The role of occipital cortex hyperexcitability in visual snow syndrome

Isin Unal-Cevik

doi:10.4103/nsn.nsn_193_21

REVIEW ARTICLE

Year : 2022 | Volume : 39 | Issue : 2 | Page : 61-67

The role of occipital cortex hyperexcitability in visual snow syndrome

Isin Unal-Cevik
Department of Neurology, Faculty of Medicine, Pain and Headache Unit, Hacettepe University, Ankara, Turkey

Date of Submission	06-Oct-2021
Date of Decision	15-Dec-2021
Date of Acceptance	17-Dec-2021
Date of Web Publication	29-Jun-2022

Correspondence Address:
Isin Unal-Cevik
Department of Neurology, Faculty of Medicine, Pain and Headache Unit, Hacettepe University, Sihhiye 06100, Ankara
Turkey

Source of Support: None, Conflict of Interest: None

DOI: 10.4103/nsn.nsn_193_21

Abstract

Visual snow syndrome (VSS) is an emerging clinical entity, mainly characterized by persistent, bilateral, whole-visual field, disturbing, small flickering dots or pixelation, floaters, palinopsia, nyctalopia, photopsia, and photophobia. Patients with VSS also describe associated symptoms such as tinnitus, concentration difficulty, lethargy, depression, anxiety, and irritability, all of which affect the patients' quality of life. The consistency of these visual and nonvisual symptoms has recently led to proposed criteria for VSS. The diagnosis relies on the exclusion of other ophthalmic or neuropsychiatric disorders. Interestingly, many patients may have a comorbid migraine, and the symptoms were previously attributed as a persistent visual phenomenon in migraine. VSS is listed in the International Classification of Headache Disorders-Third Edition Appendix as a complication of migraine; however, VSS is a new disease entity distinct from persistent migraine aura. Some patients with VSS recall exposure to illicit hallucinogenic drugs, amphetamines, cannabis, or Lysergic acid diethylamide (LSD). The stereotypic clinical characteristics of VSS are currently well defined, and the pathophysiology is under investigation. Due to the subjective perceptual descriptions of patients with VSS, objective electrophysiologic parameters and functional brain imaging studies using magnetic resonance imaging and positron emission tomography are warranted for defining the quantifiable and reliable outcome measures. Patients with migraine, idiopathic occipital epilepsies, patients with Alice in Wonderland syndrome, patients with Charles Bonnet syndrome, visual hallucinations in recovery from cortical blindness, and recreational 3,4-methylenedioxymethamphetamine/ecstasy users have been suggested to have occipital cortex hyperexcitability. VSS is attributed to involving a dysfunctional magnocellular pathway, thalamocortical dysrhythmia, dysfunctional central visual processing, and occipital cortex hyperexcitability as possible underlying mechanisms. This review will focus on the role of occipital cortex hyperexcitability in VSS and hopefully provide insight into its pathophysiology and therapeutic strategies.

Keywords: Functional, neuroimaging, neurophysiology, pathophysiology, structural, visual evoked potential

How to cite this article:
Unal-Cevik I. The role of occipital cortex hyperexcitability in visual snow syndrome. Neurol Sci Neurophysiol 2022;39:61-7

How to cite this URL:
Unal-Cevik I. The role of occipital cortex hyperexcitability in visual snow syndrome. Neurol Sci Neurophysiol [serial online] 2022 [cited 2023 Jun 4];39:61-7. Available from: http://www.nsnjournal.org/text.asp?2022/39/2/61/348900

Introduction

Visual snow syndrome (VSS) is an emerging clinical entity. A clinical phenomenon resembling VSS symptoms was first described as a disturbing visual perception, characterized by small flickering dots such as TV static or pixelation, snow, lines of ants, and rain, lasting months to years, related to persistent positive visual phenomena in 10 patients with migraine.^[1] Later, VSS was proposed to be a different disorder from persistent migraine aura, with additional visual symptoms present in 33% of patients, characterized by palinopsia (trailing and afterimages), entoptic phenomena (floaters, blue field entoptic phenomenon, and spontaneous photopsia), photophobia, and nyctalopia (impaired night vision).^[2] Tiny flickering dots in the entire visual field are one of the most frequently described visual symptoms in patients with VSS [Figure 1].

