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Case Report

A Case of COVID-Related MERS (Clinically Mild Encephalitis/Encephalopathy with a Reversible Splenial Lesion) with a Typical Imaging Course and Hyponatremia in Adults—A Case Report and Literature Review

by
Mieko Tokano
1,2,
Norihito Tarumoto
1,*,
Iichiro Osawa
3,
Jun Sakai
1,
Mariko Okada
4,
Kazuhide Seo
4,
Yoshihiko Nakazato
4,
Toshimasa Yamamoto
4,
Takuya Maeda
5 and
Shigefumi Maesaki
1
1
Department of Infectious Disease and Infection Control, Saitama Medical University, 38 Morohongo, Saitama 350-0495, Japan
2
Departments of Allergy and Immunology, Faculty of Medicine, Saitama Medical University, 38 Morohongo, Saitama 350-0495, Japan
3
Department of Radiology, Faculty of Medicine, Saitama Medical University, 38 Morohongo, Saitama 350-0495, Japan
4
Department of Neurology, Faculty of Medicine, Saitama Medical University, 38 Morohongo, Saitama 350-0495, Japan
5
Department of Clinical Laboratory, Faculty of Medicine, Saitama Medical University, 38 Morohongo, Saitama 350-0495, Japan
*
Author to whom correspondence should be addressed.
COVID 2023, 3(2), 183-191; https://doi.org/10.3390/covid3020013
Submission received: 21 December 2022 / Revised: 31 January 2023 / Accepted: 31 January 2023 / Published: 1 February 2023
Browse Figures
Versions Notes

Abstract

:
Clinically mild encephalitis/encephalopathy with reversible splenial lesions (MERS) is a mild form of encephalitis/encephalopathy that appears in association with various conditions, including infection. COVID-19 is also known to cause MERS. MERS more commonly occurs in children, and adult cases are relatively rare. Typical head MRI findings include a round lesion in the mid-layer of the corpus callosum with a high signal intensity on diffusion-weighted images. Most improve within a week. Although the exact mechanism by which the cerebral corpus callosum is affected is still unknown, several hypotheses have been proposed, including the involvement of electrolyte abnormalities (e.g., hyponatremia) and inflammatory cytokines (e.g., IL-6). In this report, we describe the first case of COVID-associated MERS with a typical imaging course and hyponatremia, with a review of the relevant literature. When psychiatric symptoms and the disturbance of consciousness appear in COVID patients, MERS should be considered in addition to delirium due to fever and hypoxia.

1. Introduction

Coronavirus disease 2019 (COVID-19) is an infectious disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). After an incubation period of 4–7 days, respiratory symptoms such as fever, fatigue and a dry cough appear in some patients, and pneumonia develops in some cases [1]. Known complications include acute respiratory distress syndrome (ARDS), cardiovascular complications, thromboembolism, inflammatory complications (such as Guillain–Barre syndrome and multisystem inflammatory syndrome) and secondary bacterial and fungal infections [2]. In addition, the involvement of a cytokine storm is often problematic [3]. There are also reports of COVID-19-associated neurological disorders, including encephalopathies, inflammatory central nervous system syndromes, ischemic strokes, peripheral neurological disorders and neuroplexopathy, but much is still unknown about these disorders [4]. Clinically mild encephalitis/encephalopathy with reversible splenial lesions (MERS) was identified by Tada et al. in 2004 [5]. It is a mild form of encephalitis/encephalopathy that appears in association with various conditions, including infection, the use of antiepileptic drugs, hypoglycemia and head injury. Among infectious diseases, viral infections are the most common cause [5]. For example, the cause of encephalopathy in influenza has not been established, but it is also considered one possible explanation for the condition [6]. On the other hand, COVID-19 is also known to cause MERS, and a cytokine storm has been implicated [7]. However, MERS is more common in children, and adult cases are relatively rare [8]. This trend is also true for COVID-19. More recently, a new, broader term, CLOCC (cytotoxic lesions of the corpus callosum), was proposed by Jay et al. [9]. In this report, we describe the first reported case of COVID-associated MERS with a typical imaging course and hyponatremia, with a review of the relevant literature.

