Reversible lesion in the splenium of the corpus callosum

Abstract Aim of Review The presence of isolated, reversible lesions in the splenium of the corpus callosum (SCC) is essential to confirm the diagnosis of mild encephalitis/encephalopathy. The lesions usually heal within a month after the onset of neurological symptoms. Magnetic resonance imaging (MRI) has increasingly been used as a diagnostic tool, which has led to the publication of an increasing number of case reports. These have highlighted some inconsistencies about encephalitis/encephalopathy. First, the condition is not always mild and may be severe. Second, reversible lesions in the SCC have been identified in various diseases and conditions other than viral encephalitis/encephalopathy. Third, lesions in SCC are not always completely reversible. On this note, this review describes the specific clinical and radiological features of encephalitis/encephalopathy. Findings The reversible lesion in SCC is an MRI finding observable in a wide variety of diseases and conditions. Thus, it should be considered as a secondary change rather than a peculiar feature associated with mild encephalitis/encephalopathy. If reversible lesions are present in the SCC, the symptoms and prognosis are not necessarily favorable, with manifestations of encephalitis/encephalopathy varying from absent to severe. Neuroradiological features that appear as isolated high‐intensity signals on diffusion‐weighted images and a decreased apparent diffusion coefficient of the lesion might indicate a diagnosis of cytotoxic edema. Findings of previous studies suggest that cytokine‐mediated cytotoxic edema of the SCC may be an important pathophysiological manifestation of this condition. Conclusion The reversible lesions in the SCC found on MRI are not exclusive to encephalitis/encephalopathy but may be secondary to other disorders.

the onset of neurological symptoms (Fang, Chen, Chen, Lin, & Yang, 2017;Tada et al., 2004;Takanashi, 2009). The radiological features of MERS include an appearance on magnetic resonance imaging (MRI) of an ovoid reversible lesion in the central portion of the splenium of the corpus callosum (SCC) in the acute phase.
Sometimes, the lesion spreads throughout the whole corpus callosum and into the adjacent white matter without additional lesions, disappearing within approximately two weeks with neither residual signal changes on MRI nor atrophy (Hoshino et al., 2012;Tada et al., 2004;Takanashi et al., 2006). Because the use of MRI has become widespread, many cases of various conditions accompanied by MERS have been reported. One such condition is encephalitis/ encephalopathy in which a reversible lesion is present in the SCC.
Although MERS occurs in the context of mild encephalitis originally described in children, MERS as a terminology has been recently used in more adult reports and studies. As these case reports have increased in number, some inconsistencies about the associated disease concept have emerged. First, encephalitis/encephalopathy is not always mild but can be severe and isolated reversible lesions in the SCC are not always a good prognostic marker for a benign disease course in patients with MERS. However, in some cases, central nervous system disturbances are absent (Doherty, Jayadev, Watson, Konchada, & Hallam, 2005;Tetsuka & Ogawa, 2016;Zhang, Ma, & Feng, 2015). Second, a reversible lesion in the SCC has been recognized in patients with various diseases and conditions other than viral encephalitis/encephalopathy (Qing et al., 2019;Zhang et al., 2015). Third, the lesions are not always completely reversible (Doherty et al., 2005). In view of these three facts, a lesion in the SCC found on MRI might be secondary to other disorders. A similarity in neuroimaging features may suggest that there are common mechanisms that have different causes but lead to the same result. Thus, in this review, the clinical and radiological features that help clinically define the encephalitis/ encephalopathy are described. The potential pathophysiological mechanisms of MERS and the associated pathological conditions are also discussed.

| ANATOMY AND DE VELOPMENT
The corpus callosum is the major commissural area of the brain, consisting of white matter tracts of approximately 200 million myelinated nerve fibers that connect the left and right cerebral hemispheres. Anatomically from the anterior to the posterior, the corpus callosum comprises four parts: the rostrum, genu, body, and splenium, each connecting the bilateral cerebral hemispheres (Figure 1).
The size of the fibers of the SCC that connect the posterior cortex varies: Those in the anterior part are thin, late-myelinating fibers that mainly connect the parietal and temporal areas and those in the posterior part are thick, early-myelinating fibers that link primary and secondary visual areas (Knyazeva, 2013). The function of the posterior fibers in the SCC is to connect the occipital lobes, enabling the processing of visual cues. During brain development, at twelve to thirteen weeks of gestation, nerve fibers begin to cross the midline, giving rise to connections that later become the corpus callosum. During infancy, the corpus callosum expands rapidly as a result of an increase in the number of axons and myelin, and the development of the corpus callosum is complete by the age of four. Axonal myelination-the elaboration of myelin surrounding neuronal axons that is essential for normal brain function-begins at the age of 3-4 months in the SCC (Deoni et al., 2011). With regard to vascular distribution, the internal carotid artery network provides arterial blood supply to most of the corpus callosum, but the splenium receives arterial blood by the anterior pericallosal artery from the anterior circulation, and by the posterior pericallosal artery and posterior accessory pericallosal artery from the posterior circulation (Kahilogullari et al., 2013;Kakou, Velut, & Destrieux, 1998).

