Clinical Management of Systemic Inflammatory Diseases Affecting the Posterior Segment
Part 2 of this article explores Susac's syndrome, Wegener's granulomatosis, polyarteritis nodosa and Takayasu's arteritis.
THOMAS E. FLYNN, MD ∙ GALE A. MCCARTY, MD, FACP, FACR
In the first part of this two-part series,1 retinal and choroidal manifestations of systemic inflammatory diseases commonly affecting the retina and its circulation, including giant cell arteritis, Adamantiades-Behçet's disease, systemic lupus erythematosus and the recently characterized antiphospholipid antibody syndrome, were reviewed. These are important diagnostic entities that retinal physicians should consider when analyzing a patient with an indicative pattern of retinal or choroidal circulatory disturbance and related systemic disease.
Part 1 also emphasized the need for a close collaboration between the consulting ophthalmologist and his or her colleagues, including specialists in internal medicine, rheumatology and infectious disease, as well as other sub-specialists as required. A limited discussion of treatment options for these diseases was presented.
In Part 2, other inflammatory vascular diseases are herein reviewed that are less common or that only involve the retina in rare circumstances. These entities need to be considered within a framework of differential diagnoses when evaluating a patient with retinitis, choroiditis, optic nerve findings, vasculitis or occlusive vasculopathy.2 One working diagnostic approach is to separate the primary vasculitides in which the vessel itself is the target, from vasculitides, where inflammation secondarily affects the vessels — such as infections (eg, tuberculosis, syphilis, herpes), paraneoplastic or masquerade syndromes that simulate inflammation of the retina and its vessels (eg, large-cell lymphoma, autoimmune disease with secondary vasculitis), and rare drug-induced entities (eg, opioids, antibiotics, antithyroid drugs, leukotriene receptor antagonists).3,4
While infections and masquerade syndromes are beyond the scope of this article, these will need to be kept firmly in mind when approaching a systemically ill patient with apparent inflammation affecting the eye and retina. Several recent reviews of clinical, rheumatologic and ophthalmologic manifestations of vasculitis, general concepts of immunopathogenesis, diagnostic segregation by vessel size, and a critical overview of the classification and diagnostic criteria for systemic vasculitis are available.5,6
Worldwide, the most commonly used nomenclature for vasculitis is the 1994 Chapel Hill Consensus Conference Classification (CHCC) scheme (which built upon validated 1990 American College of Rheumatology [ACR] criteria encompassing clinical and pathologic standards) but created standard terminology, immunodiagnostic markers where applicable, and histological characteristics specific for some vasculitides.7
|Thomas E. Flynn, MD, was assistant professor of ophthalmology at the Harkness Institute of Columbia University in New York. Gale A. McCarty, MD, FACP, FACR, heads the Center for Lupus and APS at the Center for Rheumatology, Ocular Immunology and Inflammation with Dr. Flynn at Ellsworth Uveitis and Retina Care in Maine. Neither author has any financial interests in any products mentioned in this article. Dr. Flynn can be reached at firstname.lastname@example.org.|
Susac's syndrome (Figure 1) is an uncommon disease presenting as a triad of microangiopathy of the brain, cochlea and retina, typically affecting young women between 20 and 40 years of age.8,9 Synonyms and mnemonics are variable: retinocochlearcerebral vasculopathy, RED-M syndrome (retinopathy, encephalopathy, deafness associated with microangiopathy) and SICRET syndrome (small infarcts of cochlear, retinal and encephalic tissues).10
Figure 1. Red-free photos and fluorescein angiograms of Susac's syndrome. Left eye: (A) red-free, (B) FA showing a white retinal edema due to the inferior temporal retinal arterial occlusion as well as multifocal wall hyperfluorescences. Right eye: (C, D) FA showing peripheral retinal arterial occlusion (arrow) and arterial wall hyperfluorescence distant from the occlusion site. IMAGE REPRINTED FROM RETINA: THE JOURNAL OF RETINAL AND VITREOUS DISEASES AND APPEARS WITH PERMISSION OF OPHTHALMIC COMMUNICATIONS SOCIETY, INC.
