COVID-19 and isolated oculomotor nerve palsy: Clinical features and outcomes

Abstract

Aim

This study aims to describe the clinical characteristics of patients with isolated oculomotor nerve palsy from COVID-19 infection, and provide guidance on their treatment and management.

Methods

We performed a systematic review and retrospective analysis on the clinical features and outcomes of patients with isolated oculomotor nerve palsy from COVID-19 reported in literature over the past three years.

Results

We analyzed a total of 11 cases; 9 identified in literature from January 2020 to September 2022, together with our two patients. Their median age was 46 years (range 2–65), and three were children. More than half (6/11, 55 %) were without medical history. Oculomotor nerve palsies tended to occur early (longest interval of 16 days), but they can also occur concurrently (2/11, 18 %) or before the appearance of COVID-19 symptoms (1/11, 9 %). COVID-19 symptoms tended to be mild (8/11, 73 %). Oculomotor nerve palsies, however, displayed neither a clear gender predilection, nor consistent clinical features in terms of the severity of extraocular weakness and the involvement of pupillary light responses. Nearly two-thirds (7/11, 64 %) received no pharmacological treatment. Regardless, recovery was complete in nearly all (9/10, 90 %), with most occurring within a month (8/9, 89 %)

Conclusion

Isolated oculomotor nerve palsies are early but uncommon complications of COVID-19. They affect patients with mild infections, and can be the first symptom. Prognosis is excellent, with recovery being often complete and early. Early discharge and outpatient clinical review, with or without short courses of oral steroids, are reasonable treatment measures.

1. Introduction

The severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) pandemic continues its global rampage as it nears its third year. Neurological complications of COVID-19, both acute and subacute, are well-described in early Chinese case series, with patients experiencing perturbations of both the central and peripheral nervous systems [1]. COVID-19-related cranial nerve palsies, either singly or in combination, have been reported in significant numbers, with facial nerve and abducens nerve palsies being the two commonest [2]. Oculomotor nerve palsies (OMNPs) in the setting of COVID-19 infections have also been reported, although mostly as part of peripheral demyelinating disorders such as Guillain-Barré and Miller-Fisher syndrome rather than on its own [2]. Contrastingly, reports of isolated and idiopathic OMNPs associated with COVID-19 infections are far rarer, with their clinico-radiologic features and outcomes described only sporadically in case reports. We, therefore, conducted a review of earlier literature on COVID-19-related iOMNPs, retrospectively analyzing them together with our two patients described herein, so as to better bridge this knowledge gap and subsequently guide the treatment and management of these patients.

2. Methods and definitions

We conducted a systemic review through a search on PubMed and Google Scholar, using keywords ‘COVID-19′, ‘SARS-CoV-2′, ‘coronavirus-19′, ‘oculomotor nerve palsy’, and ‘third nerve palsy’. OMNPs are considered ‘isolated’ when without other neurologic deficits. COVID-19 symptoms include fever, cough, tiredness, anosmia, ageusia, sore throat, headache, diarrhea, and dyspnoea, amongst other rarer symptoms [3]. ‘Complete OMNP’ describes severe weakness of the extraocular and levator palpabrae superioris muscles, while ‘partial OMNP’ refers to milder deficits of similar muscles. ‘Pupillary involvement’ is present when pupillary light responses were reduced or absent. We excluded articles with incomplete descriptions of clinico-radiologic features and outcomes, and patients whose OMNPs were due to other causes (e.g., aneurysms or cavernous sinus thrombosis). Additionally, cases with concomitant sensorimotor deficits and/or ataxia of the limbs, ophthalmoparesis involving lateral rectus and/or superior oblique muscles, or fatigability, or with neurological deficits attributed by their respective authors to Guillain-Barre or Miller-Fisher syndromes were also excluded. Thereafter, the clinical features of identified cases of isolated and idiopathic OMNPs were then retrospectively analyzed together with our two patients. Informed consent was obtained from both, and their identifiers were anonymized.

