No full-text available
To read the full-text of this research,
you can request a copy directly from the authors.
The Syndrome of Irreversible Lithium-Effectuated Neurotoxicity
Abstract
Persistent sequelae of lithium intoxication gained clinical attention in the 1980s and were named Syndrome of Irreversible Lithium-Effectuated Neurotoxicity (SILENT). The authors review the published cases of SILENT reported in the literature and discuss various clinical manifestations.
The authors' inclusion criteria included persistence of sequelae for at least 2 months after the cessation of lithium administration. They conducted a MEDLINE and Pub Med search for journal articles from the year 1965 to 2004. They also cross-referenced available papers.
The authors identified 90 cases of SILENT in peer-reviewed publications. Persistent cerebellar dysfunction was the most commonly reported sequela. Other atypical presentations have also been reported.
Although the biologic mechanism remains unclear, the authors hypothesize that the putative cause of SILENT is demyelination caused by lithium at multiple sites in the nervous system, including the cerebellum. Recent advances in the understanding of the molecular basis of lithium-induced neurotoxicity may be able to provide a means of defining a pathway associated with the long-term prophylactic properties of lithium, distinct from its toxicity profile. This identification of differential gene expression patterns that distinguish between therapeutic and toxic actions of lithium may help in the discovery of new drugs for mood stabilization. Clinically and heuristically, it is important to raise the awareness of this syndrome so that clinicians are able to avoid it. A precise definition, operational diagnostic criteria, and a descriptive name will aid in the early identification and prevention of SILENT.
... Additionally, sequelae usually persist at the 1-year follow-up. 6 While there is no definitive treatment for SILENT, 7 the main treatment is physical rehabilitation. 6 Most reports on SILENT have focused on motor impairment, with few detailing cognitive decline. ...
... 6 While there is no definitive treatment for SILENT, 7 the main treatment is physical rehabilitation. 6 Most reports on SILENT have focused on motor impairment, with few detailing cognitive decline. 8 Here, we report a patient in whom cognitive function decreased after lithium overdose and hardly recovered, as evaluated using multiple neuropsychological tests during a 1-year hospitalisation period. ...
... Although the neurological damage mechanism in SILENT is unclear, magnetic resonance imaging of the head shows cerebellar or cerebral atrophy. 6,9,10,11 To our knowledge, no other imaging findings have been reported yet. Here, the only characteristic finding, other than ischaemic changes, was cerebellar atrophy. ...
Introduction: Lithium-induced neurotoxicity is almost always reversible but can cause irreversible neurological sequelae, namely the syndrome of irreversible lithium-effectuated neurotoxicity (SILENT). As there is no definitive treatment for SILENT, caution is required when administering lithium. Reports on the effect of lithium-effectuated neurotoxicity on cognitive function are limited. We report a case in which high cognitive function was lost after lithium overdose and hardly recovered, as evaluated using multiple neuropsychological tests during a 1-year hospitalisation period.Patient presentation: A 52-year-old man on lithium medication with bipolar disorder was admitted to the intensive care unit because of lithium overdose. The patient achieved lucid consciousness after continuous haemodiafiltration. However, he could not move his body as desired or produce appropriate verbal expressions; thus, he was moved to our psychiatric ward, where his treatment continued.Management and outcome: After several months, the patient was diagnosed with SILENT owing to persistent motor and cognitive dysfunctions. Multiple neuropsychological tests were performed, and cognitive function was evaluated. The Neurobehavioural Cognitive Status Examination showed a worsening trend, and the full intelligence quotient of the Wechsler Adult Intelligence Scale-Third Edition was in the mild intellectual disability range.Conclusion: This is a clear case of cognitive dysfunction due to SILENT and is difficult to treat. Thus, it is crucial to prevent the onset of SILENT.Contribution: This report is valuable because it is one of the few to track changes in cognitive function over time in a patient with SILENT using objective measures over 1 year of hospitalisation.
... 8 Although there have been some reviews on this topic in the past, they were all narrative. 7,[9][10][11] Recently, Verdoux et al 12 published a systematic review but limited their research question to the role of fever in the occurrence of neurological sequelae following lithium intoxication. 12 We therefore conducted a scoping review to assess the nature and scope of the research literature on the long-term neurological sequelae of lithium intoxication and determine the present current knowledge of SILENT. ...