Splenium of the corpus callosum lesions demonstrated on MRI in
patients with viral encephalitis/encephalopathy were thought to be findings specific to MERS and MRI splenial lesions have been a good prognostic radiological marker for patients with encephalitis/ encephalopathy (Hoshino et al., 2012;Takanashi, 2009). However, as increasing numbers of cases of MERS have been reported, the lesion has been found to be associated with various other diseases and conditions. Previously, this was often reported in children but F I G U R E 1 Midsagittal view of the splenium. Midsagittal fluidattenuated inversion recovery-weighted magnetic resonance image shows the corpus callosum and the splenium (S, in red). According to the conventional partitioning scheme, the splenium corresponds to the posterior 20% of the corpus callosum, which is separated by the border line perpendicular to the line linking the most anterior and posterior points of the corpus callosum. B, body; G, genu; R, rostrum it has become more recognized recently in adults that a reversible lesion in the SCC may no longer be a specific MRI finding in children with mild encephalitis. According to some case reports, MERS could have been triggered by (a) viral infection, including those caused by the influenza virus (Takanashi, Barkovich, Yamaguchi, & Kohno, 2004;Takatsu, Ishimaru, Ito, & Kinami, 2017), rotavirus (Fuchigami et al., 2013), measles virus (Melenotte, Craighero, Girard, Brouqui, & Botelho-Nevers, 2013), adenovirus (Hibino et al., 2014), human parvovirus B19 (Suzuki, Kusaka, & Okada, 2014), and cytomegalovirus (Feraco, Porretti, Marchiò, Bellizzi, & Recla, 2018) and (b) other types of infectious pathogens including Mycoplasma pneumoniae (Yuan et al., 2016), Legionella pneumophila (Tomizawa et al., 2015), Streptococcus pneumoniae (Avcu, Kilinc, Eraslan, Karapinar, & Vardar, 2017), and malaria parasites (Mawatari, Kobayashi, & Yamamoto, 2018).
It is difficult to ascertain the precise frequency of this syndrome.
However, it may be underestimated because MRI examination is not being performed in all patients with many of the different etiologic conditions. Greater MRI availability and an increasing awareness of reversible lesions in the SCC might cause more cases to be diagnosed TA B L E 1 Causative factors that lead to reversible lesion in the splenium of the corpus callosum

| CLINIC AL S PEC TRUM AND M A N I FE S TATI O N S
The clinical symptoms of the conditions accompanying the reversible lesion in the SCC are nonspecific and diverse, mainly because they reflect a wide spectrum of conditions that are suggestive of encephalopathy or encephalitis. A fever that precedes or accompanies neurological symptoms is the most common prodromal manifestation. Other general clinical symptoms include headache and digestive tract disturbances (vomiting and diarrhea) (Chen et al., 2016;Takanashi, 2009 (Chen et al., 2016;Tada et al., 2004;Yuan et al., 2017;Zhang et al., 2015). Other neurological symptoms include motor deterioration, slurred speech, neck stiffness, coma, tremor, ataxia, somnolence, dysarthria, visual disturbance, and dizziness (Chen et al., 2016;Tada et al., 2004;Yuan et al., 2017;Zhang et al., 2015).
In the disease concept of MERS, neurological symptoms are expected to disappear completely within a month and isolated reversible lesions in the SCC are considered to be a good prognostic marker for a benign disease course in affected patients (Tada et al., 2004;Takanashi, 2009  suggests that the lesions in type I MERS may be more widespread than previously thought (Qing et al., 2019).

