Reversible splenial lesion syndrome induced by paracetamol and lithium: two case reports

Reversible splenial lesion syndrome induced by paracetamol and lithium: two case reports | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Case Report Reversible splenial lesion syndrome induced by paracetamol and lithium: two case reports Xin Zhou, Chunhua Zhang, Liming Zhou, Leliang Zhou, Yongbiao Zou This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-4704503/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Background : Reversible splenial lesion syndrome (RESLES) is a rare neurological syndrome characterized by a reversible lesion in the splenium of the corpus callosum (SCC). Various etiologies, such as infection, high-altitude cerebral edema, seizures, antiepileptic drug (AED) withdrawal, and metabolic abnormalities, are involved in the development of RESLES. However, few studies have reported the occurrence of this disorder associated with medications, particularly paracetamol, which has not yet been documented. Case presentation : A 50-year-old man with neuropsychiatric symptoms who was receiving increased doses of paracetamol was referred to our hospital. The patient fully recovered 8 days after treatment. The second case involved a 35-year-old female who received 1500 mg/day lithium and 500 mg/day quetiapine for bipolar disorder (BD). She experienced generalized tremor, rigidity, dysarthria, high fever, hypertension, tachycardia, and tachypnea. Symptoms and brain lesions fully resolved two weeks after discontinuation of lithium. Brain magnetic resonance imaging (MRI) in both patients typically demonstrated a reversible lesion with transiently reduced diffusion in the SCC. Conclusion : RESLES is a rare finding that is usually incidentally detected. Therefore, MRI should be performed to evaluate SCC in patients taking excessive medication who present with neuropsychiatric symptoms. reversible splenial lesion syndrome paracetamol lithium cytotoxic edema neurotoxicity Figures Figure 1 Figure 2 Introduction Reversible splenial lesion syndrome (RESLES) is a new clinical-radiological syndrome characterized by the presence of a reversible lesion in the splenium of the corpus callosum (SCC)[ 1 ]. This syndrome is still unclear. According to the current literature, RESLES can occur secondary to various etiologies. These include metabolic disorders, infections, epilepsy and antiepileptic drug withdrawal, autoimmune diseases, and toxic causes such as influenza[ 2 ], encephalitis meningococcal meningitis[ 3 ], hyponatremia[ 4 ], eclampsia[ 5 ], thrombotic thrombocytopenic purpura[ 6 ], oxcarbazepine withdrawal[ 7 ] and benzodiazepine poisoning[ 8 ]. However, most recent studies have focused on the occurrence of RESLES in different diseases and have paid less attention to drug-associated cases. Here, we describe two rare cases of RESLES induced by paracetamol and lithium. Case presentation Case 1 A 50-year-old male was admitted with behavioral abnormalities and disoriented speech that persisted for 2 days. He had a history of migraine without aura for 20 + years and was irregularly taking paracetamol. Two days prior to admission, to relieve acute migraine attacks, he took 3.25 g of paracetamol sustained-release tablets in one day. On physical examination, the patient was afebrile with normal vital signs, including blood pressure, pulse, and respiration. The muscle strength of all four limbs was at level 5, and the muscle tension was moderate. No pathological reflexes or signs of meningeal irritation were noted. Laboratory investigations revealed normal total leukocyte and erythrocyte counts, mild hypohemoglobinemia (112.00 g/L), alanine aminotransferase 51.60 U/L, and serum creatine kinase 297.00 U/L, as shown in Table 1 . Urine and stool tests, serum electrolytes, C-reactive protein, renal function, blood glucose level, folate level, vitamin B12 level, coagulation, and thyroid function were all normal. The cerebrospinal fluid (CSF) was clear in appearance, with 3/mm3 leukocytes, pressure, and protein and glucose levels (Table 2 ). Chest and abdominal CT did not reveal any abnormal phenomena, and a contrast-enhanced transcranial Doppler (c-TCD) foaming experiment revealed a right-to-left shunt (RLS). Electroencephalography findings were normal and showed no seizure-related activity. Cranial magnetic resonance imaging (MRI) revealed a high-intensity lesion in the SCC on T2-weighted, fluid-attenuated inversion recovery (FLAIR), and diffusion-weighted imaging (DWI). This lesion had a low apparent diffusion coefficient (ADC) and no contrast enhancement (Fig. 1 ). After 8 days of fluid supplementation, liver protection and nutritional support symptomatic treatment, the patient recovered fully, and the lesion on follow-up MRI disappeared. Table 1 Abnormal indicators of peripheral blood analysis. Abnormal index Initials Case 1 Case 2 Normal range White blood cell count (10^9/L) WBC 8.55 10.16 3.5–9.5 Hemoglobin(g/L) Hb 112.00 133.00 120-160(male)/ 110-150(female) Aspartate aminotransferase(U/L) AST 32.60 53.80 15–40 Alanine aminotransferase(U/L) ALT 51.60 38.40 9–50 Creatine kinase (U/L) CK 297.00 1106.00 6–80 Table 2 Indicators of cerebrospinal fluid analysis. Index Case 1 Case 2 Normal range Pressure(mmH 2 0) 150 160 80-180 White blood cell count (/mm^3) 3.00 2.00 0-5 Protein(mg/L) 318.40 402.10 ＜500 Glucose level(mmol/L) 4.38* 3.39* 2.4-4.4 Chloride