Tolosa-Hunt syndrome describes episodic orbital pain associated with paralysis of one or more of the third, fourth and/or sixth cranial nerves which usually resolves spontaneously but can relapse and remit.
It was first described in 1954 by Tolosa, who found granulomatous inflammation in the cavernous sinus during autopsy of a patient with severe left-sided trigeminal pain and total ophthalmoplegia. In 1961, Hunt reported 6 cases of unilateral painful ophthalmoplegia that tested negative with angiography and lumbar puncture and rapidly resolved with steroids.
Tolosa-Hunt syndrome was first classified by the International Headache Society in 2004 and now is a part of Classification ICHD-3. ICD-10 for Tolosa Hunt Syndrome is H49.40.
Unilateral orbital or periorbital pain with paresis of third, fourth and/or VIth cranial nerves secondary to idiopathic inflammation of the cavernous sinus, superior orbital fissure or orbit.
The ICHD-3 Diagnostic criteria for Tolosa-Hunt syndrome are as follows:
A. Unilateral orbital or periorbital headache fulfilling criterion C
B. Both of the following:
a. Granulomatous inflammation of the cavernous sinus, superior orbital fissure or orbit, demonstrated by MRI or biopsy
b. Paresis of one or more of the ipsilateral third, fourth, and/or sixth cranial nerves.
C. Evidence of causation demonstrated by both of the following:
a. Headache is ipsilateral to the granulomatous inflammation
b. Headache has preceded paresis of the third, fourth, and/or sixth nerves by ≤2 weeks, or developed with it.
D. Not better accounted for by another ICHD-3 diagnosis (see differential diagnosis section for more detail)
Some reported cases of Tolosa-Hunt syndrome had additional involvement of the trigeminal nerve (commonly the first division) or optic, facial or acoustic nerves. Sympathetic innervation of the pupil is occasionally affected.
The syndrome has been caused by granulomatous material in the cavernous sinus, superior orbital fissure or orbit in some biopsied cases.
Careful follow-up is required to exclude other possible causes of painful ophthalmoplegia.
Tolosa-Hunt syndrome is idiopathic.
A possible risk factor for Tolosa-Hunt syndrome is a recent viral infection.
Tolosa-Hunt syndrome is idiopathic, sterile inflammation of the cavernous sinus. Its pathology is described as fibroblastic, lymphocytic, and plasmocytic infiltration of the cavernous sinus. Granulocytic and giant-cell infiltrations have also been described. Pathology may extend to involve the superior orbital fissure (sphenocavernous or parasellar syndrome) or orbital apex and affect the optic nerve. Involvement of cranial nerves III, IV, and VI, as well as the sympathetic fibers in the cavernous ICA or parasympathetic fibers that surround the oculomotor nerve can occur secondary to granulomatous inflammation.
Painful ophthalmoparesis or ophthalmoplegia is the hallmark of Tolosa-Hunt syndrome. The patient may complain of double vision worse at distance, headaches, dizziness, nausea, neck stiffness, photophobia, blurred vision, and a “boring” pain may be associated with the headache.
In addition to the standard ophthalmic examination of the patient including vision, IOP, pupil check for APD and nystagmus, slit-lamp and dilated fundus exam, a complete sensorimotor exam should be done. This includes oculomotor exam (to check for esotropia, exotropia, hypertropia or hypotropia), ductions, vergence, saccades, pursuit, and head tilt/turn. A common finding is abduction deficit associated with esodeviation that increases with gaze to the affected side. Lids should be checked for ptosis or lid retraction or any change in lid aperture during eye movements (to check for aberrant regeneration). Lid strength, fatigue or variability should be noted. Facial sensation should be checked. Stereopsis and color plates should also be evaluated.
Involvement of multiple contiguous cranial nerves strongly suggest a lesion in the cavernous sinus or subarachnoid space. Only one nerve may be involved, most likely the sixth cranial nerve, which is the only one not protected within the dural wall of the cavernous sinus.
