- Email: [email protected]
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SURVEY OF OPHTHALMOLOGY
VOLUME 49 • NUMBER 4 • JULY–AUGUST 2004
CLINICAL CHALLENGES PETER SAVINO AND HELEN DANESH-MEYER, EDITORS
Optic Neuropathy: Puls/Minus Anil Sharma, MD, MS, John Crompton, FRACO, and Dinesh Selva, FRACO Department of Ophthalmology, Royal Adelaide Hospital, Adelaide, South Australia, Australia
Comments by Rod Foroozon, MD (In keeping with the format of a clinical pathologic conference, the abstract and key words appear at the end of the article.)
From the history we know that the onset of visual loss has been relatively recent, over a 5-day period. The fact that the visual acuity in the right eye is markedly decreased without the presence of a RAPD, and with relatively preserved visual function in the left eye, suggests that the retinal edema, and not an optic neuropathy, is the primary cause of the decreased vision on the right. Her other constitutional symptoms are suggestive of an underlying systemic condition, and an infection with Epstein-Barr virus (EBV) could certainly cause these symptoms. The differential diagnosis is that for a patient with bilateral optic disk edema, and includes elevated intracranial pressure and hypertensive optic neuropathy. Both acute papilledema and hypertensive optic neuropathy can result in leakage of lipid into the fovea and a macular star.9,11 Both conditions may also be accompanied by peripapillary cotton-wool spots. The evaluation should proceed in a stepwise fashion (Fig. 2). The vital signs should be measured first. All patients with bilateral optic disk edema should have their blood pressure measured at their initial examination. In addition, with a history of fever this patient’s temperature should be recorded. If a blood pressure cuff and thermometer are not readily available the patient should be sent to an acute care setting where they can be measured.
Case Report. A 26-year-old Filipino woman presented to the Department of Ophthalmology, Royal Adelaide Hospital, in October 2000 with a 5-day history of decreased vision in the right eye. Over the previous 6 weeks she had noted headaches, loss of appetite, mild fever, vomiting, and vague generalized myalgias. There was no significant past medical history and investigations by her local doctor revealed a positive IgM Epstein-Barr virus (EBV) serology. On examination, visual acuities were count fingers in the right eye and 6/4.5 in the left. No relative afferent pupillary defect (RAPD) was evident and slit-lamp biomicroscopy revealed a normal anterior segment. Automated perimetry showed a right centrocecal scotoma and an enlarged blind spot in the left eye. Ophthalmoscopy showed swollen, hyperemic optic disks with peripapillary cotton wool infarcts, gross nerve fiber layer edema, engorged veins, and a right macular star (Fig. 1). What is your differential diagnosis? What tests should be performed initially?
Comments Comments by Rod Foroozon, MD, The Cullen Eye Institute, Houston, Texas, USA 429
쑖 2004 by Elsevier Inc. All rights reserved.
0039-6257/04/$–see front matter doi:10.1016/j.survophthal.2004.04.015
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SHARMA ET AL
Fig. 1. Fundus photographs of the right and left eyes showing disk edema, peripapillary cotton-wool spots, engorged veins and a right macular star.
Assuming the vital signs are normal, neuroimaging should be performed to exclude the presence of hydrocephalus and/or a mass lesion. If these are normal then a lumbar puncture (LP) should be performed to measure the opening pressure and evaluate the constituents of the cerebrospinal fluid (CSF). In this patient I am concerned about the possibility of an infection, such as meningitis, from EBV involving the central nervous system (CNS).6 The incidence
Fig. 2. Flow chart illustrating a stepwise evaluation of optic disk edema.
of neurologic involvement from EBV has been estimated to be 5%, and CNS infection may be the first or only manifestations of the infection.31 Encephalitis and meningitis are thought to be the most common forms of CNS-related EBV, and in most patients the disease is self-limiting.13 The CSF shows a mononuclear pleocytosis, a moderately elevated white count, and may show atypical lymphocytes. I would perform magnetic resonance imaging (MRI)/magnetic resonance venography (MRV) and LP urgently. If MRI and MRV are not available, computed tomography (CT) of the head should be done. I would perform these tests prior to discharging the patient and this might require hospitalization or evaluation in the emergency room. In addition, I would obtain a complete blood count (CBC) and erythrocyte sedimentation rate (ESR). The CBC might show leukocytosis and atypical lymphocytes suggestive of EBV and an elevated ESR would be suggestive of an inflammatory process. A medical evaluation would be helpful to evaluate for lymphadenopathy and examine the liver and spleen. If these tests are unrevealing, then an underlying vascular process might be suspected because of the presence of nerve fiber layer infarcts. The finding of even a single cotton-wool infarct in a patient without known vascular conditions such as hypertension and diabetes necessitates further evaluation.5 In 24 patients with cotton-wool infarcts and without a history of diabetes mellitus, ocular ischemic syndrome was found in two patients and dermatomyositis, systemic lupus erythematosus, polyartertis nodosa, and giant cell arteritis were each found in four others.5 I would start with a review of systems aimed at uncovering symptoms consistent with rheumatologic and vascular disorders. The following blood tests might be helpful: antinuclear antibody, human immunodeficiency virus titer, hepatitis B and C titers, antinuclear
OPTIC NEUROPATHY
and cytoplasmic antibody, and rapid plasma reagin testing for syphilis. Other considerations would include Behc¸et’s disease and sarcoidosis. Several infections may cause optic disk edema with exudates in the fovea resulting in a macular star pattern (neuroretinitis).25 Included in these are Lyme disease, cat scratch disease, and Rocky Mountain Spotted Fever. Neuroretinitis is more commonly unilateral, but patients with bilateral optic disk edema as the presenting sign of systemic infection have been described.4 Neuroretinitis is frequently accompanied by inflammatory cells in the vitreous so that slit lamp biomicroscopy of the vitreous would be important.
