69 PROFESSIONAL ARTICLE Entoptic phenomena, photopsias, phosphenes Copyright (c) 2022 Slovenian Medical Journal. This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License. Entoptic phenomena, photopsias, phosphenes Entoptični pojavi, fotopsije in fosfeni Miha Sevšek,1,2 Xhevat Lumi2 Abstract In medicine the term entoptic phenomena is used to describe perception of visual effects that are rendered by the eye’s own structures or visual system under suitable lighting conditions or stimulus. Customary such conditions are rarely met and hence do not produce an image. Entoptic phenomena produced or influenced by the native optical structures of one’s own eye result from either refractive or diffractive causes. What all have in common is that they are subjective and require direct attention and cooperation of the observer for their perception. They differ from optical illusions which do not have a physical substrate. Special form of visual disturbances are photopsias and phosphenes. Photopsias are visual symptoms or sensations of structured images such as geometric figures or other simple pictures often recurring in a repetitive pattern in the absence of external light stimuli. Phosphenes are a subgroup of photopsias that patients describe as either static or moving unstructured patterns of colourful lights, sparkles or zig-zag lines. Photopsias predominately suggest ocular causes, less commonly they may suggest neurologic or systemic causes and thus require a meticulous examination as they occur. Izvleček Entoptični pojavi v medicini pomenijo zaznavanje struktur in vidnih pojavov v lastnem očesu ob izpolnjenih določenih pogojih osvetlitve ali dražljaja. Ker teh pogojev v vsakdanjih normalnih razmerah ni, ne povzročajo zaznave optične slike. Entoptični pojavi so lahko povezani z lastnostmi optičnih medijev ali s strukturnimi in fiziološkimi lastnostmi mrežnice ter vidne poti. Entoptični pojavi, ki so povezani z lastnostmi optičnih medijev, nastanejo zaradi refraktivnih ali difraktivnih vzrokov. Skupna lastnost vseh entoptičnih pojavov je, da je njihovo dojemanje subjektivno in odvisno od preiskovančeve pozornosti ter sodelovanja. Entoptični pojavi se razlikujejo od optičnih iluzij, ki nimajo osnove v resničnem okolju. Posebna skupina vidnih pojavov so fotopsije in fosfeni. Fotopsija je subjektivno zaznavanje svetlobe brez dejanskega fotonskega ali svetlobnega dražljaja in se pojavlja v obliki strukturiranih slik oz. geometričnih vzorcev ali kot enostavne ponavljajoče se slike. Fosfeni so fotopsije, ki jih bolniki zaznavajo kot nestrukturirane statične ali premikajoče se svetlobne vzorce različnih barv, bliske svetlobe, iskre ali t.i. cik-cakaste črte. Fotopsije v večji meri nastajajo v očesu, redkeje v centralnem živčnem sistemu, ali pa so znak sistemskih okvar, zato je ob njihovem pojavu potreben natančen pregled. 1 General Hospital Novo mesto, Novo mesto, Slovenia 2 University Eye Clinic, University Medical Centre Ljubljana, Ljubljana, Slovenia Correspondence / Korespondenca: Miha Sevšek, e: sevsek.miha88@gmail.com Key words: entoptic phenomena; optical media of the eye; flashes of light; photopsias; phosphenes Ključne besede: entoptični pojavi; optični mediji očesa; bliski svetlobe; fotopsije; fosfeni Received / Prispelo: 20. 10. 2020 | Accepted / Sprejeto: 28. 6. 2021 Cite as / Citirajte kot: Sevšek M, Lumi X. Entoptic phenomena, photopsias, phosphenes. Zdrav Vestn. 2022;91(1–2):69–78. DOI: https:// doi.org/10.6016/ZdravVestn.3183 eng slo element en article-lang 10.6016/ZdravVestn.3183 doi 20.10.2020 date-received 28.6.2021 date-accepted Ophtalmology Oftalmologija discipline Professional article Strokovni članek article-type Entoptic phenomena, photopsias, phosphenes Entoptični pojavi, fotopsije in fosfeni article-title Entoptic phenomena, photopsias, phosphenes Entoptični pojavi, fotopsije in fosfeni alt-title entoptic phenomena, optical media of the eye, flashes of light, photopsias, phosphenes entoptični pojavi, optični mediji očesa, bliski svetlobe, fotopsije, fosfeni kwd-group The authors declare that there are no conflicts of interest present. Avtorji so izjavili, da ne obstajajo nobeni konkurenčni interesi. conflict year volume first month last month first page last page 2022 91 1 2 69 78 name surname aff email Miha Sevšek 1,2 sevsek.miha88@gmail.com name surname aff Xhevat Lumi 2 eng slo aff-id General Hospital Novo mesto, Novo mesto, Slovenia Splošna bolnišnica Novo mesto, Novo mesto, Slovenija 1 University Eye Clinic, University Medical Centre Ljubljana, Ljubljana, Slovenia Očesna klinika, Univerzitetni klinični center Ljubljana, Ljubljana, Slovenija 2 Slovenian Medical Journallovenian Medical Journal 70 OPHTALMOLOGY Zdrav Vestn | January – February 2022 | Volume 91 | https://doi.org/10.6016/ZdravVestn.3183 1 Introduction Ophthalmologists often encounter concerned pa- tients with a fear of losing their sight when they sense something that has no source in visible reality or when they notice distorted images of objects in their surroundings. Subjective sensations of structures and phenomena in one’s eye or visual system, that under regular condi- tions does not result in visual