Figure 1: (a) A normal vision of a healthy person. (b) The same view but perceptual descriptions of a patient with visual snow syndrome, characterized by tiny flickering dots in the entire visual field, resembling the view of TV static or a badly tuned analog television

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VSS is listed in the International Classification of Headache Disorders-Third Edition Appendix^[3] as a complication of migraine; however, VSS is a new disease entity, distinct from persistent migraine aura.^[2] Patients with VSS also describe associated symptoms such as tinnitus, concentration difficulty, lethargy, depression, anxiety, and irritability, all of which affect the patients' quality of life. The consistency of these visual and nonvisual symptoms has recently led to proposed criteria for VSS.^[4] The diagnosis relies on the exclusion of other ophthalmic or neuropsychiatric diseases.

Patients with migraine, idiopathic occipital epilepsies, patients with Alice in Wonderland syndrome, patients with Charles Bonnet syndrome, visual hallucinations in recovery from cortical blindness, and recreational 3,4-methylenedioxymethamphetamine/ecstasy users have visual symptoms and thus should be excluded for the correct diagnosis of VSS.^[2] Some patients with VSS recall exposure to illicit hallucinogenic drugs, amphetamines, cannabis, or LSD.^[5] In a recent retrospective case series of patients with VSS, most patients did not report an inciting event; however, the patients who reported an inciting event or contributing comorbidity were more likely to have some improvement in their symptoms.^[5] The stereotypic clinical characteristics of VSS are currently well defined, and the pathophysiology is under investigation. Due to the subjective perceptual descriptions of patients with VSS, objective parameters are warranted for defining the quantifiable and reliable outcome measures. Besides, a consensus on effective treatment strategies is lacking.^[6]

VSS is attributed to involving a dysfunctional magnocellular pathway, thalamocortical dysrhythmia, dysfunctional central visual processing,^[7] and occipital cortex hyperexcitability as possible underlying mechanisms.^{[6],[8],[9],[10],[11],[12],[13]} There is a growing consensus in the literature that VSS is considered to be due to dysfunctional central visual processing.^{[4],[6],[8],[12]} This review focuses on the role of occipital cortex hyperexcitability in VSS and various diseases. An insight into the pathophysiology of VSS will further open a window for possible therapeutic strategies in future.

Visual Snow Syndrome and Occipital Cortex Hyperexcitability

Evidence from neurophysiologic and behavioral studies

The original studies that provided the potential pathophysiologic role of occipital cortex hyperexcitability in VSS are listed in [Table 1] and [Table 2].

Table 1: Neurophysiologic studies in patients with visual snow syndrome investigating the hyperexcitability of the occipital cortex

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Table 2: Behavioral studies in patients with visual snow syndrome investigating the hyperexcitability of the occipital cortex

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Patients with VSS report continuous dynamically flickering dots in the entire visual field, floaters, palinopsia, nyctalopia, photopsia, and photophobia. Our first experience with VSS was a young female patient who had comorbid migraine with aura (MWA) and depression who was admitted to our tertiary headache clinic.^[11] The patient described bright colors (white, light gray, yellow, and pink) in the form of spots, strands, and swirls (floaters) in both of her eyes and the entire visual field. During the daytime, looking at the blue sky, she described fast-moving white dots and strands (blue field entoptic phenomenon). She also described afterimages of the objects (palinopsia), impaired night vision (nyctalopia), and short flashing lights (photopsia).^[11] Dynamic, flickering white dots were the most bothersome symptom, which was continuously present even when her eyes were closed and interrupted her sleep. Ophthalmologic examinations were reported to be normal. These continuous visual features of VSS symptoms suggested an overactive visual pathway functionality, thus deserving further diagnostic tests. The electroencephalogram was normal. Left occipital bending was noticed in brain magnetic resonance imaging (MRI). This finding prompted us to investigate if this structural signature was also reflected by occipital cortex hyperactivity. Thus, occipital cortex activity was quantitatively assessed using visual evoked habituation.

