Spinal cord involvement in COVID-19: A review

Abstract

Context: Recent literature points towards myelitis, like encephalitis, as a common central nervous system complication of COVID-19. This review elaborates on disorders of the spinal cord caused by the SARS-CoV-2 virus.

Objectives: To review the published data about SARS-CoV-2-associated spinal cord disorders and assess their clinical, neuroimaging, treatment, and prognostic aspects.

Methods: The PubMed and Google Scholar databases were searched for published cases using the search items “COVID-19 OR SARS-CoV-2 AND myelitis”, “COVID-19 OR SARS-CoV-2 AND myelopathy”, and “COVID-19 OR SARS-CoV-2 AND spinal cord”.

Results: Thirty-three isolated cases were included in the present review, of which 14 were aged 60 years and above (range: 3–70 years). Eighteen patients had lung abnormalities on chest imaging. Eight patients had developed either an areflexic paraparesis or quadriparesis. In 17 patients, neuroimaging demonstrated longitudinally extensive transverse myelitis, while 3 cases showed neuroimaging changes in the spinal cord as a part of acute disseminated encephalomyelitis syndrome. Cerebrospinal fluid (CSF) examinations revealed inflammatory changes in 18 patients. However, the SARS-CoV-2 virus in the CSF was discovered in 2 patients. In 2 patients, anti-SARS-CoV-2 antibodies were demonstrated in the CSF. Following treatment, 13 patients were able to walk.

Conclusions: A variety of COVID-19-related spinal cord manifestations, such as acute transverse myelitis, acute necrotizing myelitis, SARS-CoV-2 myelitis, acute disseminated encephalomyelitis, neuromyelitis optica spectrum disorder, hypoxic myelopathy, MOG antibody-associated myelitis, spinal cord infarction, and spinal epidural abscess, have been reported. The possible mechanisms of this involvement being direct invasion, cytokine storm, coagulopathy, and an autoimmune response. However, response to treatment has been generally unsatisfactory, with many patients having residual weakness necessitating long-term rehabilitation.

Background

Acute transverse myelitis is clinically characterized by sensorimotor disturbances, bladder/bowel dysfunction, and/or autonomic dysfunction attributable to the spinal cord. Typically, it manifests as a rapid disease progression within a few hours to up to 21 days, with a sharp sensory affection level, bilateral pyramidal signs, and bladder/bowel dysfunction. While neuroimaging is not usually suggestive of compressive myelopathy, cerebrospinal fluid (CSF) examination may reveal inflammatory changes.^1,2 Acute demyelinating diseases of the central nervous system, such as multiple sclerosis, neuromyelitis optica spectrum disorder, and acute disseminated encephalomyelitis are other frequently encountered causes of acute myelitis. Moreover, many viruses can be directly implicated in the etiopathogenesis of acute transverse myelitis, including varicella-zoster, herpes simplex, Epstein–Barr, West Nile, Dengue, Japanese encephalitis, Zika, influenza, echovirus & hepatitis B, mumps, measles, and rubella viruses. However, most often, it is difficult to differentiate between a viral-induced and immune-mediated transverse myelitis.^2,3 Furthermore, there is an increasing number of reports that have linked the SARS-CoV-2 virus to the pathogenesis of acute transverse myelitis.^4–6 The spinal cord involvement can result either from the direct invasion of the spinal cord, cytokine storm, or an autoimmune response.

The SARS-CoV-2 is a positive-sense, enveloped, single-stranded RNA virus that primarily affects the lungs, and the recent disease has been designated as COVID-19. In severe COVID-19 cases, other organ systems of the body, including the nervous system, are also reportedly affected. The usual clinical manifestation of patients infected with the SARS-CoV-2 virus ranges from no symptoms to severe respiratory failure, with or without multiple organ failure.⁷

Current reports from the World Health Organization state that the COVID-19 pandemic is active in 220 countries, with more than 6.91 million confirmed cases worldwide, and 1576516 COVID-19 related deaths so far.⁸ A systemic review analyzing data from 24,410 COVID-19 patients revealed fever, cough, and fatigue to be the most common symptoms. Overall, 19% of admitted patients required non-invasive ventilation, 17% required intensive care, 9% required mechanical ventilation, and 2% needed extracorporeal membrane oxygenation. The mortality rate was approximately 7%.⁹

A variety of neurological manifestations, both central and peripheral, have been reported in COVID-19, which include loss of smell, loss of taste, stroke, Guillain-Barré syndrome, encephalopathy, headache, myelitis, myalgia, myositis, rhabdomyolysis, and neuropsychiatric manifestations.¹⁰ Neurological complications are generally more common in older age groups and patients with pre-existing comorbidities, including diabetes mellitus, hypertension, malignancies, immunological disorders, obesity, chronic respiratory disease, coronary artery disease, and liver failure.¹¹ Hence, the need for a comprehensive review of the neurological involvement in terms of the spinal cord and related disorders caused by the SARS-CoV-2 virus.

