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Review Article *Corresponding author Dieter Schmidt, Department of Ophthalmology, University Eye Hospital Freiburg, Germany, Email: dieter. The Low-Prothrombine- Submitted: 01 December 2018 Accepted: 12 December 2018 Phosphene Phenomenon Published: 15 December 2018 ISSN: 2378-9344 of Atrial Fibrillation: First Copyright © 2018 Schmidt Description of a Warning Sign OPEN ACCESS Keywords Dieter Schmidt* • Atrial fibrillation; Zigzag phosphanes; Scintillations; Department of Ophthalmology, University Eye Hospital Freiburg, Germany Prothrombine time; Anticoagulants

Abstract Background: Atrial fibrillation (AF) is a precursor of stroke. Vitamin K antagonist has revealed risk reduction in ischemic stroke in many studies. Methods: Description of an unusual, hitherto unknown phenomenon in a patient Result: Rare attacks of blue-margined zigzag phosphenes in an elderly patient with atrial fibrillation that occurred binocularly in homonymous fields. The attacks only occurred during periods of low prothrombine, and disappeared within five to fifteen minutes after taking a vitamin K antagonist. The attacks were not influenced by valsalva provoking activity (coughing or bending). The patient had consistently normal visual acuity, and had never had a visual field defect or neurological deficits. Conclusions: The appearance of zigzag phosphenes in this patient with a low prothrombine time is an important warning sign. This phenomenon may be considered as a biological marker for stroke prevention. The occurrence of coloured zigzag phosphenes may refer to areas of hyperexcitable cortical . This phenomenon may be explained by an event involving cerebral microemboli that occurred during periods of low INR values reversible via medications.

INTRODUCTION Devastating events in patients with atrial fibrillation reduction in ischemic stroke by about two-thirds in 568 patients with AF [5]. precursor of stroke. Wolf & coworkers [1] assessed in a follow- Five randomized clinical trials of patients with AF revealed Several trials have shown that atrial fibrillation (AF) is a a nearly 70% ischemic stroke reduction via anticoagulant treatment [6]. In most of 150 patients, AF had been undetected up study carried out over 24 years that individuals with AF, aged prior to cerebral infarction [7]. Most of the infarcts were large 30 to 62, and exhibited a fivefold increase in stroke [2] incidence. revealed and not preceded by a transient ischemic attack [7]. Increased Embolism in patients with chronic AF may lead to cerebral use of oral anticoagulants led to a marked reduction in ischemic infarction. A review of clinical studies by Petersen strokes without exacerbating the bleeding rate. These studies that patients with chronic AF had an annual 3-6% risk of were carried out between 2012 and 2017 [8]. thromboembolic complications. This risk was 5-7 times greater thanIn in a control retrospective examinations study of of individuals 140 patients with with sinus strokes rhythm. who The key role of anticoagulation in a patient with non-valvular AF is emphasized In the following report. To my best of my theknowledge, literature. the occurrence of phosphenes as warning signs in had suffered from AF, 53 patients (38%) died after the initial periods of low prothrombine time INR has not been described in infarct. That review study of records applied to the years 1970 ZIGZAG PHOSPHENES AS WARNING SIGNS through 1980. Eighty-nine of the 140 patients (63.6%) revealed DURING LOW PROTHROMBINE TIME systemic emboli [3]. Patients with non-cardioembolic strokes were likely to present left ventricular wall motion abnormalities as demonstrated echocardiographically [4]. A 79-year-old ophthalmologist, who suffers from non- A greatly increased stroke risk may be reduced by treatment. valvular AF, noticed episodic attacks of hemianopic scintillations. Anticoagulants are highly effective at preventing cardioembolic During these attacks, the teichopsias appeared continuously as stroke in patients with AF. Thromboembolic events in non- luminous, zigzag forms with blue margins. He saw bilateral, slowly rheumatic AF were markedly reduced in patientsR treated with moving flaring phosphenes, in the outer hemianopic periphery anticoagulators. Examinations involving anti-thrombotic therapy of his visual field - without scotomas. The patient noticed the with an oral vitamin K antagonist (Warfarin ) showed a risk phosphenes when looking toward a bright background. The Cite this article: Schmidt D (2018) The Low-Prothrombine-Phosphene Phenomenon of Atrial Fibrillation: First Description of a Warning Sign. Ann Vasc Med Res 5(3): 1096. Schmidt (2018) Email: [email protected] Central

