Cytotoxic lesion of the corpus callosum in pediatrics: A case report

Abstract

Cytotoxic lesions of the corpus callosum are considered a clinical-radiological syndrome that generates transitory damage to the corpus callosum; especially in the splenium, with a multicausal origin such as drugs, malignant neoplasms, infections, subarachnoid hemorrhage, metabolic disorders, and traumas. The clinical presentation varies in severity. Some patients have complete recovery in a few days, while others present a more serious clinical, requiring admission to pediatric intensive care. We present a case of a pediatric patient with cytotoxic lesions of the corpus callosum (CLOCCs) confirmed by brain magnetic resonance imaging (MRI). The patient was admitted due to gastrointestinal symptoms, progressing to altered consciousness, postural instability, dysarthria, and paroxysmal events. A literature search of all reported cases of compromises of CLOCCs was carried out to identify the different terms used to describe this syndrome and consolidated a report of utility in the clinic of this pathology.

Introduction

Currently, the pediatric cases reported in the literature due to cytotoxic lesions of the corpus callosum (CLOCCs) are scarce. No series of pediatric cases expose their wide etiological spectrum. In addition, this pediatric entity is rare, and its name has varied over time, being called mild encephalopathy with reversible splenial lesions (MERS), reversible splenial lesion syndrome (RESLES), reversible splenial lesions, transient splenial lesions, clinically silent in the splenius of the corpus callosum, or later term CLOCCs; which has generated difficulties in the diagnosis and the consolidated report of cases [1].

We present a case of an infant with a history of gastrointestinal symptoms, who was admitted to emergency department with neurological symptoms, requiring hospitalization in the pediatric intensive care unit (PICU), with evidence of cytotoxic lesions of the splenius of the corpus callosum (CC) by brain magnetic resonance imaging (cMRI).

Case report

A 2 years and 11-months old female patient, previously healthy, consulted the emergency room with 3 days of gastrointestinal symptoms, consisting of diarrheal stools, and multiple emetic episodes (evolution to drowsiness 24 hours after the onset of symptoms). Postural instability, indifferent lateropulsion, and dysarthria. At 72 hours she presented paroxysmal events of short duration, with the tonic posture of the 4 limbs, decreased strength in the right lower limb, and disconnection from the environment with no fever or respiratory symptoms. Upon admission, Grade I dehydration, ataxia, dysarthria, bradypsychia, and bradylalia were observed. During the evaluation, she presented an episode of gaze disconnection, guttural cry, the rigidity of the 4 extremities, nonreactive 4 mm pupils, generalized tonic-clonic movements for 5 seconds, and blood sugar of 42 mg/dL. Requiring correction with DAD at 10% with subsequent recovery of alertness and control of blood sugar at 168 mg/dL. However, bradypsychia and bradylalia persisted. Subsequently, she presented 2 new episodes of abnormal movements with the same characteristics, considered generalized tonic-clonic seizures, requiring doses of intravenous midazolam and initiation of divalproex sodium (30 mg/kg) with a resolution of the seizures.

The epidemiological analysis identified 3 schoolchildren, with whom she shared classes, who had presented gastrointestinal symptoms of the same evolution time but without a neurological component. She received immunization with booster doses of measles and influenza vaccines 1 week before admission. Likewise, administration of amoxicillin at usual doses for 10 days for acute otitis media and laryngitis 3 weeks before the emergency room visit.

On admission to the PICU, she was sleepy, bradypsychic, oriented, and responsive to stimuli. Focused isochoric pupils nonreactive to light, facial symmetry, no passive or active tongue deviation, no dysarthria with bradylalia. Preserved tone, strength 5/5 in all limbs, muscle-tendon reflexes ++/++++ in all 4 limbs. Bilateral plantar flexor response, no nuchal rigidity, no meningeal signs. In a sitting position with the presence of ataxia and other normal physical examination.

Hemogram, venous gases, renal and hepatic function, electrolytes, and postcorrection glycemia in usual ranges. Normal insulin and elevated cortisol at 819.6 nmol/L (NV 185-624 nmol/L) were explained by the response to stress without criteria of adrenal insufficiency. Brain tomography ruled out space-occupying lesions.

Given the suspicion of neuro infection, antimicrobial management was started with ceftriaxone, vancomycin, and acyclovir, an extended study of cerebrospinal fluid (CSF) not compatible with neuro infection, cultures, direct fungal examination, and India ink in CSF negative, video telemetry, and neuron conduction within normal limits.

