AUTHOR AND EDITOR INFORMATION

Section 1 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

INTRODUCTION

Section 2 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Background

Tolosa-Hunt syndrome (THS) is a painful ophthalmoplegia caused by nonspecific inflammation of the cavernous sinus or superior orbital fissure.

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 or 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.

Frequency

United States

This disorder is uncommon in both the United States and internationally.

Mortality/Morbidity

THS 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.

Sex

Males and females are equally affected.

Age

This disorder is rare during the first 2 decades of life; in people older than 20 years, it appears to have an even distribution.

CLINICAL

Section 3 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

History

• 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.
• THS is most often unilateral, although bilateral cases have been described.
• THS 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 THS can have significant associated morbidity if not diagnosed and treated appropriately.

Physical

• 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.
• 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 THS 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 48 hours of steroid therapy initiation Exclusion of other conditions by neuroimaging and (not compulsory) angiography

Causes

The cause of THS is unknown (idiopathic).

DIFFERENTIALS

Section 4 of 11  

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• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Other Problems to be Considered

Carotid-cavernous fistula
Cavernous angioma
Fungal infections
Lymphoma
Melanoma
Miller Fisher Syndrome
Orbital myositis
Orbital pseudotumor
Syphilis
Vasculitis
Giant cell arteritis

WORKUP

Section 5 of 11  

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• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Lab Studies

• The diagnosis of THS is usually one of exclusion.
• Laboratory workup: 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.
• Cerebrospinal fluid (CSF) studies: 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 THS; a mild (lymphocytic) pleocytosis within the spinal fluid may occur in patients with THS.
• Anti-GQ1b antibodies may be helpful in distinguishing early, painless THS from Miller Fisher syndrome.

Imaging Studies

• MRI 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. 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 THS 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.
• Note that findings on all imaging studies may be normal in some cases of THS.
• Narrowing of the internal carotid artery within the cavernous sinus may be identified on angiography. Note that these changes are not specific to THS.
• 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.

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.

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.

TREATMENT

Section 6 of 11  

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• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

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 has been employed.

Surgical Care

Surgical extirpation is not generally a feasible treatment of THS; the primary value of surgical intervention is a histopathologic diagnosis

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.

MEDICATION

Section 7 of 11  

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• Follow-up
• Miscellaneous
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Steroids are used to treat the inflammation of THS. Pain relief usually occurs rapidly, ie, within 24-72 hours. 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 THS should be reevaluated.

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

Drug Category: Corticosteroids

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

Drug Category: Immunosuppressive agents

Decrease autoimmune reaction.

FOLLOW-UP

Section 8 of 11  

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• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Further Outpatient Care

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

Complications

• 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.

Prognosis

• Typically, the prognosis is considered good. Patients usually respond to corticosteroids, and spontaneous remission can occur, although permanent ocular motor deficits may remain.
• Thirty to 40% of patients successfully treated for THS may experience relapse. 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.

Patient Education

• 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 THS 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.

MISCELLANEOUS

Section 9 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Medical/Legal Pitfalls

• THS is usually a diagnosis of exclusion, typically made in the absence of histopathologic verification. As such, other causes of orbital pain and/or ophthalmoparesis that potentially threaten the patient's vision or are potentially fatal should be fully evaluated prior to making this diagnosis; keep these other conditions in mind through prolonged follow-up (eg, patients with posterior communicating artery aneurysms often present with painful ophthalmoplegia [third nerve palsy pattern]). A response to steroids with resolution of pain is not diagnostic of THS; other pathophysiologies may respond to steroids, at least transiently, including infections and neoplasms.
• The use of steroids and possible associated complications may be a source of medicolegal difficulty.

MULTIMEDIA

Section 10 of 11  

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• Introduction
• Clinical
• Differentials
• Workup
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• Follow-up
• Miscellaneous
• Multimedia
• References

Media file 1:  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 nerve palsy OS (image 1 is axial; image 2 is coronal). Axial imaging without (left) and with (right) enhancement demonstrates nonspecific fullness involving the left cavernous sinus, consistent with Tolosa-Hunt syndrome within the context of the history. Treatment with steroids produced complete resolution of symptoms. Image courtesy of Eric Eggenberger, DO.
	View Full Size Image
Media type:  MRI

Media file 2:  Coronal T1-weighted MRI with (below) and without (above) enhancement demonstrates left cavernous sinus fullness consistent with Tolosa-Hunt syndrome (THS). The imaging features are nonspecific and must be placed into the context of the history, examination, and clinical course to avoid misdiagnosis of infiltrating, infectious, or neoplastic cavernous sinus processes. Image courtesy of Eric Eggenberger, DO.
	View Full Size Image
Media type:  MRI

REFERENCES

Section 11 of 11

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

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• Vallat JM, Vallat M, Julien J, et al. Painful ophthalmoplegia (Tolosa-Hunt) accompanied by peripheral facial paralysis. Ann Neurol. Dec 1980;8(6):645. [Medline].
• Yagi A, Sato N, Taketomi A, et al. Normal cranial nerves in the cavernous sinuses: contrast-enhanced three-dimensional constructive interference in the steady state MR imaging. AJNR Am J Neuroradiol. Apr 2005;26(4):946-50. [Medline].
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Article Last Updated: Dec 8, 2006