Methods

An extensive search on the PubMed and Google Scholar databases was conducted, and the last search was undertaken on 12 December 2020. The search items used were “COVID-19 OR SARS-CoV-2 AND myelitis”, “COVID-19 OR SARS-CoV-2 AND myelopathy”, and “COVID-19 OR SARS-CoV-2 AND spinal cord”. Full-text articles from journal websites were retrieved. The articles were analyzed for the clinical, neuroimaging, treatment, and prognostic aspects of COVID-19-associated spinal cord disorders. The authors have discussed the pathogenesis of COVID-19-associated spinal cord disorders. However, the impact of COVID-19 on pre-existing spinal cord diseases was not included in this review.

Results

We identified 30 case reports describing clinical data of 33 isolated cases, of which 14 patients were aged 60 years or older (ranging from 3 to 70 years of age), and 18 patients had pre-existing comorbidities. Chest imaging revealed lung abnormalities in 18 patients, while only 12 reported respiratory symptoms. Nineteen patients had sensory-motor paraplegia, and the rest had quadriparesis. In 8 patients, there was either areflexic paraparesis or quadriparesis. On neuroimaging, 17 patients demonstrated longitudinally extensive transverse myelitis, while in only 3 cases, neuroimaging changes of the spinal cord were a part of acute disseminated encephalomyelitis syndrome.

Laboratory investigations revealed either lymphopenia and/or elevation of the markers of inflammation in 17 of the 32 cases. Cerebrospinal fluid (CSF) evaluation of 18 patients revealed inflammatory changes. However, the SARS-CoV-2 virus was demonstrated in the CSF in only 2 patients by the reverse transcriptase-polymerase chain reaction (RT–PCR) method. In 2 patients, anti-SARS-CoV-2 antibodies were demonstrated in the CSF. Treatment details were available for 32 patients who were treated with corticosteroids, intravenous immunoglobulin, and/or plasmapheresis, along with antiviral drugs and other supportive treatment. Patients with spinal epidural abscess were subjected to surgery. Only 13 of the 33 patient were able to walk after treatment^12–41 (Tables 1 and 2).

Table 1.

Spinal cord involvement in COVID-19: A review of all published isolated cases.

