Visual Snow: Studying the visual snow phenotype and shared mechanisms with migraine pathophysiology

Visual snow is a relatively unknown but disabling disorder characterized by the
continuous presence of countless small dots moving in the entire visual field,
resembling *floating snow* or *tv static*. It was originally postulated that
these patients had persistent visual migraine auras, because visual snow
patients often have a history of migraine aura. Unfortunately, the phenotype
has not been extensively investigated and there are no objective diagnostic
tests. Patients often report to be poorly understood by healthcare
professionals and a subgroup of patients has psychiatric comorbidities (anxiety
disorders, depression). Conventional migraine prophylaxes have small to no
effect on the visual snow. In some patients the onset of visual snow occurs
after intoxication with drugs and they are diagnosed with *Hallucinogen
Persisting Perception Disorder* (HPPD). Recently, it was discovered that visual
snow patients have additional visual symptoms (i.e. sensitivity to light,
palinopsia) besides the visual snow and it was proposed that visual snow is a
clinical syndrome that is distinct from persistent migraine aura and consists
of multiple visual symptoms. Interestingly, migraine patients also have
increased visual sensitivity and palinopsia outside their migraine attack.

The relationship with migraine is highly interesting and the main rationale for
us to study the clinical characteristics of visual snow and its
pathophysiology. Our hypothesis is that visual snow and migraine with aura are
both disorders of cortical hyperexcitability and are therefore part of a
spectrum. To test this hypothesis we aim to apply the techniques that provided
valuable information on cortical hyperexcitability in migraine research: i)
visual sensitivity tests, ii) electro-encephalograms (EEG) with specific visual
evoked potentials (VEPs) and iii) proton magnetic resonance spectroscopy
(1H-MRS) combined with biochemical analyses of blood and urine.

Objectives:
1. To describe the clinical characteristics (visual symptoms, non-visual
symptoms, time course, triggers, neurological and psychiatric comorbidities) of
visual snow.
2. To investigate whether patients with visual snow have hyperexcitability of
the visual cortex resulting in visual sensitivity and specific EEG and VEP
profiles (such as increased amplitude of the posterior dominant rhythm or
increased photic drive response).
3. To investigate the biochemical profile of visual snow using in vivo 1H-MRS
and ex vivo biochemical analysis and compare this profile with migraine (focus
on neuro-excitatory and *inhibitory molecules such as glutamate and GABA).
4. To investigate the correlation between these techniques focused on
hyperexcitability (EEG/VEP, in vivo 1H-MRS and ex vivo biochemical analysis)

First we will clinically characterize patients with visual snow, both patients
with no clear relation with drug use (true visual snow syndrome) and patients
with onset after drug use (often diagnosed as HPPD). For clinical
characterization we aim to include all patients from our outpatient clinic with
visual snow (current estimate of n=50) and strive for a similar sample size of
patients with visual snow onset after drug use (HPPD). As control groups we
include n=50 migraine patients with frequent auras to compare visual symptoms
and comorbidities, n=50 tinnitus patients to compare (psychological) impact of
the persistent symptoms and comorbidities, and n=50 healthy controls as
reference to the healthy general population. This part will include a
structured interview on potential visual symptoms, non-visual symptoms,
triggers, disease history and comorbidities and, when indicated, a neurological
examination. Additionally participants are asked to fill in electronic
questionnaires on severity of the symptoms, impact on daily life, psychological
well-being, possible psychiatric comorbidity and on comorbid headaches and
tinnitus. Patients with visual snow and HPPD will be included in prospective
follow-up, where routine clinical data will be combined with questionnaires.

Next we will perform observational measurements in a case-control design with
n=30 visual snow patients, n=30 migraine with frequent aura patients and n=30
healthy controls (sample sizes indicate successful measurements; see 4.5 for
power calculation). Participants do not have to participate in all study parts;
there will be separate informed consents. The following measurements will be
performed: visual sensitivity tests, EEG and VEP recordings, blood and urine
collection for ex vivo biochemical analyses and 1H MRS for in vivo biochemical
analyses.

The burden of the clinical characterization part is minimal. Although some
questionnaires might be confronting for patients we strongly believe this is
outweighed by the advantages. It is directly relevant for clinical practice to
know the involved psychological factors, especially for burdensome disorders
which medical professionals cannot (yet) explain and cannot (yet) effectively
treat. Furthermore, it is important for the interpretation of study outcomes
and for future research.

The measurements are non-invasive (visual sensitivity testing, EEG and VEP
profiling, MRS). We expect that the results of this study will lead to valuable
clinical information that GPs, neurologists, ophthalmologist, addiction
specialists and psychiatrists can use in their clinical diagnosis of visual
disturbances. Hopefully it will also lead to objective diagnostic tests. The
pathophysiological knowledge and understanding should benefit both visual snow
research and migraine research. Therefore, we believe the burdens and risks are
acceptable.