SURVEY OF OPHTHALMOLOGY VOLUME25*NUMBER Z=SEPTEMBER-OCTOBER 1980 CLINICAL CHALLENGES RONALD M. BURDE AND PAUL HENKIND, EDITORS Significance of Scintillating Scotoma of Late Onset LAWRENCE A. RAYMOND, MARY ANN MILLER, B.S. M.D., GEORGE KRANIAS, M.D., HELEN GLUECK, M.D., AND Tke Retina and Vitreous Service of the Department of Ophthalmology. and the Department of Pathology, University of Cincinnati Medical Center, Cincinnati, Ohio Scintillating hemianopic scotomas are usually caused either by migraine or, more rarely, vertebral-basilar insufficiency. We report two patients in whom this symptom was probably caused by platelet microthrombi or microemboli in pial vessels of the visual cortex. These patients were similar in that they had scintillating scotomas which began after the age of fifty and abnormal platelet aggregability. Since Abstract. increased platelet aggregability is associated with cerebral vascular accidents and is treatable, older patients who develop teichopsias should have appropriate hematological tests. (Sun Ophthalmol 25: 107- 113, 1980) Key words. - T scintillating estrogen scotoma l l migraine teichopsia l he scintillating hemianopic scotoma begins often as a luminous, zigzag, shimmering sensation at its outer boundary, expanding toward the periphery and lasting for ten minutes or longer.‘J* The onset of these scotomas after the fortieth year of age is rare and should arouse suspicion that the patient has another cerebral vascular disease.” Scintillating scotomas of late onset have been described with cerebral vascular insufficiency,‘” systemic lupus erythematosus (SLE),’ estrogens,88 migraine,12 mitral valve prolapse syndrome (Barlow’s syndrome),2’ and after cardiac surgery.6 platelet aggregability transient cerebral ischemia l We report two patients who experienced their first teichopsias after the age of fifty. These teichopsias of late onset have received little attention from ophthalmologists. The confusion with migraine in the stroke-prone age warrants the description of this ischemic entity. Case Reports CASE 1 A 51-year-old medical secretary had her first scintillating scotoma in early February 1977 while driving home. She noted the upper right portion of a stopsign was missing when 107 108 Surv Ophtholmol 25 (2) September-October RAYMOND 1980 viewed by either eye; a crescent of bright colors formed the outer edge of the scotoma. The episode persisted for twenty minutes. On May 7, 1977, a similar attack occurred while she was in a room lit only by candlelight. She had not had “sick” headaches with nausea, vomiting, speech difficulty, weakness, ataxia, epilepsy, or a family history of migraine. One episode of teichopsia was followed by transient hemihypesthesia. She had taken conjugated equine estrogen (Premarin@) 1.25 mg daily for the past eight years since a hysterectomy and bilateral oophorectomy. Her eyes and visual field were normal. A neurosurgeon found no abnormalities when he examined her; there were no bruits in the neck or clinical features of SLE. Cardiac evaluation did not reveal a midsystolic click and late systolic murmur of the mitral valve prolapse syndrome or murmur of mitralannulus calcification. Serum antinuclear antibodies (ANA) and the Westergren erythrocyte sedimentation rate were normal. Radiography of the skull and computerized axial tomography with contrast were normal. Arteriography of the aortic arch, cervical vessels vessels and the intracranial demonstrated no abnormality. During the arteriogram the patient had a scintillating scotoma in the left visual field which persisted for at least ten minutes. We suspected that her scintillating scotomas were related to platelet microthrombi or microemboli in the pial vessels of the visual cortex.‘5 While on 300 mg dipyramidole (Persantin”‘) and 900 mg aspirin daily to prevent future platelet aggregation,25*32 she experienced only two abortive visual episodes lasting two minutes each. Her platelet aggregability was studied after stopping aspirin, dipyramidole and conjugated equine estrogen for ten days. Platelet aggregation with adenosine diphosphate (ADP), epinephrine, and collagen was normal as compared to a normal control.