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Aortoarteritis and sensorineural hearing loss in an adolescent black male
Aortoarteritis and Sensorineural Hearing Loss in an Adolescent Black Male J. Clinton Smith, MD, MPH,* James E. Peck, PhD,† Linda I. Ray, MD,* and Edward C. Smith, MD* We describe an adolescent male having sudden onset of sensorineural hearing loss. Evaluation led to the discovery of marked aortoarteritis. This patient exhibited findings of both Takayasu arteritis and Cogan syndrome. This report emphasizes the importance of ensuring a thorough systemic evaluation in individuals having sudden hearing loss. (Am J Otolaryngol 2004;25:370-376. © 2004 Elsevier Inc. All rights reserved.)
Takayasu arteritis (TA) is an inflammatory vasculitis most commonly affecting the ascending aortic arch and the arch vessels. Although the disease has been reported with the greatest frequency among young Asian women, it is clear that the disease can occur in any ethnic group and it is not rare in children.1 Sensorineural hearing loss (SNHL) has been reported rarely in individuals having TA. Cogan syndrome (CS) commonly involves SNHL and ophthalmologic abnormalities, as well as evidence of systemic vasculitis.2 We report a 14-year-old black young man whose initial complaint of hearing loss led to a diagnosis of aortitis with arch vessel involvement and SNHL that did not improve with corticosteroids. Manifestations of both TA and CS were present. CASE REPORT An otherwise healthy 14-year-old black male complained of difficulty hearing. On presenting to an emergency department and general pediatrics clinic, he was diagnosed and treated for “wax buildup” and bilateral serous otitis media. Mild to moderate tympanosclerosis was noted. He had no complaints related to his eyes, such as redness, pain,
From the *Department of Pediatrics; and †Department of Otolaryngology and Communicative Sciences, University of Mississippi Medical Center, Jackson, MS. Address correspondence to: J. Clinton Smith, MD, Department of Pediatrics (Cardiology), University of Mississippi Medical Center, 2500 North State Street, Jackson, MS 39216. E-mail: [email protected]. © 2004 Elsevier Inc. All rights reserved. 0196-0709/$ - see front matter doi:10.1016/j.amjoto.2004.04.009 370
photophobia, or changes in visual acuity. He was referred to the otolaryngology clinic at the University of Mississippi Medical Center, where he was discovered to have mild conductive hearing impairment in the right ear and profound SNHL in the left ear (Fig 1). Distortion product otoacoustic emissions testing, performed only on the left ear, showed absent otoacoustic emissions, indicating a lesion of the cochlear outer hair cells. He was admitted to our medical center 3 months after onset of his symptoms for further evaluation. Medical history revealed that a cleft palate was repaired in early infancy. He had been treated for asthma, atopic dermatitis, and psoriasis in early childhood. Bilateral middle ear tubes were placed at age 15 months. He was an honor student in school and was in his age-appropriate grade. He was allergic to sulfa drugs. There was no family history of hearing impairment or collagenvascular diseases. Review of systems was unremarkable except for a 2-lb weight loss, a chronic scaly rash on his back, and transient vertigo after onset of SNHL but no ataxia. He had not had unexplained fevers, joint pain, or tinnitus. On physical examination, weight was 49.4 kg (25th percentile) and height was 163 cm (25th percentile). Vital signs were normal except that blood pressures were lower in the left arm than in the right. He appeared to be in good health, and general examination was normal except for a grade 2/6 systolic ejection murmur loudest at the upper left sternal border and transmitted into the right and left neck. A scaly, faintly erythematous rash was present on his back. There was no evidence of
American Journal of Otolaryngology, Vol 25, No 5 (September-October), 2004: pp 370-376
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Fig 1. Audiogram showing the asymmetrical SNHL. The right ear exhibits a borderline loss in the low and middle frequencies and a mild loss for high frequencies. The left ear exhibits a profound hearing loss. The down arrows indicate no response.
