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Show J. Clin. Neuro-ophthalmol. 5: 169-176,1985 <D 1985 Raven Press, New York Amaurosis Fugax and Retinal Vasculitis Associated with Methamphetamine Inhalation HAROLD E. SHAW, JR., M.D. JEFFREY G. LAWSON, M.D. R. DOYLE STULTING, M.D., Ph.D. Abstract A 26-year-old male drug abuser developed amaurosis fugax followed by retinal vasculitis in the right eye after nasal inhalation of methamphetamine. He gradually recovered, but required prolonged systemic corticosteroid therapy. We believe that the amaurosis fugax was due to drug-induced vasospasm and that the retinal vasculitis was a drug-induced hypersensitivity vasculitis. Introduction Numerous medical complications of illicit drug use have been documented, but specific ocular complications have been reported infrequently . To our knowledge, this is the first report of amaurosis fugax and retinal vasculitis associated with nasal inhalation of methamphetamine. Case Report A 26-year-old white male was seen with a history of 8-12 episodes of transient loss of vision in the right eye over the previous 18 hours. Each of the episodes was associated with a vague prodromal tingling sensation on the right side of his head followed by total or near total loss of vision in the right eye lasting 1-2 minutes. Each episode resolved completely and ther.e were no other associated symptoms. ApproXImately 36 hours prior to the onset of the visual disturbances he had sniffed methamphetamine mixed with mannitol through his right nostril. The patient had a long history of drug abuse From the Departments of Ophthalmology and Medicine, Greenville Hospital System, GreenvIlle, South CarolIna (HES, }GL); and the Department of Ophthalmology, Emory University Clinic, Atlanta, GeorgIa (RDS). Write for reprints to: Harold E. Sha~, Jr., M.D., 7-B Cleveland Court, Greenville, South Carohna 29607. September 1985 which included numerous classes of illicit drugs. He smoked marijuana and drank alcohol heavily and used intranasal cocaine and oral amphetamines occasionally, but he had not used drugs intravenously for several years. He had not recently used cocaine intranasally. Twelve years previously he had a left pyeloplasty for hydronephrosis. On three occasions he was treated for gonorrhea. His sexual contacts were strictly heterosexual. His general and ocular health had been good otherwise. Ocular examination on February 15, 1983, revealed 20/20 visual acuity in each eye. Confrontation and tangent screen visual field testing, external, pupillary, motility, slit lamp, and dilated ophthalmoscopic examinations were normal. Tensions by applanation were 18 mm of mercury in each eye. The patient was observed and after several hours he experienced sudden loss of vision with no light perception in the right eye. During the episode indirect ophthalmoscopy revealed generalized attenuation of the retinal arterioles in the right eye which lasted 45-60 seconds. As he began regaining vision, the retinal arterioles pulsated briefly and then returned to their normal caliber. No emboli were seen. Vision returned to 20/20 with no residual abnormal findings at that time (Fig. 1). Over the next 24 hours he experienced several more brief episodes at amaurosis in the right eye and then became asymptomatic. Three days later he awakened with persistent blurred vision in the right eye. Upon reexamination on February 21, his visual acuity was still 20/20 in each eye. Ophthalmoscopic examination revealed prepapillary vitreous cells, mild optic disc edema, irregular venous. dilatation, and fluffy white penvenous depOSits and sheathing in the posterior pole of the right eye (Fig. 2). The retinal periphery was normal. ~ fluorescein angiogram showed segmental penvenous leakage in the right eye (Fig. 3). The left eye was normal. General physical examination 169 Methamphetamine Inhalation (b) Figure la and lb. Ocular iundi iollowing amaurotic attack in the right eye. Note normal appearance in both eyes. disclosed no abnormalities. Treatment was started with prednisone 80 mg daily. A complete blood count, urinalysis, erythrocyte sedimentation rate, biochemical profile, antinuclear antibodies, rheumatoid factor, hepatitis B antigen, serum cryoglobulins, serum protein electrophoresis, fungal serologies, tox-oplasmosis titer, fluorescent treponemal antibody absorption test, urine culture for cytomegalovirus, immune complex Clq binding test, Raji cell immunoassay, and C4 levels were all normal. C3 levels were decreased to 63 mg/dl (n 83-177 mg/dl). The HLA type was A26, A28, B14, and