Neuro-ophthalmic Manifestations of Coronavirus Disease 19

Alanna K. Tisdale; Bart K. Chwalisz

Disclosures

Curr Opin Ophthalmol. 2020;31(6):489-494. 

In This Article

Clinical Features

At present, it is difficult to provide data on the prevalence of neuro-ophthalmic disorders in COVID-19-positive patients. Several neuro-ophthalmic conditions have been documented in the context of COVID-19 infection, but the literature remains sparse, with only a handful of case reports available. Thus far, there are documented cases of optic neuritis, visual disturbance and visual loss, cranial neuropathies, and Miller Fisher syndrome, that have been associated with SARS-COV-2 infection.

Optic Neuritis

Zhou et al.[22] reported a unique case of a patient with bilateral severe optic neuritis and myelitis, determined to be both myelin oligodendrocyte glycoprotein (MOG) IgG antibody and SARS-COV-2 positive. A 26-year-old man presented to an outpatient practice in Los Angeles due to bilateral vision loss, first impacting his left eye, and then the right eye 3 days later. Prior to his vision loss, he had experienced bilateral pain with eye movements, dry cough, numbness on the soles of his feet, and neck discomfort with forward flexion. On exam, he was found to have significant vision loss in both eyes, disc edema in both eyes, and retinal hemorrhages in the right eye. His visual acuity was hand motion in the right eye, and 20/250 in the left eye. His severe bilateral optic neuritis with disc edema raised suspicion for MOG-antibody disease. A broad work up was conducted, including lab work for infectious, inflammatory, and infiltrative conditions. His results returned positive for SARS-COV-2 and anti-MOG antibodies. MRI revealed bilateral enhancement and thickening of his optic nerves, extending from the globes to their intracranial prechiasmal segments. MRI of the spine showed T2 hyperintensities in the upper thoracic and lower cervical spinal cord. His cerebrospinal fluid (CSF) was negative for SARS-COV-2. He was treated with intravenous methylprednisolone, followed by an oral prednisone taper. Three weeks later, he had dramatic improvement of his vision in both eyes, with resolution of his disc edema. This case of MOG-antibody-associated optic neuritis in the setting of COVID-19 is an example of a parainfectious demyelinating syndrome with a prodromal viral illness. It remains to be seen whether the COVID-19 pandemic will be followed by an increased incidence in demyelinating central nervous system (CNS) disease.

It is not clear whether SARS-COV-2 can directly affect the optic nerves. Animal models have developed optic neuritis, when infected with coronaviruses.[18] In a study by Shindler et al.[23] in 2008, the murine coronavirus MHV-A59 was used for the creation of viral-induced optic neuritis models.

Miller Fisher Syndrome

Miller Fisher syndrome, a condition characterized by acute onset ataxia, loss of tendon reflexes, and ophthalmoplegia, has been observed in a number of patients with newly diagnosed COVID-19.

Dinkin et al.[24] reported a case of a 36-year-old man with a history of infantile strabismus who presented with left ptosis, diplopia, and bilateral distal leg paresthesias. He also experienced fever, cough, and myalgias which began 4 days earlier, and resolved prior to presentation. On exam, a left ptosis, mydriasis and limitations in depression and adduction were noted, indicating a partial left 3rd nerve palsy. Neurologic exam was significant for lower extremity hyporeflexia and hypesthesia, as well as gait ataxia. On MRI, there was T2 hyperintensity and enlargement of the left 3rd nerve. Upon nasal swab, SARS-COV-2 PCR was positive. The patient went on to develop progression of left ptosis, and loss of left eye depression and horizontal eye movements. In addition, right eye abduction was lost. Due to coexisting ophthalmoparesis, leg paresthesia, and areflexia, the patient was presumed to have Miller Fisher syndrome. He was treated with intravenous immunoglobulin and hydroxychloroquine, with partial improvement of deficits.

Gutierrez-Ortiz et al. reported another case of Miller Fisher syndrome in a COVID-19-positive patient. A 50-year-old man presented to an emergency room in Madrid, Spain due to a new onset vertical diplopia, perioral paresthesias, and gait instability.[25] Five days prior to presentation, he had experienced fever, cough, headache, malaise, and low back pain. He also had anosmia and ageusia. On exam, he had a broad-based ataxic gait, absent deep tendon reflexes in upper and lower limbs. A right hypertropia was noted in all fields of gaze, as well as right eye limitations in adduction and downgaze movements, and left nystagmus. His findings were indicative of a right internuclear ophthalmoplegia and right fascicular oculomotor palsy. On work-up, he was positive for antibodies to ganglioside GD1b complex. He was concluded to have Miller Fisher syndrome, and also found to be positive for SARS-COV-2 on oropharyngeal swab. He was treated with intravenous immunoglobulin, with significant improvement in his cranial neuropathies and ataxia.

Cranial Neuropathies

There are a number of reports of patients who presented to medical centers with 6th nerve palsies, with subsequent diagnosis of COVID-19. Some of these may represent more limited forms of the Miller Fisher syndrome.

