This article includes discussion of ulnar neuropathies, Guyon canal neuropathy, ulnar neuropathy at the wrist, and flexor carpi ulnaris exit compression.
Jun. 07, 2021
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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.
• 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.
• 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.
• 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.
• 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.
• 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.
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).
Inflammation in either the orbit or cavernous sinus can cause pain in 1 orbit with ipsilateral but variable radiation to the brow, temple, and even occiput as well as ophthalmoplegia due to cranial nerve or extraocular muscle involvement. Little about the pain in either orbital or cavernous sinus inflammation specifies the exact characteristics of the underlying pathology. 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. The pain in cavernous sinus inflammation shares many of the same features, though some authors suggest that it can radiate somewhat more widely with spread to the frontal, temporal, and even occipital areas on the involved side (42; 75; 08).
Important differences between cavernous sinus (Tolosa-Hunt syndrome) and orbital (orbital pseudotumor) localization are sensory loss in the ipsilateral cheek (V2 distribution) in the former and the presence of "orbital signs" in the latter. The relative incidence of these various signs in patients with nonvasculitic orbital inflammatory tumors was tabulated by Henderson as follows: (1) unilateral lid swelling or ptosis in 82%; (2) globe protrusion (proptosis) or displacement in 67%; (3) palpable or visible orbital mass in 33% (29). Most patients had several or all of these signs and symptoms at onset and variably throughout the course of the illness. The clinical profile was much the same in a series of 132 patients with orbital inflammation, of which 82% had proptosis and 38% had optic nerve involvement with loss of visual acuity (27). Optic nerve involvement was present in 13 (41%) of 32 patients studied by Mombaerts and colleagues (60). The disease is quite protean, however, and has been reported even to present with upper eyelid retraction in isolation (77).
It is important to note that pain and ophthalmoplegia are not universal in cases of orbital inflammation (and presumably also in cavernous sinus inflammation), with case series reporting disturbance of ocular motility with diplopia in 49% to 54% and orbit pain or headache in 33% of patients with nonvasculitic orbital inflammatory masses and orbital inflammation (29; 27).
An alternative to localization-based classification is histopathology-based. This is particularly important as there are etiologies besides idiopathic inflammation that can cause painful ophthalmoplegia that have profoundly different prognosis and treatment implications (See Clinical vignette). Henderson found that there were no clinical features that reliably predicted the microscopic characteristics in any given case (29). Analysis of his material also showed that all the types of inflammatory lesions could involve either single tissues or foci within the orbit or, more commonly, multiple tissues and sites including lacrimal gland, sclera and Tenon capsule around the globe, tendinous muscle insertions, extraocular muscles, the dural sheath of the optic nerve, and the orbital fat.
The clinical course of both idiopathic orbital inflammation (orbital inflammatory pseudotumor) and idiopathic cavernous sinus inflammation (Tolosa-Hunt syndrome) is most often characterized by remission, either spontaneous or induced by treatment with corticosteroids, other immunosuppressive drugs, or radiotherapy. The duration of active inflammation in Henderson's patients with nonvasculitic inflammatory orbital lesions ranged from 3 to 12 months, after which time there was usually sustained remission off treatment. This compares with patients with vasculitic inflammatory orbital lesions, either nongranulomatous (hypersensitivity angiitis) or granulomatous (limited form of granulomatosis) with polyangiitis (Wegener disease), who had a more severe course characterized by greater numbers of exacerbations and more protracted intervals of active inflammation. This occurred even with aggressive treatment and featured a greater tendency for bilateral orbital involvement and spread to adjacent paranasal sinuses and to intracranial structures, most commonly middle cranial fossa and the cavernous sinus (29). Others have published cases in which the process extended from the orbit to involve intracranial structures, but in many of these cases there was no pathologic examination to establish what type of inflammatory lesion was involved (21; 23; 12; 04).
The prognosis of painful ophthalmoplegia depends on the cause.
The prognosis of both idiopathic orbital inflammation (orbital inflammatory pseudotumor) and idiopathic cavernous sinus inflammation (Tolosa-Hunt syndrome) must be regarded as usually good. Although some cases require protracted treatment with steroids and other immunosuppressive agents or suffer multiple relapses over a long period of time, these patients are the exception rather than the rule. Also, a great deal of discussion centers around the few patients who go on to have a systemic malignancy, most commonly lymphoma; this is a rare occurrence and is usually the subject of single case reports. The fact that this outcome was encountered in only 1 of 50 patients with nonvasculitic orbital inflammatory tumor followed by Henderson for a mean of 5 years suggests that the magnitude of the problem is small and that most patients truly have a relatively benign inflammatory condition that can be managed using fairly short courses of corticosteroids.
Henderson noted that among his patients with orbital nonvasculitic orbital lesions, though the inflammation became inactive, many were left with variable residual dysfunction of ocular motility and vision (29). Using the degree of residual dysfunction as the parameter, he tabulated his patients' clinical status at final follow-up as compared with presentation and found 18 of 45 improved, 20 of 45 unchanged, and 7 of 45 worse. In contrast, patients in his series with vasculitic inflammatory tumors, either granulomatous (granulomatosis with polyangiitis [Wegener disease]) or nongranulomatous, the prognosis was considerably worse than for those with nonvasculitic orbital tumors. These vasculitic lesions tended to run a protracted course requiring high doses of corticosteroids to maintain remission. Also, these patients often required radiation therapy and cyclophosphamide at various times in their course.
Mannor and colleagues reviewed the clinical features and radiographic findings in 26 patients with orbital myositis in an effort to identify early signs that would predict either a relapsing or prolonged course (53). They found that the following features correlated with prolonged course or recurrences at the P=0.05 level: male gender, lack of proptosis, eyelid retraction, horizontal extraocular muscle involvement, and bilateral muscle involvement. Muscle tendon sparing and failure to respond to either corticosteroids or nonsteroidal anti-inflammatory agents correlated with a more severe course at the P=0.01 level. The authors suggested that presence of 1 or more of the “high risk” features might call for early treatment with corticosteroids.