Bw53. A tuberculin skin test was non- Journal of Clinical Neuro-ophthalmology Shaw, Lawson, Stuiting lAi) (b) Figure 2a and 2b. Right fundus at onset of retinal vasculitis. Note blurring of optic disc. irregular venous caliber. and perivenous dl'Pllsits ,lnJ sheathing. reactive. Blood cultures showed no growth. xray films of the chest and sacroiliac joints showed normal findings. An echocardiogram and a computerized axial tomogram of the brain and orbits with contrast enhancement were normal. September 1985 Over a 1O-week period, the patient's ocular inflammation improved. C3 levels returned to normal. With tapering of prednisone to 10 mgt day in May, vitreous haze increased and new perivenous deposits and hemorrhages, irregularities of venous caliber, and focal chorioretinal 171 Methamphetamine Inhalation Figure 3. Fluorescein angiogram of right fundus. late phase. shows perivenous staining. (al Figure 4a-c. Right fundus :.1 months after onset of retinal vasculitis. Note prepapillary vitreous haze. irregular wnous caliber. and perivenous hemorrhages and infiltratt'S. 172 Journal of Clinical Neuro-ophthalmology Shaw, Lawson, Stulting Ibl Ie) infiltrates developed in the right eye (Fig. 4). Prednisone was increased to 60 mg daily and he improved. He did well until October, when prednisone was tapered to 20 mg daily and he again developed increased vitritis, perivasculitis, and chorioretinitis in the right eye. Prednisone was increased to 80 mg daily and he again improved. He was treated with a gradually tapering dosage of prednisone over the next September 1985 6 months, during which time the inflammation was controlled, leaving preretinal gliosis and macular pigmentary changes in the right eye (Fig. 5). The left eye remained normal and no other systemic abnormalities developed. During that time he continued to drink alcohol and smoke marijuana, but he abstained from other drugs. Prednisone was discontinued and when the patient was last examined on April 17, 1984 173 Methamphetamine Inhalation Figure 5. Right fundus 14 months after onset of retinal vasculitis shows preretinal gliosis and macular pigment changes. There is no active inflammation. his visual acuity ..",as 20/20 and there was no evidence of active ocular inflammation. Discussion Methamphetamine is a member of the amphetamine group of sympathomimetic amines. It is a potent central nervous system stimulant and has been used extensively by drug abusers for its euphoric effects. A variety of psychiatric and medical complications have been attributed to methamphetamine but, to our knowledge, no complications related to intranasal methamphetamine use have been described. I In our patient, this unconventional route of administration appeared to playa major role in the initiation of ocular events. Within 36 hours of recreationally inhaling methamphetamine through his right nostril he began having multiple attacks of amaurosis fugax in the right eye. The exact mechanism by which this occurred is speculative. Amaurosis fugax usually signifies extracranial carotid occlusive disease, but other causes such as migraine, cardiac disease, and collagen vascular disorders are more likely in younger patients. 2- tl No underlying systemic abnormality was identified in our patient. Blindness due to retinal emboli from intranasal injections has been well documented, and in some cases vasospasm without emboli has been postulated. 9 - 11 The anterior and posterior ethmoid- 174 al arteries are branches of the ophthalmic artery and it is thought that retinal embolization occurs by retrograde flow through these anastomoses under the pressure of forceful intraarterial injection. In the absence of direct intravascular injection, however, this mechanism seems implausible in our patient. A more likely explanation is that the amaurosis fugax resulted from vasospasm due to the sympathomimetic effects of methamphetamine. The amphetamines are potent vasoconstrictors and diffuse vascular spasm after their ingestion have been described. 12 We postulate that a similar localized effect might have been precipitated by intranasal methamphetamine. Another possible explanation, in view of subsequent developments, is that the amaurosis fugax was due to vasospasm induced by vascular irritation associated with incipient retinal vasculitis. Whatever the mechanism, we believe that the time relationship between drug inhalation and onset of ocular symptoms, the proximity of the nasal absorption site to the ocular circulation, and the known pharmacologic properties of methamphetamine strongly implicate this agent as the cause of amaurosis fugax in our patient. Among the complications associated with methamphetamine abuse is a necrotizing angitis which involves mainly small and medium-sized arteries and has clinical, arteriographic, and histopathologic features strikingly similar to polyarteritis nodosa. 