Syndrome of Irreversible Lithium-Effectuated NeuroToxicity (SILENT) Despite Therapeutic Serum Lithium Levels: A Case Report

Syndrome of Irreversible Lithium-Effectuated NeuroToxicity (SILENT) Despite Therapeutic Serum Lithium Levels: A 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 Syndrome of Irreversible Lithium-Effectuated NeuroToxicity (SILENT) Despite Therapeutic Serum Lithium Levels: A Case Report can colakoglu This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-8754450/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 Lithium is widely used in the long-term treatment of bipolar disorder but is limited by a narrow therapeutic window. Although serum lithium monitoring is routinely performed, increasing evidence suggests that serum concentrations do not reliably reflect central nervous system accumulation or neurotoxicity, particularly in patients receiving chronic therapy. The Syndrome of Irreversible Lithium-Effectuated NeuroToxicity (SILENT) is a rare but devastating complication characterized by persistent neurological deficits that continue despite drug discontinuation and normalization of serum lithium levels. Neurotoxicity SILENT Lithium Hypoxic–Ischemic Encephalopathy Figures Figure 1 Figure 2 Figure 3 Introduction Lithium remains a cornerstone in the long-term management of bipolar disorder; however, its widespread clinical use is constrained by a narrow therapeutic window, which necessitates close and regular serum level monitoring. Despite this precaution, accumulating evidence indicates that serum lithium concentrations do not reliably reflect tissue accumulation or the extent of neurotoxicity, particularly in patients receiving long-term therapy. Lithium readily crosses the blood–brain barrier and may accumulate within neuronal and glial cells, leading to persistent neurotoxic effects even when serum levels remain within the accepted therapeutic range. In rare cases, this process culminates in the Syndrome of Irreversible Lithium-Effectuated NeuroToxicity (SILENT), characterized by permanent neurological sequelae that persist despite drug discontinuation and normalization of serum lithium levels ( 1 ). We report a case of SILENT syndrome in which the severity and persistence of neurological impairment could not be explained by hypoxic–ischemic brain injury, highlighting the importance of considering lithium-induced neurotoxicity in the differential diagnosis of unexplained neurological deterioration in the intensive care setting ( 1 , 2 ). Case Presentation A 56-year-old female patient was admitted to the intensive care unit after developing ventricular fibrillation during elective endotracheal intubation, which was performed due to syncope, shallow breathing, and oxygen desaturation. Rapid defibrillation and cardiopulmonary resuscitation were initiated, and return of spontaneous circulation was achieved within approximately three minutes. She was subsequently transferred to the intensive care unit for further management. Medical history obtained from relatives revealed a diagnosis of bipolar disorder treated with lithium for approximately 20 years, with regular outpatient follow-up. Over the preceding six months, she had experienced progressive neurological symptoms, including tremor and gait instability, followed by fluctuating mental status with episodes of confusion and syncope in the days prior to admission. On admission to the intensive care unit, the patient was intubated and mechanically ventilated. Neurological examination demonstrated impaired consciousness with absent spontaneous eye opening and no purposeful motor response, while pupillary light reflexes were preserved. Vital signs were stable, and electrocardiography showed sinus rhythm without acute ischemic changes. Initial laboratory investigations, including serum electrolytes and renal function tests, were within acceptable ranges, and serum lithium concentration was within the therapeutic range (0.6 mmol/L). Cranial computed tomography performed on admission showed no evidence of intracranial hemorrhage, mass effect, or cerebral edema ( Fig. 1 ) . Transthoracic echocardiography revealed preserved left ventricular systolic function without structural abnormalities. Despite optimal supportive intensive care management and discontinuation of lithium therapy, the patient showed no meaningful neurological improvement. During follow-up, intermittent myoclonic movements and horizontal nystagmus were observed, and antiepileptic therapy was initiated with midazolam and levetiracetam. In the context of suspected lithium-related neurotoxicity, intermittent hemodialysis was performed on two separate