perception, are referred to as entoptic phenomena (gr. entós + optikós, within the visual) (1-5). These perceptions are often produced or influenced by the native structures of the eye or patho- logic imperfections under certain lighting conditions. They may happen as a result of other types of stimula- tion (mechanical, radiation, endogenous factors) (1-5) but may also indicate pathological activity within the eye or represent symptoms of neurological or systemic dis- eases that affect the vision (1-4,6-9). Before the development of ophthalmoscopy, entop- tic phenomena were important for discovering ophthal- mic pathology. With the help of these phenomena, the French mathematician Claude François Milliet Dechales was the first to describe myopic ocular changes in short sighted people as far back as 1672 (10). Johann Bene- dikt Listings was the first to use the term “entoptic” to describe some of the optical phenomena in 1845 (11). With the development of modern examination tech- niques in medicine, entoptic phenomena were gradually becoming less important. Nonetheless, knowing these phenomena can be useful, as changes in the subjective perception of external images commonly precede ob- jectively discernible pathological changes seen by uti- lizing diagnostic examination techniques (7-9,12). By knowing the causes of entoptic phenomena, thoroughly asking patients about their medical history, and a com- prehensive ophthalmologic examination, physicians can exclude the more serious pathological processes with a high level of certainty, putting patients at ease, and avoid sending them for further unnecessary diagnostic exam- inations (1-4,6-9). In the first part of this paper, we focus on entoptic phenomena that occur in optical structures when certain special lighting conditions are met (1-5). In the second part, we focus on photopsias and phosphenes, the phe- nomena that frequently occur on the retina without any external light stimulus and less frequently occur in the central nervous system (6,14,15). Photopsias most often represent a symptom of pathological developments in the eye itself or in the central nervous system, or they are a result of haemodynamic or other homeostatic changes in the body (6,14,15). They do not represent a pathog- nomonic sign of a certain clinical entity, but rather indi- cate a possible deviation from the normal condition. By knowing the causes of photopsias, physicians can per- form a more targeted examination and discover specific pathologies (2,3,12,16). 2 Entoptic phenomena Depending on the location of their origin, entoptic phenomena are subdivided in phenomena that result from irregularities in the optical structures of the eye and phenomena that depend on the physiology of the retina and the visual pathway (Table 1). These two categories are not independent, as unhindered vision requires the coordinated operation of both eye segments. 2.1 Entoptic phenomena related to the characteristics of optical structures Different and heterogeneous compositions of optical structures result in their different refractive indices. Ex- cept for water, these structures are, by the nature of their cellular structure and their irregular refractive indexes, not perfectly transparent (1). The optical density and the refractive index of the structures are important in the formation of entoptic phenomena. The location of the inner-eye structure that casts the shadow can be estimat- ed using relative entoptic parallax (1,2,13). By changing the illuminating angle (using spot lighting), the eye can detect the direction of the movement of the shadow that the object casts on the retina with regard to its anterior or posterior location and distance from the pupil (1,2,13). If the object is located in front of the pupil, the shadow’s movement follows the movement of the light, whereas if the object is located behind the pupil the shadow moves against the movement of the light (1,2,13). Therefore, if the shadows are cast on the retina by opacities in the lens or in the vitreous body, they move in the opposite direc- tion to the illuminating source, while the shadows cast by corneal opacities or imperfections follow the move- ment of the light (1,2,13). The structure’s distance from the pupil also plays an important role. The further away the structure is from the pupil, a greater shift of the shadow is observed Optic media Retina and visual pathway Refractive causes Retinal circulation Anterior segment: • eyelashes, • tear film (retinal mosaic), • mucous and oil from Meibom’s glands, • folds of the Descement’s membrane, • pupil. Posterior segment (myodesopsia): • degenerative changes to the vitreous, • vitreous hemorrhage. • Purkinje tree, • blue field phenomenon. Retinal pigmentation • Haidinger’s brushes (carotenoid), • Maxwell’s spot (xanthophyll). Neuron action and disorders • Troxler’s fading, • blue arcs of the retina (Purkinje). Diffractive causes • corneal halo, • ciliary corona, • lenticular halo. Table 1: Division of entoptic phenomena by location of their origin. Summarized from Trick GL, 2006 (2). 