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Abstract

Background

Visual Snow Syndrome is a recently recognized neurological condition presenting, continuous, tiny dots across the entire visual field, accompanied by nyctalopia, photophobia and palinopsia that persist for months. It may be part of migraine aura spectrum, yet its definition is still questionable. Diagnostic criteria for Visual Snow Syndrome are included in the supplemental material of ICHD-3. We aimed to summarize recent data to improve the understanding of Visual Snow Syndrome.

Methods

After presenting four new cases, we conducted a PRISMA systematic search in PubMed/MEDLINE and Embase databases using the keyword “visual snow” with specific inclusion and exclusion criteria.

Results

From the 855 articles identified 30 were included for the qualitative analysis. These reports covered five aspects related to Visual Snow Syndrome: epidemiology, clinical features, comorbidities, pathophysiology, and treatment. We found limited data concerning Visual Snow Syndrome’s epidemiology (one study). Clinical presentation (22 articles) and the comorbidities (migraine with aura and tinnitus most often, five reports) are described in detail. The pathophysiology of Visual Snow Syndrome is only approached with hypotheses, but several neuroimaging studies have been identified (seven articles). Treatment is based on single case reports only.

Conclusion

Data for Visual Snow Syndrome are few and not strong enough to support Visual Snow Syndrome as a medical identity. Further investigation is needed.

Keywords

Visual Snow Syndrome persistent visual disturbances entopic phenomena comorbidity migraine

Introduction

The first case series of 10 patients with migraine who developed positive visual phenomena consisting of diffuse small particles such as TV static, snow, lines of ants, dots, and rain that were covering the entire visual field was published in the middle of the 1990s (1). Two cases with advanced neuroimaging investigations were published, 10 years later (2). In 2014, a three-step approach study (retrospective chart review, retrospective web-based survey and prospective semi-structured telephone interview) aiming to identify the phenotype of the condition was published (3) and in 2018, Visual Snow Syndrome (VSS) was included in the supplemental material of the International Classification of Headache Disorders (ICHD-3, code A1.4.6), as a complication of migraine, although it is not considered as a part of the migraine spectrum per se (4). ICHD-3 diagnostic criteria (4) require that patients experience persisting visual snow (dots across the entire visual field) accompanied by excessive entoptic phenomenon, palinopsia, photophobia and/or nyctalopia. Recent evidence suggests that Visual Snow (VS) may be the main symptom of a compound neurological syndrome (3,5) but data are lacking, thus collection of clinical material is essential to promote awareness of it, expand our understanding and develop useful therapeutic approaches (6). To date, just one systematic review study exists regarding only the pathophysiology and treatment of VSS (7). Prompted by a series of four VSS cases from our headache clinic, we conducted a systematic review to summarize the current understanding.

Case series

Out of 890 patients visiting the tertiary Headache Centre at Eginition Hospital during 2021, four patients fulfilled the ICHD-3 criteria for VSS (Table 1). All patients provided informed consent for this publication.

Table 1.

Case series summary: Main visual snow features.

	Case 1	Case 2	Case 3	Case 4
Age in years/gender	18/male	37/male	19/male	35/female
Duration of visual dots	6 months	3 months	4 months	2 months
Additional	Photopsia	Photopsia	Photopsia	Photopsia
Visual symptoms	Palinopsia Nyctalopia	Palinopsia	Palinopsia	Palinopsia
Comorbid conditions
Migraine with aura	No	Yes (∼5 years)	Yes (4 years)	Yes (∼18 years)
Migraine without aura	No	No	Yes (4 months)	No
Tinnitus	Yes (6 months)	Yes (5 years)	No	Yes (1 year)
Psychotropic drug intake	No	No	No	No
Family history for migraine	No	No	Yes	Yes
Clinical examination
Neurological	Normal	Normal	Normal	Normal
Ophthalmological	Normal	Normal	Normal	Normal
Laboratory tests
Brain MRI	Normal	Normal	Normal	Normal
Blood tests	Normal	Normal	Normal	Normal
Treatment	Lamotrigine 75 mg/day	Lamotrigine 75 mg/day	None	Amitriptyline 25 mg/day