Reference/Country	Age/sex	Co-morbidities	Clinical presentation	Respiratory symptoms at presentation	Blood parameters	CSF parameters	Chest imaging	Neuroimaging	Diagnosis	Treatment	Outcome
Zhao et al.18 March, 2020/China12	66/M	None	Fever, fatigue. Acute flaccid paraparesis with sensory involvement at level T10, urinary and bowel incontinence.	No	Lymphocytopenia, raised ferritin, CRP, and CK	NA	Patchy changes in both lungs	Not done	Acute transverse myelitis	IVIG and dexamethasone	Improved but not able to walk
Saberi et al.10 Apr, 2020/Iran13	60/M	Diabetes, hyperlipidemia, hypertension	Fever, nausea, vomiting. Progressive weakness of lower limbs, urinary incontinence, and constipation.	No	Normal	Normal	Ground glass appearance in lungs	LETM in cervical region	Acute transverse myelitis	IVIG and plasmapheresis	No improvement, power remained 1/5 on 26th day
Wong et al.1 May, 2020/UK14	40/M	Hypertension, closed angle glaucoma	Fever, dyspnoea, malaise, diarrhoea. Unsteady gait, diplopia, oscillopsia, upbeat nystagmus, limb ataxia, altered sensation in right arm, facial weakness, tongue weakness with deviation to right side.	Yes	Raised CRP, GGT	Normal	NA	Increased signal lesion in right inferior cerebellar peduncle and upper cord with swelling and microbleeds	Brainstem encephalitis with cervical cord myelitis	Symptomatic	Improved and discharged on 11th day
Sarma et al.12 May, 2020/USA15	28/F	Hypothyroidism	Fever, productive cough, low backache, myalgias, rhinorrhea. Paraesthesia in lower extremities extending to numbness in upper limbs, trunk up to mid-chest, urinary retention.	No	NA	Lymphocytic pleocytosis	NA	Widespread signal changes throughout spinal cord to the conus medullaris and involving the medulla	Acute transverse myelitis	Methylprednisolone and plasma exchange	Improved with minimal residual deficit at discharge
Munz et al.26 May, 2020/Germany16	60/M	Hypertension, fatty liver, ureterolithiasis	Flu-like symptoms. Spastic paraparesis with sensory involvement at level T9, bladder dysfunction.	No	Raised CRP	Raised protein, lymphocytic pleocytosis	Ground glass appearance in lungs	Signal changes at T9 level	Acute transverse myelitis	Methylprednisolone	After 2 weeks, able to walk independently
Giorgianni et al.2 Jun, 2020/Italy17	22/F	Diabetes	Fever, dyspnea, loss of consciousness. Acute flaccid quadriparesis, fecal and urinary incontinence, dysesthesia.	Yes	Raised CRP, D-Dimer, LDH	Raised protein	Ground glass appearance in lungs	CT head- Right frontal parenchymal bleed MRI spine- normal	Acute transverse myelitis	Mechanical ventilation, antiviral, immunomodulatory medications, rehabilitation	Patient had mild improvement only and needed long-term rehabilitation
Alketbi et al.1 Sep, 2020/UAE18	32/M	None	Flu-like symptoms. Sudden onset paraplegia, urinary retention, trunk weakness.	No	Raised CRP, D-Dimer, CPK, lupus anticoagulant positive, low protein-S	Not done	CT angiography- pulmonary embolism	Extensive hyperintense signal involving cervical, dorsal, and lumbar regions along with mild enlargement and swelling of the cervical cord	Acute transverse myelitis	Methylprednisolone, acyclovir, and enoxaparin	After 5 days, power improved to 4/5
Valiuddin et al.6 Jun, 2020/USA19	61/F	None	Rhinorrhea, chills. Lower and upper limbs weakness along with tingling sensation in B/L hands and feet, constipation, difficulty voiding.	No	Lymphocytopenia	Raised protein	NA	Extensive intramedullary hyperintense signal throughout the central aspect of spinal cord with mild enlargement of the cord	Acute transverse myelitis	Methylprednisolone and plasmapheresis, rehabilitation	Patient did not improve and was in long-term rehabilitation
Domingues et al., 20 Jun, 2020/Brazil20	42/F	None	Coryza, nasal obstruction. Paraesthesia of left upper limb, left hemithorax, hemiface.	No	Normal	RT-PCR for SARS-CoV-2 detected	Normal	Small left lateral ventral lesion with T2/STIR hyperintensity	SARS-CoV-2 myelitis	NA	NA
Durrani et al.22 Jun, 2020/New Jersey21	24/M	None	Fever, chills, nausea, vomiting, tachypnea. Lower limb weakness with overflow incontinence.	Yes	Normal	Lymphocytic pleocytosis	Multifocal pneumonia	Non enhancing T2 hyperintense signal abnormality spanning from T7 to T12	Acute transverse myelitis	Methylprednisolone	Improved power strength
Zoghi et al.24 Jun, 2020/Iran22	21/M	None	Fever, chills, dry cough, sore throat. Vomiting, paraesthesia, weakness in lower limbs, urinary retention, drowsiness.	No	Raised Covid-19 IgG levels	Raised protein, lymphocytic pleocytosis	Left lung ground glass appearance	Bilateral long corticospinal tract lesions in internal capsules extending to the cerebral peduncles and pons. MRI spine revealed LETM	Acute disseminated encephalomyelitis	Plasma exchange	NA