occasions, despite serum lithium levels remaining within the normal range ( 5 , 6 ). Owing to the persistence of severe neurological impairment, further diagnostic evaluation was undertaken to assess potential etiologies, including nonconvulsive status epilepticus and hypoxic–ischemic brain injury. Electroencephalography demonstrated diffuse background slowing without epileptiform discharges or ictal activity. Cranial magnetic resonance imaging revealed preserved cortical gray–white matter differentiation, open basal cisterns, and no radiological evidence of global hypoxic–ischemic injury. The cerebellum, brainstem, and basal ganglia showed no focal pathological signal abnormalities. Age-compatible cerebral atrophy and nonspecific periventricular T2/FLAIR hyperintense gliotic changes were noted ( Fig. 2 ) and Diffusion-weighted imaging did not demonstrate restricted diffusion, and corresponding ADC maps showed no reduction in diffusivity ( Fig. 3 ) . After 31 days of intensive care unit follow-up, the patient exhibited spontaneous eye opening (E4) with no purposeful motor response (M2) and remained flaccid. She was breathing via tracheostomy in pressure support ventilation mode. Given the persistence of severe neurological impairment, the patient was discharged from the intensive care unit with a plan for ongoing physiotherapy and palliative care. Discussion and Conclusions Hypoxic–ischemic brain injury is a frequent cause of persistent neurological impairment in critically ill patients following cardiac arrest ( 2 ). However, several features in the present case argue strongly against hypoxic–ischemic encephalopathy as the primary mechanism underlying the observed neurological outcome. The duration of circulatory arrest was brief, with rapid defibrillation and return of spontaneous circulation achieved within approximately three minutes, a timeframe generally insufficient to cause severe and irreversible global hypoxic brain injury in the absence of prolonged hypotension or recurrent arrest ( 2 ). Moreover, serial neuroimaging demonstrated preserved gray–white matter differentiation, open basal cisterns, and no diffusion or signal abnormalities suggestive of global hypoxic–ischemic injury. Electroencephalography showed diffuse background slowing without epileptiform activity, a nonspecific finding that does not support severe hypoxic–ischemic encephalopathy or nonconvulsive status epilepticus as the primary diagnosis ( 2 ). Importantly, the patient’s neurological deterioration was preceded by a prolonged prodromal phase characterized by tremor, gait instability, and fluctuating mental status over several months. This gradual and progressive course is well described in chronic lithium-related neurotoxicity and is considered a hallmark of SILENT syndrome ( 1 , 3 ). The persistence of profound neurological deficits despite optimal supportive care, absence of radiological markers of hypoxic–ischemic injury, and lack of neurological recovery following lithium discontinuation and hemodialysis strongly suggest that lithium-related neurotoxicity was the dominant factor determining neurological outcome ( 1 , 5 – 7 ). The Syndrome of Irreversible Lithium-Effectuated NeuroToxicity (SILENT) represents the most severe end of the spectrum of lithium-induced neurological injury. A defining characteristic of SILENT is the poor correlation between serum lithium concentrations and clinical severity, reflecting lithium’s accumulation within neural tissue and delayed clearance from the central nervous system ( 1 , 3 , 4 ). In the present case, serum lithium levels remained within the therapeutic range, yet severe and irreversible neurological impairment developed and persisted. This observation reinforces the concept that serum lithium concentrations alone are insufficient to exclude clinically significant neurotoxicity, particularly in patients receiving long-term therapy ( 3 – 6 ). The lack of neurological improvement over a prolonged intensive care course, combined with the exclusion of alternative explanations such as hypoxic–ischemic encephalopathy and nonconvulsive status epilepticus, fulfills the clinical criteria for SILENT syndrome ( 1 ). Once established, SILENT is associated with a poor neurological prognosis, and interventions aimed at reducing circulating lithium levels may have limited efficacy when irreversible tissue-level neuronal injury has already occurred ( 5 – 7 ). This case illustrates a rare but devastating presentation of the Syndrome of Irreversible Lithium-Effectuated NeuroToxicity (SILENT), characterized by persistent severe neurological impairment despite therapeutic serum lithium