Euglycemic diabetic ketoacidosis associated metabolic encephalopathy caused by dapagliflozin：a rare case report

Euglycemic diabetic ketoacidosis associated metabolic encephalopathy caused by dapagliflozin：a rare case report | 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 Euglycemic diabetic ketoacidosis associated metabolic encephalopathy caused by dapagliflozin：a rare case report Lulu Chu, Zhenhua Xi, Runzhi Ma, Weiliang Shi, Guoshen Yu This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-4723882/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 14 Jan, 2025 Read the published version in BMC Neurology → Version 1 posted 14 You are reading this latest preprint version Abstract Background Sodium–glucose cotransporter-2(SGLT-2) inhibitors are a newer class of anti-diabetic drugs with the incresed risk of euglycemic diabetic ketoacidosis(EuDKA). Encephalopathy is a rare but life-threatening event of EuDKA. Due to paradoxically normal or slightly elevated serum glucose levels, it's easy to be mimicked by cerebral infarction, structural brain damage, thus leading to delayed diagnosis and causing seriously irreversible brain injury. Case presentation: We report a severe EuDKA with metabolic encephalopathy secondary to dapagliflozin in a type 2 diabetes mellitus(T2DM) patient. A 72-year-old female presented with complaining of 70 minutes of coma. Laboratory evaluation revealed a severe metabolic acidosis with an elevated anion gap, and ketones were elevated in blood and positive in urine. The patient eventually was diagnosed with metabolic encephalopathy associated with EuDKA and managed accordingly. Unfortunately, owing to the irreversible brain damage, the patient's state of consciousness is not fully recovered. Conclusions Metabolic encephalopathy is a rare but life-threatening complication of EuDKA caused by SGLT-2 inhibitors, the imaging features are similar to those of other metabolic encephalopathy such as poisoning and hypoxia. The precise pathogenesis of encephalopathy in EuDKA remains poorly understood, potentially resulting from the toxic consequences of electrolyte disturbances, ketosis, and acidosis. For unconscious patients with taking SGLT-2 inhibitors, commonly testing the level of ketones and magnetic resonance imaging of the brain are essential. dapagliflozin euglycemic diabetic ketoacidosis metabolic encephalopathy sodium–glucose cotransporter-2 inhibitors case report Figures Figure 1 Introduction SGLT-2 inhibitors are a new class of oral hypoglycemic drugs, one of the most widely used medications is dapagliflozin. EuDKA, a serious and potentially life-threatening acute complication of diabetes mellitus, with a mortality rate as high as 1. 5% [ 1 ] , occurs with normal or mildly elevated blood glucose(< 14 mmol/L), and is commonly defined as the presence of ketosis and metabolic acidosis [ 2 ] . An increasing number of reports have demonstrated the association between SGLT-2 inhibitors and EuDKA [ 3 , 4 ] . The possible mechanisms by which SGLT-2 inhibitors cause EuDKA are intricate and uncertain. SGLT-2 inhibitors decrease serum glucose primarily by promoting excretion and inhibiting glucose reabsorption in urine. The loss of urinary glucose results in a state of carbohydrate starvation and volume depletion, increasing the glucagon/insulin ratio and leading to severe dehydration and ketosis [ 5 ] . Decreasing insulin release combined with high levels of competitive hormones including glucagon, cortisol and catecholamines accelerates the conversion of fatty acids to ketone bodies [ 1 ] . SGLT-2 inhibitors also reduce ketone clearance [ 6 ] . Eventually, there will be a buildup of ketosis in the presence of lower glucose levels. EuDKA is not always observed in patients taking SGLT-2 inhibitors; possible precipitants and risk factors include underlying autoimmune diabetes in adults (LADA), surgery, low carbohydrate diet, insulin withdrawal or dose reduction, dehydration, excessive exercise, heavy alcohol intake, etc [ 7 , 8 ] . Currently, there are few reports on EuDKA-associated metabolic encephalopathy, and its imaging characteristics remain unclear. In this report, our objective was to present a case of a patient with T2DM who was admitted to the emergency department with complaints of coma. Through analysis of clinical symptoms, imaging features, and disease triggers, the patient was ultimately diagnosed with EuDKA-related metabolic encephalopathy induced by SGLT-2 inhibitors. Case presentation A 72-year-old female with T2DM presented to our Emergency Department complaining of 70 minutes of coma on May 17, 2024. Living alone, the patient and her family members typically communicated via telephone. They mentioned that from the last time performing normally to now had already lasted for 10 hours. In the past week, she hadn't complained to her family about the following conditions, including fever, nausea, vomiting, abdominal pain, diarrhea, reduced appetite, substance abuse, or alcohol consumption. She has had T2DM for the past 10 years, previously treated with a combination of Dapagliflozin 10mg once daily and Acarbose 100mg twice daily, with subcutaneous insulin injection twice daily being added to the regimen 10 days ago. She adhered to a regular insulin injection schedule and had no history of liver disease. Vital signs at presentation were: temperature 36. 6°C, pulse rate 102beats/min, respiratory rate 18breaths/min, blood pressure 175/86mmHg. Physical examination with no obvious Kussmaul breathing and dehydration. The pupil diameter and light reflexes were in the normal range. Besides hypermyotonia of extremities, no other focal neurologic deficits were observed. Laboratory and imaging assessments Blood test results indicated a potential concurrent infection, while arterial blood gases revealed severe metabolic acidosis with an elevated anion gap (pH 7. 243, bicarbonates 12. 7mmol/L, anion gap 22. 6mmol/L). Elevated levels of β-hydroxybutyrate at 8. 