Optic neuropathies post-Covid 19 - review

The Corona virus infection started at the end of 2019 in Wuhan - China and spread rapidly throughout the world, generating the Covid 19 pandemic. The manifestations of the Covid disease were extremely varied, from a simple flu, with fever, cough, weakness, headache, joint pain, up to severe pneumonia, with severe acute respiratory syndrome (SARS-Cov2) and even death. The symptomatology of the disease, the evolution and the complications that appeared varied, depending on the associated pathology - diabetes mellitus (DM), hypertension (HT), the age and the immune status of the patient. Aim: The ocular manifestations related to Covid 19 were mostly represented by conjunctivitis, but the neurotropic character of Corona virus could justify the appearance of certain neuro-ophthalmological manifestations, such as: optic neuritis (ON), cranial nerve palsies, visual field (VF) anomalies. The aim of this paper was to research the cases of optic neuropathy post-Covid 19, published in the specialty literature between 2020 and 2022. The following were evaluated: risk factors, distribution by age group and gender, evolution and complications, as well as the clinical forms of optic neuropathies. Materials and methods: We used Google Scholar and PubMed databases to find articles on optic neuropathies related to the Covid-19 infection. We followed the articles published during the pandemic and selected 21 cases, belonging to 17 authors, irrespective of their origin and the language in which they were written. Results: 21 patients affected by ON in the Covid-19 disease, 11 women and 10 men, were mentioned. The optic neuropathies described by the authors were: retrobulbar optic neuropathy, only one associated with myelin oligodendrocyte glycoprotein (MOG), papillitis, neuroretinitis, anterior ischemic optic neuropathy (AION), out of which one arteritic anterior ischemic optic neuropathy (AAION) and the others non-arteritic anterior ischemic optic neuropathy (NAAION), one being related to pronation in an oro-tracheal intubated (OTI) patient with acute respiratory distress syndrome (ARDS). Discussions: The neuro-ophthalmological complications associated with Covid 19 disease can be severe, so the patients should be monitored continuously. Many investigations (serological, immunological and imaging exams) are necessary to exclude other etiologies of ON. Conclusions: A complete ophthalmological exam is mandatory for each patient diagnosed with Covid 19 disease, even if they have ocular manifestations or not. Abbreviations: SARS-Cov2 = severe acute respiratory syndrome; DM = Diabetes mellitus; HT = Hypertension; ON = Optic neuritis; VF = Visual field ; NS = Nervous system; CRP = C-reactive Protein; CL = cytokines; IL = interleukins; TNFɑ = tumor necrosis factor; CNS = central nervous system; ACE = angiotensin-converting enzyme; CRVO = central retinal vein occlusion; MOG = myelin oligodendrocyte glycoprotein; MOG-AD = myelin oligodendrocyte glycoprotein antibody disease; BBB = blood-brain barrier; ARDS = acute respiratory distress syndrome; IOP = intraocular pressure; CVP = central venous pressure; MSOF = multiple systems organ failure; AAION = arteritic anterior ischemic optic neuropathy; NAION = non-arteritic anterior ischemic optic neuropathy; AION = anterior ischemic optic neuropathy; OCT = optical coherence tomography; CT = computer tomography; AFG = angiofluorography; MRI = magnetic resonance imaging; ESR = erythrocyte sedimentation rate; RF = rheumatoid factor; ANA = antinuclear antibodies; ANCA = antineutrophil cytoplasmic antibodies; AQP4 = anti aquaporin 4; NMO = neuromyelitis optica; CSF = cerebrospinal fluid; OTI = oro-tracheal intubated; VA = visual acuity; ONTT = optic neuritis treatment trial; RNFL = retinal nerve fiber layer; ICU = intensive care unit; LE = left eye; RE = right eye; MS = multiple sclerosis; ICH = intracranial hypertension; BCVA = best correction visual acuity; LP = light perception; APD = afferent pupillary defect; BM = biomicroscopy; PDN = prednisone; MTX = methotrexate; MTPN = methylprednisolone; NSAID = non-steroidal anti-inflammatory drugs; CGL = cells ganglion layer; VEP = visual evoked potential; CF = counting fingers


Introduction
Optic neuropathies represent a vast chapter of ophthalmology, with multiple etiopathogenic mechanisms, varied, sometimes unpredictable evolutions and often irreversible complications. The neurotropic and neuroinvasive character of the Corona virus was highlighted throughout the COVID-19 pandemic by the installation of various forms of optic neuropathies in infected patients. Sars-Cov-2 infection can affect the nervous system (NS) through different mechanisms: either through a direct, neurotoxic action of the Corona virus, or through an immune mechanism of breaking the blood-brain barrier (BBB), or through a disruption of the coagulation system with hypercoagulability and the formation of blood clots [1].