2. Case Presentation

An 18-year-old man, with no history of chronic disease, presented to the emergency department with a 4-day history of fever and a 2-day history of diarrhea. Two days before admission into our hospital, he suffered confusion and was hospitalized at another hospital. He was not taking any medications and had no significant travel history. He was a life-long nonsmoker and never consumed alcohol or used illicit drugs. A nasopharyngeal swab specimen tested using a real-time reverse transcriptase-polymerase chain reaction (RT-PCR) assay was positive for SARS-CoV-2.
Upon presentation, his oxygen saturation was 99% on room air. A neurological examination revealed altered sensorium with disorientation; otherwise, there were no focal neurologic deficits or meningeal signs. The other findings of the physical examination were normal. Laboratory exams showed normal leukocyte and platelet counts, decreased serum sodium (128.9 mEq/L), decreased serum chloride (90 mEq/L) decreased plasma osmolality (266.9 mOsm/L) and elevated C-reactive protein (13.68 mg/dL). Thoracic computed tomography (CT) showed multiple ground glass opacities and consolidation throughout both lungs. Brain magnetic resonance imaging (MRI) showed an oval high-signal area in the midline of the corpus callosum from diffusion-weighted imaging (DWI), and a low apparent diffusion coefficient (ADC) value on the ADC map in the same area. The fluid-attenuated inversion recovery (FLAIR) sequence showed hyperintense lesions in the same area (Figure 1). A cerebrospinal fluid (CSF) examination revealed a normal glucose level (serum glucose level 126 mg/dL), chemistry and cell count. A BIOFIRE FILMARRAY Meningitis/Encephalitis (ME) Panel (BioFire Diagnostics, Salt Lake City, UT, USA) was negative.
He received remdesivir to treat COVID-19. He did not suffer from hypoxia during hospitalization. Laboratory results suggested that the cause of his hyponatremia was syndrome of inappropriate secretion of antidiuretic hormone (SIADH). Therefore, he received fluid restriction and a 3% saline infusion. As a result, his hyponatremia improved on the fourth day. However, his psychiatric symptoms persisted even after his hyponatremia improved.
We suspected psychiatric symptoms due to intracranial disease based on the following features: (1) prolonged psychiatric symptoms, (2) a young age, (3) no diurnal fluctuation in psychiatric symptoms, (4) atypical for delirium and (5) no history of drug use that could have caused the psychiatric symptoms. Based on the brain MRI findings, medical history, examination findings and spinal fluid findings, he was considered to have psychiatric symptoms caused by MERS. Psychiatric symptoms appeared on the third day of illness, with the day of onset of COVID-19 as the first day of illness, but he began to improve on the eighth day of illness with symptomatic treatment alone. Brain MRI on the tenth day showed that the abnormal findings on admission had been obscured (Figure 2). On the eleventh day, his psychiatric symptoms and abnormal neurological findings resolved, and he was discharged.
We found 21 adult patients of ≥18 years of age who were diagnosed with COVID-19 via PCR and CLOCC or MERS via MRI between 2020 and June 2022 using PubMed and Google Scholar (Table 1). Including our case, 12 of these patients underwent serial MRI. On the other hand, we found 50 or more pediatric patients. We reviewed these 12 patients. The mean age was 45.1 years, 11 patients (91.7%) were male, and 10 patients (83.3%) had no underlying disease of any kind. These patients had low COVID-19 severity, with no evidence of hypoxia in seven cases (58.3%). Among these 12 cases, only our case showed hyponatremia in a blood analysis. Six patients (50.0%) underwent spinal fluid testing, and one had mildly elevated protein. All other patients showed normal findings. Nine patients (75.0%) had no focal signs. Five patients (41.7%) had psychiatric symptoms. Three patients (25.0%) were treated with corticosteroids, and four patients (33.3%) were treated with antimicrobial agents. One patient each received favipiravir and remdesivir. Five patients (41.7%) were untreated for COVID-19. Treatment was not described in three cases. Brain MRI showed that the splenium of the corpus callosum was hyperintense from DWI, and it showed decreased ADC values in all cases in which the findings of the ADC map were described. However, the ADC map was not described in two cases. In addition, all patients who underwent T2-weighted and FLAIR MRI showed high signal intensity on T2-weighted and FLAIR images; however, four cases were not described. The abnormal brain MRI findings and clinical symptoms recovered in ten cases (83.3%); in the remaining two cases, the abnormal brain MRI findings showed no improvement. These patients had severe COVID-19 infection requiring ventilator management: one patient had a hemorrhage, and the other had a lesion that extended beyond the corpus callosum.