Gutierrez-Ortiz et al.[25] reported a case of multiple cranial neuropathy in a COVID-19 patient. A 39-year-old man presented to an emergency room in Madrid, Spain due to new onset diplopia. He reported fever, diarrhea, malaise, and ageusia which began 3 days prior. He had no respiratory symptoms. He was found to have bilateral 6th nerve palsies on exam, with significant abduction deficits in both eyes. All deep tendon reflexes were absent on neurologic exam. His oropharyngeal swab was found to be positive for COVID-19. An antiganglioside antibody profile could not be performed, due to the fact that the hospital was above capacity with COVID patients. Two weeks after presentation, he had fully recovered from a neurologic standpoint, with return of complete eye movements, normal deep tendon reflexes, and resolution of ageusia.

A case reported by Dinkin et al.[24] described a 71-year-old hypertensive woman who presented to an outpatient practice in New York City with the complaint of diplopia and inability to abduct her right eye. Due to her report of cough and fever for several days, she was sent to the emergency room for further work up. She was found to be febrile and hypoxemic. On MRI, there was enhancement of her optic nerve sheaths and posterior Tenon capsules. She had bilateral airspace opacities on chest radiograph, and her nasal swab was positive for SARS-COV-2. She was treated with hydroxychloroquine. She reported gradual improvement of her diplopia when contacted 2 weeks after discharge.

Greer et al. reported the cases of two patients who presented with cranial nerve 6 palsies, in the setting of COVID-19 infection.[26] The first was a 43-year-old woman with a history of well controlled hypertension and migraines who presented to the emergency department (ED) with new onset binocular, horizontal diplopia. On exam she was found to have an isolated abducens nerve palsy. She reported a history of 3 days of fever, cough, fatigue, and lightheadedness. Her MRI of the brain and orbits was unrevealing. She declined a lumbar puncture (LP). She tested positive for SARS-COV-2 on nasopharyngeal swab. The second patient was a 52-year-old man with a history of well controlled hypertension, who came to medical attention due to the complaint of 1 week of new horizontal binocular diplopia, in the setting of viral illness. He reported a history of fever, anosmia, ageusia, myalgias, headache, fatigue, accompanied by the new double vision. At this time, New York City was experiencing the peak of its pandemic, and hospitals were overwhelmed. As a result, patients were encouraged to remain at home, unless experiencing distress. Consequently, this patient was followed via telemedicine, and found to have an isolated 6th nerve palsy on self-performed alternate cover testing during a tele-visit. He declined neuroimaging because he did not want to put others at risk for contracting COVID-19. His diplopia, fever, myalgias, and fatigue resolved by his 6-day follow-up. He continued to experience ageusia and anosmia.

Falcone et al. documented the case of a 32-year-old man with no significant past medical history who reported acute onset binocular, horizontal diplopia which began after 3 days of upper respiratory symptoms.[27] He tested positive for COVID-19, developed acute hypoxemic respiratory failure, and was hospitalized. He was treated with hydroxychloroquine and his respiratory symptoms improved. Five weeks after the onset of his diplopia, his visual symptoms were unchanged, and he presented for ophthalmic evaluation at a Miami outpatient practice. He was found to have complete limitation in left eye abduction, consistent with a left 6th nerve palsy. On MRI, he was found to have an atrophic left lateral rectus muscle, which displayed hyperintensity on T2.

Vision Loss

Cyr et al.[28] reported two cases of COVID-19-positive patients with severe bilateral vision loss, in the setting of CVAs. The first patient was a 61-year-old diabetic man who was brought to the ED 7 days after the onset of fever, myalgias, and cough, and 2 days after the onset of sudden, bilateral, painless vision loss. His visual acuity was no light perception in both eyes. On chest radiograph he was found to have bilateral ground glass opacities, and computed tomography of the head (CT head) without contrast showed loss of gray–white matter differentiation, which indicated cytotoxic edema in the bilateral occipital polar regions. He was diagnosed with acute bilateral occipital territorial ischemic infarct. A COVID-19 PCR test was found to be positive. He deteriorated rapidly, and passed away 3 days after admission.

The second patient reported by Cyr et al. was a 34-year-old woman with a history of systemic lupus erythematosus, hypertension, end stage renal disease on hemodialysis, chronic obstructive pulmonary disease, and prior CVA, who was admitted to the hospital for confirmed SARS-COV-2-positive pneumonia. During her stay, her home medications were continued: hydroxychloroquine, prednisone, and aspirin. After her first week in the hospital, she experienced sudden, bilateral, painless vision loss. On exam, she was found to have light perception vision in both eyes. On dilated exam, she had trace pallor in both optic discs. MRI of the brain without contrast showed acute infarct in the right frontal lobe, likely along the territory of the right middle cerebral artery, acute left posterior temporal–occipital territorial infarction following the posterior cerebral artery, and chronic infarction in the right temporal–parietal lobe and bilateral medial occipital lobes, likely in arterial distribution. MRA of the brain demonstrated an occlusion of the M2 branches of the right middle cerebral artery. These two cases highlight the high prevalence of CVAs, among COVID-19-positive patients. In addition, they suggest that patients with preexisting endothelial dysfunction may have heightened risk for thrombotic occlusive events, in the setting of COVID-19 infection. During this pandemic, COVID-19 should be kept on the differential for any patient presenting with new bilateral vision loss or CVA.