474mmol/L and positive ketonuria were also observed. Detailed results are shown in Table 1 . The findings from the cranial magnetic resonance imaging (MRI) are depicted in Fig. 1 : Panels a and b show low signal changes in the bilateral basal ganglia and hippocampal regions on ADC (Apparent Diffusion Coefficient) images (black arrows); Panels c and d show high signal changes on DWI (Diffusion Weighted Imaging) (white arrows); Panels e and f show slightly high signal changes on FLAIR (Fluid-Attenuated Inversion Recovery) images (white arrows). Table 1 Inpatient laboratory values Laboratory aassessments Result Referrnce Serum glucose, (mmol/L) 13. 3 3. 3–6. 1 White blood cell, (*10^9/L) 17. 4 17. 4 Hemoglobin, (g/L) 160 115–150 Hs-CRP, (mg/L) 52. 0 0–8 D-dimer, (ng/mL) 3291 0-500 Uric acid, (µmol/L) 739 150–350 Urea nitrogen, (mmol/L) 16. 0 1. 7–8. 3 Creatinine, (µmol/L) 110 40–110 Serum potassium, (mmol/L) 3. 95 3. 5–5. 3 β-hydroxybutyrate, (µmol/L) 8474 30–300 Urine ketones ++ - Lactic acid, (mmol/L) 1. 4 1. 0–2. 5 HbA1c, (%) 12 4–6 PH 7. 243 7. 35−7. 45 Bicarbonates, (mmol/L) 12. 7 22–27 Anion gap, (mmol/L) 22. 6 8–16 Osmotic pressure, (osmo/kg) 283 280–320 Abbreviation: HbA1c:glycosylated hemoglobin. Hs-CRP: high-sensitivity C-reactive protein. Treatment At our institution, due to the inability to completely rule out cerebral infarction, we administered intravenous thrombolytic treatment using a 36mg dose of alteplase. However, there was no improvement in symptoms. The patient was subsequently transferred to a tertiary hospital where they were diagnosed with metabolic encephalopathy associated with EuDKA. She was promptly admitted to the intensive care unit (ICU) , with a low-dose insulin infusion to manage hyperglycemia, glucose supplementation to prevent hypoglycemia, and administration of mannitol to reduce intracranial pressure. Given the elevated inflammatory markers and the initial uncertain infection, empirical antimicrobial therapy with cefoperazone/sulbactam was used. Following this treatment, serial blood gas analyses showed gradual resolution of her ketoacidosis. Unfortunately, owing to the irreversible brain damage, the patient's state of consciousness is not fully recovered. Discussion We report a case of altered mental status in a patient with type 2 diabetes treated with dapagliflozin. Only several reports of disturbance of consciousness with dapagliflozin have been documented and triggered in different scenarios [9-11] . The patient's serum β-hydroxy butyrate was 8474 μmol/L, nearly 30 times higher than normal. Blood sugar was found to be mildly elevated (12. 8mmol/l) and PH was 7. 243. Combinating imaging manifestations and excluding various brian diseases including poisoning, seizures, cerebrovascular accident, central infection. A conclusive diagnosis of EuDKA-associated metabolic encephalopathy was established. Metabolic encephalopathy refers to diffuse or focal brain dysfunction which is attributed to impaired brain metabolism in the absence of primary structural dysfunction [12] . The augmented β-hydroxybutyric acid and acidemia play key roles in the upregulation of vascular endothelial growth factor expression and indirectly increasing cerebral vascular permeability [13] , resulting in brain edema and dysfunction. The limited clinical experience and ambiguous MRI features led us to a misdiagnosis of cerebral infarction, resulting in unnecessary thrombolysis treatment. Despite the absence of bleeding and other complications, delayed diagnosis and treatment imposed a significant economic burden on the patient. Symptoms of EuDKA, similar to Diabetic Ketoacidosis(DKA), usually include nausea, vomiting, abdominal pain, polyuria, polydipsia, weight loss, dehydration, weakness, fatigue, tachycardia, dyspnea and Kussmaul breathing. Mental states range from awakeness to deep lethargy or coma [14-16] . The reported patient had presented with coma for more than 10 hours and displayed an uncommon MRI result indicative of metabolic encephalopathy（figure 1）. Identical with poisoning and hypoxia metabolic encephalopathy, it involves multiple sites, including bilateral basal ganglia, cortex, and periventricular white matter (PVWM) [17] . Treatment for EuDKA parallels that of DKA except that the risk of relapse into DKA is high in the setting of SGLT-2 inhibitor use [15] . Infused insulin is a major therapeutic tool for EuDKA, other management measures covering aggressive rehydration, glucose supplementation, and correction of electrolyte imbalance, as well as control of precipitating factors [18] . Severe acidosis may require bicarbonate therapy [14] . Resolution of EuDKA is defined as pH >7. 3, bicarbonate >15. 0mmol/L, and serum ketones <0. 6mmol/L. In a retrospective study, EuDKA patients experienced a 5. 9-hour reduction in insulin infusion time but had more than three times the frequency of hypoglycemia compared to those with DKA [19] . Hence, When the blood gluose level falls below 250 mg/dl, the insulin infusion rate should be reduced and dextrose can be added to the intravenous fluids to avoid hypoglycemia [14] . Other studies [20] have also indicated that in the treatment of EuDKA, approximately 61. 5% of patients required intensive care, with some needing organ protection treatment such as invasive mechanical ventilation (13%), vasopressors (6. 5%), or renal replacement therapy (5. 9%). The overall mortality rate was 2. 