The visual evoked potential (VEP) response to uninterrupted visual stimuli at 3.1 Hz was recorded during 10 sequential blocks. Each block consisted of 100 averaged VEP responses.^[14] To assess the habituation or potentiation response, the subaverage peak-to-peak amplitudes at blocks 5 and 10 were compared with that at block 1.^[11] Normally, after repetitive stimulation, the brain protects against over-excitation and lactate accumulation, and the magnitude of the amplitude of evoked cortical response normally decreases, characterized by a “habituation” response.^[15] In this patient with VSS, instead of a physiologic habituation response, a cortical potentiation response was detected. Three months after lamotrigine treatment, compatible with subjective symptom improvement, the improvement in the habituation response was also quantified^[11] [Table 1].

These initial findings led to a comment that the potentiation effect could not be unequivocally attributed to VSS but rather seemed to be related to the underlying MWA.^[16] Thus, a prospective, case–control, neurophysiologic study investigating the habituation response through repetitive pattern-reversal visual evoked potentials (rVEPs) and the phosphene threshold (PT) using transcranial magnetic stimulation (TMS) in patients with VSS with or without migraine and healthy controls was conducted.^[13] The loss of habituation and lower threshold for occipital cortex excitability were demonstrated in patients with VSS with or without migraine. This study supported the hypothesis of occipital cortex hyperexcitability in patients with VSS and provided a possible objective and quantitative assessment tool in affected patients.^[13]

The exact pathophysiology of VSS is still unknown, but accumulating evidence suggests that VSS may originate from the overactive neuronal structures within the occipital cortex. In a detailed study to investigate and compare visual perceptual measures in patients with VSS and healthy controls, an imbalance between inhibition and excitation in the visual cortex was demonstrated in patients with VSS, consistent with elevated excitability in the primary visual cortex^[9] [Table 2]. Contrary to this report, in a study of magnetic suppression of perceptual visual accuracy conducted in 17 patients VSS with or without migraine, compared with 17 migraine-matched controls, the authors concluded that although the hyperexcitability apparently occurred in both VSS and migraine aura, hyperexcitability did not arise from the primary visual cortex in patients with VSS.^[17]

In another neurophysiologic study, a 22-year-old patient with VSS without comorbid migraine was tested with VEP habituation and compared with age and five sex-matched healthy controls^[18] [Table 1]. The authors reported that VEP habituation was observed in the controls, and the patient with VSS had a potentiation response.^[18] Interestingly, in contrast to these reports, a VEP study enrolled 18 patients with VSS (11 had comorbid migraine), 18 migraineurs, and 18 age-matched controls.^[19] The authors reported that all 18 patients with VSS (comorbid with or without migraine) had increased N145 latency compared with the migraineurs (n = 18) and the healthy controls (n = 18). They concluded that the primary disturbance in VSS was due to dysfunction of the visual association cortex but not to the primary visual cortex.^[19] In their study, 11 out of 18 patients with VSS had comorbid migraine. These conclusions should be interpreted with caution because the authors did not separately analyze the results of the seven patients with VSS without comorbid migraine. The effects of comorbid migraine could not be eliminated in their VSS group.

The authors also reported reduced N75–P100 amplitudes in 18 patients with VSS compared with the migraineurs and healthy controls^[19] and made a misstatement that their results were compatible with previous studies.^{[20],[21],[22]} However, these previous studies^{[20],[21],[22]} also clearly demonstrated loss of habituation and potentiation responses (N1P1 amplitudes) in migraineurs. Another explanation for the discrepancy in the authors' results may be due to the rVEP protocol,^[19] possibly because of different stimulation parameters, compared with previous studies.^{[11],[13],[23]}