At presentation, central nervous system features occur in 80% of patients, cochlear involvement in 52% and retinal findings in 46%. Only 20% of patients present with the complete triad.11 Its prevalence is unknown, the female-to-male ratio is 3:1, and it has been reported in North America, Europe and Asia,12-14 as well as in children and adolescents.15 Because of the prominence of neurological and neuropsychiatric manifestations, patients with Susac's syndrome are often first evaluated by neurologists; the overwhelming neurologic symptoms and encephalopathy may initially obscure the diagnosis of cochlear and retinal involvement.16 The occurrence of deafness and eye involvement may lag behind the neurological findings by weeks or years.17 Finally, the syndrome may show a multiphasic pattern with a spontaneously relapsing-remitting course.18,19
There is no definitive laboratory test, clinical test or procedure to diagnose Susac's syndrome. The prompt involvement of a neuro-ophthalmologist or retinal consultant is often critical to arriving at this diagnosis, and longitudinal historical accuracy is key. As in the first part of this series, elevated inflammation parameters (sedimentation rates, C-reactive protein) may be present but nonspecific. A variety of case reports have found normal or elevated antiphospholipid antibodies, elevated von Willebrand factor, and/or other concurrent coagulopathies. Audiometry often shows sensorineural pancochlear hypacusis.
Susac's syndrome is underdiagnosed, due to its multisystem involvement and need for differentiation from mimickers such as multiple sclerosis.10 Neuroradiologists may not be as aware of this syndrome as ophthalmologists or otolaryngologists are, and this discordance is important as the diagnostic study of choice is diffusion-weighted magnetic resonance imaging. Common findings are multiple small hyperintense foci on T2-weighted images, with contrast-enhancing lesions in white and gray matter both supratentorially and infratentorially and with corpus callosal and leptomeningeal involvement. These lesions can appear as “snowballs.” Callosal lesions involving the central fibers are considered almost pathognomic for Susac's syndrome in the appropriate clinical setting, and occasional linear stranding from these areas may be seen.10
Retinal findings include hallmark focal areas of narrowing and occlusions of small arterioles both in the posterior pole and periphery of the retina,8,9 giving the appearance of retinal arteritis or vasculitis.14 The findings are often seen initially in one eye but become bilateral over time if the disease is unrecognized and untreated.20 Even though an inflammatory pathogenesis has been posited for Susac's syndrome, the retinal vascular changes occur in eyes that are quiet or only minimally inflamed on slit-lamp examination. This is one point of differ entiation from Adamantiades-Behçet's disease or other forms of panuveitis.
Acutely, the focal occlusions can resemble branch retinal artery occlusions due to embolic or inflammatory processes such as giant cell arteritis. Careful retinal examination and systemic evaluation of the patient may be necessary to differentiate Susac's syndrome from cardiovascular disease or other forms of vasculitis affecting the eye and brain.21 Retinal ischemia is seen in the areas fed by the occluded arterioles, and remodeling of arterioles, microaneurysms and retinal hemorrhages characteristic of microangiopathy can be seen on retinal examination in more chronic cases.22 Retinal arterio-arteriolar collaterals may be seen in areas of ischemia resulting from the focal arteriolar occlusions, appearing as tortuous vessels crossing the area of ischemia.23 These collaterals are less common than their venous counterparts and thus indicate an arteriolar disease process such as Susac's syndrome. Additionally, a focal disruption of the endothelium associated with deposition of atheromatous, sometimes refractile, material called a Gass plaque has been described.11
Fluorescein angiography (FA) and, to a lesser extent, indocyanine green (ICG) angiography are essential in diagnosing Susac's syndrome in the eye.20 The pathognomonic lesion in Susac's syndrome is multifocal and has segmental areas of arteriolar narrowing with leakage of dye from the involved segments. If these leakages occur in multiple portions of a single arteriole, they may resemble boxcars. The occurrence of focal arteriolar occlusions in different retinal vessels, in different quadrants, and in one or both eyes points to this disease; indications of multiple emboli or thrombophlebitis would implicate another disease process. The occlusions do not necessarily occur at the branches of the arterioles,24 in contrast to emboli or thrombi.
The presence of scattered, geographically diverse areas of retinal ischemia with microvascular changes and arterio-arteriolar collaterals could also appear in an FA, suggesting a more chronic process. FA also shows that retinal veins are not involved in the occlusive vasculopathy, although changes in venules may occur in areas of chronic retinal ischemia.22 In contrast to the other entities discussed in these articles, ICG angiography shows no evidence of significant choroidal involvement in this retinal vasculopathy.
