Should Visual Snow and Visual Snow Syndrome Be Evaluated Outside of Standard In-clinic Ophthalmologic Testing?

Point Counter-Point Section Editors: Andrew G. Lee, MD Gregory P. Van Stavern, MD Should Visual Snow and Visual Snow Syndrome Be Evaluated Outside of Standard In-clinic Ophthalmologic Testing? Clare E. Fraser, MD, Michael S. Vaphiades, DO, Gregory P. Van Stavern, MD, Andrew G. Lee, MD Drs. Lee and Van Stavern Patients with visual snow (VS) symptoms present to neuro-ophthalmology clinics with increasing frequency. The differential diagnosis is large, and it remains unclear as to whether these patients need diagnostic testing beyond what is accomplished in the clinic. Two experts debate this topic. Pro: Clare Fraser, MD Visual snow syndrome (VSS) is the perception of constant, diffuse, flickering dots across the entire visual field (VS) akin to that seen on a poorly tuned analog television. Recently, diagnostic criteria have been proposed for VSS including (1) dynamic continuous tiny dots in the entire visual field lasting longer than 3 months; presence of at least 2 additional symptoms: palinopsia, photophobia, nyctalopia, and other persistent positive visual phenomenon; symptoms not consistent with typical migraine visual aura; and symptoms not better explained by another disorder. Although most VSS are idiopathic and ophthalmic, other neurological conditions can present with features such as VSS. The diagnostic criteria for idiopathic VSS require that no other disorder could be a better explanation for the symptoms; therefore, I believe that it is incumbent on us to fully investigate these patients. Case for requesting an electroretinogram The most common ophthalmic causes of photopsia and other entopic phenomenon are seen in ocular conditions such as posterior vitreous detachment, retinal tears, ageFaculty of Health and Medicine (CF), Department of Ophthalmology, Save Sight Institute, University of Sydney, Sydney, Australia; Departments of Ophthalmology, Neurology and Neurosurgery (MV), University of Alabama, Birmingham, Alabama; Department of Ophthalmology and Visual Sciences (GPV), Washington University in St. Louis School of Medicine, St Louis, Missouri; and Department of Ophthalmology, Blanton Eye Institute (AGL), Houston Methodist Hospital, Houston, Texas. The authors report no conflicts of interest. Address correspondence to Gregory P. Van Stavern, MD, Department of Ophthalmology and Visual Sciences, Washington University in St. Louis School of Medicine, St Louis, MO 63110; E-mail: [e-mail] 384 related macular degeneration (AMD), and retinitis pigmentosa (2). These cases would often not require testing outside of a standard ophthalmic consultation. However, up to 11% of retinitis pigmentosa (RP) can present in the early phases without clinically visible pigmentary deposits (i.e., RP sine pigmento) (3). In a Korean study of 28 patients referred for a suspected diagnosis of VSS, 6 of 28 (20%) had an alternative diagnosis. One patient with VS had typical migraine with a scintillating scotoma and another had transient photopsia after refractive surgery. One case had rod–cone dystrophy (4) and was aged 36 years with 6 months of VS affecting the whole visual field, photosensitivity, excess floaters, and blue field entoptic phenomenon. Full-field electroretinography (ffERG) demonstrated severely attenuated rod responses and mildly attenuated cone responses. Although VS or an increased awareness of photopsia has been described in RP, this generally occurs in patients with abnormal ocular examinations and reduced central acuity (5). A case of birdshot chorioretinopathy with VS described as a constant flickering disturbance in the vision and was misdiagnosed as VSS until an electroretinogram (ERG) was performed (6). Autoimmune retinopathy is characterized by circulating antiretinal antibodies that cause photoreceptor dysfunction. Patients present with photophobia and positive visual scintillations that are often described as gold or silver shimmering in the visual periphery (7). The shimmering is most noticeable in the dark and persists with the eyes closed. A careful history can usually differentiate this symptom from VSS, and the diagnosis can be confirmed with an ERG. Further evidence for an ERG in cases of VSS comes Fraser et al: J Neuro-Ophthalmol 2022; 42: 384-389 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Point Counter-Point from a case series of patients