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A previously healthy 24-year-old woman presents to an emergency department in Marrakesh, Morocco, reporting double vision and misalignment of her left eye. She says the symptoms have worsened since starting about 3 days earlier, but she has no eye pain or redness.

She explains that about 4 days ago, she developed a fever (38.5°C) and dry cough, and lost her sense of smell, and notes that her father -- whom she sees regularly -- tested positive for COVID-19 the day before.

Clinicians confirm strabismus and diplopia of the patient's left eye. Her medical history is unremarkable, and includes no risk factors for ischemic ophthalmoplegia (i.e., diabetes, high blood pressure, dyslipidemia, vasculitis, smoking, obesity, or familial neurological disease).

Clinical examination shows her blood pressure and hemodynamic state are within normal ranges:

• Blood pressure -- 110/70 mm Hg

• Oxygen saturation -- 95%

• Heart rate -- 67 bpm

• Respiratory rate -- 21 bpm

Clinicians perform an ophthalmological exam, which shows visual acuity of 0.1 logMAR in both eyes. Palpebral examination notes no ptosis. Both pupils are equal in size and reactive to light and accommodation, with no afferent pupillary defect.

Assessment of the patient's ocular motility reveals restricted upgaze, adduction, and downgaze of the left eye. The diplopia increased in adduction, and findings of the slit lamp and fundus examinations are unremarkable.

Results of the rest of the physical exam are unremarkable and do not identify any neurological impairment. Clinicians diagnose the patient with incomplete palsy of the third cranial nerve.

Results of a nasopharyngeal swab for SARS-CoV-2 by reverse transcription polymerase chain reaction come back positive, and the patient is admitted to the COVID-19 ward.

On the patient's first day in the hospital, subsequent laboratory workup and radiological investigations are performed. Magnetic resonance angiography of the brain and orbits shows no evidence of lesions or aneurysmal compression of the third left cranial nerve. Blood test results suggest mild normocytic regenerative anemia, with no evidence of inflammation, thrombophilia, or renal or hepatic impairment. The corrected QT interval is 380 ms on electrocardiogram.

Clinicians start the patient on the following standard treatment recommended for COVID-19 in Morocco:

• Chloroquine (500 mg BID for 10 days)

• Azithromycin (500 mg once a day for the first day, then 250 mg once daily for 6 days)

• Vitamin C (1 g BID for 10 days)

• Zinc (90 mg BID for 10 days)

The patient's fever resolves on the second day and her overall clinical status shows improvement, as does the exotropia and diplopia of her left eye.

On the sixth day, her ocular motility returns to normal, and she shows complete recovery.

Four days later, the patient's hemoglobin levels have returned to within the normal range, and she shows no signs of any treatment adverse effects. She is discharged home.

Follow-up to the time of writing of the case report in summer 2020 finds the patient healthy and doing well.

Discussion

Clinicians reporting this of a patient who develops incomplete unilateral palsy of the third cranial nerve during the acute phase of COVID-19 infection note that ophthalmological manifestations of COVID-19 are relatively rare compared with the typical clinical features of fever, dry cough, dyspnea, myalgia, and fatigue.

Although various disorders – including cerebral aneurysms, vascular disorders, tumors, and diabetes mellitus – can lead to unilateral oculomotor nerve palsy, this patient had no clinical, laboratory, or imaging evidence of an underlying structural etiology. This led the team to suspect COVID-19 infection as the cause of the transient oculomotor nerve palsy.

The novel coronavirus, SARS-CoV-2, first emerged in patients presenting with pneumonia symptoms in Wuhan, China, in December 2019. Less than 3 months later, the first cases of COVID-19 were identified in Morocco in March 2020. As of October 26, 2020, the country has reported nearly 200,000 confirmed cases and 3,301 deaths, which have primarily occurred in patients with COVID-19 pneumonia.

The case authors explain that although COVID-19 infection has been associated primarily with respiratory symptoms, the variety of organs affected appears to be expanding to involve different body systems.

The wide range of affected organs is thought to reflect the common expression of the major SARS-CoV-2 entry-receptor angiotensin-converting enzyme 2 (ACE2), which appears to be the gateway for the virus into the cell. Given the overexpression of ACE2 receptors in the lungs, the typical respiratory presentation of COVID-19 infection is not surprising.

In a 2004 from patients who died of SARS, researchers reported that while the virus (SARS-CoV) was found predominantly in the lungs, trachea, and bronchus, it was also detected in many other organs and tissues, including the stomach, small intestine, kidney, adrenal glands, skin, and parathyroid, which harbored 25-49% positive cells. There was no evidence of SARS‐CoV in the esophagus, spleen, lymph node, bone marrow, heart, aorta, cerebellum, thyroid, testis, ovary, uterus, or muscles.

The case authors for the current patient note that penetration of SARS-CoV-2 through the cribriform lamina of the ethmoid bone may damage the olfactory bulb, causing loss of sense of smell – and that this can be the entry route to the nervous system. In addition, expression of ACE2 receptors in nerve cells explains the neurological damage that can occur with COVID-19 infection.

Regarding the hypothetical neurotropic nature of the virus, the authors point to a of 214 cases, which found neurological manifestations in over one-third of COVID-19 patients. Such neurological lesions can be secondary to neuronal damage without inflammation or caused by direct action of the virus on the nerves or vessels -- in particular in the setting of a necrotizing hemorrhagic encephalopathy.

The ophthalmological effects of coronavirus infection generally present in the form of conjunctivitis -- in some cases as the initial manifestation of COVID-19 infection before development of respiratory symptoms.

COVID-19 has been linked with inflammatory neuropathies, and the case authors cite a report of a patient with a complete isolated third oculomotor nerve palsy, who ultimately died of respiratory failure 12 days later. Two other cases of ophthalmoplegia associated with neurological impairment were slower to improve, and in this case the patient had no headache or other signs of central nervous system involvement.

In the absence of specific treatment, this patient received chloroquine, azithromycin, and supportive treatment, according to the Moroccan protocol. The case authors note that while some studies have proven that chloroquine can be effective against COVID-19, it is not harmless: adverse effects include cardiac problems, which can be severe, and potentially irreversible macular damage.

Indeed, in a recent of use of hydroxychloroquine and chloroquine in hospitalized patients with COVID-19, the agency reported that of 109 patients with a serious cardiac adverse event:

• 80 (73%) reported QT prolongation

• 7 (6%) reported bradycardia

• 4 (4%) reported torsades de pointes

• 4 (4%) reported tachyarrhythmia

• 14 (13%) reported ventricular arrhythmia, ventricular tachycardia, or ventricular fibrillation

• 92 (84%) reported concomitant use of at least one other medication that prolongs the QT interval, primarily use of azithromycin

• 25 (23%) had a fatal outcome involving a cardiac adverse event, with 22 of 25 reporting use of a concomitant QT-prolonging medication

Conclusion

The case authors conclude that as shown in this patient, unilateral palsy of the third cranial nerve can be a sign of COVID-19 in adults, and can occur in patients with mild symptoms and without other central nervous system involvement. It is also reassuring, the authors say, that while the condition is difficult to identify through radiological evaluation, complete recovery can occur within a few days of acute onset.

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