Visual Snow: Visual Misperception

Visual snow (VS) is a constant visual disturbance described as flickering dots occupying the entire visual field. Recently, it was characterized as the defining feature of a VS syndrome (VSS), which includes palinopsia, photophobia, photopsias, entoptic phenomena, nyctalopia, and tinnitus. Sixty percent of patients with VSS also experience migraine, with or without aura. This entity often is considered psychogenic in nature, to the detriment of the patient's best interests, but the high frequency of similar visual symptoms argues for an organic deficit. The purpose of this review is to clarify VSS as a true entity and elaborate the nature of individual symptoms and their relationship to each other.

State-of-the-Art Review Section Editors: Valérie Biousse, MD Steven Galetta, MD Visual Snow: Visual Misperception Owen B. White, MD, PhD, FRACP, Meaghan Clough, PhD, Allison M. McKendrick, PhD, Joanne Fielding, PhD Background: Visual snow (VS) is a constant visual disturbance described as flickering dots occupying the entire visual field. Recently, it was characterized as the defining feature of a VS syndrome (VSS), which includes palinopsia, photophobia, photopsias, entoptic phenomena, nyctalopia, and tinnitus. Sixty percent of patients with VSS also experience migraine, with or without aura. This entity often is considered psychogenic in nature, to the detriment of the patient's best interests, but the high frequency of similar visual symptoms argues for an organic deficit. The purpose of this review is to clarify VSS as a true entity and elaborate the nature of individual symptoms and their relationship to each other. Evidence Acquisition: The literature was reviewed with specific regard to the clinical presentation and psychophysical, neurophysiological, and functional imaging studies in patients with defined visual disturbances that comprise VSS. Results: Consideration of the individual symptoms suggests that multiple factors are potentially involved in the development of VSS, including subcortical network malfunction and cortical hyperexcitation. Although there is substantial overlap between VSS and migraine syndromes in terms of co-occurring symptoms, both neurophysiological and neuroimaging studies provide substantial evidence of separate abnormalities of processing, supporting these as separate syndromes. Conclusions: VSS is likely associated with either hyperactive visual cortices or, alternatively, impaired processing of simultaneous afferent information projecting to cortex. VSS likely results from widespread disturbance of sensory processing resulting in sensory misperception. There may be a number of syndromes associated with impaired sensory processing resulting in sensory misperception, including migraine, persistent perceptual postural dizziness, and tinnitus, which overlap with VSS. Elucidation of Department of Neurosciences (OBW, MC, JF), Central Clinical School, Alfred Hospital, Monash University, Prahran, Australia; and Department of Optometry and Vision Sciences (AMM), Melbourne University, Parkville, Australia. The authors report no conflicts of interest. Address correspondence to Owen B. White, MD, PhD, FRACP, Department of Neurosciences, Central Clinical School, Alfred Hospital, Monash University, Prahran, Victoria 3181, Australia; E-mail: [e-mail] 514 abnormality in one defined syndrome may provide a path forward for investigating all. Journal of Neuro-Ophthalmology 2018;38:514-521 doi: 10.1097/WNO.0000000000000702 © 2018 by North American Neuro-Ophthalmology Society V isual disturbances are common in medical practice. Until recently, positive visual phenomena not arising from the retina have been considered migrainous, whether associated with headache or not (1-7). Notably, migraine "aura" occurs in approximately one-third of patients who experience migraine, and may be positive (e.g. fortification spectra, teichopsia, scintillating scotomata, and polyopia) and/or negative (e.g. scotomata). Aura is typically a transient phenomenon, building gradually over minutes. Persistence of visual aura, extending beyond weeks is uncommon, (2,4,8,9) with about 40 reported cases (6,10). The International Classification of Headache Disorders, Version 3 (ICHD-3 beta version) codes this as "persistent aura without infarction" (code 1.4.2) or "migraine aura status" (Appendix A1.4.5) (7). However, one form of prolonged visual disturbance commonly associated with migraine is "visual snow" (VS), which has the characteristic of global "static" or "pixellation." Visual snow syndrome (VSS) is poorly recognized, not only in the neurological and ophthalmic communities, but also in the neuro-ophthalmic community. It is often designated as being psychogenic, to the detriment of the patient and their capacity to function, socially and within the work environment. The purpose of this review is to discuss the emergence of VSS as a separate syndrome, often associated with migraine but separable, and to review the underlying pathophysiology of the symptoms considered fundamental to making the diagnosis. Only with such understanding can this clinical entity be correctly diagnosed and appropriately managed. EVIDENCE ACQUISITION A comprehensive literature review was undertaken, using Google Scholar and PubMed, searching for: visual snow, White et al: J Neuro-Ophthalmol 2018; 38: 514-521 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. State-of-the-Art Review persistent visual disturbances, migraine, palinopsia, nyctalopia, tinnitus, entoptic phenomena, photopsia, photophobia, and sensory processing. We found 1,578 articles covering a wide spectrum of topics, and reviewed for information relevant to this review. In all cases, the abstract was reviewed to evaluate whether they were clinical, physiological, or radiological. Reports where the abstract was in English but the article