with glycine receptor autoimmunity who described symptoms of VS, palinopsia, and positive visual phenomena. This was believed to be due to dysregulation of the GlyRa1 inhibitory neurotransmitter in the human retina (8). One patient in this series had classic VS, palinopsia, and photophobia. Based on these cases, visual electrophysiology, including an ERG, could be considered. Case for requesting MRI Any neurological abnormality of the visual cortex has the potential to trigger the perception of VS. The differential diagnosis could include stroke, epilepsy, multiple sclerosis, neoplastic disease, and degenerative diseases (9). Episodic VS may also occur in migraine and occipital lobe epilepsy, but as noted above, the presence of alternative etiologies for VS would not fulfill the diagnostic criteria for idiopathic VSS (10). However, there is a published case series of 2 adolescents who otherwise fulfilled the diagnostic criteria for VSS, who both had pathological EEG findings of epileptiform activity with photic stimulation (11). In the Korean study of 28 patients referred with VSS, one had a final diagnosis of idiopathic intracranial hypertension (4). This patient presented with silver spots across the visual field for 10 years, photopsia, entoptic phenomenon, nyctalopia, and tinnitus. This patient also had headaches diagnosed as migraine and disk elevation labeled as disk drusen; however, MRI and MR venography showed a partial dural venous sinus stenosis and opening pressure of 28.5 cm H2O on lumbar puncture. After 3 weeks of acetazolamide, the VS and photopsias resolved. Another case report details a 55-year-old man with 15 months of VS across his whole visual field, poor night vision, and photopsias. Initial ophthalmic examination was normal. However, over subsequent months, he developed spatial disorientation, myoclonus, and ataxia. Cranial MRI showed occipital cortical ribboning, and he was diagnosed with Heidenhain variant of Creutzfeldt–Jakob disease on brain biopsy. These authors recommend neuroimaging with review for occipital lobe findings in this setting (12). Conclusion Given that the diagnostic criteria of VSS are still quite new in our neuro-ophthalmic lexicon, the physician’s recognition of the classic syndrome compared with the potential red flags may not be fully formed. Therefore, it could be argued that ERG and MRI are still required as part of this diagnosis of exclusion. Con: Patients With Visual Snow Syndrome Do Not Need an Extensive Workup Beyond Office-Based Testing Michael S. Vaphiades, DO In this point–counterpoint exercise, I was charged with the task of trying to convince the readership and my esteemed colleague Dr. Fraser that no further workup is required for VS and VSS beyond the standard history, ophthalmologic examination, and testing including automated visual fields and spectral domain optical coherence tomography (SDOCT) that one would perform in the clinic setting. Implicit in the statement is that electrophysiologic studies such as ffERG or multifocal ERG (mfERG) and neuroimaging such as MRI of the brain and orbits should not be obtained in patients with “typical” or “primary” VSS. To put it another way, VS or VSS originated at an early age, is nonprogressive, and is typical in historical presentation and the patient has a normal neuro-ophthalmologic examination including automated perimetry and macular SD-OCT; then, workup beyond office-based testing is generally unnecessary. To delineate my argument, it is important to divide VSS into “primary” and “secondary.” Primary VSS is defined as symptoms that develop without an inciting event or known cause, and secondary VSS is defined as symptoms arising from a secondary cause such as head trauma (immediate or delayed onset), hallucinogenic drugs, or other chronic neurological or ophthalmologic disorders (13). This is in contradistinction to VSS associations which may occur with primary VSS including Fraser et al: J Neuro-Ophthalmol 2022; 42: 384-389 migraine (reported in approximately 50%–80%) (13–16), concentration problems (80%), tinnitus (approximately 50%– 60%), irritability (55%), and lethargy (40%) (16). A recent web-based survey of 1,100 patients with VSS, however, showed that tinnitus had the highest prevalence and migraine was second, both of which were closely associated with severity of the VSS, which should be viewed as a spectrum from a mild to severe (17). Another recent study