71 PROFESSIONAL ARTICLE Entoptic phenomena, photopsias, phosphenes the eye itself or in the central nervous system, or they are a result of haemodynamic or other homeostatic changes in the body (6,14,15). They do not represent a pathog- nomonic sign of a certain clinical entity, but rather indi- cate a possible deviation from the normal condition. By knowing the causes of photopsias, physicians can per- form a more targeted examination and discover specific pathologies (2,3,12,16). 2 Entoptic phenomena Depending on the location of their origin, entoptic phenomena are subdivided in phenomena that result from irregularities in the optical structures of the eye and phenomena that depend on the physiology of the retina and the visual pathway (Table 1). These two categories are not independent, as unhindered vision requires the coordinated operation of both eye segments. 2.1 Entoptic phenomena related to the characteristics of optical structures Different and heterogeneous compositions of optical structures result in their different refractive indices. Ex- cept for water, these structures are, by the nature of their cellular structure and their irregular refractive indexes, not perfectly transparent (1). The optical density and the refractive index of the structures are important in the formation of entoptic phenomena. The location of the inner-eye structure that casts the shadow can be estimat- ed using relative entoptic parallax (1,2,13). By changing the illuminating angle (using spot lighting), the eye can detect the direction of the movement of the shadow that the object casts on the retina with regard to its anterior or posterior location and distance from the pupil (1,2,13). If the object is located in front of the pupil, the shadow’s movement follows the movement of the light, whereas if the object is located behind the pupil the shadow moves against the movement of the light (1,2,13). Therefore, if the shadows are cast on the retina by opacities in the lens or in the vitreous body, they move in the opposite direc- tion to the illuminating source, while the shadows cast by corneal opacities or imperfections follow the move- ment of the light (1,2,13). The structure’s distance from the pupil also plays an important role. The further away the structure is from the pupil, a greater shift of the shadow is observed Optic media Retina and visual pathway Refractive causes Retinal circulation Anterior segment: • eyelashes, • tear film (retinal mosaic), • mucous and oil from Meibom’s glands, • folds of the Descement’s membrane, • pupil. Posterior segment (myodesopsia): • degenerative changes to the vitreous, • vitreous hemorrhage. • Purkinje tree, • blue field phenomenon. Retinal pigmentation • Haidinger’s brushes (carotenoid), • Maxwell’s spot (xanthophyll). Neuron action and disorders • Troxler’s fading, • blue arcs of the retina (Purkinje). Diffractive causes • corneal halo, • ciliary corona, • lenticular halo. Table 1: Division of entoptic phenomena by location of their origin. Summarized from Trick GL, 2006 (2). (1,2,13). Therefore, patients are most disturbed by struc- tures (opacities) that are located in the posterior vitreous body, creating a disturbing shadow (i.e., a positive sco- toma) (1,2,13). According to the mechanism of their origin, phe- nomena are divided into those that result from refractive and diffractive causes. Refractive causes occur when the light passes through structures with different density, changing its direction, which is perceived as a shadow (2,13). Diffractive causes occur from the light bending and dispersing on the fringes of imperfections of the op- tical system (2,17,18). 2.1.1 Entoptic phenomena resulting from refractive causes Refractive causes that may result in the formation of entoptic phenomena are divided into refractive causes of the anterior and of the posterior ocular segment. 2.1.1.1 Anterior segment Observing a uniformly lit background through a pinhole (stenopeic vision), the entoptic field is the pu- pil, which is limited with the internal edge of the iris, and is perceptible as a light field with a jagged edge (the edge of the pupil). It is therefore possible to entoptical- ly observe irregularities on the pupil’s edge, as well as its contraction and dilation (2,13). Individuals can oc- casionally notice jumping shadows from their eyelashes on a brightly lit background (2). In a similar fashion, the tear film can cast a shadow, shaped like horizontal lines (striation); excessive mucus and oil excretion from Mei- bomian glands can result in perceiving mosaic patterns (1,2,13). Corneal deformations resulting from incor- rectly wearing rigid contact lenses or from squinting too hard can result in the formation of shadows that appear as horizontal sets of lines, as well can cause monocular diplopia, and can temporarily reduce visual acuity (2). In cases in which the nucleus of the lens has a significantly different focus than the periphery (e.g., developing cat- aract), the central bright image may appear broken into multiple images (polyplopia) (2). Opacities in the lens may be evident as dark, granular, stable patterns if their cast shadows reach the retina (2). 