level(mmol/L) 127.00 128.20 120-130 *Case1 synchronized blood glucose level:8.00mmol/L; Case2 synchronized blood glucose level:4.90mmol/L. Table 3 DSM-V Diagnostic Criteria for NMS[17] A. Development of severe muscle rigidity and elevated temperature associated with the use of neuroleptic medication B. Two (or more) of the following 1) Diaphoresis 2) Dysphagia 3) Tremor 4) Incontinence 6) Mutism 7) Tachycardia 8) Elevated or labile blood pressure 9) Leukocytosis 10) Laboratory evidence of muscle injury (eg, elevated creatine phosphokinase) C. The symptoms in criteria A and B are not due to another substance or a neurological or other general medical condition D. The symptoms in criteria A and B are not better accounted for by a mental disorder Case 2 A 35-year-old woman with an 11-year history of bipolar disorder (BD) was referred to our hospital with an unresponsive response and a refusal to consume food. She had been taking lithium (1000 mg/day) and quetiapine (250 mg/day) for 3 years. Fifteen days before admission, the lithium and quetiapine dosages were increased to 1500 mg/day and 500 mg/day, respectively, owing to her psychotic attack. On admission, the patient was conscious and had a normal urine output. Her vital signs were as follows: body temperature, 38.6°C; heart rate, 130 beats/min; respiration, 22 beats/min; and blood pressure, 140/86 mmHg. Physical examination showed generalized tremor, rigidity, dysarthria, hyperactive bilateral knee and tendon reflexes, and negative pathological signs and meningeal irritation. The blood test results were as follows: white blood cell count, 10.16 10^9/L; aspartate aminotransferase, 53.80 U/L; and serum creatine kinase, 1106.00 U/L. Urine testing, renal function, serum electrolytes, C-reactive protein, blood glucose level, coagulation, and thyroid functions revealed no abnormalities. Lumbar puncture revealed clear cerebrospinal fluid (CSF) with no evidence of infection (Table 2 ). The patient met the diagnostic criteria for neuroleptic malignant syndrome (NMS)[ 9 ] due to elevated WBC and CPK levels, high fever, hypertension, tachycardia, tachypnea, and rigidity. Moreover, brain MRI revealed an oval-shaped hyperintense lesion on DWI with hypointensity in the ADC maps, localized to the SCC (Fig. 2 ). Two weeks after the discontinuation of lithium and quetiapine, these abnormalities completely disappeared on the follow-up MRI. Discussion 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. Conclusion In summary, for the first time, we describe two patients with RESLES caused by lithium and paracetamol. Although the specific mechanism of RESLES remains controversial, when neuropsychiatric symptoms are detected in patients with a history of excess medication, MRI should be performed to assess and follow-up any SCC lesions. However, given that the clinical manifestations of this syndrome are diverse and nonspecific, attention must be given to this disease at an early stage. Abbreviations RESLES: reversible splenial lesion syndrome; SCC: splenium of the corpus callosum; BD: bipolar disorder; NMS: neuroleptic malignant syndrome; MRI: magnetic resonance imaging; FLAIR: fluid-attenuated inversion recovery; DWI: diffusion-weighted imaging; ADC: apparent diffusion coefficient; CSF: cerebrospinal fluid. Declarations Acknowledgments Not applicable. Author contributions XZ and YBZ participated in the design of this research. CHZ, LMZ, and LLZ collected and analyzed the raw clinical data. XZ and YBZ carried out the computational studies and wrote the manuscript. All authors contributed to the manuscript and approved the submitted version. Funding statement Not applicable. Availability of data and materials All the data and material supporting our findings are contained within the manuscript. Ethics approval and consent to participate Written informed consent was obtained from the patients for the publication of potentially identifiable images or data included in this article. The study protocol was approved by the Ethics Committee and Expert Committee of the Central Hospital of Shaoyang. All patients provided written informed consent to participate in the study. Consent for publication Written informed consent was obtained from the patient for publication of this case report and any accompanying images. Competing interests The authors declare that they have no competing interests. Author details 1 Department of Neurology, The Central Hospital of Shaoyang, Shaoyang, Hunan, China. References Garcia-Monco JC, Cortina IE, Ferreira E, Martínez A, Ruiz L, Cabrera A, Beldarrain MG: Reversible splenial lesion syndrome (RESLES): what's in a name? J Neuroimaging 2011, 21 (2):e1-14. Li Y, Wang Z, Lai S, Li M, Liang H, Qin H, Wang K: Reversible splenial lesion syndrome type II in youth mimicking acute ischemic stroke like onset: A case report . Medicine (Baltimore) 2023, 102 (31):e34568. Hayashi Y, Yasunishi M, Hayashi M, Asano T, Kimura A, Inuzuka T: Reversible splenial lesion of the corpus callosum associated with meningococcal meningitis . J Neurol Sci 2017, 373 :81-82. Takanashi J, Tada H, Maeda M, Suzuki M, Terada H, Barkovich AJ: Encephalopathy with a reversible splenial lesion is associated with hyponatremia . Brain Dev 2009, 31 (3):217-220. Yang Q, Chang CC, Liu M, Yu YQ: Sequential occurrence of eclampsia-associated posterior reversible encephalopathy syndrome and reversible splenial lesion syndrome (a case report): proposal