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.