2.1.1.2 Posterior segment With age, the vitreous body begins to change (14). In a structurally and biochemically complex process the vitreous body starts to liquefy and the structure of col- lagen fibrils breaks down (14). The broken fibrils then pool together and accumulate in the liquefied vitreous body. This results in opacities that cast a shadow on the retina (14,19). Patients describe them as moving spots or dots in their visual field. Occasionally, they describe them as flies, mosquitoes, spiders, lines, clouds, etc. Such opacities move as the eye moves, but do not follow eye movements precisely. They generally pass the location of fixation and can change shape when moving (2,13,14). When attempting to look directly at them, they appear to float away, while blinking does not get rid of them 72 OPHTALMOLOGY Zdrav Vestn | January – February 2022 | Volume 91 | https://doi.org/10.6016/ZdravVestn.3183 (unlike transitional corneal surface changes) (14,19). They become most noticeable when looking into a bright and uniformly illuminated light source (the sky or a white background) (14). The perception of floaters is known as myodaeopsia (14). Because of their appear- ance they are also called muscae volitantes, which is Lat- in word for flying flies (2,13,14). Another possible cause for formation of vitreous opacities is mild vitreous haemorrhage (14). It can oc- cur when the posterior vitreous detaches but also as a result of eye injuries, retinal tears or detachment, choroi- dal melanoma, occlusion of retinal veins and in systemic diseases (diabetes mellitus) (19,20). Perception of opacities in the visual field is a frequent occurrence, in myopic eyes. This frequently worries pa- tients (19,20). The physician must pay particular atten- tion if the patient notices a sudden onset of thick floaters and flashes of light, as they might be related to posterior vitreous detachment (14,19,20). 2.1.2 Diffractive causes When observing a point light source, it passes through different ocular structures that behave as diffractive grat- ings, dispersing the light. The result is a decline in the contrast of the image and the onset of rainbow halos (2,17,18). The size of the perceived halos depends on the distance from the structure, of which the light is diffract- ed, to the retina. The closer it is to the retina, the smaller the halo (2,17,18). These phenomena can occur in nor- mal (physiological) but also in pathologic conditions. Physiological phenomena include the ciliary coro- na, which can be noticed when watching a singular il- luminated object in the dark (e.g., a star on a dark sky, a street lamp). The illumination source is surrounded by a changing pattern of many fine, slightly coloured nee- dles (2,17). This is the result of the light reflecting from numerous tiny particles (proteins) in the lens nucleus, and the tiny irregularities in the structure of other ocular parts (deposits on the corneal endothelial cells, the cells in the anterior chamber and the anterior lens capsule) (17). When the pupil is dilated, like in a dimly illuminat- ed room, a lenticular halo may occur, which appears as a ribbon of colour around the illumination source. It is caused by light bouncing from the zonular and anterior parts of the lens, which unlike its axial part has an un- even structure (2,18). In patients with corneal oedema (acute angle glau- coma, eye injuries, after surgical procedures), the lattice arrangement of the collagen fibrils is disturbed (2). With a disrupted collagen structure, light is scattered in all directions, leading to a corneal halo (2). The presence of mucus, blood or pus on the epithelium additionally intensifies light dispersal. When viewing white light, a white central circle can be perceived, surrounded by multicoloured rings (red-yellow, purple, etc.) (2). 2.2 Entoptic phenomena related to structural and physiological characteristics of the retina and the visual pathway 2.2.1 Retinal circulation Under normal conditions retinal vessels are not visi- ble because of neuron adaptation (2,7,21). If we shine a light into the eye from a non-physiological angle (e.g., from the side), the shadows of the vessels fall on the un- adjusted part of the retina. This allows patients to briefly see the retinal vascular image (2,7,21). If the illumina- tion source does not move, the phenomenon quickly disappears. Patients being examined by a biomicroscope often notice the retinal vascular image (2,7,21). Physi- ological phenomena of neuron adaptation also include Troxler’s fading, where fixating on a certain point or object can result in static images located peripherally from the point of fixation fading and disappearing in the background (22). When observing a uniformly illuminated blue back- ground (e.g., blue sky), it is possible to notice fast mov- ing shooting spots of light in an apparent random or- der. This is called the blue field entoptic phenomenon or Scheerer’s phenomenon, and is attributed to the move- ment of leukocytes in the retinal capillaries (2,8,23). The phenomenon is also useful to estimate the blood flow in the retinal capillaries, by using blue field entoptoscopy (2,23). 