FA is also useful to follow treatment efficacy as steroids or other agents are tapered. The retinal and FA findings improve or resolve with treatment success and recur during flares of the syndrome. This information would allow the care team to intervene early, before further neurological or cochlear damage occurs.25
Treatment options for Susac's syndrome are limited and controversial.26 In general, patients seem to benefit ophthalmologically and neurologically from courses of high-dose corticosteroids, such as intravenous pulses of methylprednisolone at 500 mg to 1 g doses over several days, combined with a long-term course of tapering oral steroids. Unfortunately, the cochlear damage does not seem to respond as well to this treatment regimen. Recurrence of ocular and neurological findings occurs frequently during steroid tapers; adjunctive immunomodulators (azathioprine, cyclosporine, cyclophosphamide, mycophenolate mofetil), antiplatelet agents, anticoagulation and intravenous immunoglobulin infusions27 have been employed with varying levels of success.11,28,29
There is general agreement that prompt, sustained immunosuppression is required for this syndrome. In adults, and especially in children with this syndrome, similarities in immunopathogenesis and treatment regimens with childhood dermatomyositis, a difficult vasculopathy of unknown origin, have been cited.30 One recent citation used hyperbaric oxygen31 with some visual benefit from the treatment.28,29 In a long-term follow up of nine women with this syndrome, the possibility that pregnancy and attendant coagulopathic changes might be associated with disease flares was raised, along with the need to use immune modulators beyond steroids, which alone did not control the encephalopathy well.32 These forms of treatment would ideally be conducted and monitored by a team of specialists, including neurologists, otolaryngologists, rheumatologists and an ophthalmologist (most commonly a neuro-ophthalmologist or retinal specialist).
Wegener's granulomatosis (WG; Figure 2) is a systemic necrotizing vasculitis affecting the upper and lower respiratory tracts and the kidneys, with ocular involvement occurring commonly. It occurs in a generalized form, where there is upper and lower respiratory disease as well as renal disease, and in a limited form, without renal involvement. WG's incidence is estimated at 8.5 cases per million and usually involves patients over 50.
Figure 2. Wegener's granulomatosis. (A) Multiple puntiforms and flame-shaped retinal hemorrhages in left eye. Venous distension with edema of the retina and cotton-wool exudates. (B) Hard exudates in the left eye due to residual macular edema. No hemorrhages are seen. Venous distension has disappeared. The optic nerve head has a normal appearance. IMAGES REPRINTED FROM WANG M, KHURANA RN, SADDA SR. CENTRAL RETINAL VEIN OCCLUSION IN WEGENER'S GRANULOMATOSIS WITHOUT RETINAL VASCULITIS. BR J OPHTHALMOL. 2006;90:1435-1436, WITH PERMISSION OF OXFORD UNIVERSITY PRESS.
As a hallmark autoantibody, anti-neutrophil cytoplasmic antibody (ANCA) occurs in WG (80% of patients), and with two other vasculitides (microscopic polyangiitis [MP], 70% positive; and Churg Strauss syndrome [CSS], 50% positive), they are grouped together and are called the “ANCA-associated vasculitides” (AAVs). Ocular involvement is most prominent and most frequent in WG, ranging from orbital pseudotumor in 10% to 15%, scleritis and scleromalacia perforans with blindness, episcleritis to uveitis, and peripheral ulcerative keratitis with corneal melt syndrome. Episcleritis, scleritis and uveitis occur occasionally in MP and CSS.
The ACR 1990 criteria for WG require: (1) nasal or oral inflammation, painful/painless oral apthae, or purulent/bloody nasal discharge; (2) pulmonary nodules, fixed infiltrates or cavities; (3) an abnormal urinary sediment (microhematuria or red cell casts); and (4) granulomatous inflammation in an arterial wall or in the perivascular or extravascular area of an artery or an arteriole.33 If two of the four criteria are present, diagnostic sensitivity is 88.2% and specificity is 92.0%.
The CHCC criteria define WG as granulomatous inflammation in the respiratory tract (no site specification), with necrotizing vasculitis affecting the small- to medium-sized vessels (capillaries, venules, arterioles and arteries), commonly associated with necrotizing glomerulonephritis.7 Microscopic polyangiitis is a necrotizing vasculitis with few or no immune deposits, affecting small vessels (capillaries, arterioles or venules), necrotizing arteritis of small and medium arteries possibly present, necrotizing glomerulonephritis commonly present, and occasional pulmonary capillaritis. CSS is characterized by eosinophil-rich granulomatous inflammation in the respiratory tract and necrotizing vasculitis of small- to medium-sized vessels, with associated asthma and eosinophilia.