was in another language were eliminated. Articles not in peer-reviewed journals and anecdotal clinical reports were eliminated. In all, 140 articles remained and 105 were used for the preparation of this article, the remainder being eliminated due to overlap of authors and subject matter. RESULTS Clinical Features of Visual Snow Syndrome VS was first proposed as a separate syndrome by Liu et al (8) with patients reporting "snow" or "static" in their field of vision persisting over months. Age of onset ranged from 7 to 55 years (11,12), with a male:female ratio of 1:2 to 1:3 (13). The primary, defining symptom of VSS is continuous flickering dots present throughout the visual field that may be constant or fluctuate over months to years. This visual sensation has been likened to the "static" or "pixellation" seen on a badly tuned television. Schankin and Goadsby (14) proposed the presence of at least 2 additional symptoms from 4 categories to establish the diagnosis: (1) entoptic phenomena (2) palinopsia, (3) photophobia, and (4) nyctalopia. Those most frequently reported are palinopsia and enhanced blue field entoptic phenomena. Less commonly described are photophobia, nyctalopia, as well as spontaneous photopsia, constant high-pitched tinnitus (12,15,16), psychological disturbances (12,17), and balance disturbances (12). The demographic and clinical features from reports with the largest patient cohorts of VSS are summarized in Table 1 (12,17-20). The severity of this disorder often has been understated, particularly in regard to its impact on the patient, and often unfortunately labeled as "psychogenic." VSS is seen de novo in patients with no previous history of neurological disease. It also has been reported in patients previously exposed to hallucinogenic drugs (17), but we are unaware of systematic investigation of differentiating factors. The stereotypy of symptoms described by patients analyzed by interview and chart review (17) defines a phenotypic impairment of sensory perception representative of a unique syndrome. This, in the absence of identifiable structural abnormalities (8,17,21,22), supports an organic pathophysiology rather than a psychogenic hypothesis. The characterization of additional criteria required for diagnosis has been established by retrospective recognition of symptoms in the defined study populations (17). It is conceivable that the establishment of an underlying, and measurable, functional abnormality might White et al: J Neuro-Ophthalmol 2018; 38: 514-521 TABLE 1. Clinical features of visual snow syndrome Feature (Reference) Frequency Median age (years) (12,13,15,19,20) Sex ratio M:F (12,13,15,19,20) Palinopsia (12) After images, stationary objects (15) After images, trailing moving objects (15) Enhanced entoptic phenomena Floaters (15) Blue field entoptic phenomena (15) Spontaneous photopsia (12,15) Photophobia (15) Nyctalopia (15) Tinnitus (15) Impaired concentration (15) Lethargy (15) Anxiety (12) Depression (12) Balance disorder (12) Migraine (15) Headache (15) Tremor (12) w30 w1:1 69% 86% 60% 81% 79% 41%-63% 74% 68% 62% 60% 55% 44% 19% 19% 59% 87% 22% reveal further "formes frusta" of the syndrome and allow for the development and evaluation of therapeutic strategies. Pathophysiology The broad nature of the underlying symptomatology suggests widespread dysfunction/pathology but does not preclude the possibility of a more focal abnormality of processing of sensory information. The visual symptoms of VSS seem to derive from the optical apparatus of the eye or its direct connections (enhanced entoptic phenomena and monocular photopsia), as well as from cortical or subcortical substrates (VS and palinopsia). Other symptoms (nyctalopia, photophobia, and tinnitus) are of undetermined origin. Further exploration of the symptomatology may provide insight into potential pathophysiology. Positive Visual Disturbances It has been proposed that positive visual symptoms may be divided into either "failure to suppress visualization of the optic apparatus" or "inability to suppress the just-seen" (23-25). These disturbances may be formed or unformed. Unformed disturbances may derive from anywhere in the visual system. However, formed images must derive from portions of the visual system downstream from the primary visual cortex, given the postprocessing required to form these images. The following discussion focuses on the symptoms more commonly associated with VSS. Visual Snow VS presupposes either a bilateral retinal abnormality (26,27) generating excessive "photopsia" or, alternatively, a cortical phenomenon. Retinal pathology is relatively uncommon, 515 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. State-of-the-Art Review being recognized in 15 of 104 patients studied by Lepore (26). Findings included vascular disease, infection, pigmentary retinopathy, and multiple evanescent white dot syndrome. Positive phenomena have also been reported in paraneoplastic retinopathy (28). Comprehensive ophthalmic examination and visual electrophysiology have not demonstrated abnormality of the retina or anterior optic pathways in patients with VS (12,17,19,20), nor in patients with hallucinogen-induced persisting perception disorder with similar visual symptoms (29). However, functional brain imaging has demonstrated hypermetabolism within the lingual gyrus (26), a downstream visual processing region, providing support for symptoms being a product of cerebral network/cortical dysfunction. This will be discussed further below. Entoptic Phenomena (and Photopsia) There is substantial evidence that all living cells emit photons, spontaneously and continuously (30,31). Spontaneous luminescence (discharge of photons), which occurs within the retina, may be derived from photoreceptors and melanopsin-containing ganglion cells (32-34), or in response to physical pressure, such as rubbing