Though painful ophthalmoplegia technically describes any patient presentation in which there is pain and limitation in eye movements, it is often used more specifically to describe the syndrome of periorbital pain and multiple ipsilateral oculomotor nerve palsies sometimes accompanied by Horner syndrome and sensory impairment in the ophthalmic and, occasionally, the maxillary divisions of the trigeminal nerve suggesting a cavernous sinus lesion. Tolosa-Hunt syndrome, an idiopathic inflammatory condition causing nonspecific inflammation in the region of the cavernous sinus and superior orbital fissure, is an important cause of painful ophthalmoplegia, often termed orbital pseudotumor when the inflammation is primarily the orbit. Experts now believe that it is high time to revisit the use of the terms “Tolosa-Hunt syndrome” and “orbital pseudotumor”, with the cause of painful ophthalmoplegia more appropriately described by its location, impacted tissue, and underlying histology (when available). Many serious conditions, like malignancies and fungal infection of cavernous sinus region, can have similar clinic-radiological presentation and a high clinical suspicion needs to be maintained to diagnose and appropriately manage these.
Painful ophthalmoplegia due to inflammatory pseudotumor is generally responsive to oral corticosteroids, which form the mainstay of treatment, but occasionally the disease is refractory, and additional immunosuppressive agents or orbit radiation may be indicated. In this article, the author describes idiopathic inflammatory causes of painful ophthalmoplegia (also known as Tolosa-Hunt syndrome or orbital pseudotumor), its imaging features, and the response to corticosteroid, along with differential diagnosis of painful ophthalmoplegia.
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• Idiopathic orbital inflammatory syndrome refers to inflammation in the orbit of unknown etiology that may extend through the superior orbital fissure into the cavernous sinus. A similar process may occur primarily in the cavernous sinus and extend into the orbit secondarily.
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• Tolosa-Hunt syndrome is used to describe the clinical presentation of painful ophthalmoplegia presumed due to idiopathic cavernous sinus inflammation whereas orbital pseudotumor is used to describe the idiopathic orbital inflammation. Both of these terms are falling out of favor.
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• If any specific infectious or inflammatory etiology is discovered, the process is not called idiopathic orbital or cavernous sinus inflammation but is named for the specific infection, eg, tuberculosis or fungi or IgG4-related disease.
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• Most cases respond promptly to high-dose (60 to 100 mg/day) prednisone, which should be continued for several weeks at high dose until ocular motility returns toward normal and then tapered to seek the lowest steroid dose that will maintain clinical remission.
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• The differential diagnosis of painful ophthalmoplegia includes a variety of vascular, neoplastic, inflammatory, and infectious conditions affecting cavernous sinus region and orbit along with diabetes and ophthalmoplegic migraine.
Historical note and terminology
The concept that orbital inflammatory pseudotumor (idiopathic inflammation in the orbit) and Tolosa-Hunt syndrome (idiopathic inflammation in the cavernous sinus) are probably the same or closely related entities with different anatomic distributions developed relatively recently. The following paragraphs outline the development of our understanding of idiopathic orbital and cavernous sinus inflammation starting in the early part of this century, and then introduce the historic setting in which Tolosa-Hunt syndrome was established as a diagnostic entity. It is understandable that the pathology and immunology of orbital inflammation have been investigated much more intensively than that in the cavernous sinus because orbital tissue is relatively accessible for biopsy.
Orbital inflammation. The idea that orbital inflammation could mimic neoplastic tumor in the orbit was introduced early in this century by Birch-Hirschfeld, who coined the term "pseudotumor" (06). In the early 1940s, a distinction was drawn between cases in which the inflammation involves primarily the extraocular muscles and those in which the site of inflammation is primarily the orbital fat or other tissues (17). The term "orbital myositis" was coined to describe those with primarily muscle involvement.
In the 1960s granulomatous inflammation in the orbit was found to be clinically and histopathologically distinct from other inflammatory orbital lesions. Nongranulomatous cases were subsequently divided into vasculitic (relatively uncommon) and nonvasculitic (more common) subgroups. During the 1960s and 1970s it was found that some individuals among those with a lymphocytic, nonvasculitic type of orbital lesion developed systemic lymphoma on follow-up. The question then arose whether these were really benign, nonneoplastic orbital lesions and the systemic disease independent, or whether the original orbital lesion was neoplastic and was not recognized as such at the time of presentation (29).
In the 1970s lymphocyte phenotyping revealed a functional difference between B and T lymphocytes that was morphologically indistinguishable. Individual cases were then further subdivided into "monomorphous types" with only B lymphocytes and "polymorphous types" having a mixture of B and T lymphocytes. It was thought that the monomorphous types had a greater likelihood than the polymorphous lesions of being clonally related to a single neoplastic lymphocyte line, and hence lymphomatous. However, it became apparent that the clinical behavior was not always predicted by the phenotypic mix of cells in the original lesion.
The next important development was the ability to recognize B lymphocyte production of "monoclonal" or "polyclonal" antibodies, the former favoring a neoplastic disorder. Names applied to the polyclonal group include "benign," "reactive," or "atypical lymphoid hyperplasia." Throughout the decade between 1980 and 1990, F A Jakobiec and D M Knowles II applied these laboratory advances to the diagnosis of orbital inflammatory pseudotumor (41; 29).
Cavernous sinus inflammation. In 1954 Eduardo Tolosa of Barcelona described a 47-year-old man with recurrent retro-orbital pain and dysfunction of the third, fourth, fifth, and sixth cranial nerves (83). There had been a 3-year spontaneous remission between symptomatic episodes. The patient died a few days after an intracranial exploratory operation that had yielded no definite pathology. The autopsy, however, showed granulomatous inflammatory infiltration around the intracavernous portion of the internal carotid artery and adjacent cranial nerves.
In 1961 Hunt and colleagues reported 6 patients with orbital and brow pain along with various combinations of third, fourth, and sixth cranial nerve dysfunction on the same side (31). They reviewed Tolosa's pathologic material and judged that their patients had the same condition, although tissue samples had not been obtained. The rapid and dramatic relief of pain and ophthalmoplegia produced by systemic corticosteroid administration led these authors to conclude that their patients had the same inflammatory condition described by Tolosa.
Lakke from Utrecht reviewed clinically similar cases, calling them "superior orbital fissure syndrome," and presented pathologic material from a 47-year-old male patient with severe right retro-orbital pain followed by progressive ipsilateral ophthalmoplegia and ocular sympathetic involvement (42). At surgery, inflammatory tissue was found along the lateral wall of the cavernous sinus and the dura over the adjacent lesser wing of the sphenoid bone. His opinion was that these cases were all the same entity that Tolosa had documented pathologically and Hunt had described clinically. Further pathologic documentation was soon made available in 2 more cases of painful ophthalmoplegia (75).