Case Report (Continued) A fluorescein angiogram (FA) demonstrated peripapillary hyperfluorescence (Fig. 3A) with leakage in the late phase (Fig. 3B). The complete blood count, Westergren erythrocyte sedimentation rate, C-reactive protein, and electrolytes were normal. Serological tests for herpes simplex, varicella zoster, cytomegalovirus, toxoplasma gondii, hepatitis B and C, Lyme disease, treponemal disease, and Bartonella henselae were normal. The EBV serology was positive for IgG, but not IgM. The angiotensin converting enzyme level was within normal limits but the anti-nuclear antibody test revealed a positive titer of 1:40. Both a chest X-ray and magnetic resonance imaging of the head were unremarkable. A lumbar puncture was performed and the cerebrospinal fluid was found to be normal on microscopy and biochemical analysis. What further investigation would you perform?
Comments (Continued) It would be important to measure the opening pressure during the LP. The findings on the FA are
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not particularly helpful because all of the conditions we are considering would be expected to cause late leakage at the optic disk. The results of the EBV serology are somewhat confusing. Antibodies to several virus-specific antigens, including viral capsid antigen (VCA), early antigen (EA), and Epstein-Barr nuclear antigen (EBNA), arise during primary infection.21 Patients with recent EBV infection develop elevated IgM and IgG to VCA, with EBNA antibodies developing weeks or months after the onset of the disease. Elevated IgM or IgG to VCA in association with rising EBNA antibodies are also suggestive of recent infection to EBV. The presence of a single positive IgG titer is not helpful as up to 90% of the population will have positive IgG titers suggestive of past infection. It would be important to know the time period between the intial positive IgM titer and the present positive IgG titer because the IgM should persist for 1–2 months after initial infection. Quantitation of the anti-viral titers would also be important. A four-fold change in the EBV titers in acute and convalescent sera would be more suggestive of a recent infection. Polymerase chain reaction (PCR) has been used to detect viral DNA in the aqueous humor of some patients with EBV retinitis.34 The ophthalmic manifestations of EBV infection have included conjunctivitis, keratitis, iritis, retinitis,26,40 and optic neuritis,21,24 and histopathologic confirmation of intraretinal EBV has been demonstrated.8 Optic disk edema with macular edema akin to that seen in other causes of neuroretinitis has been described. However in these reports there was other evidence of intraocular inflammation including vitritis, retinitis, and vasculitis affecting the retinal vessels.22,35,39 The normal CBC, ESR, and C-reactive protein do not support an inflammatory etiology. Furthermore,
Fig. 3. Fluorescein angiogram of the right eye demonstrating peripapillary hyperfluorescence (left) and optic disk leakage in the late phase (right).
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although EBV infection may occur in the absence of atypical lymphocytes in the peripheral blood, even in those patients with primarily neurologic symptoms, 70% of patients with infectious mononucleosis will have evidence of lymphocytosis which peaks within the first weeks of the illness.21 These findings, the results of EBV serology, and the absence of intraocular inflammation, call into question the role of EBV in this patient. The weakly positive ANA is also not too helpful because there is little other clinical or laboratory evidence to suggest central nervous systemic involvement from systemic lupus erythematosus. Measurement of serum complement levels would be helpful in a patient suspected of having active SLE. At this point I do not have a satisfactory explanation for this patient’s findings. Magnetic resonance angiography (MRA) of the head might be useful if central nervous system vasculitis is a concern.3 I would consider empiric treatment with corticosteroids, especially if there was progressive loss of visual function. If the patient had not already been hospitalized for the previous evaluation I would recommend hospital admission and medical and perhaps rheumatologic consulation in light of the weakly positive ANA and other constitutional symptoms.
Case Report (Cont’d) A presumptive diagnosis of neuroretinitis from EBV infection was made and the patient admitted to hospital for further investigations. On admission, however, the blood pressure was recorded at 200/ 105. A medical review was obtained and systemic examination revealed an epigastric bruit. The diagnosis at this point was secondary hypertension with associated hypertensive retinopathy. She was commenced on metoprolol 25 mg BID, resulting in good blood pressure control. Her vision improved over the next 5 days to 6/18 in the right eye and 6/5 in the left.
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The evaluation would be best suited in a monitored unit, such that the heart rate and blood pressure can be continously monitored. Repeated episodes of hypertension and tachycardia might suggest pheochromocytoma. Intravenous medication may be required to lower the blood pressure. In addition, when treating the hypertension it is important not to cause a rapid drop in blood pressure because this may precipitate stroke and/or visual loss due to impaired vascular autoregulation.7
Case report (Cont’d) Further investigations in the form of blood renin, aldosterone, in addition to 24-hour urinary catecholamines revealed no abnormalities. The patient then underwent echocardiography as well as an abdominal and chest MRI. The echocardiogram was unremarkable, but the MRI revealed stenosis of both the descending aorta and left retinal artery. In view of these findings an aortagram was performed and showed a picture characteristic of Takayasu’s arteritis (Fig. 4). Vascular consultation lead to a diagnosis of Takayasu’s arteritis in the acute inflammatory phase with hypertension secondary to renal artery stenosis. Over the next few weeks her visual symptoms continued to improve and, when reviewed again in November 2000, her vision had returned to 6/5 in both eyes and retinopathy had largely resolved with only a few remaining lipid exudates in the right posterior pole. In March 2001, due to difficulties with the medical control of her blood pressure, the patient underwent a successful renal artery angioplasty and stent. On her last follow-up in August 2001, her blood pressure was well controlled with single agent therapy and the fundi had returned to normal.