zigzag phosphenes moved in conjunction with his eye movements hyperlipidemia. The patient only drank non-alcoholic beverages in any direction. The episodes had occurred six times in the and did not smoke. He had no diabetes mellitus or hypoglycemia, preceding two to three years on different occasions (but not in and no personal history of migraine, nor any history of migraine previous years). They appeared suddenly at different situations in his family. He had no retinal disease. not entailing physical strain. The phosphenes occurred in a sitting revealed no vascular stenoses or ulcerative atheromatous Duplex ultrasonography of the carotid and vertebral arteries position or during walking. There was no diurnal influence on the anomalies in the vessel walls. appearance of the . The attacks sometimes occurred DISCUSSION during the morning or occasionally several hours after dinner or in the evening, usually a few hours after dinner. The phosphenes in this patient occurred binocularly in homonymous fields, sometimes on the right, sometimes on the left side. In this report, I describe a patient who observed suddenly occurring zigzag phosphenes. The patient never noticed episodes The patient had normal visual acuity (20/20) that did not of recurrent transient cerebral ischemia that might have been change during the attacks. His visual field was always normal, a caused by cardiac emboli. He had no limb weakness. Risk factors factor he noticed particularly during the attacks. He never suffered as pointed out by Arboix & Alio [9], such as patent foramen ovale, from headaches, diplopia, or ocular pain. He suffered no nausea or complex atheromatosis of the aorta, were not present in this vertigo, nor faintness during the attacks. He measured his blood patient. As predictive clinical factors for cardioembolic cerebral during an attack; it was normal. He had never suffered a infarction, emphasized by Arboix and coworcers [10], are male transient ischemic attack (TIA). The patient usually measures his hisgender previous and age, two but years. not congestive heart failure. In all the years of InternationalR Normalized Ratio (INR) to assess the prothrombine his life, the patient was engaged in physical exercises, including time about once a week or every two weeks because he takes Marcumar (Phenprocoumon). He was alert to test his INR value when he experienced the beginning of a scintillation attack. I presume that the zigzag phosphenes might have been During his attacks, he observed that his prothrombine time was occurred by a cerebral embolism - presumably microemboli - low, namely 2.0 or under 2.0. After immediately swallowing one that occurred during periods of low INR values (2.0 or lower), tablet of Phenprocoumon (3.0 mg), the hemianopic scintillations as he realized by measuring his own INR values. But the patient never developed a neurologic deficit and he had no headaches, disappeared within five to fifteen minutes and his INR R value nausea or vertigo during the attacks. His having immediately patientrose shortly noted afterwards. that phosphenes Phenprocoumon, had occurred a cumarin a few hours derivate, after acts as a vitamin K antagonist in a similar way as Warfarin . The taken vitamin K antagonist tablet presumably prevented a stroke. Therefore, the appearance of zigzag phosphenes may consuming food especially rich in vitamin K (foods with a vitamin be considered as a warning sign for such patients. I venture to K concentration exceeding 100µg per 100g), i.e. onions, parsley, conclude that this phenomenon may be a biological marker for lettuce, broccoli, cauliflower, or cabbage. stroke prevention. The fact that