... Besides these symptoms, an acute cerebellar syndrome with symptoms such as wide-based ataxic gait, dysarthria, dysmetria, dysdiadochokinesia, hypotonia, nystagmus and (intention) tremor is also commonly observed in most cases. 9,103 As the presentation of SILENT in most cases typically starts with an acute intoxication (acute or "acute on chronic"), in the initial phase, no conclusion can be drawn regarding the development of SILENT. ...
... In the meantime, one should promptly and effectively mitigate the toxicity as much as possible. 9,103 Historically, cerebellar sequelae has been the most commonly neurological sequelae associated with SILENT, and we found a similar predominance in our study. ...
The Syndrome of Irreversible Lithium-Effectuated Neurotoxicity (SILENT) is a rare but concerning neurological complication resulting from lithium intoxication. Despite being reported since the 1960s, SILENT remains poorly understood and previous reviews on this topic commonly have been narrative. We therefore conducted a scoping review to assess the nature and scope of the research literature on the long-term neurological sequelae of lithium toxicity and determine the current knowledge of SILENT. A comprehensive and systematic literature search, using the MEDLINE, Embase, and Web of Science databases (from inception to July 2023), was conducted for English and Dutch articles, assessing the long-term neurological sequelae of lithium intoxication. Key information concerning clinical manifestations, risk factors, therapeutic approaches, or preventive measurements was extracted. We reviewed 91 articles, extracting information from 117 cases of SILENT. The prevailing outcome observed was persistent cerebellar dysfunction (77% of cases), often in combination with other sequelae. Other common sequelae included cognitive problems, parkinsonism, choreoathetosis, tardive dyskinesia, and peripheral neuropathy. The most common (61.4%) acute neurological symptom in the development of SILENT is an altered level of consciousness ranging from confusion to comatose states. Cerebellar sequelae were mentioned in 77% of cases as most common persistent sequelae. Antipsychotic use was mentioned in 59% of cases and fever was reported in 37.6% of cases. Scientific knowledge about this phenomenon has not advanced much since its initial reports in the 1960s and 1970s. While the use of lithium has become much more stringent than it had been in years past, and the occurrence of SILENT is rather exceptional, raising awareness about SILENT nevertheless remains crucial to avoid deleterious neurological consequences. Comprehensive, high-quality research in a systematic and standardized manner is therefore urgently needed to better understand this phenomenon.
... Actualmente, esta forma rara de toxicidad se conoce como SILENT (del inglés Syndrome of Irreversible Lithium-Effectuated Neurotoxicity) (Adityanjee, 1987). En efecto, en este síndrome predominan complicaciones cerebelosas (Verdoux et al., 2021) tales como ataxia y disatria (Verdoux y Bourgeois, 1991;Adityanjee et al., 2005), pero puede haber también síntomas extrapiramidales persistentes y demencia (Domínguez Ortega et al., 2006). Aunque es un cuadro propio de la intoxicación, es posible observarlo en cualquiera de las etapas del tratamiento, incluso dentro del rango terapéutico (Verdoux y Bourgeois, 1991;Adityanjee et al., 2005;Verdoux et al., 2021), por lo que los niveles de litemia no son suficientes para descartarlo. ...
... En efecto, en este síndrome predominan complicaciones cerebelosas (Verdoux et al., 2021) tales como ataxia y disatria (Verdoux y Bourgeois, 1991;Adityanjee et al., 2005), pero puede haber también síntomas extrapiramidales persistentes y demencia (Domínguez Ortega et al., 2006). Aunque es un cuadro propio de la intoxicación, es posible observarlo en cualquiera de las etapas del tratamiento, incluso dentro del rango terapéutico (Verdoux y Bourgeois, 1991;Adityanjee et al., 2005;Verdoux et al., 2021), por lo que los niveles de litemia no son suficientes para descartarlo. La presencia de fiebre e infección parecen elevar el riesgo de padecerlo, del mismo modo que la administración concomitante de otros medicamentos, particularmente el haloperidol (Cohen y Cohen 1974;Verodux et al., 2021). ...