13 -18 Ocular involvement has Journal of Clinical Neuro-ophthalmology been mentioned, but not well documented in some of these casesY·14 Our patient developed retinal vasculitis in the right eye within 1 week after he inhaled methamphetamine, and we were able to observe him closely over an extended period of time. The differential diagnosis of retinal vasculitis includes nonspecific uveitis, ocular sarcoidosis, collagen vascular disorders, Eales' disease, pars planitis, Behcet's disease, infectious retinochoroiditis such as syphilis and toxoplasmosis, early bacterial endophthalmitis, perivasculitis associated with any severe intraocular intlammation, and chorioretinal emboli. 1'1-23 Our patient had none of these conditions. The retinal vasculitis which we observed was primaril~' a retinal phlebitis which was concentrated in the posterior pole of the eye and which was characterized by perivenous cuffing and sheathing, venous irregularities, retinal hemorrhages, exudates and edema, posterior vitritis, and ultimately preretinal gliosis and macular pigmentary changes. Early in the course of the vasculitis fluorescein angiography showed segmental leakage from retinal veins. Associated with the vasculitis was a transiently decreased C3 level. Ffytche has reviewed the clinical signs of retinal vasculitis and emphasized that most cases involve an immune complex disturbance affecting the retinal veins. 24 We believe that the findings in our patient were consistent with an immune complex mediated retinal vasculitis precipitated by methamphetamine inhalation. The evidence is now substantial that most vasculitis syndromes are related to deposition of immune complexes in vessel walls. 25 The conditions necessary for this to occur have been delineated in experimental models and involve the formation of soluble antigen-antibody complexes under conditions of antigen excess. Increased vascular permeability via platelet derived vasoactive amines, IgE mediated reactions, or other mechanisms leads to the deposition of immune complexes in vessel walls. Complement is activated, and polymorphonuclear leukocytes are attracted by chemotaxis to the site of immune complex deposition. There the polymorphonuclear leukocytes release proteolytic enzymes which cause necrosis of the vessel wall. This can result in vascular occlusion, hemorrhage, and ischemia of surrounding tissues. 25 - 28 The concentration of immune complexes in the circulation, the duration of their circulating half-life, the physical characteristics of the complexes, and the site of their deposition are factors which influence the resulting disease activity. Circulating immune complexes were not identified in our patient, September 1985 Shaw, Lawson, Stulting but that does not preclude immune complex mediated disease since complexes are often rapidly cleared from the circulation and may not be detectable. 25 We suggest that ischemia from vasospasm may have increased retinal vascular permeability, leading to the localized deposition of immune complexes and subseguent vasculitis. Although there is considerable overlap in the vasculitic syndromes, we believe that our case is best classified as a hypersensitivity vasculitis. 25,28 The hypersensitivity vasculitis syndromes are thought to be initiated by immune complex deposition and characteristically involve small vessels. A precipitating antigen, such as a drug, can generally be identified. Signs and symptoms usually develop within 1 week to 10 days after antigen exposure. Although the skin is most commonly involved, hypersensitivity vasculitis can affect any organ. The condition is usually self-limited, but can recur or become chronic. Treatment consists of removal of the offending antigen and use of corticosteroids in some cases, although no therapeutic modality has universally proven efficacy. Systemic corticosteroid therapy appeared beneficial in our patient, but prolonged treatment was reguired. As others have pointed out in describing complications attributed to methamphetamine, the multiplicity of substances used by most drug abusers and the potential contamination and lack of purity of those substances make it difficult to identify positivelr. a single drug as the cause of a complication. 