3. Illustrative cases

3.1. Case 1 (Patient 12)

A 55-year-old woman presented acutely with painless binocular diplopia and right blepharoptosis. She experienced mild respiratory symptoms and was diagnosed with COVID-19 four days before. Infraduction, supraduction, and adduction of the right eye were severely impaired, and the upper eyelid was completely ptosed ( Fig. 1). Both pupils were equal and reactive to light. There was no other neurological deficit. Diagnosed with a complete right-sided iOMNP, she tested negative for diabetes mellitus and hyperlipidemia, and her inflammatory markers and autoimmune tests (anti-nuclear, anti-double stranded DNA, anti-neutrophil cytoplasmic antibodies) were unremarkable. Brain magnetic resonance imaging (MRI) with angiography (MRA) and intravenous gadolinium detected a non-compressing schwannoma within the right superior orbital fissure, near a non-enhancing oculomotor nerve (OMN), which our neurosurgeons deemed unlikely to cause her OMNP. Declining oral steroids, her deficits completely resolved within a week.

Fig. 1.

Examination of the extraocular muscles at the nine cardinal positions of gaze (A: right and up gaze, B: up gaze, C: left and up gaze, D: right gaze, E: central graze, F: left gaze, G: right and down gaze, H: down gaze, I: left and down gaze), showing severe impairment of supraduction, infraduction, and adduction of the right eye.

3.2. Case 2 (Patient 13)

A 54-year-old hypertensive lady presented acutely with binocular mixed horizontal and vertical diplopia of a day’s duration. Examination of her eyes found mildly-impaired supraduction and adduction of the right eye, together with mild ipsilateral blepharoptosis. Pupillary light reflexes were bilaterally preserved, and neurological examination found no additional cranial nerve deficits or sensorimotor abnormalities of her limbs. She was diagnosed with a partial right-sided oculomotor nerve palsy. She developed a fever and mild respiratory symptoms the next day, and later tested positive for COVID-19 through polymerase chain reaction tests. Her brain MRI with gadolinium and MRA returned negative for significant abnormalities. she tested negative for diabetes mellitus and hyperlipidemia, and her autoimmune tests (anti-nuclear, anti-double stranded DNA, anti-neutrophil cytoplasmic antibodies) were negative. Her neurological deficits were observed over two months, during which her ocular symptoms fully resolved seven days from symptom onset.

4. Results [4], [5], [6], [7], [8], [9], [10], [11], [12]

Only 9 relevant case reports between January 2020 and October 2022 were identified by our systematic review of prevailing literature. A total of 11 cases were retrospectively analyzed, with their demographic and clinical features summarized in Table 1. Amongst these are two of our patients, and 9 others described in case reports between January 2020 and October 2022. Their median age was 46 years (range 2–65), and three were children. There were nearly as many males and females. Vascular risk factors (Patients 1 and 11) were uncommon, and more than half (6/11, 55 %) were without past medical history.

Table 1.

Clinico-radiologic features of patients with isolated oculomotor nerve palsies associated with COVID-19 infections.

Ref.	Pat	Age (y)	Sex	Medical history	Initial symptoms and signs	Interval between COVID19 symptoms & CN III palsy (days)	CN III palsy features	Investigations	Treatment	Interval to complete recovery (days)
[4]	1	62	M	DM2, HTN, stroke, alcohol & tobacco use	Fatigue, CN III palsy, severe pneumonia	0	Lt, complete, pupil-sparing	Normal MRIB and MRA	Antibiotics, IV steroids, antivirals, IVIg	Died from respiratory failure
[5]	2	21	M	Nil	Fever, cough, dyspnoea, severe pneumonia	16	Lt, partial, pupil-sparing	Normal CSF; normal MRIB with Gad contrast	Observation	7
[6]	3	25	F	Nil	Fever, cough, anosmia	3	Lt, partial, pupil-sparing	Normal D-dimer, fibrinogen, ferritin; normal MRIB, orbits, and MRA	CHQ, AZI	6
[7]	4	67	M	Lyme disease	Fever, fatigue, myalgia, diarrhoea	5	Lt, with pupillary-involvement	Raised D-dimer; normal CTA; scattered non-enhancing T2 hyperintensities on MRIB with Gad contrast	Observation	60
[8]	5	2	F	Nil	CN III palsy	N/A	Rt, complete, with pupillary involvement	Normal brain imaging	Ocular PT	30
[9]	6	55	M	Epilepsy	Bilateral HA, fatigue, ageusia, CN III palsy	0	Lt, partial, pupil-sparing	Normal CTA & MRIB	Observation	7
[10]	7	2	N/A	SPLIS	MIS-C	15	Rt, with pupillary involvement	CSF: normal WCC, raised protein; normal MRIB	Oral steroids over 5 days	Partial recovery
[11]	8	10	M	Nil	CN III palsy	N/A	Rt, complete, with pupillary involvement	CSF: normal, normal D-dimer, fibrinogen, ferritin; MRIB with Gad contrast: right IR enhancement	Oral steroids over 10 days	7
[12]	9	46	F	Nil	Bifrontal headache	2	Lt, partial, pupil-sparing	Normal CSF; normal D-dimer, fibrinogen, ferritin; normal CTA; MRIB & orbits with Gad: left CN III thickened & enhanced at the OA	Observation	17
Case 1	10	55	F	Nil	Mild respiratory symptoms	4	Rt, complete, pupil-sparing	Normal CTA; MRIB with Gad: right cavernous sinus schwannoma	Observation	10
Case 2	11	54	F	HTN	CN III palsy	-1 *	Rt, partial, pupil-sparing	Normal MRA and MRIB with Gad	Observation	7