Case report 1

An 18-year-old male experienced persistent visual phenomena for six months. He described grey or black dots expanding through his entire visual field, consistent with typical visual static. The patient also experienced enhanced entoptic phenomena when his eyes were closed, described as waves or lines and spontaneous photopsia, and had an impairment of his vision during the night (nyctalopia). Prior to these symptoms, he had reported tinnitus in his left ear. He had no personal nor family history of migraine, neurological, or other diseases, no psychotropic drug intake, tobacco or alcohol consumption. Neurological, physical, and ophthalmological examinations were normal, along with 3T brain magnetic resonance tomography (MRI) scan and extensive blood tests. Therefore, VSS was diagnosed. Treatment with oral lamotrigine 75 mg/day demonstrated with a sufficient response, defined as reduction of frequency of enhanced entoptic phenomena, from twice a week to approximately once per month.

Case report 2

A 37-year-old healthy male described tiny flickers, “like snow”, in his entire visual field occasionally accompanied by palinopsia and photopsia, for three months. He experienced hyperacusis and lowered tolerance to daily environmental sounds. He had been suffering from chronic migraine, and bilateral tinnitus since 2016. The neurological and ophthalmological examination, 1.5T brain MRI scan, and blood tests were normal. After the diagnosis of VSS oral lamotrigine 75 mg/day was started. The patient reported remission of visual static symptom and migraine attacks/per month three months later. Long-term efficacy is yet to be determined.

Case report 3

A 19-year-old male described flickering dots in his entire visual field persisting for four months, accompanied by photopsia. Specifically, the patient complained about grey television static (visual snow) and bright flashes of light (spontaneous photopsia). The patient had previously experienced bilateral tinnitus, for four months. The visual static and tinnitus co-existed for a few days. He developed migraine without aura since then. There was no other medical history or psychotropic drug intake. Neurological and ophthalmological examination, 1.5T brain MRI, blood tests, and electroencephalogram (EEG) were normal. The suspicion of VSS was raised for this patient. Though the ICHD-3 criteria for VSS were fulfilled, no medication was prescribed as the patient did not find those symptoms disturbing. The patient is currently under close medical follow-up.

Case report 4

A 35-year-old female patient presented with tiny dots in her visual field, more peripherally than centrally. Visual dots started two months ago and were persistent, without remission during the day and accompanied by spontaneous photopsia and visual after-images during the last month. The patient had also been suffering from episodic migraine without aura since adolescence. Her past pertinent medical history also revealed thyroiditis Hashimoto, with normal thyroid stimulating hormone (TSH). No other drug intake was reported in the medical history. Neurological and ophthalmological examination, blood tests, brain 1.5T MRI and EEG were normal. Treatment with amitriptyline 25mg/od was started and the patient is to be re-evaluated at outpatient clinic.

Systematic review

Methods

This review has been conducted in accordance with the Preferred Reporting Items for Systematic Review and Meta-analysis Protocols (PRISMA) statement (8). A systematic literature search was conducted through June 2021 to identify original research articles for VS as a whole. The following electronic bibliographic databases were searched from inception until 1 July 2021: PubMed/MEDLINE and Embase. Two investigators (SNS and LL) independently examined all titles and abstracts retrieved from the search. The search term “visual snow” was used in combination with the terms “persistent visual disturbances”, “epidemiology”, “comorbidity”, “migraine”, “treatment”, “pathophysiology”. The full texts of articles identified as relevant during the first screening stage were obtained and reviewed. In case of disagreement during the eligibility assessment, another investigator™ reviewed the abstract/full text in question and made a final approval. DDM revised the manuscript for intellectual content and supervised the entire project. The different phases of the systematic review performed including the systematic review search strategy (Supplemental Material e-1), inclusion and exclusion criteria (Supplemental Material e-2) and PRISMA screening and eligibility strategy (Supplemental Material e-3, Figure 1) are described in the supplementary material.

Figure 1.

PRISMA flow diagram.