of a novel pathogenesis for reversible splenial lesion syndrome . BMC Med Imaging 2019, 19 (1):35. Hu S, Hou X, Liu S, Fei C, Zhou L, Xing A, Zhang J, Yong C, Wang X: Thrombotic thrombocytopenic purpura with reversible splenial lesion syndrome: a case report . BMC Neurol 2020, 20 (1):122. Jing C, Sun L, Wang Z, Chu C, Lin W: Reversible splenial lesion syndrome due to oxcarbazepine withdrawal: case report and literature review . J Int Med Res 2018, 46 (3):1277-1281. Nasri S, Abdelaouahhab H, Abbou W, Guerrouj I, Aichouni N, Kamaoui I, Skiker I: Reversible splenial lesion syndrome (RESLES): Two patients as study cases . Radiol Case Rep 2022, 17 (10):3635-3638. First MB: Diagnostic and statistical manual of mental disorders, 5th edition, and clinical utility . J Nerv Ment Dis 2013, 201 (9):727-729. Goto T, Ishitobi M, Takahashi T, Higashima M, Wada Y: Reversible Splenial Lesion Related to Acute Lithium Intoxication in a Bipolar Patient: A Case Report . J Clin Psychopharmacol 2016, 36 (5):528-529. Ryu HU, Chung JY, Shin BS, Kang HG: Lithium induced reversible Splenial lesion in neuroleptic malignant syndrome like symptoms: two case reports . BMC Neurol 2020, 20 (1):164. Gallucci M, Limbucci N, Paonessa A, Caranci F: Reversible focal splenial lesions . Neuroradiology 2007, 49 (7):541-544. Starkey J, Kobayashi N, Numaguchi Y, Moritani T: Cytotoxic Lesions of the Corpus Callosum That Show Restricted Diffusion: Mechanisms, Causes, and Manifestations . Radiographics 2017, 37 (2):562-576. Blaauw J, Meiners LC: The splenium of the corpus callosum: embryology, anatomy, function and imaging with pathophysiological hypothesis . Neuroradiology 2020, 62 (5):563-585. Domercq M, Matute C: Expression of glutamate transporters in the adult bovine corpus callosum . Brain Res Mol Brain Res 1999, 67 (2):296-302. Maher SZ, Schreibman IR: The Clinical Spectrum and Manifestations of Acute Liver Failure . Clin Liver Dis 2018, 22 (2):361-374. Dong V, Nanchal R, Karvellas CJ: Pathophysiology of Acute Liver Failure . Nutr Clin Pract 2020, 35 (1):24-29. Additional Declarations No competing interests reported. Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-4704503","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Case Report","associatedPublications":[],"authors":[{"id":333741250,"identity":"7db5f8eb-845d-499a-aff5-38a227be4f45","order_by":0,"name":"Xin Zhou","email":"","orcid":"","institution":"The Central Hospital of Shaoyang","correspondingAuthor":false,"prefix":"","firstName":"Xin","middleName":"","lastName":"Zhou","suffix":""},{"id":333741253,"identity":"63c4c79c-1b8a-47dc-9040-008354c7bab3","order_by":1,"name":"Chunhua Zhang","email":"","orcid":"","institution":"The Central Hospital of Shaoyang","correspondingAuthor":false,"prefix":"","firstName":"Chunhua","middleName":"","lastName":"Zhang","suffix":""},{"id":333741256,"identity":"9941bc30-f382-46d9-a283-d6ab3214d0c8","order_by":2,"name":"Liming Zhou","email":"","orcid":"","institution":"The Central Hospital of Shaoyang","correspondingAuthor":false,"prefix":"","firstName":"Liming","middleName":"","lastName":"Zhou","suffix":""},{"id":333741257,"identity":"232d45ab-c4dc-412f-b938-cf3fce49d98e","order_by":3,"name":"Leliang Zhou","email":"","orcid":"","institution":"The Central Hospital of Shaoyang","correspondingAuthor":false,"prefix":"","firstName":"Leliang","middleName":"","lastName":"Zhou","suffix":""},{"id":333741259,"identity":"28e14c63-d28a-4c61-a483-5761917a6c7c","order_by":4,"name":"Yongbiao Zou","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAAwElEQVRIiWNgGAWjYBAC+wOHDz5IqJDg4WdvIFbPwWPJBg/O2MhI9hwgVsvhM2aSD9vSbAxuJBCpg7ENaEvCmcM8kjMfb7zBUGMTTVALMw/YL4d5+KXTii0YjqXlNhDSwiYBs2V2jpkEY8Nhwlp45N+YSSS2HeYxuHmGSC0SDGdAWtJ4DG7wEKnFgAHsMBseyR6gXxKI8YsBw+GDD39USNjzsx/eeONDjQ1hLSjaJRJIUQ7RQqqOUTAKRsEoGBkAALEPRU9c5uA1AAAAAElFTkSuQmCC","orcid":"","institution":"The Central Hospital of Shaoyang","correspondingAuthor":true,"prefix":"","firstName":"Yongbiao","middleName":"","lastName":"Zou","suffix":""}],"badges":[],"createdAt":"2024-07-08 09:51:17","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-4704503/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-4704503/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":62151375,"identity":"57b51f5d-7f6e-4ae2-b52a-fac5fb71888b","added_by":"auto","created_at":"2024-08-09 20:42:43","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":2285989,"visible":true,"origin":"","legend":"\u003cp\u003eCase1 MRI on the day of admission showing a hyperintense signal on T2-weighted (A), FLAIR (B) and DWI (C) images of the SCC. hypointense was also found in the ADC images (d) in the same area. After treatment, DWI (E) and map (F) showed that the splenial lesion had almost disappeared in the SCC.\u003c/p\u003e","description":"","filename":"floatimage1.png","url":"https://assets-eu.researchsquare.com/files/rs-4704503/v1/dfdfb30db29a6b3bda644c76.png"},{"id":62151376,"identity":"c161892c-f73b-4414-9a07-e817a3156c97","added_by":"auto","created_at":"2024-08-09 20:42:43","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":2275463,"visible":true,"origin":"","legend":"\u003cp\u003eCase2 MRI on the day of admission showing a hyperintense signal on T2-weighted (A), FLAIR (B) and DWI (C) images of the SCC. hypointense was also found in the ADC images (D) in the same area. After treatment, DWI (E) and ADC map (F) showed the splenial lesion had almost disappeared in the SCC.