In a logistic regression analysis of 209 cases of orbital inflammatory pseudotumor, Yan and colleagues found that male gender and, notably, degree of proptosis both were positively correlated with higher relapse rate (92). The findings regarding proptosis are the opposite of Mannor’s result for reasons that are not clear. The recurrence rate varied with clinical subtype; 17% with dacryoadenitis, 44% with anterior local orbital mass, 54% with posterior orbital mass, 75% with myositis, and 100% in the diffuse subtype, but these differences did not reach statistical significance.
A patient was transported to the office by ambulance from another hospital in December 1996. She determined the onset of the current illness to be 19 August 1996, when she had 6 temporary crowns placed by her dentist. The next day she had mild pain in the suboccipital area and neck, which she attributed to an old problem with C5 that had been treated. Within days, however, the pain worsened and spread to the central vertex and right orbit, where it became a daily problem. By early September 1996 she was having severe right orbit pain and in mid-September 1996 she was started on prednisone after a temporal artery biopsy. She could not recall what the dose of prednisone was at that time, but apparently there was at least partial relief of pain for a short while. The biopsy was negative and prednisone dosage was tapered.
Soon after starting prednisone in September 1996, she developed diplopia that persisted until ptosis was noted about 3 weeks prior to her arrival in the hospital. The ptosis might have been present earlier, but she tended to keep the right eye closed voluntarily to avoid diplopia; the exact onset may have been masked by this. She was surprised to find that the right eye vision was decreased to "light and shadows" when the lid was elevated to examine the eye. Also, it was noted that the right pupil was dilated and fixed for the first time.
Radiographic work-up was read as normal, including brain and orbit MRI and CT as well as conventional carotid angiography. The steroid dose was increased from 60 to 80 mg/day (for 12 days) and then 100 mg/day (for 3 days), still without significant pain relief. The severe limitation of ocular motility and complete ptosis also did not improve with higher steroid dosage.
Pupil in dim light: 5.5 mm
Pupil in dim light: 4.0 mm
There was a prominent right eye relative afferent pupillary defect.
Motility. The right eye was virtually frozen. There was a trace adduction from a slightly abducted position with attempted left gaze.
Palpebral fissures. There was complete right eye ptosis.
• Base: 96
Visual fields. Using the Goldmann perimeter the central and peripheral isopters were normal for the left eye. We did not attempt perimetry on the right eye.
Fundus examination. The optic discs were normal in contour, color, and capillary content. The retinal arterioles and veins were normal, and the maculae were unremarkable. The retinal periphery was normal in both eyes.
Impression. There was evidence for an extremely painful destructive and space-occupying process in the right orbit. She had progressive dysfunction of cranial nerves II, III, IV, and VI, and at the time of this report, there was 3 mm relative proptosis. The nearly complete failure of high-dose, sustained corticosteroid treatment to affect the course of the disease seemed to mitigate against the usual forms of orbital inflammatory pseudotumor. Carcinomatous infiltration of the orbital apex and the cranial nerve structures in the anterior cavernous sinus was considered the most likely diagnosis.
Repeat lumbar puncture and collection of a large volume of cerebrospinal fluid for cytology and culture was recommended. We also recommended perinuclear antineutrophil cytoplasmic antibody and cytoplasmic antineutrophil cytoplasmic antibody determined for granulomatosis with polyangiitis (Wegener disease). One could consider a course of oral cyclophosphamide, which is the treatment of choice for granulomatosis with polyangiitis (Wegener disease), but it is difficult to recommend this without some specific evidence for the disease. Empirical radiation might also have been considered, but it would certainly be best to have abnormal cytology or some tissue evidence for cancer before doing this.
Further clinical course. Following our recommendation, repeat MRI showed a mass occupying the right orbital apex with extension through the superior orbital fissure and into the anterior cavernous sinus on the right side.
Her condition failed to improve after another course of intravenous methylprednisolone, and she underwent transethmoidal biopsy. Grossly, a purple mass was found occupying the orbital apex, but biopsy specimens revealed only fibrous tissue with elements of muscle and peripheral nerve. There was 1 occluded blood vessel, but this was adjacent to an area of cautery and probably not indicative of any particular disease.
The patient returned in February 1997. She related that her main problem was then a burning, aching retrobulbar and brow pain on the right side that was less severe than the earlier pain, but the pain was still keeping her from sleeping. She also reported poor appetite and a total of 26 lb of recent weight loss.
A significant new development was the appearance of 1 or 2 lung nodules. These responded to treatment with ciprofloxacin, so open biopsy was not done. The antineutrophil cytoplasmic antibody was negative for granulomatosis with polyangiitis (Wegener disease).
She continued to do poorly, with further weight loss and increasing apathy. She underwent craniotomy, and a mass in the superior orbital fissure and anterior cavernous sinus showed necrotizing granulomatous inflammation. Culture was positive for aspergillus, and she was then treated with amphotericin-B. Despite intensive antifungal and supportive treatment, the patient became progressively cachectic and died. Autopsy was not performed.
Orbital inflammatory pseudotumor and idiopathic cavernous sinus inflammation (Tolosa-Hunt syndrome), by definition, are idiopathic. Most of these patients never develop evidence for systemic autoimmune or inflammatory diseases and do not go on to have either orbital or systemic lymphoma. A variety of more specific conditions can present with much the same clinical profile of signs and symptoms as cases of orbital pseudotumor (29).
Much less nosologic information about purely intracranial inflammatory cases exists because specific pathology is only rarely obtained (83; 42; 75). There is ample evidence, however, that combined involvement of orbit and middle fossa can occur in otherwise typical cases of orbital inflammatory pseudotumor in which the pathology does not significantly differ from purely orbital cases (12; 04; 29).