levels. Differentiating hypoxic-ischemic injury from toxic-metabolic encephalopathy remains challenging; however, the overall clinicoradiological profile in this case was more consistent with SILENT. Clinicians should be aware that progressive neurological symptoms may precede irreversible injury, and that normal serum lithium concentrations do not exclude severe toxicity ( 3 – 5 ). This case underscores that SILENT should be considered a diagnosis of clinical trajectory rather than serum lithium concentration. Early identification and timely reassessment of lithium therapy remain crucial to preventing irreversible neurological outcomes. Abbreviations SILENT Syndrome of Irreversible Lithium-Effectuated NeuroToxicity ICU Intensive Care Unit CT Computed Tomography MRI Magnetic Resonance Imaging EEG Electroencephalography DWI Diffusion-Weighted Imaging ADC Apparent Diffusion Coefficient ROSC Return of Spontaneous Circulation Declarations Ethics approval and consent to participate Not applicable. Consent for publication Written informed consent was obtained from the patient’s legal representative for publication of this case report and any accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal. Competing interests The authors declare that they have no competing interests. Authors’ information Not applicable. Funding The authors received no specific funding for this work. Authors’ contributions CC was responsible for patient management, data collection, drafting of the manuscript, clinical interpretation of findings, literature review, and critical revision of the manuscript. All authors read and approved the final manuscript. Acknowledgements Not applicable. Availability of data and materials All data generated or analyzed during this study are included in this published article and its accompanying files. References Adityanjee, Munshi KR, Thampy A (2005) The syndrome of irreversible lithium-effectuated neurotoxicity. Clin Neuropharmacol 28(1):38–49 Perrone J, Hoffman RS (2011) Toxic encephalopathies. Neurol Clin 29(3):673–692 Schou M (1984) Long-lasting neurological sequelae after lithium intoxication. Acta Psychiatr Scand 70(6):594–602 Hansen HE, Amdisen A (1978) Lithium intoxication: report of 23 cases and review of 100 cases from the literature. Q J Med 47(2):123–144 Okusa MD, Crystal LJ (1994) Clinical manifestations and management of acute lithium intoxication. Am J Med 97(4):383–389 Timmer RT, Sands JM (1999) Lithium intoxication. J Am Soc Nephrol 10(3):666–674 Decker BS, Goldfarb DS, Dargan PI et al (2015) Extracorporeal treatment for lithium poisoning: systematic review and recommendations. Kidney Int 88(4):720–728 Additional Declarations The authors declare no competing interests. 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-8754450","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Case Report","associatedPublications":[],"authors":[{"id":583715081,"identity":"c40c06ab-62e5-4a4c-93d0-653562c36619","order_by":0,"name":"can colakoglu","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA+ElEQVRIiWNgGAWjYFCCBDApw8ADJB8w2ABJxsYDxGjhAWtJYEgDaWkgScthMA+vFt325IefC2psePh7Dh9+kdh23m5t+2GgLTU20bi0mJ15Ziw941gaj8TZtjSLxLbbydvOJAK1HEvLbcCl5UYOgzRvw2EehvM8ZgYgLWYHgFoYGw7j08L8G6RFHqLlXLLZ+YcEtbCBbTE422P8ILHtgJ3ZDUK2nHlmZs0D9IvhmWNpDAnnkhPMbgBtScDnl+PJj2/z1NjIyZ1JPvzhQ5mdvdn59IcPPtTY4NSCDNgkgEQiWGUCEcpBgPkDkLAnUvEoGAWjYBSMIAAAwH1lRq+TQBUAAAAASUVORK5CYII=","orcid":"https://orcid.org/0000-0002-7205-509X","institution":"Giresun University","correspondingAuthor":true,"prefix":"","firstName":"can","middleName":"","lastName":"colakoglu","suffix":""}],"badges":[],"createdAt":"2026-02-01 07:33:16","currentVersionCode":1,"declarations":{"humanSubjects":true,"vertebrateSubjects":false,"conflictsOfInterestStatement":false,"humanSubjectEthicalGuidelines":true,"humanSubjectConsent":true,"humanSubjectClinicalTrial":false,"humanSubjectCaseReport":true,"vertebrateSubjectEthicalGuidelines":false},"doi":"10.21203/rs.3.rs-8754450/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-8754450/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":101791847,"identity":"7641ea41-232f-45e3-99c4-4ad055316348","added_by":"auto","created_at":"2026-02-03 16:10:55","extension":"jpeg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":325635,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cem\u003eNon-contrast cranial computed tomography performed on admission demonstrating preserved gray–white matter differentiation, normal ventricular configuration, and absence of intracranial hemorrhage, mass effect, or cerebral edema. No radiological features suggestive of acute hypoxic–ischemic brain injury are observed\u003c/em\u003e\u003c/p\u003e","description":"","filename":"floatimage1.