Neuro-Ophthalmology & Neuro-Otology
Isolated sixth nerve palsy
Nov. 28, 2023
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Painful ophthalmoplegia is characterized by the presence of periorbital or hemicranial pain along with restricted ocular movements. In patients with painful ophthalmoplegia, there are usually multiple ipsilateral oculomotor nerve palsies, which are sometimes accompanied by Horner syndrome and sensory impairment in the ophthalmic nerve and, occasionally, the maxillary divisions of the trigeminal nerve, suggesting a cavernous sinus lesion. Tolosa-Hunt syndrome is a benign disorder characterized by idiopathic nonspecific granulomatous inflammation in the region of the cavernous sinus and superior orbital fissure. Painful ophthalmoplegia due to idiopathic orbital inflammatory syndrome is generally responsive to oral corticosteroids, which form the mainstay of treatment. Many serious conditions, like vascular aneurysms, malignancies, and fungal infection of the cavernous sinus region can present with a similar clinical radiological presentation. A high index of suspicion is needed for the timely recognition of these life-threatening disorders. Neoplastic conditions, like locally infiltrative metastasis and lymphoproliferative diseases, constitute important differential diagnoses of painful ophthalmoplegia. Fungal diseases, like rhino-orbito-cerebral mucormycosis and rhino-orbital aspergillosis require timely recognition and prompt treatment. Rhinocerebral mucormycosis is a life-threatening disease frequently seen in poorly controlled diabetics or immunocompromised patients and is a rapidly emerging infection in the post-COVID population. Indiscriminate use of corticosteroids and uncontrolled diabetes among COVID-19 patients are considered to be responsible for the mucormycosis epidemic in certain parts of the world. “Recurrent painful ophthalmoplegic neuropathy” is a term that is clinically characterized by recurrent unilateral headache attacks associated with ipsilateral ophthalmoplegia. Elevated serum calcitonin gene-related peptide (CGRP) levels in the periods between headache attacks suggest a migrainous nature of disease. In this article, the author focuses on the differential diagnosis of painful ophthalmoplegia and provides a detailed description of Tolosa-Hunt syndrome.
• Painful ophthalmoplegia is characterized by the presence of periorbital or hemicranial pain along with restricted ocular movements.
• The differential diagnosis includes a variety of vascular, neoplastic, inflammatory, and infectious conditions affecting the cavernous sinus region and orbit.
• Tolosa-Hunt syndrome is a benign disorder characterized by idiopathic nonspecific granulomatous inflammation in the region of the cavernous sinus and superior orbital fissure.
• Tolosa-Hunt syndrome responds to corticosteroids very well.
• Rhinocerebral mucormycosis is a rapidly emerging infection of the cavernous sinus region in the post-COVID population.
• The most frequent cause of recurrent painful ophthalmoplegic neuropathy is ophthalmoplegic migraine.
Painful ophthalmoplegia is clinically characterized by periorbital or hemicranial pain along with oculomotor paralysis, sensory loss in the distribution of the ophthalmic division of the trigeminal nerve, or Horner syndrome. Characteristically, the lesion lies in and around the cavernous sinus region of the brain.
In 1858, Hirschfeld first described the syndrome of a superior orbital fissure in a patient with a head injury (16). At autopsy, a hematoma was demonstrated near the superior orbital fissure. Similar cases were subsequently published (26). In 1955, Jackson described four similar cases of ocular nerve palsy associated with severe headache in diabetics (20). In 1890, the term “ophthalmoplegic migraine” was first used by Charcot to describe cases of headache with oculomotor nerve palsy (07). He tried to exclude other structural causes in these cases.
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 (09). The term "orbital myositis" was coined to describe those with primarily muscle involvement.
In 1954, Eduardo Tolosa described a 47-year-old man with recurrent retro-orbital pain and dysfunction of the third, fourth, fifth, and sixth cranial nerves (39). 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 six patients with orbital and brow pain along with various combinations of third, fourth, and sixth cranial nerve dysfunction on the same side (18). 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 (26). In 1966, Smith and Taxdal used the term “Tolosa-Hunt syndrome” for the first time and described an excellent response to corticosteroids (36). Experts now believe that it is high time to revisit the authenticity of the term “Tolosa-Hunt syndrome.” Many serious conditions, like malignancies and fungal infection of cavernous sinus region, have a similar clinical radiological presentation and are likely to be missed. In an editorial, Christian J Lueck expressed his views as follows: “With the greatest of respect to Eduardo Tolosa and William Hunt, it is probably time to retire their eponym, as it no longer fulfils a useful clinical role and is potentially dangerous” (29).
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