... Teniendo en cuenta que, en estos casos, los recursos terapéuticos son limitados, el conocimiento de esta complicación es fundamental y la mejor herramienta sigue siendo la prevención (Schou, 1984;Verdoux, 1991;Adityanjee, 2005;Verdoux, 2021). En ese sentido, la psicoeducación sobre las condiciones que pueden predisponer a este síndrome -principalmente fiebre-son de mucha utilidad, del mismo modo que los síntomas de neurotoxicidad o situaciones que modifiquen las concentraciones séricas del litio (por ejemplo, la deshidratación o la administración de AINE) (Verdoux, 2021). ...
Artículo de revisiónEl litio es un metal alcalino, usado hace más de 60 años en psiquiatría, y actualmente es considerado el estándar de oro en el tratamiento del trastorno bipolar (TB). De acuerdo con la evidencia reciente, este principio activo es útil para el tratamiento de un amplio espectro de variedades clínicas de los trastornos afectivos. Además, se estima que desde hace tiempo el litio reduce el riesgo de suicidio y de comportamiento suicida en personas con trastornos del estado de ánimo. Por otro lado, algunos estudios novedosos han demostrado que el catión posee una potencial eficacia para el tratamiento de otros procesos neuropsiquiátricos, tales como la probabilidad de disminuir el riesgo de demencia y la de ralentizar el desarrollo de enfermedades neurodegenerativas. A pesar de la enorme evidencia a favor de la utilización del litio, se sabe que, en la Argentina, las especialidades medicinales que lo contienen se prescriben menos de lo esperado. En virtud de todo lo mencionado, la Asociación Argentina de Psiquiatría Biológica (AAPB) convocó a un grupo de expertos para revisar la literatura científica disponible y elaborar un documento actualizado sobre el manejo y el uso del litio en neuropsiquiatría. Además de la utilización del ion en la práctica clínica diaria, el alcance de esta revisión incluye otros contenidos que se han considerado de interés para el médico psiquiatra, tales como ciertos aspectos farmacológicos y farmacogenéticos, posibles predictores clínicos de la respuesta al tratamiento con litio, el manejo del ion durante el período perinatal, el manejo de litio en la población infantojuvenil, el manejo de los efectos adversos vinculados con el catión y las interacciones con medicamentos y otras sustancias.
... Female gender and older age are risk factors for the development of lithium neurotoxicity (Adityanjee et al. 2005, D'Souza et al. 2011. Other risk factors are epilepsy, cognitive impairment, abnormal EEG findings (Kores and Ladder 1997), psychotic symptoms and anxiety symptoms accompanying mood symptoms in the pre-intoxication period, and the use of lithium for schizoaffective disorder Table 1. ...
... While fever may be a component of lithium neurotoxicity, it may also pose a risk for the development of neurotoxicity by stimulating protein coagulation in different parts of the CNS (Adityanjee et al. 2005). When neurotoxicity developed, there was a short-term fever response, and the accompanying confusion led to the necessity of considering infection, rheumatological diseases and NMS in the differential diagnosis. ...
... The persistence of symptoms of lithium neurotoxicity two months after the discontinuation of lithium is defined as The Syndrome of Irreversible Lithium Effectuated Neurotoxicity (SILENT) in the literature (Adityanjee et al. 2005). In the review in which ninety SILENT cases were evaluated, it was reported that the number of patients whose SILENT improved within the first year after lithium discontinuation was quite low (Adityanjee et al. 2005). ...
Lithium may cause toxicity as it has a narrow therapeutic range. Lithium intoxication may manifest in the form of acute, acute on chronic and chronic intoxication. Neurotoxicity is a common component of chronic lithium intoxication and the symptoms include tremor, ataxia, dysarthria, extrapyramidal symptoms, hyperreflexia, seizures and status epilepticus. Although rare, catatonia could as a manifestation of lithium neurotoxicity. In this report, we present a patient with bipolar disorder presenting with catatonic symptoms secondary to lithium intoxication. We will discuss the risk factors, differential diagnosis and the treatment of catatonic symptoms. Lithium neurotoxicity may present with various clinical symptoms including catatonia, and differential diagnosis should be made well in such cases. If lithium neurotoxicity is suspected, rapid and appropriate intervention is required to prevent permanent neurological damage.
... In 1987, Adityanjee et al. suggested the acronym "SILENT" to describe persistent neurotoxic sequelae of lithium toxicity [12]. SILENT is a clinical diagnosis when such sequelae persist for over two months following lithium cessation [13]. A review conducted in 2005 by Adityanjee et al. reported the typical clinical profile of SILENT to include persistent cerebellar dysfunction, extrapyramidal syndrome, brainstem dysfunction, or dementia [13]. ...
