Post-COVID-19 acute disseminated encephalomyelitis: Case report and review of the literature

Abstract

Background

Our understanding of the spectrum of neurological manifestations associated with COVID-19 keeps evolving. Reports of life-threatening neurological complications, such as acute disseminated encephalomyelitis (ADEM), are alarmingly growing in number.

Case presentation

We report a 42 years old previously healthy man who presented with left visual loss and cognition deterioration, manifesting at least ten days after infection with SARS-CoV-2. Serological work-up for potential immunological markers (i.e., antibodies against aquaporin-4 and myelin oligodendrocyte glycoprotein) were negative. Magnetic resonance imaging revealed multiple bilateral and asymmetrical lesions in the brainstem, cortical, juxtacortical, and periventricular regions, with surrounding edema. Post-contrast sequences demonstrated punctate, ring, and open ring enhancement patterns. Methylprednisolone pulse therapy was initiated for the patient, and he was placed on rituximab. After one month, his clinical symptoms had resolved, and his cognitive function was normal.

Conclusions

We conducted an extensive literature search, and COVID-19-associated ADEM cases reported thus far were identified and reviewed. ADEM often occurs in a post-infectious fashion; however, it is unclear how SARS-CoV-2 infection can trigger such rapidly progressive episodes of encephalopathy and demyelination. Nevertheless, considering the alarming number of cases of ADEM developing after SARS-CoV-2 infection, neurologists should consider this severe phenotype of COVID-19 neurological complication in mind, enabling prompt therapeutic interventions to be made.

Introduction

With the ongoing pandemic of Coronavirus disease 2019 (COVID-19), caused by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infection, significant concerns were raised regarding the spectrum of neurological manifestations associated with this infection. A wide variety of such complications can occur in COVID-19 patients, with various pathologies and degrees of severity, due to either direct or indirect involvement of the central nervous system (CNS) (Al-Sarraj et al., 2021). There are numerous reports of CNS immune-mediated conditions; the underlying pathogenesis is not clear yet.

Several cases of acute disseminated encephalomyelitis (ADEM; an immune-mediated demyelinating disorder of the CNS) after infection with SARS-CoV-2 have been reported (reviewed in Table 1 ). ADEM is more frequently observed in children, especially after infection and reports have shown that ADEM might be associated with vaccination (Baxter et al., 2016). It is generally regarded as monophasic, i.e., no new episode may occur three months after the first episode in most cases (Pohl et al., 2016). The clinical profile usually includes an initial prodromal phase, where fever, nausea, vomiting, headache, and weakness may be present, followed by acute-onset, rapidly progressive encephalopathy and multifocal neurological symptoms. A wide variety of neurological deficits (e.g., pyramidal signs, ataxia, hemiparesis, cranial nerves involvement, and seizures) can be manifested, determined mainly by the localization of lesions (Pohl et al., 2016, Tenembaum et al., 2007). Multiple large bilateral lesions are typically visualized on magnetic resonance imaging (MRI) studies as T2 and fluid-attenuated inversion recovery (FLAIR) hyperintensities; they are asymmetric in shape and location and have ill-defined margins (Pohl et al., 2016, Tenembaum et al., 2002). With variable clinical and radiologic features and no specific biomarker, diagnosis of ADEM requires exclusion of other probable diagnoses. It is worth mentioning that autoimmune encephalitis(AE) is also associated with Covid-19 and has similarities in pathophysiology and clinical manifestations, which therefore can cause diagnostic challenges. Although ADEM and AE have similar presentations, symptoms develop more rapidly in ADEM (McGetrick et al., 2021).

Table 1.

Demographic, clinical, radiological of cases with acute disseminated encephalomyelitis associated with COVID-19, along with their treatments and outcomes.