Results of the literature search

We identified 82 eligible articles for inclusion. We mainly selected publications from the past five years but did not exclude commonly referenced and highly regarded older publications. In total, 30 articles were selected for the final qualitative analysis, the remainder being eliminated due to overlap of authors and subject matter. The results were stratified into “epidemiology”, “clinical features”, “comorbidities”, “pathophysiology” and “treatment”.

Epidemiology

Only one epidemiological study conducted by Kondziella et al. (9) investigated the prevalence of VSS in a representative population sample of 1015 unprimed people from UK, using a crowdsourcing online platform. Particularly, people were queried about the presence of visual static constantly present for more than three months and additional visual symptoms in detail, as well as for presence of competing neurological and ophthalmological disorders. A total of 38 participants reported symptoms compatible with VS (3.7%; 95% CI 2.7–5.2) and 22 of them met criteria for VSS (2.2%; 95% CI 1.4–3.3%). The mean age of patients was 50.6 ± 14 years and the female-to-male ratio 1.6:1.

Clinical features

Thus far, the phenotypic description of VSS has been thoroughly studied. The clinical features of VSS consist of the visual static (main symptom), additional visual symptoms, and contributing comorbidities.

Visual static

In 22 reports (5 –7,9 –27), the main clinical feature is described as an unremitting positive visual phenomenon present in the entire visual field and characterized by uncountable tiny flickering dots interposed between the person's vision and the background. This symptom, also known as visual static, is continuous without periods of remission (with eyes both closed and open; except for black dots that disappear when eyes are closed), independent of the outside light level lacking the characteristic episodic nature of migraine. It is most experienced in black and white but may occur in different combinations of color. Notably, there is a phenotypic distinction between the visual static and typical migraine aura. The visual dots in the VSS are present in the entire visual field of both eyes, they are tiny, uncountable and last continuously without remission for several months, in contrast to the visual disturbances of migraine which are very distinct, directed over the visual field, classically homonymous, and last from minutes to one hour maximum (12).

Additional visual symptoms

Additional visual symptoms are described in detail in ICDH-3 criteria (4), including palinopsia (visual afterimages and trailing of moving objects), entoptic phenomena (floaters, blue field entoptic phenomenon, spontaneous photopsia, self-light of the eye), photophobia and nyctalopia. Reports of several surveys describing the frequency of additional visual symptoms are presented in Table 2. Findings from case series by Zambrowski et al. (28) and Berkowitz et al. (13) are in accordance with these studies. VSS patients experience a different combination of these symptoms, with a combination of at least three of them in most patients (3). Visual afterimages, floaters, blue-field entoptic phenomenon, photopsia, and photophobia seem to be the most frequent additional visual symptoms. Moreover, Viana and colleagues (14) performed a comparison of the phenotypic characteristics of a British and an Italian group of patients matched for gender and age. After statistical analysis for continuous and categorical variables, no difference was found between the two groups. The only additional visual symptom which has been quantified is photophobia by Eren et al. (29) using the Leiden Visual Sensitivity Scale (L-VISS). Patients with VSS had an increased L-VISS-score in comparison to matched controls (22.2 ± 5.9 vs 4.4 ± 4.8, p ≤ 0.001). This score was equal to chronic migraine sufferers’ scores during attacks.

Table 2.

Frequency of reported additional visual symptoms in different surveys.

	Puledda et al. [5]	Schankin et al. [3]	Schankin et al. [21]	Schankin et al. [3]	Yoo et al. [41]
N (=number of VSS patients)	1,061	120	120	78	18
Self-assessed (SAD) or Objective Diagnosis (OD)	SAD	SAD	OD	OD	OD
Palinopsia
Trailing of moving objects	59% (95% CI 0.56–0.62)	48%	58%	60% (95% CI 0.6–0.7)	61%
Afterimages	81% (95% CI 0.79–0.83)	63%	84%	86% (95% CI 0.77–0.92)	61%
Entoptic phenomena
Floaters	86% (95% CI 0.83–0.87)	73%	83%	81% (95% CI 0.71–0.9)	71%
Blue – field	67% (95% CI 0.63–0.69)	41%	76%	79% (95% CI 0.70–0.87)	65%
Photopsia	71% (95% CI 0.68–0.73)	44%	53%	63% (95% CI 0.52–0.73)	53%
Self – light of the eye	–	57%	53%	53% (95% CI 0.42–0.63)	–
Nyctalopia	78% (95% CI 0.75–0.80)	58%	63%	68% (95% CI 0.56–0.76)	44%
Photophobia	81% (95% CI 0.78–0.83)	54%	72%	74% (95% CI 0.64–0.83)	65%