| NEUROR ADIOLOG IC AL FE ATURE S
These MRI findings, however, are not specific to encephalitis/ encephalopathy as they are seen in other diseases and conditions (Table 1). Both vasogenic and cytotoxic edema show signal hyperintensity on T2-weighted images and on FLAIR sequences. However, DWI shows only markedly high density for cytotoxic edema and can show image contrast, which is dependent on the molecular movement of water. DWI is most useful for detecting conditions that are related to relative restriction of water diffusion such as increased cellularity, ischemia, viscous or mucinous degeneration, and intramyelinic sheath edema. It is also often used to diagnose acute cerebral infarction that results in cytotoxic edema that is considered to lead to an irreversible lesion and cellular death (Baehring & Fulbright, 2012

| PATHOPHYS IOLOG IC AL HYP OTHE S IS
The exact pathophysiological mechanism underlying the reversible lesion in the SCC is still obscure. There are several hypotheses about entities such as intramyelinic edema (Tada et al., 2004), inflammatory infiltrates (Tada et al., 2004), hyponatemia ), oxidative stress (Miyata et al., 2012), neuroaxonal damage (Motobayashi et al., 2017), autoimmune processes (Kaminski & Prüss, 2019), and cytotoxic edema (Garcia-Monco et al., 2011;Starkey et al., 2017). Cytotoxic edema is characterized by the swelling of the cellular elements in neurons and glial cells with a subsequent reduction in the extracellular space in the gray matter. Cytotoxic edema can also occur in glial cells, axons, and myelin sheaths of the white matter, the edema being localized in either the myelin sheath itself F I G U R E 3 Magnetic resonance images on day 10 of hospitalization of the patient described in Figure 2. Axial diffusionweighted image (a) and fluid-attenuated inversion recovery image (b) showed either disappearance or remarkable shrinking of the previously observed abnormalities. The patient was discharged without sequelae or medication or the intramyelinic cleft. Thus, intramyelinic edema is a form of cytotoxic edema that is seen in the acute phase of multiple sclerosis, toxic or metabolic leukoencephalopathy, and osmotic myelinolysis.
It has been proposed that intramyelinic edema may occur transiently in the SCC, where myelinated nerve fibers are dense rather than cytotoxic edema because intramyelinic edema causes a reduction in the ADC, does not lead to neuronal damage and is usually reversible. DWI abnormalities, however, resolve after the causative pathological factors are removed (Tada et al., 2004). In neonates with mild encephalopathy/encephalitis who do not have myelination in the SCC as mentioned previously, reversible lesions occur. As such, intramyelinic edema cannot provide a unified explanation (Sun et al., 2017). The pathophysiological hypothesis about the reversible lesion in the SCC that leads to cytotoxic edema through cytokines is as TA B L E 2 Characteristics of the reversible lesion in splenium of the corpus callosum
F I G U R E 4 Depiction of the pathophysiological hypothesis of the reversible lesion in the splenium of the corpus callosum (SCC) that leads to cytotoxic edema. Cytokines, such as tumor necrosis factor alpha (TNF-α), interleukin-1 (IL-1), and interleukin-6 (IL-6), are released. Endothelial damage causes activation of microglia that further accelerates the release of these cytokines. IL-1 can also induce astrocytes to take up glutamate, which reacts with ammonia to form glutamine, and then glutamine is transported to the extracellular fluid, where it is again taken up by neurons; then the glutamate synthesis process restarts, thus increasing extracellular glutamine. Intracellular ATP depletion, resulting in mitochondrial dysfunction and oxidative stress, is induced by activated glutamate-glutamine cycle. The excitotoxic action of receptors, such as N-methyl-d-aspartate (NMDA), α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA), and aquaporin 4 (AQP4) receptors activation, is triggered through a complex cell-cytokine, that results in an influx of water into both astrocytes and neurons, which leads to cytotoxic edema, characterized by intracellular accumulation of fluid and Na + and resulting in cell swelling. VEGF, vascular endothelial growth factor follows: At first, cytokines such as tumor necrosis factor alpha, interleukin-1, and interleukin-6 are released under causative conditions that lead to reversible lesions in the SCC. These cytokines induce the expression of adhesion molecules (intercellular adhesion molecule 1 and vascular cell adhesion molecule) that interact with leukocytes. Next, the adhesion molecules make leukocytes produce reactive oxygen species and proteases that cause endothelial damage. Endothelial damage causes the activation of microglia, which accelerates the further release of these cytokines (Xing, Li, Deng, Ning, & Lo, 2018). Tumor necrosis factor alpha and interleukin-1 can also induce astrocytes to produce vascular endothelial growth factor, which weakens the tight junction of the brain vasculature and results in the breaking down of the blood-brain barrier. In addition, interleukin-1 can induce astrocytes to take up glutamate, which reacts with ammonia to form glutamine as influenced by the activity of glutamine synthetase. After that, glutamine is transported to the extracellular fluid where it is taken up by neurons and the glutamate synthesis process resumes. This sequence is referred to as the glutamate-glutamine cycle and it increases levels of extracellular glutamine (Zhou & Danbolt, 2014).