DUGGI: removed

* : Patient 13′s COVID-19 symptoms appeared a day after her oculomotor nerve palsy.

Abbreviations: AC, anticoagulation; AP, antiplatelet; AZI, azithromycin; CHQ, chloroquine; CD, Crohn’s disease; CN III, third cranial nerve; CSF, cerebrospinal fluid; CTA, computed tomographic angiography; CVT, cerebral venous thrombosis; DM2, diabetes mellitus type 2; F, female; Gad, gadolinium; HA, headache; HTN, hypertension; ICA, internal carotid artery; IR, inferior rectus; IV, intravenous; IVIg, intravenous immunoglobulin; Lt, left; M, male; MIS-C, multisystem inflammatory syndrome in children; MRIB, brain magnetic resonance imaging; MRA, magnetic resonance angiography; NSTEMI, non-ST elevation myocardial infarction; OA, orbital apex, OMNP, oculomotor nerve palsy; Pat, patient; PT, physiotherapy; RF, renal failure; Rt, right; SPLIS, sphingosine phosphate lyase insufficiency syndrome; WCC, white cell count; y, years.

4.1. Clinical features

Most OMNPs occurred early in relation to the onset of typical COVID-19 symptoms, with the longest interval being 16 days after the development of fever and respiratory symptoms. OMNPs can appear concurrently with (Patients 1 and 6) or before COVID-19 symptoms (Patient 11). Interestingly, OMNPs were the only manifestations in Patients 5 and 8, who were otherwise without typical COVID-19 symptoms. Patient 8 was tested for COVID-19 as he was in close contact with an infected person, while why Patient 5 was tested was left unmentioned. COVID-19 symptoms were mostly mild, although slightly more than a quarter (3/11, 28 %) developed severe infections – Patients 1 and 2 were afflicted by severe pneumonia which turned out fatal for the former, while Patient 7 developed multisystem inflammatory syndrome in children (MIS-C). The pattern of oculomotor deficits showed no clear predilection in terms of severity. Of the nine patients in which the extent of OMNP was described, slightly less than half (4/9, 44 %) had complete OMNPs. Pupillary light responses were spared and normal in nearly two-thirds (7/11, 64 %).

4.2. Investigations and findings

Lumbar punctures were performed in four, of which none showed significant abnormalities. D-dimer levels were measured in four, and were elevated only in Patient 5. Non-invasive angiographies were negative for intracranial aneurysms in seven patients. All underwent imaging of the brain – at least ten were brain MRIs, of which six were performed with intravenous gadolinium. Amongst them, significant radiologic aberrations were uncommon, and include enhancement of the inferior rectus muscle in Patient 8, and enhancement and thickening of the oculomotor nerve in Patient 9. The small schwannoma demonstrated in Patient 10 was deemed incidental and irrelevant to her OMNP, a conclusion further supported by the rapidity and completeness of her recovery despite receiving no targeted treatment.