‘4 Following 16 days of oral estrogen, aggregation with all three aggregating agents was markedly increased with standard dilutions of these agents, as compared with the previous studies and a second normal control.” During these 16 days the patient experienced three classic scintillating scotomas. Because she refused to discontinue the use of estrogen, the dose was reduced to 0.625 mg daily and aspirin and ET AL dipyramidole were resumed. No teichopsias have occurred since. CASE 2 A 7%year-old right-handed physician had the first of several scintillating scotomas which persisted for about twenty minutes at the age of 65 years. He had had similar attacks about twice a year since then; they were more frequent in his left hemianopic field, but occasionally occurred in the right. He did not have “sick” headaches, numbness in the extremities, speech difficulty, weakness, ataxia, epilepsy, or family history of migraine. Propranolol hydrochloride (Inderalm) and methyldopa (Aldomet@) controlled his blood pressure at 150-160/90-100. He had a dissecting abdominal aneurysm resected with replacement by an aortic graft in May, 1975, and successful bilateral retinal detachment surgery in July, 1975. In November, 1977, his best corrected vision was limited to the counting of fingers at eight feet in the right eye and 20/60 in the left eye. Visual fields were full except for a small central scotoma in the right eye. The poor vision could be explained by the previous retina1 detachment, which involved the macula of the right eye. Mild lenticular changes were in the left eye. The neurological examination was normal. There were no bruits. Radiographs of the skull and an electroencephalogram were not remarkable. No recommendation for further evaluation or treatment was made because the condition remained stable for ten years. In early September, 1978, the patient experienced transient confusion and difficulty in writing and mathematics. No permanent localizing neurological signs were discovered. On September 8, 1978, computerized axial tomography (CAT) revealed an almost totally calcified 1.5 cm aneurysm of the left internal carotid artery, probably just above the origin of the ophthalmic artery. Multiple old infarcts were noted in both cerebral hemispheres, including the right frontal lobe, with some cerebra1 atrophy. A small low density area, which enhanced with contrast material, was present in the left parietal region, suggesting an infarct less than two weeks old. Another small, low density area in the left internal capsule near the genu represented either a new or old infarct (Figs. 1 and 2). On September 9, 1978, the patient 109 CLINICAL CHALLENGES FIG. I. (Case 2). Multiple infarcts (arrows) on computerized axial tomography (CAT) scan one day prior to right hemiparesis. FIG. 2. (Case 2). Left presellar calcified aneurysm (arrow) above the origin of the ophthalmic artery on CAT scan. suddenly developed right hemiparesis and difficulty expressing himself. Although he was readmitted to the hospital, he refused to have cerebral arteriography performed. He was treated with anticoagulants (heparin and Coumadin@). He was walking when discharged seven weeks later. In early December, 1978, he lost vision in the left eye for two hours. When we examined him several days later we found two shiny, orange emboli in the arterioles of the left retina. The carotid pulses were good and we heard no cervical bruits. His platelet aggregability was markedly increased with ADP, epinephrine, and collagen when compared with the control.44 The glucose tolerance test was normal. Because of a prior bleeding prepyloric ulcer, he was treated with 300 mg of aspirin only twice weekly along with the Coumadin@?9 On March 17, 1979, the patient experienced a sudden blackout; echocardiogram was suggestive of aortic dissection. He died on March 23. Autopsy demonstrated no prolapsed mitral valve, mitral-annulus calcification, or platelet-fibrin thrombus adherent to the valves. Dissection of the ascending aorta associated with an intimal tear was found. Permission was not granted for examination of the central nervous system. cinations of retinal or vitreous origin may be confused with scintillating scotomas. Although there are exceptions, photopsias lasting for a few seconds or less may occur with acute posterior vitreous separation,43 retinal emboli,‘5’30 retinal tear,43 retinal detachment,43 and Irvine-Gass syndrome.18 Brief punctate phosphenes have been described with acute optic neuritis.B Multiple firefly-like flashes, lasting minutes to days, are seen in paracarcinomatous retinal receptor degeneration, where the lung is usually the distant site of cancer.