The authors compared six blocks of repetitive visual stimulation, each block consisted of 75 responses, and thus they ended up with only 450 stimuli, and compared the subaveraged N1P1 amplitudes of the 6^th block with the 1^st block, which is another crucial point. In these studies, there were 10 blocks of stimuli; each block consisted of 100 stimuli and thus ended up with 1000 stimuli.^[11;13;23] “Habituation” was defined if the ratio of the 5^th-1^st or 10^th-1^st block amplitudes was lower than 1, and “potentiation” if any of these ratios was higher than 1.^{[11],[13],[23]} This stimulation paradigm lasted longer, thus the potentiation response was detected more accurately. In these rVEP studies, no differences in P100 latencies, but potentiation responses were characterized by increased peak-to-peak N1-P1 amplitudes after repetitive stimulations.^{[11],[13],[23]}

A normal P100 latency indicates normal conduction from the retina to the occipital cortex. Most abnormally prolonged P100 latencies may be caused by disease affecting the optic nerve, particularly demyelination, compression, and other optic neuropathies.^[24] The rVEP method indicated potentiation of P1-N1 amplitudes, which is compatible with previous studies indicating hyperexcitability of the occipital cortex in both migraineurs^{[14],[20],[21],[22],[23]} and patients with VSS with or without migraine.^[11],[13]

Another neurophysiologic technique used to measure occipital cortex hyperexcitability is the detection of PTs.^[25] A phosphene is a phenomenon of seeing luminous floating stars, zigzags, swirls, spirals, squiggles, and other shapes without light actually entering the eye. It may be seen when closing the eyes tight and pressing them with the fingers. Phosphenes may be experienced in patients with ocular pathology such as a blow to the eye, traction on the retina, optic nerve compression, or optic neuritis.^[26] Phosphenes can be noninvasively and experimentally induced using TMS of the occipital cortex.^[27] PTs are inversely related to the excitability of the visual cortex. In this TMS study, a lower threshold for phosphene detection was also demonstrated in patients with VSS.^[13] This is another neurophysiologic sign, a hallmark concept, compatible with occipital cortex excitability in patients with VSS.^[13]

Evidence from functional neuroimaging studies

To assess the potential pathophysiologic correlates of the occipital cortex, original studies that investigated the brain perfusion/metabolism/activity, specifically in patients with VSS, are listed in [Table 3].

Table 3: Functional neuroimaging studies demonstrating occipital cortex involvement in patients with visual snow syndrome

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The first functional brain imaging study, using ¹⁸F-2-fluoro-2-deoxy-D-glucose positron emission tomography scans, was conducted in 17 patients with VSS (of which 14 had comorbid migraine) compared with 17 (age- and sex-matched) controls.^[28] This study revealed brain hypermetabolism in the right lingual gyrus and the left cerebellar anterior lobe adjacent to the left lingual gyrus.^[28] The authors concluded that the hypermetabolic lingual gyrus confirmed brain dysfunction in patients with VSS. In a study that combined magnetic resonance spectroscopy (MRS) with functional MRI, the responses to a visual stimulation mimicking VSS were used.^[10] The study compared 24 patients with VSS (15 with VSS with migraine and 9 with VSS without migraine) and healthy controls.^[10] The authors reported reduced BOLD responses to the visual stimulus with respect to baseline in patients with VSS compared with controls in the left and right anterior insula. The MRS analysis disclosed increased lactate concentrations in patients with VSS in the right lingual gyrus.^[10] The authors concluded that patients with VSS had dysfunctions in the visual association cortex and the salience network.^[10]

In contrast to these reports, a ¹²³I-IMP single-photon emission computed tomography (SPECT) imaging study was conducted in three patients with VSS, all of whom had comorbid migraine.^[29] The authors reported that the first patient with VSS had hypoperfusion on bilateral sides of the occipital cortex and fusiform gyri with a preponderance on the right. The second patient with VSS, who had comorbid migraine, had bilateral mild frontal hypoperfusion, and it was reported that this finding was not related to VSS. The third patient had a normal cerebral perfusion pattern.^[29] These hypoperfusion results differ from the previous PET study which revealed brain hypermetabolism.^[28]