3. Discussion

MERS is mild encephalitis/encephalopathy with reversible focal lesions in the splenium of the corpus callosum, which results in abnormal behavior, seizures and impaired consciousness within one week of the onset of fever, and recovery occurs without sequelae within one month. Typical head MRI findings include a round lesion in the mid-layer of the corpus callosum with a high signal intensity for DWI, high signal intensity for T2-weighted imaging and an equal or low signal intensity for T1-weighted imaging. Lesions show decreased ADC values on the ADC map. Most cases improve within one week [5,30]. The clinical and imaging course of this case were considered typical in comparison to previous reports. The differential diagnoses of the imaging findings include cerebral infarction, multiple sclerosis, Marchiafava–Bignami disease, posterior reversible encephalopathy syndrome (PRES) and malignant lymphoma; however, these diseases were ruled out in the present case based on the clinical course, blood test results and a spinal fluid examination.
Because there have been no previous reports of COVID-associated MERS in which SARS-CoV-2 was detected in the spinal fluid, including the present case, it is believed that MERS is not caused directly by viral injury. Although the exact mechanism by which the cerebral corpus callosum is affected remains unknown, several hypotheses have been proposed, including the involvement of electrolyte abnormalities (e.g., hyponatremia) and inflammatory cytokines (e.g., IL-6). In this case, the patient’s psychiatric symptoms persisted even after the improvement of hyponatremia. In a previous report on non-COVID-related MERS, a case of prolonged psychiatric symptoms after the improvement of hyponatremia was also reported [31]. One of the known causes is vasopressin secretion by inflammatory cytokines (e.g., IL-6), which causes hyponatremia and brain edema [8,32,33,34,35]. In this case, it was suggested that this phenomenon may have caused the diffusion restriction of the cerebral corpus callosum. Furthermore, rapid improvement of edema may have improved the diffusion restriction of the corpus callosum in a relatively short period.
MERS often improves with supportive care alone; however, methylprednisolone pulse therapy is effective in severe cases [36]. In addition, in previous reports of COVID-associated MERS, COVID-19 has often been mild, and many cases did not show hypoxia. Our case did not show hypoxia, and—as in previously reported COVID-related MERS cases—the patient recovered with supportive care alone.
We reported an adult case of COVID-related MERS with a typical imaging course and hyponatremia. When psychiatric symptoms and consciousness disturbance appear in COVID patients, MERS should be considered in addition to delirium due to fever and hypoxia.

Author Contributions

Conceptualization, M.T.; resources, M.T., N.T., I.O., J.S., M.O., K.S., Y.N., T.Y., T.M. and S.M.; writing—original draft preparation M.T., N.T. and I.O.; writing—review and editing, S.M; supervision, S.M. All authors have read and agreed to the published version of the manuscript.

Funding

This research received no external funding.

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Written informed consent was obtained from the patient for publication of this case report and accompanying images.

Data Availability Statement

No extra data were used to support this study.

Conflicts of Interest

The authors declare no conflict of interest.