Case	Age/ Sex	publication date	country of study	ADEM symptoms	MRI finding	Treatment	Outcome
1 Novi et al. (2020)	64/F	September 2020	Italy	Severe visual lossSensory deficitHeadacheHyperreflexiaBabinski signRight abdominal sensory levelIrritability	Multiple T1 post-Gd enhancing lesions of the brain, associated with a single spinal cord lesion at the T8 level and with bilateral optic nerve enhancement	High-dose steroidsIVIG	Significant improvement in visual symptomsReduced number of Gd-enhancing lesions in follow-up brainMRI
2 Virhammar et al. (2020) ANE	55/F	September 2020	Sweden	StuporMultifocal myoclonus	Symmetrical FLAIR hyperintensities signal symmetrically in central thalami, subinsular regions and thalami, medial temporal lobes, and brain stem, consistent with ANE	AcyclovirIVIGPlasma exchange	The patient clinically improved
3 Dixon et al. (2020) ANE	59/F	September 2020	United Kingdom	Seizure (GTCS)Reduced level of consciousnessUnreactive left pupil	Brain stem swelling, symmetrical hemorrhagic lesions in the brain stem, amygdalae, putamina, and thalamic nuclei	High-dose steroidsLevetiracetamAcyclovirCeftriaxoneAmoxicillinClarithromycin	Died
4 Parsons et al. (2020)	51/F	May 2020	USA	UnresponsivenessDepressed deep tendon reflexesMute plantar responsesFlaccid muscle tone	Small Gd-enhancing lesion in the left frontal lobe at the gray-white interface and FLAIR hyperintensities in the deep hemispheric, periventricular and juxtacortical white matter	High-dose steroids IVIG	Fully oriented
5 de Miranda Henriques-Souza et al. (2021)	12/F	October 2020	Brazil	Flaccid tetraplegiaDeep areflexiaTingling and numbness in the inferior limbs	Extensive bilateral and symmetric restricted diffusion involving the subcortical and deep white matterFocal hyperintense T2 FLAIR lesion in the splenium of the corpus callosum with restricted diffusion	High-dose steroids	Partial improvement
6 Langley et al. (2020)	53/M	November 2020	United Kingdom	HypotoniaAgitation	Bilateral multiple hyperintense lesions within the subcortical and deep white matter of the frontoparietal lobesSmall amount of IVH within the occipital horns of the lateral ventricles	High-dose steroids	The patient clinically improved
7 Lopes et al. (2020)	59/F	October2020	Brazil	Reduced level of consciousnessAsymmetric flexor motor responsesHyporeflexia	Multiple bilateral focal areas of signal abnormalities in the cerebral and cerebellar white matter	HydroxychloroquineBroad-spectrum antibiotics	Died
8 Lopes et al. (2020)	41/M	October2020	Brazil	Reduced level of consciousnessFour-limb weaknessBlunted affectPoor verbal interaction	Focal lesions located in the centrum semiovale, bilaterally, right thalamus, globus pallidus bilaterally and anterior limb of internal capsule, characterized by hyperintensity on axial FLAIR images, high signal on DWI and apparent diffusion coefficient, representing diffusion facilitation	Not reported	Fully alert and cooperative patient, with mild attentional and executive dysfunction
9 Hussein et al. (2020)	55/F	September 2020	USA	Reduced level of consciousnessSeizureGeneralized weakness	Mild asymmetric FLAIR hyperintensities in the left>right cerebral cortex, thalami, the left sub splenial region,the left subcortical optic radiations and the mid pons	LevetiracetamLacosamideTopiramateIVIGHigh-dose steroidsPlasmapheresis	The patient clinically and electrographically improved
10 Umapathi et al. (2020)	59/M	September 2020	Singapore	DrowsyRoving eye movementsTransient ocular flutter	Multiple discrete hyperintense foci in the periventricular and deep white matter bilaterally, with foci in the temporal region, subcortical white matter as well as the forceps minor	Convalescent plasmaIVIG	He was able to open eyes spontaneously, track visually and smile meaningfully. However, he had no coherent volitionalmotor and verbal response to the environment
11 Reichard et al. (2020)	71/M	May 2020	USA	Not reported	Not reported	High-dose steroidsVasopressor	Died
12 Zhang et al. (2020)	40/F	April 2020	USA	DysphagiaDysarthriaEncephalopathy	Extensive patchy areas of abnormal signal involving bilateral frontoparietal white matter, anterior temporal lobes, basal ganglia, external capsules, and thalami	HydroxychloroquineCeftriaxoneIVIG	The patient clinically improved
13 Shahmirzaei and Naser Moghadasi (2021)	30/M	January 2021	Iran	AtaxiaConfusion	Multiple enhanced lesion	High-dose steroidsRituximab	The patient clinically improved
14 McCuddy et al. (2020)	37/F	2020	USA	Plegic in legs bilaterallySymmetric weakness in the upper extremity	Multiple T2 hyperintense lesions with restricted diffusion involving the corpus callosum, bilateral cerebral white matter, right pons and in the bilateral ventral medulla	DecadronHydroxychloroquine ZincConvalescent plasma	Partial improvement
15 McCuddy et al. (2020)	56/M	2020	USA	Unresponsive,Eyes with leftward deviation,No spontaneous limb movements, Reflexes reduced	Several T2 hyperintense lesions, many with restricted diffusion, in cerebral white matterNo hemorrhage	SolumedrolIVIGConvalescent plasma	Clinically, not opening eyes, unresponsiveRemains on ventilator with tracheostomy