Proposed Mechanisms

The mechanisms of COVID-19-induced neurologic disease remain poorly understood. The main possibilities include direct viral neurotropism, and indirect immunologic and neurovascular effects.

Angiotensin-converting enzyme 2 (ACE2), the main functional receptor for SARS-COV-2 is present on multiple human organs, including the brain.[9] Given this knowledge, it is possible that SARS-COV-2 acts directly on neuronal tissue, though definitive proof of this is lacking so far. If SARS-COV-2 enters the brain, it could do so through multiple routes, including hematogenously, by infecting choroid plexus or meninges, or via spread through the olfactory nerves. Animal models have suggested that SARS-CoV and Middle East Respiratory Syndrome coronavirus (MERS- CoV) may enter the brain via the olfactory nerves, and later spread to other regions including the thalamus and brainstem.[29] It has been hypothesized that SARS-COV-2 may directly extend through the nasal mucosa, via ACE2 receptors on the nasal epithelium's basal layer, and extend to the olfactory bulb.[10] However, for most patients loss of smell is a transient symptom that resolves within a week, suggesting that the anosmia may be mediated by a transient dysfunction of the olfactory epithelium rather than by neuronal destruction.[30] In addition, an analysis of gene expression patterns in various cell types of the upper respiratory epithelium showed that olfactory sensory neurons do not express ACE2 and transmembrane serine protease 2 (proteins that are involved in SARS-CoV-2 cellular infection), whereas these proteins are expressed in supportive cells of the olfactory epithelium, such as basal cells, secretory cells, and sustentacular cells.[31] Thus the mere symptom of anosmia (which is a much more common manifestation of COVID-19 than CNS disease) does not prove invasion of the CNS by SARS-CoV-2. However, in at least one case, radiologic changes in the olfactory bulb and gyri recti have been reported.[32]

It is likely that an abnormal immune response contributes to the neurologic dysfunction observed in infected patients as well.[25] Patients who are COVID-19 positive may display increased levels of proinflammatory cytokines in the plasma which may be involved in the damage caused by the virus.[33] In addition, there may be an upregulation or misdirection of adaptive immune responses as well. For instance, in the two patients with new onset neuro-ophthalmic disease reported by Gutierrez-Ortiz et al.,[25] the CSF was negative for SARS-COV-2, indicating that the virus may not directly cause encephalitis but the presence of GD1b-IgG antibodies in cases of Miller Fisher syndrome supports the hypothesis of immune-mediated injury. Reports of Miller Fisher/Guillain–Barre syndrome as well as MOG-antibody associated optic neuritis in the context of SARS-COV-2 suggest that the virus has the potential to stimulate autoantibody production.[22] Research on the mechanism of COVID-19-induced neurological symptoms continues.

Clinical Practice Recommendations

Possible associations between SARS-COV-2 and neuro-ophthalmic disease should be kept in mind when interviewing and examining patients, and interpreting studies. Patients who are being screened for COVID-19 in ambulatory, surgical, or emergency room settings should be asked whether they have experienced diplopia, pain with eye movements, changes in visual acuity, changes in color vision, difficultly walking, or other neurologic symptoms. Given the pandemic, at many medical institutions, patients who present to the emergency room, to outpatient clinics, and to surgical centers are screened for symptoms associated with COVID-19. In addition to asking new patients whether they have experienced 'fever, shortness of breath, cough, and sore throat', the above symptoms should be inquired about as well.

If patients present to the clinical setting with the specific complaints of diplopia, pain with eye movements, changes in visual acuity, changes in color vision, difficulty ambulating, or other neurologic symptoms, COVID-19 testing should be considered. When these symptoms are paired with even mild fever or respiratory symptoms, COVID-19 testing is highly advisable. On exam, clinicians should look for visual acuity decrease, pupillary abnormalities, extraocular motility deficits, ptosis, and optic disc swelling. Clinicians can also consider testing reflexes, to assess for hyporeflexia that would suggest Guillain–Barre/Miller Fisher syndromes. On neuroimaging, careful attention should be paid to the cranial nerves, to rule out abnormal enhancement associated with cranial neuropathy. Focus should be placed on the optic nerves, optic nerve sheaths, and perineural region, to ensure that there is not abnormal enhancement suggestive of optic neuritis. Clinicians should confirm that there are no signs of parenchymal ischemia. If anosmia is present, the bulk and enhancement pattern of the olfactory bulb may be of interest.

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