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-8754450/v1/d02a5cc3209f88b3f98e9855.jpeg"},{"id":101791684,"identity":"a318b805-31be-4b7c-8e09-f839e67bd4f8","added_by":"auto","created_at":"2026-02-03 16:10:18","extension":"jpeg","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":722343,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cem\u003eAxial T2-weighted and FLAIR images demonstrating preserved cortical architecture and open basal cisterns, with mild diffuse cerebral atrophy and nonspecific periventricular white matter hyperintensities. No characteristic signal abnormalities associated with hypoxic–ischemic encephalopathy are observed.\u003c/em\u003e\u003c/p\u003e","description":"","filename":"floatimage2.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-8754450/v1/b1cc256cf9b49c1d3077847b.jpeg"},{"id":101791510,"identity":"6e90fa96-9fa4-4300-9dbc-bb8922a0fc43","added_by":"auto","created_at":"2026-02-03 16:09:57","extension":"jpeg","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":559599,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cem\u003eDiffusion-weighted imaging did not demonstrate restricted diffusion, and corresponding ADC maps showed no reduction in diffusivity, arguing against acute or subacute hypoxic–ischemic encephalopathy.\u003c/em\u003e\u003c/p\u003e","description":"","filename":"floatimage3.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-8754450/v1/ab6bed8a473a94372d468cb3.jpeg"},{"id":101792336,"identity":"ec2740eb-bfb6-4f3b-85b3-4eb6925d9e3e","added_by":"auto","created_at":"2026-02-03 16:11:56","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1956045,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-8754450/v1/71ef21a4-a578-4096-8512-d42958c73b8a.pdf"}],"financialInterests":"The authors declare no competing interests.","formattedTitle":"\u003cp\u003e\u003cstrong\u003eSyndrome of Irreversible Lithium-Effectuated NeuroToxicity (SILENT) Despite Therapeutic Serum Lithium Levels: A Case Report\u003c/strong\u003e\u003c/p\u003e","fulltext":[{"header":"Introduction","content":"\u003cp\u003eLithium remains a cornerstone in the long-term management of bipolar disorder; however, its widespread clinical use is constrained by a narrow therapeutic window, which necessitates close and regular serum level monitoring. Despite this precaution, accumulating evidence indicates that serum lithium concentrations do not reliably reflect tissue accumulation or the extent of neurotoxicity, particularly in patients receiving long-term therapy. Lithium readily crosses the blood\u0026ndash;brain barrier and may accumulate within neuronal and glial cells, leading to persistent neurotoxic effects even when serum levels remain within the accepted therapeutic range. In rare cases, this process culminates in the Syndrome of Irreversible Lithium-Effectuated NeuroToxicity (SILENT), characterized by permanent neurological sequelae that persist despite drug discontinuation and normalization of serum lithium levels (\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eWe report a case of SILENT syndrome in which the severity and persistence of neurological impairment could not be explained by hypoxic\u0026ndash;ischemic brain injury, highlighting the importance of considering lithium-induced neurotoxicity in the differential diagnosis of unexplained neurological deterioration in the intensive care setting (\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e).\u003c/p\u003e"},{"header":"Case Presentation","content":"\u003cp\u003eA 56-year-old female patient was admitted to the intensive care unit after developing ventricular fibrillation during elective endotracheal intubation, which was performed due to syncope, shallow breathing, and oxygen desaturation. Rapid defibrillation and cardiopulmonary resuscitation were initiated, and return of spontaneous circulation was achieved within approximately three minutes. She was subsequently transferred to the intensive care unit for further management.\u003c/p\u003e \u003cp\u003eMedical history obtained from relatives revealed a diagnosis of bipolar disorder treated with lithium for approximately 20 years, with regular outpatient follow-up. Over the preceding six months, she had experienced progressive neurological symptoms, including tremor and gait instability, followed by fluctuating mental status with episodes of confusion and syncope in the days prior to admission.