At this point, what further investigations should be performed?
Comments (Cont’d) Given her young age, epigastric bruit, and without a prior history of hypertension, this patient should be evaluated for secondary causes of elevated blood pressure. Statistically the most likely cause of secondary hypertension would be from renovascular disease.10 I would start with a urinalysis, renal ultrasonography, urinary catecholamines for pheochromocytoma, and computed tomography of the abdomen. I would rely on the medical consultation to suggest the sequence and most appropriate evaluation at this point.10
Fig. 4. Aortic angiogram showing left renal artery stenosis (arrow).
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Discussion (Dr. Foroozon) Hypertensive optic neuropathy occurs in patients with markedly elevated blood pressure.11 Multiple measurements may be required in order to document the elevated blood pressure, especially in conditions that cause episodic spikes in blood pressure (pheochromocytoma). It is generally thought to be a form of ischemic optic neuropathy. The bilateral optic disk edema with macular exudates and with cotton-wool infarcts is characteristic of hypertensive optic neuropathy and retinopathy.16,17 However, the macular exudates may be seen in the absence of obvious optic disk swelling.23 One report listed several features which may help distinguish hypertensive retinopathy from neuroretinitis including: visual loss (which occurs acutely in neuroretinitis but not in hypertension), bilaterality (which occurs in hypertension and rarely in neuroretinitis), and the presence of retinal hemorrhages, venous engorgement, arteriolar narrowing, and arteriovenous “nicking” (all seen in hypertension and are not typical of neuroretinitis).16 I would add the finding of vitreous cells or other evidence of intraocular inflammation, which are commonly seen in neuroretinitis and which would be unexpected in hypertension. Despite the finding of bilateral optic disk edema, visual function in patients with hypertensive optic neuropathy is typically preserved early on unless macular edema occurs. Takayasu’s arteritis (pulseless disease) is a necrotizing large vessel vasculitis which primarily involves large elastic arteries and causes occlusion of the aortic arch and its branches, including the coronary arteries. The etiology remains unknown, although an immune reaction involving T lymphocytes with infiltration of T cells into the vessel walls appears to be the prevailing immunologic mechanism of injury.37 Some authors have speculated that an infection predisposes to the development of arteritis.27 The arteritis occurs most commonly in young women of Asian descent, with the onset usually between 10 and 30 years of age; however, it has been reported in a wide range of populations. In the United States the annual incidence is estimated to be 2.6 per million people.37 Three broad stages of disease activity have been categorized: • An early systemic illness phase characterized by constitutional symptoms including fatigue, weight loss, fever and arthralgias • A vascular inflammatory phase • A chronic phase with vascular occlusion or “burned out” phase However, there is accumulating evidence that this scheme is an oversimplification of the clinical course.
The diagnostic criteria for Takayasu’s arteritis were modified from existing criteria (Ishikawa’s criteria grouped into obligatory, major, and minor criteria) in 1990 by the American College of Rheumatology based on the findings of 63 patients studied with a larger group of 744 patients with other forms of vasculitis.2 Patients with three of six of the following criteria were said to have Takayasu’s arteritis: Age ⬍ 40 years Claudication in the extremities Decreased brachial artery pulse 10 mm Hg or more difference in systolic blood pressure between the arms • Subclavian or aortic bruit • Angiographic evidence of narrowing or occlusion of the aorta or its primary or proximal branches
• • • •
The presence of three of six criteria yielded a sensitivity of 90.5% and specificity of 97.8% in this study. Other investigators have suggested modifying the criteria,30 especially the criterion of age, because arteritis in patients over the age of 40 has been well documented.12 Although markers of systemic inflammation such as the ESR and C-reactive protein are typically elevated they do not always parallel the clinical course making the diagnosis and follow up of these patients more difficult.12 A narrowing of the arterial vessels, from granulomatous inflammation of the media and adventitia, results in diminished pulses and bruits such as the epigastric bruit in this patient.36 Systemic hypertension occurs in 50% of affected patients most commonly from narrowing of the aorta or renal arteries. Although abnormalities in the involved arteries may be seen with CT angiography or MRA, the diagnosis is typically confirmed with catheter arteriography, which shows occlusion of some arteries and smoothwalled narrowing of other affected vessels.1 Arteriography may reveal stenosis, occlusion, or an aneurysm of the affected artery, and it has been used to classify the type of disease, depending on the site of vessel involvement. Aortic stenosis most commonly occurs in the descending thoracic and abdominal aorta. Stenosis and occlusion of the proximal portions of the major branches arising from the aorta are more commonly seen in the later phases of the disease.1 The ocular findings occur relatively later in the disease course in most patients with Takayasu’s arteritis.19 Transient visual loss precipitated by a change in body position may occur with high-grade vascular stenosis.19 Characteristic retinal arteriovenous anastomoses or shunts are thought to occur from severe ocular ischemia.32 The most common ocular findings include retinal hemorrhages,14,15 micoraneurysms,
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and ocular ischemic syndrome may develop with carotid occlusion.19,38 Optic atrophy from ischemia has been described,18,20 and anterior ischemic optic neuropathy resembling that seen in patients with giant cell arteritis may be the initial ocular manifestation of the disease and may occur in the absence of clinically obvious retinopathy.29 Immunosuppression with corticosteroids and other agents may be helpful in the acute inflammatory stages.28 In Japan clinicians rely almost exclusively on corticosteroids, monitoring acute phase reactants and altering the dose accordingly. In the United States other cytotoxic agents are used in combination with corticosteroids if inflammation persists during attempts to taper the corticosteroids. However, in contrast with other forms of vasculitis, Takayasu’s arteritis is less sensitive to cytotoxic agents.28 Because acute phase reactants may not be accurate markers of the activity of vascular disease, periodic vascular imaging may be warranted. Unfortunately, in most patients the inflammation can only be partially controlled and progressive arterial occlusion requires surgical intervention with vascular bypass or percutaneous transluminal procedures.33 The prognosis for patients with Takayasu’s arteritis depends on the presence of major complications that include hypertension, retinopathy, aortic insufficiency, and aneurysm formation. In the Japanese literature the overall survival rates are markedly different in patients with (66%) and without (96%) one of these major complications. Early diagnosis and aggressive treatment with corticosteroids appear to offer the best chances to avoid progression and complications of the vascular lesions.