the zigzag phosphenes occurred without a scotoma in his visual field may be attributable to The patient had normal while under treatment an incipient process involving superficial cortical neurons’ with antihypertensive agents. ArterialR hypertension had been hyperexcitability without damaging cells located deeper within successfully treated for about 25 years; in the last three years the . As the phosphenes in this patient occurred binocularly treatment withR 1 tablet/day Exforge (10 mg Amlodipine; 160 in homonymous fields, sometimes on the right, other times on mg Valsartan). In addition, he was treated with Phenprocoumon the left, these teichopsias may be explained by microembolic (Marcumar ). His AF had been treated continuously for 20 years attacks not associated with any particular cerebral vessel. The with Phenprocoumon. For osteoporosis propylaxis, he was occurrence in homonymous fields may be related to attacks in treated with 1 tablet/day Calcium (100 mg) and 1 tablet vitamin the posterior visual pathway. The occurrence of coloured zigzag D (1 tablet every two weeks). Brain CT, MRI or transcranial phosphenes may have to do with areas of hyperexcitable cortical doppler sonography was not carried out, because the patient had neurons, i.e., local hyperactivation of neurons belonging to no neurological problems. He never had seizures (no EEG study specific cortical orientation columns. was performed). Echocardiography revealed an enlarged left atrium and a mitral insufficiency stage 2. In the literature, hemianopic scintillations with scotomas have been observed in patients who suffered either from migraine or, The patient had no health disorders otherwise and was more seldom, from cerebral vascular insufficiency, particularly used to engaging in physical exercises such as biking or jogging. involving vertebral-basilar disease. Investigators assumed that His vascular risk factors were normal and had been monitored scintillating scotomas might be caused by platelet microthrombi several1 times in previous years, with the last time in November or microemboli in pial vessels in the [11]. 2018. He presented no increased platelet aggregation or Fortification scintillations most often occur in individuals 1 A new zigzag phosphene attack recently occurred when the patient bent forward who suffer from migraine. These phosphenes may be caused by with a strenuous head position lasting several minutes. However, his INR value at the hyperexcitability of cortical neurons. Fortification patterns that time revealed a normal prothrombine time (2.4). After swallowing one tablet and their scintillations are attributed to a local hyperactivation of Phenprocoumon, the zigzag phosphenes disappeared after 10 minutes. This observation signifies that phosphenes due to a microembolism may rarely occur in of neurons belonging to certain cortical areas in the brain. These special situations without a low prothrombine time. To dissolve presumed emboli phenomena may be triggered by local cerebral ischaemia and by and arrest the phosphenes, it is essential that a patient taking Phenprocoumon be functional impairment of the sodium-potassium exchange pump treated even when their prothrombine time is normal. in glial cell membranes [12]. Ann Vasc Med Res 5(3): 1096 (2018) 2/4 Schmidt (2018) Email: [email protected] Central

My patient’s zigzag phosphenes differ essentially from direction.Phosphenes were induced when the subject’s eyes were open or migrainous phosphenes as fortification phosphenes always occur closed. The spatial location of phosphenes changed with the gaze in the peripheral visual field. In migraine patients, however, VISUAL FLEETING PHENOMENA IN PATIENTS scintillations usually begin at or near the fovea centralis, and WITH DIFFERENT DISEASES extend slowly into the visual field periphery of one hemifield. Migrainous phosphenes can move into the upper or lower quadrant only, or into the entire hemifield. Defective vision at the Causes for amaurosis fugax may be cardiogenic diseases, such beginning of the , is considered to be typical in migrainous as AF or valvular heart disease leading to embolism. Other causes patients [12], but it differs essentially