4%. The diagnostic dilemma of EuDKA portends worse outcomes compared with classic DKA. Conclusions Metabolic encephalopathy is a rare but life-threatening complication of EuDKA caused by SGLT-2 inhibitors, the imaging features are similar to those of other metabolic encephalopathy such as poisoning and hypoxia. The precise pathogenesis of encephalopathy in EuDKA remains poorly understood, potentially resulting from the toxic consequences of electrolyte disturbances, ketosis, and acidosis. For unconscious patients with taking SGLT-2 inhibitors, commonly testing the level of ketones and magnetic resonance imaging of the brain are essential. Abbreviations EuDKA Euglycemic Diabetic Ketoacidosis SGLT-2 Sodium-Glucose Cotransporter-2 T2DM Type 2 Diabetes Mellitus DKA Diabetic Ketoacidosis LADA Latent Autoimmune Diabetes In Adults PVWM Periventricular White Matter MRI Magnetic Resonance Imaging HS-CRP High-Sensitivity C-Reactive Protein HBA1C Hemoglobin A1c Declarations Acknowledgements We would like to thank Dr. Huang for providing some information. Authors’ contributions L. L. C. , Z. H. X. , G. S. Y. , R. Z. M. , W. L. S. collected data, searched the literature, and wrote case reports. L. L. C. , Z. H. X. , G. S. Y. were in charge of conducting the final review and making modifications to the manuscript. Funding None. Availability of data and materials All data analysed during this study are included in this manuscript. Ethics approval and consent to participate Not applicable. Consent for publication The patient gave written consent for their personal or clinical details along with any identifying images to be published in this study. Competing interests All the authors declare that they have no competing interests. References Sitina M, Lukes M, Sramek V. Empagliflozin-associated postoperative mixed metabolic acidosis. Case report and review of pathogenesis. BMC Endocrine Disorders. 2023; DOI: 10. 1186/s12902-023-01339-w. Clark A, Mohammed AS, Raut A, et al. Prevalence and Clinical Characteristics of Adults Presenting With Sodium-Glucose Cotransporter-2 Inhibitor-Associated Diabetic Ketoacidosis at a Canadian Academic Tertiary Care Hospital. Canadian Journal of Diabetes. 2021; DOI: 10. 1016/j. jcjd. 2020. 08. 100. Sampani E, Sarafidis P, Dimitriadis C, et al. Severe euglycemic diabetic ketoacidosis of multifactorial etiology in a type 2 diabetic patient treated with empagliflozin: case report and literature review. BMC Nephrology. 2020; DOI: 10. 1186/s12882-020-01930-6. Secinaro E, Ciavarella S, Rizzo G, et al. SGLT2-inhibitors and euglycemic diabetic ketoacidosis in COVID-19 pandemic era: a case report. Acta Diabetol. 2022; 1391-1394. DOI: 10. 1007/s00592-022-01909-9. Altowayan WM. Empagliflozin induced euglycemic diabetic ketoacidosis. A case reports. Annals of Medicine & Surgery. 2022; DOI: 10. 1016/j. amsu. 2022. 104879. Long B, Lentz S, Koyfman A, et al. Euglycemic diabetic ketoacidosis: Etiologies, evaluation, and management. The American Journal of Emergency Medicine. 2021; DOI: 10. 1016/j. ajem. 2021. 02. 015. Barski L, Eshkoli T, Brandstaetter E, et al. Euglycemic diabetic ketoacidosis. European Journal of Internal Medicine. 2019; DOI: 10. 1016/j. ejim. 2019. 03. 014. Sethi S. Euglycemic Diabetic Ketoacidosis (EDKA) in a Patient Receiving Dapagliflozin. Acta Endocrinologica (Bucharest). 2021; DOI: 10. 4183/aeb. 2021. 266. Karakaya Z, Topal FE, Firdes Topal UP, et al. Euglisemic diabetic ketoacidotic coma caused by dapagliflozin. American Journal of Emergency Medicine. 2018; DOI: 10. 1016/j. ajem. 2018. 08. 054. Banakh I, Kung R, Gupta S, et al. Euglycemic diabetic ketoacidosis in association with dapagliflozin use after gastric sleeve surgery in a patient with type II diabetes mellitus. Clinical Case Reports. 2019; DOI: 10. 1002/ ccr3. 2147. Iqbal I, Hamid M, Khan MAA, et al. Dapagliflozin-induced Late-onset Euglycemic Diabetic Ketoacidosis. Cureus. 2019; DOI: 10. 7759/cureus. 6089. Tomkins M, McCormack R, O Connell K, et al. Metabolic encephalopathy secondary to diabetic ketoacidosis: a case report. BMC Endocrine Disorders. 2019; DOI: 10. 1186/s 12902-019-0398-8. Jones R, Redler K, Witherick J, et al. Posterior reversible encephalopathy syndrome complicating diabetic ketoacidosis; an important treatable complication. Pediatric Diabetes. 2017; DOI: 10. 1111/pedi. 12362. Bonora BM, Avogaro A, Fadini GP. Euglycemic Ketoacidosis. Current Diabetes Reports. 2020; DOI: 10. 1007/s11892-020-01307-x. Chow E, Clement S, Garg R. Euglycemic diabetic ketoacidosis in the era of SGLT-2 inhibitors. BMJ Open Diabetes Research & Care. 2023; DOI: 10. 1136/ bmjdrc-2023-003666. Dutta S, Kumar T, Singh S, et al. Euglycemic diabetic ketoacidosis associated with SGLT2 inhibitors: A systematic review and quantitative analysis. Journal of Family Medicine and Primary Care. 2022; DOI: 10. 4103/jfmpc. jfmpc_644_21. Koksel Y, McKinney AM. Potentially Reversible and Recognizable Acute Encephalopathic Syndromes: Disease Categorization and MRI Appearances. AJNR Am J Neuroradiol. 2020; DOI: 10. 3174/ajnr. A6634. Jarvis PRE. Euglycemic diabetic ketoacidosis: a potential pitfall for the emergency physician. Clinical and Experimental Emergency Medicine. 2023; DOI: 10. 15441/ ceem. 22. 410. Sell J, Haas NL, Korley FK, et al. Euglycemic Diabetic Ketoacidosis_ Experience with 44 Patients and Comparison to Hyperglycemic Diabetic Ketoacidosis. Western Journal of Emergency Medicine. 2023; DOI: 10. 5811/westjem. 60361. Juneja D, Nasa P, Jain R, et al. Sodium-glucose Cotransporter-2 Inhibitors induced euglycemic diabetic ketoacidosis: A meta summary of case reports. World Journal of Diabetes. 2023; DOI: 10. 4239/wjd. v14. i8. 1314. Additional Declarations No competing interests reported. Cite Share Download PDF Status: Published Journal Publication published 14 Jan, 2025 Read the published version in BMC Neurology → Version 1 posted Editorial decision: Revision requested 01 Oct, 2024 Reviews received at journal 30 Sep, 2024 Reviewers agreed at journal 30 Sep, 2024 Reviewers agreed at journal 30 Sep, 2024 Reviewers agreed at journal 30 Sep, 2024 Reviewers agreed at journal 01 Aug, 2024 Reviewers agreed at journal 31 Jul, 2024 Reviews received at journal 29 Jul, 2024 Reviewers agreed at journal 17 Jul, 2024 Reviewers invited by journal 17 Jul, 2024 Editor invited by journal 15 Jul, 2024 Editor assigned by journal 11 Jul, 2024 Submission checks completed at journal 11 Jul, 2024 First submitted to journal 10 Jul, 2024 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. 