\u003c/p\u003e \u003cp\u003eOn admission to the intensive care unit, the patient was intubated and mechanically ventilated. Neurological examination demonstrated impaired consciousness with absent spontaneous eye opening and no purposeful motor response, while pupillary light reflexes were preserved. Vital signs were stable, and electrocardiography showed sinus rhythm without acute ischemic changes. Initial laboratory investigations, including serum electrolytes and renal function tests, were within acceptable ranges, and serum lithium concentration was within the therapeutic range (0.6 mmol/L).\u003c/p\u003e \u003cp\u003eCranial computed tomography performed on admission showed no evidence of intracranial hemorrhage, mass effect, or cerebral edema \u003cem\u003e(\u003c/em\u003eFig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e\u003cem\u003e)\u003c/em\u003e. Transthoracic echocardiography revealed preserved left ventricular systolic function without structural abnormalities.\u003c/p\u003e \u003cp\u003eDespite optimal supportive intensive care management and discontinuation of lithium therapy, the patient showed no meaningful neurological improvement. During follow-up, intermittent myoclonic movements and horizontal nystagmus were observed, and antiepileptic therapy was initiated with midazolam and levetiracetam. In the context of suspected lithium-related neurotoxicity, intermittent hemodialysis was performed on two separate occasions, despite serum lithium levels remaining within the normal range (\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e, \u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eOwing to the persistence of severe neurological impairment, further diagnostic evaluation was undertaken to assess potential etiologies, including nonconvulsive status epilepticus and hypoxic–ischemic brain injury. Electroencephalography demonstrated diffuse background slowing without epileptiform discharges or ictal activity. Cranial magnetic resonance imaging revealed preserved cortical gray–white matter differentiation, open basal cisterns, and no radiological evidence of global hypoxic–ischemic injury. The cerebellum, brainstem, and basal ganglia showed no focal pathological signal abnormalities. Age-compatible cerebral atrophy and nonspecific periventricular T2/FLAIR hyperintense gliotic changes were noted \u003cem\u003e(\u003c/em\u003eFig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e\u003cem\u003e)\u003c/em\u003e and Diffusion-weighted imaging did not demonstrate restricted diffusion, and corresponding ADC maps showed no reduction in diffusivity \u003cem\u003e(\u003c/em\u003eFig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e\u003cem\u003e)\u003c/em\u003e.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eAfter 31 days of intensive care unit follow-up, the patient exhibited spontaneous eye opening (E4) with no purposeful motor response (M2) and remained flaccid. She was breathing via tracheostomy in pressure support ventilation mode. Given the persistence of severe neurological impairment, the patient was discharged from the intensive care unit with a plan for ongoing physiotherapy and palliative care.\u003c/p\u003e "},{"header":"Discussion and Conclusions","content":"\u003cp\u003eHypoxic–ischemic brain injury is a frequent cause of persistent neurological impairment in critically ill patients following cardiac arrest (\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e). However, several features in the present case argue strongly against hypoxic–ischemic encephalopathy as the primary mechanism underlying the observed neurological outcome. The duration of circulatory arrest was brief, with rapid defibrillation and return of spontaneous circulation achieved within approximately three minutes, a timeframe generally insufficient to cause severe and irreversible global hypoxic brain injury in the absence of prolonged hypotension or recurrent arrest (\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e). Moreover, serial neuroimaging demonstrated preserved gray–white matter differentiation, open basal cisterns, and no diffusion or signal abnormalities suggestive of global hypoxic–ischemic injury. Electroencephalography showed diffuse background slowing without epileptiform activity, a nonspecific finding that does not support severe hypoxic–ischemic encephalopathy or nonconvulsive status epilepticus as the primary diagnosis (\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e).