Zachariadis et al., 29 Jun, 2020/Switzerland23	63/F	Obesity, smoker, alcohol use	Headache, rhinorrhea, odynophagia, myalgias. Spastic paraparesis with hypoesthesia in feet up to abdomen at level T10, sphincter dysfunction.	No	Leukopenia, raised CRP	Raised protein, lymphocytic pleocytosis	Ground glass appearance in lungs	Normal	Acute transverse myelitis	IVIG and methylprednisolone	After 1 month, mild improvement, needed rehabilitation
Sotoca et al.1 Sep, 2020/Spain24	69/F	None	Fever, dry cough. Sensory and motor deficits in both hands, paraparesis with sphincter dysfunction.	No	NA	Traumatic, raised protein, lymphocytic pleocytosis	NA	T2 hyperintensities extending from medulla oblongata to C7 with patchy enhancement	Acute necrotizing myelitis	Methylprednisolone and plasma exchange	After 4 weeks able to perform occupational duties
Lisnic and Memon, 2020/Moldova25	27/M	HIV (on ART)	Paraesthesia in lower limbs and in right upper limb, spastic quadriparesis. Urinary retention.	No	Raised WBC, CD4 count = 310 cells/µL	Normal	Slight patchy ground-glass opacity basal on the left side	Extensive C4-T5 lesion, mainly in posterior columns and right lateral column	Acute transverse myelitis	Methylprednisolone and plasma exchange	Improved with a significant reduction in paresis.
Maideniuc et al., Aug 2020/USA26	61/F	Hypertension, hyperlipidemia, hypothyroidism, a remote history of nasopharyngeal and uterine cancer	Rhinorrhea, chills. Tingling in lower limbs fingers and toes, spastic paraparesis, ataxia. 10 days later- areflexic quadriparesis.	No	Normal	Hemorrhagic tape with normal WBC, raised protein Repeat tap- albumin cytological dissociation	Normal	T2 hyperintensities in central cord extending from foreman magnum, proximal C1-C2, to cervicothoracic junction	Acute necrotizing myelitis	Methylprednisolone and plasma exchange	After 4 weeks, patient walked few steps needed rehabilitation
Abdelhady et al., Jul 2020/Qatar27	52/M	Type2DM, G6PD deficiency	Fever, abdominal pain, urinary retention, flaccid paraparesis.	No	Lymphocytosis	Raised WBC and protein	Bilateral scattered lung infiltrates most pronounced in the right lower lung zone	Long segment T2WI hyperintensity in the ventral horns of gray matter in the upper and mid-thoracic cord	Acute flaccid paralysis	Steroid and acyclovir	Died due to cardiac arrest
Chow et al., Aug 2020/Australia28	60/M	Hypertension, hypercholesterolemia, ex-smoker	Fever, cough, dysgeusia, anosmia. Urinary retention, spastic paraparesis, constipation, paraesthesia in lower limbs.	No	Raised CRP, ESR, d-dimer, lymphopenia	Raised protein	Ground-glass opacities and consolidation in both lungs	Hyperintense T2 signal centrally from T7 to T10	Acute transverse myelitis	Methylprednisolone	All symptoms completely resolved on 11th day
Chakraborty et al., Aug 2020/India29	59/F	Obesity	Fever, acute onset ascending flaccid paraplegia, urinary retention, constipation, diminished sensations below T10.	Yes	Normal	NA	Initially normal	Hyperintensity in the spinal cord at T6–T7 vertebral level	Acute transverse myelitis	Intravenous methylprednisolone	Died
Kaur et al., July 2020/USA30	3/F	None	Acute flaccid quadriparesis, neurogenic respiratory failure, no sensations below neck.	Yes	Normal	Raised WBC and protein and red blood cells	Initially normal	LETM extending from mid-medulla to mid-thoracic level	Acute transverse myelitis	Methylprednisolone, IVIG, plasmapheresis, rituximab and mechanical ventilation	Not improved
Zhou et al., Sep 2020/USA31	26/M	None	Cough, numbness in soles. Painful bilateral, subacute, sequential vision loss first affecting the left eye, and then, the right eye.	No	MOG-IgG positive	Raised WBCs	Normal	Enhancement and thickening of both optic nerves	MOG antibody-associated myelitis	Methylprednisolone	After 3 weeks, vision in both eyes improved to 20/30
Zanin et al., May 2020/Italy32	54/F	Brain aneurysm (treated surgically)	Anosmia, ageusia, loss of consciousness, seizures.	Yes	Raised WBC, lymphopenia, Raised CRP, fibrinogen	Normal	Interstitial pneumonia	Patchy T2 hyperintensities in the lower cervical and upper thoracic spinal cord associated with mild central thickening and enhancement	Hypoxic myelopathy	Mechanical ventilation and dexamethasone	No improvement and patient needed long term rehabilitation