References 1.
2.
3. 4.
5. 6. 7.
Angeli E, Vanzulli A, Venturini M, et al: The role of radiology in the diagnosis and management of Takayasu’s arteritis. J Nephrol 14:514–24, 2001 Arend WP, Michel BA, Bloch DA, et al: The American College of Rheumatology 1990 criteria for the classification of Takayasu arteritis. Arthritis Rheum 33:1129–34, 1990 Atalay MK, Bluemke DA: Magnetic resonance imaging of large vessel vasculitis. Curr Opin Rheumatol 13:41–7, 2001 Bafna S, Lee AG: Bilateral optic disc edema and multifocal retinal lesions without loss of vision in cat scratch disease. Arch Ophthalmol 114:1016–7, 1996 Brown GC, Brown MM, Hiller T, et al: Cotton-wool spots. Retina 5:206–14, 1985 Connelly KP, DeWitt LD: Neurologic complications of infectious mononucleosis. Pediatr Neurol 10:181–4, 1994 Cove DH, Seddon M, Fletcher RF, Dukes DC: Blindness after treatment for malignant hypertension. Br Med J 2:245–6, 1979
SHARMA ET AL 8. Freigassner P, Ardjomand N, Radner H, El-Shabrawi Y: Coinfection of the retina by Epstein-Barr virus and cytomegalovirus in an AIDS patient. Am J Ophthalmol 134:275–7, 2002 9. Gittinger JW, Asdourian GK: Macular abnormalities in papilledema from pseudotumor cerebri. Ophthalmology 96:192– 4, 1989 10. Hall WD: Resistant hypertension, secondary hypertension, and hypertensive crises. Cardiol Clin 20:281–9, 2002 11. Hayreh SS, Servais GE, Virdi PS: Fundus lesions in malignant hypertension. V. Hypertensive optic neuropathy. Ophthalmology 93:74–87, 1986 12. Hoffman GS: Takayasu arteritis: lessons from the American National Institutes of Health experience. Int J Cardiol 54(Suppl):S99–102, 1996 13. Kennard C, Swash M: Acute viral encephalitis: its diagnosis and outcome. Brain 104:129–48, 1981 14. Kiyosawa M, Baba T: Ophthalmological findings in patients with Takayasu disease. Int J Cardiol 66(Suppl 1):S141–7; discussion S149, 1998 15. Kuwahara C, Imamura Y, Okamura N, et al: Severe proliferative retinopathy progressing to blindness in a Japanese woman with takayasu disease. Am J Ophthalmol 135:722– 3, 2003 16. Leavitt JA, Pruthi S, Morgenstern BZ: Hypertensive retinopathy mimicking neuroretinitis in a twelve-year-old girl. Surv Ophthalmol 41:477–80, 1997 17. Lee AG, Beaver HA: Acute bilateral optic disk edema with a macular star figure in a 12-year-old girl. Surv Ophthalmol 47:42–9, 2002 18. Leonard TJ, Sanders MD: Ischaemic optic neuropathy in pulseless disease. Br J Ophthalmol 67:389–92, 1983 19. Lewis JR, Glaser JS, Schatz NJ, Hutson DG: Pulseless (Takayasu) disease with ophthalmic manifestations. J Clin Neuroophthalmol 13:242–9, 1993 20. Malik KP, Kapoor K, Mehta A, et al: Bilateral anterior ischaemic optic neuropathy in Takayasu arteritis. Indian J Ophthalmol 50:52–4, 2002 21. Matoba AY: Ocular disease associated with Epstein-Barr virus infection. Surv Ophthalmol 35:145–50, 1990 22. Morishima N, Miyakawa S, Akazawa Y, Takagi S: A case of uveitis associated with chronic active Epstein-Barr virus infection. Ophthalmologica 210:186–8, 1996 23. Noble KG: Hypertensive retinopathy simulating Leber idiopathic stellate neuroretinitis. Arch Ophthalmol 115:1594– 5, 1997 24. Pflugfelder SC, Crouse CA, Atherton SS: Ophthalmic manifestations of Epstein-Barr virus infection. Int Ophthalmol Clin 33:95–101, 1993 25. Ray S, Gragoudas E: Neuroretinitis. Int Ophthalmol Clin 41:83–102, 2001 26. Raymond LA, Wilson CA, Linnemann CC, et al: Punctate outer retinitis in acute Epstein-Barr virus infection. Am J Ophthalmol 104:424–6, 1987 27. Robbs JV, Human RR, Rajaruthnam P: Operative treatment of nonspecific aortoarteritis (Takayasu’s arteritis). J Vasc Surg 3:605–16, 1986 28. Sabbadini MG, Bozzolo E, Baldissera E, Bellone M: Takayasu’s arteritis: therapeutic strategies. J Nephrol 14:525–31, 2001 29. Schmidt MH, Fox AJ, Nicolle DA: Bilateral anterior ischemic optic neuropathy as a presentation of Takayasu’s disease. J Neuroophthalmol 17:156–61, 1997 30. Sharma BK, Jain S, Suri S, Numano F: Diagnostic criteria for Takayasu arteritis. Int J Cardiol 54(Suppl):S141–7, 1996 31. Silverstein A, Steinberg G, Nathanson M: Nervous system involvement in infectious mononucleosis. The heralding and-or major manifestation. Arch Neurol 26:353–8, 1972 32. Tanaka T, Shimizu K: Retinal arteriovenous shunts in Takayasu disease. Ophthalmology 94:1380–8, 1987 33. Teoh MK: Takayasu’s arteritis with renovascular hypertension: results of surgical treatment. Cardiovasc Surg 7:626– 32, 1999 34. Tran TH, Rozenberg F, Cassoux N, et al: Polymerase chain reaction analysis of aqueous humour samples in necrotising retinitis. Br J Ophthalmol 87:79–83, 2003