joint disease. An ophthalmologic examination revealed no evidence of interstitial keratitis or uveitis. Visual acuity was normal. A skin test for tuberculosis was negative. Chest roentgenograms revealed prominence of the ascending aorta and were otherwise normal. An electrocardiogram showed left axis deviation, nonspecific ST-T wave changes, and was otherwise normal. Several echocardiograms were basically alike (Figs 2 and 3), showing a normal valve annulus and a dilated aortic root, ascending aorta, transverse aortic arch, and isthmus. Mild aortic valve insufficiency was present. Left ventricular function and measurements were within normal limits. Laboratory evaluation revealed moderately severe anemia, with hemoglobin of 9.8 g/dL, hematocrit 31%, mean corpuscular volume of 71.4 fL, mean corpuscular hemoglobin of 22.6 fmol/cell, and mean corpuscular hemoglobin concentration of 31.6% Hgb/cell. White blood cell count was 10,200/mm3, and platelet count was 760,000/mm3. A glucose-6-phosphate dehydrogenase level was grossly deficient and explained his anemia. A reticulocyte count was 1.3%. Basic blood chemistries were normal. His erythrocyte sedimentation rate (ESR) was 126 mm/h, and his C-reactive
protein (CRP) was 17.9 mg/dL. Other studies were negative including rapid plasma reagin, antistreptolysin O antibodies, streptozyme test, antinuclear antibodies, anti-DNA antibodies, antineutrophil cytoplasmic antibodies, anti-Sm and anti-RNP antibodies, rheumatoid factor, myeloperoxidase antibodies, and hepatitis screen. Anti– double-stranded DNA level was elevated at 274 IU/mL (normal 0-100 IU). Complement factors 3 and 4 were normal. Anticardiolipin immunoglobulin (Ig) G and IgM levels were normal. Lupus anticoagulant activity was negative. Prothrombin time was 13.5 seconds (normal 10.8-13.4 seconds). Activated partial thromboplastin time was 45.3 seconds (normal 28.0-42.5 seconds). Fibrinogen was slightly increased at 490 mg/dL (normal 175-400 mg/dL). Coagulation factors VII, XI, XII and proteins C, S, and free S were normal, but factor VIII was slightly prolonged at 179% (normal 50%-150%) and plasminogen increased at 143% (normal 70%-130%). Kaolin clotting time was slightly prolonged at 75.9 seconds (normal ⬍65 seconds), and a dilute Russell pit viper venom titer was negative. These findings were consistent with a mild acute phase hypercoagulable state. Re-
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Fig 2. Transthoracic echocardiogram, parasternal long-axis view, showing real-time measurements of diameters of (A) aortic valve annulus and (B) aortic root at sinuses of Valsalva. Based on patient’s calculated body mass index of 1.5 m2, estimated upper limit of normal20 for aortic root diameter is 2.85 cm. LA, left atrium; LV, left ventricle; Ao, aorta.
evaluation 3 years later was entirely normal. An MRI of the brain was normal except for a nonspecific area of increased signal in the left forceps minor region, which was thought to represent a perivascular space or a developmental venous anomaly. Duplex Doppler examination of the aortic arch vessels revealed moderately increased velocity in the common carotid arteries consistent with 50% to 79% stenotic flow on the left, and 40% to 59% stenotic flow on the right. Examination of the left vertebral artery revealed a prominent systolic notch interpreted as subclavian steal. Systolic blood pressure in the right arm was 124 mm Hg, and in the left arm it was 82 mm Hg. Blood flow velocity was moderately decreased in both internal carotid arteries. An aortic arch arteriogram showed irregular dilatation of the aortic root; the proximal aortic arch; and the brachiocephalic, left common carotid and left subclavian arteries. High-
grade stenosis of the left subclavian artery just proximal to the origin of the left vertebral artery and mild stenosis at the origin of the proximal left common carotid artery were present. There was no evidence of subclavian steal on this study. The left vertebral artery was smaller than the right. An outpouching at the origin of the left main coronary artery was thought to represent either a dilated aortic valve cusp or aneurysmal dilatation. The right subclavian, right common carotid, and right vertebral arteries appeared to be normal. Nerve conduction studies were normal, but electromyography showed a mild generalized myopathy with normal spontaneous activity, suggesting a nonnecrotizing myopathy. A presumptive diagnosis of TA was made, and he was started on prednisone 40 mg twice daily, aspirin 82 mg daily, and atenolol 50 mg daily. Coumadin 5 mg daily was begun, and the dose adjusted thereafter based on frequent
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Fig 3. Transthoracic echocardiogram, suprasternal long-axis view, showing real-time measurements of diameters of (A) proximal ascending aorta, (B) transverse arch, and (C) aortic isthmus. Based on patient’s calculated body mass index of 1.5 m2, estimated upper limits of normal21 for proximal ascending aorta diameter is 2.4 cm and for transverse aorta diameter is 2.0 cm.
prothrombin time–international normalized ratio values. There was no exacerbation of asthma with atenolol. Four months after onset of his illness, his ESR was 8 mm/h and his CRP was less than 0.4 mg/dL. Because of concern about hypertension secondary to corticosteroid administration, hydrochlorothiazide 50 mg daily was begun. Routine urinalysis was normal. A 24hour urinalysis showed a creatinine clearance of 116 mL/min (corrected using body surface area of 1.5 m2 to 134 mL/min/m2; normal 124 ⫾ 25.8 mL/min/m2), a urine protein of 244 mg/24 hours (normal ⬍2 g/24 hours), and a spot protein-to-creatinine ratio of 0.06 (normal ⬍0.2). Creatinine kinase level was slightly elevated to 400 to 600 U/L (normal 0-175 U/L) but soon returned to normal. Coumadin was discontinued after 1 year of use. In the ensuing months, prednisone dose was adjusted according to ESR and CRP lev-
els, and hydroxychloroquine (Plaquenil, Sanofi Winthrop, Morrisville, PA) and methotrexate added as prednisone was tapered. Because of continuing concern about his rash, he was referred to our dermatology clinic, where a diagnosis of guttate psoriasis was made on the basis on a punch biopsy and appropriate therapy started. Consultation from our geneticist revealed no evidence of Marfan syndrome. The most recent echocardiogram in January 2002 showed that the degree of aortic dilatation was stable. Continuing audiologic reevaluation has revealed no significant change from presentation except that distortion product otoacoustic emissions were now absent in each ear at 1,000 to 8,000 Hz. The right ear had a borderline SNHL for low and middle frequencies and a mild SNHL for high frequencies with normal word recognition ability. The left ear has continued to have profound
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SNHL with no word recognition ability at any intensity. DISCUSSION Our patient had SNHL leading to the discovery of aortoarteritis. These 2 findings are rare in children and even rarer in combination with each other. Although a definitive diagnosis has not been made, it appears likely that these 2 primary findings were related. Because he had not had other symptoms of vasculitis, we cannot determine whether, or for how long, the vasculitis preceded the SNHL. He clearly had evidence of systemic inflammatory disease at the time his SNHL occurred, and although he had not had fevers, he had mild weight loss, 2 conditions commonly reported with vasculitis in children. Of the childhood vasculitides associated with SNHL, we believe that our patient exhibited findings of either TA or CS or perhaps both. Takayasu Arteritis TA is named for Mikito Takayasu, a Japanese ophthalmologist who in 1908 described characteristic fundal signs of retinal ischemia. In the same year, other Japanese investigators reported these findings in patients having absent radial pulses. TA has been reported to be the third most common vasculitis in the pediatric age group.3,4 Our patient met several of the criteria promulgated in 1990 by the American College of Rheumatology for the diagnosis of TA.5 He was less than 40 years of age at the time of diagnosis, had a decreased brachial artery pulse, had a blood pressure difference of greater than 10 mm Hg between his 2 arms, had bruits over both carotid arteries, and had radiographically proven stenoses of the left common carotid and left subclavian arteries. His ascending aorta was also markedly dilated, and there was mild aortic regurgitation. An abdominal bruit suggested stenosis of a branch of the abdominal aorta, but this possibility has not yet been investigated. Although involvement of the pulmonary arterial tree has been reported in many patients having TA, we have not investigated this possibility because he has had no symptoms or signs of pulmonary disease. He did not have the retinopathy resulting from retinal isch-
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emia that is commonly associated with TA in about one third of patients. He developed hypertension only when taking corticosteroids, and this was easily controlled with a diuretic. Differential diagnoses that were unlikely were syphilis (negative rapid plasma reagin) and tuberculosis (negative skin test). Aortitis or aortic aneurysm has been reported only rarely with systemic lupus erythematosus and more rarely still with antiphospholipid antibody syndrome.6,7 On repeated testing, our patient had no evidence of either of these entities, including normal renal function. He had no clinical evidence of rheumatoid arthritis, such as of unexplained fevers, morning stiffness, or joint symptoms. He was too old for a diagnosis of Kawasaki disease to be seriously considered and too young for giant-cell arteritis. That Marfan syndrome was not present was confirmed by a geneticist’s evaluation, and there were no physical findings or family history of neurofibromatosis. He has exhibited no findings to suggest either a spondyloarthropathy or Behcet’s disease. We cannot say that our patient’s aortoarteritis was or was not affected by administration of corticosteroids, Plaquenil, or methotrexate. We can only say that he has not developed other symptoms or signs of aortic branch involvement, such as claudication, fixed hypertension, syncope, stroke, or progressive aortic insufficiency. Cogan Syndrome This disease may be better known to otolaryngologists than is TA. It was described by David Cogan in 1945, also an ophthalmologist. CS is a rare disease affecting many organ systems. It is characterized by acute nonsyphilitic interstitial keratitis and evidence of auditory and vestibular dysfunction, such as SNHL, vertigo, and tinnitus. Ophthalmologic changes include thickening of the corneal epithelium, neovascularization of the peripheral cornea, and uveitis. Systemic manifestations are less common (50%-75%). Its onset is generally in the latter half of the third decade; it is especially rare in childhood. The majority of patients reported have been white. Affected individuals may have fever, chills, weight loss, arthralgias, and myalgia. Respiratory, gastrointestinal, and neurologic involvement
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are common. Nonspecific signs of inflammation are present, such as elevated ESR and CRP. Vasculitis can involve large, medium, and small arteries and veins and can affect the skin, kidneys, muscles, and other organ systems. Cardiovascular involvement has been reported in about 10% of cases and includes aortitis, aortic dilatation, aortic insufficiency, and arterial stenosis or occlusion.8,9 Our patient had only minimal evidence of keratitis and no evidence of uveitis or changes in visual acuity. An electromyogram suggested a nonnecrotizing myopathy but no abnormality of nerve conduction. Sensorineural Hearing Loss It is likely that the patient that we describe had “immune-mediated” inner ear disease (IMIED) as suggested by McCabe10 and described by Stone and Francis.11 This condition can occur in primary vasculitides, such as CS, as well as in vasculitis complicating SLE, Wegener’s granulomatosis, and polyarteritis nodosa. It nearly always includes SNHL and may include vertigo and tinnitus. It usually occurs rapidly, as opposed to Meniere’s disease, which occurs over several years. It is usually bilateral, but each side may be affected at different times and to different degrees. It is characterized by either loss of hearing acuity and decreased ability to discriminate spoken words, either by others or by one’s self. Over half of reported patients are women. This condition has frequently responded to aggressive management with corticosteroids and cyclophosphamide.12 There has been an intense search over the past 15 years to understand the immunologic processes of IMIED and to perfect a diagnostic assay to identify inner ear autoantibodies. Harris and Sharp,13 using bovine inner ear extracts and Western blot analysis, identified a 68-kd protein that was 5 times more prevalent in a group of patients having IMIED than in normal controls, suggesting an autoimmune basis for disease in patients reacting against this antigen. Billings et al,14 however, suggested that the 68-kd protein was widely distributed in the body and not specific to the inner ear. They speculated that this protein might instead represent a 70-kd heat shock
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protein (hsp 70), an inducible stress protein known to be uniquely associated with ulcerative colitis and progressive sensorineural hearing loss. IgG and IgM antibodies against heat shock proteins have been found in patients with certain rheumatic diseases.15,16 KHRI-3 is an antibody that binds the 68-kd protein from guinea pig inner ear membrane supporting cells. Infusion of this antibody results in hearing loss in experimental animals by binding with proteins on such cells. Disher et al17 have reported that some patients with autoimmune sensorineural hearing loss produce autoantibodies to guinea pig inner ear supporting cell antigen that are dispersed in a pattern similar to that found when KHRI-3 murine monoclonal antibody is injected experimentally. These investigators conclude that human autoantibodies and murine KHRI-3 antibody have the same protein target but that hsp 70 is not that target. Our patient was not tested by Western blot for 68-kd inner ear antigen. SUMMARY The patient described here had SNHL occurring in a context of systemic vasculitis including aortitis, aortic valve insufficiency, and arterial stenoses. Cardiovascular pathology was more consistent with TA, but SNHL was characteristic of CS. Yet, he did not satisfy basic criteria for CS, in that he had no clear evidence of nonsyphilitic interstitial keratitis. His manifestations are therefore similar to the aortitis syndrome described by Kanzaki et al.18 Thus, there was likely an overlapping of these 2 entities and is best described as “an aortitis syndrome with auditory disorder that is a variant of aortitis syndrome and Cogan’s syndrome.”19 We conclude that otolaryngologists and other practitioners who care for children should ensure that a diligent search be made for evidence of systemic vasculitis in patients referred for SNHL. REFERENCES 1. Kerr GS: Takayasu’s arteritis. Rheum Dis Clin North Am 21:1041-1058, 1995 2. Chynn EW, Jakobiec FA: Cogan’s syndrome: Ophthalmic, audiovestibular, and systemic manifestations and therapy. Int Ophthalmol Clin 36:61-77, 1996 3. Brogan PA, Dillon MJ: Vasculitis from the pediatric perspective. Curr Rheum Rep 2:411-416, 2000
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4. Johnston SL, Lock RJ, Gompels MM: Takayasu arteritis: A review. J Clin Pathol 55:481-486, 2002 5. Arend WP, Michel BA, Block DA, et al: The American College of Rheumatology 1990 criteria for the classification of Takayasu arteritis. Arthritis Rheum 33:11291134, 1990 6. Tagaki H, Mori Y, Iwat H, et al: Nondissecting aneurysm of the thoracic aorta with arteritis in systemic lupus erythematosus. J Vasc Surg 35:801-804, 2002 7. Seror O, Fain O, Dordea M: Aortitis with antiphospholipid antibodies: CT and MR findings. Eur Radiol 8:1373-1375, 1998 8. Vollertsen RS, McDonald TJ, Younge BR, et al: Cogan’s syndrome: 18 cases and a review of the literature. Mayo Clin Proc 61:344-361, 1986 9. Raza K, Karokis D, Kitas GD: Cogan’s syndrome with Takayasu’s arteritis. Br J Rheumatol 37:369-372, 1998 10. McCabe BF: Autoimmune sensorineural hearing loss. Ann Otol Rhinol Laryngol 88:585-589, 1979 11. Stone JH, Francis HW: Immune-mediated inner ear disease. Curr Opin Rheumatol 12:32-40, 2000 12. McCabe BF: Autoimmune inner ear disease: Results of therapy. Adv Otorhinolaryngol 46:78-81, 1991 13. Harris JP, Sharp PA: Inner ear autoantibodies in patients with rapidly progressive sensorineural hearing loss. Laryngoscope 100:516-524, 1990
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14. Billings PB, Keithley EM, Harris JP: Evidence linking the 68 kilodalton antigen identified in progressive sensorineural hearing loss patient sera with heat shock protein 70. Ann Otol Rhinol Laryngol 104:181-188, 1995 15. Yoo TJ, Du X, Kwon SS: Molecular mechanism of autoimmune hearing loss. Acta Otolaryngol 48:3-9, 2002 (suppl 5) 16. Winfield JB, Jarjour WN: Stress proteins, autoimmunity, and autoimmune disease. Curr Top Microbiol Immunol 167:161-189, 1991 17. Disher MJ, Ramakrishnan A, Nair TS, et al: Human autoantibodies and monoclonal antibody KHRI-3 bind to a phylogenetically conserved inner-ear-supporting cell antigen. Ann N Y Acad Sci 830:253-265, 1997 18. Kanzaki J, Ouchi T: Steroid-responsive bilateral sensorineural hearing loss and immune complexes. Arch Otorhinolaryngol 230:5-9, 1981 19. Kanzaki J: Immune-mediated sensorineural hearing loss. Acta Otolaryngol 514:70-72, 1994 (suppl) 20. De Paepe A, Devereux RB, Dietz HC, et al: Revised diagnostic criteria for the Marfan syndrome. Am J Med Genet 62:417-426, 1996 21. Snider AR, Enderlein MA, Teitel DF, et al: Twodimensional echocardiographic determination of aortic and pulmonary artery sized from infancy to adulthood in normal subjects. Am J Cardiol 53:218-224, 1984
Takayasu arteritis (TA) is an inflammatory vasculitis most commonly affecting the ascending aortic arch and the arch vessels. Although the disease has been reported with the greatest frequency among young Asian women, it is clear that the disease can occur in any ethnic group and it is not rare in children.1 Sensorineural hearing loss (SNHL) has been reported rarely in individuals having TA. Cogan syndrome (CS) commonly involves SNHL and ophthalmologic abnormalities, as well as evidence of systemic vasculitis.2 We report a 14-year-old black young man whose initial complaint of hearing loss led to a diagnosis of aortitis with arch vessel involvement and SNHL that did not improve with corticosteroids. Manifestations of both TA and CS were present. CASE REPORT An otherwise healthy 14-year-old black male complained of difficulty hearing. On presenting to an emergency department and general pediatrics clinic, he was diagnosed and treated for “wax buildup” and bilateral serous otitis media. Mild to moderate tympanosclerosis was noted. He had no complaints related to his eyes, such as redness, pain,
From the *Department of Pediatrics; and †Department of Otolaryngology and Communicative Sciences, University of Mississippi Medical Center, Jackson, MS. Address correspondence to: J. Clinton Smith, MD, Department of Pediatrics (Cardiology), University of Mississippi Medical Center, 2500 North State Street, Jackson, MS 39216. E-mail: [email protected]. © 2004 Elsevier Inc. All rights reserved. 0196-0709/$ - see front matter doi:10.1016/j.amjoto.2004.04.009 370
photophobia, or changes in visual acuity. He was referred to the otolaryngology clinic at the University of Mississippi Medical Center, where he was discovered to have mild conductive hearing impairment in the right ear and profound SNHL in the left ear (Fig 1). Distortion product otoacoustic emissions testing, performed only on the left ear, showed absent otoacoustic emissions, indicating a lesion of the cochlear outer hair cells. He was admitted to our medical center 3 months after onset of his symptoms for further evaluation. Medical history revealed that a cleft palate was repaired in early infancy. He had been treated for asthma, atopic dermatitis, and psoriasis in early childhood. Bilateral middle ear tubes were placed at age 15 months. He was an honor student in school and was in his age-appropriate grade. He was allergic to sulfa drugs. There was no family history of hearing impairment or collagenvascular diseases. Review of systems was unremarkable except for a 2-lb weight loss, a chronic scaly rash on his back, and transient vertigo after onset of SNHL but no ataxia. He had not had unexplained fevers, joint pain, or tinnitus. On physical examination, weight was 49.4 kg (25th percentile) and height was 163 cm (25th percentile). Vital signs were normal except that blood pressures were lower in the left arm than in the right. He appeared to be in good health, and general examination was normal except for a grade 2/6 systolic ejection murmur loudest at the upper left sternal border and transmitted into the right and left neck. A scaly, faintly erythematous rash was present on his back. There was no evidence of
American Journal of Otolaryngology, Vol 25, No 5 (September-October), 2004: pp 370-376
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Fig 1. Audiogram showing the asymmetrical SNHL. The right ear exhibits a borderline loss in the low and middle frequencies and a mild loss for high frequencies. The left ear exhibits a profound hearing loss. The down arrows indicate no response.
joint disease. An ophthalmologic examination revealed no evidence of interstitial keratitis or uveitis. Visual acuity was normal. A skin test for tuberculosis was negative. Chest roentgenograms revealed prominence of the ascending aorta and were otherwise normal. An electrocardiogram showed left axis deviation, nonspecific ST-T wave changes, and was otherwise normal. Several echocardiograms were basically alike (Figs 2 and 3), showing a normal valve annulus and a dilated aortic root, ascending aorta, transverse aortic arch, and isthmus. Mild aortic valve insufficiency was present. Left ventricular function and measurements were within normal limits. Laboratory evaluation revealed moderately severe anemia, with hemoglobin of 9.8 g/dL, hematocrit 31%, mean corpuscular volume of 71.4 fL, mean corpuscular hemoglobin of 22.6 fmol/cell, and mean corpuscular hemoglobin concentration of 31.6% Hgb/cell. White blood cell count was 10,200/mm3, and platelet count was 760,000/mm3. A glucose-6-phosphate dehydrogenase level was grossly deficient and explained his anemia. A reticulocyte count was 1.3%. Basic blood chemistries were normal. His erythrocyte sedimentation rate (ESR) was 126 mm/h, and his C-reactive
protein (CRP) was 17.9 mg/dL. Other studies were negative including rapid plasma reagin, antistreptolysin O antibodies, streptozyme test, antinuclear antibodies, anti-DNA antibodies, antineutrophil cytoplasmic antibodies, anti-Sm and anti-RNP antibodies, rheumatoid factor, myeloperoxidase antibodies, and hepatitis screen. Anti– double-stranded DNA level was elevated at 274 IU/mL (normal 0-100 IU). Complement factors 3 and 4 were normal. Anticardiolipin immunoglobulin (Ig) G and IgM levels were normal. Lupus anticoagulant activity was negative. Prothrombin time was 13.5 seconds (normal 10.8-13.4 seconds). Activated partial thromboplastin time was 45.3 seconds (normal 28.0-42.5 seconds). Fibrinogen was slightly increased at 490 mg/dL (normal 175-400 mg/dL). Coagulation factors VII, XI, XII and proteins C, S, and free S were normal, but factor VIII was slightly prolonged at 179% (normal 50%-150%) and plasminogen increased at 143% (normal 70%-130%). Kaolin clotting time was slightly prolonged at 75.9 seconds (normal ⬍65 seconds), and a dilute Russell pit viper venom titer was negative. These findings were consistent with a mild acute phase hypercoagulable state. Re-
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Fig 2. Transthoracic echocardiogram, parasternal long-axis view, showing real-time measurements of diameters of (A) aortic valve annulus and (B) aortic root at sinuses of Valsalva. Based on patient’s calculated body mass index of 1.5 m2, estimated upper limit of normal20 for aortic root diameter is 2.85 cm. LA, left atrium; LV, left ventricle; Ao, aorta.
evaluation 3 years later was entirely normal. An MRI of the brain was normal except for a nonspecific area of increased signal in the left forceps minor region, which was thought to represent a perivascular space or a developmental venous anomaly. Duplex Doppler examination of the aortic arch vessels revealed moderately increased velocity in the common carotid arteries consistent with 50% to 79% stenotic flow on the left, and 40% to 59% stenotic flow on the right. Examination of the left vertebral artery revealed a prominent systolic notch interpreted as subclavian steal. Systolic blood pressure in the right arm was 124 mm Hg, and in the left arm it was 82 mm Hg. Blood flow velocity was moderately decreased in both internal carotid arteries. An aortic arch arteriogram showed irregular dilatation of the aortic root; the proximal aortic arch; and the brachiocephalic, left common carotid and left subclavian arteries. High-
grade stenosis of the left subclavian artery just proximal to the origin of the left vertebral artery and mild stenosis at the origin of the proximal left common carotid artery were present. There was no evidence of subclavian steal on this study. The left vertebral artery was smaller than the right. An outpouching at the origin of the left main coronary artery was thought to represent either a dilated aortic valve cusp or aneurysmal dilatation. The right subclavian, right common carotid, and right vertebral arteries appeared to be normal. Nerve conduction studies were normal, but electromyography showed a mild generalized myopathy with normal spontaneous activity, suggesting a nonnecrotizing myopathy. A presumptive diagnosis of TA was made, and he was started on prednisone 40 mg twice daily, aspirin 82 mg daily, and atenolol 50 mg daily. Coumadin 5 mg daily was begun, and the dose adjusted thereafter based on frequent
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Fig 3. Transthoracic echocardiogram, suprasternal long-axis view, showing real-time measurements of diameters of (A) proximal ascending aorta, (B) transverse arch, and (C) aortic isthmus. Based on patient’s calculated body mass index of 1.5 m2, estimated upper limits of normal21 for proximal ascending aorta diameter is 2.4 cm and for transverse aorta diameter is 2.0 cm.
prothrombin time–international normalized ratio values. There was no exacerbation of asthma with atenolol. Four months after onset of his illness, his ESR was 8 mm/h and his CRP was less than 0.4 mg/dL. Because of concern about hypertension secondary to corticosteroid administration, hydrochlorothiazide 50 mg daily was begun. Routine urinalysis was normal. A 24hour urinalysis showed a creatinine clearance of 116 mL/min (corrected using body surface area of 1.5 m2 to 134 mL/min/m2; normal 124 ⫾ 25.8 mL/min/m2), a urine protein of 244 mg/24 hours (normal ⬍2 g/24 hours), and a spot protein-to-creatinine ratio of 0.06 (normal ⬍0.2). Creatinine kinase level was slightly elevated to 400 to 600 U/L (normal 0-175 U/L) but soon returned to normal. Coumadin was discontinued after 1 year of use. In the ensuing months, prednisone dose was adjusted according to ESR and CRP lev-
els, and hydroxychloroquine (Plaquenil, Sanofi Winthrop, Morrisville, PA) and methotrexate added as prednisone was tapered. Because of continuing concern about his rash, he was referred to our dermatology clinic, where a diagnosis of guttate psoriasis was made on the basis on a punch biopsy and appropriate therapy started. Consultation from our geneticist revealed no evidence of Marfan syndrome. The most recent echocardiogram in January 2002 showed that the degree of aortic dilatation was stable. Continuing audiologic reevaluation has revealed no significant change from presentation except that distortion product otoacoustic emissions were now absent in each ear at 1,000 to 8,000 Hz. The right ear had a borderline SNHL for low and middle frequencies and a mild SNHL for high frequencies with normal word recognition ability. The left ear has continued to have profound
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SNHL with no word recognition ability at any intensity. DISCUSSION Our patient had SNHL leading to the discovery of aortoarteritis. These 2 findings are rare in children and even rarer in combination with each other. Although a definitive diagnosis has not been made, it appears likely that these 2 primary findings were related. Because he had not had other symptoms of vasculitis, we cannot determine whether, or for how long, the vasculitis preceded the SNHL. He clearly had evidence of systemic inflammatory disease at the time his SNHL occurred, and although he had not had fevers, he had mild weight loss, 2 conditions commonly reported with vasculitis in children. Of the childhood vasculitides associated with SNHL, we believe that our patient exhibited findings of either TA or CS or perhaps both. Takayasu Arteritis TA is named for Mikito Takayasu, a Japanese ophthalmologist who in 1908 described characteristic fundal signs of retinal ischemia. In the same year, other Japanese investigators reported these findings in patients having absent radial pulses. TA has been reported to be the third most common vasculitis in the pediatric age group.3,4 Our patient met several of the criteria promulgated in 1990 by the American College of Rheumatology for the diagnosis of TA.5 He was less than 40 years of age at the time of diagnosis, had a decreased brachial artery pulse, had a blood pressure difference of greater than 10 mm Hg between his 2 arms, had bruits over both carotid arteries, and had radiographically proven stenoses of the left common carotid and left subclavian arteries. His ascending aorta was also markedly dilated, and there was mild aortic regurgitation. An abdominal bruit suggested stenosis of a branch of the abdominal aorta, but this possibility has not yet been investigated. Although involvement of the pulmonary arterial tree has been reported in many patients having TA, we have not investigated this possibility because he has had no symptoms or signs of pulmonary disease. He did not have the retinopathy resulting from retinal isch-
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emia that is commonly associated with TA in about one third of patients. He developed hypertension only when taking corticosteroids, and this was easily controlled with a diuretic. Differential diagnoses that were unlikely were syphilis (negative rapid plasma reagin) and tuberculosis (negative skin test). Aortitis or aortic aneurysm has been reported only rarely with systemic lupus erythematosus and more rarely still with antiphospholipid antibody syndrome.6,7 On repeated testing, our patient had no evidence of either of these entities, including normal renal function. He had no clinical evidence of rheumatoid arthritis, such as of unexplained fevers, morning stiffness, or joint symptoms. He was too old for a diagnosis of Kawasaki disease to be seriously considered and too young for giant-cell arteritis. That Marfan syndrome was not present was confirmed by a geneticist’s evaluation, and there were no physical findings or family history of neurofibromatosis. He has exhibited no findings to suggest either a spondyloarthropathy or Behcet’s disease. We cannot say that our patient’s aortoarteritis was or was not affected by administration of corticosteroids, Plaquenil, or methotrexate. We can only say that he has not developed other symptoms or signs of aortic branch involvement, such as claudication, fixed hypertension, syncope, stroke, or progressive aortic insufficiency. Cogan Syndrome This disease may be better known to otolaryngologists than is TA. It was described by David Cogan in 1945, also an ophthalmologist. CS is a rare disease affecting many organ systems. It is characterized by acute nonsyphilitic interstitial keratitis and evidence of auditory and vestibular dysfunction, such as SNHL, vertigo, and tinnitus. Ophthalmologic changes include thickening of the corneal epithelium, neovascularization of the peripheral cornea, and uveitis. Systemic manifestations are less common (50%-75%). Its onset is generally in the latter half of the third decade; it is especially rare in childhood. The majority of patients reported have been white. Affected individuals may have fever, chills, weight loss, arthralgias, and myalgia. Respiratory, gastrointestinal, and neurologic involvement
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are common. Nonspecific signs of inflammation are present, such as elevated ESR and CRP. Vasculitis can involve large, medium, and small arteries and veins and can affect the skin, kidneys, muscles, and other organ systems. Cardiovascular involvement has been reported in about 10% of cases and includes aortitis, aortic dilatation, aortic insufficiency, and arterial stenosis or occlusion.8,9 Our patient had only minimal evidence of keratitis and no evidence of uveitis or changes in visual acuity. An electromyogram suggested a nonnecrotizing myopathy but no abnormality of nerve conduction. Sensorineural Hearing Loss It is likely that the patient that we describe had “immune-mediated” inner ear disease (IMIED) as suggested by McCabe10 and described by Stone and Francis.11 This condition can occur in primary vasculitides, such as CS, as well as in vasculitis complicating SLE, Wegener’s granulomatosis, and polyarteritis nodosa. It nearly always includes SNHL and may include vertigo and tinnitus. It usually occurs rapidly, as opposed to Meniere’s disease, which occurs over several years. It is usually bilateral, but each side may be affected at different times and to different degrees. It is characterized by either loss of hearing acuity and decreased ability to discriminate spoken words, either by others or by one’s self. Over half of reported patients are women. This condition has frequently responded to aggressive management with corticosteroids and cyclophosphamide.12 There has been an intense search over the past 15 years to understand the immunologic processes of IMIED and to perfect a diagnostic assay to identify inner ear autoantibodies. Harris and Sharp,13 using bovine inner ear extracts and Western blot analysis, identified a 68-kd protein that was 5 times more prevalent in a group of patients having IMIED than in normal controls, suggesting an autoimmune basis for disease in patients reacting against this antigen. Billings et al,14 however, suggested that the 68-kd protein was widely distributed in the body and not specific to the inner ear. They speculated that this protein might instead represent a 70-kd heat shock
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protein (hsp 70), an inducible stress protein known to be uniquely associated with ulcerative colitis and progressive sensorineural hearing loss. IgG and IgM antibodies against heat shock proteins have been found in patients with certain rheumatic diseases.15,16 KHRI-3 is an antibody that binds the 68-kd protein from guinea pig inner ear membrane supporting cells. Infusion of this antibody results in hearing loss in experimental animals by binding with proteins on such cells. Disher et al17 have reported that some patients with autoimmune sensorineural hearing loss produce autoantibodies to guinea pig inner ear supporting cell antigen that are dispersed in a pattern similar to that found when KHRI-3 murine monoclonal antibody is injected experimentally. These investigators conclude that human autoantibodies and murine KHRI-3 antibody have the same protein target but that hsp 70 is not that target. Our patient was not tested by Western blot for 68-kd inner ear antigen. SUMMARY The patient described here had SNHL occurring in a context of systemic vasculitis including aortitis, aortic valve insufficiency, and arterial stenoses. Cardiovascular pathology was more consistent with TA, but SNHL was characteristic of CS. Yet, he did not satisfy basic criteria for CS, in that he had no clear evidence of nonsyphilitic interstitial keratitis. His manifestations are therefore similar to the aortitis syndrome described by Kanzaki et al.18 Thus, there was likely an overlapping of these 2 entities and is best described as “an aortitis syndrome with auditory disorder that is a variant of aortitis syndrome and Cogan’s syndrome.”19 We conclude that otolaryngologists and other practitioners who care for children should ensure that a diligent search be made for evidence of systemic vasculitis in patients referred for SNHL. REFERENCES 1. Kerr GS: Takayasu’s arteritis. Rheum Dis Clin North Am 21:1041-1058, 1995 2. Chynn EW, Jakobiec FA: Cogan’s syndrome: Ophthalmic, audiovestibular, and systemic manifestations and therapy. Int Ophthalmol Clin 36:61-77, 1996 3. Brogan PA, Dillon MJ: Vasculitis from the pediatric perspective. Curr Rheum Rep 2:411-416, 2000
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4. Johnston SL, Lock RJ, Gompels MM: Takayasu arteritis: A review. J Clin Pathol 55:481-486, 2002 5. Arend WP, Michel BA, Block DA, et al: The American College of Rheumatology 1990 criteria for the classification of Takayasu arteritis. Arthritis Rheum 33:11291134, 1990 6. Tagaki H, Mori Y, Iwat H, et al: Nondissecting aneurysm of the thoracic aorta with arteritis in systemic lupus erythematosus. J Vasc Surg 35:801-804, 2002 7. Seror O, Fain O, Dordea M: Aortitis with antiphospholipid antibodies: CT and MR findings. Eur Radiol 8:1373-1375, 1998 8. Vollertsen RS, McDonald TJ, Younge BR, et al: Cogan’s syndrome: 18 cases and a review of the literature. Mayo Clin Proc 61:344-361, 1986 9. Raza K, Karokis D, Kitas GD: Cogan’s syndrome with Takayasu’s arteritis. Br J Rheumatol 37:369-372, 1998 10. McCabe BF: Autoimmune sensorineural hearing loss. Ann Otol Rhinol Laryngol 88:585-589, 1979 11. Stone JH, Francis HW: Immune-mediated inner ear disease. Curr Opin Rheumatol 12:32-40, 2000 12. McCabe BF: Autoimmune inner ear disease: Results of therapy. Adv Otorhinolaryngol 46:78-81, 1991 13. Harris JP, Sharp PA: Inner ear autoantibodies in patients with rapidly progressive sensorineural hearing loss. Laryngoscope 100:516-524, 1990
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14. Billings PB, Keithley EM, Harris JP: Evidence linking the 68 kilodalton antigen identified in progressive sensorineural hearing loss patient sera with heat shock protein 70. Ann Otol Rhinol Laryngol 104:181-188, 1995 15. Yoo TJ, Du X, Kwon SS: Molecular mechanism of autoimmune hearing loss. Acta Otolaryngol 48:3-9, 2002 (suppl 5) 16. Winfield JB, Jarjour WN: Stress proteins, autoimmunity, and autoimmune disease. Curr Top Microbiol Immunol 167:161-189, 1991 17. Disher MJ, Ramakrishnan A, Nair TS, et al: Human autoantibodies and monoclonal antibody KHRI-3 bind to a phylogenetically conserved inner-ear-supporting cell antigen. Ann N Y Acad Sci 830:253-265, 1997 18. Kanzaki J, Ouchi T: Steroid-responsive bilateral sensorineural hearing loss and immune complexes. Arch Otorhinolaryngol 230:5-9, 1981 19. Kanzaki J: Immune-mediated sensorineural hearing loss. Acta Otolaryngol 514:70-72, 1994 (suppl) 20. De Paepe A, Devereux RB, Dietz HC, et al: Revised diagnostic criteria for the Marfan syndrome. Am J Med Genet 62:417-426, 1996 21. Snider AR, Enderlein MA, Teitel DF, et al: Twodimensional echocardiographic determination of aortic and pulmonary artery sized from infancy to adulthood in normal subjects. Am J Cardiol 53:218-224, 1984