2.2.2 Polarizing light (Haidinger’s brush) The human eye is capable of detecting the direction of polarized light with the assistance of the so-called Haidinger’s brushes entoptic phenomenon (2,7,9). When looking at a source of polarized light, many peo- ple can notice the pale interlinked blue and yellow bar or bow tie shape, visible in the centre of the visual field. At fixation this phenomenon fades in approximately five seconds, but can be sustained if the direction of the polarization changes. The phenomenon is the result of dichromatic carotenoid pigments in the macula, which are on average arranged perpendicular to Henle fibres 73 PROFESSIONAL ARTICLE Entoptic phenomena, photopsias, phosphenes (2,7,9). The phenomenon is useful for early detection of macular dysfunction as patients are unable to visualize Haidinger’s brushes even before the onset of clinically apparent signs of macular disease or oedema (7-9). 2.2.3 Retinal pigmentation (Maxwell spot) When observing a source of neutral light through a fast-alternating green and blue filter a person can notice a central dark point, surrounded by a brighter circle with a halo (2,7). The central dark circle is the result of blue light absorption in the xanthophyll pigment of the cen- tral fovea. The phenomenon can be used to test eccentric fixation (deviation of concentric circles) and for moni- toring the course of central serous retinopathy (the spot begins to reappear when the condition improves) (2,7). 2.2.4 Blue arc phenomenon When viewing a pale illumination source in a dark- ened room and when the temporal parafoveal retina is stimulated, we can observe two blue-grey gently flicker- ing arcs spiralling above and below the fixation point for a short period of time (up to 1 second) (2,7). These arcs arise at the illumination source and extend to the blind spot (2,7). The position and orientation of the arcs are generally held to correspond to the route of the parafo- veal arcuate nerve fibre bundles extending to the optic disk (2,7). This visualization is thought to be the result of secondary electrical stimulation of the retina whereby action potentials in the arcuate bundles excite adjacent neurons (2,7). 3 Photopsias and phosphenes Photopsias are defined as subjective perceptions of light without an actual photonic or light stimulation (6,14,15). Photopsias (flashes) (gr. phos – light + opsis – perception or sight) occur in the shape of structured im- ages, i.e., geometric patterns (triangles, cubes, pyramids, etc.) or as simple recurring images (16). Photopsias can accompany numerous pathological ocular or systemic conditions, and determining their origin can be a diag- nostic challenge (15). In the majority of cases the unilateral photopsias have their origin in the eye (15). Even photopsias that were primarily unilateral and then spread to both sides, most often have the origin in the eye (15). Bilateral photopsias suggest abnormalities in the central nervous system or systemic conditions (6,15). In such cases the physician must first obtain thorough information from the patient on any known comorbidities, potential malignant dis- eases, previous ocular, intracranial or other surgical pro- cedures, as well as whether they are taking any drugs or substances with known toxic side effects (15). A special group of photopsias are unstructured pho- topsia or phosphenes. Phosphenes (gr. phos – light + phainein – show) are described by patients as unstruc- tured static or moving light patterns of different colours, flashes of light, sparks or zig-zag lines (6,15,16). 3.1 Photopsias Photopsias most often occur as result of direct reti- nal stimulation (vitreomacular traction, neovascular age related macular degeneration and optic disc oedema) (6,15). It is assumed that their origin is primarily in the retina, and that only in about 10% of the cases they re- sult from abnormalities in the central nervous system or systemic disorders (6,15). 3.1.1 Vitreous detachment Posterior vitreous detachment is among frequent causes of photopsias (6,14,15,19,20). Patients notice uni- lateral flashes of light in the peripheral part of their vi- sual field. They also frequently notice floaters. The sepa- ration of posterior vitreous from the optic disk results in appearance of central large annular opacity (Weiss ring). With vitreous detachment there is no central or periph- eral loss of vision (19,20). When examining the fundus, we must look carefully for the presence of Weiss’s ring and the pigment cells in the anterior vitreous (tobacco dust, Schaffer’s sign), which are strongly suggestive of retinal tear (19,20). A visual field defect can be a sign of retinal detachment (19,20). Patients often describe this as a shadow or a curtain that blocks their view and is spreading from the periphery towards the centre (19,20). 