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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-4723882","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Case Report","associatedPublications":[],"authors":[{"id":335500418,"identity":"569b7361-a12b-44be-8bd5-210c0c01b4a3","order_by":0,"name":"Lulu Chu","email":"","orcid":"","institution":"Haiyan People's Hospital","correspondingAuthor":false,"prefix":"","firstName":"Lulu","middleName":"","lastName":"Chu","suffix":""},{"id":335500420,"identity":"2081a122-2a5a-4feb-900a-2f5191c3e3b4","order_by":1,"name":"Zhenhua Xi","email":"","orcid":"","institution":"Haiyan People's Hospital","correspondingAuthor":false,"prefix":"","firstName":"Zhenhua","middleName":"","lastName":"Xi","suffix":""},{"id":335500421,"identity":"7e728635-d920-448f-93f1-a974c445a1ed","order_by":2,"name":"Runzhi Ma","email":"","orcid":"","institution":"Haiyan People's Hospital","correspondingAuthor":false,"prefix":"","firstName":"Runzhi","middleName":"","lastName":"Ma","suffix":""},{"id":335500422,"identity":"a6dc397e-d6ad-4717-9ef3-d5971f900566","order_by":3,"name":"Weiliang Shi","email":"","orcid":"","institution":"Haiyan People's Hospital","correspondingAuthor":false,"prefix":"","firstName":"Weiliang","middleName":"","lastName":"Shi","suffix":""},{"id":335500423,"identity":"cc74f4ad-bab7-4399-a94e-57e87b498d7c","order_by":4,"name":"Guoshen Yu","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAAtklEQVRIie3PoQ7CMBSF4bMs6UwzDWbbI1yyFypqZvjJJSRVBN4AJG+Abg2YLbNLMEuwCOREBTNo7hwJ/VyT8ye3gOf9sEREWzNjb0B5LK9qXrI+LsqMt6buPIQv5wqNEhirCyPpnwSraaPRmmDX3DlJA9h6SoK9CgPNSm4DjKNChJKYSVcTjCAlBDdZ9pLQ6nylpVCW9Ze4mw6rXJKmp4cdxoqRZL2Kxs/DfN9P0gNv53me98/eSbw+peb3DhgAAAAASUVORK5CYII=","orcid":"","institution":"Haiyan People's Hospital","correspondingAuthor":true,"prefix":"","firstName":"Guoshen","middleName":"","lastName":"Yu","suffix":""}],"badges":[],"createdAt":"2024-07-11 11:44:20","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-4723882/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-4723882/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1186/s12883-025-04027-5","type":"published","date":"2025-01-14T15:57:12+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":62218272,"identity":"a22df8ff-8835-4e8e-8517-7d178cdc82f7","added_by":"auto","created_at":"2024-08-11 12:01:59","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":531049,"visible":true,"origin":"","legend":"\u003cp\u003ePanels a and b show low signal changes in the bilateral basal ganglia and hippocampal regions on ADC (Apparent Diffusion Coefficient) images (black arrows); Panels c and d show high signal changes on DWI (Diffusion Weighted Imaging) (white arrows); Panels e and f show slightly high signal changes on FLAIR (Fluid-Attenuated Inversion Recovery) images (white arrows).\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-4723882/v1/c261bcdc56da7f7c0f8ab120.png"},{"id":74284724,"identity":"6d9f3b6e-40c1-4212-880b-f8e512cfc2ee","added_by":"auto","created_at":"2025-01-20 16:11:43","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1338399,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-4723882/v1/980502b3-5d42-4dc4-8d4a-35045d838118.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Euglycemic diabetic ketoacidosis associated metabolic encephalopathy caused by dapagliflozin：a rare case report","fulltext":[{"header":"Introduction","content":"\u003cp\u003eSGLT-2 inhibitors are a new class of oral hypoglycemic drugs, one of the most widely used medications is dapagliflozin. EuDKA, a serious and potentially life-threatening acute complication of diabetes mellitus, with a mortality rate as high as 1. 5%\u003csup\u003e[\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]\u003c/sup\u003e, occurs with normal or mildly elevated blood glucose(\u0026lt;\u0026thinsp;14 mmol/L), and is commonly defined as the presence of ketosis and metabolic acidosis\u003csup\u003e[\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]\u003c/sup\u003e. An increasing number of reports have demonstrated the association between SGLT-2 inhibitors and EuDKA\u003csup\u003e[\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]\u003c/sup\u003e. The possible mechanisms by which SGLT-2 inhibitors cause EuDKA are intricate and uncertain. SGLT-2 inhibitors decrease serum glucose primarily by promoting excretion and inhibiting glucose reabsorption in urine. The loss of urinary glucose results in a state of carbohydrate starvation and volume depletion, increasing the glucagon/insulin ratio and leading to severe dehydration and ketosis\u003csup\u003e[\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]\u003c/sup\u003e. Decreasing insulin release combined with high levels of competitive hormones including glucagon, cortisol and catecholamines accelerates the conversion of fatty acids to ketone bodies\u003csup\u003e[\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]\u003c/sup\u003e. SGLT-2 inhibitors also reduce ketone clearance\u003csup\u003e[\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]\u003c/sup\u003e. Eventually, there will be a buildup of ketosis in the presence of lower glucose levels. EuDKA is not always observed in patients taking SGLT-2 inhibitors; possible precipitants and risk factors include underlying autoimmune diabetes in adults (LADA), surgery, low carbohydrate diet, insulin withdrawal or dose reduction, dehydration, excessive exercise, heavy alcohol intake, etc\u003csup\u003e[\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e, \u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]\u003c/sup\u003e. Currently, there are few reports on EuDKA-associated metabolic encephalopathy, and its imaging characteristics remain unclear.\u003c/p\u003e \u003cp\u003eIn this report, our objective was to present a case of a patient with T2DM who was admitted to the emergency department with complaints of coma. Through analysis of clinical symptoms, imaging features, and disease triggers, the patient was ultimately diagnosed with EuDKA-related metabolic encephalopathy induced by SGLT-2 inhibitors.