Mild Encephalitis/Encephalopathy with a Reversible Lesion in The Splenium

Abstract

Mild encephalitis/encephalopathy with a reversible lesion in the splenium (MERS) is a clinico-radiological syndrome with mild central nervous system symptoms and a reversible lesion in the splenium of the corpus callosum. It is mainly associated with a number of viral and bacterial infections, including Coronavirus disease 2019 (COVID-19). In this paper, we report four MERS patients. One had a mumps infection, the second had aseptic meningitis, the third had Marchiafava-Bignami disease, and the fourth had atypical pneumonia associated with COVID-19 infection.

INTRODUCTION

Mild encephalitis/encephalopathy with a reversible lesion in the splenium (MERS) was first described by Tada et al. (1). Later, Garcia-Monco et al. proposed the term reversible splenial lesion syndrome (2). These two terms are both clinical and radiological definitions for the condition. Having clarified the neuropathological basis of the splenial lesion, a new term has also been proposed for the condition: cytotoxic lesions of the corpus callosum (CLOCCs) (3). Today, these terms are more or less used interchangeably. Since CLOCCs are not always reversible and do not always cause mild encephalopathy, we prefer to use MERS for the clinical entity and CLOCCs for the lesion pattern in this text.

CLOCCs show high-signal-intensity on T2-weighted (T2) images, fluid-attenuated inversion recovery images (FLAIR), and diffusion-weighted images (DWI) with restricted diffusion and without contrast enhancement on T1-weighted imaging. They tend to be midline and are relatively symmetric (3).

CLOCCs are secondary lesions associated with drug therapy, malignancies, infections (adenovirus, aseptic meningitis or encephalitis, Epstein-Barr virus, Escherichia coli, herpes, influenza virus A, influenza, Legionella, malaria, measles, Mycoplasma, mumps, rotavirus, Salmonella, Staphylococcus, Streptococcus, tick-borne encephalitis, varicella-zoster virus), subarachnoid hemorrhage, metabolic disorders, head trauma and lately with Coronavirus disease 2019 (COVID-19) (3–6).

In this report, we present clinico-radiological features of four patients with MERS, accompanied by a literature review.

Highlights

• MERS is an infrequent clinicoradiological diagnosis with several etiological causes.

• SARS-CoV-2 may cause MERS/CLOCCs.

• MERS may manifest with sixth cranial nerve paralysis.

• Mumps infection may cause MERS even in adults.

METHODS

Two cases (Case 1 and 2) from Bağcılar Training and Research Hospital and two cases (Case 3 and 4) from Sancaktepe Sehit Prof. Dr. Ilhan Varank Training and Research Hospital were included to this report. All participants provided written informed consent.

RESULTS

Case 1

A 26-year-old, previously healthy female patient was admitted to the hospital with acute apathy and decreased comprehension. Reportedly, fever, malaise, muscular pains had started four days ago, followed by swelling on the right side of the face. On admission, apathy and attention deficit were prominent, temporal orientation was impaired, and there was left-sided hemihypesthesia. The swelling of the right parotid gland was evident.

Routine laboratory investigations (including complete blood count, blood biochemistry, thyroid function tests, ferritin, folate, vitamin B12 levels, hepatitis markers, syphilis markers, anti-HIV antibody, chest radiogram, electrocardiography) were normal except for mild leukopenia and thrombocytopenia.

DWI and T2 sequences demonstrated a hyperintense oval lesion in the splenium of the corpus callosum (CC) with restricted diffusion (Figure 1). There was no abnormal contrast enhancement. Ischemic stroke panel (cerebral MRI-angiogram, transthoracic echocardiography, vasculitis, and thrombophilia markers) and electroencephalography (EEG) revealed no abnormalities.

Figure 1.

Magnetic resonance imaging (MRI) of the patients (ADC: apparent diffusion coefficient image; DWI: diffusion-weighted image).

The cerebrospinal fluid (CSF) showed no abnormalities. CSF and plasma viral and bacterial panel (CSF aerobic and anaerobic culture, CSF Herpes simplex virus (HSV) type 1 and type 2 and Mycobacterium tuberculosis polymerase chain reaction (PCR), plasma Varicella zoster virus, Cytomegalovirus, Borrelia, and Brucella IgM and IgG antibodies) revealed no abnormalities. Anti-mumps virus IgM antibodies were detected using the ELISA technique (Enzyme-Linked ImmunoSorbent Assay), and the result came out positive both times. The MRI findings have regressed ten days later. The patient was discharged on the twelfth day of admission with full remission.

Case 2

A 16-year-old, previously healthy, female patient was admitted to the hospital with a ten-day history of headache and double vision. Neurological examination showed bilateral abducens nerve paralyses and bilateral stage III papilledema.

Routine laboratory investigations were normal. DWI-MRI and T2 sequences demonstrated a hyperintense oval lesion in the splenium of the CC with restricted diffusion without abnormal contrast enhancement (Figure 1). CSF examination showed an elevated CSF pressure of 470 mmH₂O, a high white blood cell (WBC) count (242/mm³), 90% of which was monocytes, an elevated protein level (95 mg/dl), and decreased glucose (26.8% of blood glucose). Na⁺, K⁺, and Cl^– levels of CSF were normal. CSF and plasma viral and bacterial panel, ischemic stroke panel, and EEG revealed no abnormalities.

The patient was put on acetazolamide (1500 mg/day), acyclovir (1500 mg/day), and ceftriaxone 2x2 g IV.

The MRI findings have regressed nine days later.

Her diplopia and papilledema got better in the follow-up. LPs were repeated twice and showed decreased opening pressure and decreased WBC count.

The patient was discharged on the twenty-fifth day of admission with full remission.

Case 3

A 58-year old female patient was admitted to the emergency department with a three-day history of nausea, vomiting, delusional thinking. Her previous medical history included three intragastric balloon surgeries for obesity treatment. The last one was seven days before admission. Neurological examination showed attention deficits and perseverations. Routine laboratory investigations were normal except for hypokalemia (2.7 mmol/L). DWI-MRI and FLAIR sequences demonstrated a hyperintense oval lesion in the splenium of the CC with restricted diffusion (Figure 1). The lesion was isointense on T2 images, and there was no abnormal contrast enhancement. Ischemic stroke panel and EEG revealed no abnormalities.

The patient was put on intravenous K⁺, metoclopramide, intravenous fluid replacement, vitamin supplementation, haloperidol 0.5 mg twice a day, and olanzapine 2.5 mg twice a day. Patient’s family refused lumbar puncture. After 14 days, the patient’s complaints completely regressed, antipsychotic treatment was discontinued, and the MRI and laboratory findings have improved. She was diagnosed with nonalcoholic Marchiafava-Bignami Disease (MBD).

Case 4

A 17-year-old female patient was admitted to the hospital with a seven-day history of drug-resistant headache, malaise, loss of appetite, and dry cough. Her parents had been diagnosed with COVID-19 with upper respiratory tract symptoms and she had also tested positive, although being asymptomatic, with reverse transcriptase polymerase chain reaction (RT-PCR) 45 days before her admission. Having been quarantined for two weeks, her final nasopharyngeal swab RT-PCR test was negative.

On admission, neurological examination was normal.

Routine laboratory investigations were normal except an elevated CRP (35 mg/dL), leukocytosis (16.000/mm³), mild hyponatremia (130 mEq/L) and hypocalcemia (7 mg/dL). Chest radiography showed bilateral minimal reticular infiltration.

DWI-MRI and FLAIR sequences demonstrated a hyperintense oval lesion in the splenium of the CC with restricted diffusion. There was no abnormal contrast enhancement (Figure 1).

CSF showed no abnormalities. We could not perform the CSF severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) PCR test. CSF and plasma viral and bacterial panel, ischemic stroke panel, and EEG revealed no abnormalities.

The patient was put on replacement of Ca⁺⁺ and Na⁺, ceftriaxone (80 mg/kg/d) and azithromycin (2x600 mg/d).

Nasopharyngeal swab RT-PCR test was repeated and the result came out negative. On the 14th day of treatment, the patient had no more complaints, and the imaging and biochemical findings were totally resolved.

DISCUSSION

In this article, we reported four MERS cases, each with a different etiology. The neuroradiological and clinical findings of patients have resolved in nine to fourteen days.

Tada et al. (2004) were the first to describe and name the MERS (1). Their series consisted of fifteen patients who had seizures or blurred consciousness. They used the term encephalitis for those six patients who had CSF pleocytosis and encephalopathy for the rest who did not have it. Subsequent case reports and studies have shown a diverse etiology: viral, bacterial, and parasitic infections, epilepsy, drugs, withdrawal of anti-epileptic drugs, malignancies, cerebrovascular diseases, trauma, and mumps-vaccine have so far been associated with MERS (3,7,8). A detailed list of etiologies is shown in Table 1.

Table 1.

The etiology of MERS/CLOCCs (see the reviews by Starkey et al., 2017 [3] and Tetsuka, 2019 [7])

Infections
Influenza, rotavirus, measles, adenovirus, human parvovirus B19, cytomegalovirus, varicella-zoster, rubella, human herpesvirus-6, human herpesvirus-7, human immunodeficiency virus, mumps, parainfluenza, enterovirus, Epstein–Barr virus, SARS-CoV-2 virus, aseptic meningitis or encephalitis, Mycoplasma pneumoniae, malaria, dengue fever, Legionella pneumophila, Staphylococcus, Streptococcus, Salmonella enteritidis, Escherichia coli, Enterococcus faecalis, Klebsiella pneumoniae, Campylobacter jejuni
Drugs
Antiepileptic drugs (carbamazepine, phenytoin, valproate, and lamotrigine) and withdrawal of antiepileptic drugs, cyclosporine, 5-fluorouracil, cisplatin, carboplatin, glufosinate ammonium, methyl bromide, corticosteroids, intravenous immunoglobulin, metronidazole, tetracycline, diet pills with a sympatho-mimetic stimulant, neuroleptic malignant syndrome
Malignancies
Lymphocytic leukemia, esophageal cancer, glioblastoma, spinal meningeal melanocytoma
Metabolic and toxic
Hypoglycemia, hypernatremia, hyponatremia, Marchiafava–Bignami disease, acute renal failure, hemolytic–uremic syndrome, hepatic encephalopathy, hyperammonemia, thyroid storm, Wernicke encephalopathy, vitamin B12 deficiency, extrapontine and central pontine myelinolysis, malnutrition, Wilson disease, alcoholism, carbon monoxide poisoning
Cerebrovascular diseases
Subarachnoid hemorrhage, ischemic stroke
Traumatic and diffuse axonal injury
Other
Mumps vaccine, Kawasaki disease, systemic lupus erythematosus, autoimmune encephalitis, autoimmune thyroid disease, radiation therapy, preeclampsia, anorexia nervosa, Charcot-Marie-Tooth disease, epilepsy, status migrainosus, high-altitude disease, transient global amnesia

SARS-CoV-2: severe acute respiratory syndrome coronavirus 2.

The differential diagnosis of splenium lesions includes ischemic infarction, acute disseminated encephalomyelitis, multiple sclerosis, lymphoma, glioblastoma multiforme, posterior reversible encephalopathy syndrome, diffuse axonal injury, hydrocephalus, and extrapontine myelinolysis (1,3,8).

These alternative diagnoses were excluded clinically and radiologically in our patients, primarily by their complete recovery in both respects, as was the case in the initial report (1).

MERS after mumps vaccination has been reported primarily in Japan (9,10), and MERS due to mumps infection has also been reported in three children, two of whom had CSF pleocytosis (1). The third had an acellular CSF (11). Zhang et al. reported a 34-year-old female patient due to acute mumps virus infection (8). CSF showed mild pleocytosis. In our first patient, CSF was aseptic. To our best knowledge, our patient is the second adult patient with MERS due to mumps infection in the literature.

Since splenial lesions are associated with many etiologies, their clinical manifestation is also dependent on the underlying disease. Fever, headache, seizure, delirium, vomiting, diarrhea, cognitive impairment, disturbance of consciousness, behavioral changes, dysarthria, drowsiness, ataxia, papilledema, visual disturbance, stiff-neck, motor deterioration are the clinical manifestations reported in the literature (1,2,7,8,12).

Headache and impaired consciousness have been reported as the most common neurological manifestations of MERS in adults (12). Our second patient had an atypical presentation with diplopia.

Intracranial hypertension (ICH) has also been reported in three patients, one with mycoplasma infection, one with HSV infection, and one with unknown viral etiology (8,13) as in our second patient.Although these three patients had ICH in common, sixth cranial nerve palsy has not been reported.

Although the exact pathophysiological mechanism of CLOCCs is unknown, it is suggested that splenium of the CC is vulnerable to cytokinopathy since neurons and glia of the CC and especially the splenium have a high density of cytokine, glutamate, and aquaporin 4 (AQP4) receptors (7). Inflammation leads to the release of inflammatory cytokines and the arising cytokinopathy cascade results in increased levels of extracellular glutamate. Hyperexcited glutamate leads to the entry of extracellular fluid and Na+ into the astrocytes and neurons, resulting in cytotoxic edema (3,7). Intramyelinic edema, a form of cytotoxic edema, is another potential mechanism, and it may explain the reversible character of the splenium of the CC lesions (7).

MBD is a rare disorder that was initially reported in Italian red wine drinkers. Although it has been associated with chronic alcoholism, non-alcoholic cases have also been reported (14). Bachar et al. reported a very similar case who was diagnosed with nonalcoholic MBD after gastric bypass surgery and whose clinical and radiological findings improved with10 days of treatment (15). Two subtypes of MBD have been described (16). While type A is characterized by a severe presentation involving the entire CC, Type B is characterized by a milder one with focal callosal lesions. Our patient’s clinical and radiological findings were compatible with type B MBD.

Hyponatremia is often reported in patients with MERS (1), as one of our patients showed hyponatremia.

CLOCCs or MERS associated with SARS-CoV-2 have increasingly been reported (4-6). SARS-CoV-2 may cause neurologic damage with different mechanisms, such as neurotropism, cytokinopathy in an inflammatory state, hypoxic damage, and ischemia caused by hypercoagulable state (17). Siracusa et al. stated that neurological involvement may arise during COVID-19 with direct invasion of CNS, during multisystem inflammatory syndrome in children, or after the recovery of COVID-19 with a post-infectious immune-mediated mechanism. Blood-brain barrier disruption due to cytokinopathy during the hyperinflammatory state of COVID-19 is blamed for the cytotoxic edema of the corpus callosum (18).

The frequency of corpus callosum lesions had been reported as 48% ranging between 4–100% (19). Besides the temporary lesion in the splenium of the corpus callosum, ischemia, hemorrhage, acute necrotizing encephalopathy, or ADEM lesions are seen in the corpus callosum in COVID-19 patients (18,20–26). Elevated cytokine levels in CSF have been shown to be associated with neurological complications in COVID-19, including CLOCCs (27). Table 2 summarizes cases of CLOCCs/MERS associated with COVID-19 (Table 2).

Table 2.

COVID-19 associated MERS/CLOCCs cases

Age, Sex	Initial central nervous system manifestations	Respiratory/Infectious symptoms	Diagnosis of COVID-19	Reference
75y, M	Cerebellar ataxia and disorientation	Fever and hypoxemia	NP RT-PCR (+)	Hayashi, 2020 (44)
10y, M	Visual hallucinations, agitation, and disorientation	Fever, dyspnea, diarrhea, rash	NP RT-PCR (-) anti-SARS-CoV-2 IgM and IgG (+)	Bektas, 2021 (45)
11y, F	Personality changes, agitation	Fever, dyspnea, rash	NP RT-PCR (-) anti-SARS-CoV-2 IgM and IgG (+)	Bektas, 2021 (45)
60y, M	Intermittent disturbance of consciousness	Cough, headaches	NP RT-PCR (-) anti-SARS-CoV-2 IgM and IgG (+)	El Aoud, 2020 (46)
47y, M	Confusion	Febrile dry cough and headache	NP RT-PCR (+)	Chauffier, 2020 (47)
33y, F	Delusions, dysphoria	NA	NP RT-PCR (-) anti-SARS-CoV-2 IgM (+)	Sen, 2021 (48)
73y, M	Altered consciousness	Respiratory distress and fever	NP RT-PCR (+)	Agarwal, 2020 (20)
69y, M	Acute-onset encephalopathy	Fever	NP RT-PCR (-) anti-SARS-CoV-2 IgA and IgG (+)	Kakadia, 2020 (49)
8y, M	Headache, meningism, confusion, agitation, muscular weakness	Fever, rash, abdominal pain, vomiting, circulatory shock	NP RT-PCR (+)	Abdel-Mannan, 2020 (34)
15y, F	Headache, confusion, muscular weakness	Fever, dyspnea, rash, emesis, circulatory shock	NP RT-PCR (+)	Abdel-Mannan, 2020 (34)
40y, M	Paresthesias, mild headache, visual turbidity	Flu-like symptoms	NP RT-PCR (+)	De Oliveira, 2020 (50)
12y, M	Headache, lethargy	Fever, abdominal pain, diarrhea, vomiting, conjunctivitis, shock	NP RT-PCR (-) anti-SARS-CoV-2 IgG (+)	Gaur, 2020 (38)
9y, M	Lethargy, ataxia, dysarthria	Fever	NP RT-PCR (-) Broncho-alveolar lavage PCR (+)	Gaur, 2020 (38)
40s, F	Impaired consciousness and paretic extremities	NA	NA	Klironomos, 2020 (33)
55y, M	Headache, dizziness, and impaired consciousness	Fever	NP RT-PCR (+)	Forestier, 2020 (5)
49y, M	Acute encephalopathy	NA	NP RT-PCR (+)	Edjlali, 2020 (4)
51y, M	Acute encephalopathy	NA	NP RT-PCR (+)	Edjlali, 2020 (4)
13y, F	Dizziness, gait instability, hallucinations, agitation	Fever, vomiting, diarrhea, cough	NP RT-PCR (+)	Lin, 2020 (51)
34y, M	Encephalopathy, absent corneal and gag reflexes, multifocal myoclonus, absent withdrawal to painful stimuli	Fever, shortness of breath, cough	NP RT-PCR (+) anti-SARS-CoV-2 S1 IgM (+)	Benameur, 2020 (27)
11y, M	Hallucination	Bilateral conjunctival hyperemia and fever	NP RT-PCR (-) anti-SARS-CoV-2 IgG (+)	Celebi, 2021 (52)
26y, M	Acute confusion	Dry cough	NP RT-PCR (-)	Moreau, 2020 (6)
22y, M	Headache	Fever	RT-PCR (-)	Youn, 2021 (39)
23y, M	Auditory hallucinations, headache, disorientation and delayed verbal responses	Fever, malaise, dizziness, vomiting	NP RT-PCR (+)	Elkhaled, 2020 (53)
45y, M	Headache	Myalgias, fever	NP RT-PCR (+)	Micci, 2021 (54)
42y, M	Headache, and weakness	Fever, coughing, nausea, vomiting	NP RT-PCR (-) Diagnosed with thorax CT	Gursoy, 2021 (55)
58y, M	Weakness, presyncope	Malaise, coughs	NP RT-PCR (+)	Gursoy, 2021 (55)

F: female; M: male; NP: nasopharyngeal; RT-PCR: reverse transcriptase polymerase chain reaction; SARS-CoV-2: severe acute respiratory syndrome coronavirus 2.