At the PICU, she presented improvement in dysarthria and drowsiness. However, she continued with ataxia and postural instability with lateropulsion. cMRI was performed showing an intraracial focal lesion in the splenium of the CC with diffusion restriction attributable to cytotoxic edema within the spectrum of CLOCCs (Fig. 1), an etiological study was extended with meningeal FilmArray that ruled out infections by Escherichia coli K1, Haemophilus influenzae, Listeria monocytogenes, Neisseria meningitidis, Streptococcus agalactiae, Streptococcus pneumoniae, Cytomegalavirus, Enterovirus, Herpes simplex virus type 1, Herpes simplex virus type 2, human herpes virus type 6, human parechovirus, Varicella zoster virus, IgM, IgG, and PCR for Epstein virus Barr and IgM and IgG for SARS COV2 negative (Fig. 1).

Fig 1.

cMRI Intraaxial focal lesion in the splenium of the CC with diffusion restriction attributable to cytotoxic edema.

Gastrointestinal studies such as FilmArray gastrointestinal, stool, and stool were not performed due to the absence of new stools.

The clinical evolution was satisfactory. Therefore, the suspension of the empiric antimicrobial regimen established upon admission was considered. Achieved resolution of drowsiness, ataxia, and postural instability, without new convulsive episodes, allowing discharge with valproic acid for 4 weeks, with subsequent progressive withdrawal. A cMRI at 2 months showed complete resolution of the diffusion restriction focus on the splenium of the CC, without residual lesions (Fig. 2).

Fig 2.

MRI complete resolution of the diffusion restriction focuses on the splenium of the CC, without residual lesions.

Discussion

A total of 35 pediatric case reports were found and 123 patients were analyzed (Supplementary). Of these, 80 were described as MERS, 9 as RESLES, and 4 as CLOCCs. The most-reported causes were infectious (39.8%), viral as rotavirus (10.6%), Kawasaki disease (5.7%), coronavirus disease-19 (COVID-19) (5.7%), Influenza A (4.9%), M. pneumoniae (3.2%), Adenovirus (2.4%), Echovirus (2.4%), Cytomegalovirus (1.6%), Herpes virus type 6 (1.6%), and S.pneumoniae (1.6%). Many studies reported unknown origin (21.1%) or infectious from the respiratory tract (6.5%) or gastrointestinal (3.2%) without causal origin (Fig. 3).

Fig 3.

Causes distribution. Viral infections include adenovirus infection (n = 3), COVID-19 (n = 7), Cytomegalovirus (n = 2), Echovirus 6 (n = 3), Epstein Barr (n = 1), Herpesvirus type 6 (n = 3), Influenza A (n = 7), Influenza B (n = 2), Parainfluenza 1-3 (n = 1), and Rotavirus (n = 13). Bacterial infections include Campylobacter infection (n = 1), Enterococcus Faecalis (n = 1), Escherichia Coli (n = 1), Listeria Monocytogenes (n = 1), Mycoplasma (n = 4), Neisseria Meningitidis (n = 1), Salmonella (n = 1), and Streptococcus Pneumoniae (n = 2).

The main symptoms reported were fever, seizures, vomiting, lethargy, irritability, incoherent language, hallucinations, diarrhea, and abdominal pain (Fig. 4).

Fig. 4.

Symptoms more frequent. Altered consciousness (n = 38), fever (n = 30), seizures (n = 24), vomiting (n = 23), motor impairment (n = 15), headache (n = 13), cough (n = 12), hallucinations (n = 12), dysarthria (n = 10), diarrhea (n = 8), abdominal pain (n = 7) and drowsiness (n = 7).

The most-reported findings in cMRI were lesions in the splenius of the corpus callosum (n = 74), lesion throughout corpus callosum and periventricular white matter (n = 13), lesion in splenius and genu of corpus collosum (n = 8), parietal lesions and corona radiata (n = 1), lesion in splenius of corpus callosum and the dentate nucleus and white matter of the cerebellum (n = 1), lesions in splenius of corpus collosum with lateral extension to callous radiations and frontoparietal white matter (n = 1), and reduced diffusion in splenius and subcortical white matter (n = 1).

CLOCCs is a clinical-radiological syndrome consisting of transient lesions in the splenium of the CC with splenial diffusion restriction on MRI. These lesions were first described in Japan in 1990 [2]. However, the terminology has changed using terms such as encephalopathy with reversible splenial lesions (MERS), reversible splenial lesion syndrome (RESLES), reversible splenial lesions, transient splenial lesions, and clinically silent lesions in the splenium of the CC [1].

In the first description of CLOCCs in the late 1990s, it was associated with transient ovoid splenial lesions in epileptic patients [2]. Subsequently, infectious causes, such as influenza and rotavirus, were identified in patients with splenial injuries. These findings have been published as case reports [2]. In 2004, encephalitis/MERS was described as a new clinical-radiological syndrome [2]. However, the term MERS led to confusion with other entities such as the Middle East respiratory syndrome, for which the general term called RESLES was proposed [2]. Recently, the term CC cytotoxic lesions (CLOCCs) has been used, replacing the rest of the terms, and including the different etiologies that can cause this entity [2] (Fig. 5).