Autoantibody testing for ANCAs involves both indirect immunofluorescence (IIF) and enzyme immunoassays (EIAs). Three patterns by IIF exist: (1) the cytoplasmic (c-ANCA) pattern, which correlates with EIA positivity for proteinase-3 (PR-3) and the most common ANCA in WG; (2) the peripheral (p-ANCA), which correlates with myeloperoxidase (MPO) by EIA; and (3) atypical patterns. Positivity for c-ANCA by IIF and MPO by EIA are most specific for WG. Since only 10% to 50% of patients may exhibit any ANCA, the gold standard for diagnosis remains the characteristic histopathology.34
In the AAVs, tissue injury occurs in response to an unknown inflammatory (or perhaps infectious) event, which causes tissue injury by ANCAs having multilevel interactions with upregulated leukocytes and endothelial cells. However, in some patients ANCAs correlate with remission and relapse, and in others they do not. A new cytokine, osteopontin, has recently been touted as a possible new marker for disease activity; data from 24 patients with AAV showed elevated osteopontin levels at the start of immunosuppressive therapy, which decreased over time and correlated with a widely used activity measure called the Birmingham Vasculitis Activity Scale, a decrease in C reactive protein, red blood cell casts, and proteinuria.35
Ocular involvement may be the presenting sign of WG in 16% of patients;36 ocular and orbital manifestations may occur in 28% to 58% of patients,37,38 followed in longitudinal studies. Ocular involvement has been reported but is unusual in children.39 While the eyes are frequently involved during the course of WG, related retinal and choroidal disease isolated from scleritis or uveitis is uncommon, occurring in 1% to 13% of patients.40-42 Intercurrent infections arising in immunosuppressed patients may also present in the posterior pole and choroid.43 Timely recognition of retinal and choroidal involvement and prompt differentiation between immune mediated and infectious disease processes are critical in treatment selection and maintaining sight in patients with systemic necrotizing vasculitis.39,44
Scleritis, corneal inflammation and orbital and eyelid involvement are the eye findings most often cited in the literature in the eyes of patients with WG.45 A number of posterior-segment complications, such as optic nerve swelling and optic atrophy, may occur as a consequence of orbital inflammation with nerve compression,40,46 as well as due to vasculitis. Similarly, serous retinal detachments may result from a local reaction to necrotizing scleritis,47,48 manifesting in the retina and choroid. Thus, interpreting any report of isolated posterior-segment involvement with WG requires caution, paying close attention to related inflammation involving the orbit, sclera or interior of the eye. Aside from that caution, a number of convincing reports of retinal and choroidal findings in WG can be found.
Microvascular changes such as cotton wool spots49 may be seen, although hypertension resulting from renal failure needs to be considered as a cause. Retinal arterial occlusions are infrequently noted (six cases since 1960) in classical WG50,51 and limited disease.52,53 A recent report notes multiple retinal arterial occlusions in one eye of a 13-year-old girl with limited disease54 without evidence of any other form of ocular involvement. Retinal vasculitis is another manifestation of systemic vasculitis55,56 in both forms of WG. There may be some overlap between findings attributed to arteriolar occlusion and retinal vasculitis in various reports. Venous-side occlusive disease has also rarely been cited,37,40,57-59 with fewer than 10 cases in the literature. In addition to aggressive systemic treatment, local therapy for retinal complications of occlusive vasculopathy is an important consideration.60
Patients with clinically evident retinitis37,61 often present with related scleritis or orbital inflammation and active uveitis. Cytomegalovirus (CMV) retinitis may present a similar picture, with vascular occlusive disease, uveitis and retinal neovascularization.62-64 CMV retinitis has a distinct and well recognized pattern in most instances; other potential viral, fungal or bacterial pathogens may prove more difficult to characterize. Given the different treatment algorithms for inflammatory vs infectious retinitis, recognition of related systemic and local eye findings and rapid involvement of other members of the care team are critical. Beyond systemic infectious disease evaluation and cultures of blood and other bodily fluids, a vitreous biopsy or aspiration of intraocular fluids for cytology, culture and organism-specific polymerase chain reaction (PCR) may be necessary in truly difficult cases.
