Clinical manifestations

Presentation and course

Painful ophthalmoplegia is a clinical presentation of cavernous sinus syndrome. Cavernous sinus syndrome clinically manifests as unilateral multiple ocular motor nerve (third, fourth, and sixth) palsies. In addition, patients may have Horner syndrome and involvement of the first or second divisions of the trigeminal nerve. Many patients may complain of facial or ocular pain. If there is optic nerve involvement as well, the condition is termed “orbital apex syndrome.” The causes of cavernous sinus syndrome and orbital apex syndrome include a variety of vascular, neoplastic, infectious, and inflammatory disorders (13).

Tolosa-Hunt syndrome. Tolosa-Hunt syndrome is an uncommon disease that is characterized by a nonspecific inflammatory granuloma formation in and around the cavernous sinus, superior orbital fissure, or orbit. In Tolosa-Hunt syndrome, the pain is ipsilateral to the involved side and is most intense in the orbit, brow, or directly in or behind the eye, with orbital inflammation. Tolosa-Hunt syndrome most often clinically manifests with ophthalmoplegia involving one or multiple cranial nerves and ocular or periocular pain (Table 1).

Table 1. Diagnostic Criteria of Tolosa-Hunt Syndrome

Acute painful oculomotor neuropathy. Many diabetic and hypertensive patients present with painful ischemic cranial nerve palsies that clinically manifest as an acute oculomotor mononeuropathy. Unilateral frontal or periorbital pain coincides with the side of cranial nerve palsy. Pupils are generally spared in patients with ischemic third nerve palsy. Ischemic lesions of the third nerve are considered to spare the circumferential fibers of the third nerve (Table 2) (22; 41).

Table 2. Diagnostic Criteria of Ischemic Ocular Motor Nerve Palsy

Recurrent painful ophthalmoplegic neuropathy (ophthalmoplegic migraine). Recurrent painful ophthalmoplegic neuropathy is clinically characterized by recurrent (at least two attacks) ocular cranial nerve (frequently the third cranial nerve) palsy along with ipsilateral headache (17; 01). Ipsilateral headache generally develops up to 2 weeks prior to ocular motor nerve dysfunction (08). Recurrent painful ophthalmoplegic neuropathy is considered to be the result of migrainous attacks. However, this link is not universally accepted as neuroimaging demonstrates inflammatory changes in oculomotor nerve trunks (Table 3) (37). Elevated serum calcitonin gene-related peptide (CGRP) levels in the periods between headache attacks suggests migraine as the underlying cause of recurrent headache and ophthalmoplegia (38).

Table 3. Diagnostic Criteria of Recurrent Painful Ophthalmoplegic Neuropathy

Idiopathic orbital inflammatory syndrome. Idiopathic orbital inflammatory syndrome is a benign disorder characterized by an idiopathic inflammatory mass within the orbit. Orbital pseudotumor frequently presents with painful ophthalmoplegia. Collection of inflammatory tissue in orbital structures can additionally manifest as proptosis, periorbital swelling and redness, ptosis, diplopia, and painful ocular movements. Orbital myositis (involvement of extraocular muscles) results in painful ophthalmoplegia. Ophthalmoplegia is unilateral and generally affects young women (19).

Orbital cellulitis. Periorbital and orbital cellulitis are serious conditions that frequently affect children. Orbital cellulitis is generally associated with devastating consequences like vision loss, painful ophthalmoplegia secondary to cavernous sinus thrombosis, meningitis, cerebral venous thrombosis, subdural empyema, and, rarely, brain abscess. In the current COVID-19 pandemic, rhinocerebral mucormycosis is an important cause of periorbital and orbital cellulitis as well (14; 02).

Carotid-cavernous fistula. Carotid-cavernous fistula is an anomalous communication between the internal carotid artery and the cavernous sinus. Carotid-cavernous fistulas are often traumatic in nature. Distinguishing clinical manifestations include an audible bruit or pulsatile exophthalmos and conjunctival pulsations. Other clinical findings in addition to painful ophthalmoplegia include chemosis, proptosis, ptosis, pupillary abnormalities, and optic neuropathy (42).

Intracranial aneurysms. Intracavernous sinus aneurysms of the internal carotid artery can cause of painful ophthalmoplegia. Zhang and colleagues reported a patient with intracavernous sinus internal carotid artery aneurysm who presented with headache and bilateral ptosis (44). The patient improved following aneurysm embolization.