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OPTIC NEUROPATHY 35. Usui M, Sakai J: Three cases of EB virus-associated uveitis. Int Ophthalmol 14:371–6, 1990 36. Vanoli M, Bacchiani G, Origg L, Scorza R: Takayasu’s arteritis: a changing disease. J Nephrol 14:497–505, 2001 37. Weyand CM, Goronzy JJ: Medium- and large-vessel vasculitis. N Engl J Med 349:160–9, 2003 38. Worrall M, Atebara N, Meredith T, Mann ES: Bilateral ocular ischemic syndrome in Takayasu disease. Retina 21:75–6, 2001 39. Yamamoto M, Ohga S, Ohnishi Y, Inomata H: Optic disk vasculitis associated with chronic active Epstein-Barr virus infection. Ophthalmologica 216:221–5, 2002
40.
Yoser SL, Forster DJ, Rao NA: Systemic viral infections and their retinal and choroidal manifestations. Surv Ophthalmol 37:313–52, 1993
The authors reported no proprietary or commercial interest in any product mentioned or concept discussed in this article. Reprint address: John Crompton, MD, Department of Ophthalmology, Royal Adelaide Hospital, North Terrace, Adelaide 5000, South Australia, Australia.
Abstract. A 26-year-old Asian woman presented with bilateral disk swelling, retinal exudates and infarcts. Evaluation found the underlying cause of the hypertensive optic neuropathy to be renal artery stenosis due to Takayasu’s arteritis. (Surv Ophthalmol 49:429–435, 2004. 쑖 2004 Elsevier Inc. All rights reserved.) Key words. arteritis • hypertensive optic neuropathy infarcts • Takayasu vasculitis
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optic disk edema
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renal disease
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retinal
VOLUME 49 • NUMBER 4 • JULY–AUGUST 2004
CLINICAL CHALLENGES PETER SAVINO AND HELEN DANESH-MEYER, EDITORS
Optic Neuropathy: Puls/Minus Anil Sharma, MD, MS, John Crompton, FRACO, and Dinesh Selva, FRACO Department of Ophthalmology, Royal Adelaide Hospital, Adelaide, South Australia, Australia
Comments by Rod Foroozon, MD (In keeping with the format of a clinical pathologic conference, the abstract and key words appear at the end of the article.)
From the history we know that the onset of visual loss has been relatively recent, over a 5-day period. The fact that the visual acuity in the right eye is markedly decreased without the presence of a RAPD, and with relatively preserved visual function in the left eye, suggests that the retinal edema, and not an optic neuropathy, is the primary cause of the decreased vision on the right. Her other constitutional symptoms are suggestive of an underlying systemic condition, and an infection with Epstein-Barr virus (EBV) could certainly cause these symptoms. The differential diagnosis is that for a patient with bilateral optic disk edema, and includes elevated intracranial pressure and hypertensive optic neuropathy. Both acute papilledema and hypertensive optic neuropathy can result in leakage of lipid into the fovea and a macular star.9,11 Both conditions may also be accompanied by peripapillary cotton-wool spots. The evaluation should proceed in a stepwise fashion (Fig. 2). The vital signs should be measured first. All patients with bilateral optic disk edema should have their blood pressure measured at their initial examination. In addition, with a history of fever this patient’s temperature should be recorded. If a blood pressure cuff and thermometer are not readily available the patient should be sent to an acute care setting where they can be measured.
Case Report. A 26-year-old Filipino woman presented to the Department of Ophthalmology, Royal Adelaide Hospital, in October 2000 with a 5-day history of decreased vision in the right eye. Over the previous 6 weeks she had noted headaches, loss of appetite, mild fever, vomiting, and vague generalized myalgias. There was no significant past medical history and investigations by her local doctor revealed a positive IgM Epstein-Barr virus (EBV) serology. On examination, visual acuities were count fingers in the right eye and 6/4.5 in the left. No relative afferent pupillary defect (RAPD) was evident and slit-lamp biomicroscopy revealed a normal anterior segment. Automated perimetry showed a right centrocecal scotoma and an enlarged blind spot in the left eye. Ophthalmoscopy showed swollen, hyperemic optic disks with peripapillary cotton wool infarcts, gross nerve fiber layer edema, engorged veins, and a right macular star (Fig. 1). What is your differential diagnosis? What tests should be performed initially?