using an online questionnaire relating to psychiatric symptomology revealed that psychiatric symptoms were highly prevalent in VSS including anxiety, depression, depersonalization, and disrupted sleep (18). Thus, before we diagnose VSS and determine what is a typical association and what is not, it is important to understand the question, “What exactly is VS and VSS?” Historically, VS was first described by Liu et al (19) in 1995 as an “unusual complication of migraine” manifesting as “persistent diffuse small particles such as TV static, snow, lines of ants, dots, and rain” occupying the patient’s entire visual field. It is a continuous pan-field visual disturbance (usually black and white or transparent dots) like looking at an old analog television where the reception is poor (17,20). It generally occurs at an early age and in 40% has been present from the patient’s earliest memories, there is no sex predilection, and it lasts for months to years without underlying etiology identified (13,17). The syndrome was 385 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Point Counter-Point first referred to as “visual snow phenomena” in 2005 (21) and later as VSS (22) with VS as the defining characteristic of the VSS, which includes other visual and perceptual symptoms (20,23). In 2014, Schankin et al proposed a definition of VSS as dynamic, continuous, tiny dots across the entire visual field, persisting for .3 months plus at least 2 of the following 4 types: 1. Palinopsia. 2. Enhanced entoptic phenomena with at least one of the following: excessive floaters in both eyes, excessive blue field entopic phenomena (uncontrollable grey/white/black dots or rings shooting over the visual field in both eyes when looking at homogeneous bright surfaces such as the sky), self-light of the eye (colored waves or clouds when closing the eyes in the dark), or spontaneous photopsia. 3. Photophobia. 4. Nyctalopia with symptoms not consistent with typical migraine visual aura and symptoms which are not better accounted for by another disorder (20). In 2018, these criteria were adopted by the International Headache Society (24). Pathophysiologically, there seems to be changes in the visual and auditory cortices in studies using [18F]fluorodeoxyglucose (FDG) positron emission tomography (PET) and magnetic resonance Imaging (MRI) suggesting a difference in interoceptive processing with constant perception of altered visual input (15,25). Thus, perhaps, explaining the association of VSS with migraine aura and tinnitus. However, recent data indicate that the most likely pathophysiology of VS is a combination of peripheral, thalamic, and cortical dysfunction (7). Beyond the ophthalmological history and examination, it is controversial whether ancillary testing such as brain imaging and electrophysiological testing is required in the workup of patients presenting with VSS. In 2014, Schankin et al retrospectively identified 22 patients with VS, 15 patients had additional visual symptoms, and 20 patients had comorbid migraine, 5 of which had migraine aura. The authors concluded that “remarkably, most patients with VS have normal best corrected visual acuity, perimetry, and fundoscopy” and “any association with visual loss or acute onset of visual symptoms such as VS, especially floaters and photopsia, would therefore require appropriate assessment by a specialist before calling it VSS” (20). Finally, the cost and safety concerns of MRI and ERG testing need addressing. It is difficult to obtain figures concerning the financial impact of unnecessary testing in primary patients with VSS. The disorder is estimated in the United Kingdom at only 2% of the population (26). However, financial impact to the patient may be considerable depending on their insurance carrier. The cost of a brain MRI varies by city and facility and can be substantial, costing thousands of dollars. An ERG is less costly, typically in the hundreds, both of which may be financially devastating to an uninsured patient. The safety issues associated with MRI and ERG are not inconsequential. There are a myriad 386 of potential complications from cranial MRI and ERG outside the scope of this article; however, in the primary VSS population which are usually younger and healthy, anxiety and claustrophobia are the main MRI concerns as is the retention of gadolinium-based contrast agents in the brain for months to years after receiving it. Corneal