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Show Journal of Neuro- Ophthalinologij 15( 1): 1- 8, 1995. © 1995 Raven Press, Ltd., New York Microangiopathy of Brain, Retina, and Inner Ear Corey M. Notis, M. D., Robert A. Kitei, M. D., Maureen S. Cafferty, M. D., Jeffrey G. Odel, M. D., and John P. Mitchell, M. D. Microangiopathy of brain, retina, and inner ear is a rare syndrome manifesting as arteriolar occlusions of the brain, retina, and inner ear, with resultant encephalopathy, visual, and hearing loss. Despite exhaustive laboratory examinations in these patients, no evidence of a systemic disease can be found. We treated and followed an adolescent with this disorder who initially presented with a branch retinal artery occlusion. A unique finding in this case was retinal vessel wall hyperfluorescence noted five days prior to retinal infarction. The patient developed recurrent branch artery occlusions, sensorineural hearing loss, and central nervous system infarctions despite anticoagulation and immunosuppressive treatment. Key Words: Branch retinal artery occlusion- Hearing loss- Tinnitus- Transient ischemic attacks. Since 1973 reports in the literature have described a distinctive syndrome consisting of encephalopathy, hearing loss, and branch retinal arteriolar occlusions ( 1- 13). In 1979, Susac and colleagues ( 1) coined the term microangiopathy of brain, retina, and inner ear to describe this syndrome, and to date 24 cases have been published in the literature. The disease manifests as arteriolar occlusions of the brain, retina, and inner ear predominantly affecting women of childbearing age. Recently, cases have been reported involving young men ( 2- 3). While various etiologies have been proposed, an immunologic basis for the disease is most likely. A multiphasic illness, the disease is characterized by exacerbations with only partial recovery into lengthy remissions. The following is another example of this syndrome, which presented with a branch retinal arteriolar occlusion. Manuscript received February 18, 1993; accepted April 17, 1993. From the Departments of Ophthalmology ( C. M. N., R. A. K., J. P. M.) and Neurology ( M. S. C.), The St. Luke's/ Roosevelt Hospital Center; Department of Ophthalmology ( J. G. O), Columbia Presbyterian Medical Center, New York, New York, U. S. A. Address correspondence and reprint requests to Dr. Corey M. Notis, 1044 Fifth Avenue, New York, NY 10028, U. S. A. REPORT OF A CASE A 19- year- old woman complained of blurry vision in her left eye preceded by a bifrontal headache and flashing lights in December 1991. Her past medical history was significant for the use of Triphasyl, an oral contraceptive, for 15 months without cigarette use. Additionally, she had a 10- month history of headaches occasionally associated with scintillating scotoma. Eight months prior to this event, she had an episode of transient left-sided numbness. Visual acuity was 20/ 20 OD, 20/ 30 OS, and a left afferent pupillary defect was present. The slit- lamp examination was unremarkable. Dilated fundus examination revealed the presence of left superotemporal and superonasal branch retinal arteriolar occlusions ( BRAOs). Fluorescein angiography confirmed the nonperfusion 2 C. M. NOTIS ET AL. of these arterioles, and revealed vessel wall hyperfluorescence with late leakage in the arteriolar segments immediately proximal to the nonperfused segments ( Fig. 1). No evidence of ocular inflammation, retinal vessel sheathing, or venous involvement was noted. A presumptive diagnosis of vaso- occlusive phenomenon secondary to oral contraceptives with atypical migraine headaches was made. The oral contraceptives were discontinued and migraine prophylaxis with Inderal and Elavil was initiated. Initial laboratory studies consisted of a normal complete blood count, prothrombin time, partial thromboplastin time, antithrombin III activity, an-tithrombin III antigen, Lyme antibody, protein C, and protein S ( free). Sickle prep, rapid plasma re-agin, fluorescent treponeamal antibody