3.1.2 Age-related macular degeneration Age-related macular degeneration is a frequent cause of photopsias (6). Approximately 50% of the patients with this type of macular degeneration notice white flashes, pulsations and twinkles (6). With the advance- ment of the disease and the onset of choroidal neovascu- lar membranes, the probability of photopsias increases (6). Unlike posterior vitreous detachment, where the in- ternal part of the retina is stimulated, in age related mac- ular degeneration outer retinal layers (photoreceptors) 74 OPHTALMOLOGY Zdrav Vestn | January – February 2022 | Volume 91 | https://doi.org/10.6016/ZdravVestn.3183 are stimulated (6). Differentiation between the two based only on photopsias can be difficult. In age-related macular degeneration photopsias are more often located centrally, whereas in cases with posterior vitreous de- tachment they tend to be peripherally located (6). 3.1.3 Central serous chorioretinopathy Patients with a serous detachment of the macular neurosensory retina with adjacent loss or hyperplasia of the retinal pigment epithelium have unilateral cen- tral white flashes, which last up to a few seconds (6,15). Flashes can occur on a daily basis or a few times per week. Similar photopsias are also caused by other condi- tions that disrupt photoreceptors (Best disease, macular dystrophies) (6,15). 3.1.4 Diabetic retinopathy Diabetic patients with a proliferative diabetic retinop- athy can develop formation of fibrovascular tissue as a re- sult of long-term retinal hypoxia (24). This tissue’s growth and contraction causes traction of the retina, which caus- es photopsias. This traction can lead to tractional retinal detachment with potential vitreous haemorrhage (24). Patients with tractional retinal detachment can also no- tice floaters, flashes (photopsias) and a visual field defect. Bilateral photopsias have been observed in insulin dependent diabetic patients during episodes of hypogly- caemia. They disappeared when blood sugar levels nor- malized (6). 3.1.5 Optic neuritis Patients with optic neuritis can have photopsias alongside pain that is induced by eye movement (25-27). Patients notice photopsias when entering a darkened room, and describe them as bright colourful short-last- ing flashes. Eye movement in the horizontal direction aggravates them (25-27). It was noted that the phenom- enon is not maintained and temporarily ceases by re- peated eye movements (25-27). The cause for photopsias is attributed to a mechanical deformation and firing of hyperexcitable nerve axons secondary to demyelization process. It is described as a visual equivalent of Lher- mitte’s sign (25-27). 3.1.6 Retinitis pigmentosa Patients with retinitis pigmentosa often notice bi- lateral small, white flashes of light in the central part of their visual field, both in dark and bright conditions (6,15). They may persist throughout the day, while some patients only notice them several times daily (6,15). They may also be triggered by intense blinking (6,15). 3.1.7 Paraneoplastic retinopathy In paraneoplastic retinopathy photopsias are caused as a result of dysfunction of the photoreceptors. In can- cer associated retinopathy antibodies against retinal an- tigens develop (28-30). It occurs most frequently with small cell lung cancer (28-30). Patients may also com- plain of flickering, reduced visual acuity, reduced colour vision, night blindness and scotomas (28-30). 3.1.8 Vertebrobasilar insufficiency Patients with vertebrobasilar insufficiency may no- tice bilateral photopsia, manifested as jagged flashes that last from a few seconds to a few minutes (6,31). This condition is often accompanied by vertigo, nausea, atax- ia and general weakness (31). Symptoms may be similar to migraine attacks, but do not last as long, and are not followed by a headache (6,32). 3.1.9 Photopsias related to severe coughing attacks There have been reports of patients who noticed short-term, bilateral, temporal, flashes of light during severe coughing attacks (6). They appeared on both temporal visual fields at once or alternating from one to another visual field at different intervals. The reason for the onset is attributed to fast movements of the vitreous during straining, and consequent retinal traction (6). There were no cases of confirmed vitreous detachment (6). 3.1.10 The Charles Bonnet syndrome With injury or damage of the visual pathway, uni- lateral or bilateral so-called release hallucinations may occur as part of the Charles Bonnet syndrome (33,34). Patients see multicoloured shapes, patterns, even faces and silhouettes, which can last between a few seconds and a few minutes (6). They are aware that the phenom- ena are not real (33,34). The mechanism is not yet fully explained, but in general the sensory deprivation theory has been accepted. According to that theory long-term visual cortex stimulus deficiency results in disinhibition of visual cortical neurons, which in turn lead to random 75 PROFESSIONAL ARTICLE Entoptic phenomena, photopsias, phosphenes activation of action potential even without stimulation (35). The phenomenon is more common in individuals with bilateral reduced visual acuity and patients who had their eye covered for a long time after eye surgery (33-36). 