Apart from the occasional case in which the orbital or intracranial inflammation is shown to be a reaction to a foreign body or other specific local condition, the disease has no known specific biology apart from that of inflammation (38). A variety of immunohistochemical findings have been reported in biopsy specimens of orbital cases, including deposition of complement and presence of immune competent cells expressing both class I and class II HLA antigens (47).
The following histopathologic categories of orbital inflammatory disease were distinguished by Henderson in the Mayo Clinic series collected between 1948 and 1987: (1) nonvasculitic inflammatory tumors in 58 patients; (2) nongranulomatous vasculitic inflammatory tumors in 23 patients; and (3) granulomatous vasculitic inflammatory tumors or granulomatosis with polyangiitis (Wegener disease) in 17 patients, 6 of whom had known extraorbital granulomatosis with polyangiitis (Wegener disease) before the onset of orbital disease, and 11 of whom presented first with orbital disease (29).
Nonvasculitic inflammatory tumors were characterized by tissue infiltration with a mixed cell population including lymphocytes (which predominated), plasma cells, macrophages, eosinophils, and polymorphonuclear leukocytes. The lymphocytes often were found in nodular arrangements resembling follicles, and germinal centers were sometimes present. Cellular infiltrates often form cuffs around small veins, but there is no vessel wall infiltration or destruction as opposed to cases described as vasculitic. Henderson suggests that large numbers of eosinophils should suggest the presence of vasculitis that may be present in a part of the involved tissue not included in the specimen (29). He also notes that sclerosis or fibrosis often results from prolonged refractory inflammation in some cases, but does not constitute a separate entity in his opinion. This is contrary to opinions of other authors that sclerosing inflammatory conditions are biologically separate (88).
In nongranulomatous vasculitic tumors, blood vessel walls were infiltrated by inflammatory cells, and destruction included necrosis of the vascular wall. There was usually diffuse, extravascular inflammatory infiltration similar to that in the nonvasculitic cases. Eosinophils tended to be the predominant cell in the vascular infiltrates, which led Henderson to postulate that the orbital disease is a variant of the disorder called "hypersensitivity vasculitis" by the American College of Rheumatology Subcommittee on Classification of Vasculitis (48).
Granulomatous orbital vasculitis is probably 1 of the limited forms of granulomatosis with polyangiitis (Wegener disease) that in its complete manifestation includes necrotizing granulomatous lesions in the upper and lower respiratory tract, necrotizing and crescentic glomerulonephritis, and small-vessel vasculitis involving both arteries and veins (44; 29). A small biopsy specimen may not contain any typical granulomas, but show only the vasculitis component leading to delay in specific diagnosis. Chappelow and colleagues reported on a 52-year-old man who presented with intraconal granulomatous inflammation on biopsy consistent with idiopathic orbital inflammatory disease (10). However, further examination with polarizing light microscopy revealed speckled acetate fibers in which the speckles proved to be impregnated titanium. The authors pointed out that titanium-impregnated acetate is commonly employed in textile and clothing manufacture as the titanium reduces the sheen of the fabric. The paper concluded that idiopathic granulomatous orbital inflammatory disease is uncommon outside of systemic disease such as granulomatosis with polyangiitis (Wegener disease) and predominates in the relatively superficial lacrimal gland, suggesting that occult foreign bodies may underlie some or even many of these cases.
The 1 patient of Henderson's series of 58 with nonvasculitic inflammatory tumor who went on to die of systemic lymphoma 4 years later raises the serious problem that even with histologic material and immunohistochemical analysis, it is not always possible to predict the eventual behavior of the lesion. Speculation ranges from the idea that the eventual neoplasm was an independent second disease to the thought that lymphoid neoplasia may somehow be triggered by prolonged independent antigenic and inflammatory stimulation (29).
Knowles and colleagues excluded 9 patients said to have inflammatory pseudotumor from their series of patients with "lymphoid hyperplasia" and "malignant lymphoma" in the orbit, describing the inflammatory condition as a relatively hypocellular lesion with pronounced fibrosis (41). These authors went on to point out that on analysis of 108 patients with either benign "lymphoid hyperplasia" or malignant "lymphoma" there were no presenting or early clinical, laboratory, or tissue morphologic features that reliably predicted the benign or malignant behavior of the lesion over the entire course of the illness. The heterogeneity of the inflammatory lesion was underscored in a review of orbital inflammatory pseudotumor, although the authors still consider it to be a clinical entity (59).
Ishikawa and colleagues reported a 53-year-old woman who had an orbital tumor resected in 1986 and then presented in 1997 with bilateral orbital masses (34). Resection of these masses and reexamination of the tissue from 1986 showed identical tissues in all specimens. The tissue was consistent with a lymphoid form of orbital inflammatory pseudotumor, having polyclonal B cell immunohistologic staining. Southern blot hybridization was used to detect immunoglobulin gene rearrangement, which was also found in all specimens. Based on the latter findings, the authors classified the original lesion as low-grade malignant lymphoma with systemic (bilateral orbital) dissemination 11 years later. This case is an example of the long-term course of an orbital lymphoproliferative lesion with positive immunoglobulin gene rearrangement.
Histologic and immunohistochemical examination of 55 orbital lymphoid lesions retrieved from the pathology laboratories at 2 institutions demonstrated that inflammatory pseudotumor, lymphoid hyperplasia, and lymphoma could be reliably distinguished based on the percentage of B lymphocytes in the tissue and the nature of the light chain immunoglobulin expressed. The percentages of B cells were for inflammation, 35%; hyperplasia, 65.9%; and lymphoma, 87.3%. These differences were statistically significant (p < 0.001). Inflammation and lymphoid hyperplasia were associated with polyclonal light chain expression and lymphoma with monoclonal light chains (mainly kappa) (50).