absorption, antinuclear antibody, rheumatoid factor, and lupus anticoagulant ( DTi, dRVV), were negative. Toxoplasmosis titers were 407 IgG EU/ ml ( strongly positive), 45 IgM EU/ ml ( equivocal). A computed tomography ( CT) scan of the brain was performed and was normal. Carotid Doppler and venous Doppler studies were normal. Transesophageal echocardiogram showed mild mitral valve prolapse without vegetations. One week after the initial event the patient experienced a severe right- sided headache, with flashing lights and blurred vision in the right eye. Examination at this time revealed the presence of a right superotemporal branch retinal arteriolar occlusion. The fluorescein angiogram, however, did not show nonperfusion in the supertemporal vessel, but did demonstrate hyperfluorescence of an inferotemporal arteriole ( Fig. 2). The patient was treated with a regimen of intravenous heparin and prednisone 60 mg p. o. daily. Additional diagnostic studies were obtained. Hemoglobin electrophoresis, and serum viscosity was normal. HIV antibody, cryoglobulins, and antineutrophil cytoplasmic staining were negative. Serum antinuclear antibody was positive at 1: 40 ( speckled), but hemolytic complement levels 109 HU ( 100- 300) and autoantibodies ( ENAI, RNP, Sm, ENA II SS-A, and SS- B) were negative. Serum protein S ( total) was 40% ( 62- 170), and serum protein S ( free) quantitative was 20 mcg/ ml ( 13- 32). Lumbar puncture yielded CSF protein 35 mg/ dl, glucose 62 mg/ dl, VDRL negative, and no oligoclonal bands. Cerebral angiogram was normal. A T2- weighted MRI revealed a hyperintense lesion in the left pons, consistent with an infarction ( Fig. 3). Skin and muscle biopsy revealed no evidence of a systemic vasculitis. Five days after the initiation of anticoagulation, the patient developed an episode of flashing lights and blurred vision in the right eye without an associated headache. Examination revealed the presence of a right inferotemporal branch retinal arteriolar occlusion, in the exact distribution of the arteriole that was noted to be hyperfluorescent on fluorescein angiogram approximately 1 week prior ( Fig. 4). Additional treatment with pyrimethamine and sulfadiazine was then initiated for a possible FIG. 1. Left eye, November 1991. A: Fundus photograph revealing nerve fiber layer edema from superotemporal and superonasal branch artery occlusions ( arrows). B: Fluorescein angiogram demonstrating segments of arteriolar nonperfusion. Note the hyperfluorescence of the vessel proximal to the sites of obstruction ( arrows), as well as retrograde filling of the occluded arteriole. / Neuw- Ophthalmol, Vol. 15, No. 1, 1995 MICROANGIOPATHY OF THE BRAIN, RETINA, AND INNER EAR 3 FIG. 2. Right eye, December 1991. A: Fundus photograph revealing superotemporal branch artery occlusion. B: Fluorescein angiogram demonstrating hyperfluorescence of the inferior vessel. occult toxoplasmosis infection. The patient remained stable without any further episodes for 2 weeks, and was discharged after being changed to oral anticoagulation. In February 1992 the patient underwent visual field testing, which revealed dense scotomas consistent with the distribution of her retinal infarctions. The patient voluntarily stopped the prednisone in March 1992 and subsequently presented to the hospital complaining of shadows in the peripheral vision of the right eye. In addition, she complained of pain and diminished hearing in her right ear. Examination of the right eye revealed the presence of multiple nonperfused arteriolar segments in the nasal retina. Some of these nonperfused arteriolar segments were noted to contain a FIG. 3. December 1991. MRI scan, T2- weighted image revealing a hyperintense lesion in the left pons ( arrow). FIG. 4. Right eye, December 1991. A: Fundus photograph revealing inferior branch arteriolar occlusion. Compare distribution of infarction to fluorescein angiogram taken 1 week prior as in Fig. 2B. ] Neuro- Ophthalmol, Vol. 15, No. 1, 1995 4 C. M. N0T1S ET AL. white material within the vessel