The corpus callosum is composed of densely bundled white matter tracts and plays an important role in interhemispheric communication and coordination. It is divided into four parts: the rostrum, the genu, the body, and the splenium. Characterized by a higher density of receptors including cytokine receptors, glutamate and other excitatory amino acid receptors, toxin receptors, and drug receptors17–19, the corpus callosum, particularly the splenium, is more vulnerable to cytotoxic edema than other brain areas1,20,21.
The terms of “mild encephalopathy with reversible splenial lesions (MERS),” “reversible/transient splenial lesions,” “clinically silent lesions in the splenium of the corpus callosum,” “transient focal lesions in the splenium of the corpus callosum” and “cytotoxic lesions of the corpus callosum” which are similar to RESLES were reported in a wide spectrum of clinical conditions. Meanwhile, the conditions were classified as malignancy, infections, trauma, metabolic abnormalities,drug therapy, subarachnoid hemorrhage (SAH) and other entities13.
Consistent to the review, three cases in our study developed metabolic abnormalities. MBD is one of the forms of metabolic abnormalities8. The pathogenesis of MBD is associated with chronic alcoholism, nutritional deficiency and metabolic disorders8,22. Consistently, both of our case 1 and case 2 are diagnosed as alcohol dependence. Long-term alcohol might lead to severe malnutrition (especially lack of B vitamins). The lesions were resolved in five weeks after treatment of vitamin B complex. Case 3 was diagnosed as Asperger's syndrome and showed decreased serum vitamin B12 level. He had a seriously irregular intake, and thus developed serious malnutrition, which may explain his markedly decreased serum vitamin B12 level. Given that there is no evidence of an association between Asperger's syndrome and RESLES, we believe that malnutrition is more likely to be the cause. The alcohol abuse and malnutrition increase the susceptibility to injury pro-apoptotic drive and then lead to endothelial dysfunction, which result in the cytokines released from microglia and eventually cause the cytotoxic edema of corpus callosum13,23.
Similar to previous reports, our case 4 had a history of infection in forms of recurrent of maculopapular. Previous studies have indicated that RESLES triggered by infection often occurs in children and young adults5,16. The virus is the main pathogen16, as well as the bacteria11, mycoplasma pneumoniae24 and plasmodium25 are also reported as the causes of RESLES. Unfortunately, we failed to find the source of the infection because of the light symptom and the transfer of the patient. However, the good outcome of anti-inflammatory treatment after transfer supports the inference of infection-associated, while outcome of antipsychotic treatment was not satisfactory.
Although the cases of RESLES with other malignancies might be caused by chemotherapy12,26, the RESLES was also found in CNS malignancies before treatment12,13. Case 5 had pituitary adenomas and did not get any treatment at the onset. The effect of the pituitary adenomas on RESLES has not been determined. In some cases of CNS malignancies, the author suggests that the RESLES is attributed to a release of cytokines into the cerebrospinal fluid resulted by infiltration of malignant cells13. Also, we speculate that the metabolic abnormality caused by endocrine disorders is likely to be a precipitating factor of RESLES with pituitary adenomas. However, without exact evidences, further researches are needed to reveal the underlying mechanism.
Interestingly, the other five cases (case 6–10) are special owing to that they might give a new sight to identify the etiologies of RESLES. In the one hand, most of the etiologies described above were ruled out through clinical history, examinations, and clinical diagnosis. There was no evidence of history of malignancy or chemotherapy, the symptom of infection (fever, leukocytosis, nuchal rigidity and history of travel to endemic areas), SAH (thunderclap headache), metabolic pathology (Fluid-electrolyte imbalances, cirrhosis or hepatic dysfunction, liver transplantation, malnutrition, or AIDS, Wernicke encephalopathy or Marchiafava-Bignami disease and Wilson disease) and Trauma. In the other hand, they start with mental disorders without prodromal symptoms, and were clinically diagnosed with different mental disorders. Moreover, although the drugs used in these cases like Olanzapine27 have been reported as an inducement of RESLES, the possibility of drug cause was also ruled out based on the remarkable improvement of symptoms after treatment of psychotropic drugs.
In addition, we found that a case report about postpartum psychosis without any other physical diseases was similar to case 7. She presented two weeks postpartum with new onset of behavioral alteration and irrelevant talking without fever, headache, or seizures. A possibility of postpartum psychosis was considered to be the associated condition after ruling out various etiologies for RESLES28. Given the evidences, the mental disorders are inclined to be considered as the possible etiology of the RESLES.
There are three limitations in our study. Firstly, the sample is limited, since the patients were all from the same hospital and the simple size was relatively small. Further studies with a larger number of patients from multiple centers are necessary to confirm our results. Secondly, since the patients were diagnosed as different mental disorders, more homogenous sample is needed in the future researches. Lastly, restricted to retrospective studies, the role of nutritional deficiency or unidentified viral infection cannot be ruled out with certainty because of the lack of more detailed examination results.