Comments Comments by Rod Foroozon, MD, The Cullen Eye Institute, Houston, Texas, USA 429
쑖 2004 by Elsevier Inc. All rights reserved.
0039-6257/04/$–see front matter doi:10.1016/j.survophthal.2004.04.015
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Fig. 1. Fundus photographs of the right and left eyes showing disk edema, peripapillary cotton-wool spots, engorged veins and a right macular star.
Assuming the vital signs are normal, neuroimaging should be performed to exclude the presence of hydrocephalus and/or a mass lesion. If these are normal then a lumbar puncture (LP) should be performed to measure the opening pressure and evaluate the constituents of the cerebrospinal fluid (CSF). In this patient I am concerned about the possibility of an infection, such as meningitis, from EBV involving the central nervous system (CNS).6 The incidence
Fig. 2. Flow chart illustrating a stepwise evaluation of optic disk edema.
of neurologic involvement from EBV has been estimated to be 5%, and CNS infection may be the first or only manifestations of the infection.31 Encephalitis and meningitis are thought to be the most common forms of CNS-related EBV, and in most patients the disease is self-limiting.13 The CSF shows a mononuclear pleocytosis, a moderately elevated white count, and may show atypical lymphocytes. I would perform magnetic resonance imaging (MRI)/magnetic resonance venography (MRV) and LP urgently. If MRI and MRV are not available, computed tomography (CT) of the head should be done. I would perform these tests prior to discharging the patient and this might require hospitalization or evaluation in the emergency room. In addition, I would obtain a complete blood count (CBC) and erythrocyte sedimentation rate (ESR). The CBC might show leukocytosis and atypical lymphocytes suggestive of EBV and an elevated ESR would be suggestive of an inflammatory process. A medical evaluation would be helpful to evaluate for lymphadenopathy and examine the liver and spleen. If these tests are unrevealing, then an underlying vascular process might be suspected because of the presence of nerve fiber layer infarcts. The finding of even a single cotton-wool infarct in a patient without known vascular conditions such as hypertension and diabetes necessitates further evaluation.5 In 24 patients with cotton-wool infarcts and without a history of diabetes mellitus, ocular ischemic syndrome was found in two patients and dermatomyositis, systemic lupus erythematosus, polyartertis nodosa, and giant cell arteritis were each found in four others.5 I would start with a review of systems aimed at uncovering symptoms consistent with rheumatologic and vascular disorders. The following blood tests might be helpful: antinuclear antibody, human immunodeficiency virus titer, hepatitis B and C titers, antinuclear
OPTIC NEUROPATHY
and cytoplasmic antibody, and rapid plasma reagin testing for syphilis. Other considerations would include Behc¸et’s disease and sarcoidosis. Several infections may cause optic disk edema with exudates in the fovea resulting in a macular star pattern (neuroretinitis).25 Included in these are Lyme disease, cat scratch disease, and Rocky Mountain Spotted Fever. Neuroretinitis is more commonly unilateral, but patients with bilateral optic disk edema as the presenting sign of systemic infection have been described.4 Neuroretinitis is frequently accompanied by inflammatory cells in the vitreous so that slit lamp biomicroscopy of the vitreous would be important.
Case Report (Continued) A fluorescein angiogram (FA) demonstrated peripapillary hyperfluorescence (Fig. 3A) with leakage in the late phase (Fig. 3B). The complete blood count, Westergren erythrocyte sedimentation rate, C-reactive protein, and electrolytes were normal. Serological tests for herpes simplex, varicella zoster, cytomegalovirus, toxoplasma gondii, hepatitis B and C, Lyme disease, treponemal disease, and Bartonella henselae were normal. The EBV serology was positive for IgG, but not IgM. The angiotensin converting enzyme level was within normal limits but the anti-nuclear antibody test revealed a positive titer of 1:40. Both a chest X-ray and magnetic resonance imaging of the head were unremarkable. A lumbar puncture was performed and the cerebrospinal fluid was found to be normal on microscopy and biochemical analysis. What further investigation would you perform?
Comments (Continued) It would be important to measure the opening pressure during the LP. The findings on the FA are
431
not particularly helpful because all of the conditions we are considering would be expected to cause late leakage at the optic disk. The results of the EBV serology are somewhat confusing. Antibodies to several virus-specific antigens, including viral capsid antigen (VCA), early antigen (EA), and Epstein-Barr nuclear antigen (EBNA), arise during primary infection.21 Patients with recent EBV infection develop elevated IgM and IgG to VCA, with EBNA antibodies developing weeks or months after the onset of the disease. Elevated IgM or IgG to VCA in association with rising EBNA antibodies are also suggestive of recent infection to EBV. The presence of a single positive IgG titer is not helpful as up to 90% of the population will have positive IgG titers suggestive of past infection. It would be important to know the time period between the intial positive IgM titer and the present positive IgG titer because the IgM should persist for 1–2 months after initial infection. Quantitation of the anti-viral titers would also be important. A four-fold change in the EBV titers in acute and convalescent sera would be more suggestive of a recent infection. Polymerase chain reaction (PCR) has been used to detect viral DNA in the aqueous humor of some patients with EBV retinitis.34 The ophthalmic manifestations of EBV infection have included conjunctivitis, keratitis, iritis, retinitis,26,40 and optic neuritis,21,24 and histopathologic confirmation of intraretinal EBV has been demonstrated.8 Optic disk edema with macular edema akin to that seen in other causes of neuroretinitis has been described. However in these reports there was other evidence of intraocular inflammation including vitritis, retinitis, and vasculitis affecting the retinal vessels.22,35,39 The normal CBC, ESR, and C-reactive protein do not support an inflammatory etiology. Furthermore,
Fig. 3. Fluorescein angiogram of the right eye demonstrating peripapillary hyperfluorescence (left) and optic disk leakage in the late phase (right).