Choroidal vascular occlusions and masses are also reported in WG. Infarction of choroidal vessels with resultant ischemia of the choriocapillaris, RPE and outer retina can result in significant loss of vision in WG and related vasculitides.65 An early report of eye findings in limited WG confirms choroidal vascular inflammation in an enucleated eye40 with prior CRVO and neovascular glaucoma. A pattern of choroidal involvement consistent with APMPPE on fluorescein and ICG angiography has been seen in patients with WG.66,67 A report of a WG patient with bilateral retinal arterial and choroidal arterial occlusive disease in both eyes68 raises an interesting question of whether the underlying process involves vasculitis affecting vessels in the eyes or a widespread thromboembolic phenomenon caused by the underlying systemic vasculitis. Choroidal masses69,70 may present unrelated to active scleritis and may prove difficult to distinguish from ocular melanoma or another type of tumor until they respond to immunosuppressive therapy. Choroidal and serous retinal detachments have been described71,72 related to severe coexisting scleritis or orbital inflammation.
Treatment of WG with significant ocular involvement is indistinguishable from treatment of the disease in other organ systems. Aggressive use of corticosteroids (oral or intravenous, as well as local) is in order, along with prompt initiation of oral or intravenous cyclophosphamide to induce remission of active, severe disease. Given the significant risk with long-term use of alkylating agents, including cyclophosphamide, the therapy is often changed after the disease has been brought under control. Other agents, including methotrexate, azathioprine, cyclosporine A, mycophenolate mofetil, leflunamide, rituximab, anti–tumor necrosis factor-α agents, IV immunoglobulin and plasmapheresis45,73-76 have been employed in patients with ocular involvement. Concomitant use of trimethoprim-sulfamethoxazole has been advocated, both as antibacterial prophylaxis and for a possible direct effect on the underlying vasculitis.73
Polyarteritis nodosa (PAN; Figure 3) is a multisystem necrotizing vasculitis affecting medium-sized arteries. It presents more commonly in men and has a usual age of onset between 40 and 60 years old.77 PAN may be triggered by prior hepatitis B78 and hepatitis C79 and hepatitis viral coinfections.80 Otherwise, PAN should be distinguished from various secondary vasculitides81 associated with infections, cancer, medications and other autoimmune diseases (eg, rheumatoid arthritis, Sjögren's syndrome, in flammatory bowel disease, relapsing polychondritis and Cogan's syndrome).
Figure 3. Polyarteritis nodosa. Left: Fundus photograph of left eye shows a triangular area of pigment epithelial disturbance temporal to the fovea (asterisk). Note mildly swollen and hyperemic optic disc. Right: Fundus photograph of right eye shows retinal edema in the posterior pole, primarily temporal to the optic disc, except for an area of cilioretinal sparing. Note the normal optic disc and cherry red spot in macula. IMAGE REPRINTED FROM RETINA: THE JOURNAL OF RETINAL AND VITREOUS DISEASES AND APPEARS WITH PERMISSION OF OPHTHALMIC COMMUNICATIONS SOCIETY, INC.
The ACR Criteria for the Classification of PAN require three of the following: (1) weight loss >4 kg; (2) myalgias or paresis of an extremity (excluding that of the shoulder or hip girdle); (3) mono- or polyneuropathy; (4) diastolic blood pressure >90 mm Hg; (5) elevation of blood urea nitrogen >40 mg/dL or creatinine >1.5 mg/dL; (6) hepatitis B viral infection; (7) livedo reticularis; (8) testicular pain/tenderness; and (9) abnormal arteriography showing aneurysms or occlusions of the visceral arteries (not due to atherosclerosis or fibromuscular hyperplasia) and histology on biopsy of small- or medium-sized artery with polymorphonuclear cells only, or polymorphonuclear cells and monocytes in the vessel wall.82
Polyarteritis nodosa has an equal sex ratio and affects patients worldwide — approximately two to nine patients per million with a peak onset when patients are in their 50s. Its differential diagnosis is wide and includes vasculitis mimics previously mentioned, particularly systemic rheumatic diseases, MP discussed above, numerous infections beyond hepatitis B, Goodpasture's syndrome, cryoglobulinemia and lymphoma.83 Elevated inflammation parameters, a complete blood count with leukocytosis and anemia, hepatitis serologies and ANCAs by IIF and EIA for specific profiling, MRI, and magnetic resonance arteriography are important diagnostic tools, along with nerve conduction testing and electromyography.
The pathology of PAN is of a small- to medium-sized arterial necrotizing vasculitis without glomerulonephritis, or a vasculitis in arterioles, capillaries or venules. A penchant for bifurcations and tendency toward aneurysm formation is characteristic. Renal arteries are involved 70% to 80% of the time, gastrointestinal vessels 50%, peripheral nerves 50%, and the central nervous system 10% of the time.