‘O Occipital arterio-venous malformations are characterized by brief light flashes, generalized seizures, and cranial bruits.45 Discussion llNFORMED VISUAL HALLUCINATIONS Photopsias or unformed visual hallu- LASHLEY’S SCINTILLATING SCOTOMA Lashley,20 a neurophysiologist, mapped his own expanding scintillating scotomas of migraine. Starting on either side of fixation, the scotoma subtended less than one degree. Over a twenty minute period, it drifted toward the temporal field of one side, increasing in size. Its shape was maintained during this spread. The scotoma was symmetrical in both eyes. Its leading edge was the fortification figures, consisting of luminous, dancing, angular lines. Rarely, there was complete hemianopia. He did not suffer the headache at the conclusion of the scotoma. LashleyZO predicted that the fortification figures were a function of the anatomic substrate of the visual cortex. Hoyt and Walsh4’ Surv Ophtholmol 110 25 (2) September-October 1980 RAYMOND ET AL aminobutyric acid (GABA) and 3’, 5’ cyclic adenosine monophosphate (cyclic AMP) indicate that ischemia occurs in both migraine and TIA, but does not differentiate them.49 Angiography in either condition rarely reveals a vascular lesion to explain the SPREADING CORTICAL DEPRESSION OF LEA0 teichopsias because they are transient and apLashleyzO calculated a rate of 3 mm/min parently due to alterations in the cerebral microcirculation.10.‘1+7 for the propagation of the scintillating disturThe exacerbation of a scintillating scotoma bance in his visual cortex. Milner3’ hypothesized that this visual phenomenon is with arteriography in the patient described in related to the spreading depression (SD) of Case I strongly suggests migraine. This increased morbidity of arteriography in Leao,21,22because they both have a striking migraine patients stresses the importance of similarity in their rate of spread. The SD of cortical activity of Leao,21~22+‘7 discovering by other means whether the scotoma is described in experimental animals, consists of patient with a scintillating Five of 27 migraine patients a marked reduction of electrical activity, migrainous. 23.33,37 appearing first in the area stimulated and ( 19%) experienced neurological complications with carotid angiography.33 However, the spreading out from there; this negative phase overall complication rate in 604 arteriograms is preceded and succeeded by smaller in 5000 amplitude positive phases. Concurrently, the was 4.6%.33 More recently, pial veins acquire an arterial hue and their arteriographies, Mani*” noted a 1.6% overall flow increases, suggesting the possibility of complication rate, including a 0.02% mortality rate. arteriovenous shunting. FisherI recently described 37 patients with SD can be elicited by mechanical, elecvisual transient migrainous accompaniments trical, photic, thermal, and chemical stimuli, (TMAs) of late onset with normal arterial occlusion, and intense neuronal angiography. He believed a strong argument stimulation.21~27~46 Recently, cortical glucose can be made for the migrainous nature of utilization has been found to be increased such transient deficits despite the absence of during SD and in columnar units running prior headache or transient attacks. perpendicularly through the cortex during Both conditions lack clinicopathological recovery from SD.” that correlation. A rare exception is reported by Hoyt and Walsh I7 hypothesized spreading cortical events may be initiated by Polyak.36 He describes the case of F. B. Mallory, the eminent pathologist, who had a a focus of ischemia or chemovascular permanent visual field defect after a scintillatdecompensation resulting in a scintillating ing scotoma of migraine. A shrunken malacic scotoma. scar in the lower calcarine lip of the right ocPROBLEMS DIFFERENTIATING MIGRAINE cipital lobe was discovered at autopsy. hypothesized that the orderly, repetitive patterns in columnar units found in Hubel and Wiesel’s’6*‘7 surface maps of the cat’s visual cortex were similar to Lashley’s fortification figures. AND VERTEBROBASILAR ISCHEMIC TRANSIENT ATTACKS There are problems in differentiating the scintillating scotomas of vertebrobasilar transient ischemic attacks (TIAs) and migraine. The teichopsias are closely akin, if not identical.15+7 Headache may sometimes follow a TIA I5 