\u003c/p\u003e"},{"header":"Case presentation","content":"\u003cp\u003eA 72-year-old female with T2DM presented to our Emergency Department complaining of 70 minutes of coma on May 17, 2024. Living alone, the patient and her family members typically communicated via telephone. They mentioned that from the last time performing normally to now had already lasted for 10 hours. In the past week, she hadn\u0026apos;t complained to her family about the following conditions, including fever, nausea, vomiting, abdominal pain, diarrhea, reduced appetite, substance abuse, or alcohol consumption. She has had T2DM for the past 10 years, previously treated with a combination of Dapagliflozin 10mg once daily and Acarbose 100mg twice daily, with subcutaneous insulin injection twice daily being added to the regimen 10 days ago. She adhered to a regular insulin injection schedule and had no history of liver disease. Vital signs at presentation were: temperature 36. 6\u0026deg;C, pulse rate 102beats/min, respiratory rate 18breaths/min, blood pressure 175/86mmHg. Physical examination with no obvious Kussmaul breathing and dehydration. The pupil diameter and light reflexes were in the normal range. Besides hypermyotonia of extremities, no other focal neurologic deficits were observed.\u003c/p\u003e\n\u003cdiv id=\"Sec3\"\u003e\n \u003ch2\u003eLaboratory and imaging assessments\u003c/h2\u003e\n \u003cp\u003eBlood test results indicated a potential concurrent infection, while arterial blood gases revealed severe metabolic acidosis with an elevated anion gap (pH 7. 243, bicarbonates 12. 7mmol/L, anion gap 22. 6mmol/L). Elevated levels of \u0026beta;-hydroxybutyrate at 8. 474mmol/L and positive ketonuria were also observed. Detailed results are shown in Table \u003cspan\u003e1\u003c/span\u003e.\u003c/p\u003e\n \u003cp\u003eThe findings from the cranial magnetic resonance imaging (MRI) are depicted in Fig. \u003cspan\u003e1\u003c/span\u003e: Panels a and b show low signal changes in the bilateral basal ganglia and hippocampal regions on ADC (Apparent Diffusion Coefficient) images (black arrows); Panels c and d show high signal changes on DWI (Diffusion Weighted Imaging) (white arrows); Panels e and f show slightly high signal changes on FLAIR (Fluid-Attenuated Inversion Recovery) images (white arrows).\u0026nbsp;\u003c/p\u003e\u0026nbsp;\u003ctable id=\"Tab1\" border=\"1\"\u003e\n \u003ccaption language=\"En\"\u003e\n \u003cdiv\u003eTable 1\u003c/div\u003e\n \u003cdiv\u003e\n \u003cp\u003eInpatient laboratory values\u003c/p\u003e\n \u003c/div\u003e\n \u003c/caption\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eLaboratory aassessments\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eResult\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eReferrnce\u003c/p\u003e\n \u003c/th\u003e\n \u003c/tr\u003e\n \u003c/thead\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eSerum glucose, (mmol/L)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e13. 3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e3. 3\u0026ndash;6. 1\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eWhite blood cell, (*10^9/L)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e17. 4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e17. 4\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eHemoglobin, (g/L)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e160\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e115\u0026ndash;150\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eHs-CRP, (mg/L)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e52. 0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0\u0026ndash;8\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eD-dimer, (ng/mL)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e3291\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0-500\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eUric acid, (\u0026micro;mol/L)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e739\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e150\u0026ndash;350\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eUrea nitrogen, (mmol/L)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e16. 0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1. 7\u0026ndash;8. 3\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eCreatinine, (\u0026micro;mol/L)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e110\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e40\u0026ndash;110\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eSerum potassium, (mmol/L)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e3. 95\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e3. 5\u0026ndash;5. 3\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u0026beta;-hydroxybutyrate, (\u0026micro;mol/L)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e8474\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e30\u0026ndash;300\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eUrine ketones\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e++\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eLactic acid, (mmol/L)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1. 4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1. 0\u0026ndash;2. 5\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eHbA1c, (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e12\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e4\u0026ndash;6\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003ePH\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e7. 243\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e7. 35\u0026minus;7. 45\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eBicarbonates, (mmol/L)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e12. 7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e22\u0026ndash;27\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eAnion gap, (mmol/L)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e22. 6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e8\u0026ndash;16\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eOsmotic pressure, (osmo/kg)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e283\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e280\u0026ndash;320\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003c/table\u003e\n \u003cp\u003e\u003c/p\u003e\n \u003cp\u003eAbbreviation: HbA1c:glycosylated hemoglobin. Hs-CRP: high-sensitivity C-reactive protein.