Clinical manifestations

Presentation and course

Painful ophthalmoplegia is a clinical syndrome that includes ipsilateral single or multiple ocular motor nerve palsies involving the third, fourth, or sixth cranial nerves, in addition to unilateral periocular pain. Patients may also have Horner syndrome and reduced sensation in the first or second divisions of the trigeminal nerve. If there is optic nerve involvement as well, the condition is considered to extend to the orbital apex. The causes include a variety of vascular, neoplastic, infectious, ischemic, and autoimmune inflammatory disorders (11).

Idiopathic pachymeningitis (formerly Tolosa-Hunt syndrome). This a sometimes granulomatous inflammation in and around the cavernous sinus or superior orbital fissure with MRI evidence of thickening and enhancement in those regions. Imaging typically cannot rule out specific inflammatory or neoplastic causes. Because obtaining tissue from this region is dangerous, examiners must look for evidence of a similar process in an accessible region (such as a paranasal sinus) or settle for empiric anti-inflammatory treatment. Sarcoidosis, IGG4 disease, and primary vasculitides should be identified as they may have specific treatments (25). Otherwise, the diagnosis remains idiopathic pachymeningitis (idiopathic hypertrophic meningitis).

Acute painful ischemic ocular motor mononeuropathy. A painful, single third, fourth, or sixth cranial nerve palsy may occur in patients with diabetes or systemic hypertension. Attributed to ischemia of the extra-axial portion of the nerve, the process is self-limiting, with spontaneous recovery within 12 weeks. The onset may be somewhat more acute than in idiopathic pachymeningitis, but otherwise the distinction depends on imaging, which will be negative in this condition. The reversibility of this deficit is attributed to a minimal degree of ischemia compatible with axon regeneration.

Recurrent painful ophthalmoplegic neuropathy (ophthalmoplegic migraine). When there are recurrent bouts of a single ocular motor palsy with ipsilateral periocular pain in a patient without vasculopathic risk factors, the label “recurrent painful ophthalmoplegic neuropathy” has been assigned (14; 01). The pain may precede the palsy by as much as 2 weeks (07). Neuroimaging sometimes demonstrates inflammatory changes in the extra-axial portion of the affected nerve (30). Formerly known as “ophthalmoplegic migraine,” this condition has been associated with elevated serum calcitonin gene-related peptide (CGRP) levels in the periods between headache attacks (31), but the imaging abnormality favors an inflammatory disorder.

Idiopathic orbital inflammation. Idiopathic orbital inflammation (also known as “orbital pseudotumor”) is believed to represent an autoimmune process. It is characterized by thickening and enhancement within the orbital intraconal fat, extraocular muscles, lacrimal gland, or sclera. Congestive orbital features are often present, including proptosis, ocular adnexal tissue swelling, conjunctival hyperemia, and ptosis (16). Imaging cannot easily differentiate this process from Graves disease or from malignancy, especially lymphoma.

Orbital cellulitis. Orbital cellulitis is an infection of orbital tissues that frequently affects children but may also occur in adults. In children, the infection usually arises in infected paranasal sinuses (mostly the ethmoid sinus). In adults, a common source is the facial skin. The presumptive pathogens are common skin and mucosal organisms. Antibiotic treatment is empirical, as smears and cultures are not typically drawn. Full resolution is usual. However, in immunocompromised individuals and in infections arising from unconventional sources, such as the mouth, orbital cellulitis may lead to vision loss, cavernous sinus thrombosis, meningitis, cerebral venous thrombosis, subdural empyema, and brain abscess. Mucormycosis and aspergillosis are important infectious causes in patients who have uncontrolled diabetes or who are immunocompromised (12; 02). Imaging typically shows sino-orbital abnormalities, but differential diagnosis can be challenging.