16 McCuddy et al. (2020)	70/F	2020	USA	severe diffuse weaknessUnresponsive to verbal stimuliWithdraws to pain slightly	Several T2 hyperintense lesions, most with restricted diffusion, in deep cerebral white matterMinimum enhancement and no hemorrhage	SolumedrolIVIGConvalescent plasma	Spontaneously opens eyesdecorticate posturing in upper extremityWithdraws lower extremity to stimuli Weaning from the ventilator
17 AHL Handa et al. (2020)	33/M	September 2020	India	Four-limb weaknessSeizure (GTCS)DTR: absentBabinski sign	Symmetrical FLAIR hyperintensities involving bilateral subcortical fronto-parietal lobes, splenium of corpus callosum, medulla and visualised cervical cord with petechial haemorrhages and evidence of diffusion restriction involving splenium of corpus callosum	AcyclovirCeftriaxoneLacosamideHigh-dose steroids	Died
18 Manzo et al. (2021)	6/M	May 2021	Italy	Seizure (GTCS)	T2-FLAIR hyperintense lesions in the right cerebellar hemisphere, cortical-subcortical cuneus gyrus of the right parietal lobe, left side of the corpus callosum and corona radiata, cortical-subcortical inferior left parietal gyrus	High-dose steroids	The patient clinically improved
19 AHL Varadan et al. (2021)	46/M	February 2021	India	HeadacheReduced level of consciousnessLoss of power in the left limbsLeft facial nerve palsy	Hyperintense white matter lesions in bilateral frontal, parietal lobes, left thalamus, left cerebral peduncle, and medulla T2W and FLAIR, hypointense onT1WPre and postcontrast of lesions show patchy, rim enhancement with central nonenhancingcomponent	High-dose steroids	Died
20 McLendon et al. (2021)	17-month /F	March 2021	USA	IrritabilityWeakness of upper extremitiesAtaxiaNeck stiffnessBrudzinski's sign	Revealed multifocal hyperintense FLAIR signals in bilateral subcortical and periventricular whitematter without contrast enhancement	IVIGHigh-dose steroids	The patient clinically improved
21 ANHLE Alqahtani et al. (2021)	59/M	June 2021	Saudi Arabia	Reduced level of consciousnessAbsence of some brainstem reflexes	Extensive brain abnormality predominantly involving the deep white matter with micro haemorrhages	Health guidelines of Saudi Ministry	Died
22 ANHLE Alqahtani et al. (2021)	47/F	June 2021	Saudi Arabia	Reduced level of consciousnessBlurred visionAbnormal movement of the right upper limb and left lower limb	Diffuse petechial hemorrhages especially in the basal ganglia that is compatible with diffuse necrotizing leukoencephalitis	Not reported	Coma
23 Kumar et al. (2020)	35/F	September 2020	USA	Gait instabilitySymmetric distal neuropathyReduced level of consciousness	Hemispheric white matter signal in juxtacortical regions extending to anteromedial temporal lobesSymmetric periventricular white matter FLAIR hyperintensities involving bilateral cerebral peduncles with mild diffusion restriction	High-dose steroidsIVIGplasma exchange	She had not improved, and was transferred to a long term care facility
24 AHL Haqiqi et al. (2021)	56/F	January 2021	United Kingdom	Reduced level of consciousness	Extensive symmetrical FLAIR abnormal signal throughout the white matter bilaterally with hemorrhage compatible with haemorrhagic leukoencephalitis	AnticoagulationAntihypertensive	The patient neurological condition hasremained stableHe discharged to a neurorehabilitation center.
25 AHL Yong et al. (2020)	61/M	July 2020	Singapore	Flaccid tetraplegiaAbsent plantar reflexes	Asymmetrical, multifocal lesions in the subcortical white matter of bilateral cerebral hemispheres, cortex, Bilateral thalami, and cerebellar hemispheres, petechial hemorrhage and vasogenic edema within the lesions10 mm rightward midline shift	RemdesivirPlasma exchangeIVIG	The patient clinically improved
26 Abdi et al. (2020)	58/M	June 2020	Iran	Reduced level of consciousnessInability to walkStatus epilepticus	Diffuse confluent white matter hyperintensity on FLAIR, particularly at the left-side without prominent enhancement on T1	High-dose steroids	Died
27 Walker et al. (2021)	51/F	April 2021	USA	Increased seizure activityIncontinenceAphasia	Not reported	Remdesivir	Died
28 Walker et al. (2021)	64/M	April 2021	USA	Nonresponsive with a fixed and dilated right pupil	Not reported	RemdesivirConvalescent plasma Corticosteroids	Died
29 Delamarre et al. (2020)	51/M	September 2020	France	Unresponsive comaPyramidal syndromeRight-sidedsixth nerve palsyNo cornealreflex	Diffuse hyperintense lesions on FLAIR images without Gd-enhanced lesions	High-dose steroids IVIG	The patient showedcomplete motor recovery
30 Karapanayiotides et al. (2020)	57/M	October 2020	Greece	Reduced level of consciousnessHyperreflexiaBlunted vestibulo-ocular reflexes	Concentric demyelination pattern	AzithromycinHydroxychloroquineRitonavir Interleukin-1 antagonist	The patient recovered, and 1 month later, he only had moderate tetraparesis
31 Poyiadji et al. (2020) ANE	?/F	March 2020	USA	Altered mental status	hemorrhagic rim enhancing lesions within the bilateral thalami, medial temporal lobes, and subinsular regions	IVIG	Not reported