Hazrati E et al., 2020/Iran33	63/M	Diabetes, ischemic heart disease, renal failure	Flu-like symptoms. Acute flaccid areflexic paraparesis, truncal sensory loss, urinary retention.	Yes	Raised WBCs, CRP, CPK, LDH, thrombocytopenia	Lymphocytic pleocytosis, raised protein, RT-PCR for SARS-CoV-2 positive	Pneumonia	Periventricular hyperintensities along with hyperintensities in bulbo-medullary junction and cervical and dorsal spinal cord	SARS-CoV-2 myelitis	Mechanical ventilation, hemodialysis, methylprednisolon, and IVIG	After 1 week, he could walk unassisted
Utukuri et al., Jul 2020/USA34	44/M	None	Lethargy, urinary retention, acute paraparesis, numbness in lower limbs, and dysarthria.	No	Raised d-dimer, cardiolipin IgM antibody	Normal	Normal	T2 hyperintensities with cord expansion from C7 to T12	Acute disseminated encephalomyelitis	Methylprednisolone, IVIG	Modest improvement needed rehabilitation
Novi et al., Sep 2020/Italy35	64/F	Vitiligo, hypertension, MGUS	Flu-like illness, ageusia, anosmia. Visual impairment, sensory loss in right lower limb, hyperreflexia in left limb.	No	Normal	Lymphocytic pleocytosis, raised protein	NA	T2 hyperintensity of conus medullaris and hyperintense lesions throughout the cervical and thoracic spinal cord Periventricular and juxtacortical lesions within the brain	Acute disseminated encephalomyelitis	Methylprednisolone, IVIG	Significant improvement in vision
Baghbanian and Namazi, Sep 2020/Iran36	53/F	Diabetes mellitus, hypertension, ischemic heart disease	Lower backache, transient urinary incontinence, acute asymmetric areflexic paraparesis with numbness in b/l lower limbs.	No	Normal	Lymphocytic pleocytosis	CT chest- patchy ground-glass consolidation in the middle and lower lobes of the right lung	Multiple enhancing lesions of the brain and a single spinal cord lesion at the T8 level Bilateral optic nerve enhancement	Acute transverse myelitis	Plasmapheresis	Some improvement and started on rehabilitation treatment
Sampogna et al., Sep 2020/Italy37	69/M	Hypertension and diabetes mellitus	Fever, cough, anosmia, dyspnea, paraplegia, urinary retention. Evidence of lower limb venous thrombosis.	Yes	Raised d-dimer, fibrinogen, lymphopenia	Not done	NA	Infarction of anterior spinal cord from T8 to the conus medullaris	Spinal cord infarction	Mechanical ventilation and tocilizumab	Improved to wheelchair level, require assistance
	56/M	Hypertension, dyslipidemia, trigeminal neuralgia	Fever, cough, dyspnea, neck pain, right upper limb dysesthesia and weakness, urinary retention.	Yes	Lymphopenia, pus culture- MSSA	Not done	Atypical pneumonia	C4–C6 spinal epidural abscess	Spinal epidural abscess	Mechanical ventilation, and tocilizumab C3–C4 hemilaminectomy	Improved and able to walk with assistance
	48/M	Hypertension, obesity	Fever, cough, dyspnea, backache, paraparesis.	Yes	Lymphopenia, pus culture- MSSA	Not done	NA	T1-T7 spinal epidural abscess	Spinal epidural abscess	Mechanical ventilation, tocilizumab, corticosteroids, T3–T4 laminectomy	Improved but not yet independent
Aguila-Gordo et al., July 2020/Spain38	50/M	None	Fever, backache, cough, dysesthesia at lower limbs and genital area till T6, acute spastic paraparesis.	No	Raised CRP, LDH, ferritin	Normal	Normal	Disk herniation at C5–6	Acute transverse myelitis	Dexamethasone, IVIG	Improved
Shaw et al., 2020/UK39	70/M	Hypertension, atrial fibrillation	Dyspnea, visual blurring, paraparesis, urinary incontinence.	Yes	Raised CRP, aquaporin-4 antibodies positive	Normal	Ground-glass opacities and consolidation in both lungs	MRI brain- normal MRI spine- patchy multifocal areas of enhancement from T5 to T11	NMOSD	Mechanical ventilation	Died
Batum et al., Dec 2020/Turkey40	50/F	None	Fever, cough, numbness in lower limbs till T4, acute areflexic flaccid paraplegia with urinary retention.	Yes	Raised CRP, ferritin	CSF- raised protein, aquaporin-4 IgG positive	Ground-glass opacities and consolidation in both lungs	MRI spines- long segment myelitis extending from C3 to conus MRI brain- normal	NMOSD	IVIG, plasmapheresis, methylprednisolone	No improvement
Rifino et al., Sep 2020/Italy41	62/M	None	Back pain, paraparesis, and sensory changes upto T11.	No	Anti-SARS-CoV-2 antibodies present	Normal	Normal	MRI spine- degenerative changes	Acute transverse myelitis	MPS, IVIG, plasmapheresis	Improved and able to walk
	66/M	None	Fever, ageusia, anosmia, and spastic sensory motor paraparesis.	No	Anti-SARS-CoV-2 antibodies present	Normal	CT chest- ground glass opacities	MRI brain – normal MRI spine- degenerative changes changes	Acute transverse myelitis	MPS, plasmapheresis	Improved and able to walk