Persistent visual phenomena in 10 patients with migraine with symptoms that resembled VSS was described by Liu et al.^[1] In this case study, two patients (the 1^st and the 9^th patients) were reported as having normal cerebral blood flow patterns; the 2^nd patient had decreased left temporal lobe activity; the 3^rd patient had asymmetric activity in the visual association areas, the right greater than left; the 5^th patient had bilateral decreased parietal activity; the 7^th patient had biparietal hypoperfusion, and the 8^th patient demonstrated bilateral parieto-occipital hypoperfusion in SPECT studies.^[1] The authors reported that the inconsistent localization of the SPECT abnormalities and the subjectivity of SPECT interpretations without normative data prevented drawing a definite conclusion, but they reported that the patients' positive visual phenomena might have resulted from spontaneous cortical discharges.^[1] The overlap of clinical features and pathophysiologic concepts of typical migraine aura, migraine aura status, persistent migraine aura, other persistent positive visual phenomena, and visual snow was reviewed in detail, with a special focus on cortical spreading depression.^[30]

Evidence from structural neuroimaging studies

The original studies that investigated the potential role of structural brain signatures in patients with VSS are listed in [Table 4].

Table 4: Structural neuroimaging studies demonstrating occipital cortex involvement in patients with visual snow syndrome

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By definition, secondary causes due to ophthalmic or neuropsychiatric disorders and gross neuroanatomic lesions should be excluded in patients with VSS.^[2] Nonetheless, there is a growing literature on subtle structural signatures in patients with VSS. The first report was on left occipital bending detected on standard brain MRI in a patient with VSS.^[11] Later, the brain MRI of 14 patients with VSS (nine with VSS with migraine and five with VSS patients without migraine) was retrospectively evaluated^[13] using a method defined by Maller et al.^[31] Occipital bending was defined if the unilateral occipital pole extended across the interhemispheric fissure and wrapped around the other occipital lobe.^[31] Left occipital bending was noticed in 4 out of the 9 patients with VSS and migraine.^[13]

Compatible with these preliminary findings, a detailed voxel-based whole-brain morphometry (VBM) study was conducted on 24 patients with VSS (15 with VSS with migraine and 9 without migraine), compared with 24 healthy controls.^[32] The authors reported increased gray matter in patients with VSS in the left primary visual cortex and increased gray matter volume in crus I/lobule VI of the left cerebellar hemisphere.^[32] There were no significant structural differences in the lingual gyrus.^[32]

Accumulating evidence from patients with cerebellar lesions has revealed the role of the cerebellum in cognitive, affective, autonomic, and behavioral functions.^[33] The cerebellar region was reported to be directly involved in widespread cerebello-cortical connections, spatial processing functions, and the “preparation” of somatosensory integration, the so-called “cognitive cerebellum.”^[32] The authors also addressed that the morphologic changes that were detected on the left side were not due to handedness because this variable was corrected for in the analysis.^[32] In a VBM study conducted in migraineurs, a gray matter volume decrease in V5 was reported.^[34] Thus, the authors further supported that the increased gray matter in patients with VSS in the left primary visual cortex was correlated with VSS but not comorbid migraine in their study population.^[32]

Conclusion

VSS is an emerging visual perceptual disorder, mainly characterized by persistent, bilateral, whole-visual field, disturbing, small flickering dots or pixelation, floaters, palinopsia, nyctalopia, photopsia, and photophobia. Patients with VSS also describe associated symptoms such as tinnitus, concentration difficulty, lethargy, depression, anxiety, and irritability, all of which affect the patients' quality of life. For many years, the subjective perceptual descriptions of patients with VSS also led to misinterpretation, even labeling these patients as having a psychiatric disorder. Recently, neurophysiologic, behavioral, functional, and structural imaging studies of the occipital cortex have provided further insight into a relatively unknown condition. A further understanding of the role of occipital cortex hyperexcitability may lead us to consider strategies for treatment modalities, such as pharmacologic or neuromodulation treatments. These objective and quantitative tools may also function for the assessment of the efficacy of different therapeutic strategies in patients with VS.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

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