from the observation of amaurosis fugax are hypercoagulable disorders, vasculitis, reported herein, as this patient suffered no visual defect during a such as giant cell arteritis, or migraine. Bruno & coworkers [22] zigzagINFLUENCE phosphene OF attack. MEDICATIONS ON SCINTILLATIONS who examined 100 subjects with transient monocular visual loss, IN THE LITERATURE reported on 42 patients suffering altitudinal (38) or lateralized (4)REFERENCES transient monocular visual loss. 1. Siekert & coworkers [13] emphasized that the use of anticoagulants may prevent severe vascular disability. Wolf PA, Dawber TR, Thomas HE, Kannel WB. Epidemiologic assessment of chronic atrial fibrillation and risk of stroke: The Scintillating scotomas were reported in a 51-year-old woman 2. Framingham Study. . 1978; 28: 973-977. by Raymond & coworkers [9]. The phosphenes were explained Petersen P. Thromboembolic complications in atrial fibrillation. by platelet microthrombi or microemboli of cortical pial vessels. 3. Stroke. 1990; 21: 4-13. coworkersThe patient was successfully treated with dipyramidole and aspirin to prevent additional platelet aggregation. Mundall & Sage JI, van Uitert RL. Risk of recurrent stroke in patients with atrial 4. [14] reported on transient monocular blindness due fibrillation and non-valvular heart disease. Stroke. 1983; 14: 537-540. to increased platelet aggregability in a 63-year-old patient. The Miller VT, Rothrock JF, Pearce LA, Feinberg WM, Hart RG, Anderson transient ischemic episodes were abolished by aspirin. DC. Ischemic stroke in patients with atrial fibrillation: Effect of asprin according to stroke mechanism. Neurology. 1993; 43: 32-36. Most of twelve patients with vertobrobasilar. insufficiency (VBI) who suffered from transient visual phenomena were 5. Anderson DC. The Stroke Prevention in atrial fibrillation Investigators. Predictors of thromboembolism in atrial fibrillation: I. Clinical features successfullyEXAMINATIONS treated with ON aspirinPHOSPHENES [15] 6. of patients at risk. Ann Intern Med. 1992; 116: 1-5. Hart RG, Halperin JL. Atrial fibrillation and stroke. Revisiting the dilemmas. Stroke. 1994; 25: 1337-1341. Scintillations should not be[16] confused reported with on phosphenes, the occurrence which of are luminous sensations elicited by various stimuli acting on 7. Sherman DG, Goldman L, Whiting RB, Jurgensen K, Kaste M, Easton the eye. Hitchcock & Taira JD. Thromboembolism in patients with atrial fibrillation. Arch Neurol. phosphenes due to intracerebral stimulation during stereotactic 1984; 41: 708-710. surgery in 23 subjects. Thirteen subjects reportedflashing white 8. Forslund T, Komen JJ, Andersen M, Wettermark B, von Euler M, phosphenes and nine patients’ coloured phosphenes. The most Mantel-Teeuwisse AK, et al. Improved stroke prevention in atrial common phosphenes were white or described as “ “. fibrillation after the introduction of non-Vitamin K antagonist oral The colour combination of phosphenes was red and blue. anticoagulants.ó Stroke. 2018; 49: 2122-2128. 9. Arboix A, Ali J. Acute cardioembolic stroke: an update. Expert Rev & coworkersIn vascular or in demyelinating optic nerve diseases, bright . 10. Cardiovasc Ther. 2011; 9: 367-379. flashes of light described as phosphenes were reported by Page factors of in-hospital mortality in 231 consecutive patients with [17] A 56-year-old patient suffered from right- Arboix A, Garcia-Eroles L, Massons J, Oliveres M. Predictive cliniical sided hemianopic scintillating scotomas that occurred 12 times 11. in a year, followed by migrainelike headaches after the attacks. cardioembolic cerebral infarction. Cerebrovasc Dis. 1998; 8: 8-13. But once, the scintillating scotomas failed to recede because a left 113.Raymond LA, Kranias G, Glueck H, Miller MA. Significance of homonymousPHOSPHENES hemianopia CAUSED had BY developed EXPERIMENTS [18]. of late onset. Surv Ophthalmol. 1980; 25: 107- 12.

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Cite this article Schmidt D (2018) The Low-Prothrombine-Phosphene Phenomenon of Atrial Fibrillation: First Description of a Warning Sign. Ann Vasc Med Res 5(3): 1096.

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