ADEM – Acute disseminated encephalomyelitis, CRP – C-reactive protein, CT – Computerized tomography, CPK – Creatine phosphokinase, ESR- Erythrocyte sedimentation rate, F-female, GGT-Gamma-glutamyl transferase, IgG – Immunoglobulin G, IgM – Immunoglobulin M, IVIG-Intravenous immunoglobulin, LETM – Longitudinally extensive transverse myelitis, LDH – Lactate dehydrogenase, MRI – Magnetic resonance imaging, M-Male, MOG – Myelin Oligodendrocyte Glycoprotein, NMOSD-Neuromyelitis optica spectrum disorder, NA – Not available, RT-PCR-Reverse transcription polymerase chain reaction, STIR – Short T1 inversion recovery, MGUS – Monoclonal gammopathy of undetermined significance,WBC- White blood cells.

Table 2.

Summary of clinical and outcome data of 33 reported patients of COVID-19-associated spinal cord disorders.

Parameters	Values
Age(years)	Mean = 49.24; Median = 54 Range = 3–70 years
Sex	Male = 20 (60.60%)
Respiratory symptoms	12 (36.36%)
Co-morbidities	Diabetes = 6(18.18%), Hypertension = 11(33.33%), Hyperlipidemia = 4(12.12%), Hypothyroidism = 2(6.06%), Obesity = 3(9.09%) HIV = 1(3.03%), Cancer = 1(3.03%) G6PD deficiency = 1(3.03%) CKD = 1(3.03%) IHD = 2(6.06%) MGUS = 1(3.03%) Atrial fibrillation = 1(3.03%) Vitiligo = 1(3.03%) Trigeminal neuralgia = 1(3.03%) GERD = 1(3.03%)
Elevated inflammatory markers	17 (51.51%)
CSF abnormality (Not done in 6 patients)	18 (66.66%)
Chest imaging finding (Not available in 7 patients)	18 (69.23%)
Outcome	Clinically improved and able to walk = 13 (39.39%) Bedridden or unable to walk unassisted = 15 (45.45%) Death = 3 (9.09%) Information not available = 2 (6.06%)

CSF- cerebrospinal fluid; HIV- human immunodeficiency virus; G6PD- Glucose-6-phosphate dehydrogenase; IHD- Ischemic heart disease; MGUS- Monoclonal gammopathy of undetermined significance.

Discussion

In this review, based on case reports of 33 COVID-19 patients with spinal cord involvement, a variety of manifestations, such as acute transverse myelitis, acute necrotizing myelitis, SARS-CoV-2 myelitis, hypoxic myelopathy, myelin oligodendrocyte glycoprotein (MOG) antibody-associated myelitis, neuromyelitis optica spectrum disorder, hypoxic myelitis, spinal cord infarction, and spinal epidural abscess, were noted. We noted that the majority (64%) of these patients, on presentation, did not have respiratory symptoms, and in many, even imaging lungs were normal. These observations suggested that spinal cord involvement might occur early in the course of the disease and might be a presenting manifestation. Therefore, COVID-19 should be considered in the differential diagnosis of acute myelitis.

Imaging abnormalities in the brain were observed in COVID-19-associated acute disseminated encephalomyelitis. Besides, generally unsatisfactory treatment response was seen in patients with COVID-19-associated myelopathies, and the majority of the cases retained a residual weakness (Table 3).

Table 3.

Spinal cord involvement in COVID-19 (n = 33).

Type of myelitis	Number
Acute transverse myelitis	18
SARS-CoV-2 myelitis	2
Acute disseminated encephalomyelitis	3
Acute necrotizing myelitis	2
MOG antibody-associated myelitis	1
Hypoxic myelopathy	1
Acute flaccid myelitis	1
Spinal cord infarction	1
Spinal epidural abscess	2
Neuromyelitis optica spectrum disorder	2

MOG – Myelin Oligodendrocyte Glycoprotein.

Henceforth, we briefly describe the various reviewed presentations in which spinal cord related disorders may be seen in COVID-19 patients, followed by a description of the pathogenesis of the SARS-CoV-2 virus in these disorders.

Clinical presentations of different COVID-19-associated spinal cord disorders

Acute transverse myelitis

Acute transverse myelitis was the commonest postinfectious/parainfectious myelitis reported in COVID-19 patients. Neuroimaging in these patients revealed a longitudinally extensive transverse myelitis. This type of myelitis is generally a post-infectious disorder, and response to treatment with methylprednisolone or plasmapheresis is variable (Table 1).