one's eye, which may explain some of the positive phenomena. Phosphenes, retinal dark noise, and negative after images, normally suppressed, may come to consciousness in the visual network in VSS (34,35). As most of us are aware of these phenomena (36,37) rather than questioning why they are so intrusive in patient groups, the real question may be, why are they not more intrusive in all of us? In part, this may be due to the fact that vision is a percept of the visual environment, sourced from approximately 1 · 108 photoreceptors in each eye (38) projecting to approximately 1 · 106 retinal ganglion cells (39), forming the axons of each optic nerve. The axons of the optic nerves project to the lateral geniculate nuclei where they synapse, and then course through the optic radiations to ramify widely within primary visual cortex, to an estimated 1.4 · 108 neurons (40). The system then projects downstream to various visual association areas. This funneling of information can only permit updating of the visual scene rather than "stream of consciousness" visual perception, the relative reduction of optic nerve axons, with respect to the number of photoreceptors likely restricts information transfer, thus filtering out much of the spontaneous activity. Persistence of entoptic phenomena and VS suggests failure of an inhibitory cortical or subcortical filtering system that normally prevents the visual events coming to consciousness. Palinopsia Palinopsia is the persistence of viewed images that have definable structure and derive from postprocessing regions of the cerebral hemispheres that are distal to the primary 516 visual cortex. The unifying feature is either the persistence of an image beyond its time, or the imposition of a recently seen image on a newly acquired visual scene. Gersztenkorn and Lee (41) defined the complexity of the symptom and proposed that it reflects an abnormal persistence of visual memory. Lesions of the posterior visual pathways have been identified in temporal, parietal, and occipital lobes, with various mechanisms proposed, including deafferentation, metabolic disorder, cortical pathology of various types, and idiopathic epilepsy. Consistent with our discussion of the visual percept above, and the requirement to explain what seems to be a temporal phenomenon, palinopsia may involve inappropriate loading and unloading of visual information into and from visual working memory. Conceptually, working memory is the short-term storage of information for processing and immediate execution of tasks. Efficiency of filtering relevant from irrelevant information and the speed of loading and unloading data into a limited capacity buffer determine individual differences in functional capacity (42). Working memory, including visual working memory, is reliant on a widely distributed network involving frontal cortex, basal ganglia, and parietal cortex. It can be classified as object or spatial recognition and, in functional MRI studies, the activated areas overlap, including superior frontal cortex, basal ganglia, and the lateral occipital gyrus, inclusive of lingual gyrus and parts of visual areas 3a and 4 (43-47). We hypothesize that palinopsia, image persistence, and trailing phenomena may reflect dysfunctional clearance of visual information from the buffer of this system. Photophobia Photophobia is poorly understood despite being a ubiquitous symptom in ophthalmic and neurological conditions. It is best defined as pain deriving from a light stimulus that is not normally painful and commonly occurs in headache syndromes, including migraine, tension headache, cluster headache, hemicrania continua, and trigeminal autonomic cephalalgias (48). It also has been reported in diffuse cerebral pathology, such as traumatic head injury (49-51) and, less commonly, progressive supranuclear palsy, where it has been postulated as a characteristic symptom (52). Seventyfour percent of patients with VSS experience photophobia, with or without migraine (17). The pathophysiology of photophobia is unclear (53). Intrinsically photosensitive retinal ganglion cells contain melanopsin, sensitive to red and blue light, and seem to subserve non-image-related visual functions, including light sensitivity (54). Central structures implicated in the genesis of photophobia include the circuitry for circadian rhythms, a proposed pathway for aggravation of the thalamotrigeminovascular pain mechanism (55-57), visual cortex (including lingual gyrus), somatosensory cortex (58), and the anterior cingulate gyrus (an area associated with the interpretation of unpleasantness (57)). White et al: J Neuro-Ophthalmol 2018; 38: 514-521 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. State-of-the-Art Review Nyctalopia Interpretation of nyctalopia is even more problematic. As a symptom, it is associated with rod dysfunction in retinal disease, whether nutritional, inherited, metabolic, or paraneoplastic in origin (59-65). There is no evidence of anterior visual pathway disease in VS. Therefore, it seems likely that the central interpretation of information from rod photoreceptors is affected. There is some evidence to suggest that nyctalopia can be due to an impaired interaction between rod and cone receptors, possibly reflecting a central dysregulation of visual inputs (61). It also is possible that nyctalopia may be due to interference from VS. Studies of dark adaptation have not been reported in patients with VS. Tinnitus Tinnitus is a common feature in VSS (12,15,16), usually described as high pitched and continuous. Although the cause is unknown, it is to some degree dependent on peripheral input with there being evidence, on fMRI studies, for disordered regulation of inputs to both limbic and auditory networks (66). Sedley et al (67) proposed a model of tinnitus based on central spontaneous activity in subcortical auditory