Discussion
Since VKH syndrome was firstly described, the need for diagnostic
criteria became evident because of the complexity and the variety of
symptoms associated with the disease. The American Uveitis Society (AUS)
created the initial diagnostic criteria.1 However, its
lack of specificity and sensitivity led to the development of the
Revised Diagnostic Criteria (RDC) for VKH disease created by Read et al.
in 2001, which is the standard in current practice.5,6It includes five criteria: (1) the exclusion criteria for sympathetic
ophthalmia, (2) the exclusion of other uveitis entities, (3) the ocular
manifestations of the early and late stages, (4) the
neurological/auditory findings, and (5) the integumentary
findings.7 Based on the presence of all 5 criteria or
less, VKH can be categorized as complete, incomplete, and
probable.1 Some other attempts to optimize the
criteria were made in China. Although the new study showed higher
sensitivity compared to RDC, its external validity was limited, given it
included only Chinese patients.8 Our patient presented
with all the RDC criteria findings except for integumentary. However,
integumentary findings are less common; therefore, the patient was
diagnosed with VKH.
Some authors argue that the diagnosis of VKH can be established through
clinical and imaging findings alone without the need for other ancillary
tests, such as CSF analysis, and ultimately question their
utility.9 However, when performed, CSF studies reveal
a lymphocyte predominant pleocytosis in 75% of
patients.1,10 Our patient’s CSF study also
demonstrated this finding. It is important to note that CSF analysis
contributes more to ruling out other infectious/inflammatory conditions
than ruling in the diagnosis of VKH,11 especially
because the differential diagnoses for VKH-associated uveitis/meningitis
are numerous.12 Those differentials include, but not
limited to, other viral meningitis, uveitis, scleritis, syphilis,
carcinoma. Our patient’s CSF, meningoencephalitis panel, syphilis
testing, and cytology were negative, and thus, a diagnosis of VKH was
favored.13
Imaging study has been reported to be positive in 75 to 100% of the
patients.1,5,6,12,14 Yang et al. reported retinal
detachment in 87% in a series of 261 patients on optical coherence
tomography and hypo and hyperfluorescence on ICG and FFA in 91% of the
patients.8 All of those findings were seen in our
patient. Leptomeningeal enhancement is reported in the
literature15 and was also observed in our patient.
There is no definitive etiological mechanism to explain the instigation
of the pathogenesis of VKH. Over time, accumulating evidence has shown
that genetic factors, including VKH disease-specific risk factors
(HLA-DR4) and general risk factors for immune-mediated diseases (IL-23R)
play a role in the development of VKH disease. However, dysfunction of
the immunological response of both the innate and adaptive immune
system, independent of congenital mutations, is involved as well,
triggered by environmental and microbiological factors. These
microbiological factors majorly consist of viruses, which have been
discovered in patients with VKH disease. Symptoms of such viruses may
even be observed in the VKH prodromal phase. Cellular and molecular
mimicry is thought to be the triggering factor for VKH. For instance,
tyrosinase enzyme is found mostly in melanocytes and has a similar
peptide sequence as one of the proteins seen in CMV. Therefore,
antibodies against CMV cross react with this enzyme and lead to VKH
symptoms.1,4 Patients with VKH had been reported to
have positive CSF for EBV and CMV, though the pathogenesis is
unclear.2,12,16
Although COVID-19 PCR tests are positive for about 5-8 days after
symptom onset, patients may continue to test positive for up to 3 months
after their infection.17,18 Therefore, it is possible
that the immunological trigger for VKH in our patient was COVID-19 if
COVID infection onset was prior to the 2-week history of VKH symptom
onset, or during the prodromal VKH phase. Santamaria et al. reported one
of multiple possible associations between COVID-19 and
VKH.19 Their patient presented six weeks after acute
respiratory infection and was found to have positive COVID-19 viral PCR
in addition to typical VKH findings.19
Many other ocular manifestations of COVID-19 infection have been
reported in a systematic review by Aggarwal.20 He
reported that ocular manifestations are found in 8% to 15% of COVID-19
infected patients. Such manifestations include, but not limited to,
follicular conjunctivitis, eye redness, ocular pain and
discharges.20 Panuveitis and unilateral optic neuritis
were also reported.21
COVID-19 has viral endovascular, neurological, and ophthalmological
manifestations. The novel SARS-CoV-2 virus may cause atypical
neurological impairment via ischemic and immunological alteration due to
megakaryocyte infiltration.22 COVID-19 has been
demonstrated to cause not only both hemorrhagic and thrombotic stroke,
venous sinus thrombosis, endotheliosis, but also dysfunction of smell
and taste, muscle injury, Guillain-Barre syndrome, and encephalopathy,
most likely mediated by neurotoxins and dysfunctional immunological
response.23–25 Demonstrated by ophthalmological
research, clinical observation, and analysis of social media
posts,26 SARS-CoV-2 has also been found to instigate
conjunctivitis, anterior uveitis, retinitis, and optic neuritis in
patients.27–29 It is not beyond reason that given
COVID-19’s immunological, neurological, and ophthalmological
manifestations, it was the possible inducing microbiological trigger in
the development of VKH disease in our patient.
Although the definitive underlying mechanism by which COVID-19 can
trigger VKH has yet to be elucidated, decreased immune tolerance,
increased antigenicity, spike protein toxicity, and molecular mimicry
are plausible. VKH has even been reported in patients after COVID-19
vaccines in various instances.30,31 Nevertheless, we
also acknowledge that due to a high rate of COVID-19 infection, the
association between COVID-19 and VKH could be fortuitous.