Acute disseminated encephalomyelitis

Acute disseminated encephalomyelitis is an immune-mediated disorder that affects the white matter of the brain and spinal cord. Utukuri et al. reported about a 44-year-old male presenting with acute myelopathy. Magnetic resonance imaging (MRI) revealed T2/FLAIR hyperintensity in the conus medullaris and periventricular regions of the brain. Later, the patient tested positive for SARS-CoV-2 and showed moderate improvement following intravenous immunoglogulin (IVIG) treatment and plasmapheresis.³⁴ Novi et al. reported about a 64-year-old woman complaining of acutely developed bilateral vision loss along with sensory deficit in the right leg, and neuroimaging showed a single spinal cord lesion at the T8 level with bilateral optic nerve sheath enhancement. The serum of the patient tested negative for antiaquaporin-4 and MOG antibodies; however, the patient tested positive for serum anti-SARS-CoV-2 antibodies. The patient improved significantly following corticosteroid treatment.³⁵

Neuromyelitis optica spectrum disorder

Neuromyelitis optica spectrum disorder is an inflammatory demyelinating disorder that involves the spinal cord, optic nerve, and the brain. Neuromyelitis optica spectrum disorder is clinically characterized by longitudinally extensive transverse myelitis, optic neuritis, and area postrema involvement. Positive anti–aquaporin-4 antibody, a serum biomarker of neuromyelitis optica spectrum disorder, is present in the majority of patients. Two recent reports have described neuromyelitis optica in association with severe COVID-19.^39,40

Hypoxic myelopathy

Zanin et al. described a 54-year-old woman who was brought to the emergency department with altered sensorium and tested positive for SARS-CoV-2 infection. Her blood inflammatory parameters were mildly raised. However, the patient had severe hypoxia and required mechanical ventilation. Neuroimaging revealed T2/FLAIR hyperintense lesions in the periventricular regions of the brain and the cervical and thoracic regions of the spinal cord. The patient was treated with dexamethasone in an intensive care unit. She improved subsequently and was then shifted to the rehabilitation unit. This case suggested that hypoxic damage is not restricted to the periventricular region, but the spinal cord may also be affected.³²

MOG antibody-associated myelitis

Zhou et al. reported a COVID-19 patient with MOG-IgG antibody-associated optic neuritis and myelitis. The patient had presented with acute bilateral vision loss and numbness on the soles. The fundus examination demonstrated bilateral disc edema, and an MRI-brain revealed enhancement and thickening of both optic nerves. Magnetic resonance imaging of the spinal cord revealed T2 hyperintensities in the lower cervical and upper thoracic regions. Fortunately, the patient improved rapidly following treatment with methylprednisolone.³¹

Acute necrotizing myelitis

Acute necrotizing myelitis is caused by cytokine storm, a characteristic phenomenon of severe COVID-19 and is pathologically characterized by focal necrosis in the spinal cord.²⁴ In the case described by Sotoca and Rodríguez-Alvarez, an elderly patient presented with loss of sensation in the right face and upper limb along with hyperreflexia. Neuroimaging revealed extensive T2/FLAIR hyperintensity extending from the medulla oblongata to the cervical cord. In the follow-up MRI, the lesion size increased, and a new lesion appeared at the T1 level, which showed peripheral contrast enhancement. The patient improved following treatment.

SARS-CoV-2 myelitis

In case reports of two patients with acute transverse myelitis, CSF examination demonstrated the presence of SARS-CoV-2. In these two cases, the clinical and neuroimaging picture was indistinguishable from other varieties of SARS-CoV-2-associated acute transverse myelitis.^20,33

Acute flaccid myelitis

Acute flaccid myelitis is a polio-like illness characterized by acute flaccid paraparesis and long T2/FLAIR hyperintensity of the gray matter in the spinal cord. Abdelhady et al. described a 52-year-old man presenting with acute urinary retention and flaccid motor paraparesis. He later tested positive for SARS-CoV-2. Spinal cord MRI showed a long segment of T2/FLAIR hyperintensity in the ventral horns of gray matter in the upper and mid-thoracic cord. Two days later, the patient died of cardiac arrest.²⁷

Spinal cord infarction

In a report about a 69-year-old male with severe COVID-19 and presenting with acute paraplegia, neuroimaging revealed infarction in the anterior spinal cord extending from T8 to the conus medullaris, with a suspected occlusion of the artery of Adamkiewicz. After 60 days, the patient became wheelchair-bound.³⁷