Intracellular ATP depletion that leads to mitochondrial dysfunction and oxidative stress is induced by activated the glutamate-glutamine cycle (Haldipur et al., 2014;Rodrigo & Felipo, 2007). The Cytotoxic edema is characterized by the intracellular accumulation of fluid and Na + , which results in cell swelling. However, cytotoxic edema is thought to lead to an irreversible lesion and cellular death. While this is contrary to the most notable characteristics of reversible lesions in the SCC, the lesions are not always completely reversible (Doherty et al., 2005;McLeod et al., 1987). In the case of ischemia, neurons in the penumbra undergo cytotoxic edema that are potentially reversible if perfusion is restored within the first few hours but with cytotoxic edema caused by cytokine release, the margin of time to recovery is longer than that for ischemia. In addition, the lesion in SCC tends to show signs of recovery on MRI findings but there may be inflammatory tissue damage histopathologically (Starkey et al., 2017).
The SCC may have more abundant blood flow and be susceptible to cytotoxic edema caused by cytokine release in the blood than are other brain areas because the SCC is supplied not only by the anterior circulation but also from the posterior circulation, unlike the rest of the corpus callosum that is solely supplied by the internal carotid artery network (Kahilogullari et al., 2013;Kakou et al., 1998).
In the neurons, astrocytes, and oligodendrocytes of the corpus callosum, there is also a higher density of receptors including cytokine receptors and glutamate (Hassel, Boldingh, Narvesen, Iversen, & Skrede, 2003). This higher density may be more likely to cause cytotoxic edema in the corpus callosum when cytokines release occurs.
This has been experimentally proven that as follows: N-methyl-Daspartate receptors are expressed in the CC and are involved in excitotoxic activity in CC slices in vitro (Zhang, Liu, Fox, & Xiong, 2013).
Moreover, there is also a higher density of aquaporin 4 (AQP4) receptors in the SCC that can lead to the development of cytotoxic edema (Badaut, Fukuda, Jullienne, & Petry, 2014). Recently, Yu et al. propose pathogenic mechanism for the reversible lesion in the SCC as related to AQP4 receptors as follows (Qing et al., 2019;Yang, Chang, Liu, & Yu, 2019): Various of conditions which have been reported to trigger the reversible lesion in the SCC (Table 1) can also affect the AQP4 protein expression, leading to an increased expression levels through a complex cell-cytokine interaction. As the basis for that mechanism, there are previous animal experiments that cytokine (interleukin-1β) induces the activation of AQP4 through a the nuclear factor-κB pathway in the rat brain (Ito et al., 2006), accelerated progression of cytotoxic brain edema was recognized in transgenic mice (AQP4-overexpressing) (Yang, Zador, & Verkman, 2008), and the absence of AQP4 was associated with decreased mortality and increased motor recovery after transient cerebral ischemia in AQP4-knockout mice (Hirt et al., 2017). AQP4 receptors activation will result in an influx of water into astrocytes, leading to cytotoxic edema ( Figure 4).

| CON CLUS IONS
A reversible lesion in the SCC is recognized on MRI in a wide variety of disease conditions. Thus, it may be better to consider it as a secondary change rather than a characteristic finding associated with mild encephalitis/encephalopathy. If there are reversible lesions in the SCC, the symptoms and prognosis are not necessarily favorable, inasmuch as the neurological symptoms of encephalitis/ encephalopathy can vary from absent to severe. These results may suggest that physicians should not diagnose or initiate treatment for encephalitis/encephalopathy merely because of the finding of a lesion in the SCC on MRI. This is because neuroradiological features such as isolated high-intensity signals on DWI and decreased ADC value of the lesion may be indicative of cytotoxic edema. Findings of previous studies suggest that cytokine-mediated cytotoxic edema of the SCC through cytokines may be an important pathophysiological mechanism underlying this condition.

ACK N OWLED G M ENTS
The author would like to thank Enago (www.enago.jp) for the English language review.

CO N FLI C T O F I NTE R E S T
The author declares no conflict of interest.