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Covid 03 00013 g001 550
Figure 1. (A) Brain MRI on admission showing an oval high-signal area in the midline of the corpus callosum with diffusion-weighted imaging (DWI). (B) Apparent diffusion coefficient (ADC) value on ADC map in the same area was low. (C) Fluid-attenuated inversion recovery (FLAIR) sequence showed hyperintense lesions in the same area.
Figure 1. (A) Brain MRI on admission showing an oval high-signal area in the midline of the corpus callosum with diffusion-weighted imaging (DWI). (B) Apparent diffusion coefficient (ADC) value on ADC map in the same area was low. (C) Fluid-attenuated inversion recovery (FLAIR) sequence showed hyperintense lesions in the same area.
Covid 03 00013 g001
Covid 03 00013 g002 550
Figure 2. (A) DWI, (B) ADC map and (C) FLAIR images on the 10th day. The findings seen on admission had been obscured.
Figure 2. (A) DWI, (B) ADC map and (C) FLAIR images on the 10th day. The findings seen on admission had been obscured.
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Table
Table 1. Reported cases of MERS or CLOCC with COVID-19.
Table 1. Reported cases of MERS or CLOCC with COVID-19.
References DiagnosisAge/SexPast HistoryClinical SymptomsPneumonia (Chest CT)HypoxiaBronchial Intubation and Mechanical VentilationSerum SodiumCSF ExaminationBrain MRI (Diffusion-Weighted Images)Brain MRI (Apparent Diffusion Coefficient Map)Brain MRI (Fluid-Attenuated Inversion Recovery)Changes in Brain MRI over TimeLesion Extension beyond the Corpus CallosumTreatmentOutcome
[10]CLOCC40/mNoneFlu-like symptoms presenting progressive paresthesia in the extremities, mild headache and visual turbidityYesNoNoN.d.N.d.HighLowhighFollow-up MRI (1 month): complete regression of the corpus callosum lesionNoIvermectin and azithromycinRecovery
[11]CLOCC30’s/mNoneBehavioral changes.YesYesYesN.d.N.d.HighLowN.d.Follow-up MRI (7 days): demonstrated marked progression of the restricted diffusion now involving the bilateral frontal, parietal temporal and occipital lobes as well as the corpus callosum and basal gangliaYesAcyclovir, ceftriaxone and vancomycinDeath
[12]CLOCC73/mNoneMild influenza-like symptoms which rapidly progressed to respiratory distress, high fever (38℃) and altered consciousness (no focal symptoms)YesYesYesN.d.NormalHighLowN.d.Follow-up MRI (5 weeks): focal residual hemosiderin deposits and myelomalacia in the former region of the hemorrhageNoDarunavir/Cobicistat, antibiotics and hydroxychloroquine Recovery
[13]MERS55/mNoneFever, minor headache, dizziness and impaired consciousness (no focal symptoms)YesYesYesNormalN.d.HighLowN.d.Follow-up MRI (20 days): complete regression of the corpus callosum lesionNoN.d.Recovery
[14]CLOCC20’s/fUntreated depressionAuditory and visual hallucinations, paranoia and false beliefs of being a twin and pregnant (no focal symptoms) N.d.NoNoN.d.NormalHighN.d.N.d.Follow-up MRI (30 days): complete regression of the corpus callosum lesionNoNoneRecovery
[15]CLOCC58/mNoneWeakness and malaise (no focal symptoms),YesNoNoN.d.N.d.HighLowN.d.Follow-up MRI (half a month): complete regression of the corpus callosum lesionNoN.d.Recovery
occasional coughs and presyncope
[16]MERS50/mNoneFever, nausea, vomiting, myalgias, hoarse voice, fatigue, cough and impaired consciousness; tandem gait was clumsy, Romberg sign was positive, and finger-to-nose testing was impairedYesNoNoN.d.NormalHighLowN.d.Follow-up MRI (8 days): complete regression of the corpus callosum lesionNoCeftriaxone, acyclovir and low dose cortisoneRecovery
[17]MERS47/mNonePersonality changes, confusion and aggression (no focal symptoms)YesNoNoNormalN.d.HighLowN.d.Follow-up MRI (15 days): complete regression of the corpus callosum lesionNoPrednisoneRecovery
[18]CLOCC45/mNoneLeft hemiparesis and psychomotor retardation (no focal symptoms)N.d.NoNoN.d.N.d.HighN.d.HighFollow-up MRI (7 days): almost total regression of the initial patternYesNoneRecovery
[19]CLOCC62/mHypertension and diabetes mellitusThe patient did not present any neurological manifestation during hospitalizationN.d.N.d.N.d.N.d.NormalHighLowHighFollow-up MRI (3 months): complete regression of the corpus callosum lesionNoN.d.Recovery
[20]CLOCC43/mNoneFever, signs of upper respiratory tract infection, cough, dyspnea and speech disorderYesN.d.N.d.N.d.No pathology was found in the cerebrospinal fluid except for the protein height (143 mg/dL)HighLowN.d.Follow-up MRI (40 days): complete regression of the corpus callosum lesionNoFavipiravir, methylprednisolone and tocilizumabRecovery
[7]CLOCC66/mDiabetes mellitus and hypertensionRight-sided weakness, decreased alertness and aphasicYesYesYesN.d.N.d.HighN.d.N.d.N.d.YesAzithromycin and hydroxychloroquineRecovery
[21]CLOCC23/mNoneAuditory hallucinations, fever, headache, restlessness and suicidal thoughts (no focal symptoms)YesYesYesNormalNormalHighLowN.d.N.d.NoDexamethasone, favipiravir, piperacillin tazobactam and azithromycinDeath
[22]MERS75/mMild Alzheimer’s disease Altered sensorium, tremors, ataxia and urinary incontinenceYesNoNoNormalN.d.HighLowN.d.N.d.NoFavipiravir, corticosteroid pulse, ciclesonide and meropenemDeath (Neurological symptoms resolved after 3 days)
[23]CLOCC34/mHypertensionFever, shortness of breath, cough, consciousness disturbance and myoclonusYesYesYesN.d.CSF showed a high opening pressure of 48 cm H2O, no pleocytosis, 27 erythrocytes/mL, a mildly increased protein level and glucose level within the reference rangeHighN.d.HighN.d.NoHydroxychloroquineN.d.
[24]CLOCC49/mNoneConfusionN.d.N.d.N.d.N.d.N.d.HighLowN.d.N.d.NoN.d.N.d.
CLOCC51/mNoneConfusionN.d.N.d.N.d.N.d.N.d.HighLowN.d.N.d.NoN.d.N.d.
[25]CLOCC40’s/fN.d.Consciousness and paretic extremitiesN.d.N.d.N.d.N.d.N.d.HighN.d.N.d.N.d.NoN.d.N.d.
[26]CLOCC66/mN.d.ConsciousnessN.d.N.d.N.d.N.d.N.d.HighN.d.N.d.N.d.NoN.d.N.d.
[27]CLOCC55/mN.d.N.d.N.d.N.d.N.d.N.d.N.d.HighN.d.N.d.N.d.NoNoneN.d.
[28]MERS47/mNoneConfusion, fever, dry cough and headache (no focal symptoms) YesYesNoModerate hyponatremiaN.d.HighN.d.N.d.N.d.NoNoneRecovery
[29]CLOCC24/mN.d.Gait ataxia, scanning speech and otherwise unremarkable neurological examinationN.d.NoNoN.d.N.d.HighLowN.d.N.d.NoIntravenous immunoglobulin following methylprednisolone treatment Recovery
This CaseMERS18/mOrthostatic hypotensionConfusionYesNoNo128.9 mEq/LNormalHighLowHighFollow-up MRI (11 days): complete regression of the corpus callosum lesionNoRemdesivirRecovery
Abbreviations: MERS, clinically mild encephalitis/encephalopathy with reversible splenial lesions; CLOCC, cytotoxic lesions of the corpus callosum; CSF, cerebrospinal fluid; CT, computed tomography; MRI, magnetic resonance imaging; N.d., no data.
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MDPI and ACS Style

