To the best of our knowledge, this is the first reported case of RESLES due to the ingestion of paracetamol. For lithium intoxication, three patients had previously been reported to be affected by RESLES[10, 11]. The clinical manifestations of RESLES are diverse and atypical. The most common neurological symptoms include delirium, headaches, seizures, disturbance of consciousness, and mental abnormalities. Most patients generally recover without neurological sequelae after a short disease course[1, 12]. The diagnosis of this disease mainly depends on brain MRI findings. The characteristic radiological features of RESLES include lesions mostly confined to the splenium of the corpus callosum with clear boundaries; a few can involve the white matter area outside the SCC without obvious edema or mass effects around the lesions[1, 12]. MRI of SCC lesions revealed hypointense signals on T1 and hyperintense signals on T2 and FLAIR sequences. Restricted diffusion was also observed on DWI, with low ADC values within the lesions, without gadolinium enhancement.
Several theories, such as transient damage to the blood‒brain barrier, reversible demyelination, intramyelinic cytotoxic edema, exocytotoxic edema, and arginine vasopressin release (AVP), have been proposed to explain the etiopathogenesis of RESLES[12]. Many RESLES cases support the idea that cytotoxic edema plays a significant role in this disease[2, 5, 6, 8]. Starkey J et al. noted that various conditions, such as infection, trauma, and metabolic disorders, trigger cell-cytokine interactions, which in turn lead to massively elevated extracellular glutamate levels[13]. The excitotoxic effects of glutamate on N-methyl-d-aspartate receptors, α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptors, sodium-potassium pumps, and aquaporins cause water influx into astrocytes and myelin sheaths[13]. Owing to their abundant high-affinity glutamate receptors and transporters, the spread of edema to astrocytes and myelin sheaths protects axons from permanent damage. Therefore, edema is usually transitory, and MRI signal abnormalities normalize with time or following the removal of causative pathologic factors.
The corpus callosum, also called the neocortical commissure, is the largest fiber bundle connecting the contralateral hemispheres of the cerebrum[12]. It plays a vital role in interhemispheric communication and coordination and participates in the integration of motor, sensory, and cognitive functions. It can be divided into four parts: the rostrum, genu, body, and splenium[12]. Compared with other brain areas, the corpus callosum has a greater density of receptors, including cytokine receptors, glutamate and other excitatory amino acid receptors, toxin receptors, and drug receptors, which increases its vulnerability to cytotoxic edema[13]. The splenium was located at the posterior end of the corpus callosum. The reason why reversible cytotoxic edema selectively involves the splenium remains unclear. The SCC has been postulated to be a vulnerable structure because of its close functional relationship with limbic and temporal lobe structures, which are critical to the spread of excitation in seizures[12]. However, other conditions, such as encephalitis or hypoglycemia, in which the splenium is also involved, cannot be explained by this relationship. An alternative explanation is that the splenium contains different-caliber axonal fibers and the most compact area of callosal gliacytes[14]. Carlos et al. reported that the susceptibility of SCC to edema is due to a large number of glutamate receptors and high enzymatic activity[15]. Despite these theories, a common pathophysiological mechanism explaining the splenial predilection in different disease processes remains to be elucidated.
Excessive paracetamol usually induces liver injury, and ingestion of greater than 10 g/day or sometimes as low as 3–4 g/day can result in hepatotoxicity[16]. The most serious complication of paracetamol toxicity is cerebral edema[16]. There is evidence of an association between elevated serum ammonia levels and the pathogenesis of cerebral edema and hepatic encephalopathy[16]. The toxic effects of ammonia cause a cytokine surge and increase glutamate levels with excessive activation of N-methyl-D-aspartate receptors[17]. In the first case, the patient experienced neuropsychiatric symptoms after taking excessive paracetamol. DWI revealed lesions in the early phase as hyperintense lesions with decreased ADC and findings that represented cytotoxic edema. Therefore, we speculate that excessive ingestion of paracetamol causes cytotoxic edema, leading to RESLES.
Lithium has a narrow therapeutic range, which may lead to neurological toxicity[10]. Previous studies have suggested that the neurotoxic effects of lithium are associated with NMS[10]. Han et al. reported two patients with RESLES with lithium-associated neurotoxicity who were diagnosed with schizophrenia or BD[11]. The authors suspected that the etiology of RESLES was lithium-associated neurotoxicity, which was also associated with NMS symptoms. Moreover, interactions with other neuroleptic drugs may increase lithium-associated neurotoxicity and clinical symptoms[10, 11]. In our case, the patient received increased doses of lithium with quetiapine and presented with NMS, which led to the development of RESLES. Taken together, these findings indicate that lithium neurotoxicity may be related to the etiology of RESLES with NMS.