By Lori Baker-Schena, MBA, EdD; COVID-19, the Eye, and the Brain; American College of Ophthalmology<\/p>\n\n\n\n
As the COVID-19 pandemic began, Prem S. Subramanian, MD, PhD, did not anticipate a direct connection between this novel respiratory disease and the neuro-oph\u00adthalmic conditions he treated.<\/p>\n\n\n\n
\u201cYet as it became evident that neuro\u00adlogical symptoms were being associated with COVID-19, we sat up and took notice,\u201d said Dr. Subramanian, at the University of Colorado in Aurora. And in the ensuing year, neuro-ophthal\u00admologists have identified and reported cases of optic neuritis, visual distur\u00adbance and visual loss, cranial neuropathies, and Miller Fisher syndrome in patients with COVID-19.<\/p>\n\n\n\n
Even as the science continues to evolve, neuro-ophthalmologists are beginning to see patterns and gain insights from the various case studies that have been reported.<\/p>\n\n\n\n
Two current areas of focus in neuro-ophthalmology are the autoimmune cascade that appears to be triggered in the disease, and the vascular problems resulting from the hypercoagulation that seems to be induced by COVID-19, Dr. Subramanian said.<\/p>\n\n\n\n
A word of caution. <\/strong>It\u2019s important to not get ahead of the science, Dr. Sub\u00adramanian cautioned. To date, \u201cthere is no direct cause and effect link between COVID-19 and neuro-ophthalmic findings, as COVID-19 cases are so widespread, and some of our findings can be pure coinci\u00addence. Our hope is that, as we continue to study these eye conditions, we will better understand if there is a true connection to the disease.\u201d<\/p>\n\n\n\n From the beginning of the pandemic, researchers que\u00adried whether SARS-CoV-2 directly invaded the nervous system or if a secondary autoimmune process was responsible for the onset of neuro-ophthalmic disease.<\/p>\n\n\n\n There is precedent for the invasion hypothesis, said Vivek R. Patel, MD, at the University of California, Irvine. Animal data showed that both the SARS coronavirus 1 (SARS-CoV-1) and Middle East respiratory syndrome coronavirus (MERS-CoV) could di\u00adrectly access the central nervous system (CNS) through a transsynaptic route, traveling to the medulla and affecting respiration.<\/p>\n\n\n\n \u201cHowever, with COVID-19, given the millions of cases, if there was a significant neuroinvasion, we would see evidence of this,\u201d Dr. Patel said. \u201cInstead, at this time, we need to look at other explanations of neuro-ophthalmic presentations, and we have two possible explanations: autoimmune dysregulation and hypercoagulation.\u201d<\/p>\n\n\n\n According to Dr. Patel, it appears that SARS-CoV-2 itself is not invading the nervous system. Rather, the virus may be triggering an autoimmune cascade\u2014which, in turn, can have a broad array of clinical manifestations depending on the target organ of the autoantibodies. This may explain why patients are presenting with neuro-ophthalmic conditions secondary to immune system dysregulation.<\/p>\n\n\n\n Myelin oligodendrocyte glycopro\u00adtein. <\/strong>One such condition is myelin oligodendrocyte glycoprotein (MOG) antibody demyelination, which presents as optic neuritis with severe vision loss. Some investigators have suggested that as many as 50% of cases may be linked to a viral trigger.1<\/sup><\/p>\n\n\n\n Dr. Patel and his colleagues reported the case of a 27-year-old Hispanic man who presented early in the pandemic with bilateral severe optic neuritis and myelitis and tested positive for the MOG immunoglobulin G (IgG) antibody.1<\/sup> The patient had reported a few days of progressive dry cough before the onset of eye pain and vision loss.<\/p>\n\n\n\n Although the cough was his only COVID-19\u2013related symptom, it prompted Dr. Patel to order a poly\u00admerase chain reaction test for the virus, which came back positive.<\/p>\n\n\n\n However, SARS-CoV-2 was not detected in the patient\u2019s cerebrospinal fluid, suggesting that the virus itself was not directly causing the neurologi\u00adcal presentation.<\/p>\n\n\n\n \u201cInterestingly, MOG antibodies can circulate freely but do not exhibit a pathologic effect unless they gain access to the CNS through disruption of the blood-brain barrier,\u201d Dr. Patel said. \u201cIn this case, rather than COVID-19 directly invading the brain, the disease may have induced an autoimmune cascade that allowed the blood-brain barrier to be breeched, granting MOG antibodies access to the CNS.\u201d<\/p>\n\n\n\n The patient was treated with intra\u00advenous methylprednisolone for five days, followed by an oral prednisone taper. After seven days in the hospital, his visual acuity improved to 20\/50 in each eye, which further improved to 20\/25 three weeks after discharge with complete resolution of disc edema and retinal findings.