pathways, normally suppressed. Influences external to this pathway can raise the gain of the intrinsic tendency of "hear something" as opposed to silence. Focused attention can increase the tinnitus. This theory encapsulates the concept of disordered regulation of sensory input, similar to sensory input dysregulation being a prominent theory for VSS (12,19,68). Differential Diagnosis The main differential diagnoses of VSS include migraine and psychogenic disease. The stereotypic descriptions of VSS and the, albeit limited, physiological data available strongly support an organic pathology as the cause. Consequently, psychogenic pathology will not be discussed further. Approximately 60% of patients with VSS also experience concomitant migraine, with or without migrainous visual phenomena (15). Differentiation of VSS from migraine can be difficult, given the fact that they superficially share many characteristics and that VSS symptoms are frequently confused with persistent migrainous visual aura. Because there is a significant risk of cerebral infarction in persistent migrainous visual aura unlike VSS, this syndromic classification provides a means of differentiation from prolonged migraine aura (21). Migrainous visual disturbances are classically homonymous and do not usually involve the whole of the visual field. VSS symptoms are either global (visual flickering), monocular, or differ between the 2 eyes (entoptic phenomena). In migraine, the symptoms seem to be positively generated within the cerebral cortex (69), whereas, in VSS, we would posit that the phenomena are related to impaired processing/filtering/suppression of afferent information. This may be at the cortical or subcortical level. Given the fact that overlap between VSS and migraine syndromes with palinopsia, photophobia, nyctalopia, and tinnitus is commonly co-occurring (15), discussion of similarities and differences is appropriate. At a superficial level, positive visual phenomena occur, and may persist, in both syndromes, although substantially more so (3 months by definition) in VSS (7). Typical visual features differ, there being a more rapidly, dynamically changing nature to those features seen in migraine compared with VSS (Table 2). Neurophysiological Studies McKendrick et al (19) identified an imbalance between visual cortical inhibition and excitation in patients with VSS, consistent with elevated spontaneous, cortical excitability in primary visual cortex. Patients with VSS demonstrated elevated thresholds for differentiating target luminance from background luminance, independent of background luminance noise levels, anomalies in surround suppression of perceived contrast (a complex process involving wide-ranging networks (70,71)), and deficits seemingly relating to contrast perception rather than global form or motion (19). In migraine, patients have demonstrated elevated luminance increment thresholds multiplicative with background noise (72,73) and impaired interpretation of global form and motion, thought to be properties of areas V4 and V5, respectively (74,75). Interestingly, adaptation of visual evoked potentials to double pulses is impaired in patients with VSS, and there is reduced gamma-band frequency power after the initial stimulus (76). Gamma-band frequencies have been posited to be driven by inhibitory interneurons. This would be further supportive evidence of dysregulation of inhibitory systems in VSS. TABLE 2. Comparison of visual features of visual snow syndrome and migraine Visual Snow Syndrome Constant flickering globally in visual field Palinopsia (after images or trailing images) Nyctalopia Monocular entoptic phenomena (floaters, blue field entoptic phenomena, photopsia, and self-light of an eye) Photophobia White et al: J Neuro-Ophthalmol 2018; 38: 514-521 Migraine Gradual development of unilateral phenomena Fortification spectra Teichopsia Homonymous scotomata, with or without scintillations Photophobia 517 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. State-of-the-Art Review Neuroimaging Studies Neuroimaging studies in migraine and VSS have shown unique characteristics as well as overlap consistent with the observation of clinical overlap of these 2 disorders. Migraine On the basis of functional studies in (fMRI and positron emission tomography [PET]) patients with migraine with and without aura, there seem to be 4 types of findings: 1. Hypoperfusion: commonly spreading from the occipital region, more commonly with aura, but also without clinical aura (77). This may be a perfusion analogue of the spreading depression of Leão associated with migraine aura (78). 2. Hyperperfusion: seen in the dorsal rostral pons and midbrain, concomitant with the pain component of migraine. This is not reported with acephalgic migraine. These areas are associated with pain integration (79-81). 3. Areas of hyperperfusion and hyperactivity: on the basis of PET and fMRI imaging in cortex, commonly bilateral cingulate and other polymodal cortices, as well as in thalamus. It has been postulated that these areas are associated with conscious perception of pain rather than with pain itself. 