Tokano, M.; Tarumoto, N.; Osawa, I.; Sakai, J.; Okada, M.; Seo, K.; Nakazato, Y.; Yamamoto, T.; Maeda, T.; Maesaki, S. A Case of COVID-Related MERS (Clinically Mild Encephalitis/Encephalopathy with a Reversible Splenial Lesion) with a Typical Imaging Course and Hyponatremia in Adults—A Case Report and Literature Review. COVID 2023, 3, 183-191. https://doi.org/10.3390/covid3020013

AMA Style

Tokano M, Tarumoto N, Osawa I, Sakai J, Okada M, Seo K, Nakazato Y, Yamamoto T, Maeda T, Maesaki S. A Case of COVID-Related MERS (Clinically Mild Encephalitis/Encephalopathy with a Reversible Splenial Lesion) with a Typical Imaging Course and Hyponatremia in Adults—A Case Report and Literature Review. COVID. 2023; 3(2):183-191. https://doi.org/10.3390/covid3020013

Chicago/Turabian Style

Tokano, Mieko, Norihito Tarumoto, Iichiro Osawa, Jun Sakai, Mariko Okada, Kazuhide Seo, Yoshihiko Nakazato, Toshimasa Yamamoto, Takuya Maeda, and Shigefumi Maesaki. 2023. "A Case of COVID-Related MERS (Clinically Mild Encephalitis/Encephalopathy with a Reversible Splenial Lesion) with a Typical Imaging Course and Hyponatremia in Adults—A Case Report and Literature Review" COVID 3, no. 2: 183-191. https://doi.org/10.3390/covid3020013

APA Style

Tokano, M., Tarumoto, N., Osawa, I., Sakai, J., Okada, M., Seo, K., Nakazato, Y., Yamamoto, T., Maeda, T., & Maesaki, S. (2023). A Case of COVID-Related MERS (Clinically Mild Encephalitis/Encephalopathy with a Reversible Splenial Lesion) with a Typical Imaging Course and Hyponatremia in Adults—A Case Report and Literature Review. COVID, 3(2), 183-191. https://doi.org/10.3390/covid3020013

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