\u003c/p\u003e","description":"","filename":"floatimage2.png","url":"https://assets-eu.researchsquare.com/files/rs-4704503/v1/79167171605d469151d7a02d.png"},{"id":73138883,"identity":"6d497fd5-baba-4ae1-880a-9acf6b04a503","added_by":"auto","created_at":"2025-01-07 06:31:59","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":8947097,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-4704503/v1/118b91ce-717c-4d67-976a-480ce98025bc.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Reversible splenial lesion syndrome induced by paracetamol and lithium: two case reports","fulltext":[{"header":"Introduction","content":"\u003cp\u003eReversible splenial lesion syndrome (RESLES) is a new clinical-radiological syndrome characterized by the presence of a reversible lesion in the splenium of the corpus callosum (SCC)[\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. This syndrome is still unclear. According to the current literature, RESLES can occur secondary to various etiologies. These include metabolic disorders, infections, epilepsy and antiepileptic drug withdrawal, autoimmune diseases, and toxic causes such as influenza[\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e], encephalitis meningococcal meningitis[\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e], hyponatremia[\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e], eclampsia[\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e], thrombotic thrombocytopenic purpura[\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e], oxcarbazepine withdrawal[\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e] and benzodiazepine poisoning[\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]. However, most recent studies have focused on the occurrence of RESLES in different diseases and have paid less attention to drug-associated cases. Here, we describe two rare cases of RESLES induced by paracetamol and lithium.\u003c/p\u003e"},{"header":"Case presentation","content":"\u003cp\u003e\u003cstrong\u003eCase 1\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eA 50-year-old male was admitted with behavioral abnormalities and disoriented speech that persisted for 2 days. He had a history of migraine without aura for 20\u0026thinsp;+\u0026thinsp;years and was irregularly taking paracetamol. Two days prior to admission, to relieve acute migraine attacks, he took 3.25 g of paracetamol sustained-release tablets in one day. On physical examination, the patient was afebrile with normal vital signs, including blood pressure, pulse, and respiration. The muscle strength of all four limbs was at level 5, and the muscle tension was moderate. No pathological reflexes or signs of meningeal irritation were noted. Laboratory investigations revealed normal total leukocyte and erythrocyte counts, mild hypohemoglobinemia (112.00 g/L), alanine aminotransferase 51.60 U/L, and serum creatine kinase 297.00 U/L, as shown in Table \u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e. Urine and stool tests, serum electrolytes, C-reactive protein, renal function, blood glucose level, folate level, vitamin B12 level, coagulation, and thyroid function were all normal. The cerebrospinal fluid (CSF) was clear in appearance, with 3/mm3 leukocytes, pressure, and protein and glucose levels (Table \u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003e). Chest and abdominal CT did not reveal any abnormal phenomena, and a contrast-enhanced transcranial Doppler (c-TCD) foaming experiment revealed a right-to-left shunt (RLS). Electroencephalography findings were normal and showed no seizure-related activity. Cranial magnetic resonance imaging (MRI) revealed a high-intensity lesion in the SCC on T2-weighted, fluid-attenuated inversion recovery (FLAIR), and diffusion-weighted imaging (DWI). This lesion had a low apparent diffusion coefficient (ADC) and no contrast enhancement (Fig. \u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e). After 8 days of fluid supplementation, liver protection and nutritional support symptomatic treatment, the patient recovered fully, and the lesion on follow-up MRI disappeared.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable 1\u0026nbsp;\u003c/strong\u003eAbnormal indicators of peripheral blood analysis.\u003c/p\u003e\n\u003cdiv\u003e\n \u003ctable id=\"Tab1\" border=\"1\"\u003e\u003c/table\u003e\n\u003c/div\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd width=\"40.84507042253521%\" valign=\"top\"\u003e\n \u003cp\u003eAbnormal index\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.387323943661972%\" valign=\"top\"\u003e\n \u003cp\u003eInitials\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.964788732394366%\" valign=\"top\"\u003e\n \u003cp\u003eCase 1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.5%\" valign=\"top\"\u003e\n \u003cp\u003eCase 2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"21.302816901408452%\" valign=\"top\"\u003e\n \u003cp\u003eNormal range\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"40.84507042253521%\" valign=\"top\"\u003e\n \u003cp\u003eWhite blood cell count (10^9/L)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.387323943661972%\" valign=\"top\"\u003e\n \u003cp\u003eWBC \u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.964788732394366%\" valign=\"top\"\u003e\n \u003cp\u003e8.55\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.5%\" valign=\"top\"\u003e\n \u003cp\u003e10.16\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"21.302816901408452%\" valign=\"top\"\u003e\n \u003cp\u003e3.5\u0026ndash;9.5\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"40.84507042253521%\" valign=\"top\"\u003e\n \u003cp\u003eHemoglobin(g/L)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.387323943661972%\" valign=\"top\"\u003e\n \u003cp\u003eHb \u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.964788732394366%\" valign=\"top\"\u003e\n \u003cp\u003e112.00\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.5%\" valign=\"top\"\u003e\n \u003cp\u003e133.00\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"21.302816901408452%\" valign=\"top\"\u003e\n \u003cp\u003e120-160(male)/\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"40.84507042253521%\" valign=\"top\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"10.387323943661972%\" valign=\"top\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"14.964788732394366%\" valign=\"top\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"12.5%\" valign=\"top\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"21.302816901408452%\" valign=\"top\"\u003e\n \u003cp\u003e110-150(female)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"40.84507042253521%\" valign=\"top\"\u003e\n \u003cp\u003eAspartate aminotransferase(U/L) \u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.387323943661972%\" valign=\"top\"\u003e\n \u003cp\u003eAST\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.964788732394366%\" valign=\"top\"\u003e\n \u003cp\u003e32.60\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.5%\" valign=\"top\"\u003e\n \u003cp\u003e53.80\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"21.302816901408452%\" valign=\"top\"\u003e\n \u003cp\u003e15\u0026ndash;40\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"40.84507042253521%\" valign=\"top\"\u003e\n \u003cp\u003eAlanine aminotransferase(U/L)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.387323943661972%\" valign=\"top\"\u003e\n \u003cp\u003eALT\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.964788732394366%\" valign=\"top\"\u003e\n \u003cp\u003e51.60\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.5%\" valign=\"top\"\u003e\n \u003cp\u003e38.40\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"21.302816901408452%\" valign=\"top\"\u003e\n \u003cp\u003e9\u0026ndash;50\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"40.84507042253521%\" valign=\"top\"\u003e\n \u003cp\u003eCreatine kinase (U/L)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.387323943661972%\" valign=\"top\"\u003e\n \u003cp\u003eCK\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.964788732394366%\" valign=\"top\"\u003e\n \u003cp\u003e297.00\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.5%\" valign=\"top\"\u003e\n \u003cp\u003e1106.00\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"21.302816901408452%\" valign=\"top\"\u003e\n \u003cp\u003e6\u0026ndash;80\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cdiv\u003e\n \u003cp\u003e\u003cstrong\u003eTable 2\u0026nbsp;\u003c/strong\u003eIndicators of cerebrospinal fluid analysis.\u003c/p\u003e\n \u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" width=\"100%\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd width=\"41.83673469387755%\" valign=\"top\"\u003e\n \u003cp\u003eIndex \u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.387755102040817%\" valign=\"top\"\u003e\n \u003cp\u003eCase 1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.367346938775512%\" valign=\"top\"\u003e\n \u003cp\u003eCase 2 \u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.408163265306122%\" valign=\"top\"\u003e\n \u003cp\u003eNormal range\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"41.83673469387755%\" valign=\"top\"\u003e\n \u003cp\u003ePressure(mmH\u003csub\u003e2\u003c/sub\u003e0) \u0026nbsp;\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.387755102040817%\" valign=\"top\"\u003e\n \u003cp\u003e150 \u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.367346938775512%\" valign=\"top\"\u003e\n \u003cp\u003e160\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.408163265306122%\" valign=\"top\"\u003e\n \u003cp\u003e80-180\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"41.83673469387755%\" valign=\"top\"\u003e\n \u003cp\u003eWhite blood cell count (/mm^3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.387755102040817%\" valign=\"top\"\u003e\n \u003cp\u003e3.00\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.367346938775512%\" valign=\"top\"\u003e\n \u003cp\u003e2.00\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.408163265306122%\" valign=\"top\"\u003e\n \u003cp\u003e0-5\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"41.83673469387755%\" valign=\"top\"\u003e\n \u003cp\u003eProtein(mg/L)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.387755102040817%\" valign=\"top\"\u003e\n \u003cp\u003e318.40\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.367346938775512%\" valign=\"top\"\u003e\n \u003cp\u003e402.10\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.408163265306122%\" valign=\"top\"\u003e\n \u003cp\u003e＜500\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"41.83673469387755%\" valign=\"top\"\u003e\n \u003cp\u003eGlucose level(mmol/L)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.387755102040817%\" valign=\"top\"\u003e\n \u003cp\u003e4.38* \u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.367346938775512%\" valign=\"top\"\u003e\n \u003cp\u003e3.39*\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.408163265306122%\" valign=\"top\"\u003e\n \u003cp\u003e2.4-4.4\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"41.83673469387755%\" valign=\"top\"\u003e\n \u003cp\u003eChloride level(mmol/L)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.387755102040817%\" valign=\"top\"\u003e\n \u003cp\u003e127.00\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.367346938775512%\" valign=\"top\"\u003e\n \u003cp\u003e128.20\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.408163265306122%\" valign=\"top\"\u003e\n \u003cp\u003e120-130\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003c/table\u003e\n \u003cp\u003e*Case1 synchronized blood glucose level:8.00mmol/L;\u0026nbsp;\u003c/p\u003e\n \u003cp\u003eCase2 synchronized blood glucose level:4.90mmol/L.\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003eTable 3\u003c/strong\u003e DSM-V Diagnostic Criteria for NMS[17]\u0026nbsp;\u003c/p\u003e\n \u003ctable style=\"width: 100%;\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 100.0000%;\"\u003e\n \u003cp\u003eA. Development of severe muscle rigidity and elevated temperature associated with the use of neuroleptic medication\u003c/p\u003e\n \u003cp\u003eB. Two (or more) of the following\u003c/p\u003e\n \u003cp\u003e1) Diaphoresis\u003c/p\u003e\n \u003cp\u003e2) Dysphagia\u003c/p\u003e\n \u003cp\u003e3) Tremor\u003c/p\u003e\n \u003cp\u003e4) Incontinence\u003c/p\u003e\n \u003cp\u003e6) Mutism\u003c/p\u003e\n \u003cp\u003e7) Tachycardia\u003c/p\u003e\n \u003cp\u003e8) Elevated or labile blood pressure\u003c/p\u003e\n \u003cp\u003e9) Leukocytosis\u003c/p\u003e\n \u003cp\u003e10) Laboratory evidence of muscle injury (eg, elevated creatine phosphokinase)\u003c/p\u003e\n \u003cp\u003eC. The symptoms in criteria A and B are not due to another substance or a neurological or other general medical condition\u003c/p\u003eD. The symptoms in criteria A and B are not better accounted for by a mental disorder\u003cbr\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003c/table\u003e\n\u003c/div\u003e\n\u003cdiv\u003e\u003cbr\u003e\u003c/div\u003e\n\u003cp\u003e\u003cstrong\u003eCase 2\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eA 35-year-old woman with an 11-year history of bipolar disorder (BD) was referred to our hospital with an unresponsive response and a refusal to consume food. She had been taking lithium (1000 mg/day) and quetiapine (250 mg/day) for 3 years. Fifteen days before admission, the lithium and quetiapine dosages were increased to 1500 mg/day and 500 mg/day, respectively, owing to her psychotic attack. On admission, the patient was conscious and had a normal urine output. Her vital signs were as follows: body temperature, 38.6\u0026deg;C; heart rate, 130 beats/min; respiration, 22 beats/min; and blood pressure, 140/86 mmHg. Physical examination showed generalized tremor, rigidity, dysarthria, hyperactive bilateral knee and tendon reflexes, and negative pathological signs and meningeal irritation. The blood test results were as follows: white blood cell count, 10.16 10^9/L; aspartate aminotransferase, 53.80 U/L; and serum creatine kinase, 1106.00 U/L. Urine testing, renal function, serum electrolytes, C-reactive protein, blood glucose level, coagulation, and thyroid functions revealed no abnormalities. Lumbar puncture revealed clear cerebrospinal fluid (CSF) with no evidence of infection (Table \u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003e). The patient met the diagnostic criteria for neuroleptic malignant syndrome (NMS)[\u003cspan class=\"CitationRef\"\u003e9\u003c/span\u003e] due to elevated WBC and CPK levels, high fever, hypertension, tachycardia, tachypnea, and rigidity. Moreover, brain MRI revealed an oval-shaped hyperintense lesion on DWI with hypointensity in the ADC maps, localized to the SCC (Fig. \u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003e). Two weeks after the discontinuation of lithium and quetiapine, these abnormalities completely disappeared on the follow-up MRI.\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eTo 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[\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e, \u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]. 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[\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]. 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[\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]. 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.\u003c/p\u003e \u003cp\u003eSeveral 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[\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]. Many RESLES cases support the idea that cytotoxic edema plays a significant role in this disease[\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e, \u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e, \u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]. 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[\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]. 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[\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]. 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.