4. Reversible vascular perfusion defects: seen in patients with aura and focal neurological symptoms in association with their migraine, in the absence of structural changes on MRI (86). Visual Snow There is to date a single neuroimaging study in VSS. Schankin et al (15) undertook combined MRI and PET studies in patients with VS syndrome. Seventeen patients with VS, 14 patients with migraine including 5 with visual aura, and 17 healthy controls were studied. The VSS group showed clear hypermetabolism of the right lingual gyrus, and the left anterior cerebellum, adjacent to the left lingual gyrus, after adjusting for the presence of typical migraine aura. The involvement of that portion of cerebellum seems counterintuitive because that region is not known to be involved with image or visual motion processing. Further investigation is required for confirmation. Migraine vs Visual Snow Studies have suggested that the lingual gyrus, which shows abnormal activity in VS, and fusiform gyrus, making up visual area V4, may be associated with photophobia (58,82,83), visual memory (84), color perception (85), and the recognition of emotion or facial expressions (86). Studies in migraine have failed to show hypermetabolism in this area in patients with interictal migraine (87-89). Other studies have demonstrated primary hypermetabolism in side-fixed aura to be in the inferior parietal lobule and the inferior frontal gyrus of the affected cortex (90), regions generally accepted as being involved in advanced visual processing (44,91). Such changes are not seen in VSS. Management of Visual Snow Syndrome Evaluation All patients require complete ophthalmic and neurological evaluation of their symptoms, paying particular attention to any history of previous disease or substance exposure that may have contributed to VSS. A careful history is essential to ensure that findings are compatible with the defined clinical syndrome (Table 3). Therapeutic Approaches VSS seems to be due to impaired processing rather than structural pathology. Characteristically, apart from early progression, which may partially represent increased awareness, it seems to be stable throughout life and is not associated with progressive visual loss. One treatment is unlikely to suit all patients. There is a paucity of clinical trials of therapy (92). Current options include: 1. Modification of subjective visual dysfunction with the selection of different hued glasses. Lauschke et al (12) investigated intuitive colorimetry in patients with VSS using dyslexia protocols, attempting to find a combination of hue, saturation, and brightness that suited each patient. Most patients believed that they improved with TABLE 3. Evaluation of patients with visual snow syndrome History Date of onset and duration Primary symptoms: visual snow, palinopsia, blue field entoptic phenomena, photophobia, nyctalopia, tinnitus, balance disorder, and peripheral sensory disturbances. History of previous investigations History of trials of therapy Examination Visual acuity, color vision, dilated fundus examination (by ophthalmologist), and computerized perimetry Investigations OCT, MRI (with SWI and DWI protocols), EEG, visual electrophysiology (including at least VEPs, photopic and scotopic ERG, and visual-evoked ERG) Research VEP habituation; studies of inhibition in visual system; neuropsychological studies; studies of cognition in the studies ocular motor system; and functional imaging (fMRI and PET scanning). DWI, diffusion-weighted imaging; EEG, electroencephalography; ERG, electroretinogram; OCT, optical coherence tomography; PET, positron emission tomography; SWI, susceptibility-weighted imaging; VEP, visual evoked potential. 518 White et al: J Neuro-Ophthalmol 2018; 38: 514-521 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. State-of-the-Art Review a particular colored filter. All patients preferred colored filters in the blue-yellow spectrum. Although far from conclusive, and substantially sensitive to methodologically induced placebo responses, this is consistent with impaired visual processing. The authors inferred that this may be part of a widespread sensory processing disorder, possibly at the thalamic level, given the frequency of tinnitus, tremor, and balance disorder, as well as migraine (12,15,41). 2. Modifying central neurochemical transmission within the central processing networks. There is some evidence that lamotrigine, which blocks voltage-sensitive sodium channels, thus downregulating glutamate, can be effective in some patients (9,93). Acetazolamide has been tried in small numbers with mixed, but encouraging, results (11,94,95). There are anecdotal reports for multiple drugs, seemingly effective in a very small number of patients. We do not recommend them in the absence of any supportive clinical trials. 3. The emotional response to the presence of VS has, in our experience, been the most successful therapeutic strategy. Careful explanation of the underlying physiological processes is imperative. We discuss the developing evidence for an abnormality of central processing of visual information. The nature of sensory processing as a learned phenomenon is discussed in lay terms but in some detail, with examples of disordered sensory processing in other systems. The structural integrity of the eye itself and also of the conducting pathways is emphasized. We also discuss the relative lack of progression of the disorder, beyond the first few months, and the lack of evidence for significant visual failure. In short, we emphasize the fact that people with VS "see" the world differently once the syndrome is established, but that they will not go blind. We find that this reassurance often allows the patient to cope better with VSS. In the presence of mild degrees of discomfort, we try counseling the patients first, and find this the most effective therapy. In the presence of intolerable symptoms, we prescribed lamotrigine, progressively increasing slowly, up to 200 mg twice a day. If no effect within 30 days at full dose or in the presence of side effects, we discontinue the medication. We then will try acetazolamide, commencing at 250 mg twice a day and increasing to a maximum dose of 1000 mg per day in divided dose if tolerated and effective. SUMMARY Cerebral processing represents the interaction of competitive processes involving the intrinsic excitability of cerebral neurons, and an array of stimulus-driven and endogenous, top-down signals. All is dependent on a pervasive inhibitory system responsible for determining the hierarchy of neural responses. Superimposed on