The eye is involved in 10% to 20% of patients with PAN.84 The choroid is the ocular structure most commonly involved in PAN.5 In general, the findings in the posterior pole are similar to those seen in WG patients, with similarly located ocular involvement. Retinal arterial and venous occlusions, with FA confirmation of arterial caliber irregularity and leakage of dye, capillary dilation and nonperfusion, and delayed venular filling and occlusions85 show a mixed picture of retinal vascular involvement. Other forms of retinal vascular lesions include cotton wool spots, retinal and subhyaloid hemorrhages, macular star and retinal exudates.85-88 Anterior ischemic optic neuropathy (AION) may happen in one or both eyes concurrently with retinal arteriolar occlusive disease.88-91 Central retinal vein occlusion has also been reported in a patient with PAN and thrombocytosis.92
Choroidal abnormalities are more commonly reported in PAN than retinal abnormalities, with which they often coexist. Choroidal vascular infarction and necrosis resulting in Elschnig's spots93,94 have been documented on clinical examination and FA. The choroidal vascular involvement may also occur with AION;95,96 in the former case, bilateral triangular patterns of RPE scarring abutting the macula (the triangular sign of Amalric) are observed. This sign is indicative of choroidal ischemia but is not specific to PAN; it occurs in other diseases associated with ocular ischemia, such as giant cell arteritis, lupus and carotid artery disease.
Other choroidal manifestations of PAN include choroiditis97 and serous retinal detachments occurring with98 and without scleritis.99 The latter case includes ocular pathologic confirmation of inflammatory cells and fibrinoid necrosis in the choriocapillaris with ischemia and necrosis of the RPE. As with WG, a pattern consistent with APMPPE has also been reported in a patient with PAN.100 As with other vasculitides, the retinal and choroidal abnormalities are attributable to vasculitis, hypertension, hypercoagulability, hypercholesterolemia or a combination of these factors.5,101-103 Again, caution is in order when evaluating the posterior poles of any patient with one or more simultaneously active multisystem diseases.
Polyarteritis nodosa is a fatal disease if untreated, with a five-year survival rate as low as 13% before effective therapy became available.104 As with WG and other systemic vasculitides, the survival rate has improved to over 80% over a similar time period with aggressive and closely monitored immunosuppressive therapy.105,106 The basic principles of treatment were outlined in the previous section. Besides high-dose systemic and local steroids, agents including cyclophosphamide, azathioprine, methotrexate, cyclosporine A and tacrolimus have been employed in patients with ocular involvement. Close coordination between the consulting ophthalmologist and the other members of the patient's care team is critical.
Takayasu's arteritis (Figure 4) or “pulseless disease” presents in women twice as often as men and in patients between 30 and 40 years of age on average, although adolescent girls and women are the classic patients in whom complete occlusion of upper extremity arteries occurs — hence the name “pulseless disease.” Initially described in Asia, where the incidence rates (one case per million) are the highest in the world and where late-onset disease occurs, it is worldwide.
Figure 4. Takayasu's arteritis. (A) Fundus photograph of the left eye shows dilated, beaded retinal veins, cotton-wool spots, and microaneurysms. (B) Fluorescein angiogram of the left eye shows microaneurysms and late retinal vascular staining, primarily arterioles. IMAGE REPRINTED FROM RETINA: THE JOURNAL OF RETINAL AND VITREOUS DISEASES AND APPEARS WITH PERMISSION OF OPHTHALMIC COMMUNICATIONS SOCIETY, INC.
It is characterized as an idiopathic granulomatous inflammatory disease of the aorta and its proximal branches, all of which are large elastic arteries, with less common involvement of the coronary and pulmonary arteries.107
Presenting symptoms of Takayasu's arteritis mimic a systemic infection: fever, night sweats, malaise, anorexia, myalgias, weight loss. Historically, the positional nature of impeded blood flow is not always obvious. A targeted history of activities, positions and motions (such as sustained positioning of the arms overhead) affecting upper extremity circulation is crucial for identification. Symptoms relate to the arterial territory involved. In the common carotid bed, visual defects, transient ischemic events, cerebrovascular accident or syncope is common, and in the vertebrals, visual impairment and dizziness occur. Rarely, tinnitus, facial muscle atrophy and jaw claudication occur.