Carotid-cavernous fistula. Carotid-cavernous arteriovenous fistula is an anomalous communication between the intracavernous carotid artery or cavernous dural arterioles and the cavernous sinus. High-flow fistulas, which emanate from a hole in the intracavernous carotid artery, arise in head trauma, atherosclerotic aneurysms, or elastotic degenerations, especially Ehlers-Danlos type IV. Apart from periocular pain and ophthalmoplegia, manifestations include some combination of an audible bruit, pulsatile exophthalmos, high intraocular pressure, optic neuropathy, dilated retinal veins, and hyperemic (“arterialized”) conjunctival vessels. Low-flow fistulas, which emanate from newly opened channels between the dural arterioles and the cavernous sinus, generally have similar but less florid clinical features. Attributed to a change in hormonal status, low-flow fistulas most often arise spontaneously in women in the postpartum or post-menopausal period (33). Cross-sectional imaging frequently shows a dilated superior ophthalmic vein, but definitive diagnosis depends on dynamic vascular imaging that reveals the arteriovenous communications, with early filling of the venous channels in and around the cavernous sinus, including the superior ophthalmic vein. The clinical manifestations are attributed to an altered arteriovenous gradient that leads to arterial ischemia (“steal”) and venous hypertension.

Intracavernous aneurysms. Intracavernous aneurysms represent atherosclerotic fusiform dilation of the internal carotid artery. Sudden expansion of the vessel wall typically compresses the trigeminal nerve, causing the periocular pain. Compression of the ocular motor nerves, most commonly the sixth nerve, produces ductional deficits and diplopia. Vascular imaging is distinctive.

Fungal infection. Mucormycosis and aspergillosis are sino-orbital fungal infections that arise in patients with poorly controlled diabetes and other immunocompromised states. The infection begins in the paranasal sinuses, spreading into the orbit and often the cranial base, including the cavernous sinus. Rapidly progressive vascular occlusion with necrosis manifests as infarction of orbital and adjacent intracranial tissues. Careful examination of nasal and sinus tissues may reveal the characteristic necrotic ulcers. Rapid institution of anti-fungal treatment is essential to prevent death. Orbital exenteration was formerly the favored treatment for disease limited to the orbit, but aggressive intravenous and direct intraorbital infusion may avert that disfiguring intervention. A single case of cavernous sinus actinomycosis has been reported (26). Mycobacterial infection is a rare cause that must be considered in endemic areas (27).

Vasculitis. ANCA-positive and ANCA-negative primary and secondary vasculitides may selectively invade the cavernous sinus to cause painful ophthalmoplegia. Imaging may show only subtle enhancement, sometimes with involvement of a paranasal sinus, allowing biopsy confirmation. The necrotizing vasculitides pose a special threat and must be promptly diagnosed. Serologic testing is a valuable lead, and systemic clinical features are crucial in diagnosis (25).

Malignancy. Primary and metastatic cancer often involves the cavernous sinus. The neoplasms may extend from the pituitary fossa, sphenoid sinus, or orbit. Lymphoma and histiocytosis are commonly implicated. Imaging is rarely diagnostic. Evaluation heavily depends on finding tumors in sites accessible to biopsy. Cerebrospinal fluid may be positive for malignancy.

Prognosis and complications

The prognosis of painful ophthalmoplegia depends on the cause. In idiopathic pachymeningitis, recovery is generally good, but not uniformly so. Moreover, some patients require prolonged corticosteroid or other immunosuppressive treatment because they have a relapsing-remitting course. A few patients do not recover at all. In one study, approximately 50% of patients with “Tolosa-Hunt syndrome” reported recurrence (03). Steroid-sparing immunosuppressive treatment is required to prevent recurrence in such cases. Corticosteroids are effective in relieving facial pain within 24 to 72 hours following initiation of treatment.

Orbital myositis typically recovers more completely than idiopathic pachymeningitis, but in many cases, there is recurrence when treatment is discontinued. The patients who do not respond may need immunosuppressive drugs or even radiotherapy (23). In 209 cases of idiopathic orbital inflammation, male gender and degree of proptosis predicted a higher relapse rate (34).

Necrotizing vasculitis and mucormycosis are most threatening because they advance by invading arteries and infarcting tissue. Early treatment is essential.

With sudden expansion, intracavernous aneurysms may cause florid clinical manifestations and severe trigeminal pain, but these manifestations often subside spontaneously. Although frequently treated with endovascular stents, the indications for intervention are debated. High-flow fistulas are usually successfully treated with coils introduced into the cavernous sinus transvenously. Low-flow fistulas may spontaneously resolve over many months but can also be successfully treated with transvenous coil embolization if diplopia, periocular pain, very high intraocular pressure, disfiguring congestion, or optic neuropathy are intractable.