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although EBV infection may occur in the absence of atypical lymphocytes in the peripheral blood, even in those patients with primarily neurologic symptoms, 70% of patients with infectious mononucleosis will have evidence of lymphocytosis which peaks within the first weeks of the illness.21 These findings, the results of EBV serology, and the absence of intraocular inflammation, call into question the role of EBV in this patient. The weakly positive ANA is also not too helpful because there is little other clinical or laboratory evidence to suggest central nervous systemic involvement from systemic lupus erythematosus. Measurement of serum complement levels would be helpful in a patient suspected of having active SLE. At this point I do not have a satisfactory explanation for this patient’s findings. Magnetic resonance angiography (MRA) of the head might be useful if central nervous system vasculitis is a concern.3 I would consider empiric treatment with corticosteroids, especially if there was progressive loss of visual function. If the patient had not already been hospitalized for the previous evaluation I would recommend hospital admission and medical and perhaps rheumatologic consulation in light of the weakly positive ANA and other constitutional symptoms.
Case Report (Cont’d) A presumptive diagnosis of neuroretinitis from EBV infection was made and the patient admitted to hospital for further investigations. On admission, however, the blood pressure was recorded at 200/ 105. A medical review was obtained and systemic examination revealed an epigastric bruit. The diagnosis at this point was secondary hypertension with associated hypertensive retinopathy. She was commenced on metoprolol 25 mg BID, resulting in good blood pressure control. Her vision improved over the next 5 days to 6/18 in the right eye and 6/5 in the left.
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The evaluation would be best suited in a monitored unit, such that the heart rate and blood pressure can be continously monitored. Repeated episodes of hypertension and tachycardia might suggest pheochromocytoma. Intravenous medication may be required to lower the blood pressure. In addition, when treating the hypertension it is important not to cause a rapid drop in blood pressure because this may precipitate stroke and/or visual loss due to impaired vascular autoregulation.7
Case report (Cont’d) Further investigations in the form of blood renin, aldosterone, in addition to 24-hour urinary catecholamines revealed no abnormalities. The patient then underwent echocardiography as well as an abdominal and chest MRI. The echocardiogram was unremarkable, but the MRI revealed stenosis of both the descending aorta and left retinal artery. In view of these findings an aortagram was performed and showed a picture characteristic of Takayasu’s arteritis (Fig. 4). Vascular consultation lead to a diagnosis of Takayasu’s arteritis in the acute inflammatory phase with hypertension secondary to renal artery stenosis. Over the next few weeks her visual symptoms continued to improve and, when reviewed again in November 2000, her vision had returned to 6/5 in both eyes and retinopathy had largely resolved with only a few remaining lipid exudates in the right posterior pole. In March 2001, due to difficulties with the medical control of her blood pressure, the patient underwent a successful renal artery angioplasty and stent. On her last follow-up in August 2001, her blood pressure was well controlled with single agent therapy and the fundi had returned to normal.
At this point, what further investigations should be performed?
Comments (Cont’d) Given her young age, epigastric bruit, and without a prior history of hypertension, this patient should be evaluated for secondary causes of elevated blood pressure. Statistically the most likely cause of secondary hypertension would be from renovascular disease.10 I would start with a urinalysis, renal ultrasonography, urinary catecholamines for pheochromocytoma, and computed tomography of the abdomen. I would rely on the medical consultation to suggest the sequence and most appropriate evaluation at this point.10
Fig. 4. Aortic angiogram showing left renal artery stenosis (arrow).
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Discussion (Dr. Foroozon) Hypertensive optic neuropathy occurs in patients with markedly elevated blood pressure.11 Multiple measurements may be required in order to document the elevated blood pressure, especially in conditions that cause episodic spikes in blood pressure (pheochromocytoma). It is generally thought to be a form of ischemic optic neuropathy. The bilateral optic disk edema with macular exudates and with cotton-wool infarcts is characteristic of hypertensive optic neuropathy and retinopathy.16,17 However, the macular exudates may be seen in the absence of obvious optic disk swelling.23 One report listed several features which may help distinguish hypertensive retinopathy from neuroretinitis including: visual loss (which occurs acutely in neuroretinitis but not in hypertension), bilaterality (which occurs in hypertension and rarely in neuroretinitis), and the presence of retinal hemorrhages, venous engorgement, arteriolar narrowing, and arteriovenous “nicking” (all seen in hypertension and are not typical of neuroretinitis).16 I would add the finding of vitreous cells or other evidence of intraocular inflammation, which are commonly seen in neuroretinitis and which would be unexpected in hypertension. Despite the finding of bilateral optic disk edema, visual function in patients with hypertensive optic neuropathy is typically preserved early on unless macular edema occurs. Takayasu’s arteritis (pulseless disease) is a necrotizing large vessel vasculitis which primarily involves large elastic arteries and causes occlusion of the aortic arch and its branches, including the coronary arteries. The etiology remains unknown, although an immune reaction involving T lymphocytes with infiltration of T cells into the vessel walls appears to be the prevailing immunologic mechanism of injury.37 Some authors have speculated that an infection predisposes to the development of arteritis.27 The arteritis occurs most commonly in young women of Asian descent, with the onset usually between 10 and 30 years of age; however, it has been reported in a wide range of populations. In the United States the annual incidence is estimated to be 2.6 per million people.37 Three broad stages of disease activity have been categorized: • An early systemic illness phase characterized by constitutional symptoms including fatigue, weight loss, fever and arthralgias • A vascular inflammatory phase • A chronic phase with vascular occlusion or “burned out” phase However, there is accumulating evidence that this scheme is an oversimplification of the clinical course.