4.3. Treatment, clinical outcomes, and prognosis

Only two received short courses of oral steroids, while Patient 1 who administered methylprednisolone to treat his severe pneumonia rather than his OMNP. Amongst the remaining, nearly two-thirds (7/11, 64 %) received no pharmacological treatment for their OMNPs beyond a period of observation, or ocular physiotherapy (Patient 5). Regardless, recovery was often complete and early. Omitting Patient 1 who died from respiratory failure, resolution of OMNP-related deficits was complete in nearly all (9/10, 90 %), with most occurring within a month (8/9, 89 %).

5. Discussion

Our findings revealed isolated OMNPs to be uncommon complications of COVID-19 in both children and adults, and afflicted mainly those with mild infections. Though without a clear gender predilection or a predominant pattern of clinical deficits in terms of oculomotor weakness and pupillary dysfunction, ocular deficits occurred early in most, and can occur before or concurrently with the development of typical COVID-19 symptoms. Prognosis appeared excellent, with most ocular deficits resolving completely within a month even when without steroid treatment.

SARS-CoV-2′s neuroinvasive propensity was hypothesized as a major pathomechanism behind COVID-19-related nerve palsies, mediated by the binding of S-proteins S1-subunit to angiotensin-converting enzyme 2 (ACE2) resulting in membrane fusion with the host cell and entry of the virus into the neurone [13]. Autopsy studies of 43 patients who died from severe COVID-19 infections demonstrated SARS-CoV-2 viral proteins in the lower cranial nerves, while another showed viral particles within both neurons and axons, lending support to this hypothesis [13], [14]. The close temporal proximity between OMNPs and COVID-19 symptoms in some patients supports a neuroinvasive mechanism. Para- or post-infectious immune-mediated processes induced by molecular mimicry between viral and neuronal antigens provide an alternative pathomechanism, similar to those causing Bell’s Palsy in patients with COVID-19 [15]. This perhaps explains the slightly longer interval of one to two weeks in some patients between OMNPs and COVID-19 symptoms. Likewise, reports of iOMNPs after COVID-19 vaccinations, lend further credence to an immune-mediated pathomechanism [16], [17], [18].

Our study highlights two clinically-impactful points. Firstly, isolated OMNP mostly occur with or soon after the onset of COVID-19 symptoms, and was the only presenting symptom in some. It is thus prudent to screen for COVID-19 symptoms in patients with iOMNPs, and test those at risk of infection (i.e., close contact), even when without COVID-19 symptoms. Secondly, patients with isolated OMNPs with otherwise mild COVID-19 symptoms may be discharged after angiographic and brain imaging studies excluded relevant vascular, ischemic, or structural abnormalities. Thereafter, outpatient review a month later for clinical recovery appears appropriate, this being especially vital given the burgeoning inpatient workload at medical facilities combatting the pandemic. Short courses of oral steroids seem reasonable, relying on prior reports of their effectiveness in treating idiopathic cranial nerve palsies [19], [20]. However, clinicians should be aware of emerging evidence illustrating increased risks of complications from brief bursts (≤14 days) of oral steroids [21].

Our study was limited by its small size, retrospective nature, and incomplete clinico-radiological data. Also, isolated OMNPs were attributed by the respective authors to COVID-19 based mainly on their chronological relationships but without a clearly-defined time window. However, their temporal proximity and concurrence in most of the cases rendered them less likely to be entirely happenstance. Regardless, this is an early attempt at characterizing the clinical features and outcomes of COVID-19-related iOMNPs, providing preliminary guidance on its management.

6. Conclusion

Isolated OMNPs are early but uncommon complications of COVID-19 in both children and adults. They affect patients with mild infections, and can be the sole symptom. Prognosis is excellent, with recovery being often complete and early. Early discharge and outpatient clinical review at one month, with or without short courses of oral steroids, are reasonable treatment measures.

Funding

None.

CRediT authorship contribution statement

You-Jiang Tan: Conceptualization, Methodology, Formal analysis, Writing – original draft, Writing – review & editing, Supervision. Ritika Ramesh: Conceptualization, writing (editing). You-Hong Tan: Writing – review & editing. Sarah Ming Li Tan: Writing – review & editing. Stella Setiawan: Writing – review & editing.

Declarations of interest

None.

Appendix A. Supplementary material

Supplementary material.

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