\u003c/p\u003e\u003cp\u003eImportantly, the patient’s neurological deterioration was preceded by a prolonged prodromal phase characterized by tremor, gait instability, and fluctuating mental status over several months. This gradual and progressive course is well described in chronic lithium-related neurotoxicity and is considered a hallmark of SILENT syndrome (\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e). The persistence of profound neurological deficits despite optimal supportive care, absence of radiological markers of hypoxic–ischemic injury, and lack of neurological recovery following lithium discontinuation and hemodialysis strongly suggest that lithium-related neurotoxicity was the dominant factor determining neurological outcome (\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan additionalcitationids=\"CR6\" citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e–\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e).\u003c/p\u003e\u003cp\u003eThe Syndrome of Irreversible Lithium-Effectuated NeuroToxicity (SILENT) represents the most severe end of the spectrum of lithium-induced neurological injury. A defining characteristic of SILENT is the poor correlation between serum lithium concentrations and clinical severity, reflecting lithium’s accumulation within neural tissue and delayed clearance from the central nervous system (\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e). In the present case, serum lithium levels remained within the therapeutic range, yet severe and irreversible neurological impairment developed and persisted. This observation reinforces the concept that serum lithium concentrations alone are insufficient to exclude clinically significant neurotoxicity, particularly in patients receiving long-term therapy (\u003cspan additionalcitationids=\"CR4 CR5\" citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e–\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e).\u003c/p\u003e\u003cp\u003eThe lack of neurological improvement over a prolonged intensive care course, combined with the exclusion of alternative explanations such as hypoxic–ischemic encephalopathy and nonconvulsive status epilepticus, fulfills the clinical criteria for SILENT syndrome (\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e). Once established, SILENT is associated with a poor neurological prognosis, and interventions aimed at reducing circulating lithium levels may have limited efficacy when irreversible tissue-level neuronal injury has already occurred (\u003cspan additionalcitationids=\"CR6\" citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e–\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e).\u003c/p\u003e\u003cp\u003eThis case illustrates a rare but devastating presentation of the Syndrome of Irreversible Lithium-Effectuated NeuroToxicity (SILENT), characterized by persistent severe neurological impairment despite therapeutic serum lithium levels. Differentiating hypoxic-ischemic injury from toxic-metabolic encephalopathy remains challenging; however, the overall clinicoradiological profile in this case was more consistent with SILENT. Clinicians should be aware that progressive neurological symptoms may precede irreversible injury, and that normal serum lithium concentrations do not exclude severe toxicity (\u003cspan additionalcitationids=\"CR4\" citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e–\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e). This case underscores that SILENT should be considered a diagnosis of clinical trajectory rather than serum lithium concentration. Early identification and timely reassessment of lithium therapy remain crucial to preventing irreversible neurological outcomes.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cdiv class=\"DefinitionList\"\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eSILENT\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eSyndrome of Irreversible Lithium-Effectuated NeuroToxicity\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eICU\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eIntensive Care Unit\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eCT\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eComputed Tomography\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eMRI\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eMagnetic Resonance Imaging\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eEEG\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eElectroencephalography\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eDWI\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eDiffusion-Weighted Imaging\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eADC\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eApparent Diffusion Coefficient\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eROSC\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eReturn of Spontaneous Circulation\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003c/div\u003e"},{"header":"Declarations","content":"\u003cp\u003e \u003cstrong\u003eEthics approval and consent to participate\u003c/strong\u003e \u003cp\u003eNot applicable.