Rare forms

An extremely rare episodic form of self-limiting, not continuous visual snow symptom has been reported in the context of migraine, by Hodak et al. (30) in 3 of 1934 migraine-sufferers (< 0.2%) recorded. These patients presented initially for migraine and VSS was linked exclusively to the attacks. The only additional symptom found in those patients was photophobia.

Comorbidities

Several comorbidities have been identified in six studies (Table 3) (3,5,9,21,22,25,33). Migraine (with or without aura), tinnitus and psychiatric disorders have been linked to VSS. Regarding tinnitus, Puledda et al. (5) reported that tinnitus had the highest prevalence amongst other comorbidities in VSS patients (75%). Schankin et al. (21) highlighted the high prevalence of tinnitus in patients with VSS (52%) in comparison to the general population (7.9%). Kondziella et al. (9), studied the statistical significance of comorbidities reported using a multivariable logistic regression analysis to adjust for age and gender. Only the association between VSS and tinnitus remained significant (OR: 3.93; 95% CI, 1.63–9.9; p = 0.003). Migraine is one of the most frequent comorbid conditions in VSS. Kondziella et al. (9) found that the co-occurrence of migraine and VSS was 54.5% (p = 0.06), whereas other studies showed a prevalence ranging from 51.7% to 72% (3,5,22). Nevertheless, the association between VSS and migraine was not significant in the above-mentioned logistic regression statistical analysis (9). The hypothesis that VSS manifests differently in patients with migraine has been examined in two studies. Schankin et al. (21), revealed that migraine was associated with an increased likelihood of having palinopsia (OR 2.8; 95% CI 1.0–7.8; p = 0.04 for visual afterimages and OR 2.6; 95% CI 1.2–5.5; p = 0.01 for trailing), spontaneous photopsia (OR 2.9; 95% CI 1.4–6.2; p = 0.004), photophobia (OR 3.2; 95% CI 1.4–7.2; p = 0.005), nyctalopia (OR 2.7; 95% CI 1.2–5.8; p = 0.01), and tinnitus (OR 2.9; 95% CI 1.3–6.2; p = 0.006). Only the entoptic phenomena were independent of migraine. In addition, Puledda et al. (5) mentioned that these comorbidities were associated with a higher number of visual symptoms in patients (tinnitus OR: 2.10 CI: 1.55–2.85, p < 0.001 and migraine OR: 2.67 CI: 1.96–3.64, p < 0.001). Psychiatric disorders, such as anxiety or depression, have also been studied as possible comorbid conditions in patients suffering from VSS (3,12).

Table 3.

Frequency of comorbid conditions in patients with visual snow.

N	SAD or OD (Diagnosis)	Migraine	Migraine With aura	Depression-like disorders	Anxiety-like disorders	Tinnitus	Reference
1,061	OD	72%	37%	–	–	75%	Puledda et al. [5]
210	SAD	76%	49%	28%	49%	34%	Mehta et al. [33]
120	OD	58%	31%	–	–	52%	Schankin et al. [21]
78	OD	59%	27%	21%	23%	62%	Schankin et al. [3]
58	OD	51.7%	46.6%	41.4%	44.8%	52%	Robin et al. [21]
37	OD	54.1% (p < 0.01)	40.5%	–	–	–	Van Dongen et al. [25]
22	OD	54.5% (p = 0.06)	22.7%(P = 0.15)	72.7% (p = 0.01)	72.7%	59.1% (p < 0.001)	Kondziella et al. [9]

OD: Objective Diagnosis; SAD: Self-assessed diagnosis.