<\/p>\n\n\n\n \u201cGiven that we believe a viral trigger may be involved in many cases of MOG-associated antibody disease, we won\u00addered whether SARS-CoV-2 could serve as that agent,\u201d Dr. Patel said. \u201cOur patient was the first case of its kind to be reported in the literature.\u201d<\/p>\n\n\n\n Miller Fisher syndrome. <\/strong>Marc J. Dinkin, MD, at Weill Cornell Medical College in New York City, reported the first COVID-19\u2013related case of Miller Fisher syndrome, a variant of Guillain-Barr\u00e9 syndrome, in the United States.2<\/sup> (The first international case was report\u00aded by Spanish investigators.3<\/sup>)<\/p>\n\n\n\n A 36-year-old man presented with left ptosis, diplopia, and bilateral distal leg paresthesias along with COVID-19 symptoms, and an examination was consistent with third nerve palsy. \u201cOn day 2, the patient developed the Miller Fisher triad: ataxia, loss of deep tendon reflexes, and progressive worsening of eye movements,\u201d Dr. Dinkin said. After treatment, which included IV immuno\u00adglobulin for the Miller Fisher symp\u00adtoms, the patient was discharged three days later with partial recovery.<\/p>\n\n\n\n \u201cSimilar to Guillain-Barr\u00e9 syn\u00addrome, Miller Fisher syndrome is an antibody-mediated attack on certain ganglioside proteins within the nervous system, and it typically occurs after a precedent infection. In our case, and in subsequent Miller Fisher cases asso\u00adciated with COVID-19 in the literature, we presume that the virus provoked this immunological response,\u201d Dr. Dinkin said.<\/p>\n\n\n\n Additional nuances. <\/strong><\/em>In the same report, Dr. Dinkin and his colleagues presented an additional case of a 71-year-old woman with COVID-19 who presented with painless diplopia. Her case might reflect a direct viral lep\u00adtomeningeal invasion, for two reasons: The neurologic presentation occurred within two days of the respiratory symptoms, and there was optic nerve sheath enhancement of the involved eye. However, Dr. Dinkin noted, a direct infection of the nervous system was not proven.<\/p>\n\n\n\n Since then, multiple reports of oculomotor, trochlear, and abducens palsy occurring in association with COVID-19 have been reported.<\/p>\n\n\n\n Researchers are tracking cases of COVID-19\u2013associated hypercoagula\u00adtion, which in turn can lead to strokes, with all of their visual manifestations, including homonymous visual field loss and higher order visual disorders.4<\/sup><\/p>\n\n\n\n Acute cerebrovascular disease appears to be the most common neurologic manifestation of COVID-19, occurring in 2.8% of patients.5<\/sup> While this includes mostly ischemic stroke, intracerebral hemorrhages and venous sinus throm\u00adboses also may occur.<\/p>\n\n\n\n In the New England Journal of Med\u00adicine<\/em>,6<\/sup> Oxley et al. reported a two-week period in which five patients younger than 50 years presented with new-onset symptoms of large-vessel isch\u00ademic stroke. In contrast, during every two-week period in the previous 12 months, the researchers\u2019 health service treated, on average, 0.73 patients younger than age 50 for large-vessel stroke. All five patients in this report had COVID-19.<\/p>\n\n\n\n \u201cThe most common theory for this hypercoagulation is that it is the downstream result of the COVID-19 cytokine storm,\u201d Dr. Dinkin said. \u201cHowever, the binding of SARS-CoV-2 to the angiotensin-converting enzyme 2 [ACE2] receptor on endothelial cells may lead to endothelial dysfunction7<\/sup> and secondary microvascular infarc\u00adtion.\u201d<\/p>\n\n\n\n The occurrence of an otherwise un\u00adexplained cranial neuropathy should prompt consideration of SARS-CoV-2 infection even in patients with mild COVID-19 symptoms, Dr. Dinkin said.<\/p>\n\n\n\n Other signs and symptoms to watch for include the following:<\/p>\n\n\n\n Homonymous visual field loss. <\/strong>This could occur following ischemic stroke or hemorrhage but may also result from posterior reversible leukoenceph\u00adalopathy syndrome, which has been re\u00adported in association with COVID-19.8<\/sup><\/p>\n\n\n\n Myasthenia gravis. <\/strong>Eight patients have been described in the literature, with a parainfectious autoimmune response mechanism presumed.9<\/sup><\/p>\n\n\n\n Nystagmus or saccadic intrusions. <\/strong>These may occur from either brainstem strokes or rhomboencephalitis. They also may be related to an autoimmune encephalitis affecting the brainstem, although this is rare.<\/p>\n\n\n\n Optic neuritis without traditional risk factors. <\/strong>Some cases have been asso\u00adciated with the MOG antibody.<\/p>\n\n\n\n Intracranial hypertension. <\/strong>This includes some patients with Multi\u00adsystem Inflammatory Syndrome in Children (MIS-C) in which multiple organ systems and tissues can become severely inflamed following COVID-19 infection.