The diagnostic criteria for Takayasu’s arteritis were modified from existing criteria (Ishikawa’s criteria grouped into obligatory, major, and minor criteria) in 1990 by the American College of Rheumatology based on the findings of 63 patients studied with a larger group of 744 patients with other forms of vasculitis.2 Patients with three of six of the following criteria were said to have Takayasu’s arteritis: Age ⬍ 40 years Claudication in the extremities Decreased brachial artery pulse 10 mm Hg or more difference in systolic blood pressure between the arms • Subclavian or aortic bruit • Angiographic evidence of narrowing or occlusion of the aorta or its primary or proximal branches
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The presence of three of six criteria yielded a sensitivity of 90.5% and specificity of 97.8% in this study. Other investigators have suggested modifying the criteria,30 especially the criterion of age, because arteritis in patients over the age of 40 has been well documented.12 Although markers of systemic inflammation such as the ESR and C-reactive protein are typically elevated they do not always parallel the clinical course making the diagnosis and follow up of these patients more difficult.12 A narrowing of the arterial vessels, from granulomatous inflammation of the media and adventitia, results in diminished pulses and bruits such as the epigastric bruit in this patient.36 Systemic hypertension occurs in 50% of affected patients most commonly from narrowing of the aorta or renal arteries. Although abnormalities in the involved arteries may be seen with CT angiography or MRA, the diagnosis is typically confirmed with catheter arteriography, which shows occlusion of some arteries and smoothwalled narrowing of other affected vessels.1 Arteriography may reveal stenosis, occlusion, or an aneurysm of the affected artery, and it has been used to classify the type of disease, depending on the site of vessel involvement. Aortic stenosis most commonly occurs in the descending thoracic and abdominal aorta. Stenosis and occlusion of the proximal portions of the major branches arising from the aorta are more commonly seen in the later phases of the disease.1 The ocular findings occur relatively later in the disease course in most patients with Takayasu’s arteritis.19 Transient visual loss precipitated by a change in body position may occur with high-grade vascular stenosis.19 Characteristic retinal arteriovenous anastomoses or shunts are thought to occur from severe ocular ischemia.32 The most common ocular findings include retinal hemorrhages,14,15 micoraneurysms,
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and ocular ischemic syndrome may develop with carotid occlusion.19,38 Optic atrophy from ischemia has been described,18,20 and anterior ischemic optic neuropathy resembling that seen in patients with giant cell arteritis may be the initial ocular manifestation of the disease and may occur in the absence of clinically obvious retinopathy.29 Immunosuppression with corticosteroids and other agents may be helpful in the acute inflammatory stages.28 In Japan clinicians rely almost exclusively on corticosteroids, monitoring acute phase reactants and altering the dose accordingly. In the United States other cytotoxic agents are used in combination with corticosteroids if inflammation persists during attempts to taper the corticosteroids. However, in contrast with other forms of vasculitis, Takayasu’s arteritis is less sensitive to cytotoxic agents.28 Because acute phase reactants may not be accurate markers of the activity of vascular disease, periodic vascular imaging may be warranted. Unfortunately, in most patients the inflammation can only be partially controlled and progressive arterial occlusion requires surgical intervention with vascular bypass or percutaneous transluminal procedures.33 The prognosis for patients with Takayasu’s arteritis depends on the presence of major complications that include hypertension, retinopathy, aortic insufficiency, and aneurysm formation. In the Japanese literature the overall survival rates are markedly different in patients with (66%) and without (96%) one of these major complications. Early diagnosis and aggressive treatment with corticosteroids appear to offer the best chances to avoid progression and complications of the vascular lesions.
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Angeli E, Vanzulli A, Venturini M, et al: The role of radiology in the diagnosis and management of Takayasu’s arteritis. J Nephrol 14:514–24, 2001 Arend WP, Michel BA, Bloch DA, et al: The American College of Rheumatology 1990 criteria for the classification of Takayasu arteritis. Arthritis Rheum 33:1129–34, 1990 Atalay MK, Bluemke DA: Magnetic resonance imaging of large vessel vasculitis. Curr Opin Rheumatol 13:41–7, 2001 Bafna S, Lee AG: Bilateral optic disc edema and multifocal retinal lesions without loss of vision in cat scratch disease. Arch Ophthalmol 114:1016–7, 1996 Brown GC, Brown MM, Hiller T, et al: Cotton-wool spots. Retina 5:206–14, 1985 Connelly KP, DeWitt LD: Neurologic complications of infectious mononucleosis. Pediatr Neurol 10:181–4, 1994 Cove DH, Seddon M, Fletcher RF, Dukes DC: Blindness after treatment for malignant hypertension. Br Med J 2:245–6, 1979
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The authors reported no proprietary or commercial interest in any product mentioned or concept discussed in this article. Reprint address: John Crompton, MD, Department of Ophthalmology, Royal Adelaide Hospital, North Terrace, Adelaide 5000, South Australia, Australia.
Abstract. A 26-year-old Asian woman presented with bilateral disk swelling, retinal exudates and infarcts. Evaluation found the underlying cause of the hypertensive optic neuropathy to be renal artery stenosis due to Takayasu’s arteritis. (Surv Ophthalmol 49:429–435, 2004. 쑖 2004 Elsevier Inc. All rights reserved.) Key words. arteritis • hypertensive optic neuropathy infarcts • Takayasu vasculitis
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optic disk edema
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renal disease
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retinal