Materials and methods
The article proposed a synthesis of several cases of post-Covid optic neuropathy, which were published in the specialty literature between 2020 and 2022. 17 publications analyzing 21 cases of ON were encountered, using the PubMed and Google Scholar search engines, by entering the keywords: optic neuropathy post Covid, neuro-ophthalmological manifestations, ON. Table 1 presents the data related to the authors of the articles, as well as all the details regarding the age and gender of the patient, the form of the Covid disease, the interval between the confirmation of the Covid-19 disease by a positive nasopharyngeal PCR test and the appearance of ocular symptoms, ocular manifestations, the ophthalmological examination and the evolution of optic neuropathies after treatment.  Although the infection with Covid-19 virus mainly affects the respiratory system, ocular manifestations have also been described, from conjunctivitis with changes in the ocular surface (most of the cases) to diseases of the uvea, retina, optic nerve and neuroophthalmological complications [19,20]. The tropism of the Corona virus on the cranial nerves manifests itself on the sensory function, while the motor function is rarely affected [21]. In Sars-Cov-2 infection, complications generally occur within the second week after the onset of the symptoms [13]. There are two main mechanisms: a severe inflammatory response and a state of hypercoagulability, by activating the coagulation cascade [22]. In the first mechanism, proinflammatory factors such as C-reactive Protein (CRP), ferritin, cytokines (CK) and interleukins (IL) 2,6,7,10, and tumor necrosis factor (TNFɑ) are activated [13,22]. Regarding the neuroophthalmological manifestations associated with Covid-19, the physiopathogenic mechanisms involved are related to hypoxia, severe HT, toxic metabolic processes, ischemic stroke, hemorrhages associated with certain parainfectious and postinfectious inflammatory processes [23].
There are 3 theories: 1. Postviral inflammatory syndrome -the sequel of a proinflammatory state with hypercoagulability and "CK storm". 2. The result of certain systemic anomalies that include hypoxia and severe HT. 3. Direct viral invasion that seems to be less involved [23]. The coronavirus has a neurotropic and neuroinvasive character. The central nervous system (CNS) is reached in several ways: hematogenous/ lymphatic, in which the permanently infected leukocytes serve as a reservoir and at the same time as a vector in the propagation of the infection at the level of the CNS [24]. The way of dissemination is transneuronal, retrograde and follows the nasal infection and the involvement of the olfactory bulb [25]. The infection of the host cell is mediated by the angiotensin-converting enzyme 2 (ACE2) receptor of Sars-cov1 and Sars-cov2 [26,27].
The coronavirus shows a high tropism for ACE2 receptors that are present in endothelial cells and in most organs. Systemic endothelial dysfunction will induce a procoagulant state and ischemia with the triggering of venous/ arterial thromboembolic complications. In severe and moderate forms of the disease, the probability of these complications is higher, and their incidence is over 30% in the patients with Covid-19 infection [28]. So, thromboembolic events are the consequence of an excessive inflammatory phenomenon, endothelial dysfunction, platelet activation and stasis. This state of hypercoagulability with the formation of thrombi will lead to the compromise of the vascular circulation at the level of the eyeball, with the installation of ischemic phenomena in the form of ischemic optic neuropathies or central retinal vein occlusion (CRVO). The presence of ACE2 receptors at the level of neurons and vascular endothelium justifies the tropism of the Sars-Cov-2 virus for neuroepithelium and endothelium [29][30][31][32]. The virus was also detected in the nerves and neurons of autopsied patients, associated thrombotic episodes being also described [30][31][32]. At the ocular level, ACE 2 receptors are present in retinal cells: Muller cells, ganglion cells, photoreceptors, retinal vascular endothelium cells and choroidal cells [33].