<\/p>\n\n\n\n Dr. Dinkin treated a young teen who presented with MIS-C and devel\u00adoped severe headaches, papilledema, and an abducens palsy suggestive of elevated intracranial pressure. Fortu\u00adnately, the syndrome resolved sponta\u00adneously.<\/p>\n\n\n\n Verkuil and colleagues reported a similar case,10<\/sup> and Silva and col\u00adleagues described six patients who had COVID-19 and were found to have isolated intracranial pressure.11<\/sup><\/p>\n\n\n\n Exacerbation of IIH. <\/strong><\/em>One of Dr. Dinkin\u2019s patients had a three-year his\u00adtory of mild idiopathic intracranial hy\u00adpertension (with only pulsatile tinnitus and MRI findings of elevated intracra\u00adnial pressure but no papilledema). Yet within days of contracting COVID-19, the patient developed grade IV papill\u00adedema and visual field loss refractory to medical therapy. She improved with placement of a venous sinus stent.<\/p>\n\n\n\n Proposed mechanism. <\/strong><\/em>The underlying mechanism by which the inflammatory state associated with COVID-19 might affect cerebrospinal fluid dynamics remains unclear. One theory involves dysfunction of the spinal fluid\u2013producing choroid plexus, based on the expression of ACE2 receptors in some of its cells.12<\/sup><\/p>\n\n\n\n Dr. Subramanian noted that researchers and clinicians continue to report new neuro-ophthalmic findings related to COVID-19. One of his papers in pub\u00adlication presents a new constellation of conditions in a patient: severe vision loss combined with ischemia of the oculomotor system.<\/p>\n\n\n\n \u201cWe have also heard of COVID-19 patients showing up with unusual late vision loss from an optic neuropathy, as well as visual field loss, trouble reading, and so forth,\u201d he said. \u201cOphthalmol\u00adogists should consider an association with COVID-19 when they see these patients.\u201d<\/p>\n\n\n\n Dr. Subramanian also predicted that neuro-ophthalmologists will see a disproportionate number of patients with \u201clong COVID,\u201d who are commonly known as \u201clong-haulers,\u201d even as this initial phase of the pandemic subsides.<\/p>\n\n\n\n \u201cThese patients, who continue to experience symptoms months after their initial symptoms appear, will need to be seen by neuro-ophthalmologists to exclude either some visual effects or symptoms related to the optic nerve or orbital dysfunction,\u201d Dr. Subramani\u00adan said. \u201cIt is important to keep these patients on your radar.\u201d<\/p>\n","protected":false},"excerpt":{"rendered":" By Lori Baker-Schena, MBA, EdD; COVID-19, the Eye, and the Brain; American College of Ophthalmology As the COVID-19 pandemic began, Prem S. Subramanian, MD, PhD, did not anticipate a direct […]<\/p>\n","protected":false},"author":2,"featured_media":9021,"comment_status":"open","ping_status":"open","sticky":false,"template":"","format":"standard","meta":{"footnotes":""},"categories":[51,789,160,161,289],"tags":[],"class_list":["post-8760","post","type-post","status-publish","format-standard","has-post-thumbnail","hentry","category-blindness","category-dry-eye","category-eye-illnesses","category-eyesight","category-long-haul-disease"],"_links":{"self":[{"href":"https:\/\/cov19longhaulfoundation.org\/index.php?rest_route=\/wp\/v2\/posts\/8760","targetHints":{"allow":["GET"]}}],"collection":[{"href":"https:\/\/cov19longhaulfoundation.org\/index.php?rest_route=\/wp\/v2\/posts"}],"about":[{"href":"https:\/\/cov19longhaulfoundation.org\/index.php?rest_route=\/wp\/v2\/types\/post"}],"author":[{"embeddable":true,"href":"https:\/\/cov19longhaulfoundation.org\/index.php?rest_route=\/wp\/v2\/users\/2"}],"replies":[{"embeddable":true,"href":"https:\/\/cov19longhaulfoundation.org\/index.php?rest_route=%2Fwp%2Fv2%2Fcomments&post=8760"}],"version-history":[{"count":2,"href":"https:\/\/cov19longhaulfoundation.org\/index.php?rest_route=\/wp\/v2\/posts\/8760\/revisions"}],"predecessor-version":[{"id":9020,"href":"https:\/\/cov19longhaulfoundation.org\/index.php?rest_route=\/wp\/v2\/posts\/8760\/revisions\/9020"}],"wp:featuredmedia":[{"embeddable":true,"href":"https:\/\/cov19longhaulfoundation.org\/index.php?rest_route=\/wp\/v2\/media\/9021"}],"wp:attachment":[{"href":"https:\/\/cov19longhaulfoundation.org\/index.php?rest_route=%2Fwp%2Fv2%2Fmedia&parent=8760"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"https:\/\/cov19longhaulfoundation.org\/index.php?rest_route=%2Fwp%2Fv2%2Fcategories&post=8760"},{"taxonomy":"post_tag","embeddable":true,"href":"https:\/\/cov19longhaulfoundation.org\/index.php?rest_route=%2Fwp%2Fv2%2Ftags&post=8760"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}A Matter of Neuroinvasion?<\/h2>\n\n\n\n
Theory of Immune System Disregulation<\/h2>\n\n\n\n
Threat of Hypercoagulation<\/h2>\n\n\n\n
What to Look For<\/h2>\n\n\n\n
Emerging Associations<\/h2>\n\n\n\n
In for the Long Haul<\/h2>\n\n\n\n