Abbreviations: Gd, Gadolinium; ANE, Acute necrotizing encephalopathy; AHL, Acute hemorrhagic leukoencephalitis/leukoencephalomyelitis; ANHLE, Acute necrotic hemorrhagic leukoencephalitis; GTCS, Generalized tonic-clonic seizure; IVIG, intravenous immunoglobulin G; IVH, Intraventricular hemorrhage; DWI, Diffusion weighted imaging.

We describe the case of an adult patient who developed an ADEM episode shortly after he was infected with SARS-CoV-2. We conducted an extensive search of relevant literature and summarized the existing data on post-infectious ADEM in the context of COVID-19.

Case presentation

In early January 2021, a previously healthy 42-year-old man presented with visual loss in the left eye, bilateral ptosis, drowsiness, and declined cognition from three days before admission. He had been quarantined in a non-healthcare setting from 10 days before the onset of his neurological symptoms for a history of low-grade fever, dyspnea, cough, and myalgia. Nasopharyngeal swab polymerase chain reaction (PCR) was positive for SARS-CoV-2 and negative for influenza H1N1.

Upon physical examination, he was not febrile, and his vital signs were stable. The patient was lethargic and irritable. His-left visual acuity was 20/50; reflex afferent papillary defect in the corresponding eye was 3+. Bilateral ptosis, more prominent in the left side, was detected. There was mild paraparesis in the lower extremities (4/5). Sensory and cerebellar functions, deep tendon reflexes, and plantar reflexes were normal. Results from optical coherence tomography (OCT) performed by an ophthalmologist were normal.