Pathophysiology

VSS pathophysiology has been investigated in seven studies. Neuroimaging methods include Positron Emission Tomography (PET), Functional Magnetic Resonance Imaging (fMRI) and Single-Photon Emission Computed Tomography (SPECT) while structural abnormalities have been investigated through voxel-based morphometry. Visual evoked potentials have been studied in VSS patients once.

PET studies

Thus far, two PET studies have been conducted using [¹⁸F]-FDG (Fluoro-Deoxy-D-Glucose) by Schankin et al. The first (21) included 17 VSS patients and 17 age and gender-matched controls. After adjusting for typical migraine aura, brain hypermetabolism was detected in the right lingual gyrus (kE = 101; ZE = 3.41; p < 0.001) and the left cerebellar anterior lobe adjacent to the left lingual gyrus (kE = 152; ZE = 3.28; p = 0.001) of patients in comparison to controls. The second study (31) included 20 VSS patients in comparison to 20 matched controls. The researchers demonstrated hypermetabolism and cortical volume increase in the extrastriate visual cortex at the junction of the right lingual and fusiform gyrus and hypometabolism in the right superior temporal gyrus in VSS patients.

fMRI studies

Functional MRI has been used by Puledda et al. (17) in combination with magnetic resonance spectroscopy study in 24 patients diagnosed with VSS. Reduced responses were detected in patients compared to controls in the left (k = 291; p = 0.025) and right (k = 100; p = 0.003) anterior insula. The spectroscopy analysis showed significantly increased lactate concentrations in the right lingual gyrus in VSS patients (0.66 ± 0.9 mmol/L vs. 0.07 ± 0.2 mmol/L in controls; p < 0.001).

SPECT studies

Shibata et al. (32) presented the results of [123I]-IMP SPECT imaging in three VSS patients. The patients demonstrated hypoperfusion of bilateral sides of the occipital cortex and fusiform gyri (mainly on the right).

Voxel-based morphometry studies

Voxel-based morphometry has been used by Schankin et al. (31) to identify structural-functional correspondence, guided by the above-mentioned PET results. Grey matter volume was increased in the temporal and limbic lobes and decreased in the superior temporal gyrus of patients. Another voxel-based morphometry study was performed by Puledda et al. (26), to detect volumetric differences in the brain structure of VSS patients. The study results demonstrated anatomical alterations in VSS patients, such as increased gray matter volume in the left primary and secondary visual cortices, the left visual motion area V₅, the limbic lobe and the left cerebellar lobule VI area.

Visual evoked potentials studies

In 2018 Eren et al. (18) performed a study using visual evoked potentials. 54 people (18 VSS patients, 18 age-matched migraineurs and 18 healthy controls) were compared concerning N145 latency and N75–P100 amplitudes. Patients with VSS demonstrated increased N145 latency (152.7 ± 7.9 milliseconds) in comparison to migraineurs (145.3 ± 9.8) and healthy controls (145.5 ± 9.4) and reduced N75–P100 amplitudes (7.4 ± 3.5 microvolts, migraineurs: 12.5 ± 4.7 and healthy controls: 10.8 ± 3.4).

Treatment

No randomized control trials for the treatment of VSS have been performed. Treatment choices proposed include pharmacologic and non-pharmacologic approaches.

Pharmacologic treatment

The rationale for reported, treatment approaches are the following: lamotrigine, because it downregulates the effect of glutamate in NMDA receptors associated with positive visual symptoms and cortical-spreading depression in migraine (19), acetazolamide, because it decreases the susceptibility of neurons to cortical-spreading depression (19) and medications which have also been used in migraine such as verapamil and topiramate. Results of studies regarding the most frequently prescribed medications are shown in Table 4. These medications have shown partial effectiveness. The most preferred medical treatment for patients with VSS is lamotrigine (7,22,33). Lamotrigine was chosen as an expert opinion treatment in few patients with VSS and medical history of migraine, with partial improvement of symptoms (around 20%) (34,35). Although the rationale for this choice is not clearly stated in those studies, its mechanism of action is the most probable reason. Effectiveness of acetazolamide, verapamil, and topiramate varies in those studies and, hence, efficiency cannot be substantiated. Moreover, lamotrigine has been used as treatment for chronic tinnitus, resulting in a positive effect on a small fraction of patients (36,37).

