Cerebrospinal fluid

2019-20 coronavirus outbreak

Cranial nerve palsy

Diplopia

Surgery

Virology

Psychiatry

Lumbar puncture

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)

Outbreak

Coronavirus disease 2019 (COVID-19)

Alternative medicine

Emergency department

Pediatrics

Cranial nerves

Anatomy

Infectious disease (medical specialty)

Internal medicine

Palsy

Outpatient clinic

Medicine

Disease

Pathology

Journal of Neuro-Ophthalmology

Emerging data suggest the central nervous system (CNS) complications of coronavirus disease (COVID-19) occur with greater frequency than related coronaviruses, severe acute respiratory syndrome coronavirus (SARS-CoV-1) and Middle East respiratory syndrome (1). A large, retrospective report from Wuhan described neurological symptoms in 36.5% of patients (2). We previously reported 2 cases of cranial nerve–related complications of COVID-19 (3). During the peak of COVID-19–related hospitalizations and fatalities in New York City, 2 additional cases of isolated sixth nerve palsy presented in an outpatient and inpatient setting. CASE 1 A 43-year-old right-handed woman with a history of migraines and well-controlled systemic hypertension presented to the emergency department (ED) with acute onset of painless diplopia. She had a fever for 3 days with a maximum temperature of 102°F, cough, fatigue, and lightheadedness. The morning of admission she awoke with binocular, horizontal diplopia, worse in far gaze and on left lateral gaze. Her neurologic examination was consistent with an isolated left sixth nerve palsy (Fig. 1). She was admitted for fever and respiratory symptoms, and a nasal swab for SARS-CoV-2 polymerase chain reaction was positive. Additional inflammatory and infectious serologic studies were negative, including Lyme western blot, antinuclear antibody, and angiotensin-converting enzyme. A contrast-enhanced MRI of the brain and orbits was unrevealing. The patient declined inpatient lumbar puncture and was discharged home after being afebrile for 72 hours.FIG. 1.: Motility examination of Patient 1 on Day 10 after the onset of diplopia revealed mild residual limitation of left eye abduction (right panel).CASE 2 A 52-year-old man with a history of well-controlled systemic hypertension presented with acute onset diplopia for about 1 week amidst a viral illness. On Day 1 of illness, he developed a fever of 103°F, anosmia, and ageusia. On Day 2, he developed an acute sense of imbalance with "a parallel view of everything" when looking in the distance. He described horizontal binocular diplopia, worse in the distance and left gaze. He denied facial weakness or changes in sensation. Fevers persisted and he developed myalgias and fatigue. On Days 3–5, he endorsed severe headache but no meningismus. As EDs were overwhelmed at the peak of the COVID-19 pandemic in New York City, symptomatic individuals without respiratory or other distress were not encouraged to visit the ED. Furthermore, outpatient in-person visits were limited to urgent and emergent cases alone, and evaluation of febrile individuals within the clinic was highly discouraged to mitigate viral exposure and spread. The patient was therefore evaluated by a telehealth visit on Day 8; during which he was noted to have an abduction deficit of the left eye as well as decreased saccadic velocity and an esotropia on an alternate cover test self-performed by the patient (Fig. 2). An isolated sixth nerve palsy was diagnosed. The patient declined neuroimaging for his fear of exposing others. At follow-up 6 days later (Day 14 of symptoms onset), he noted fever, myalgias, fatigue, and double vision had resolved. His anosmia and ageusia persisted.FIG. 2.: Motility examination of Patient 2 revealed limitation of left eye abduction (right panel).DISCUSSION Over the course of the COVID-19 pandemic the spectrum of clinical symptoms related to the virus has evolved and expanded. The symptoms initially reported in Wuhan, China, (4) were limited to hospitalized patients, which likely biased the outcomes. Other common presenting symptoms emerged, such as sore throat, diarrhea, ageusia, and anosmia (5,6). More serious complications have also been encountered, including those affecting the CNS (7–9). The pathophysiology of COVID-19's neurotropism is not entirely understood, but based on our knowledge of other respiratory viruses, several hypotheses have been proposed. Hematogenous spread is believed to occur by direct invasion of endothelial cells by the virus, leading to breakdown of the blood–brain barrier. Alternatively, it may also occur secondary to infected leukocytes inciting proinflammatory mediators and subsequent blood–brain barrier permeability (10). On the other hand, COVID-19 may access the CNS by direct invasion of the virus through peripheral nerves (11,12). Investigations of akin coronaviruses and influenza A in animal models suggest the CNS entry may occur through retrograde, transsynaptic invasion of the virus through the olfactory bulb or through the mechanoreceptors and chemoreceptors sending afferent fibers to the medulla (11,13–17). In Case 1, the patient's neuroimaging was unremarkable, without abnormal enhancement involving the sixth nerve along its course. Similarly, in the case of COVID-19–related isolated sixth nerve palsy previously described by our group, there were no radiologic findings related to the sixth nerve (3). However, the presence of optic nerve sheath enhancement suggested possible viral leptomeningeal invasion. Although other respiratory viruses are known to gain access to the CNS hematogenously (18), pathologic studies have failed to demonstrate presence of SARS-CoV-2 particles in adjacent nonneuronal cells of infected areas (11), suggesting an alternative mode of viral transmission. This may explain why enhancement of the sixth nerve did not occur in these cases because there was no immediate breakdown of the blood–brain barrier. Other considerations would include a hypertensive episode in the state of acute viral illness (19,20). The 2 patients described here, as well as the isolated sixth nerve palsy case previously described (3), all suffered from comorbid hypertension. Such observation leads one to speculate the possibility of hypertension as a risk factor for COVID-19–related sixth nerve palsy. Although some neurologists and neuro-ophthalmologists may not pursue imaging in the case of an isolated sixth nerve palsy in a patient with vascular risk factors, our clinical experience during this pandemic emphasizes the value of MRI brain and orbits with gadolinium. This additional clinical data may improve our understanding of disease pathogenesis and neurotropic mechanisms of COVID-19. In addition, managing patients with COVID-19 early in the height of the pandemic in New York City created an opportunity to trial telemedicine as an effective mode of delivering care. Telemedicine allowed us to provide safe and effective care by allowing patients to remain isolated while still acquiring sufficient clinical data to make an assessment and plan. Evaluation of the efferent system by video is feasible and may include a motility examination and alternate cover testing (21). Without distancing restrictions, patient education and counseling could also be addressed more satisfactorily. STATEMENT OF AUTHORSHIP Category 1: a. Conception and design: C. Greer, J. Bhatt, and M. Dinkin; b. Acquisition of data: C. Greer, J. Bhatt, and Marc Dinkin; c. Analysis and interpretation of data: C. Greer, J. Bhatt, C. Oliveira, and M. Dinkin. Category 2: a. Drafting the manuscript: C. Greer; b. Revising it for intellectual content: C. Greer, J. Bhatt, C. Oliveira, and M. Dinkin. Category 3: a. Final approval of the completed manuscript: C. Greer, J. Bhatt, C. Oliveira, and M. Dinkin.

Isolated Cranial Nerve 6 Palsy in 6 Patients With COVID-19 Infection