A quantitative study of the distribution of mast cells in histopathologic specimens from 53 patients with 3 subtypes of orbital inflammation, including 19 with lymphocytic infiltrative type, 22 with the fibrotic type, and 12 with mixed pathology, as well as in 4 specimens with normal orbital tissue, was carried out using tryptase monoclonal antibody as a cell surface marker for mast cells. The average number of mast cells in the normal orbital tissue was 33.33 +/- 4.72 /mm3. Among the patients with orbital inflammation the counts were 306.35 +/- 55.81 /mm3 for lymphocytic infiltrative subtype, 662.93 +/- 115.28 /mm3 for the mixed subtype, and 813.44 +/- 146.56 /mm3 for the fibrotic subtype. The authors conclude that mast cells play a more important role in the pathogenesis of orbital inflammatory disease than heretofore recognized, especially in cases that feature prominent fibrosis (91).
Considerably less information is available on the pathology of idiopathic cavernous sinus inflammation (Tolosa-Hunt syndrome). There have been no recent reports of patients with inflammation confined to the intracranial compartment in which pathologic examination was undertaken. Pathologic material, usually from the orbit, is available for some cases in which there was combined involvement of orbit and middle cranial fossa, but it is not certain if the purely intracranial disease called Tolosa-Hunt syndrome is the same entity (21; 23; 12; 04).
In 1962 Lakke published pathology from intracranial biopsy in 1 patient with what was described as superior orbital fissure syndrome (42), and in 1972 Schatz and Farmer presented pathologic documentation on 3 patients with the clinical picture of Tolosa-Hunt syndrome. Lakke only referred to his patient's pathology as "pachymeningitis of indeterminate cause." The inflammatory exudate consisted of "polynuclear and mononuclear" cells showing no tendency to aggregate around blood vessels. This involved the wall of the cavernous sinus, but that wall itself was said to be normal. The dura in the region of the superior orbital fissure was necrotic.
The pathology in all 3 of Schatz and Farmer's cases was characterized by granuloma formation with lymphocyte and plasma cell infiltration and presence of multinucleated giant cells along with variable fibrosis and patches of necrosis, but no organisms (75). The specimen was from the intracranial cavity in 3 of the patients and from a parotid gland biopsy in the third. No patient had clinical evidence of either tuberculosis or sarcoidosis.
A new category of sclerosing diseases with elevated serum IgG4 and infiltration of various organs with IgG4 plasma cells and lymphocytes was first delineated in patients with autoimmune pancreatitis by Hamano and colleagues in 2001. Since then, a number of other tissue-specific autoimmune sclerosing disorders have been linked to elevated IgG4 in the same way (55). In a retrospective review of orbital biopsies excluding lymphoma at Mayo Clinic, Plaza and coworkers found that 11 of 21 patients demonstrated increased (> 10 cells) IgG4-positive cells, of which 2 patients had elevated serum IgG4 levels (66). Six of the 11 patients had lesions in other organs, whereas none of the 10 IgG4-negative patients had systemic involvement. Compared with the IgG4-negative patients, the IgG4-positive patients had longer symptom duration, and the biopsy specimens demonstrated more fibrosis, lymphoid hyperplasia, plasma cells, and eosinophils. The authors concluded that these patients have an orbital manifestation of a systemic IgG4-associated systemic disease.
Treatment of steroid-resistant IgG4-related orbital inflammatory disease has been the subject of investigation. One report concerns 10 patients with IgG4-related orbital inflammation that failed to respond completely to corticosteroids or disease-modifying antirheumatic drugs, 9 of whom had dramatic remission after two 1-gram infusions of rituximab given at an interval of 15 days (40). The remaining patient demonstrated arrest of progression but not remission of disease, and 4 required repeat treatments within 6 months but remained responsive. Wallace and colleagues reported an additional case of a man with a 30-year history of what turned out to be IgG4-related orbital myositis and dacryocystitis that had been refractory to corticosteroids, methotrexate, and mycophenolate mofetil, but who responded briskly to intravenous rituximab (87).
Orbital inflammatory pseudotumor primarily presents in adults between the ages of 36 and 64 years, though in 1 series the extremes included patients as young as 5 and as old as 80 years (61; 27). Other authors have documented childhood occurrence of otherwise typical disease (32). Childhood cavernous sinus inflammatory disease may rarely present with painless ophthalmoplegia and may remit spontaneously without steroid treatment (13). Both Moro and Henderson found equal distribution between the sexes but females predominated 2 to 1 in Ingalls' material (33; 61; 29). One report describes a family with 4 members in 2 generations who had recurrent orbital myositis (56). This provides evidence for the role of genetic factors in determining susceptibility to the disease.
The Mayo Clinic series is 1 of the largest with information available on epidemiology. The series was published in 1994, though the analysis included 58 patients entered between 1948 and 1987 with biopsy-proven disease (29). The authors found roughly the same concentration of cases between the fourth and the eighth decades of age, though there was a small predominance of the fifth decade for first presentation. Only 1 of their cases was bilateral. There was a small predominance for left-side involvement, which the authors could not explain.
Keane found that self-limited inflammation (idiopathic cavernous sinus inflammation/Tolosa-Hunt syndrome) was the third most common cause (34 patients, 23%) of cavernous sinus syndrome in his personal series of 151 cases accumulated over a 26-year period (37). The most common cause was trauma (36 patients, 24%) if surgical cases were included, but tumor (45 patients, 30%) if patients with cavernous sinus involvement as a complication of surgery were eliminated.
A variety of diseases affecting cavernous sinus, superior orbital fissure, or orbital apex can lead to painful ophthalmoplegia. Idiopathic inflammation (Tolosa-Hunt syndrome) remains a diagnosis of exclusion. 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 diagnosis (62).
In addition to idiopathic cavernous sinus inflammation (Tolosa-Hunt syndrome), neoplastic disorders and fungal infections and are most common causes of cavernous sinus syndrome (05). Many inflammatory conditions like sarcoidosis and vasculitis can also present with painful ophthalmoplegia (68). 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.