\u003c/p\u003e \u003cp\u003eThe corpus callosum, also called the neocortical commissure, is the largest fiber bundle connecting the contralateral hemispheres of the cerebrum[\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]. 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[\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]. 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[\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]. 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[\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]. 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[\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]. Carlos et al. reported that the susceptibility of SCC to edema is due to a large number of glutamate receptors and high enzymatic activity[\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]. Despite these theories, a common pathophysiological mechanism explaining the splenial predilection in different disease processes remains to be elucidated.\u003c/p\u003e \u003cp\u003eExcessive paracetamol usually induces liver injury, and ingestion of greater than 10 g/day or sometimes as low as 3\u0026ndash;4 g/day can result in hepatotoxicity[\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]. The most serious complication of paracetamol toxicity is cerebral edema[\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]. There is evidence of an association between elevated serum ammonia levels and the pathogenesis of cerebral edema and hepatic encephalopathy[\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]. The toxic effects of ammonia cause a cytokine surge and increase glutamate levels with excessive activation of N-methyl-D-aspartate receptors[\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e]. 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.\u003c/p\u003e \u003cp\u003eLithium has a narrow therapeutic range, which may lead to neurological toxicity[\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]. Previous studies have suggested that the neurotoxic effects of lithium are associated with NMS[\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]. Han et al. reported two patients with RESLES with lithium-associated neurotoxicity who were diagnosed with schizophrenia or BD[\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]. 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[\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e, \u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]. 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.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eIn summary, for the first time, we describe two patients with RESLES caused by lithium and paracetamol. Although the specific mechanism of RESLES remains controversial, when neuropsychiatric symptoms are detected in patients with a history of excess medication, MRI should be performed to assess and follow-up any SCC lesions. However, given that the clinical manifestations of this syndrome are diverse and nonspecific, attention must be given to this disease at an early stage.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cp\u003eRESLES: reversible splenial lesion syndrome; SCC: splenium of the corpus callosum; BD: bipolar disorder; NMS: neuroleptic malignant syndrome; MRI: magnetic resonance imaging; FLAIR: fluid-attenuated inversion recovery; DWI: diffusion-weighted imaging; ADC: apparent diffusion coefficient; CSF: cerebrospinal fluid.\u003c/p\u003e\n"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAcknowledgments\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eXZ and YBZ participated in the design of this research. CHZ, LMZ, and LLZ collected and analyzed the raw clinical data. XZ and YBZ carried out the computational studies and wrote the manuscript. All authors contributed to the manuscript and approved the submitted version.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding statement\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data and materials\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll the data and material supporting our findings are contained within the manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWritten informed consent was obtained from the patients for the publication of potentially identifiable images or data included in this article. The study protocol was approved by the Ethics Committee and Expert Committee of the Central Hospital of Shaoyang. All patients provided written informed consent to participate in the study.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWritten informed consent was obtained from the patient for publication of this case report and any accompanying images.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare that they have no competing interests.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor details\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003csup\u003e1\u0026nbsp;\u003c/sup\u003eDepartment of Neurology, The Central Hospital of Shaoyang, Shaoyang, Hunan, China.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eGarcia-Monco JC, Cortina IE, Ferreira E, Mart\u0026iacute;nez A, Ruiz L, Cabrera A, Beldarrain MG: \u003cstrong\u003eReversible splenial lesion syndrome (RESLES): what\u0026apos;s in a 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report and literature review\u003c/strong\u003e. \u003cem\u003eJ Int Med Res \u003c/em\u003e2018, \u003cstrong\u003e46\u003c/strong\u003e(3):1277-1281.