... SILENT is a clinical diagnosis when such sequelae persist for over two months following lithium cessation [13]. A review conducted in 2005 by Adityanjee et al. reported the typical clinical profile of SILENT to include persistent cerebellar dysfunction, extrapyramidal syndrome, brainstem dysfunction, or dementia [13]. Furthermore, atypical presentations of SILENT include retrobulbar optic neuritis, downbeat nystagmus, choreoathetoid movement, persistent papilledema, peripheral neuropathy, myopathy, and blindness [13]. ...
... A review conducted in 2005 by Adityanjee et al. reported the typical clinical profile of SILENT to include persistent cerebellar dysfunction, extrapyramidal syndrome, brainstem dysfunction, or dementia [13]. Furthermore, atypical presentations of SILENT include retrobulbar optic neuritis, downbeat nystagmus, choreoathetoid movement, persistent papilledema, peripheral neuropathy, myopathy, and blindness [13]. In the presented case, the diagnosis of SILENT was proposed because despite improving lithium levels, the patient did not improve clinically. ...
Lithium, a medication commonly used to treat bipolar disorders, has a narrow therapeutic index, putting patients at risk of lithium toxicity. Such toxicity could entail neurological-related complications and could be precipitated by several factors. In this paper, the authors discuss a case of a middle-aged woman taking lithium for bipolar disorder who presented to the emergency department with altered mental status, tremors, generalized weakness, and dysarthria. Multiple differential diagnoses were considered during her hospitalization, which included an admission to the intensive care unit. This case highlights the variability of lithium toxicity presentations and its management challenges. Further research is needed to understand such manifestations, potential precipitating factors, differential diagnoses, and effective detection and management.
... Fortunately, in most cases, full recovery follows when the lithium treatment is discontinued. However, in rare cases, lithium-induced persistent neurological sequelae have been reported [4]. Herein, we are presenting a 61-year-old male patient who developed expressive aphasia, cogwheel rigidity, ataxia, and fine tremors secondary to lithium toxicity, which showed partial improvement; however, it did not resolve completely after four months. ...
... However, if these symptoms, such as cerebellar impairment, extrapyramidal symptoms, and dementia, persist for two months or more after drug cessation, toxicity is labeled irreversible. In 1987, Adityanjee et al. suggested the acronym SILENT to describe the lithium-induced neurological symptoms that persist for at least two months after the discontinuation of the drug in the absence of previous neurological impairment [4,13]. In this case, we described a 61-year-old male patient who developed expressive aphasia, ataxia, fine tremors, and extrapyramidal symptoms after an acute on chronic lithium toxicity; these symptoms improved with time but did not resolve completely. ...
... Other precipitating factors include hypertension, chronic renal failure, heart failure, the rapid correction of hyponatremia or hyperlithemia, preexisting neurologic illness, and epilepsy [4]. Fever can be secondary to the intoxication itself, or it can be caused by secondary infection. ...
Lithium can have toxic effects on the central nervous system (CNS) that can be both acute and chronic. The syndrome of irreversible lithium-effectuated neurotoxicity (SILENT) was suggested in the 1980s to describe lithium intoxication-induced persistent neurological sequelae. In this article, we report a 61-year-old patient with bipolar disorder who had developed expressive aphasia, ataxia, cogwheel rigidity, and fine tremors after acute on chronic lithium toxicity. These neurological symptoms remained for four months after discontinuation of lithium, confirming the persistence of CNS signs and symptoms, which makes this case meets the SILENT syndrome criteria. Although rare, our report - which shows a severe and disabling form of SILENT syndrome - highlights the need for additional caution when treating patients with lithium and the need to perform strict control of the putative risk factors argued to be associated with the development of this syndrome.
... R apidly progressive dementia (RPD) is a neurological condition characterized by a decline in more than one cognitive domain with functional impairment in less than 1-2 years. Specific diagnosis is crucial, since 20-30% of the cases can be related to potentially reversible disorders [1][2][3] . There are several possible etiologies for RPD, including iatrogenic causes, such as medication toxicity. ...
... Patients using other medications are at higher risk of intoxication due to drug interaction. Both acute and chronic forms may occur, depending on the dose of lithium and the patient's risk factors 1,7 . In this case report, an important cognitive dysfunction occurred after at least 12 months of lithium intake, with worsening of cognitive symptoms after an episode of diarrhea and dehydration. ...
... Several tests have been described for the differential diagnosis of RPD. The investigation approach includes electroencephalogram (EEG), brain MRI, 18 F-FDG PET/CT, cerebrospinal fluid analysis, and AD biomarkers together with the measurement of lithium serum levels 1 . EEG has been described as an important follow-up method. ...
Rapidly progressive dementia (RPD) is a rare neurological disorder. Drug toxicity is among the differential diagnoses, including the use of lithium, in which an overdosage might cause cognitive dysfunction. Clinical suspicion, laboratory confirmation, and drug interruption are key points in the management of lithium intoxication. We described a 66-year-old female patient under treatment with lithium who developed an RPD associated with parkinsonian symptoms. 18F-fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG PET/CT) showed an “Alzheimer-like” pattern, while cerebrospinal fluid biomarkers for the disease were negative. There was a significant clinical and radiological improvement after lithium interruption. Lithium intoxication is a potentially reversible cause of RPD, as demonstrated in this case report. Drug discontinuation should be considered even in patients with normal levels of this metal, if cognitive impairment is detected. 18F-FDG PET/CT images may show an “Alzheimer-like” image pattern in acute intoxication and are useful for monitoring these patients.
... Finalement, le dysfonctionnement neurologique prolongé con stitue une importante complication de l'empoisonnement au lithium 4 . Le syndrome de neurotoxicité irréversible imputable au lithium (syndrome of irreversible lithiumeffectuated neurotox icity ou SILENT) se caractérise par des changements neurologiques persistant sur une période d'au moins 2 mois malgré le retrait de la thérapie au lithium 10 . Ce syndrome se manifeste largement au niveau du cervelet et peut comprendre des tremblements, un nystagmus et de la dysarthrie, entre autres 10 . ...
... Le syndrome de neurotoxicité irréversible imputable au lithium (syndrome of irreversible lithiumeffectuated neurotox icity ou SILENT) se caractérise par des changements neurologiques persistant sur une période d'au moins 2 mois malgré le retrait de la thérapie au lithium 10 . Ce syndrome se manifeste largement au niveau du cervelet et peut comprendre des tremblements, un nystagmus et de la dysarthrie, entre autres 10 . Il demeure incertain si une hémodialyse précoce ou agressive prévient le syndrome de neurotoxicité irréversible imputable au lithium et quels sont les principaux facteurs de risque qui prédisposent à ce trouble 10 . ...
... Ce syndrome se manifeste largement au niveau du cervelet et peut comprendre des tremblements, un nystagmus et de la dysarthrie, entre autres 10 . Il demeure incertain si une hémodialyse précoce ou agressive prévient le syndrome de neurotoxicité irréversible imputable au lithium et quels sont les principaux facteurs de risque qui prédisposent à ce trouble 10 . ...
... También tiene presentaciones atípicas, que incluyen nistagmo hacia abajo, neuritis óptica retrobulbar, papiledema persistente, movimientos coreoatetoides, neuropatía periférica (tanto motora como sensorial), miopatía y ceguera (debido a mielinolisis pontina central). Solo un caso reportó enfermedad encefalopática como déficit (tabla 1) 5 . ...
... La neurotoxicidad grave ocurre casi exclusiva-mente en el contexto de la administración terapéutica crónica de litio 3 ; en este contexto, el aumento de los niveles de litio inicia la cascada de acontecimientos que llevan al paciente al estado encefalopático. Se supone que la desmielinización extendida del sistema nervioso es la causa de SILENT 5 . ...
... Por lo tanto, no se puede exagerar el monitoreo de los niveles de litio. El síndrome de neurotoxicidad irreversible provocada por litio (SILENT) se acuñó después de informes de casos de déficits neurológicos persistentes después de la toxicidad por litio a pesar de la normalización de los niveles de litio (5). Es una rara secuela de la toxicidad por litio. ...
... En el contexto de la exposición crónica al litio, el aumento de los niveles de litio ha iniciado la cascada de eventos que llevan a nuestro paciente a este estado encefalopático. Se supone que la desmielinización causada por el litio en múltiples sitios del sistema nervioso es la causa de SILENT (5). ...
El litio sigue siendo el agente de primera línea para el trastorno bipolar. A pesar del conocimiento común sobre el monitoreo de los niveles de litio para prevenir la toxicidad, todavía ocurre en diversos grados. A continuación se presenta una rara secuela de toxicidad por litio, el Síndrome de Neurotoxicidad Irreversible secundaria a Litio (SILENT). Una mujer de la sexta década de la vida funcional a pesar de estar en terapia crónica con litio para el trastorno de estrés postraumático (TEPT) y el trastorno bipolar se presentó en la sala de emergencias con estado mental alterado y convulsiones asociadas con niveles elevados de litio e insuficiencia renal. Se administraron fármacos antiepilépticos para el control de las convulsiones. A pesar de la eliminación del agente agresor, la paciente siguió teniendo una ralentización generalizada en el EEG repetido con solo la apertura de los ojos y los movimientos de las extremidades sin propósito recuperados incluso después de más de 2 meses de suspensión del litio. SILENT se acuñó después de que se observaran informes de déficits neurológicos persistentes en pacientes que experimentaron toxicidad por litio más de 2 meses después de suspender el litio. La desmielinización es la característica típicamente reportada en el SILENT. También puede dejar al paciente en un estado encefalopático persistente. La toxicidad crónica por litio debido a la falta de seguimiento pone en riesgo a los pacientes que reciben terapia con litio razón por la cual debe hacerse un control adecuado de estos pacientes.
... In 1987, Adityanjee coined a new term: "SILENT"-the syndrome of irreversible lithium-effectuated neurotoxicity. 3 The subsequent body of literature in this area has focused on patients with long-lasting cerebellar effects, including ataxia and dysarthria. Neurologic imaging findings often correlate with the phenotypic presentation. ...
... 2 Separate from the cerebellum, there are reports of myelinolysis, both in the peripheral nerves as well as central pontine myelinolysis, as a sequelae of lithium poisoning. 3 The exact mechanism is not well understood. In settings of severe lithium toxicity, patients can develop hyperthermia, which can result in long-term neuropathologic sequelae secondary to protein coagulation and direct nervous tissue injury. ...
... Indeed, these pathological findings are not always related to serum [Li + ] levels and can be attributable to individual susceptibility [5]. Lithium neurotoxicity can range from confusion, ataxia, convulsions, lithium encephalopathy to the most problematic condition also known as syndrome of irreversible lithium-effectuated neurotoxicity (SILENT) [9][10][11]. 3 24.6 mEq/L BE − 0.10 mmol/L SILENT causes chronic, largely cerebellar sequelae, tremor, extrapyramidal symptoms, gait alterations, nystagmus, dysarthria and cognitive impairment. Actually, the prevalence of SILENT is not known as well as the definitive management [9][10][11]. ...
... 3 24.6 mEq/L BE − 0.10 mmol/L SILENT causes chronic, largely cerebellar sequelae, tremor, extrapyramidal symptoms, gait alterations, nystagmus, dysarthria and cognitive impairment. Actually, the prevalence of SILENT is not known as well as the definitive management [9][10][11]. ...
Lithium intoxication is still an undefined and underestimated disease, especially those cases requiring extracorporeal treatment. Lithium is a monovalent cation with small molecular mass of 7 Da that has been regularly and successfully used since 1950 in the treatment of mania and bipolar disorders. However, its careless assumption can lead to a wide spectrum of cardiovascular, central nervous system and kidney diseases in case of acute, acute on chronic and chronic intoxications. In fact, lithium serum range is strict between 0.6 and 1.3 mmol/L, with a mild lithium toxicity observed at the steady-state of 1.5–2.5 mEq/L, moderate toxicity when lithium reaches 2.5–3.5 mEq/L, and severe intoxication with observed serum levels > 3.5 mEq/L. Its favorable biochemical profile allows the complete filtration and partial reabsorption in the kidney due to the similarity to sodium and also the complete removal by renal replacement therapy, that should be considered in specific poisoning conditions. In this narrative and updated review we discussed a clinical case of lithium intoxication, the different pattern of diseases attributable to excessive lithium load and the current indications for extracorporeal treatment.
... In general, when treatment is discontinued, and the patient is hemodialyzed, the neurologic symptoms subside and the patient's consciousness returns to normal. 20 However, in some cases, those symptoms may persist for a long time despite hemodialysis, resulting in neurologic sequelae such as extrapyramidal symptoms or blindness. 20 Mr A did not receive hemodialysis because the neurologic symptoms developed acutely, and his symptoms were treated sufficiently with aggressive IV hydration upon arrival in the emergency department. ...
... 20 However, in some cases, those symptoms may persist for a long time despite hemodialysis, resulting in neurologic sequelae such as extrapyramidal symptoms or blindness. 20 Mr A did not receive hemodialysis because the neurologic symptoms developed acutely, and his symptoms were treated sufficiently with aggressive IV hydration upon arrival in the emergency department. Apart from IV hydration and hemodialysis, other treatment regimens for Li toxicity are gastric lavage and intestinal irrigation to limit the gastrointestinal absorption of lithium. ...
Lithium is among the mainstays of treatment for bipolar disorder. Bariatric surgery can considerably change the oral bioavailability of drugs, particularly lithium. In this review, a 36-year-old male patient is described, who presented with lithium toxicity, including neurologic and gastric symptoms after undergoing Roux-en-Y gastric bypass. The mechanism of lithium toxicity is discussed; recommendations for clinicians regarding lithium use in postsurgical patients are provided; and previous case reports of lithium toxicity post-gastric bypass surgery are analyzed. Awareness and education of lithium absorption changes postbariatric surgery is essential for optimal patient care. Close clinical and drug concentration level monitoring is warranted.
... First described by Verbov in 1965 [8], this complication was defined by Schou in 1984 as the persistence of neurological sequelae more than two months after lithium discontinuation [9]. In 1987, Adityanjee proposed to name this complication SILENT (Syndrome of Irreversible Lithium-Effectuated NeuroToxicity) [10]. Although a wide range of persisting neurological syndromes have been reported, a consistent finding across the literature is the high proportion of cerebellar sequelae, especially ataxia and dysarthria [9,[11][12][13][14][15]. ...
... We considered articles meeting the following inclusion criteria: (i) published in English, French, Spanish, Portuguese, Italian or German in peer-reviewed journals; (ii) reporting cases of neurological sequelae persisting more than two months after lithium discontinuation [9,10]. We did not consider cases for which the observation period after lithium discontinuation was not specified or lasted less than two months, including cases with fatal outcome within the two-month period. ...
Aim We aimed to review cases of Syndrome of Irreversible Lithium-Effectuated Neurotoxicity (SILENT) characterized by neurological sequelae following acute lithium toxicity and to explore whether cerebellar sequelae are more frequent in cases presenting with fever and/or infection. Methods Case reports were identified from: (i) 6 reviews published up to 2005; (ii) MEDLINE, Web of Sciences, Cochrane Library and PsycINFO search. Results We identified 123 SILENT cases published from 1965 to 2019, in which cerebellar sequelae were observed in an overwhelming proportion (79%). Nearly two out of three cases (63%) had maximal lithium plasma level <2.5 mEq/l (low/mild toxicity). Fever and/or infection were reported in nearly half of the patients (48%). The likelihood of presenting with cerebellar vs. other neurological sequelae was independently increased by elevated plasma lithium level ( 2.5 mEq/l) (OR=4.36, 95%CI 1.31-14.52, p = 0.02) and by a history of fever and/or infection (OR=6.48, 95%CI 2.0-21.0, p = 0.002). Conclusions During the SARS-CoV-2 pandemic, prescribers have to be aware of the risks of cerebral sequelae associated with infection and fever in lithium users, and should warn them of the need to consult in case of fever to adjust their lithium dosage. As the occurrence of SILENT is exceptional, there is no need to modify lithium treatment preventively because of the pandemic as the benefit/risk balance of this drug remains largely positive.
... Other neurological manifestations occasionally seen include extrapyramidal features, generalised polyneuropathies and neuromuscular features such as fasciculations and myoclonus (Grandjean 2009). Most symptoms and signs of lithium intoxication resolve as serum lithium levels normalise, but there is a risk of long-term neurological sequelae such as the syndrome of irreversible lithium-effectuated neurotoxicity (SILENT), which predominantly manifests as cerebellar dysfunction, with features of ataxia, dysarthria and dysmetria (Adityanjee 1987). ...