1 -15 Whether the ocular events in our patient were due to the direct effect of methamphetamine or whether other factors might have been involved cannot be determined with absolute certainty. The circumstantial evidence is strong; however, methamphetamine taken intranasally can cause serious ocular conseguences. References 1. Yatsu, F. M., Wesson, D. R., and Smith, D. E.: Amphetamine abuse. In Medical Aspects of Drug Ahl/se, R. W. Richter, Ed. Harper & Row, Publishers, Hagerstown, Maryland, 1975, pp. 50-56. 2. Walsh, F. B., and Hoyt, W. F.: Clil/ical Nel/ro-ophthalmology (3rd ed.). Williams & Wilkins, Baltimore, 1969, pp. 1671- 1672; 1806. 3. Kearns, T. P.: Ophthalmology and the carotid artery. Am. J. Ophthalmol. 88: 714-722, 1979. 4. Caltrider, N. D., Irvine, A. R., Kline, H. J., and Rosenblatt, A.: Retinal emboli in patients with mitral valve prolapse. Am. f. Ophthalmol. 90: 534539, 1980. 5. Lesser, R. L., Heinemann, M. H., Borowski, H., 175 Methamphetamine Inhalation and Cohen, L. S.: Mitral valve prolapse and amaurosis fugax. ,. Clill. Ncuro-ophthalmol. 1: 153- lhO, IYH I. 6. Shaw, H. E., Osher, R. H., and Smith, J. L.: Amaurosis fugax associated with SC hemoglobinopathy and lupus erythematosus. Am. f. 0l'hthollllol, 87: 2HI-2H5, 1979. 7. Glaser, J. S.: Topical diagnosis: Prechiasmal visual pathways. In Clillical Ophthalmology, Vol. 2, T. D. Duane and E. A. Jaeger, Eds. Harper & Row, Publishers, Philadelphia, 1982, chap. 5, pp.6-9. 8. Troost, B. T.: Migraine. In Clinical Ophthalmology, Vol. 2, T. D. Duane and E. A. Jaeger, Eds. Harper & Row, Publishers, Philadelphia, 1982, chap. 19, pp. 11-12. 9. Byers, B.: Blindness secondary to steroid injections into the nasal turbinates. Arch. Ophthalmol. 97: 79-80, 1979. 10. Evans, D. E., Zahorchak, J. A., and Kennerdell, J. S.: Visual loss as a result of primary optic nerve neuropathy after intranasal corticosteroid injections. Am, f. Ophthalmol. 90: 641-644,1980. 11. Mabry, R. L.: Visual loss after intranasal corticosteroid injection. Arch, Otolaryngol. 107: 484486, 1981. 12. Bowen, J. S., Davis, G. B., Kearney, T. E., and Bardin, J.: Diffuse vascular spasm associated with 4-bromo-2, 5-dime-thoxyamphetamine ingestion. JAMA 249: 1477-1479, 1983. 13. Citron, B. P., Halpern, M., McCarron, M., Lundberg, G. D., McCormick, R., Pincus, 1. J., Tatter, D., and Haverback, B. J.: Necrotizing angiitis associated with drug abuse. N. Engl. f. Med. 283: 1003-1011,1970. 14. Halpern, M., and Citron, B. P.: Necrotizing angiitis associated with drug abuse. AJR 111: 663671, 1971. 15. Margolis, M. T., and Newton, T. H.: Methamphetamine ("speed") arteritis. Neuroradiology 2: 179-182,1971. . 16. Rumbaugh, C. L., Bergeron, R. T., Fang, H. C. H., and McCormick, R.: Cerebral angio- 176 graphic changes in the drug abuse patient. Radiology 101: 335-344, 1971. 17. Rumbaugh, C. L., Bergeron, R. T., Scanlan, R. L., Teal, J. S., Segall, H. D., Fang, H. C. H., and McCormick, R.: Cerebral vascular changes secondary to amphetamine abuse in the experimental animal. Radiology 101: 345-351, 1971. 18. Yu, Y. J., Cooper, D. R., Wellenstein, D. E., and Black, B.: Cerebral angiitis and intracerebral hemorrhage associated with methamphetamine abuse. f. Neurosurg. 58: 109-111, 1983. 19. Duke-Elder, S., and Dobree, J. H.: Diseases of the retina. In System of Ophthalmology, Vol. 10, S. Duke-Elder, Ed. C. V. Mosby, St. Louis, 1967, pp. 218-233. 20. Wise, G. N., Dollery, C. T., and Henkind, P.: The Retinal Circulation. Harper & Row, Hagerstown, Maryland, 1971, p. 208. 21. Yanoff, M., and Fine, B. S.: Ocular Pathology. A Text and Atlas, Harper & Row, Hagerstown, Maryland, 1975, p. 73. 22. Patrinely, J. R., Green, W. R., and Randolph, M. E.: Retinal phlebitis with chorioretinal emboli. Am. f. Ophthalmol. 94: 49-57, 1982. 23. Packer, A. J., Weingeist, T. A., and Abrams, G. W.: Retinal periphlebitis as an early sign of bacterial endophthalmitis. Am. f. Ophthalmol. 96: 66-71, 1983. 24. Ffytche, T. J.: Retinal vasculitis: A review of the clinical signs. Trans. Ophthal. Soc. U.K. 97: 457461, 1977. 25. Fauci, A. S., Haynes, B. F., and Katz, P.: The spectrum of vasculitis: Clinical, pathologic, immunologic, and therapeutic considerations. Ann. Intern. Med. 89: 660-676, 1978. 26. Cochrane, C. G.: Mechanisms involved in the deposition of immune complexes in tissues. f. Exp. Med. 134: 75s-89s, 1971. 27. Cochrane, C. G., and Koffler, D.: Immune complex disease in experimental animals and man. Adt'. ImmwlOl. 16: 185-264, 1973. 28. Moor~, P: M., and Cupps, T. R.: Neurological complications of vasculitis. Ann. 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