Electrolytes, white blood cells, hemoglobin, C-reactive protein, transaminases, Serum creatinine levels were within the normal range, as were his TSH, T3, and FT4 levels.

Additional tests showed negative neuromyelitis Optica antibody (NMO-IgG) and negative myelin oligodendrocyte glycoprotein antibody (MOG-IgG) results.

Brain magnetic resonance imaging (MRI) sequences were obtained. Multiple bilateral and asymmetrical lesions were observed in the brainstem, cortical, juxtacortical, and periventricular regions, appearing as hyperintensities with surrounding edema on T2-weighted and Fluid-attenuated inversion recovery (FLAIR) images. Post-contrast T1-weighted sequences revealed punctate, ring, and open ring enhancement patterns. Electroencephalogram (EEG) showed generalized slowing with no epileptiform discharge.

The patient underwent methylprednisolone pulse therapy for five days (1 g/day), followed by two doses of rituximab infusion (1 g/infusion; with a two-week interval). After one month, the patient's clinical symptoms resolved, visual acuity was normal (10/10), ptosis and mental status evaluation were also normal.

Discussion

Adding to the growing body of evidence, we reported a case of post-COVID-19 ADEM with manifestations of cognitive deficits and visual loss in a 42-year-old man. Although this demyelinating disorder of the CNS tends to occur after infections, an exact, causal relationship between infections and ADEM is yet to be determined (Pohl et al., 2016). The absence of NMO-IgG and MOG-IgG excluded the probability of Neuromyelitis optica spectrum disorder and MOG-associated Disease, resulting in ADEM diagnosis. Unlike the predominance of ADEM occurrence in children, our patient, similar to most reported cases of COVID-19-associated ADEM, was a middle-aged individual.

Our extensive search of the existing literature on COVID-19 and associated ADEM yielded 31 cases; data extracted from those cases are presented in Table 1. As interpreted from Table 1, there was no gender predominance among the cases (16 females, 15 males). Most patients (90.3%; 28/31) were adults with an average age of 52.3 years. Only a few patients had severe COVID-19-associated symptoms and required intensive care. 55.8% (17/31) had reduced levels of consciousness and a decreased GCS. Muscle weakness or decreased muscle tone was observed in 35.4% (11/31); 4 patients (Novi et al., 2020, Langley et al., 2020, Shahmirzaei and Naser Moghadasi, 2021, McCuddy et al., 2020) developed seizures, and the frequency of seizures was increased in one patient who had seizures before COVID-19 infection (Yong et al., 2020). In addition to our case, visual impairments were reported in two patients (Tenembaum et al., 2002, Varadan et al., 2021). MRI findings of these patients showed multiple lesions in various regions of the CNS Fig. 1 .

Fig. 1.

Fluid-attenuated inversion recovery images (a–f) of the brain showing multiple high-signal lesion in the brainstem, cortical, juxtacortical, and periventricular areas. Post-contrast T1-weighted sequences (g–l) showing enhanced lesion as target sign with low-signal dot in the center of lesion.

Different outcomes ensued with the treatments applied in the reported cases. In 58% (18/31) of cases, symptoms improvement and MRI lesions reduction were achieved. Unfortunately, 25% died. Others showed no progression of their symptoms. One patient's treatment outcome was not mentioned (Karapanayiotides et al., 2020). The neurological manifestations associated with ADEM after the COVID-19 course can significantly increase morbidity and mortality and can multiple the hospitalization time. Although corticosteroids can be beneficial in the resolution of symptoms in ADEM patients, prescription of corticosteroids should be done with caution as it can increase the risk of increased viral replication (McCuddy et al., 2020).

It is notable that while COVID-19-associated ADEM patients predominantly presented with reduced level of consciousness and muscle weakness, a review shows that the most common symptoms in patients with COVID-19-associated autoimmune encephalitis are altered mental status, seizures and ataxia (Payus et al., 2021).

In conclusion, given the significant number of ADEM cases associated with SARS-CoV-2 infection reviewed above, neurologists should bear in mind severe neurological complications that might occur after an unfortunate COVID-19 infection and promptly take action to prevent further potential damages.