Table 4.

Studies with pharmacologic treatment of visual snow.

	Mehta et al. [33]	Eren et al. [18]	Van Dongen et al. [22]
N (=VSS patients included in study)	210	153	58
N (=patients who received medication)	126	78	40
Lamotrigine
N	30	36	26
Effective in	5 (16.7%)	8 (22.2%)	5 (19.2%)
Adverse events in	–	–	13 (50%)
Verapamil
N	18	3	0
Effective in	1 (5.6%)	1 (33.3%)	0
Acetazolamide
N	14	0	2
Effective in	3 (21%)	0	0
Topiramate
N	56	13	4
Effective in	3 (5.4%)	2 (15.4%)	1 (25%)
Adverse events in	–	–	4 (100%)

Among other medications, propranolol, naproxen, benzodiazepines (31), sertraline (33), and amitriptyline (38) have been reported to lead to improvement at least once. A case series of three patients with VSS taking mirtazapine conducted by Eren et al. (27) has shown no positive or negative effect on visual symptoms.

A recent web-based prospective questionnaire study by Puledda et al. (39), in which patients with VSS reported the use of various medications, such as antiepiletics, antibiotics, benzodiazepines and antidepressants, showed that none of the aforementioned drug classes were effective for the majority of the patients, with the exception of vitamins/nutriceuticals and benzodiazepines, which could be beneficial in some cases.

Non-pharmacologic treatment

Concerning non-pharmacological treatment, cognitive therapy and color filters have been suggested. Cognitive therapy has not been studied yet, however due to its effectiveness in reducing tinnitus severity and impairment, Van Dongen et al. (22) assumed that it might be effective in VSS as well. Color filters have been studied by Lauschke et al. (24) in a cohort of 32 VSS patients resulting in significant improvement in the main symptom of visual static in 92%. That improvement was attributed to the use of color filters concerning the yellow-blue spectrum in 83% of patients. Eren et al. (7) also used glasses with color filters of the yellow-blue color spectrum in 12 patients with partial relief of the visual static in 11 of them (91.7%).

Discussion

Since VSS is a recently described syndrome, its epidemiologic features have not been studied thoroughly. To date, in the only epidemiologic study in the UK population, the authors concluded that the lifetime prevalence of VSS in general population is around 2% (9). In this study, participants were not queried about VSS, but about “certain medical conditions” (including headache and diabetes), hence they were unaware of the topic of the study and were not seeking medical attention. Findings lead us to the conclusion that people with VSS correspond to a higher percentage than expected, however, they do not usually seek medical attention and, over the years, many of them habituate to the symptoms as part of their normal life. For the same reason, the mean age of patients was 50.6 ± 14 years, much higher than the mean age of the 1100 VSS cases (29 years) presented by Puledda et al. (5). Thus, further investigation is needed to discover the true age span of this syndrome. The female-to-male ratio seems to be similar in the above-mentioned studies (from 1.1:1 to 1.6:1). Additional research is essential to determine whether prevalence of VSS is similar in different populations.

The findings of our systematic survey are consistent with the diagnostic criteria of ICHD-3 for VSS. The visual static is the defining/prominent symptom (5 –7, 9 –27). Among additional visual symptoms described (13 –15,28), floaters, palinopsia, and photophobia are almost invariably present and might constitute a hallmark of the syndrome as Puledda et al. (5) suggested. Furthermore, (13,29) palinopsia is the most common additional symptom, a finding also consistent with our case series. In our opinion, clinicians should be aware that palinopsia may be suggestive of various disorders, such as migraine, drug effects, stroke, epilepsy, or metabolic disorders (40). We recommend a thorough investigation in patients with possible VSS, who present with palinopsia, even when these patients fulfill the criteria for the diagnosis. A brain MRI and EEG should be performed to rule out potentially severe conditions. Notably, all patients of our case series did not report this symptom without being specifically asked, indicating that palinopsia may be a habituation symptom (i.e., manifestation of symptoms that are part of the patient’s life are not worth mentioning) and highlighting the need for better medical interviewing and clinical examination. Considering the high prevalence of palinopsia (with stationary scenes and/or trailing) and entoptic phenomena (excessive floaters and/or blue field entoptic phenomenon), we suggest that further clinical trials are needed to clarify the significance of these features and their necessity for a certain diagnosis of VSS. According to appropriate studies’ results, it will be clarified whether palinopsia and possibly enhanced entoptic phenomena should be mandatory and the present diagnostic criteria need modification.