Fig. 6.

Year of diagnosis and terminology. 2020-2022: Reversible splenial injury (MERS) (n = 35), cytotoxic injury of the corpus callosum (ClOCCs) (n = 4), reversible splenial injury syndrome (RESLES) (n = 27). 2017-2019: Reversible splenial injury (MERS) (n = 5), cytotoxic injury of the corpus callosum (ClOCCs) (n=0), reversible splenial injury syndrome (RESLES) (n = 5). 2014-2016: Reversible splenial injury (MERS) (n=30), cytotoxic injury of the corpus callosum (ClOCCs) (n = 0), reversible splenial injury syndrome (RESLES) (n = 5). 2011-2013: reversible splenial injury (MERS) (n = 7), cytotoxic injury of the corpus callosum (ClOCCs) (n = 0), reversible splenial injury syndrome (RESLES) (n = 1). 2008-2010: reversible splenial injury (MERS) (n = 3), cytotoxic injury of the corpus callosum (ClOCCs) (n = 0), reversible splenial injury syndrome (RESLES) (n = 0). 2005-2007: reversible splenial injury (MERS) (n = 0), cytotoxic injury of the corpus callosum (ClOCCs) (n = 0), reversible splenial injury syndrome (RESLES) (n = 1).

Fig. 5.

Timeline of designations of CC cytotoxic lesion. However, it is noteworthy that when searching for cases reported in the literature, the term CLOCCs is not frequently used in the publications, with only 4 case reports in which the term is included, 3 of them from 2020 and 1 from 2021 (Fig. 6). This may mean that the different scientific associations have not yet unified the term, which may lead to confusion when identifying, diagnosing, and treating any patient with this condition.

Most patients with CLOCCs only involved the splenium of CC showing 3 patterns [2]: 1) a small round or oval lesion located in the center of the splenius, 2) a lesion centered on the splenius but extending through the callosal fibers laterally into the adjacent white matter, and 3) a lesion centered posteriorly but extending into the anterior CC [1]. Among the main causes of CLOCCs are associated drugs, malignant neoplasms, infections, subarachnoid hemorrhage, metabolic disorders, and traumas, among others (Table 1) [1].

Table 1.

Causes of CC cytotoxic lesion (ClOCCs) [1].

Entity	Cause
Drugs	•Carabamazepine •Cyclosporine •Intravenous immunoglobulin therapy •lamotrigine •Metronidazole •Amitriptyline •Clozapine •Phenytoin •Corticosteroids
Malignant neoplasms	•Acute lymphocytic leukemia •Esophageal cancer •Leptomeningeal glioblastomatosis •Spinal meningeal melanocytoma
Infections	•Adenoviruses •Aseptic meningitis •Encephalitis •Epstein–Barr virus •Escherichia coli •Herpes •Influenza virus A (H1N1) •Influenza •legionella •Malaria •Measles •Mycoplasma •Mumps •Rotavirus •Salmonella •Staphylococcus •Streptococcus •Tick bite encephalitis •Varicella-zoster virus
Subarachnoid hemorrhage	•Aneurysm •Arteriovenous malformation
Metabolic disorders	•Acute kidney failure •Alcoholism •Extrapontine myelinolysis •Central pontine myelinolysis •Hepatic encephalopathy •Hyperammonemia •Hypernatremia •Hypoglycemia •Hyponatremia •Malnutrition •Wernicke's encephalopathy •Wilson's disease •Marchiafava-Bignami disease
Trauma	•Secondary trauma to different causes
Other entities	•Acute altitude sickness •Antiglutamate receptor antibodies •Antivoltage gated potassium channel antibodies •Eclampsia •Hemolytic uremic syndrome •Vaccination •Kawasaki disease •Posterior reversible encephalopathy syndrome •Postpartum cerebral angiopathy •Epileptic status

At the global or regional level, it is difficult to determine exact figures on the distribution and frequency of reported cases of CLOCCs, due to the few reports and case series in the literature. One of the largest pediatric case series is that of Aksu Uzunhan et al [2] which included 41 children of 0-18 years diagnosed with CLOCCs and treated at 5 different pediatric neurology/radiology centers between February 2017 and May 2020. Patients had splenial lesions showing diffusion restriction on cMRI, isolated or involving other brain areas, and a follow-up cMRI within 30 days after the first cMRI to establish resolved lesions. This study determined that the mean age of the patients was 7.82 ± 4.84 years, with a median of 7 years (range: 0.25-17) [2].

Of the 41 patients included in the case series carried out by Aksu Uzunhan et al [2], 22 were men. Additionally, 25 patients had CLOCCs whose cause was attributed to infectious processes (COVID-19, Influenza A H1N1, meningococcemia, and amoeba cysts), 9 patients were found to be associated with trauma as a cause of CLOCCs, 3 associated with metabolic disorders, including hereditary disorders of metabolism (Saposin B deficiency and argininosuccinic aciduria), and 4 patients had other entities.