\u003c/li\u003e\n\u003cli\u003eNasri S, Abdelaouahhab H, Abbou W, Guerrouj I, Aichouni N, Kamaoui I, Skiker I: \u003cstrong\u003eReversible splenial lesion syndrome (RESLES): Two patients as study cases\u003c/strong\u003e. \u003cem\u003eRadiol Case Rep \u003c/em\u003e2022, \u003cstrong\u003e17\u003c/strong\u003e(10):3635-3638.\u003c/li\u003e\n\u003cli\u003eFirst MB: \u003cstrong\u003eDiagnostic and statistical manual of mental disorders, 5th edition, and clinical utility\u003c/strong\u003e. \u003cem\u003eJ Nerv Ment Dis \u003c/em\u003e2013, \u003cstrong\u003e201\u003c/strong\u003e(9):727-729.\u003c/li\u003e\n\u003cli\u003eGoto T, Ishitobi M, Takahashi T, Higashima M, Wada Y: \u003cstrong\u003eReversible Splenial Lesion Related to Acute Lithium Intoxication in a Bipolar Patient: A Case Report\u003c/strong\u003e. \u003cem\u003eJ Clin Psychopharmacol \u003c/em\u003e2016, \u003cstrong\u003e36\u003c/strong\u003e(5):528-529.\u003c/li\u003e\n\u003cli\u003eRyu HU, Chung JY, Shin BS, Kang HG: \u003cstrong\u003eLithium induced reversible Splenial lesion in neuroleptic malignant syndrome like symptoms: two case reports\u003c/strong\u003e. \u003cem\u003eBMC Neurol \u003c/em\u003e2020, \u003cstrong\u003e20\u003c/strong\u003e(1):164.\u003c/li\u003e\n\u003cli\u003eGallucci M, Limbucci N, Paonessa A, Caranci F: \u003cstrong\u003eReversible focal splenial lesions\u003c/strong\u003e. \u003cem\u003eNeuroradiology \u003c/em\u003e2007, \u003cstrong\u003e49\u003c/strong\u003e(7):541-544.\u003c/li\u003e\n\u003cli\u003eStarkey J, Kobayashi N, Numaguchi Y, Moritani T: \u003cstrong\u003eCytotoxic Lesions of the Corpus Callosum That Show Restricted Diffusion: Mechanisms, Causes, and Manifestations\u003c/strong\u003e. \u003cem\u003eRadiographics \u003c/em\u003e2017, \u003cstrong\u003e37\u003c/strong\u003e(2):562-576.\u003c/li\u003e\n\u003cli\u003eBlaauw J, Meiners LC: \u003cstrong\u003eThe splenium of the corpus callosum: embryology, anatomy, function and imaging with pathophysiological hypothesis\u003c/strong\u003e. \u003cem\u003eNeuroradiology \u003c/em\u003e2020, \u003cstrong\u003e62\u003c/strong\u003e(5):563-585.\u003c/li\u003e\n\u003cli\u003eDomercq M, Matute C: \u003cstrong\u003eExpression of glutamate transporters in the adult bovine corpus callosum\u003c/strong\u003e. \u003cem\u003eBrain Res Mol Brain Res \u003c/em\u003e1999, \u003cstrong\u003e67\u003c/strong\u003e(2):296-302.\u003c/li\u003e\n\u003cli\u003eMaher SZ, Schreibman IR: \u003cstrong\u003eThe Clinical Spectrum and Manifestations of Acute Liver Failure\u003c/strong\u003e. \u003cem\u003eClin Liver Dis \u003c/em\u003e2018, \u003cstrong\u003e22\u003c/strong\u003e(2):361-374.\u003c/li\u003e\n\u003cli\u003eDong V, Nanchal R, Karvellas CJ: \u003cstrong\u003ePathophysiology of Acute Liver Failure\u003c/strong\u003e. \u003cem\u003eNutr Clin Pract \u003c/em\u003e2020, \u003cstrong\u003e35\u003c/strong\u003e(1):24-29.\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"reversible splenial lesion syndrome, paracetamol, lithium, cytotoxic edema, neurotoxicity","lastPublishedDoi":"10.21203/rs.3.rs-4704503/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-4704503/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eBackground\u003c/strong\u003e: Reversible splenial lesion syndrome (RESLES) is a rare neurological syndrome characterized by a reversible lesion in the splenium of the corpus\u003c/p\u003e\n\u003cp\u003ecallosum (SCC). Various etiologies, such as infection, high-altitude cerebral edema, seizures, antiepileptic drug (AED) withdrawal, and metabolic abnormalities, are involved in the development of RESLES. However, few studies have reported the occurrence of this disorder associated with medications, particularly paracetamol, which has not yet been documented.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCase presentation\u003c/strong\u003e: A 50-year-old man with neuropsychiatric symptoms who was receiving increased doses of paracetamol was referred to our hospital. The patient fully recovered 8 days after treatment. The second case involved a 35-year-old female who received 1500 mg/day lithium and 500 mg/day quetiapine for bipolar disorder (BD). She experienced generalized tremor, rigidity, dysarthria, high fever, hypertension, tachycardia, and tachypnea. Symptoms and brain lesions fully resolved two weeks after discontinuation of lithium. Brain magnetic resonance imaging (MRI) in both patients typically demonstrated a reversible lesion with transiently reduced diffusion in the SCC.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusion\u003c/strong\u003e: RESLES is a rare finding that is usually incidentally detected. Therefore, MRI should be performed to evaluate SCC in patients taking excessive medication who present with neuropsychiatric symptoms.\u003c/p\u003e","manuscriptTitle":"Reversible splenial lesion syndrome induced by paracetamol and lithium: two case reports","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-08-09 20:42:38","doi":"10.21203/rs.3.rs-4704503/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"6e6604d8-ff56-4987-8e3e-13b5bb9db4c0","owner":[],"postedDate":"August 9th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2025-01-07T06:23:46+00:00","versionOfRecord":[],"versionCreatedAt":"2024-08-09 20:42:38","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-4704503","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-4704503","identity":"rs-4704503","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}