Biological basis

Painful ophthalmoplegia predominantly represents damage to the ocular motor nerves and the first division of the trigeminal nerve, which lie in the outer dural wall of the cavernous sinus and enter the superior orbital fissure. Lesions in that vicinity do their damage by inflammation, ischemia, or compression. In the active phase of inflammation, appropriately dosed corticosteroid therapy is usually effective; in the chronic (cicatricial) phase of inflammation, deficits are less reversible with treatment. Rapid expansion of tumors, aneurysm, or cysts may cause acute deficits, but more often such lesions produce slowly progressive worsening. High-flow fistulas, which often follow head trauma, typically produce acute deficits, probably by creating ischemia via arterial steal; low-flow fistulas are more likely to produce chronic evolving deficits by slowly mounting orbital venous pressure. Aspergillus infections and vasculitides generally cause slowly progressive deficits by inflammation, whereas mucormycosis causes rapidly evolving deficits by vascular invasion and infarction. Malignancies generally manifest a slow tempo of progression.

Etiology and pathogenesis

In a series of 151 patients with a cavernous sinus syndrome, the most frequent cause was malignancy (30%) (18). Head trauma was next most common (24%), followed by idiopathic inflammation (23%). The remaining 12% of patients were diagnosed with carotid aneurysms and carotid-cavernous fistulas, infection, and other uncommon causes, such as pituitary apoplexy. In another series of 126 patients, malignancies were again the most frequent cause, followed by aneurysms, carotid-cavernous fistulas, and idiopathic inflammation (called Tolosa-Hunt syndrome) (09). In a retrospective analysis of 77 patients, the most common diagnosis was idiopathic inflammation, followed by aneurysm and “diabetic ophthalmoplegia” (35). Middle cranial fossa tumors and one fungal infection accounted for the remaining cases. Of the 46 patients with idiopathic cavernous sinus inflammation (Tolosa-Hunt syndrome), only 52% had MRI abnormalities in the appropriate region. In a review of 73 patients, 86% had a definitive cause, most commonly malignancies, fungal infections, and idiopathic inflammation (Tolosa-Hunt syndrome) (04).

Epidemiology

Keane analyzed causes of cavernous sinus syndrome in 151 patients (18). 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 (09). 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 (35). 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.

Diagnostic workup

Painful ophthalmoplegia is not a disease but a clinical syndrome. There are many causes. The diagnostic challenge is that the lesion is in an area that cannot be accessed for biopsy without serious hazard unless it has a component in the adjacent paranasal sinuses or an identifiable remote source. Orbital extension, if discrete and forward enough, might permit biopsy, but the procedure may cause permanent ophthalmoplegia, ptosis, and optic neuropathy. Therefore, evaluation depends on finding contributory abnormalities on imaging, serology, and spinal fluid examination (28).

In addition to neuroimaging, diagnostic evaluation in a case of painful ophthalmoplegia requires testing for a battery of blood and cerebrospinal fluid parameters (Table 1).

Table 1. Suggested Workup for a Patient with Painful Ophthalmoplegia

Management

Painful ophthalmoplegia should be managed according to the underlying etiology. Corticosteroid therapy is the mainstay of management for patients with idiopathic orbital inflammation syndrome and retro-orbital pachymeningitis.

Oral prednisone (1 mg/kg/day) is the preferred initial regimen. Major resolution of clinical manifestations often occurs within days. Corticosteroids are gradually tapered over the next 2 weeks. A minority of patients require longer corticosteroid treatment (03).

If the response to corticosteroid treatment is incomplete, tacrolimus, cyclosporine, azathioprine, methotrexate, mycophenolate mofetil, infliximab, or adalimumab are often prescribed. Radiotherapy has shown benefit in isolated case reports (19; 20; 21).

Outcomes

The long-term follow-up of 37 patients with Tolosa-Hunt syndrome disclosed that recurrences occurred in 50% (03). The duration of recurrences varied from 8 months to 7 years. In one patient, the diagnosis was revised to leptomeningeal malignancy.

Special considerations

Pregnancy

Tolosa-Hunt syndrome has been described as relapsing in pregnancy (24). The first attack remitted spontaneously. It remitted completely following corticosteroid treatment.