Spinal epidural abscess

Sampogna et al. also described two cases with spinal epidural abscess; both patients had severe COVID-19. One patient presented with acute quadriplegia. The MRI showed a spinal epidural abscess in the cervical region. The other patient presented with paraplegia and had a thoracic epidural abscess on MRI. After surgery, one of the two patients was able to walk, but the other patient was not able to sit.³⁷

Pathogenesis

Invasion of spinal cord

The SARS-CoV-2 virus can enter the spinal cord via the hematogenous route infecting the endothelial cells and invading the spinal cord. The SARS-CoV-2 virus can bypass the blood-brain-barrier since it uses the inflammatory cells as a Trojan horse.⁷ The inflammatory changes produced by the virus thus result in spinal cord inflammation. It has been observed that the virus enters inside the sensory neurons after peripheral inoculation, resulting in ganglionitis.⁴² Shiers et al. have also demonstrated that the human dorsal root ganglia contain the angiotensin-converting enzyme 2 receptors that help the SARS-CoV-2 virus to spread to the spinal cord. The entry point can be free-nerve endings present in the skin as well as the intestinal mucosa.⁴³

Perdomo-Pantoja et al. observed that the neuroimaging of patients with cervical myelopathy and a history of hypertension (receiving renin-angiotensin system blocking drugs) demonstrated lesser T2/FLAIR hyperintensity in the cervical cord than in non-hypertensive controls.⁴⁴ Direct viral infection of the central nervous system by this virus remains controversial and has not been elucidated. In spite of the availability of several autopsy studies of COVID patients, there is minimal evidence of any direct encephalitis, and the rare recovery of the virus in CSF might probably be contamination rather than being good evidence of viral invasion.⁴⁵

Cytokine storm

Severe COVID-19 incites an excessive systemic inflammatory response, described as a cytokine storm. This cytokine storm manifests as high levels of circulating proinflammatory cytokines, severe lymphopenia, massive inflammatory changes in multiple body organs, and widespread thromboembolism. The proinflammatory cytokines, tumor necrosis factor, interleukin-6, and interleukin −1β are predominantly elevated in a cytokine storm, resulting in enhanced vascular hyperpermeability, multiorgan failure, and death.⁷

Coagulopathy

Another devastating consequence of the cytokine storm is marked hypercoagulability.

The spinal cord predominantly receives blood from three main arteries – the anterior spinal artery and two posterior spinal arteries. Reinforcement of blood supply comes from the ascending cervical arteries (branches of the thyrocervical trunk), radicular-medullary branches (branches of the aorta), and the artery of Adamkiewicz (a branch of the aorta) at the level of the lower thoracic or lumbar vertebra. The occlusion of the artery of Adamkiewicz can result in spinal cord ischemia in the thoracolumbar region. Predominantly, this infarction is caused by aortic disease, thoracolumbar surgery, sepsis, hypotension, and thromboembolic disorders. Therefore, we suggest that spinal cord infarction because of hypercoagulability can lead to myelopathy in patients with COVID-19.^46,47

Thromboembolism in the aorta or the major branches in COVID-19 patients has recently been described as leading to splanchnic infarctions.^48,49 On neuroimaging, a spinal cord infarction and acute transverse myelitis have a close resemblance, and differentiation may be difficult in a patient with COVID-19-associated acute myelopathy.

Autoimmunity

Post-infectious acute transverse myelitis is largely thought to be caused by an autoimmune process triggered by the systemic SARS-CoV-2 infection. Furthermore, neuronal damage is believed to be caused by the phenomenon of molecular mimicry. The molecular mimicry theory is based on the fact that the SARS-CoV-2 virus particle contains many proteins that have a close structural resemblance to some human neuronal proteins. Antibodies against the virus incite an intense immune response resulting in neuronal damage.^50,51

Conclusion

Spinal cord manifestations of COVID-19 are a rare problem despite the huge number of cases globally. This review suggests that spinal cord complications can be caused by multiple aetiologies, such as post-infectious transverse myelitis, acute necrotizing myelitis, SARS-CoV-2 myelitis, acute disseminated encephalomyelitis, neuromyelitis optica spectrum disorder, hypoxic myelopathy, MOG antibody-associated myelitis, spinal cord infarction, hypoxic myelitis, and spinal subdural abscess. Although many of these are potentially treatable, a general response to treatment has remained unsatisfactory, leaving many patients with significant residual weakness. Lack of autopsy examination of the spinal cord leading to speculation of multiple descriptive diagnoses in these cases has been the only way to characterize the pathophysiology of spinal cord complications in COVID-19 affected patients.

Disclosure statement

No potential conflict of interest was reported by the author(s).