this, executive function perWhite et al: J Neuro-Ophthalmol 2018; 38: 514-521 mits the recalculation of response depending on momentary exigencies. Processing is driven by a matrix of networks interactive at multiple levels. Inputs are polymodal, but responses are unimodal in primary cortices (96,97). Thus, if there is hyperexcitability, primary or secondary to impaired inhibition, the response will be unimodal, for example, a visual response from visual cortex. In the past, our perception of pathological sensation was restricted to loss of specific functions, defined by the conventional neurological examination. In recent years, in the basic science literature, there has emerged unequivocal evidence for convergence of multimodal afferents at multiple levels that is involved in sensory processing and augmentation of appropriate responses (97-99). Despite increasing neurophysiological evidence of multilevel, multisensory modality interaction affecting generated responses, there has been little acknowledgment in the clinical literature that such interactions occur and can be detected and measured. VSS seems to be due to dysfunctional central sensory processing, which overlaps with migraine, for which there is evidence of a different deficit of sensory processing (100). There are almost certainly other overlap syndromes, which might include auditory, vestibular, and somatosensory cortices. REFERENCES 1. Liu T, Slotnick SD, Serences JT, Yantis S. Cortical mechanisms of feature-based attentional control. Cereb Cortex. 2003;13:1334-1343. 2. Haas DC. Prolonged migraine aura status. Ann Neurol. 1982;11:197-199. 3. Hachinski VC, Porchawka J, Steele JC. Visual symptoms in the migraine syndrome. Neurology. 1973;23:570-579. 4. Luda E, Bo E, Sicuro L, Comitangelo R, Campana M. Sustained visual aura: a totally new variation of migraine. Headache. 1991;31:582-583. 5. Rastogi RG, Vanderpluym J, Lewis KS. Migrainous aura, visual snow, and "Alice in Wonderland" syndrome in childhood. Semin Pediatr Neurol. 2016;23:14-17. 6. Relja G, Granato A, Ukmar M, Ferretti G, Antonello RM, Zorzon M. Persistent aura without infarction: description of the first case studied with both brain SPECT and perfusion MRI. Cephalalgia. 2005;25:56-59. 7. Headache Classification Committee of the International Headache Society (IHS). The International Classification of Headache Disorders, 3rd edition (beta version). Cephalalgia. 2013;33:629-808. 8. Liu GT, Schatz NJ, Galetta SL, Volpe NJ, Skobieranda F, Kosmorsky GS. Persistent positive visual phenomena in migraine. Neurology. 1995;45:664-668. 9. Chen WT, Fuh JL, Lu SR, Wang SJ. Persistent migrainous visual phenomena might be responsive to lamotrigine. Headache. 2001;41:823-825. 10. Chen WT, Lin YY, Fuh JL, Haemaelaeinen MS, Ko YC, Wang SJ. Sustained visual cortex hyperexcitability in migraine with persistent visual aura. Brain. 2011;134:2387-2395. 11. Simpson JC, Goadsby PJ, Prabhakar P. Positive persistent visual symptoms (visual snow) presenting as a migraine variant in a 12-year-old girl. Pediatr Neurol. 2013;49:361- 363. 12. Lauschke JL, Plant GT, Fraser CL. Visual snow: a thalamocortical dysrhythmia of the visual pathway? J Clin Neurosci. 2016;28:123-127. 519 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. State-of-the-Art Review 13. Breslau N, Rasmussen BK. The impact of migraine: epidemiology, risk factors, and co-morbidities. Neurology. 2001;56:S4-S12. 14. Schankin CJ, Goadsby PJ. Visual snow-persistent positive visual phenomenon distinct from migraine aura. Curr Pain Headache Rep. 2015;19:23. 15. Schankin CJ, Maniyar FH, Sprenger T, Chou DE, Eller M, Goadsby PJ. The relation between migraine, typical migraine aura and "visual snow". Headache. 2014;54:957-966. 16. Renze M. Visual snow syndrome and its relationship to tinnitus. Int Tinnitus J. 2017;21:74-75. 17. Schankin CJ, Maniyar FH, Digre KB, Goadsby PJ. Visual snow -a disorder distinct from persistent migraine aura. Brain. 2014;137:1419-1428. 18. Schankin CJ, Maniyar FH, Goadsby PJ. Field-testing the criteria for visual snow (positive persistent visual disturbance). Headache. 2012b;52:898. 19. McKendrick AM, Chan YM, Tien M, Millist L, Clough M, Mack H, Fielding J, White OB. Behavioral measures of cortical hyperexcitability assessed in people who experience visual snow. Neurology. 2018;88:1243-1249. 20. Bessero AC, Plant GT. Should "visual snow" and persistence of after-images be recognized as a new visual syndrome? J Neurol Neurosurg Psychiatry. 2014;85:1057-1058. 21. Wang YF, Fuh JL, Chen WT, Wang SJ. The visual aura rating scale as an outcome predictor for persistent visual aura without infarction. Cephalalgia. 2008;28:1298-1304. 22. Jäger HR, Giffin NJ, Goadsby PJ. Diffusion-and perfusionweighted MR imaging in persistent migrainous visual disturbances. Cephalalgia. 2005;25:323-332. 23. Puledda F, Schankin C, Digre K, Goadsby PJ. Visual snow syndrome: what we known to far. Curr Opin Neurol. 2017;31:1-58. 24. Tyler CW. Some new entoptic phenomena. Vis Res. 1978;18:163301639. 25. Critchley M. Types of visual perseveration: "paliopsia" and "illusory" visual spread. Brain. 1951;74:267-299. 26. Lepore FE. Spontaneous visual phenomena with visual loss: 104 patients with lesions of retinal and neural afferent pathways. Neurology. 1990;40:444-447. 27. Trenholm S, Awatramani GB. Origins of spontaneous activity in the degenerating retina. Front Cell Neurosci. 2015;9:277. 28. Boeck K, Hofmann S, Klopfer M, Ian U, Schmidt T, Engst R, Thirkill CE, Ring J. Melanoma-associated paraneoplastic retinopathy: case report and review of the literature. Br J Dermatol. 1997;137:457-460. 29. Halpern JH, Pope HG. Hallucinogen persisting perception disorder: what do we know after 50 years? Drug Alcohol Depend. 2003;69:109-119. 30. Li Z, Dai J. Biophotons contribute to retinal dark noise. Neurosci Bull. 2016;32:246-252. 