The pathophysiology shows 3 fundamental pillars [1]. First, cell-cytokine relationships can be activated by trauma, infection, and inflammation, with consequent activation of macrophages that generates the release of inflammatory cytokines such as interleukin 1 (IL-1) and interleukin 6 (IL-6), leading to an inflammatory cytokine cascade. This is followed by the recruitment of T cells and endothelial cells, which damage the blood-brain barrier, causing leakage and stimulating the production of tumor necrosis factor-α (TNF-α). Astrocytes, in turn, are stimulated by IL-1 to release glutamate and block glutamate uptake, increasing extracellular glutamate. Microglia (macrophages of the central nervous system) are simultaneously activated, amplifying the production of cytokines, and initiating demyelination. These cell-cytokine relationships create feedback loops that increase exponentially, which ultimately translates into a massive increase in glutamate concentrations in the extracellular space reaching levels 100 times higher than normal [1]. Second, cytotoxic edema is generated from the cytotoxic action of glutamate on N-methyl-D-aspartate and α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptors, the sodium-potassium, and aquaporins, leading to an influx of water inside neurons, oligodendrocytes, and astrocytes, resulting in intracellular edema and reduced diffusion [1]. Finally, vulnerable regions of the CC, neurons, astrocytes, and oligodendrocytes of the CC and particularly its splenium, compared to other brain areas, have a higher density of receptors for cytokines and glutamate as well as excitatory receptors for amino acids, toxins, and drugs, which makes it much more susceptible to developing cytotoxic edema in the context of cytokinopathy [1].

CLOCCs can cause impaired consciousness, seizures, ataxia, paresthesias of the face and extremities, headache, vision loss, and diplopia. To make an adequate diagnosis, clinical and radiological findings must be gathered [3] (Table 2).

Table 2.

Clinical and radiological criteria for CLOCCs [3].

1.The onset of neuropsychiatric symptoms such as abnormal speech and/or behavior, as well as altered consciousness or seizures, within a week of the onset of fever. 2.Complete recovery without sequelae, mainly within 10 d after the onset of neuropsychiatric symptoms 3.High signal intensity lesion in the splenium of the CC (during the acute stage). Signal changes on T1 and T2 are light. 4.The lesion may involve the entire CC and cerebral white matter symmetrically. 5.The lesion disappears within a week, with no residual signal changes or atrophy

Diffusion cMRI is the ideal imaging method for diagnosis [1]. Showing in T2 hyperintense lesions of the splenium of the CC and diffusion (DWI) marked hyperintensities with reduced diffusion in lesion [1], like those found in our patient.

The prognosis of this entity is generally benign, one with an excellent clinical and radiological outcome. No irreversible causes have been found to date, and in all the patients the radiological lesions by cMRI have resolved, as well as the clinical symptoms, without clinical sequelae [2].

Immunomodulatory treatment may not be justified on many occasions [3], because no change has been seen in the outcome of the disease, and there are no clinical trials to support it to date. In the cases in which only support treatment was administered, they presented similar clinical evolutions and outcomes, compared to the cases in which different schemes with antibiotics, antivirals, corticosteroids, and intravenous immunoglobulin were administered [4].

In our patients, it is relevant to consider their history of gastrointestinal symptoms and booster vaccination for measles and influenza days before the neurological condition since these could be the triggers for CLOCCs (Table 2) [3,4]. Unfortunately, although several infections have been associated with this entity (Adenovirus, Epstein-Barr virus, Escherichia coli, herpes, influenza, legionella, malaria, measles, mycoplasma, mumps, rotavirus, salmonella, staphylococcus, streptococcus, varicella-zoster virus, among others) [1] in our case, microbiological isolation was not achieved, which could explain the condition or associate an underlying cause.

Conclusions

CC cytotoxic lesions (CLOCCs) are a clinical-radiological syndrome with different etiologies, which generate cytotoxic edema in vulnerable regions of the CC. Throughout history, this entity has been changing its name. Nowadays it is called CLOCCs, in very few case reports, it is designated in this way and terms such as MERS and RESLES are still used. We consider that it is important to unify the use of the term CLOCCs by scientific associations to avoid confusion and to have a better identification of the identity, diagnosis, and management. Although its clinical course may vary depending on its cause, in general, the literature has shown a complete recovery of patients [2]. Early detection of CLOCCs associated with the infection will avoid unnecessary treatment and testing providing peace of mind due to its excellent clinical and radiological prognosis [2].

Patient consent

I, Camilo Novoa Garnica, declare that prior to the completion of this case report, written informed consent was obtained from the patient's parents and/or legal guardians for the publication of the case.