Even though the clinical features of VSS have been clarified, most physicians are unaware of its existence. Misdiagnosis includes disorders with similar symptoms such as migraine aura and post-hallucinogen psychogenic disorder leading to numerous unnecessary examinations and treatment attempts. That is the main reason why careful application of the current VSS diagnostic criteria (4) is very important. Several inciting events for VS including concussion, infection, ocular abnormalities and idiopathic intracranial hypertension (33) have been described. Migraine (with and without aura), which is a frequent comorbidity, must be considered as well. Hence, all patients with VS must undergo EEG and brain MRI to rule out brain pathology. Additionally, a thorough ophthalmologic exam is required to exclude ocular diseases, given that neuro-ophthalmologic findings are mostly normal in VSS, as previously mentioned (41). To date, VSS remains a diagnosis of exclusion, as all the above-mentioned diseases are very frequent in general population and far more well-known among physicians.

Concerning the natural course of the syndrome, it isn’t clearly understood, and more clinical reports are needed. In the clinical description of 1100 cases by Puledda et al. (5), many patients recall symptoms since childhood. According to the vast majority of case reports (3,13,17) the condition seems to be non-progressive and typically benign, however, occasionally it can be part of a serious underlying brain disease, like the patient described by Chen et al. (20) who was finally diagnosed with Heidenhain variant of Creutzfeldt-Jakob disease.

The usual co-existence of VSS and migraine is the main reason VSS has not been recognized as a separate entity until recently. Numerous reports and studies (13,21) agree that migraine with aura is the most frequent among comorbidities. Although in most cases visual disturbances in migraine sufferers are episodic and associated with the headache attack, there is a small subgroup of patients in which visual symptoms are dominant due to frequency (migraine aura status) or duration (persistent migraine aura) (6). However, according to existing data, the main clinical features can be distinguished between VSS patients and migraine-sufferers. Schankin et al. (21) concluded that only when migraine and VSS are both present, palinopsia, photophobia, nyctalopia, and tinnitus appear more often as common symptoms and it possible that migraine may aggravate the manifestation of VSS. On the other hand, patients with VSS experience the entoptic phenomena floaters, blue field entoptic phenomena and self-lighting of the eye independently of a migraine history, suggesting a probable non-migrainous pathophysiological mechanism. Additionally, there is evidence that VSS is associated with different processing abnormalities in relation to migraine. Cortical-spreading depression generated within the cerebral cortex is accepted by many researchers as the pathogenetic mechanism of aura. On the contrary, the pathophysiology of VSS seems to be more complicated, it is not yet fully understood. Migraine and tinnitus are associated with manifestation of more additional visual symptoms in VSS patients, consequently it can be assumed that migraine might aggravate the manifestation of VSS (5).

Three hypotheses seem relevant concerning VSS pathogenesis. Each hypothesis corresponds to a different stage of visual perception. Visual sensory input originates from the eyes and travels through the lateral geniculate nucleus to finally reach the visual cortex. Hence the possible dysfunction can be located in ocular, subcortical or cortical level. The hypothesis of dysfunction in subcortical level seems to have more fundamental basis. Ocular dysfunction cannot be substantiated as the normality of basic eye electrophysiology (23) and the absence of neuro-ophthalmologic findings in VSS patients (41) cannot be overlooked. Regarding cortical dysfunction, although both functional (22,31) and structural cortical changes have been detected (26,31) in neuroimaging studies, the absence of abnormal EEG findings in VSS patients (26 –28), makes the specific hypothesis less probable. If subcortical dysfunction is concerned, the manifestation of bilateral visual symptoms in VSS presupposes the stimulation of both hemispheres. Given that the thalamus is capable of spreading the visual stimulus to both hemispheres (42), the same way neuronal stimulus is spread in focal to bilateral tonic-clonic seizures (43), the specific hypothesis seems the most probable.