31. Burgos RCR, Cervinková K, van der Laan T, Ramautar R, van Wijk EPA, Cifra M, Koval S, Berger R, Hankemeier T, van der Greef J. Tracking biochemical changes correlated with ultraweak photon emission using metabolomics. J Photochem Photobiol B. 2016;163:237-245. 32. Barlow RB, Birge RR, Kaplan E, Tallent JR. On the molecular origin of photoreceptor noise. Nature. 1993;366:64-66. 33. Luo DG, Yue WWS, Ala-Laurila P, Yau KW. Activation of visual pigments by light and heat. Science. 2011;332:1307-1312. 34. Salari V, Scholkman F, Bókkon I, Shahbazi F, Tuszynski J. The physical mechanism for retinal discrete dark noise: thermal activation or cellular ultraweak photon emission? PLoS One. 2016;11:e0148336. 35. Salari V, Scholkmann F, Vimal RLP, Császár N, Aslani M, Bókkon I. Phosphenes, retinal discrete dark noise, negative after images and retinogeniculate projections: a new explanatory framework based on endogenous ocular luminescence. Prog Retin Eye Res. 2017;60:101-119. 36. Bókkon I. Phosphene phenomenon: a new concept. Biosystems. 2008;92:168-174. 37. Bókkon I, Scholkmann F, Salari V, Császár N, Kapocs G. Endogenous spontaneous ultraweak photon emission in the 520 38. 39. 40. 41. 42. 43. 44. 45. 46. 47. 48. 49. 50. 51. 52. 53. 54. 55. 56. 57. 58. 59. 60. formation of eye-specific retinogeniculate projections before birth. Rev Neurosci. 2016;27:411-419. Curcio CA, Sloan KR, Kalina RE, Hendrickson AE. Human photoreceptor topography. J Comp Neurol. 1990;292:497- 523. Curcio CA, Allen KA. Topography of ganglion cells in human retina. J Comp Neurol. 1990;300:5-25. Leuba G, Kraftsik R. Changes in volume, surface estimate, three-dimensional shape and total number of neurons of the human primary visual cortex from midgestation until old age. Anat Embryol. 1994;190:351-366. Gersztenkorn D, Lee AG. Palinopsia revamped: a systematic review of the literature. Surv Ophthalmol. 2015;60:1-35. Awh E, Vogel EK. The bouncer in the brain. Nat Neurosci. 2008;111:5-6. McNab F, Varrone A, Farde L, Jacaite A, Bystritsky P, Forssberg H, Klingberg T. Changes in cortical dopamine D1 receptor binding associated with cognitive training. Science. 2009;323:800-802. Courtney SM, Ungerleider LG, Keil K, Haxby JV. Transient and sustained activity in a distributed neural system for human working memory. Nature. 1997;386:608-611. Sala JB, Rama P, Courtney SM. Functional topography of a distributed neural system for spatial and nonspatial information maintenance in working memory. Neuropsychologia. 2003;41:341-356. McNab F, Klingberg T. Prefrontal cortex and basal ganglia control access to working memory. Nat Neurosci. 2008;11:103-107. Grill-Spector K, Kourtzi Z, Kanwisher N. The lateral occipital complex and its role in object recognition. Vis Res. 2001;4:1409-1422. Digre KB. Shedding light on photophobia. J Neuroophthalmol. 2012;32:68-81. Waddell PA, Gronwall DMA. Sensitivity to light and sound following minor head injury. Acta Neurol Scand. 1984;69:270-276. Bohnen N, Twijnstra A, Wijnen G, Jolles J. Tolerance for light and sound of patients with persistent post-concussional symptoms 6 months after mild head injury. J Neurool. 1991;238:443-446. Kapoor N, Ciuffreda KJ. Vision disturbances following traumatic brain injury. Curr Treat Options Neurol. 2002;4:271-280. Cooper AD, Josephs KA. Photophobia, visual hallucinations, and REM sleep behavior disorder in progressive supranuclear palsy and corticobasal degeneration: a prospective study. Parkinsonism Relat Disord. 2009;15:59-61. Main A, Vlachonikolis I, Dowson A. The wavelength of light causing photophobia in migraine and tension-type headache between attacks. Headache. 2000;40:194-199. Benarroch EE. The melanopsin system:phototransduction, projections, functions, and clinical implications. Neurology. 2011;76:1422-1427. Noseda R, Kainz V, Jakubowski M, Gooley JJ, Saper CB, Digre K, Burstein R. A neural mechanism for exacerbation of headache by light. Nat Neurosci. 2010;13:239-245. Noseda R, Burstein R. Advances in understanding the mechanisms of migraine-type photophobia. Curr Opin Neurol. 2011;23:197-202. Moulton EA, Becerra L, Borsook D. An fMRI case report of photophobia: activation of the trigeminal nociceptive pathway. Pain. 2009;145:358-363. Denuelle M, Boulloche N, Payoux P, Fabre N, Trotter Y, Gèraud G. A PET study of photophobia during spontaneous migraine attacks. Neurology. 2011;76:213-218. Ohba N, Ohba A. Nyctalopia and hemeralopia: the current usage trend in the literature. Br J Ophthalmol. 2006;90:1548-1549. Munk M, Fernandes J, Mets M, Patel JD, Johnson ML, Jampul LM. Reversible nyctalopia and retinopathy in a patient with metastatic cancer treated with anti-heat shock protein 90 therapy. JAMA Ophthalmol. 2014;132:899-901. White et al: J Neuro-Ophthalmol 2018; 38: 514-521 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. State-of-the-Art Review 61. Falcao-Reis FM, Hogg CR, Frumkes TE, Arden GB. Nyctalopia with normal rod function: a suppression of cones by rods. Eye (Lond). 1991;5:138-144. 62. Hansen BA, Mendoza-Santiesteban CE, Hedge TR III. Reversible nyctalopia associated with vitamin A deficiency after resected malignant ileal carcinoid and pancreatic adenocarcinoma. Retin Cases Brief Rep. 2018;12:127-130. 63. Moss HE. Bariatric surgery and the neuro-ophthalmologist. J Neuroophthalmol. 2016;36:78-84. 64. Bessette AP, DeBenedictis MJ, Traboulsi EL. Clinical characteristics of recessive retinal degeneration due to mutations in the CDHR1 gene an a review of the literature. Ophthalmic Genet. 2017;39:51-55. 65. Carr RE, Ripps H. Visual ISO, 1966. Visual functions in congenital night blindness. Invest Ophthalmol. 1966;5:508- 514. 66. Leaver AM, Renier L, Chevillet MA, Morgan S, Kim JH, Rauschecker JP. Dysregulation of limbic and auditory networks in tinnitus. Neuron. 2011;69:33-43. 67. Sedley W, Friston KJ, Gander PE, Kumar S, Griffiths TD. An integrative tinnitus model based on sensory precision. Trends Neurosci. 