lumen that did not appear to move during examination. Fluorescein angiogram confirmed these observations and revealed new areas of arteriolar hyperfluorescence that were clinically undetected ( Fig. 5). A repeat magnetic resonance imaging ( MRI) was unchanged, however, pure tone audiometric testing revealed mild low- frequency hearing loss in the right ear. All previous laboratory blood tests were repeated and were all noted to be within normal limit. In May 1992 the patient developed progressive hearing loss, pain, and tinnitus in the right ear as well as a transient episode of left- sided weakness. Physical examination revealed a normal mental status, hyperactive reflexes with a mild pronator drift, and absent Babinski signs. No abnormal arteriolar segments were noted, and this was confirmed by fluorescein angiography. Optic nerve atrophy was present bilaterally. Audiometric evaluation revealed moderate low- frequency hearing loss in the right ear presumably of cochlear origin ( Fig. 6). MRI revealed a new infarction in the right thalamus ( Fig. 7). Visual fields, however, demon- • fy< .'-. j ^ H tjjj*] ILi "'• m t v*.. A V ^ * 1. > k a£ 3 HM " * • * * hi*> . * - J , * * * < f% > k <^ s | r * & . sr FIG. 5. Left eye, March 1992. A: Fundus photograph demonstrating arterioles with absent blood column ( closed arrow), and white material within the arteriole ( open arrow). B, C: Fluorescein angiogram demonstrating progressive segmental arteriolar hyperfluorescence ( closed arrow), with an area of distal nonperfusion. Note hyperfluorescence of white material within arteriolar lumen ( curved arrow). D: Multiple areas of segmental vessel wall hyperfluorescence ( open arrows). ) Neuro- Ophllmlnwl, Vol. 15, No. 1, 1995 MICROANGIOPATHY OF THE BRAIN, RETINA, AND INNER EAR 5 " 10 0 10 20 30 | 4 0 ISD 1 60 2 70 ? 8 0 90 100 110 120 130 PURE TONE AUDIOGRAM m<> 125 250 500 1000 2000 4000 8000 12000 HERTZ WEBER < > V 750 1600 3000 i "- V \< l 6000 1 10000 ! 10 0 10 20 30 40 50 60 70 80 90 100 110 120 130 FIG. 6. May 1992. Pure tone audiogram demonstrating low- frequency hearing loss AD. strated a mild improvement in both eyes. The patient was continued on Coumadin and prednisone 40 mg was restarted daily. In June 1992 the patient noted a worsening of hearing in both ears. Audiometric evaluation at this time revealed moderate low- frequency hearing loss in both ears ( Fig. 8). Immuran was added to the medical regimen when cyclophosphamide was declined by the patient. In July 1992 audio-metric evaluation revealed a 20% improvement in the hearing of the right ear. Ophthalmic examination at this time revealed a macular star exudate pattern in the right eye. The left eye was without change. Repeat MRI showed no change as well. DISCUSSION Our patient demonstrated an association of branch arteriolar occlusions, hearing loss, and multiple central nervous system infarctions without evidence of a systemic disease. We believe this represents a case of microangiopathy of brain, retina, and inner ear as described by Susac and colleagues ( 1). The first published report of this syndrome we can find in the literature was in 1973 by Pfaffenbach and Hollenhorst ( 4), who presented two patients with a dementia, long tract signs, and branch retinal arteriolar occlusions. These cases were attributed to systemic lupus erythema-tosis, but no clinical or laboratory evidence for this diagnosis was present. Additionally in 1973, Wei-dauer and Tenner ( 5) described women with bilateral sensory neuronal hearing loss with subsequent retinal artery occlusions without evidence of a systemic disorder. Most often the neurologic abnormalities, such as altered cognitive function, predominate early in the disease process. This is only the second case whereby the presenting sign was a branch arteriolar occlusion. The history of atypical headaches, oral contraceptives, and mitral valve prolapse was initially felt to be contributory, as these elements can initiate an embolic or occlusive retinopathy and lead to recurrent branch retinal