\u003c/p\u003e\n\u003c/div\u003e\n\u003cp\u003e\u003cstrong\u003eTreatment\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAt our institution, due to the inability to completely rule out cerebral infarction, we administered intravenous thrombolytic treatment using a 36mg dose of alteplase. However, there was no improvement in symptoms. The patient was subsequently transferred to a tertiary hospital where they were diagnosed with metabolic encephalopathy associated with EuDKA. She was promptly admitted to the intensive care unit (ICU) , with a low-dose insulin infusion to manage hyperglycemia, glucose supplementation to prevent hypoglycemia, and administration of mannitol to reduce intracranial pressure. Given the elevated inflammatory markers and the initial uncertain infection, empirical antimicrobial therapy with cefoperazone/sulbactam was used. Following this treatment, serial blood gas analyses showed gradual resolution of her ketoacidosis. Unfortunately, owing to the irreversible brain damage, the patient\u0026apos;s state of consciousness is not fully recovered.\u0026nbsp;\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eWe report a case of altered mental status in a patient with type 2 diabetes treated with dapagliflozin. Only several reports of disturbance of consciousness with dapagliflozin have been documented and\u0026nbsp;triggered in different scenarios\u003csup\u003e[9-11]\u003c/sup\u003e. The patient\u0026apos;s serum \u0026beta;-hydroxy butyrate was 8474\u0026nbsp;\u0026mu;mol/L, nearly\u0026nbsp;30\u0026nbsp;times\u0026nbsp;higher\u0026nbsp;than\u0026nbsp;normal. Blood\u0026nbsp;sugar\u0026nbsp;was\u0026nbsp;found\u0026nbsp;to\u0026nbsp;be\u0026nbsp;mildly\u0026nbsp;elevated\u0026nbsp;(12. 8mmol/l)\u0026nbsp;and PH was 7. 243.\u0026nbsp;Combinating imaging manifestations and excluding various\u0026nbsp;brian diseases including poisoning, seizures, cerebrovascular accident, central infection. A conclusive diagnosis of EuDKA-associated metabolic encephalopathy was established. Metabolic encephalopathy refers to diffuse or focal brain dysfunction which is attributed to impaired brain metabolism in the absence of primary structural dysfunction\u003csup\u003e[12]\u003c/sup\u003e. The augmented \u0026beta;-hydroxybutyric acid and acidemia play key roles in the upregulation of vascular endothelial growth factor expression and indirectly increasing cerebral vascular permeability\u003csup\u003e[13]\u003c/sup\u003e, resulting in brain edema and dysfunction. The limited clinical experience and ambiguous MRI features led us to a misdiagnosis of \u0026nbsp;cerebral infarction, resulting in unnecessary thrombolysis treatment. Despite the absence of bleeding and other complications, delayed diagnosis and treatment imposed a significant economic burden on the patient.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eSymptoms of EuDKA, similar to Diabetic Ketoacidosis(DKA), usually include nausea, vomiting, abdominal pain, polyuria, polydipsia, weight loss, dehydration, weakness, fatigue, tachycardia, dyspnea and Kussmaul breathing. Mental states range from awakeness to deep lethargy or coma\u003csup\u003e[14-16]\u003c/sup\u003e. The reported patient had presented with coma for more than 10 hours and displayed an uncommon MRI result indicative of metabolic encephalopathy（figure 1）. Identical with poisoning and hypoxia metabolic encephalopathy, it involves multiple sites, including bilateral basal ganglia, cortex, and periventricular white matter (PVWM)\u003csup\u003e[17]\u003c/sup\u003e.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eTreatment\u0026nbsp;for\u0026nbsp;EuDKA\u0026nbsp;parallels\u0026nbsp;that\u0026nbsp;of\u0026nbsp;DKA\u0026nbsp;except\u0026nbsp;that\u0026nbsp;the\u0026nbsp;risk\u0026nbsp;of\u0026nbsp;relapse\u0026nbsp;into\u0026nbsp;DKA\u0026nbsp;is\u0026nbsp;high\u0026nbsp;in\u0026nbsp;the\u0026nbsp;setting\u0026nbsp;of\u0026nbsp;SGLT-2\u0026nbsp;inhibitor\u0026nbsp;use\u003csup\u003e[15]\u003c/sup\u003e.\u0026nbsp;Infused\u0026nbsp;insulin\u0026nbsp;is\u0026nbsp;a\u0026nbsp;major\u0026nbsp;therapeutic\u0026nbsp;tool\u0026nbsp;for\u0026nbsp;EuDKA, other management measures covering aggressive rehydration, glucose supplementation, and correction of \u0026nbsp;electrolyte imbalance, as well as control of precipitating factors\u003csup\u003e[18]\u003c/sup\u003e. Severe acidosis may require bicarbonate therapy\u003csup\u003e[14]\u003c/sup\u003e. Resolution of EuDKA is defined as pH \u0026gt;7. 3, bicarbonate \u0026gt;15. 0mmol/L, and serum ketones \u0026lt;0. 6mmol/L. In a retrospective study, EuDKA patients experienced a 5. 9-hour reduction in insulin infusion time but had more than three times the frequency of hypoglycemia compared to those with DKA\u003csup\u003e[19]\u003c/sup\u003e. Hence,\u0026nbsp;When\u0026nbsp;the\u0026nbsp;blood gluose level\u0026nbsp;falls\u0026nbsp;below\u0026nbsp;250\u0026nbsp;mg/dl,\u0026nbsp;the\u0026nbsp;insulin\u0026nbsp;infusion\u0026nbsp;rate\u0026nbsp;should\u0026nbsp;be\u0026nbsp;reduced\u0026nbsp;and\u0026nbsp;dextrose\u0026nbsp;can\u0026nbsp;be\u0026nbsp;added\u0026nbsp;to\u0026nbsp;the\u0026nbsp;intravenous\u0026nbsp;fluids\u0026nbsp;to avoid\u0026nbsp;hypoglycemia\u003csup\u003e[14]\u003c/sup\u003e.\u0026nbsp;Other studies\u003csup\u003e[20]\u003c/sup\u003ehave also indicated that in the treatment of EuDKA, approximately 61. 5% of patients required intensive care, with some needing organ protection treatment such as invasive mechanical ventilation (13%), vasopressors (6. 5%), or renal replacement therapy (5. 9%). The overall mortality rate was 2. 4%. The diagnostic dilemma of EuDKA \u0026nbsp;portends worse outcomes compared with classic DKA.\u0026nbsp;\u003c/p\u003e"},{"header":"Conclusions","content":"\u003cp\u003eMetabolic encephalopathy is a rare but life-threatening complication of EuDKA caused by SGLT-2 inhibitors, the imaging features are similar to those of other metabolic encephalopathy such as poisoning and hypoxia. The precise pathogenesis of encephalopathy in EuDKA remains poorly understood, potentially resulting from the toxic consequences of electrolyte disturbances, ketosis, and acidosis. For unconscious patients with taking SGLT-2 inhibitors, commonly testing the level of ketones and magnetic resonance imaging of the brain are essential.