In addition to the complete ophthalmic exam as described, the physician must closely look for Horner syndrome, facial hypoesthesia or engorgement of ocular surface vessels, orbital venous congestion, increased IOP or pulse pressure.
All positive findings should be noted and the differential diagnoses listed below should be considered.
The most appropriate imaging includes MRI /MRA (DWI series) which provides information about the cavernous sinus and orbital apex in greater detail than a CT. MRI may be able to provide detail of granulomatous inflammation, aiding in formal diagnosis of Tolosa-Hunt syndrome. However, these results may be unreliable. Biopsy can also be used to demonstrate granulomatous inflammation and may be more reliable, but the procedure may be more difficult
A CTA w/ and w/o contrast can also be obtained if an MRI/MRA is not available. A lumbar puncture may be done to check for opening pressure and CSF should be evaluated for infection/oligoclonal bands.
Recent evidence supports the use of High resolution 3D skull base MRI with isotropic constructive interference in steady state (CISS) and 0.6-mm cut images with and without contrast as effective way to visualize cranial nerves and cavernous sinus lesions that were not previously visualized.
Work up should include tests that can rule out the various diseases listed above given the history and context of the patient. This can include
- CBC w diff
- RPR and FTA-ABS
- p-ANCA, c-ANCA
- Anti dsDNA
- HBa1C and fasting glucose
- If no pain: myasthenia antibodies (binding/blocking/modulating antibodies and anti-MUSK antibodies)
Tolosa-Hunt syndrome is considered a diagnosis of exclusion. Thus, the following entities must be considered and ruled out before a diagnosis of Tolosa-Hunt syndrome is made:
- Ischemic disease: Hemorrhage, ischemic mononeuropathy
- Infectious process: post viral syndrome, chronic inflammation of petrous bone (recurrent ear infections), syphilis, basal meningitis
- Anatomical malformation: aneurysm, AVM, carotid-cavernous fistula, cavernous sinus thrombosis, pseudotumor cerebrii, Duane syndrome/Moebius syndrome, Chiari malformation
- Inflammatory disease: Sarcoidosis, granulomatosis with polyangiitis (formerly Wegener's), Behcet’s disease, IgG4 Disease
- Autoimmune condition: myasthenia gravis, thyroid disease, lupus
- Neoplastic disease: meningioma, neurogenic tumor, hemangioma, lymphoma/leukemia, schwannoma, pituitary adenoma, metastasis, CPA lesion, nasopharyngeal carcinoma, chordoma, chondrosarcoma, brain stem glioma in children
- Demyelinating disease: MS
- Others: Diabetes mellitus, Head trauma, BBPV, Meniere’s, ophthalmoplegic migraine
Oral steroids are the mainstay of treatment. Both symptoms and physical exam findings (headache, ptosis, ophthalmoplegia, etc) can be expected to resolve rapidly with an oral steroid taper regimen over 3-4 months. The patient can be co-managed with the Neurology service to rule out other entities listed in the differential diagnosis of Tolosa-Hunt syndrome.
Before starting steroid, fungal infection of the orbit with fungal sinusitis (mucormycosis in diabetic/immunocompromised) is a differential diagnosis that must be considered, because in that case starting steroid will worsen the disease.
Several therapies have been investigated for instances of steroid-resistant Tolosa-Hunt syndrome. A case report by Lee, et al. has been published in which gamma-knife radiation therapy is used to provide marked short-term relief without relapse of symptoms. Antimetabolic agents such as methotrexate, infliximab, and mycophenolate mofetil have also been shown to cause dramatic improvement in patients whom are deemed to be steroid-resistant
A rare complication is aberrant regeneration of cranial nerves.
Prognosis of Tolosa-Hunt syndrome is excellent. Full recovery is expected with steroid treatment. The disease may have a relapsing-remitting course.
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