abrasion from the Burian–Allen electrode used in the mERG (not the ffERG) is also very distressing to both the patient, technician performing the test, and physician interpreting the test. There is also a risk of an incidental MRI and ERG finding being blamed as the cause of the VS which may result in further unnecessary testing and even surgery. The extended workup can be costly and is not without risk. It is important for the clinician to distinguish between primary vs secondary VSS that originates from a potentially life-threatening or vision-threatening disorder. Like other higher visual disorders that neuro-ophthalmologists evaluate, it is a complex syndrome characterized in some by debilitating symptoms (27) and likely results from widespread disturbance of sensory processing and sensory misperception (28). This is not a diagnosis which should be made over the phone; it is nuanced and thus illustrates the importance of a thorough history and examination when evaluating these patients. The key to a primary VSS diagnosis is that the VS typically presents at an early age, is constant, involves the entirety of the visual field, and has a completely normal ophthalmic examination including automated perimetry and macular SD-OCT. This type of patient with VSS generally does not require further workup with electrophysiologic testing and neuroimaging. Pro Rebuttal: Clare Fraser, MD There will always be a balance between overinvestigating and underinvestigating patients, with the risk of false positive or incidental results. This patient group often has some health-related anxiety, which can be alleviated or exacerbated by certain investigations. The history is crucial in visual snow syndrome. With these newer diagnostic criteria, we need to make sure that we are aware of all the features, particularly if the diagnostic criteria are updated. We also need to know which secondary causes of visual snow need to be detailed in the history. A thorough ophthalmic investigation, including visual fields, OCT with raster images at the macula, and even wide-field fundus autofluorescence, should be adequate to exclude the pathologies listed in the literature. Further investigations with ERG and MRI remain available if the symptoms are not completely in keeping with visual snow or if the patient’s history changes and progresses with time. In the past, patients with visual snow syndrome were dismissed as having migraine or purely psychiatric problems. Even with better recognition and understanding of the condition, it remains important that patients with secondary visual snow or other unusual positive visual phenomenon are not dismissed as merely having visual snow syndrome. Fraser et al: J Neuro-Ophthalmol 2022; 42: 384-389 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Point Counter-Point Rebuttal: Michael Vaphiades, DO Dr. Fraser makes some excellent points, and we agree that the cases of patients with secondary VS and VSS should be evaluated beyond the usual testing obtained in the clinic if there is any indication of disorders reported that can mimic VS such as rod–cone dystrophy and idiopathic intracranial hypertension (IIH) as noted above by Yoo et al (4), Creutzfeldt–Jakob disease (12), paraneoplastic syndromes such as glycine receptor antibody syndrome (8), head trauma (immediate or delayed onset) (13), and hallucinogen-persisting disorder (7,9,29). Basically, any neurological condition that affects the occipital lobe may trigger or mimic VS including epilepsy, posterior cortical atrophy, stroke (10), and positive spontaneous visual phenomena from visual deprivation (Charles Bonnet syndrome) from ocular, optic nerve, and tract, chiasmal, or postchasmal etiologies (7,30,31). In addition, retinal diseases such as cancer-associated or melanoma-associated retinopathy (32), retinitis pigmentosa, uveitis, age-related macular degeneration, central serous retinopathy, multifocal choroiditis with macular involvement, birdshot chorioretinopathy, and optic atrophy have been associated with VS (10). Again, a thorough history and ophthalmologic examination and testing in the clinic should easily identify these secondary patients with VSS. Dr. Fraser reviewed the article on the novel clinical features of GlyRa1-IgG–positive patients. These patients usually exhibit muscle cramping, spasticity, hyperekplexia, gait disturbance, cerebellar and/or parkinsonian signs, and stiff person syndrome (SPS) (8). One patient Dr. Fraser discussed (patient 2 in the table on-line) was a 41-yearold woman who had a several year history of visual snow, palinopsia, photophobia, intermittent diplopia, and visual hallucinations before lower extremity stiffness and spasms. I submit that the diplopia and visual hallucinations and the relatively recent onset of symptoms (compared with classic visual snow patients who note the VS “their whole life”) move the case to secondary VSS and thus does indeed warrant further workup but should not be confused with primary VSS. Dr. Fraser referenced a published case series of 2 adolescents who would otherwise fulfill the diagnostic criteria for VSS, both of whom had pathological EEG findings of epileptiform activity with photic stimulation (11). In this series, the authors state that “both patients fulfill the diagnostic criteria for visual snow.” They further go on to list the 2014 Schankin et al (20) criteria for VSS. However, after reviewing these cases, neither patient does fulfill these criteria. The first was an 11-year-old girl with VS who in bright light had difficulties to identifying objects associated with photophobia. She also had paroxysms of seeing unreal objects. I submit this is much more than photophobia and does not therefore fulfill the criteria for VSS. The second patient with VS was a 13-year-old Fraser et al: J Neuro-Ophthalmol 2022; 42: 384-389 boy had a focal visual seizure evolving to bilateral tonicclonic at the age of 12 years. The patient’s vision would suddenly get dark, objects seemed to move, and he felt as if he was “compressed.” He heard sounds repetitively, and he had “blackouts,” where he was not able to react immediately. This is obviously much more than VS with the altered consciousness, auditory hallucinations, and inability to react. Both these cases do not fulfill the criteria of VSS. Dr. Fraser also specifically referenced the Korean article in 2020 by Yoo et al (4) who retrospectively reviewed 28 patients with “positive visual disturbance” with VS diagnosed in 20 subjects according to the proposed Schankin et al criteria (20), noted above. These patients had ophthalmic examinations, standard automated perimetry, retinal nerve fiber layer (RNFL) assessment using SD-OCT, pupillometry, and contrast sensitivity testing; ffERG and mfERG were also performed. Among the 8 patients excluded, 2 had secondary VSS with underlying pathologies of IIH and rod–cone dystrophy which were obvious from the history, examination, and in-clinic testing without MRI, ERG, or EEG. The IIH patient discussed by Dr. Fraser had papilledema, enlarged blind spots on the automated field on my interpretation of the fields (but read as “normal” in the article), and abnormal RNFL assessment using SD-OCT. This case was easily diagnosed with in-clinic testing as secondary VSS without an MRI or ERG. The patient with rod–cone dystrophy had a color deficit on the color plates and binasal defects on automated perimetry. Again, easily diagnosed as secondary VSS prompting the ERG which was abnormal but not necessary to rule-out primary VSS. The authors concluded that “visual snow can be the chief complaint of an underlying retinal or neurological disease, and a thorough ophthalmic examination including electrophysiological testing is necessary before making a diagnosis of visual snow syndrome” (4). After reading this article, I believed that these 2 patients were easily excluded from having primary VSS using standard diagnostic testing in the clinic without ERG or brain MRI. Dr. Fraser discussed the article by Chen et al of the patient with the Heidenhain variant of CJD. These authors reported a 55-year-old man with 15 months of slowly progressive visual symptoms that began in June 2013 with snowing of his vision and photopsia, and 3 months after onset of symptoms, he noticed that whenever he tilted his head objects in his visual field appeared to rotate in the opposite direction. This history already puts the case into secondary VSS category in that the VS started at a late age was progressive, and there was a torsional component. On examination, there was a profound color vision deficit, and he struggled to use familiar items such as jackets with zippers, he became disoriented in unfamiliar places and had problems locating items in space. The neurological examination revealed left homonymous hemianopia, ocular 387 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Point