3.1.11 Migraine headache Binocular photopsias or flashes most frequently rep- resent visual auras as part of migraine headaches and are often referred to as “visual migraines” (6,15,37-39). Their source is in the occipital lobe of the brain and not in the structures of the eye or the retina; therefore, it affects the vision of both eyes at the same time (37,38). These photopsias are also known as scintillating scoto- ma (lat. scotoma scintillans) and represent a character- istic symptom preceding the headache. They rarely oc- cur without a headache (acephalgically) (6,15,37-39). They usually begin bilaterally as a point of flickering light close to the centre of the visual fields, gradually spreading outwards. The vision outside the scotoma’s edges is generally undisturbed, although scotoma can sometimes fill the entire visual fields (6,37,38). 3.1.12 Retinal migraine Retinal or ocular migraine should be distinguished from the headache type migraine or migraine with aura (37,39). The former has its origin in the eye and therefore impacts the vision unilaterally, namely in the eye where it develops (37,39). Characteristic for retinal migraine are transitional unilateral episodes of gradually spreading positive or negative phenome- na in the visual field, lasting up to an hour. Positive phenomena include flashing beams of light, zig-zag patterns and perception of flickering-coloured tracks, rings or diagonal lines, while negative phenomena is characterized by blurred vision, dark spots – scoto- ma or transitional total blindness (37,39). These may be accompanied or followed by a migraine headache within an hour (37,39). Pathophysiology of retinal mi- graine is not completely understood. According to one theory, the cause is in the vasospasm of the retinal or ciliary circulation, which causes ischaemia of the optic nerve, while according to another the cause is in the spread of depolarization over retinal neurons (37,39). Medical exam should exclude all other possible causes of transient unilateral visual field loss (a diagnosis of exclusion). Aamaurosis fugax must always be excluded first (37,39). 3.1.13 Other causes of photopsias Even though they are not the leading symptom, pho- topsias accompany numerous other conditions. The presence of the permanent violet flashing indicates a retinal ischaemia (6). It has been described to accompa- ny the blockage of the central retinal artery, its branches and with the blockage of the central retinal vein (6,15). Similarly, photopsias have been reported in cases with optic nerve oedema and optic neuropathy (15). Bilateral photopsias can also occur in patients with orthostatic hypotension (6) and in cases where posterior visual pathway is affected, e.g., with vascular causes (ar- teriovenous malformations, transient ischaemic attacks, cortical venous sinus thrombosis, stroke in the occipital lobe), occipital epilepsy and prion diseases (15). A more detailed list is included in Table 2. 3.2 Phosphenes Phosphenes are photopsias usually described sep- arately since patients describe them as unstructured static or moving multi-coloured light patterns (rainbow, white, black), or as sparks, flashes and zig-zag lines (16). They are associated with random activation of individ- ual neurons at any part of the visual pathway (from the retina to the geniculate and striate cortex) (5,12,16,27). The most frequent type are deformation phosphenes, which are caused by the digital pressure to the eyeball (3,5,12). They may also be caused by: traction and pres- sure on the optic nerve (2,3), contraction of the ciliary muscle (2,40), the effect of extraocular muscles on the retina with a rapid accommodation or overaccommoda- tion (2,40,41) and with convergence (2,3,40). Phosphenes also occur when a person is exposed to electromagnetic radiation, e.g., during transcranial magnetic stimulation (2,5,12,42,43), or when exposed to alternate current during transcranial electric stimu- lation (2,5,12,16,42,43). There are reports of homoge- neous green tinting of the whole field of vision after be- ing exposed to x-rays. The cause is assumed to be direct ionizing effect on the pigment of rods and cones (44). Because the phenomenon is only possible in the eye, that is capable of detecting light, it is potentially useful for testing the retinal function when optical media are completely opaque (43,44). Patients who were exposed to ionized radiation (β-rays) noted a similar phenom- enon (2,5,12,44). Astronauts exposed to cosmic rays during space flight also reported flashes and beams of blue-white light (2,5,12,16,45). 76 OPHTALMOLOGY Zdrav Vestn | January – February 2022 | Volume 91 | https://doi.org/10.6016/ZdravVestn.3183 Causes of unilateral photopsias mechanical posterior vitreous detachment retinal tear/detachment Macula age-related macular degeneration central serous retinopathy hereditary Best’s disease Retina inflammation white dots syndrome: APMPPE, MEWDS, AZOOR, MCP, including idiopathic blind spot syndrome, birdshot chorioretinopathy, serpiginous choroiditis, acute macular neuroretinopathy neoplastic choroidal melanoma choroidal metastasis venous retinal artery occlusions (central, cilioretinal) Optic nerve unilateral optic disc swellingoptic neuropathy Unilateral photopsias can gradually expand to both eyes Causes of unilateral photopsias optic nerve papilledema paraneoplastic cancer-associated retinopathy melanoma-associated retinopathy Anterior visual pathway Charles-Bonnet syndrome Posterior visual pathway migraine with aura aura without migraine occipital lobe epilepsy visual snow syndrome venous transient ischaemic attack stroke cortical venous sinus thrombosis vertebrobasilar insufficiency arteriovenous malformation inflammation posterior reversible encephalopathy syndrome iatrogenic deep-brain stimulator infective prion diseases (Creutzfeldt-Jakob’s disease) neoplastic any type Table 2: Causes of photopsias. Summarized from Virdee J, 2020 (15). 