The association between ON and myelin oligodendrocyte glycoprotein (MOG) + antibodies in the patients diagnosed with Covid-19 infection is still unclear. MOG is part of the class of glycoproteins, being located in the outermost area of myelin at the level of oligodendrocytes in the CNS. When MOG antibodies enter the CNS, MOG antibody disease (MOG-AD) is triggered. This disease is part of a group of demyelinating diseases, sometimes manifested only by the appearance of ON. MOG-AD was cited even before the emergence of the Covid-19 pandemic, being defined as a non-specific viral infection that includes prodromal symptoms in up to 61% of the patients [34]. Therefore, an immune-type reaction takes place, thus triggering an immune response associated with post-infectious demyelinating processes after various types of infections, such as Herpes Simplex, Borellia, Epstein Barr. The titer of MOG serum antibodies will increase because of the present infectious and inflammatory process, thus triggering the MOG disease through BBB rupture. The disease evolves unpredictably, monophasically or with periods of relapses, often mild ones, with a favorable prognosis compared to other demyelinating diseases [6]. The data from literature show that the titer of MOG antibodies is higher in the relapsed forms, compared to the remitted ones [35,36]; therefore, several hypotheses were issued: 1. Is ON caused by a postinfection? 2. Can the Covid-19 infection trigger or predispose to ON? Two hypotheses regarding the triggering of the first ON attack with MOG + antibodies are cited: 1. Covid antigen determines the formation of antibodies that will attack the protein in the external sheath of myelin, through a mechanism of molecular mimicry. A primary or secondary immune response will be triggered with variable duration, from a few hours even up to 10 days. The vast majority of ON cases started approximately one week after the diagnosis of Covid-19 infection, which supports this hypothesis.
2. The second hypothesis assumes a severe inflammation, accentuated by the growth of CK and the destruction of BBB, which determines the invasion of circulating anti-MOG antibodies. Thus, the sudden onset of ON after Covid-19 infection can be explained. The role of MOG antibodies is still unclear; they contribute to the regulation of the microtubule stability at the level of oligodendrocytes, acting as a cellular adhesive molecule [37].
Optic neuropathies related to pronation. In patients with Covid 19 infection and ARDS, prone positioning is a risk factor for the onset of ischemic optic neuropathy. Indeed, the prone positioning saves the life of the critical patient, but there is the risk of irreversible vision loss, which is minimized by the medical staff. Pronation favors intraocular pressure (IOP) fluctuations with hypoperfusion of the optic nerve. It produces an external compression of the orbit through a process similar to orbital compartment syndrome. We could also consider another indirect mechanism, increasing central venous pressure (CVP), with a consequence of increasing IOP due to the lack of valves at the level of the orbital veins [38]. The eye becomes very vulnerable to changes in position, with an increase in IOP along with an increase in CVP [39]. Other risk factors involved in the installation of ischemic phenomena of the optic nerve could be the medication initiated in the treatment of multiple systems organ failure (MSOF): sedatives, vasopressors, anesthetics, which alter the selfregulating mechanisms of optic nerve perfusion [40]. NAION can be prevented by positioning the patient in the inverted Trendelenburg position for 10 degrees, which can reduce IOP compared to the neutral position [40]. Immobilizing the patient on one side or malpositioning him causes pressure directly on the abdomen, with obstruction of the venous return to the heart. Trying to position the head at the same level with the heart or above the heart, helps to maintain the blood pressure within a range of 20% compared to the initial value and thus decreases the risk of installing AION [41].