Subclavian arterial involvement is the most common symptom, occurring in 80% of patients, with 50% having common carotid findings. Abdominal aortic claudication, hypertension and abdominal angina occur in 40% of patients, and vertebral, aortic arch and renal involvement approximately equal at 20%. A detailed physical exam determining comparative bilateral pulse contour, rate, blood pressure (at rest and with cervical spine/shoulder motion) and complete vascular exam for bruits are mandatory. Ethnicity is associated with vascular territory involvement: Indian, Chinese and Korean patients have more abdominal and renovascular disease.
By the CHCC criteria, Takayasu's arteritis is defined as granulomatous inflammation of the aorta and its major branches, usually occurring in patients younger than 50 years old.7 The 1990 ACR criteria specify that the symptoms begin below the age of 40, with extremity claudication, fatigue, discomfort with use of the upper extremities, decrease in one or both brachial arterial pulses with a >10 mm Hg BP difference, and an audible bruit over one or both subclavian arteries or the abdominal aorta, along with arteriographic narrowing/occlusion of the aorta or its large artery branches, usually focal or segmental, with fibromuscular hyperplasia and atherosclerosis excluded.108
The presence of any three or more criteria is diagnostically sensitive at 90.5% and specific at 97.8%. The Ishikawa modification addresses more specific subclavian arteriographic loci and adds transient amaurosis and blurred vision to the characteristic signs and symptoms, with a temporal caveat of having been present for at least one month.109 A striking thickening of the vessel adventitia with intense cellular infiltrates around the vasa vasorum is characteristic, along with granulomas and giant cells in the media of large elastic arteries. Elastic smooth muscle cell destruction and replacement with fibrosis results in vessel wall dilation and aneurysms. Significant tapering and luminal narrowing occurs due to intimal proliferation often with thrombosis. The cellular infiltrate phenotype is primarily CD8 positive T-cells.110
Ocular symptoms, such as blurring of vision, transient visual loss with change in position, or gradual painless loss of vision, occur in almost half of Takayasu's arteritis patients.111,112 Hypertensive retinopathy and choroidal changes are seen in most patients with moderate and advanced Takayasu's disease and are nonspecific.112 The changes specific to Takayasu's ocular involvement are due to ischemia of the retina and choroid resulting from involvement of the aortic arch and carotid arteries in the disease process. The severity of ocular findings parallels the degree of stenosis of the major branches of the aorta affected by the vasculitis.113 These findings may improve after vascular surgery.114-116
While inflammation is sometimes noted in eyes of patients with Takayasu's disease, it is more likely a consequence of ocular ischemia rather than direct immune-mediated attack on intraocular structures.117,118
The incidence of retinopathy in Takayasu's arteritis ranges from 13%112 to 33%.119,120 Arteriovenous anastomoses and shunt vessels around the optic nerves are frequently described in late stage Takayasu's arteritis,121-123 along with microaneurysms, capillary remodeling and vascular tortuosity. The optic nerves are often described as pale, whether because of AION,124 which is uncommon, or because of hypoperfusion of the optic nerve and the rest of the eye.125,126 The disc vessels may represent shunt vessels or disc neovascularization115,121 with resultant vitreous hemorrhage. The disc vessels may regress without treatment as vascular remodeling proceeds.127
Typical findings in Takayasu's retinopathy include retinal venous congestion and microaneurysms in early stages of ocular disease,128,129 which worsen as the large-vessel inflammation progresses. Arteriovenous shunts in the posterior pole and midperiphery are seen in the intermediate stage of retinopathy as the vascular changes move toward increasing ischemia130 and permanent changes in the retinal circulation, even in the face of effective therapy. Tanaka notes two distinct types of anastomosis: one with direct intraluminal contact between the arteriole and venule at an arteriovenous junction and the second involving a collateral channel through intervening capillaries. It should be noted that arteriovenous shunts, while almost universal in advanced disease, are not specific for Takayasu's retinopathy;131 these occur in diverse conditions, including diabetic retinopathy, arterial and vein occlusions, and retinal vasculitis.
“Boxcarring” represents clumped red blood cells traveling like boxcars in a train in the retinal vessels, another intermediate-stage finding. After this, capillary dropout, retinal nonperfusion and retinal neovascularization predominate.132 Cystoid macular edema is seen both on ophthalmoscopic or biomicroscopic examination and FA at this stage of retinopathy.133,134 Vitreous hemorrhage, fibrovascular proliferation of neovascular membranes, and changes accompanying anterior-segment ischemia, including corneal changes, cataract, iris neovascularization, and uveitis, limit both vision and visualization of the retina.118,135,136 Visual recovery is extremely unlikely at this late stage, in spite of aggressive local and systemic therapy with steroids, immunomodulators and vascular surgery. Hypotony and neovascular glaucoma are mirror image problems for endstage eyes in patients with Takayasu's disease.136
Cotton wool spots, retinal exudates, macular star and retinal emboli are unusual findings in Takayasu's retinopathy.137 Retinal arterial occlusions are also rarely reported138,139 as isolated findings. The prevalence of concurrent hypertension and cardiovascular disease in Takayasu's patients needs to be considered in evaluating the significance of these retinal arteriolar findings. Thrombosis has been described related to the underlying vasculitis,140 occasioning some caution in evaluating the cause of retinal vascular changes.