77 PROFESSIONAL ARTICLE Entoptic phenomena, photopsias, phosphenes References 1. Friedman B. Observations on Entoptic Phenomena. Arch Ophthalmol. 1942;28(2):285-312. DOI: 10.1001/archopht.1942.00880080103012 2. Trick GL, Kronenberg A. Entoptic Imagery and Afterimages. In: Duane TD, Tasman W, Jaeger EA, Anderson DR, Glaser JS, et al. Entoptic Imagery and Afterimages. Philadelphia: Lippincott Williams & Wilkins; 2006. 3. Tyler CW. Some new entoptic phenomena. Vision Res. 1978;18(12):1633- 9. DOI: 10.1016/0042-6989(78)90255-9 PMID: 726316 4. Brewerton EW. President’s Address: entoptic Phenomena. Proc R Soc Med. 1930;24(1):45-8. DOI: 10.1177/003591573002400111 PMID: 19987826 5. Salari V, Scholkmann F, Vimal RL, Császár N, Aslani M, Bókkon I. Phosphenes, retinal discrete dark noise, negative afterimages and retinogeniculate projections: A new explanatory framework based on endogenous ocular luminescence. Prog Retin Eye Res. 2017;60:101-19. 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Phosphene phenomenon: a new concept. Biosystems. 2008;92(2):168-74. DOI: 10.1016/j.biosystems.2008.02.002 PMID: 18358594 13. Donders FC. On the Anomalies of Accommodation and Refraction of the Eye: With a Preliminary Essay on Physiological Dioptrics. London: New Sydenham Society; 1864. 14. Lumi X, Hawlina M, Glavač D, Facskó A, Moe MC, Kaarniranta K, et al. Ageing of the vitreous: from acute onset floaters and flashes to retinal detachment. Ageing Res Rev. 2015;21:71-7. DOI: 10.1016/j.arr.2015.03.006 PMID: 25841656 15. Virdee J, Mollan SP. Photopsia. Pract Neurol. 2020;20(5):415-9. DOI: 10.1136/practneurol-2019-002460 PMID: 32536606 16. Celesia GG. The mystery of photopsias, visual hallucinations, and distortions. Suppl Clin Neurophysiol. 2006;59:97-103. DOI: 10.1016/ s1567-424x(09)70018-2 PMID: 16893099 3.2.1 Side effects of certain drugs More than 300 drugs from different groups have been reported to cause visual sensations (phosphenes, as well as visual hallucinations) as a side effect (46). Phosphenes often occur in patients who receive drugs from the group of phosphodiesterase inhibitors, calcium channel block- ers and cardiac glycosides (12,47). Digoxin ocular toxic- ity causes bilateral yellowish flashes of light (6,15). High doses of the antipsychotic quetiapine (Kventiax, Kvelux) and the antimycotic voriconazole (Vfend) can cause per- sisting flashes of light (15). Recreational drugs from the alkyl nitrite group (so-called poppers) can cause flashing as well as morphological changes in the macula, reduc- ing visual acuity (so-called poppers maculopathy) (15). 4 Conclusion In most cases, the entoptic phenomena described in the first part of the paper do not represent serious or threatening conditions. Photopsias and phosphenes de- scribed in the second part of the paper are conditions that physicians should always take seriously when re- viewing the patient’s medical history. Patients must be carefully asked about the time the phenomena occur, their duration and interval, any potential trigger fac- tors and a detailed description of the phenomena itself (localization, colour, shape, movement). Localization of the flashing phenomenon is important. Flashes of light in the periphery of the visual field are in most cases a sign of traction on the peripheral parts of the retina. When light flashes occur more centrally, they indicate macular diseases or changes to the central nervous system. Laterization is also important. Unilateral photopsias are mostly of ocular origin, while the occurrence of bilat- eral photopsias is usually a sign of disorders in the cen- tral nervous system or general conditions, such as hyper- glycaemia, hypoglycaemia or orthostatic hypotension. For physicians, and especially ophthalmologists, it is essential to know entoptic phenomena, photopsias and phosphenes, not only to enrich their medical knowl- edge, but also in order to more exactly interpret symp- toms that patients may detect. Even though patients describe these phenomena subjectively and differently, a good clinician will al- ways listen to the patient’s complains, the description of symptoms and strive to ascertain whether this is a seri- ous phenomenon that requires extended diagnostics or a non-dangerous, physiological phenomenon that pres- ents no risk to the patients’ health and does not require a broader or invasive diagnostic evaluation. Conflict of interest None declared. 78 OPHTALMOLOGY Zdrav Vestn | January – February 2022 | Volume 91 | https://doi.org/10.6016/ZdravVestn.3183 17. van den Berg TJ, Hagenouw MP, Coppens JE. The ciliary corona: physical model and simulation of the fine needles radiating from point light sources. 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