One of the largest series of orbital lymphoid neoplasms, 108 cases, was collected by Knowles and colleagues between 1977 and 1987 (41). Their clinical material suggests that the neoplastic disorder differs from inflammatory pseudotumor in 4 respects. First, lymphoid neoplasia develops at a somewhat later age than typical pseudotumor, with 84% of the patients presenting after the age of 50 years, most commonly in the sixth and seventh decades. Second, bilateral orbital involvement was more frequent in the lymphoid neoplasms (9 of 69 [13%] patients with orbital neoplasia) as compared with most accounts of inflammatory pseudotumor. Third, pain was a relatively minor or secondary complaint, and fourth, ocular motility disturbance was relatively infrequent in the lymphoid neoplasm group as compared with other large series of orbital inflammatory pseudotumor (41; 29).
Primary intracranial lymphoma may also present with unilateral orbital pain and diplopia, mimicking idiopathic cavernous sinus inflammation (Tolosa-Hunt syndrome) (71). Takao and colleagues reported a unique case with biopsy-demonstrated T-lymphocytic inflammatory involvement of the Gasserian ganglion in a 70-year-old woman who presented with sensory alteration in the left trigeminal distribution and abnormal ocular motility on the same side (81). Four years later she developed multiple intracranial masses, which lead to death. At autopsy, the intracranial lesions proved to be B-cell lymphoma and there was still trigeminal infiltration with B cells, histologically distinct from the lymphoma.
Orbital inflammatory disease may occur with a variety of antecedent or concurrent illnesses that activate the immune system. Bilateral orbital myositis was reported in a young woman following acute upper respiratory tract infection (07). Also, another report documents the development of orbital myositis along with posterior scleritis and polyarthropathy following influenza vaccination in 1993 (82). Another single case of what was described as orbital myositis turned out to be the presenting feature of Crohn disease (19). Orbital inflammatory pseudotumor may occur in patients who also have other fibrosclerosing disorders, including retroperitoneal fibrosis, sclerosing mediastinitis, sclerosing cholangitis, and Riedel thyroiditis (15; 52).
Sjögren syndrome, sarcoidosis, granulomatosis with polyangiitis (Wegener disease), and polyarteritis nodosa all must be considered in the differential diagnosis. A single case report described the coexistence of orbital inflammatory pseudotumor and positive temporal artery biopsy for giant cell arteritis (14). Since this patient was reported, a series of 4 cases presented as orbital inflammatory pseudotumor clinically and temporal artery biopsy documented giant cell arteritis (45). In 1 of these 4 cases, orbital biopsy confirmed the histopathology of giant cell arteritis.
Takanashi and colleagues presented 2 new patients with Churg-Strauss syndrome (allergic granulomatosis and angiitis) with orbital manifestations and reviewed 15 previously reported cases with orbital involvement (80). Two clinically and pathologically distinct groups were identified. The orbital inflammatory pseudotumor group (8 cases) was characterized clinically by chronicity, conjunctival involvement, abnormal orbital imaging, negative serum antineutrophil cytoplasmic antibodies, and good visual prognosis; these patients had granulomatosis on biopsy. The second group (9 cases) the authors characterized as ischemic cases; they had sudden onset of symptoms, no conjunctival involvement or orbital mass lesions, positive antineutrophil cytoplasmic antibodies and sometimes poor visual outcome. These patients had angiitis on biopsy.
Tornerup and colleagues reported a patient who ultimately developed acute retinal necrosis and had positive polymerase chain reaction for herpes simplex virus type 1 on 2 vitreous samples (84). This patient’s illness started with eye pain, proptosis, and swelling of the optic nerve as imaged by CT scan. The authors emphasize that this is the first report of herpes simplex virus-induced acute retinal necrosis presenting with inflammatory orbitopathy and optic neuritis. Orbital myositis has been reported as a presenting symptom complex of Herpes zoster ophthalmicus (36). MRI in this case demonstrated enlargement of the extraocular muscles, which differentiates orbital myositis from third cranial nerve involvement by the zoster virus.
Osmanovic and associates described a 71-year-old woman who presented with painful right eye vision loss and ophthalmoplegia with marked thickening of the right optic nerve sheath on MRI that started 1 month after nasal septoplasty (64). She was initially treated with high-dose corticosteroids for a presumed diagnosis of temporal arteritis. After temporal artery biopsy was negative, the steroid dose was tapered. However, she became febrile, and CSF had 480 white blood cells per microliter with 43% neutrophils. Orbital biopsy revealed purulent material in the right optic nerve sheath.
Three patients have reportedly developed orbital inflammatory pseudotumor following treatment with intravenous pamidronate (73; 79). The mechanism of this adverse effect is unknown, but pamidronate has also been reported to cause other forms of ocular inflammation, including conjunctivitis and anterior uveitis.
Panfilio and colleagues documented a case of relapsing, steroid-responsive orbital myositis in a patient who had had rheumatoid arthritis for 6 years (65). The authors reviewed 156 cases and found only 3 reports of orbital inflammatory disease associated with rheumatic diseases but none associated specifically with rheumatoid arthritis. However, another instance of this association was subsequently documented (63). Other reports describe a child with chronic relapsing psoriasis, psoriatic arthritis, and relapsing bilateral orbital myositis (01) as well as another with childhood hypothyroidism (85).
Gilliard and colleagues described a patient who developed progressive quadriplegia from a cervical extramedullary mass that on biopsy proved to be an inflammatory pseudotumor (24). The patient had had orbital pseudotumor 5 years previously. The authors were able to find 9 cases of multifocal fibrosclerosis with central nervous system involvement in the literature. Another patient was reported with bilateral orbital pseudotumor plus suprasellar mass and pulmonary infiltration in whom biopsies from retrobulbar tissue and bronchial tissue showed a similar type of inflammation (Lai et al 2000). Other extraorbital sites of myositis associated with orbital inflammatory pseudotumor include trapezius and paraspinal muscles (16) and the infratemporal fossa (46).
It has been suggested that idiopathic cavernous sinus inflammation (Tolosa-Hunt syndrome), inflammatory myofibroblastic tumor of the orbit, and idiopathic hypertrophic pachymeningitis share many pathologic features and may exist along a clinical spectrum. McKinney and colleagues describe a 50-year-old man with progressive dysfunction of multiple cranial nerves (II, V1-3 and X), orbit, and infraorbital masses and fullness of the left cavernous sinus and diffuse dural enhancement that resolved on steroid treatment (57). Biopsy of the orbital mass and the infraorbital nerve revealed histopathology consistent with inflammatory myofibroblastic tumor. In a similar vein, Singh and colleagues describe a 48-year-old man who presented with painful ophthalmoplegia, foot drop, and facial palsy with MR findings consistent with idiopathic cavernous sinus inflammation (Tolosa-Hunt syndrome) and rapid resolution with corticosteroid treatment (78).
As of 2013, there are 3 editions of the International Classification of Headache Disorders (ICHD) diagnostic criteria for Tolosa-Hunt syndrome. The most recent edition has been designated as ICHD-3 beta. Zhang and colleagues undertook a retrospective analysis of 77 patients with painful ophthalmoplegia (93). The most common final diagnosis was idiopathic cavernous sinus inflammation (Tolosa-Hunt syndrome) in 46 (mean age 44.4 years), followed by intracranial aneurysm (mean age 58.8 years) (posterior communicating artery in 10, internal carotid artery in 3), and diabetic ophthalmoplegia in 9 (mean age 63.2 years), and an assortment of middle cranial fossa tumors and 1 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, 9 the orbital apex and superior orbital fissure, and 8 in the orbital apex and cavernous sinus. Obviously, a great deal of overlap existed between anatomic compartments. Of the 46 patients with idiopathic cavernous sinus inflammation (Tolosa-Hunt syndrome), pain relief occurred within 72 hours of treatment onset in 40 patients—complete relief in 16 and partial relief in 24. After 1 week of corticosteroid treatment, 31 had achieved complete pain relief and another 9 had partial relief. Twenty-eight had achieved partial cranial nerve palsy relief within 72 hours and by 1 week, 1 had complete palsy resolution and 35 had partial resolution. The authors concluded that the ICHD-3 beta criteria for diagnosis of Tolosa-Hunt syndrome should be modified as follows: (1) to reinstate the response to steroid treatment in the diagnostic criteria even though one would like to have the diagnosis before starting treatment, and (2) to relax the requirement for contrast enhanced MRI confirmation of inflammation in the cavernous sinus and/or orbit because the MRI was abnormal in just over half the cases in this series of Tolosa-Hunt syndrome.
Hung and coworkers compared the presentation and clinical course in a cohort of 61 patients with pain and ophthalmoplegia, of which 25 were deemed to have idiopathic cavernous sinus inflammation (Tolosa-Hunt syndrome) after initial workup, and another group of 36 patients with what they called other “symptomatic painful ophthalmoplegias” (30). Clinical features that resulted in placement into the latter group include diplopia antedating the onset of pain, bilateral symptoms, and/or pain spreading outside the orbit. The symptomatic painful ophthalmoplegia group consisted in this study of 11 patients with a neoplasm, 13 patients with a vascular anomaly (10 of them carotid cavernous fistula), and 10 patients with an infectious etiology (bacterial, fungal, and viral). On imaging, all the patients with clinical idiopathic cavernous sinus inflammation (Tolosa-Hunt syndrome) had typical MRI features in the orbit or parasellar region, as did 20 of the 36 patients with symptomatic painful ophthalmoplegia. Atypical imaging findings were found in 23 patients with symptomatic painful ophthalmoplegia and 1 patient who had idiopathic cavernous sinus inflammation (Tolosa-Hunt syndrome) clinically. Atypical imaging features included lesions invading the sphenoid and ethmoid sinuses, cranial bone erosion, and cerebral parenchymal involvement.
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 similar clinic-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” (51).
CT with thin orbital cuts and bone window views and MRI are the most useful imaging techniques to evaluate patients with painful ophthalmoplegia. MRI is preferred to portray the cavernous sinus, though CT may show enlargement of the cavernous sinus on the side of the lesion in idiopathic cavernous sinus inflammation (Tolosa-Hunt syndrome) (02; 11; 72). The cavernous sinus pathology may elude both types of imaging, so one cannot rule out cavernous sinus pathology with normal studies (02). With MRI, fat suppression or frequency selective-fat saturation pulse sequences and gadolinium enhancement are necessary to show the orbital lesions of idiopathic orbital inflammation (28).
Most often, the bony walls of the orbit are radiographically normal (29), though on occasion bony destruction has been documented in otherwise typical cases of orbital inflammatory pseudotumor (89; 25).
Orbital wall sclerosis or hyperostosis can point to a diagnosis of meningioma, but in a series of 176 patients with biopsy-proven orbital inflammatory pseudotumor, 20 (11.5%) had definite sclerosis and another 10 (6%) had probable sclerosis (70). The authors suspect the true incidence to be higher because bone window CT films were available for only a few of their patients.
CT characteristics in patients with orbital pseudotumor were tabulated by Flanders and colleagues as follows: infiltration of retrobulbar fat 76%, enlargement of extraocular muscles 57%, thickening of the optic nerve sheath complex 38%, contrast enhancement 95%, and proptosis 71% (22). In another series of 84 patients with idiopathic orbital inflammation and radiographic information, diffuse orbital (fat) involvement was the most frequent radiographic pattern, occurring in 48%, followed by myositis in 25% and dacryoadenitis in 17%. The disease presented as a focal encapsulated mass in 4% (27). Valvassori and colleagues reviewed the MRI and CT characteristics of a variety of orbital lymphoproliferative disorders, including inflammatory pseudotumor (86).
Radiolabeled somatostatin analog 111 IN-pentetreotide demonstrates somatostatin receptor-positive foci in diseases with activated lymphocytes, and this nuclear medicine technique has been used to demonstrate orbital lesions in Graves ophthalmopathy, orbital inflammatory pseudotumor (18), and orbital myositis (35). It was suggested that this marker might select for lesions that would respond to immunosuppressives or octreotide (35). The response to octreotide was disappointing in 3 patients with Graves ophthalmopathy (18). This needs further investigation in patients with orbital inflammatory pseudotumor and idiopathic cavernous sinus inflammation (Tolosa-Hunt syndrome).
Imaging and scanning methods can provide some differential diagnostic and prognostic information in both orbital inflammatory pseudotumor and idiopathic cavernous sinus inflammation (Tolosa-Hunt syndrome). In a study of 17 patients with orbital inflammatory pseudotumor who underwent MRI with short inversion time inversion-recovery images, it was found that the response to corticosteroid treatment was predictable, based on the short inversion time inversion-recovery signal characteristics (03). Lesions in the good response group were usually hyperintense to the cerebral cortex, whereas those in the poor response group were hypointense or isointense to the muscle. In at least 1 patient scintigraphy with 67 Ga-citrate detected transition from a lymphocytic inflammatory orbital lesion to an aggressive non-Hodgkin T-cell lymphoma (49). The original lesion showed little uptake of gallium, but 6 weeks later, after poor response to corticosteroids prompted repeat scintigraphy, the avidity of the lesion for gallium had markedly increased, and the neoplastic transformation was documented on histologic examination of the surgical specimen.
MRI focused on cavernous sinuses documented the imaging features in 15 patients with idiopathic cavernous sinus inflammation (Tolosa-Hunt syndrome), including 15 initial episodes and 5 recurrent episodes (76). The primary criteria, a) an enhancing soft tissue lesion within the cavernous sinus and b) increase in size with lateral bulging of the anterior cavernous sinus contour, were present in all 20 episodes. Secondary criteria were tabulated as follows: a) internal carotid artery narrowing (7 patients), b) extension toward the superior orbital fissure (13 patients), c) extension toward the orbital apex (8 patients). Complete resolution of findings occurred on follow-up exams.
Miyamoto and colleagues studied 12 patients with 13 orbital tumors, 7 of which were malignant, using fluorine-18-fluorodeoxyglucose positron emission tomography ([18F]FDG-PET) (58). The accumulation ratio between the tumor and normal tissue (T/N ratio) was high for all the malignant tumors (1.81 +/- 0.27) and low for the benign lesions (1.06 +/- 0.03). Among patients with orbital inflammatory pseudotumor, both high and low ratios were found. The authors concluded that [18F]FDG-PET does not reliably distinguish inflammatory pseudotumor from orbital malignant tumor.
Because the differential diagnosis includes a variety of autoimmune and inflammatory conditions, some with systemic manifestations, serologic and hematologic workup is important in all patients with either orbital inflammatory pseudotumor or idiopathic cavernous sinus inflammation (Tolosa-Hunt syndrome). In general, the differential diagnosis includes the same conditions for both disorders. The following is abstracted from Lamkin and Raizman's review of laboratory diagnosis in patients with orbital diseases (43). This review is highly recommended for a more detailed summary of the pathogenesis and pathophysiology, specificity, and sensitivity of these tests.
Sarcoidosis classically presents with involvement of both lacrimal glands, but this systemic granulomatous disorder may present as any variety of orbital pseudotumor. Sarcoidosis also has a tendency to involve the pituitary fossa and adjacent structures intracranially, and is in the differential diagnosis of idiopathic cavernous sinus inflammation (Tolosa-Hunt syndrome). Helpful diagnostic laboratory abnormalities include hilar adenopathy revealed by chest x-ray or gallium scan (often referred to as potato nodes because of the large confluent granulomatous adenopathy that is commonly present) and abnormally high values for serum angiotensin-converting enzyme or lysozyme. These enzymes are secreted into various body fluids including serum by macrophages and epithelioid cells and are usually elevated when sarcoidosis is active, but if the activity is limited to the relatively small area of the orbit, the serum concentration may not be elevated. Also, neither test is specific for sarcoidosis, and either one may be elevated either in other pulmonary conditions or in normal individuals.
Sjögren syndrome of keratoconjunctivitis sicca, xerostomia, and autoimmune disease figures in the differential diagnosis of orbital pseudotumor because of its involvement of the lacrimal glands, but it seldom presents with painful ophthalmoplegia and involvement of the retrobulbar orbital contents. Positive antinuclear antigens and in particular, antibodies to the extractable nuclear antigens SS-A (Ro) and SS-B (La), constitute the usual laboratory confirmation for Sjögren syndrome.
Granulomatosis with polyangiitis (Wegener disease) is classically associated with autoantibodies to cytoplasmic contents of neutrophils, antineutrophilic cytoplasmic antibodies, which may also be found in patients with polyarteritis nodosa and other vasculitides. Presence of antibodies is usually ascertained using combined radioimmunoassay and immunofluorescence techniques, and the staining patterns include diffuse cytoplasmic antineutrophilic cytoplasmic antibody, most often associated with classic granulomatosis with polyangiitis (Wegener disease), and perinuclear antineutrophilic cytoplasmic antibody, which is usually an artifact of alcohol fixation but which is associated with other vasculitides. A confirmatory enzyme-linked immunosorbent assay is usually done because patients with systemic lupus may have immunofluorescence-stained antineutrophilic cytoplasmic antibodies reflecting nonspecific antinuclear antibody production. Positive c-antineutrophil cytoplasmic antibodies together with clinical systemic features can be diagnostic for granulomatosis with polyangiitis (Wegener disease) presenting as orbital inflammatory pseudotumor (90).
Imaging studies can be used to demonstrate granulomatosis with polyangiitis (Wegener disease) involvement in the orbits. In 1 study of 14 such patients, the orbital involvement was unilateral in 12 (86%) and bilateral in 2 (14%); coexistent orbital and sinus involvement was the rule (86%), and any part of the orbit might be involved (69). The lesions were hypointense to orbital fat, and gadolinium enhancement could be either homogeneous (69) or inhomogeneous (26).
Polyarteritis nodosa is an uncommon cause of orbital inflammatory disease of the vasculitic type (43; 29). Thirty percent of patients express hepatitis B surface antigenemia and have perinuclear antineutrophilic cytoplasmic antibody on immunofluorescence assays. Various collagen vascular diseases can rarely present with orbital inflammatory pseudotumor. Serologic diagnosis revolves around demonstrating 1 of several patterns of antinuclear antibody staining on immunofluorescence assay or determination of the specific nuclear antigen using enzyme-linked immunosorbent assay.
A case of angiocentric T-cell lymphoma (lymphomatoid granulomatosis) has been reported with MRI demonstration of a cavernous sinus mass and enhancement of the right temporal meninges (09). Clinically, this case would not be confused with orbital inflammatory pseudotumor or idiopathic cavernous sinus inflammation (Tolosa-Hunt syndrome) because there was involvement of the right facial nerve and both acoustic nerves in addition to the right optic nerve and the nerves in the cavernous sinus. It is important, however, to consider this diagnosis in the differential of cavernous sinus lesions.
Painful ophthalmoplegia should be managed according to the underlying etiology. Corticosteroid therapy is now considered the mainstay of management for patients with inflammatory causes (orbital inflammatory pseudotumor or Tolosa-Hunt syndrome). It is interesting to note, however, that in Henderson's patients treated before the 1960s when steroid treatment was not commonly used, surgical excision was highly successful and often led to prompt and lasting remission of symptoms. He suggested that the excision removed the antigenic stimulus for recurrence. In the later years of the series, treatment with corticosteroids proved effective in controlling the inflammation during the symptomatic interval. Henderson notes that in his patients with orbital pseudotumor the inflammation became inactive within 3 to 12 months. Presumably this means that patients remained asymptomatic without steroid maintenance after this interval (29).
Patients in Henderson's series with vasculitic inflammatory tumors, encompassing both nongranulomatous (hypersensitivity angiitis) and granulomatous (limited forms of granulomatosis with polyangiitis [Wegener disease]) varieties, had a more severe course and were often refractory to corticosteroid management alone. These patients often required cyclophosphamide and radiotherapy in addition to corticosteroids. The patients with granulomatous vasculitis have the most severe course of all and show the least satisfactory response to treatment (29). Eagle and colleagues reported a patient with radiologically diagnosed orbital inflammatory pseudotumor secondary intracranial extension whose disease continued to progress with corticosteroid, radiation, and azathioprine treatment (20). There was a dramatic and sustained clinical response and marked radiographic improvement when cyclophosphamide was introduced.
In a study of 26 orbits in 20 patients with biopsy-proven orbital inflammatory pseudotumor, Prabhu and colleagues tallied the clinical response and long-term outcome after the patients were treated with modern CT-based 3-dimensional conformal radiation therapy via opposed lateral ports (3 patients), en face electron beam therapy (1 patient), or intensity-modulated radiation therapy with opposed lateral beams (16 patients) (67). Outcomes were assessed at 4 months postradiation and were classified as follows:
(1) Partial response: improvement of orbital symptoms without increase in steroid
Seventeen of the 20 patients achieved a response to radiation by 4 months postradiation. Ten patients achieved a complete response, 9 of which had complete response 2. Patients with a relatively short duration of symptoms (6 to 12 months vs. 18 months or more) had the highest proportion of complete responses (85%). Patients with bilateral symptoms also had proportionally greater response than those with unilateral disease. The authors concluded that “modern RT is an effective treatment for improving symptoms and tapering steroids…”; that bilateral disease responds better than unilateral disease, possibly because of biological differences in the inflammatory process; and that the response at 4 months postradiation is prognostic of long-term outcome. In response to this article, Marks suggested that those with bilateral disease fared better because they are usually treated with simple opposed lateral fields whereas those with unilateral disease tend to be treated with conformal/complex approaches that are associated with “marginal misses” that allow for recurrence (54). Prabhu and colleagues responded to this suggestion by saying that in their series, both unilateral and bilateral disease patients were treated with the same intensity-modulated radiotherapy via similarly designed ports and, hence, they don’t agree that this is the basis for the outcome difference (54).
Schafranski reports the case of a 66-year-old woman with orbital inflammatory pseudotumor who initially responded to oral corticosteroids, but had intolerable glycemic response and was refractory to azathioprine as a steroid-sparing agent (74). She markedly improved after 2 infusions of rituximab, a chimeric anti-CD20+ antibody. Khosroshahi and colleagues studied 4 patients with IgG4-related rheumatic diseases, including 1 patient with orbital inflammatory disease that was refractory to treatment with prednisone and methotrexate. All of the patients had elevated IgG4 serum levels, and the levels fell after treatment with rituximab, along with prompt and lasting clinical remission of their inflammatory diseases (39). This study suggests that treatment with rituximab causing b-cell depletion may be effective in cases of orbital inflammatory disease.
Use of corticosteroids and immunosuppressive drugs is, of course, relatively contraindicated during pregnancy. This has not come up in the literature, so it seems that the coincidence of either disorder and pregnancy is rare. This is probably because the bulk of patients with both idiopathic inflammation impacting the orbit or cavernous sinus present in the fourth and fifth decades and the incidence of pregnancy in those years is relatively low.
Ravindra Kumar Garg MD
Dr. Garg of King George's Medical University in Lucknow, India, has no relevant financial relationships to disclose.See Profile
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