2016;39:799-812. 68. Schankin C, Maniyar F, Sprenger T, Chou D, Eller M, Goadsby P. Brain structural and neurometabolic correlates of visual snow disorder (P1.291). Neurology. 2015;84: P1.291. 69. Hadjikhani N, del Rio MS, Wu O, Schwartz D, Bakker D, Fischl B, Kwong KK, Cutrer FM, Rosen BR, Tootell R, Sorensen AG, Moskowitz MA. Mechanisms of migraine aura revealed by functional MRI in human visual cortex. Proc Natl Acad Sci U S A. 2001;98:4687-4692. 70. Nurminen L, Angelucci A. Multiple components of surround modulation in primary visual cortex: multiple neural circuits with multiple functions? Vis Res. 2014;104:47-56. 71. Shushruth S, Nurminen L, Bijanzadeh M, Ichida JM, Vanni S, Angelucci A. Different orientation tuning of near- and farsurround suppression in macaque primary visual cortex mirrors their tuning in human perception. J Neurosci. 2013;33:106-119. 72. Wagner D, Manahilov V, Loffler G, Gordon GE, Dutton GN. Visual noise selectively degrades vision in migraine. Invest Ophthalmol Vis Sci. 2010;51:2294-2299. 73. Webster KE, Dickinson JE, Battista J, McKendrick AM, Badcock DR. Evidence for increased internal noise in migraineurs for contrast and shape processing. Cephalalgia. 2012;32:125-139. 74. Ditchfield JA, McKendrick AM, Badcock DR. Processing of global form and motion in migraineurs. Vis Res. 2006;46:141-148. 75. McKendrick AM, Badcock DR. Motion processing deficits in migraine. Cephalalgia. 2004;24:363-372. 76. Luna S, Lai D, Harris A. Antagonistic relationship between VEP potentiation and gamma power in visual snow syndrome. Headache. 2017;117:199-144. 77. Woods RP, Iacoboni M, Mazziotta JC. Brief report: bilateral spreading cerebral hypoperfusion during spontaneous migraine headache. N Engl J Med. 1994;331:1689-1692. 78. Lauritzen M. Pathophysiology of the migraine aura. The spreading depression theory. Brain. 1994;117:199-210. 79. Weiller C, May A, Limmroth V, Jüptner M, Kaube H, Schayck RV, Coenen HH, Diener HC. Brain stem activation in spontaneous human migraine attacks. Nat Med. 1995;1:658-660. 80. Afridi SK, Matharu MS, Lee L, Kaube H, Friston KJ, Frackowiak RSJ, Goadsby PJ. A PET study exploring the laterality of brainstem activation in migraine using glyceryl trinitrate. Brain. 2005;128:932-939. 81. Bahra A, Matharu MS, Buchel C, Frackowiak RS, Goadsby PJ. Brainstem activation specific to migraine headache. Lancet. 2001;357:1016-1017. White et al: J Neuro-Ophthalmol 2018; 38: 514-521 82. Maniyar FH, Sprenger T, Schankin C, Goadsby PJ. Photic hypersensitivity in the premonitory phase of migraine-a positron emission tomography study. Eur J Neurol. 2014;21:1178-1183. 83. Boulloche N, Denuelle M, Payoux P, Fabre N, Trotter Y, Géraud G. Photophobia in migraine: an interictal PET study of cortical hyperexcitability and its modulation by pain. J Neurol Neurosurg Psychiatry. 2010;81:978-984. 84. Roland PE, Gulyás B. Visual memory, visual imagery, and visual recognition of large field patterns by the human brain: functional anatomy by positron emission tomography. Cereb Cortex. 1995;5:79-93. 85. Zeki S, Watson JD, Lueck CJ, Friston KJ, Kennard C, Frackowiak RS. A direct demonstration of functional specialization in human visual cortex. J Neurosci. 1991;11:641-649. 86. Kitada R, Johnsrude IS, Kochiyama T, Lederman SJ. Brain networks involved in haptic and visual identification of facial expressions of emotion: an fMRI study. Neuroimage. 2010;49:1677-1689. 87. Aurora SK, Barrodale PM, Tipton RL, Khodavirdi A. Brainstem dysfunction in chronic migraine as evidenced by neurophysiological and positron emission tomography studies. Headache. 2007;47:996-1003; discussion 1004- 7. 88. Kim JH, Kim S, Suh SI, Koh SB, Park KW, Oh K. Interictal metabolic changes in episodic migraine: a voxel-based FDGPET study. Cephalalgia. 2010;30:53-61. 89. Niazi AK, Andelova M, Sprenger T. Is the migrainous brain normal outside of acute attacks? Lessons learned from psychophysical, neurochemical and functional neuroimaging studies. Expert Rev Neurother. 2013;13:1061-1067. 90. Hougaard A, Amin FM, Hoffmann MB, Rostrup E, Larsson HBW, Asghar MS, Larsen VA, Olesen J, Ashina M. Interhemispheric differences of fMRI responses to visual stimuli in patients with side-fixed migraine aura. Hum Brain Mapp. 2014;35:2714-2723. 91. Van Essen DC, Gallant JL. Neural mechanisms of form and motion processing in the primate visual system. Neuron. 1994;13:1-10. 92. Bou Ghannam A, Pelak VS. Visual Snow: a potential cortical hyperexcitability syndrome. Curr Treat Options Neurol. 2017;19:9. 93. Unal Cevik I, Yildiz FG. Visual snow in migraine with aura: further characterization by brain imaging, electrophysiology, and treatment-case report. Headache. 2015;55:1436- 1441. 94. Haan J, Sluis P, Sluis LH, Ferrari MD. Acetazolamide treatment for migraine aura status. Neurology. 2000;55:1588-1589. 95. De Simone R, Marano E, Di Stasio E, Bonuso S, Fiorillo C, Bonavita V. Acetazolamide efficacy and tolerability in migraine with aura: a pilot study. Headache. 2005;45:385-386. 96. Ghazanfar AA, Schroeder CE. Is neocortex essentially multisensory? Trends Cogn Sci. 2006;10:278-285. 97. Murray MM, Thelen A, Thut G, Romei V, Martuzzi R, Matusz PJ. The multisensory function of the human primary visual cortex. Neuropsychologia. 2016;83:161-169. 98. Lewis JW. Audio-visual perception of everyday natural objects -hemodynamic studies in humans. In: Multisensory Object Perception in the Primate Brain. New York, NY: Springer, 2010:155-190. 99. Lewis R, Noppeney U. Audiovisual synchrony improves motion discrimination via enhanced connectivity between early visual and auditory areas. J Neurosci. 2010;30:12329-12339. 100. Goadsby PJ, Holland PR, Martins-Oliveira M, Hoffmann J, Schankin C, Akerman S. Pathophysiology of migraine: a disorder of sensory processing. Physiol Rev. 2017;97:553- 622. 521 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited.