A cohort study of mild encephalitis/encephalopathy with a reversible splenial lesion in children

Abstract Purpose To investigate the clinical features, imaging features, and prognosis of mild encephalitis/encephalopathy with a reversible splenial lesion (MERS) in children Methods The clinical and imaging data of a cohort of 28 children diagnosed as MERS from January 2019 to October 2020 were retrospectively analyzed Results Of the 28 patients, 17 were males and 11 were females. The onset age ranged from 8 months to 12 years old, with an average age of 4 years and 2 months. All children developed normally before onset, and three of them had a history of febrile convulsion. More than half of the patients (62.9%) had preceding infections of gastrointestinal tract. All the cases developed seizures, and most (71.4%) had more than one time. Other neurological symptoms included dizziness/headache, consciousness disorder, limb weakness, blurred vision, and dysarthria. Cranial magnetic resonance imaging (MRI) showed lesions in the splenium of the corpus callosum in all, extending to other areas of the corpus callosum, bilateral semi‐ovoid center, and adjacent periventricular in two cases. The clinical symptoms were relieved after steroids, intravenous immunogloblin, and symptomatic treatment, without abnormal neurodevelopment during the followed‐up (2 months–2 years). Complete resolution of the lesions was observed 8–60 days after the initial MRI examinations Conclusion MERS in children is related to prodromal infection mostly, with a wide spectrum of neurologic symptoms, characteristic MRI manifestations, and good prognosis.

month (Takanashi, 2009). Magnetic resonance imaging (MRI) is characterized by a reversible lesion with homogenously reduced diffusion in the corpus callosum (at least involving the splenium), sometimes associated with symmetrical white matter lesions (Takanashi, 2009).
Here, we retrospectively analyzed the clinical and imaging data of 28 children diagnosed as MERS, and discussed the clinico-radiological features and prognosis.

PATIENTS AND METHODS
After searching the inpatient medical record system of our pediatrics department (admitting patients under 18 years old) between January 2019 and October 2020, 28 children diagnosed as MERS were retrospectively collected. The diagnosis of MERS was based on the following criteria (Hoshino et al., 2012): (1)   we browsed the published papers by using "MERS," "corpus callosum," "reversible splenial lesion" as keywords in Wanfang, CNKI database, from January 2016 to December 2020. All obtained articles were reviewed to identify that the cases met the diagnostic criteria of MERS.
Eventually, a total of 183 children cases with relatively comprehensive clinico-radiological data were retrieved.

General information
Of the 28 patients, seventeen were males and 11 were females. All children developed normally previously, and three of them had a history of febrile convulsion. The onset age ranged from 8 months to 12 years old, with an average age of 4 years and 2 months. Twenty-four cases developed in winter and spring, four in summer and autumn.
Eight of the 23 patients who underwent video EEG examination showed abnormal results, presenting as medium to high amplitude bilateral paroxysmal slow waves.
All the patients received the first cranial MRI examination at 3-10 days (mean 5.4 days) of the course. Twenty-six patients revealed an isolated oval lesion in the splenium of corpus callosum (type I, Fig. 1), and 2 patients revealed lesions extending to the whole corpus callosum, bilateral semi-ovoid center, and adjacent periventricular (type II, Fig. 2).
The lesions were homogeneously hyperintense on diffusion-weighted imaging (DWI) and T2-weighted images, slightly hyperintense on T2-FLARE, isointense to slightly hypointense on T1-weighted images, and showed reduced diffusion without contrast enhancement.

Therapy and prognosis
The clinical symptoms were relieved after symptomatic treatment, such as anti-infection, reducing cranial pressure and sedation. In addition, twenty-six patients received intravenous or oral steroid (methylprednisone or prednisone) for 7-10 days, with a total dose of less than 1.5 mg/(kg⋅d) (converted to prednisone dose). One of them had limb weakness, dysarthria, and increased CSF cell count, and was further treated with 2 g/kg intravenous immunogloblin (IVIG) in 3 days.
Follow-up period ranged from 2 months to 2 years. All the children showed no abnormal neurodevelopment. There was complete resolu-tion of the lesions in all the patients 8-60 days after the initial examinations.

Literature review
Considering the small number of cases here might not fully represent the characteristics of Chinese patients, we browsed the papers on MERS published in China from January 2016 to December 2020, and a total of 183 children cases were retrieved (166 cases with type I and 17 cases with type II) (Duan et al., 2020;Chen et al., 2020;Yu et al., 2019;Zhang et al., 2015;He and Zhu, 2016;Wu et al., 2017;Dong et al., 2017;Hu et al., 2016;Tao et al., 2017;Li et al., 2020;Li and Sheng, 2017;. Of them, nintynine were males and 84 were females.
In our cohort, 35.7% of the patients had proven infectious agents, with viral infection, especially rotavirus (40%, 4/10 cases), being the most common. Similarly, the vast majority of patients reviewed from published papers had gastrointestinal tract or respiratory prodromal infection caused by rotavirus or MP, respectively (Table 3).  it was an indirect mechanism, such as immune-mediated mechanism (Takanashi, 2009) rather than direct invasion of pathogen that lead to the lesions. And the release of myelin-specific neurotoxins by the pathogen might cause inflammatory infiltrate and further lead to transient cerebral edema (Yıldız et al., 2018). Hyponatremia is another possible etiologic factor in MERS. The rate of hyponatremic patients in our study (60.7%) was similar to the rate reported previously (Takanashi, 2009). It was postulated that hypotonic hyponatremia might result in entry of water into the brain and lead to intramyelinic edema, causing transient reduced diffusion seen on MRI (Takanashi, 2009).
In our patients, the prodromal symptoms were mainly fever, diarrhea, abdominal pain, and vomiting, with fever as the most common (85.7%), which was generally similar to those reported previously (Ueda et al., 2016;Fang et al., 2017). Consistent with published reports, seizure was the most common presenting symptom (Yıldız et al., 2018).
It presented in all our patients and 69% of the patients reviewed from literatures, and occurred more than one time in most patients (71.4%).
The other neurologic symptoms here included dizziness/headache, consciousness disorder, limb weakness, blurred vision, dysarthria, and limbs numb. The corpus callosum is the biggest fiber bundle, with projections into prefrontal, premotor, primary motor, and primary sensory areas. The splenium is the posterior part of the corpus callosum, connecting different cortical areas, including occipital, parietal, and temporal lobes (Knyazeva, 2013). The disturbance in the collosal connections can cause disorder of motor control, spatial orientation, vision, hearing, and language-related behaviors (Jea et al., 2008), which may explain the neurologic symptoms of our patients here, including the limb weakness, blurred vision, and dysarthria.
There is no treatment guideline for MERS by now. Though methylprednisolone pulse therapy and IVIG are recommended for patients with infectious encephalopathy regardless of pathogen or clinicoradiological syndromes (Mizuguchi et al., 2007) In the literature, patients with type I MERS were generally reported to recover completely both clinically and on imaging (Karampatsas et al., 2015;Fong et al., 2017;Avcu et al., 2017;Abenhaim Halpern et al., 2013;Suzuki et al., 2014;Yıldız et al., 2018;Pan et al., 2015). However, type II lesions on MRI might persist for months even if their size diminished, and some patients with type II MERS could develop neurologic sequelae (Yıldız et al., 2018;Pan et al., 2015). The vast majority of our patients had type I lesions, and only two patients had type II lesions.
All of our patients recovered completely without any clinical sequelae at the last follow-up. And the full normalization of MRI was shown at 8 days-2 months.
In conclusion, MERS occurs predominantly in young children and is related to prodromal infection in most. A wide spectrum of neurologic symptoms were presented, including seizure, dizziness/headache, limb weakness, blurred vision, dysarthria, and so on. Characteristic MRI manifestations normalize in days to months with good prognosis.

ACKNOWLEDGMENTS
We thank the patients and their families for participating. This work was supported by the Taishan Scholars Program of Shandong Province