Treatment of VSS is based on single case reports and follows the above-mentioned proposed mechanisms. The most common-used medication is lamotrigine. Many researchers have used lamotrigine in VSS (34,35) because it downregulates inhibitory effects on glutamate and inhibits sodium channels (36) thus affecting cortical hyperexcitability. It may be a reasonable first choice for VSS, followed by verapamil, acetazolamide, and topiramate, but complete remission is difficult to achieved. Importantly, pharmacologic treatment in VSS should be considered only for patients with impaired quality of life, and when VSS is attributed to an inciting event or contributing comorbidity it is more likely to have some improvement in symptoms compared to spontaneous visual snow (19) while non-pharmacological approaches e.g., cognitive therapy (22), may help as well.

Conclusions

Although research concerning VSS is still in its infancy, a very detailed phenotypic description has already set the first steps to recognizing the disorder that affects the 2% of general population according to one study. The phenotype of VSS differs significantly from migraine aura in terms of duration, consistency, and location of symptoms within the visual fields. It is of high importance for neurologists and headache physicians to recognize this entity and to apprehend the difference, as misdiagnosis remains a major concern. The syndrome’s correlation with the most common comorbidities has provided insights into pathophysiology, which extends beyond the visual system and consists of cortical and subcortical brain dysfunction. The proposed pathophysiologic mechanisms may lead to new treatment approaches. Further research is needed to improve our understanding of the condition in all aspects.

Clinical implications

Visual Snow (VSS) is a recently recognized neurological condition often underdiagnosed.

Findings lead us to the conclusion that people with VSS correspond to a higher percentage than expected, however they do not usually seek medical attention and many of them over the years become habituated to the symptoms.

Considering the high prevalence of palinopsia (with stationary scenes and/or trailing) and entoptic phenomena (excessive floaters and/or blue field entoptic phenomenon), we suggest that further clinical trials are needed in order to clarify the significance of these criteria and their necessity for a certain diagnosis of VSS.

Three hypotheses seem relevant concerning VSS pathogenesis (ocular, subcortical, or cortical level). The hypothesis of dysfunction at subcortical level seems to have more fundamental basis.

Migraine and tinnitus are the most frequently recognized comorbidities in patients with VSS.

Treatment options are far from being truly effective and further research and clinical trials are needed to improve our understanding of the condition in all aspects.

Supplemental Material

sj-pdf-1-cep-10.1177_03331024221118917 - Supplemental material for Visual snow: A systematic review and a case series

Supplemental material, sj-pdf-1-cep-10.1177_03331024221118917 for Visual snow: A systematic review and a case series by Stefanos N Sampatakakis, Loukas Lymperopoulos, Theodoros Mavridis, Georgios Karagiorgis, Constantinos Papadopoulos, Christina I Deligianni and Dimos D Mitsikostas in Cephalalgia

Footnotes

Declaration of conflicting interests

The authors declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: TM has received travel grants from Merck. DDM has received consulting, research, speaking fees and/or travel grants from Allergan, Amgen, Bayer, Biogen, Cefaly, ElectroCore, Eli-Lily, Genesis Pharma, Merck-Serono, Merz, Mylan, Novartis, Roche, Sanofi-Genzyme & Teva-Specifar. All other authors have nothing to declare.

Funding

The authors received no financial support for the research, authorship, and/or publication of this article.

Author contributions

SNS: Design and conceptualized review; acquisition of data; investigation; methodology; interpretation of data; drafted the manuscript for intellectual content; editing. LL: Acquisition of data; investigation; methodology; interpretation of data; editing. TM: Acquisition of data; formal analysis; investigation; interpretation of data; review and editing. GK: Acquisition of data; review and editing. CP: Acquisition of data; review and editing. CID: Review and editing. DDM: Revised the manuscript for intellectual content; supervision of the entire process; project administration.

ORCID iD

Theodoros Mavridis

Supplemental material

Supplemental material for this article is available online.

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