\u003c/p\u003e \u003c/p\u003e \u003cp\u003e \u003cstrong\u003eConsent for publication\u003c/strong\u003e \u003cp\u003e Written informed consent was obtained from the patient\u0026rsquo;s legal representative for publication of this case report and any accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal.\u003c/p\u003e \u003c/p\u003e\u003cp\u003e \u003ch2\u003eCompeting interests\u003c/h2\u003e \u003cp\u003eThe authors declare that they have no competing interests.\u003c/p\u003e \u003c/p\u003e\u003cp\u003e \u003ch2\u003eAuthors\u0026rsquo; information\u003c/h2\u003e \u003cp\u003eNot applicable.\u003c/p\u003e \u003c/p\u003e\u003ch2\u003eFunding\u003c/h2\u003e \u003cp\u003eThe authors received no specific funding for this work.\u003c/p\u003e\u003ch2\u003eAuthors\u0026rsquo; contributions\u003c/h2\u003e \u003cp\u003eCC was responsible for patient management, data collection, drafting of the manuscript, clinical interpretation of findings, literature review, and critical revision of the manuscript. All authors read and approved the final manuscript.\u003c/p\u003e\u003ch2\u003eAcknowledgements\u003c/h2\u003e \u003cp\u003eNot applicable.\u003c/p\u003e\u003ch2\u003eAvailability of data and materials\u003c/h2\u003e \u003cp\u003eAll data generated or analyzed during this study are included in this published article and its accompanying files.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eAdityanjee, Munshi KR, Thampy A (2005) The syndrome of irreversible lithium-effectuated neurotoxicity. Clin Neuropharmacol 28(1):38\u0026ndash;49\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003ePerrone J, Hoffman RS (2011) Toxic encephalopathies. Neurol Clin 29(3):673\u0026ndash;692\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSchou M (1984) Long-lasting neurological sequelae after lithium intoxication. Acta Psychiatr Scand 70(6):594\u0026ndash;602\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHansen HE, Amdisen A (1978) Lithium intoxication: report of 23 cases and review of 100 cases from the literature. Q J Med 47(2):123\u0026ndash;144\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eOkusa MD, Crystal LJ (1994) Clinical manifestations and management of acute lithium intoxication. Am J Med 97(4):383\u0026ndash;389\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eTimmer RT, Sands JM (1999) Lithium intoxication. J Am Soc Nephrol 10(3):666\u0026ndash;674\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eDecker BS, Goldfarb DS, Dargan PI et al (2015) Extracorporeal treatment for lithium poisoning: systematic review and recommendations. Kidney Int 88(4):720\u0026ndash;728\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":true,"hideJournal":true,"highlight":"","institution":"Giresun University","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":"Neurotoxicity, SILENT, Lithium, Hypoxic–Ischemic Encephalopathy","lastPublishedDoi":"10.21203/rs.3.rs-8754450/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-8754450/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e \u003cp\u003e \u003cspan type=\"SmallCaps\" class=\"SmallCaps\" name=\"Emphasis\"\u003eLithium is widely used in the long-term treatment of bipolar disorder but is limited by a narrow therapeutic window. Although serum lithium monitoring is routinely performed, increasing evidence suggests that serum concentrations do not reliably reflect central nervous system accumulation or neurotoxicity, particularly in patients receiving chronic therapy. The Syndrome of Irreversible Lithium-Effectuated NeuroToxicity (SILENT) is a rare but devastating complication characterized by persistent neurological deficits that continue despite drug discontinuation and normalization of serum lithium levels.\u003c/span\u003e \u003c/p\u003e","manuscriptTitle":"Syndrome of Irreversible Lithium-Effectuated NeuroToxicity (SILENT) Despite Therapeutic Serum Lithium Levels: A Case Report","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2026-02-03 16:08:18","doi":"10.21203/rs.3.rs-8754450/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":"eee387db-705c-4e54-b1c7-5a8372e03213","owner":[],"postedDate":"February 3rd, 2026","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2026-02-03T16:08:20+00:00","versionOfRecord":[],"versionCreatedAt":"2026-02-03 16:08:18","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-8754450","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-8754450","identity":"rs-8754450","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}