Rhinocerebral mucormycosis. During the COVID-19 pandemic, rhinocerebral mucormycosis emerged as a leading cause of painful ophthalmoplegia. Post-COVID-19, rhinocerebral mucormycosis is a preferred differential diagnosis of painful ophthalmoplegia. Rhinocerebral mucormycosis is generally a rare opportunistic infection with devastating consequences in patients with uncontrolled diabetes mellitus. Rhinocerebral mucormycosis following COVID-19 usually starts with periorbital swelling and a necrotic palatal lesion. Patients subsequently develop facial pain, ophthalmoplegia, or orbital apex syndrome followed by cerebral involvement (10; 40).

Prognosis and complications

The prognosis of painful ophthalmoplegia depends on the cause. In Tolosa-Hunt syndrome, the prognosis for most patients is generally good. However, some patients may need prolonged corticosteroid or immunosuppressive treatment because they have a relapsing-remitting course. A few patients do not recover at all. Arthur and colleagues noted that approximately 50% of patients with Tolosa-Hunt syndrome reported recurrence (03). Steroid-sparing immunosuppressive treatment is required to prevent recurrence in such cases. Corticosteroids help in resolving facial pain within 24 to 72 hours following initiation of treatment.

Orbital myositis responds well to corticosteroids. In many cases, there is an incomplete response. The patients who do not respond may need immunosuppressive drugs or even radiotherapy (30). In a logistic regression analysis of 209 cases of idiopathic orbital inflammatory syndrome, Yan and colleagues found that male gender and, notably, degree of proptosis both predicted higher relapse rate (43).

Biological basis

In painful ophthalmoplegia, the majority of causes affect the structures in and around the cavernous sinus. The cavernous sinus is a dural venous sinus that is situated in the middle cranial fossa. The cavernous sinus lies on both sides of the sella turcica of the sphenoid bone. The contents of the cavernous sinus include third and fourth cranial nerves in its wall and sixth cranial nerve, along with internal carotid artery and sympathetic fibers that pass through the cavernous sinus. In addition, ophthalmic (V1) and maxillary (V2) branches of the trigeminal nerve pass via its wall.

Epidemiology

Keane analyzed causes of cavernous sinus syndrome in 151 patients (21). He noted that classic causes, such as aneurysm, meningioma, and bacterial infection, were uncommon. In this series, the most frequent cause of cavernous sinus syndrome was neoplastic (30%; 45/151). Traumatic disorders (24%; 36/151) were the next most common cause. Idiopathic inflammatory diseases were diagnosed in 34 (23%) patients. The remaining 12% of patients were diagnosed with carotid aneurysms and carotid-cavernous fistulas, infection, and other uncommon causes, like pituitary apoplexy. Fernandez and colleagues evaluated 126 patients and noted that neoplastic disorders were the most frequent cause of cavernous sinus syndrome (11). The next most common causes were vascular diseases (aneurysms and carotid-cavernous fistula) and Tolosa-Hunt syndrome. Zhang and colleagues undertook a retrospective analysis of 77 patients with painful ophthalmoplegia (45). The most common final diagnosis was idiopathic cavernous sinus inflammation in 46 (Tolosa-Hunt syndrome; mean age 44.4 years), followed by intracranial aneurysm in 13 (posterior communicating artery in 10, internal carotid artery in three; mean age 58.8 years) and diabetic ophthalmoplegia in nine (mean age 63.2 years) as well as an assortment of middle cranial fossa tumors and one fungal infection. Of the 46 patients with idiopathic cavernous sinus inflammation (Tolosa-Hunt syndrome), 24 had abnormal MRIs, of which 19 involved the cavernous sinus and parasellar region, nine the orbital apex and superior orbital fissure, and eight the orbital apex and cavernous sinus. Bhatkar and colleagues evaluated 73 patients with cavernous sinus syndrome and were able to establish a definitive cause in 86% of patients (04). In this series, neoplastic diseases, fungal infections, and Tolosa-Hunt syndrome were the most frequent to affect the cavernous sinus.

Differential diagnosis

A wide variety of diseases affecting the cavernous sinus, superior orbital fissure, or orbital apex lead to painful ophthalmoplegia. The diagnosis of Tolosa-Hunt syndrome is made only after excluding other possible causes. The 3rd edition of the International Classification of Headache Disorders criteria now requires the demonstration of granulomatous inflammation on MRI or biopsy. This is considered important to deal with a wide array of differential diagnoses (31).

In addition to Tolosa-Hunt syndrome, neoplastic disorders and fungal infections are the most common causes of cavernous sinus syndrome (04). Many inflammatory conditions like sarcoidosis and vasculitis can also present with painful ophthalmoplegia (33). Sjogren syndrome, sarcoidosis, Wegener disease, and polyarteritis nodosa must also all be considered in the differential diagnosis.

Lymphoproliferative disorders often mimic Tolosa-Hunt and must be considered in the deferential diagnosis. Recurrent painful ophthalmoplegic neuropathy, previously referred as ophthalmoplegic migraine, is a rare entity, and magnetic resonance imaging does not demonstrate gadolinium enhancement in the cavernous sinus region.

Confusing conditions

A wide variety of diseases, such as bacterial or fungal diseases, idiopathic inflammatory disorders, vascular diseases, and malignancy, can affect the structures in and around the cavernous sinus and clinically manifest as painful ophthalmoplegia (Table 4) (27). A diagnosis of Tolosa-Hunt syndrome should only be entertained once other treatable conditions are comprehensibly ruled out. Rodriguez and colleagues described a patient who presented with painful ophthalmoplegia and who was initially suspected to have Tolosa-Hunt syndrome (34). The patient rapidly deteriorated and died. Postmortem examination revealed the presence of cervicocephalic actinomycosis.

Table 4. Differential Diagnosis of Painful Ophthalmoplegia

Diagnostic workup

Neuroimaging is essential to promptly identify the possible etiology of painful ophthalmoplegia. MRI is the imaging method of choice because it is more beneficial in differentiating between benign and malignant causes of painful ophthalmoplegia (05).

In patients with Tolosa-Hunt syndrome, contrast-enhanced MRI demonstrates abnormal enhancing lesions in and around the cavernous sinus. The enhancing lesion may extend up to the superior orbital fissure into the orbital apex. The cavernous sinus enhancing lesion resolves following treatment with corticosteroids. If there is a recurrence of symptoms or if there is clinical deterioration, there is a need for repeat neuroimaging as there is an enhanced possibility of an alternative diagnosis. In such cases, there should be a strong suspicion of malignant disease, like locally invasive nasopharyngeal carcinoma (03).

MRI in patients with recurrent painful ophthalmoplegic neuropathy (ophthalmoplegic migraine) may reveal enhancement of the oculomotor nerve trunk on contrast-enhanced studies (35). In addition to neuroimaging, diagnostic evaluation in a case of painful ophthalmoplegia requires testing for a battery of blood and cerebrospinal fluid parameters (Table 5).

Table 5. Suggested Workup for a Patient with Painful Ophthalmoplegia

A cavernous sinus biopsy may be required if diagnosis is not confirmed by noninvasive methods. For example, a 63-year-old patient was initially diagnosed with giant cell arteritis and, subsequently, Tolosa-Hunt syndrome (28). Cerebrospinal fluid examination and (18F)-fluoro-D-glucose-positron emission tomography of the brain suggested a diagnosis of a lymphomatous disorder. However, biopsy of the cavernous sinus mass revealed features consistent with the diagnosis of actinomyces fungal infection.

Management

Painful ophthalmoplegia should be managed according to the underlying etiology. Corticosteroid therapy is now considered the mainstay of management for patients with inflammatory causes of idiopathic orbital inflammatory syndrome and Tolosa-Hunt syndrome.

Prednisone (1 mg/kg/day) is preferred over corticosteroids. The response to treatment is almost immediate, with complete resolution of symptoms within a few days. The majority of patients experience improvement in cranial nerve deficits as well. Corticosteroids are gradually tapered over the next two weeks. Few patients require longer corticosteroid treatment (03).

If there is incomplete or no response to corticosteroids, immunosuppressive drugs like tacrolimus, cyclosporine, azathioprine, methotrexate, mycophenolate mofetil, infliximab, adalimumab, and radiotherapy have shown benefit in isolated case reports (23; 24; 25).

Outcomes

Arthur and colleagues recorded the long-term follow-up of patients with Tolosa-Hunt syndrome (03). In 37 of 44 (84%) patients in their series, a follow-up of at least 6 months was available. Recurrences were noted in approximately 50% (18 of 37) of patients. The duration for recurrences to appear varied from 8 months to 7 years. During follow-up, the diagnosis needed to be revised in two patients; the revised diagnosis was leptomeningeal malignancy and hypertrophic pachymeningitis.

Special considerations

Pregnancy

Piamonte and colleagues have described Tolosa-Hunt syndrome in pregnancy (32). The patient, who was taking combined oral contraceptives, suffered two episodes of painful ophthalmoplegia. The first attack remitted spontaneously. Relapse occurred when she became pregnant. The second attack also completely remitted following steroid treatment.