resolve in some cases depending on the degree of inflammation and the aggressiveness of therapy. For refractory cases, azathioprine (Imuran), methotrexate, or radiation therapy^[8] has been employed.

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Surgical Care

Surgical extirpation is not generally a feasible treatment of Tolosa-Hunt syndrome; the primary value of surgical intervention is a histopathologic diagnosis.

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Consultations

Neuro-ophthalmology evaluation is helpful to confirm the diagnosis and to exclude other etiologies of presenting symptoms. Consultation with a neurosurgeon may be useful in cases requiring biopsy.

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Medication Summary

Steroids are used to treat the inflammation of Tolosa-Hunt syndrome. Pain relief usually occurs rapidly, ie, within 24-72 hours.^[9] Continue treatment at the initial dose for a short time (ie, 7-10 d) after pain resolves, then taper gradually. If no response to steroid therapy has occurred within 72 hours, the diagnosis of Tolosa-Hunt syndrome should be reevaluated.

If a patient is unable to tolerate steroid therapy, other immunosuppressive therapy may be considered.

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Prednisone (Sterapred)

• Dosing, Interactions, etc.

Clinical Context:  May decrease inflammation by reversing increased capillary permeability and suppressing PMN activity. Stabilizes lysosomal membranes and also suppresses lymphocytes and antibody production.

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Class Summary

Reduce pain and inflammation; diminish the size of the inflammatory mass.

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Methotrexate (Trexall)

• Dosing, Interactions, etc.

Clinical Context:  Antimetabolite used to treat many autoimmune processes. The mode of action is not known; this drug does interfere with DNA synthesis.

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Azathioprine (Imuran)

• Dosing, Interactions, etc.

Clinical Context:  Immunosuppressive agent that works primarily on T cells. Works very slowly; may require 6-12 mo of trial prior to effect. Up to 10% of patients may have idiosyncratic reaction disallowing use. Do not allow WBC count to drop below 3000/µL or lymphocyte count to drop below 1000/µL.

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Class Summary

Decrease autoimmune reaction.

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Further Outpatient Care

Supervise a tapering schedule for the steroids and monitor for steroid-related adverse effects. Because the diagnosis of Tolosa-Hunt syndrome is often made clinically without histopathologic confirmation, vigilance must be maintained for the possibility of alternative masquerading diagnosis.

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Complications

See the list below:

• Complications of high-dose and/or prolonged steroid use are common.
• In patients with extracavernous sinus involvement affecting the optic nerve, loss of vision may occur.

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Prognosis

See the list below:

• Typically, the prognosis is considered good. Patients usually respond to corticosteroids, and spontaneous remission can occur, although permanent ocular motor deficits may remain.
• Relapse can occur in as many as 40% of patients successfully treated for Tolosa-Hunt syndrome. This typically occurs on the same side as the original lesion but can be observed on the opposite side. Spontaneous remission can occur; patients who have experienced spontaneous remission appear to have as much risk of reoccurrence as those treated with medication. Gimenez-Roldan et al have reported that relapses may occur as long as 13 years after initial diagnosis and treatment.^[10]

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Patient Education

See the list below:

• Patients should understand that this is an idiopathic condition that is usually self-limited. Relapses may occur (30-40% of patients may experience relapse), and patients should know that the course of any relapse often follows the original event but may require additional testing. Patients should have an idea of the differential diagnosis of Tolosa-Hunt syndrome and report any new symptoms or side effects from treatment to the physician.
• The risks associated with the use of high-dose steroids should be emphasized prior to the onset of treatment.

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