\u0026nbsp;\u003c/p\u003e\n"},{"header":"Abbreviations","content":"\u003cp\u003eEuDKA\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;Euglycemic Diabetic Ketoacidosis \u0026nbsp;\u003c/p\u003e\n\u003cp\u003eSGLT-2\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;Sodium-Glucose Cotransporter-2\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eT2DM\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;Type 2 Diabetes Mellitus\u003c/p\u003e\n\u003cp\u003eDKA\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;Diabetic Ketoacidosis\u003c/p\u003e\n\u003cp\u003eLADA\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;Latent Autoimmune Diabetes In Adults\u003c/p\u003e\n\u003cp\u003ePVWM\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;Periventricular White Matter\u003c/p\u003e\n\u003cp\u003eMRI\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;Magnetic Resonance Imaging\u003c/p\u003e\n\u003cp\u003eHS-CRP\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;High-Sensitivity C-Reactive Protein\u003c/p\u003e\n\u003cp\u003eHBA1C \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;Hemoglobin A1c\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAcknowledgements\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe would like to thank Dr. Huang for providing some information.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors\u0026rsquo; contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eL. L. C. , Z. H. X. , G. S. Y. , R. Z. M. , W. L. S. collected data, searched the literature, and wrote case reports. L. L. C. , Z. H. X. , G. S. Y. were in charge of conducting the final review and making modifications to the manuscript.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNone.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003cstrong\u003eAvailability of data and materials\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll data analysed during this study are included in this manuscript. \u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe patient gave written consent for their personal or clinical details along with any identifying images to be published in this study.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll the authors declare that they have no competing interests.\u0026nbsp;\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eSitina M, Lukes M, Sramek V. Empagliflozin-associated postoperative mixed metabolic acidosis. Case report and review of pathogenesis. BMC Endocrine Disorders. 2023; DOI: 10. 1186/s12902-023-01339-w. \u003c/li\u003e\n\u003cli\u003eClark A, Mohammed AS, Raut A, et al. Prevalence and Clinical Characteristics of Adults Presenting With Sodium-Glucose Cotransporter-2 Inhibitor-Associated Diabetic Ketoacidosis at a Canadian Academic Tertiary Care Hospital. Canadian Journal of Diabetes. 2021; DOI: 10. 1016/j. jcjd. 2020. 08. 100. \u003c/li\u003e\n\u003cli\u003eSampani E, Sarafidis P, Dimitriadis C, et al. Severe euglycemic diabetic ketoacidosis of multifactorial etiology in a type 2 diabetic patient treated with empagliflozin: case report and literature review. BMC Nephrology. 2020; DOI: 10. 1186/s12882-020-01930-6. \u003c/li\u003e\n\u003cli\u003eSecinaro E, Ciavarella S, Rizzo G, et al. SGLT2-inhibitors and euglycemic diabetic ketoacidosis in COVID-19 pandemic era: a case report. Acta Diabetol. 2022; 1391-1394. DOI: 10. 1007/s00592-022-01909-9. \u003c/li\u003e\n\u003cli\u003eAltowayan WM. Empagliflozin induced euglycemic diabetic ketoacidosis. A case reports. Annals of Medicine \u0026amp; Surgery. 2022; DOI: 10. 1016/j. amsu. 2022. 104879. \u003c/li\u003e\n\u003cli\u003eLong B, Lentz S, Koyfman A, et al. Euglycemic diabetic ketoacidosis: Etiologies, evaluation, and management. The American Journal of Emergency Medicine. 2021; DOI: 10. 1016/j. ajem. 2021. 02. 015. \u003c/li\u003e\n\u003cli\u003eBarski L, Eshkoli T, Brandstaetter E, et al. Euglycemic diabetic ketoacidosis. European Journal of Internal Medicine. 2019; DOI: 10. 1016/j. ejim. 2019. 03. 014. \u003c/li\u003e\n\u003cli\u003eSethi S. Euglycemic Diabetic Ketoacidosis (EDKA) in a Patient Receiving Dapagliflozin. Acta Endocrinologica (Bucharest). 2021; DOI: 10. 4183/aeb. 2021. 266. \u003c/li\u003e\n\u003cli\u003eKarakaya Z, Topal FE, Firdes Topal UP, et al. Euglisemic diabetic ketoacidotic coma caused by dapagliflozin. American Journal of Emergency Medicine. 2018; DOI: 10. 1016/j. ajem. 2018. 08. 054. \u003c/li\u003e\n\u003cli\u003eBanakh I, Kung R, Gupta S, et al. Euglycemic diabetic ketoacidosis in association with dapagliflozin use after gastric sleeve surgery in a patient with type II diabetes mellitus. Clinical Case Reports. 2019; DOI: 10. 1002/ ccr3. 2147. \u003c/li\u003e\n\u003cli\u003eIqbal I, Hamid M, Khan MAA, et al. Dapagliflozin-induced Late-onset Euglycemic Diabetic Ketoacidosis. Cureus. 2019; DOI: 10. 7759/cureus. 6089. \u003c/li\u003e\n\u003cli\u003eTomkins M, McCormack R, O Connell K, et al. Metabolic encephalopathy secondary to diabetic ketoacidosis: a case report. BMC Endocrine Disorders. 2019; DOI: 10. 1186/s 12902-019-0398-8. \u003c/li\u003e\n\u003cli\u003eJones R, Redler K, Witherick J, et al. Posterior reversible encephalopathy syndrome complicating diabetic ketoacidosis; an important treatable complication. Pediatric Diabetes. 2017; DOI: 10. 1111/pedi. 12362. \u003c/li\u003e\n\u003cli\u003eBonora BM, Avogaro A, Fadini GP. Euglycemic Ketoacidosis. Current Diabetes Reports. 2020; DOI: 10. 1007/s11892-020-01307-x. \u003c/li\u003e\n\u003cli\u003eChow E, Clement S, Garg R. Euglycemic diabetic ketoacidosis in the era of SGLT-2 inhibitors. BMJ Open Diabetes Research \u0026amp; Care. 2023; DOI: 10. 1136/ bmjdrc-2023-003666. \u003c/li\u003e\n\u003cli\u003eDutta S, Kumar T, Singh S, et al. Euglycemic diabetic ketoacidosis associated with SGLT2 inhibitors: A systematic review and quantitative analysis. Journal of Family Medicine and Primary Care. 2022; DOI: 10. 