Yet, migrainous scotoma with no headache following has been described$s3 Alvarez* reported its occurrence in 12% of men and 0.7% of women. A family history of migraine lends support to the diagnosis. The nonmigrainous scintillating scotoma is difficult to diagnose if the patient has a past history of migraine in youth. Cerebrospinal abnormalities of gamma- ETIOLOGY AND PATHOCENESIS SCINTILLATING OF TIA AND SCOTOMA Hoyt hypothesized that some scintillating scotomas of late onset may be due to microemboli.16 Many other TIAs are due specifically to platelet, cholesterol or fibrin emboli arising from an atherosclerotic plaque.53 Clinical attention has been drawn to platelets because of their central importance in the formation of arterial thrombi and initiation of vascular injury.16*25Histologic study of platelet emboli reveals aggregates of platelets without fibrin, cholesterol, or red blood cells.28 Litman and Friedman*’ hypothesized that increased aggregability of platelets may allow CLINICAL CHALLENGES FIN;.3. Possible pathogenesis of scintillating scotoma of late onset. Pl. refers to plasma. (Modified after Deshmukh and MeyerlO). for embolically induced attacks of migraine from the abnormal mitral valves of Barlow’s syndrome. In their patients, propranolol, a beta-adrenergic blocking agent, eliminated these episodes; propranolo148 can decrease platelet aggregation and sympathetic tone. Kalendovsky19 found increased platelet aggregation in four patients with stroke, two of whom had classical migraine. Deshmukh’O discovered enhanced platelet aggregation during the prodrome of three migraine patients, but not during the headache phase. OthersI have indicated that platelets may play a role in migraine pathogenesis. The possible pathogenesis of scintillating scotomata of late onset in our two patients is shown in Fig. 3, where platelet aggregation may have a role. Willis and coauthorP have reviewed the rapidly developing field of prostaglandins and platelet reactivity. The production or prevention of a platelet thrombus depends on a balance in vivo between arachidonate and dihomo-y-linolenate. Linolenates are precursors of thromboxane A, which in turn is the precursor of prostaglandin E,. The latter substance inhibits platelet aggregation. On the other hand arachiodonates are precursors of thromboxane AZ, finally prostaglandin &, a potent vasoconstrictor and platelet aggregating substance. NATURAL HISTORY OF TIA It is generally agreed that patients with TIAs are more likely to develop a stroke, although the precise magnitude of the risk is controversia1.39 Among patients with TIAs who do not die of a cause other than stroke, about one-third will experience a stroke within five years of the first attack.50 Among patients with TIAs who experience a stroke within five years, more than 20% will do so within one month of the initial attack, and about 50% will do so within one year.51 Cartlidge and associates7 found no difference in the probability of the occurrence of stroke between patients with vertebral-basilar TIAs and carotid TIAs. ESTROGEN AND STROKE Women who use oral contraceptives have an increased risk of stroke.8 Scintillating scotomas have been brought on by oral contraceptives.3s In many patients taking these drugs increased blood viscosity,’ enhanced platelet adhesiveness and aggregation28~34~54 have been demonstrated. These changes are probably due to the estrogen component of the oral contraceptives.‘2 Summary Two patients with late onset of scintillating scotomas had increased platelet aggregation. The transient visual phenomena were probably related to estrogen therapy in one patient and atherosclerotic disease for the second patient. Both conditions can give rise to platelet microthrombi or microemboli, thus predisposing to cerebral ischemia includ- 112 Surv Ophtholmol 25 (2) September-October 1980 ing scintillating scotomas. Since the strokeprone patient is over 40, scintillating scotomas of late onset may have a serious import, especially if associated with increased platelet aggregation. Acknowledgments We are grateful to Doctors Ghahreman Khodadad and Samuel Trufant for the neurological evaluation of our patients, to Doctor Joel Sacks for reviewing the manuscript, and to Mrs. Joan Ausdenmoore for typing it. References 1. Airy H: On a distinct form of transient hemiopsia. 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