Uzunhan et al. evaluated 41 children with CLOCCs. 61% were infection-associated, 8% of which were COVID-19-associated (28).

In the neuroimaging studies with COVID-19 patients, CC involvement had been reported either isolated or with diffuse lesions of white matter. One study reported that reversible splenial lesion is the most common cranial MRI finding in children with COVID-19 (29), one study evaluated 64 patients and reported one patient with CLOCCs (30), another study of 37 patients showed that 2 patients had CLOCCs (31). Chougar et al. evaluated 73 patients with COVID-19 retrospectively, 4.1% of the patients had diffusion restriction in the splenium of the CC (n=3), and two of them were interpreted to be ischemic (22). La Rovere et al. evaluated 1695 COVID-19 patients, and they reported 5 patients with severe encephalopathy with diffuse lesions of white matter and genu or splenium of the corpus callosum (32). In another study, one patient had CLOCCs in the 185 patients with COVID-19 (33). Sriwastava et al. reviewed CNS inflammatory disorders associated with COVID-19, and they found that of the 40 cases, 37% had transverse myelitis, 25% had ADEM, 15% had acute hemorrhagic necrotizing encephalitis/acute hemorrhagic leukoencephalitis, and 23% had CLOCCs/MERS (25). Abdel-mannan et al. evaluated 27 children with COVID-19 pediatric multisystem inflammatory syndrome, and 4 of them had neurological symptoms with splenium lesions on brain MRI/CT either isolated or with involvement of centrum semiovale (34). Scullen et al. evaluated 27 patients and reported a patient with COVID-19 associated with acute necrotizing encephalopathy involving corpus callosum (35).

COVID-19-associated ischemic lesions of the CC splenium develop secondary to hypercoagulability. Sparr et al. reported 4 patients with ischemic infarction of the CC splenium. Although isolated infarction of the CC splenium is rare, the lesion was isolated to the CC splenium in two of these patients (36).

Case reports also reported corpus callosum lesions accompanied by spinal cord lesions (37), diffuse leukoencephalopathy and microbleeding (26), multiple areas of microhemorrhage (17), subarachnoid hemorrhage (20), deep cerebral white matter lesions (38) during COVID-19.

CLOCCs are also reported after SARS-CoV-2 mRNA vaccination (39).

Hyponatremia is often reported in patients with MERS (40,41), and sodium levels of MERS patients are lower than patients with mild upper respiratory infections, patients with other types of encephalopathy, and patients with febrile seizures (41).

It has been claimed that increased interleukin-6 (IL-6) and other proinflammatory cytokines levels during inflammation may cause hyponatremia through vasopressin release by stimulating the hypothalamus and pituitary gland. As a result, hypotonic hyponatremia occurs, and it has been suggested that CC splenium axons are more prone to develop edema because they are tightly packed (40).

IL-6 is also an important cytokine involved in COVID-19-related inflammatory state, and low sodium levels are inversely related to IL-6 in COVID-19 patients (42,43).

As the symptoms of patient 4 occurred after 45 days of asymptomatic COVID-19, we can not easily associate CLOCCs with COVID-19. We hypothesize that COVID-19-related inflammatory state and increased IL-6 levels might have caused hyponatremia, and both hyponatremia and atypical pneumonia might have contributed to the pathophysiology of MERS in Patient 4.

In conclusion, MERS is an infrequent clinical and radiological diagnosis in adults with several etiological causes. Although this study includes a small number of patients, it will contribute to understanding the pathophysiology of this condition and why it involves only the CC splenium.