4103/jfmpc. jfmpc_644_21. \u003c/li\u003e\n\u003cli\u003eKoksel Y, McKinney AM. Potentially Reversible and Recognizable Acute Encephalopathic Syndromes: Disease Categorization and MRI Appearances. AJNR Am J Neuroradiol. 2020; DOI: 10. 3174/ajnr. A6634. \u003c/li\u003e\n\u003cli\u003eJarvis PRE. Euglycemic diabetic ketoacidosis: a potential pitfall for the emergency physician. Clinical and Experimental Emergency Medicine. 2023; DOI: 10. 15441/ ceem. 22. 410. \u003c/li\u003e\n\u003cli\u003eSell J, Haas NL, Korley FK, et al. Euglycemic Diabetic Ketoacidosis_ Experience with 44 Patients and Comparison to Hyperglycemic Diabetic Ketoacidosis. Western Journal of Emergency Medicine. 2023; DOI: 10. 5811/westjem. 60361. \u003c/li\u003e\n\u003cli\u003eJuneja D, Nasa P, Jain R, et al. Sodium-glucose Cotransporter-2 Inhibitors induced euglycemic diabetic ketoacidosis: A meta summary of case reports. World Journal of Diabetes. 2023; DOI: 10. 4239/wjd. v14. i8. 1314. \u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"bmc-neurology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"nurl","sideBox":"Learn more about [BMC Neurology](http://bmcneurol.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/nurl","title":"BMC Neurology","twitterHandle":"BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"dapagliflozin, euglycemic diabetic ketoacidosis, metabolic encephalopathy, sodium–glucose cotransporter-2 inhibitors, case report","lastPublishedDoi":"10.21203/rs.3.rs-4723882/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-4723882/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eBackground\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eSodium–glucose cotransporter-2(SGLT-2) inhibitors are a newer class of anti-diabetic drugs with the incresed risk of euglycemic diabetic ketoacidosis(EuDKA). Encephalopathy is a rare but life-threatening event of EuDKA. Due to paradoxically normal or slightly elevated serum glucose levels, it's easy to be mimicked by cerebral infarction, structural brain damage, thus leading to delayed diagnosis and causing seriously irreversible brain injury.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCase presentation: \u003c/strong\u003eWe report a severe EuDKA with metabolic encephalopathy secondary to dapagliflozin in a type 2 diabetes mellitus(T2DM) patient. A 72-year-old female presented with complaining of 70 minutes of coma. Laboratory evaluation revealed a severe metabolic acidosis with an elevated anion gap, and ketones were elevated in blood and positive in urine. The patient eventually was diagnosed with metabolic encephalopathy associated with EuDKA and managed accordingly. Unfortunately, owing to the irreversible brain damage, the patient's state of consciousness is not fully recovered.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eMetabolic encephalopathy is a rare but life-threatening complication of EuDKA caused by SGLT-2 inhibitors, the imaging features are similar to those of other metabolic encephalopathy such as poisoning and hypoxia. The precise pathogenesis of encephalopathy in EuDKA remains poorly understood, potentially resulting from the toxic consequences of electrolyte disturbances, ketosis, and acidosis. For unconscious patients with taking SGLT-2 inhibitors, commonly testing the level of ketones and magnetic resonance imaging of the brain are essential.\u003c/p\u003e","manuscriptTitle":"Euglycemic diabetic ketoacidosis associated metabolic encephalopathy caused by dapagliflozin：a rare case report","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-08-11 12:01:54","doi":"10.21203/rs.3.rs-4723882/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2024-10-01T13:16:50+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2024-09-30T19:57:27+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"237640635243506203806712884744659048949","date":"2024-09-30T19:37:27+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"27302884628545713103468070796836186275","date":"2024-09-30T19:36:21+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"244103842094455070159131615628058421492","date":"2024-09-30T09:40:43+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"117616236271608754827875352867431013148","date":"2024-08-01T06:03:45+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"289161399987745329899759567858710971797","date":"2024-07-31T13:48:25+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2024-07-29T06:16:20+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"204067491648670610292268413443431337039","date":"2024-07-18T01:12:45+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2024-07-17T10:47:22+00:00","index":"","fulltext":""},{"type":"editorInvited","content":"","date":"2024-07-15T12:24:47+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2024-07-11T14:14:24+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2024-07-11T14:13:10+00:00","index":"","fulltext":""},{"type":"submitted","content":"BMC Neurology","date":"2024-07-10T10:29:33+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"bmc-neurology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"nurl","sideBox":"Learn more about [BMC Neurology](http://bmcneurol.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/nurl","title":"BMC Neurology","twitterHandle":"BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"0b9236fc-a218-4bbe-ab6f-5dcf0874494d","owner":[],"postedDate":"August 11th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2025-01-20T16:05:14+00:00","versionOfRecord":{"articleIdentity":"rs-4723882","link":"https://doi.org/10.1186/s12883-025-04027-5","journal":{"identity":"bmc-neurology","isVorOnly":false,"title":"BMC Neurology"},"publishedOn":"2025-01-14 15:57:12","publishedOnDateReadable":"January 14th, 2025"},"versionCreatedAt":"2024-08-11 12:01:54","video":"","vorDoi":"10.1186/s12883-025-04027-5","vorDoiUrl":"https://doi.org/10.1186/s12883-025-04027-5","workflowStages":[]},"version":"v1","identity":"rs-4723882","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-4723882","identity":"rs-4723882","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}