Counter-Point apraxia, and difficulty maintaining lateral gaze. This clearly is not a case of primary VSS, and he would of course be evaluated with brain MRI and ERG (12). I agree with Dr. Fraser that there are a variety of retinal and neurologic cases that require an ERG, MRI, and even EEG; however, these patients do not present nor examine as primary patients with VSS. The real question is what should be the usual or perhaps standard diagnostic evaluation in patients with VS and VSS? To answer this, my group retrospectively evaluated 52 consecutive patients with the disorder. Historical information, examination findings, ophthalmic testing, electrophysiology, and neuroimaging were collected. Of the 52 patients with VS and VSS, 8 of 52 met the clinical criteria for VSS and the rest had VS. The ages ranged from 7 to 79 years, with a mean age of 25 years (SD = 14.0). There were 22 male patients and 30 female patients. Color vision was tested in 51 cases and was normal in 47 cases (92%). A funduscopic examination was performed in all 52 cases and was normal in 46 cases (88%). The macular SD-OCT was normal in all the 19 cases that it was performed (100%). A automated visual field was performed in 50 cases and was normal in 43 (86%). A visually evoked potential (VEP) was normal in 18 of the 19 cases where it was obtained (95%). The ffERG was obtained in 28 cases and was normal in 25 (89%). The mfERG was normal in 11 of 12 cases (92%). Only 4 patients accounted for all the abnormal electrophysiological tests, and they are as follows. 1. A ffERG showed abnormally depressed in the left eye. This patient had deprivation amblyopia in the left eye secondary to congenital hemangioma of the left upper lid. 2. A mfERG was abnormal. This patient also had pathologic high myopia (214.00 diopters in the right eye and 213.00 diopters in the left eye), which appeared to be responsible for the abnormal mfERG. 3. A ffERG was abnormally depressed in the right eye. This patient complained of monocular visual loss in that eye. 4. Both VEP and mfERG were abnormal and were initially believed to be related to high myopia and keratoconus; however, the ffERG was abnormal as well, which prompted genetic testing revealing a MYO7A variant, which is associated with autosomal recessive Usher type. Thus, all 4 cases had other complaints, and examination findings accounting for the abnormalities other than the VS complaint putting these cases squarely in the secondary VSS category. Neuroimaging was also generally unrevealing. Overall, 43 patients had cranial neuroimaging: 9 had computed tomography (CT), 37 had MRI, and 3 had both. All 9 of the cases that had a CT of the head were normal (100%). In the 37 cases that had an MRI, 29 were normal (78%). The abnormalities among these 8 MRI patients ranged from 1. a right cerebellar hemispheric lesion “scar,” 2. fluid-attenuated inversion recovery MRI changes in the thalamic and subthalamic regions, 3. tonsillar ectopia and mild ventriculomegaly, 4. areas of periventricular white matter changes, 5. enhancement of the right optic nerve just before the chiasm, 6. small amount of fluid in the air cells of the right petrous pyramid, 7. right frontal deep vein abnormality, and 8. leftsided cerebellar venous angioma. Only 1 patient revealed a lesion in the visual pathway (right optic nerve enhancement in an optic neuritis patient), clearly secondary VSS (33). In summary, the diagnostic evaluation of VS and VSS can be nuanced, and the diagnosis should be made on a case-by-case basis; however, the VSS originated at an early age, is nonprogressive, and is typical in historical presentation, and the patient has a normal neuroophthalmologic examination including automated perimetry and macular SD-OCT; then, ancillary testing is generally unnecessary. Final Comments by Andrew G. Lee MD and Greg Van Stavern MD VS is the primary symptom of idiopathic VSS. Patients with VS may have primary (idiopathic) or secondary VSS. As with other idiopathic conditions (e.g., idiopathic intracranial hypertension), the symptoms should be consistent with typical VS, the ocular examination should not have any other findings to better explain VS, and there should not be other signs or symptoms other than REFERENCES 1. Metzler AI, Robertson CE. Visual snow syndrome: proposed criteria, clinical implications, and pathophysiology. 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