arteriolar occlusions ( 15). A unique ophthalmic finding in our case is the premorbid vessels wall hyperfluorescence at least 5 days prior to an actual retinal infarction, as depicted in Figs. 2B and 4. This is the first example of active disease progression, and has not been previously reported in the literature. Another interesting finding was the progressive retinal arteriolar segment hyperfluorescence demonstrated in Fig. 5. It would seem that these relatively long-diseased segments are responsible for the distal arteriolar occlusions. The arteriolar hyperfluorescence with subsequent leakage would certainly point to an underlying endothelial defect. / Neuro- Ophthalmol, Vol. 15, No. 1, 1995 6 C. M. NOTIS ET AL. FIG. 7. May 1992. MRI, T2- weighted image revealing right thalamic infarction ( arrow). Note multiple, small hyperintense lesions ( open arrows). Many of the ophthalmologic findings in our case have been noted previously in the literature ( 1- 14). The white material noted in the arteriole may represent aggregations of immune complexes themselves, or merely debris from the damaged endothelium. This white matter has only been seen distal to the diseased arteriolar segments, and would therefore appear to be a result of the arteriolar occlusions, rather than a causative factor ( 13). The white matter was not seen in the posterior pole nor in association with a nerve fiber layer infarction. It is not clear, however, whether this is real, or due to obscuration of the white material by the nerve fiber edema. On fluorescein angiography the white material was noted to hyperfluoresce, but the significance of this too is unclear. Throughout all ophthalmic examinations there was no evidence of ocular inflammation or cells within the vitreous, vessel sheathing, or venous involvement. In most reported cases, the eye findings were late in the course of the disease. This may be due to the peripheral nature of many of the described lesions in addition to an often altered mental status of the patient. The neurologic abnormalities often predominate early in the course of the disease, although this was clearly not the case in our patient. Personality changes, including paranoia and depression are often early manifestations, and followed by memory loss, dementia, hyperactive reflexes, Babin-ski's sign, nystagmus, dysmetria, and seizures in a few. These are generally the most debilitating defects to the patients. Hearing loss has been noted in all cases when pure tone audiometric testing was available, presumably secondary to occlusions of the cochlear end arterioles of the inner ear. The low frequencies are most often affected initially, but it may progress to involve all frequencies. Many patients, in addition, have complained of tinnitus, as did our patient. Extensive laboratory work- up of patients with this syndrome has been both exhaustive and fruitless. Common laboratory abnormalities have been noted in other patients, including increased CSF protein, mild lymphocytosis, and an elevated sedimentation rate, but these appear to have no diagnostic or prognostic importance. Many patients have had mild elevated ANAs, but all other serologies for systemic lupus erythematosus were negative ( 1,7,8,13). It is unclear whether these an-tiphospholipids are involved in the occlusive events. A recent case was reported involving a patient with elevated anticardiolipin antibodies, but this most likely represents a separate, though similar, clinical entity ( 6). Echocardiogram did reveal mitral valve prolapse in our patient, and a patent foramen ovale in a patient previously described, but the clinical significance of these findings remains unclear. CT scan, carotid Doppler and venous Doppler studies have been normal in all patients when tested, as was cerebral angiography, with the exception of one patient, revealing mild changes consistent with a small vessel disease. MRI, when performed, has consistently revealed hyperintense images on a T2- weighted image consistent with small central nervous system ( CNS) infarctions. These small hot spots were noted in our patient in addition to the larger pontine and thalamic infarctions described. Pathology has been confined to the CNS as a result of brain biopsies performed in three patients ( 1,8,11). This revealed sclerosis of the media and adventitia in cortical and pial vessels consistent with a healed angiitis. A second patient revealed multiple cortical microinfarctions, while a third described microinfarctions in both the white and gray matter, as well as microangiopathic changes with thickened arteriolar segments, staining intensely for lamin and fibronectin. In all of the brain biopsy specimens there was no evidence of inflammation. Foaming macrophages have been noted in two of the three patients. / Neuro- Ophtlwlmol, Vol. 15, No. 1, 1995 MICROANGIOPATHY OF THE BRAIN, RETINA, AND INNER EAR 7 FIG. 8. June 1992. Pure tone audiogram demonstrates moderate hearing loss AU. Compare with Fig. 6. " 10 0 10 20 30 2 40 5 50 S 60 2 70 5 so 90 100 110 120 130 12 PURE TONE AUDIOGRAM m,> 3 250 500 1000 2000 4000 8000 12000 HERTZ WEBER 750 1500 3000 6000 <: 10O00 10 0 10 20 30 40 50 60 70 80 90 100 110 120 130 The pathogenesis of this syndrome is unclear. It is most likely related to the distribution of the lesions, as described by Monteiro ( 7,8), noting that the arterioles of the retina and inner ear have barriers analogous to the blood- brain barrier of the CNS. The endothelium of the cells contain specialized tight junctions that are not found elsewhere in the body. Disease of the structural, functional, or antigenic features unique to these endothelial cells could conceivably cause alteration of the normal endothelial surface, with resultant occlusion of these vessels. This would also most clearly explain the finding demonstrated by fluorescein angiography. A coagulation abnormality is a less likely explanation for this syndrome. Gordon and coworkers ( 9), recently successfully treated an affected patient with anticoagulation alone, but our patient continued to have recurrences despite therapeutic anticoagulation. Microembolization remains a possible etiology, as it would explain the late fluorescein staining of the vessel wall proximal to the site of the arteriolar occlusions. Since the disease has predominately affected women, ages 18 to 42, an immunologic disorder seems likely. This could be due to direct antibody-mediated endothelial damage, or secondary to an immune complex disease. This is also evident by the similarity of this syndrome to other immunologic disorders, such as systemic lupus erythematosus or isolated angiitis of the CNS. Interestingly, oral contraceptives may serve to initiate and modify the disease process, as several of the reported cases have occurred among women who were using birth control drugs or were pregnant. It has been clearly demonstrated that either of these states can alter the coagulation status. Additionally, studies have demonstrated decreased cell-mediated immune response in the normal pregnancy ( 16,17). The differential diagnosis of this syndrome is quite large and has been covered extensively by Coppeto and Monteiro ( 7,8). Briefly, it includes systemic lupus erythematosis, polyarteritis nodosa, allergic vasculitis, granulomatous angiitis ( 18), atypical Cogan syndrome, systemic necrotizing vasculitis, Wegner granulomatosis, thrombocytopenic purpura, thromboangiitis obliterans, and multiple emboli. In addition, cases of central nervous system microvascular occlusive disease have recently been described in the literature ( 19). Regarding our patient, there were no laboratory findings or clinical features to support any of these aforementioned diagnoses. The treatment for microangiopathy of the brain, retina, and inner ear is unclear. Most authors would agree that immunosuppressive therapy is indicated. Whether this in fact alters the disease ] Neuro- Ophthalmol, Vol 15, No. 1, 1995 8 C. M. NOTIS ET AL. course in any way remains in dispute. While some authors have noted there to be no recurrences of the disease after intense immunosuppression with agents such as cycophosphamide, it is conceivable that the disease may spontaneously remit. Our case exemplifies the difficulty in managing patients with this illness, as the combination of steroids and anticoagulation was not enough to stem the disease process. As the deficits progressed and worsened, we felt it necessary to pursue more aggressive treatment regimens. It is possible that with the initial use of more potent immunosuppressive therapy, the disease process may be cut shorter with an improved prognosis. However, this must be balanced against treating an idiopathic disease with potentially fatal agents. The prognosis of patients with this disease is exceedingly variable. While in some patients the disease may remit after 1 month, there are others resigned to a state of dementia, with severe visual and auditory deficits. It would seem most likely that this disease represents a continuum ranging from idiopathic recurrent branch arteriolar occlusions, without any further episodes, to a fullblown course with resultant blindness, deafness, and encephalopathy. It is most certainly a fascinating illness, and perhaps as more cases become recognized, a better understanding of the disease, the spectrum of its presentation, pathogenesis, and treatment will be gained. REFERENCES 1. SusacJO, HardmanJN, SelhorstJB. Microangiopathy of the brain and retina. Neurology 1979; 29: 313- 6. 2. Aicardi J. Diseases of the nervous system in childhood. London, England: MacKeith Press, 1992; 885. 3. Petty GW, Yangihara T, Bartleson JD, et al. Retinocochleo-cerebral vasculopathy. Ann Neurol 1991; 30: S245. 4. Pfaffenbach DB, Hollenhorst RW. Microangiopathy of the retinal arterioles. JAMA. 1973; 225: 480- 3. 5. Weidauer H, Tenner A. Bilateral acute hearing loss with a transient occlusion of the retinal artery on both sides. / Laryngol Rhinol Otol 1973; 52: 121- 8. 6. Nicolle MW, McLachan RS. Microangiopathy with retinopathy, encephalopathy, and deafness ( RED- M) and systemic features. Semin Arthritis and Rheum 1991; 21: 1283- 8. 7. Coppeto JR, Currie JN, Monteiro MLR, Lessell S. A syndrome of arterial occlusive retinopathy and encephalopathy. Amer } Ophthalmol 1984; 98: 189- 202. 8. Monteiro MLR, Swanson RA, Coppeto JR, et al. A microangiopathic syndrome of encephalopathy, hearing loss and retinal arteriolar occlusion. Neurology 1985; 35: 1113- 21. 9. Gordon DL, Hayreh SS, Adams HP. Microangiopathy of the brain, retina and ear: improvement without immunosuppressive therapy. Stroke 1991; 22: 933- 7. 10. MacFadyen DJ, Schneider RJ, Chisolm IA. A syndrome of brain, inner ear and retinal microangiopathy. Can ] Neurol Sci 1987; 14: 315- 8. 11. Heiskala H, Somer H, Kovanen J, et al. Microangiopathy with encephalopathy, hearing loss and retinal arteriolar occlusions: two new cases. / Neurol Sci 1988; 86: 238- 50. 12. Bogousslavsky J, Gaio JM, Caplan LR, et al. Encephalopathy, deafness and blindness in young women: a distinct retinocochleocerebral arteriolopathy? / Neurol Neurosurg Psychiatry 1989; 52: 43- 6. 13. Gass JDM, Tiedeman J, Thomas MA. Idiopathic recurrent branch retinal arterial occlusion. Ophthalmology 1986; 93: 1148- 57. 14. Johnson MW, Flynn HW Jr, Gass JDM. Idiopathic recurrent branch retinal arterial occlusion. Arch Ophthalmol 1989; 107: 757. 15. Brown GC, Magaral LE, Shields JA, et al. Retinal artery obstruction in children and young adults. Ophthalmology 1981; 88: 18- 55. 16. Smith JK, Caspary EA, Field EJ. Lymphocyte reactivity to antigen in pregnancy. Am ] Obstet Gynecol 1976; 85: 94- 9. 17. Sridama VE, Pacini F, Yang SL, et al. Decreased levels of helper T cells: a possible cause of immunodeficiency in pregnancy. N Engl J Med 1982; 307: 353- 6. 18. Kolodny EH, Rebez JJ, Caviness S, Richardson EP. Granulomatous angiitis of the central nervous system. Arch Neurol 1968; 19: 510- 24. 19. Grand MG, Kaine J, Fulling K, et al. Cerebroretinal vasculopathy: a new hereditary syndrome. Ophthalmology 1988; 95: 649- 59. / Neuro- Ophthalmol, Vol. 25, No. 1, 1995 |