Fluorescein angiography is richly documented in patients with Takayasu's disease, from the earliest stages before the development of retinopathy to advanced ocular ischemia. Virtually every paper cited in this review after the 1960s includes a section on angiographic findings. A few consistent results are reported; for instance, a prolonged arm-to-retina circulation time occurs universally in patients with the earliest signs of retinopathy.112,115,129 A delay in arteriovenous filling time indicates a later stage of retinopathy, and changes in capillaries, venules and arterioles lead to nonperfusion of retina and more advanced ischemic changes.129 These changes seem to relate most closely to increasing compromise of blood vessel caliber of the major branch vessels of the ascending and transverse aorta;113 again, hypertension and other extrinsic circulatory factors related to the vasculitis should also be borne in mind. Although one earlier report seems to discount the beneficial effects of corticosteroids and vascular surgery113 for the eye, FA has documented improvement in some of the earlier stage vascular changes after effective systemic therapy and vascular surgery114-116,132 in most subsequent articles.
Therapy for Takayasu's disease involves a collaboration between medical specialists, who prescribe systemic steroids or other immunomodulators,5,127 and vascular surgeons, who reconstruct channels allowing blood flow to the upper extremities and head. The ophthalmologist plays an important role in making the initial diagnosis through a careful clinical examination and FA, consideration of Takayasu's arteritis in the differential diagnosis with an appropriate referral to a specialist, and ongoing collaboration with the rest of the team once therapy has been initiated. Local ocular complications of ocular ischemia, such as glaucoma, uveitis, cataract and hypotony, all require continuing management.120 The retinal consequences of Takayasu's arteritis are also significant and may require an aggressive course of treatment,132 including treatment of neovascularization with panretinal photocoagulation.
The role of intravitreal injections of steroid or anti-VEGF agents and placement of long-term indwelling steroid devices remain to be clarified. In spite of our best efforts, therapy still fails at times,138 and patients may die as a result of their medications.141 The largest series of 21 Indian patients on mycophenolate mofetil, followed in a major center longitudinally for a mean duration of 9.6 months, showed excellent tolerance, reduction of physician-determined disease activity, and a disease activity score composed of inflammation parameters and periodic angiography, with a statistically significant decrease in steroid dosage at study end.142 Nevertheless, the rewards of literally saving patients' lives outweighs the challenges of caring for a chronic and devastating systemic vasculitis.
This two-part review has attempted to focus on some of the retinal and choroidal findings in selected systemic vasculitides. An attempt was made to include entities involving differing immunopathogenic mechanisms and affecting different-sized vessels, including large vessels (giant cell and Takayasu's arteritis), medium-sized vessels (PAN) and small vessels (WG), as well as secondary vasculitides (Adamantiades-Behçet's disease, SLE) and the antiphospholipid antibody syndrome. These are all uncommon diagnoses for a retinal specialist to confront, but their extreme importance is emphasized by their high mortality and morbidity rates if not treated or improperly treated. As an example, the reader should consider, in a patient with recent-onset sensorineural hearing loss and “eye findings,” a differential diagnosis including Cogan's syndrome, as well as several of the vasculitides and vasculopathies mentioned in both parts of this article, and syphilis, sarcoidosis and Whipple's disease.143,144 Another patient may present with examination and fluorescein angiographic findings consistent with APMPPE and vague constitutional symptoms and complaints. The entities reviewed in this discussion should be considered and evaluated promptly.
The literature reviewed here emphasizes the major strides that have been made in the diagnosis and treatment, both ocular and systemic, of patients with systemic vasculitis on an almost annual basis. Review articles just a few years old have been overtaken by more recent publications, emphasizing new treatment modalities and re-evaluating old ones. Ophthalmologists, internists, rheumatologists and other members of teams caring for these patients are privileged to live in an era of increasing expectations and improving results. RP
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