The ocular symptomatology with the onset of physiopathogenic phenomena that heralds an ON started most of the time two weeks after the positivity of the nasopharyngeal PCR test [4,5,7,9,13,16], but there were also cases with the onset of the disease in two and a half weeks [2], in three weeks [8,18], four weeks [6,17,18], six weeks [7,10], two months [18], or later, after a period of six months [7]. There was a rarity of the onset of the ON in the first days after the positivity of the PCR test, respectively in two days [11] or in seven days [3,15]. In some cases, due to the serious condition of the patients, the authors could not specify the time interval from the positivity of PCR to the appearance of ON [14].

Discussion
Although the Sars-Cov 2 virus mainly affects the respiratory system and can cause complications that are sometimes incompatible with survival, the neuroophthalmological complications should not be overlooked either. All the patients infected with Covid-19 must be monitored continuously and accurately, even the cases that were initially thought to be asymptomatic. Routine screening is mandatory to detect possible long-term neuro-ophthalmological implications. Serological, imaging and immunological tests are necessary to exclude other etiologies of ON.
In patients with severe forms of Covid 19, who are in a prolonged pronation position in ICU sections, the risk of vision loss increases due to ischemic phenomena at the level of the optic nerve. Once CVP increases, as it is vulnerable to the changes in the patient's position, the pressure of the orbital veins lacking valves with marked periorbital edema, also increase [12].
Hypoxia and hypercoagulability are risk factors in NAION. Since it is about a microvascular inflammation and a microembolic disease in NAION, anticoagulant therapy should be used carefully to the benefit of the patients with covid who are ventilated and are in pronation [42][43][44].
In multiple sclerosis (MS), Covid 19 is rather a precipitating factor or a triggering factor than a direct consequence of the infection itself [8]. The triggering or exacerbation of autoimmune diseases in patients with Covid 19 is continuously increasing in the specialty literature and further studies will guarantee the associative cause between MS and covid 19. In adults, ON is generally unilateral with good evolution in retrobulbar forms diagnosed early and treated with general corticosteroid therapy according to the ONTT scheme. In AION, the evolution is towards optic atrophy, with irreversible vision loss [2,13,14,18].
The specialty literature shows the results of several studies conducted among patients infected with Covid 19 during the pandemic: Jaafar et al. performed a quantitative meta-analysis of published studies on post-Covid neurological complications. Out of the 60 cases with Covid 19, of whom 40 (66.7%) were male and 18 (30%) were female, with an average age of 44.95 years, ON was found in 7 patients out of whom 4 were men. The forms of Covid were mild for four patients, who were not hospitalized, and three patients were hospitalized [45]. In older adults, isolated inflammation of the optic nerve is rare encountered and generally takes the form of a papillitis; in elderly people, ON is generally associated with a systemic disease or another granulomatous disease rather than with a previous viral infection [46]. Doria et al. [23] studied the complications of coronavirus infection in 2019. In a study carried out in a hospital in Spain, they described a single case of ON, which started during the recovery phase of the disease [47]. Cases with MOG+ antibodies were also reported both in patients with suspected covid [48] and in those with confirmed covid disease [49].
Buravej et al. [15] reported 9 cases of ON post Covid with MOG+ antibodies; only one case with relapse, the other 8 being at the first set. Zhou et al. [49] described a case of bilateral ON associated with peripheral retinal hemorrhages with good therapeutic response to iv corticosteroid therapy. A case of acute disseminated encephalomyelitis with ON and other neurological changes was also described [50], and Sardar et al. [51] described an ON associated with idiopathic ICH in a patient with Covid infection.
In patients already diagnosed with MS, a possible aggravation of the disease was observed, as well as an increased probability for a possible relapse of an ON attack. The specialty literature also published a case of MS that followed Sars-Cov 2 infection in a patient with inflammation of the right optic nerve and demyelinating lesions at the level of the CNS [52].