... Medications that interact with lithium to increase toxicity risk should be discontinued. Patients must also be counselled on the long-term risk of irreversible neurological sequelae (Adityanjee 1987). ...
Lithium is a gold standard maintenance treatment in bipolar affective disorder. It has a narrow therapeutic range, and at higher serum lithium levels there is a risk of adverse effects and toxicity. There are three patterns of lithium intoxication: acute, acute-on-chronic and chronic. We describe risk factors for lithium intoxication, mechanisms of toxicity and clinical symptoms seen in lithium intoxication. We describe both the acute and chronic effects of lithium toxicity. Lithium intoxication may be life-threatening and associated with longer-term sequelae. The management of lithium intoxication involves determining the type of intoxication. We discuss treatment strategies aimed at reducing absorption and increasing elimination of lithium. We discuss clinical indications for extracorporeal methods such as dialysis, which are used to limit the time and degree of exposure of the central nervous system to toxic lithium concentrations. Haemodialysis is the most rapid method of eliminating lithium from the body, but careful monitoring is required. Preventive strategies to mitigate the risk for lithium intoxication are discussed.
... 4 The syndrome of irreversible lithium-effectuated neurotoxicity (SILENT) is characterized by persistent neurologic changes despite withdrawal of lithium therapy for at least 2 months. 10 The manifestations of SILENT are largely cerebellar and may include tremor, nystagmus and dysarthria, among others. 10 It remains unclear whether early or aggressive hemodialysis prevents SILENT, and what specific risk factors predispose to this condition. ...
... 10 The manifestations of SILENT are largely cerebellar and may include tremor, nystagmus and dysarthria, among others. 10 It remains unclear whether early or aggressive hemodialysis prevents SILENT, and what specific risk factors predispose to this condition. 10 Lithium is a commonly prescribed medication with a narrow therapeutic index and may cause acute, chronic and acute-onchronic toxicity. ...
... Episodes of lithium intoxication are associated with later development of renal damage. However, the most important potential long-term irreversible effects of lithium intoxication are neurological, especially cerebellar damage, resulting in ataxia, dysarthria and dysmetria (Adityanjee et al., 2005). ...
Background
Lithium is our oldest continuously prescribed medication in psychopharmacology, with its history as an agent for treating mood disorders extending from the 19th century. Although clinicians prescribe it less frequently than in the past, its utility in treating bipolar disorder is unquestionable. Novel potential indications for its use in psychiatry have created excitement about broader roles for lithium in treating and preventing other disorders.
Content
Lithium is effective both in treating acute mania, as an adjunctive antidepressant, and as a maintenance treatment in bipolar disorder. Lithium has also shown some efficacy in treating and preventing unipolar depression, but less clearly than for bipolar maintenance treatment and acute mania. Common side effects include nausea, polyuria, tremor, weight gain and cognitive dulling. These side effects are typically manageable with reasonable clinical strategies. Lithium affects renal, thyroid and parathyroid function. With clinical monitoring, these effects are easily managed although infrequent cases of severe renal insufficiency may occur with long term use. Although not all studies are positive, a consistent database suggests the efficacy of lithium in decreasing suicide attempts and suicides, likely due to its effect on impulsivity and aggression as well as its prophylaxis against depressive and manic recurrences. Recent data have suggested lithium’s potential efficacy for a number of new clinical indications. Lithium’s neuroprotective effects suggest potential efficacy in preventing mild cognitive impairment (MCI) and dementia as well as in aiding recovery from strokes. Higher (but still trace) lithium levels in drinking water are associated with lower rates of dementia. It is still not clear how much lithium-and what serum lithium levels- are required for either of these effects. Other preliminary research suggests that lithium may also have antiviral effects and may decrease cancer risk.
Conclusions
Lithium continues to be the mainstay treatment of mood disorders in general and in bipolar disorder specifically. Other potential clinical uses for lithium in psychiatry have re-invigorated excitement for research in other areas such as suicide, preventing cognitive impairment and possibly preventing viral infections and diminishing cancer risk.
... To view a copy of this licence, visit http://creativecommons.org/licenses/by-nc-nd/4.0/. among the elderly population (Arnaoudova 2014;Adityanjee and Thampy 2005). These concerns are perhaps exaggerated as there is controlled evidence that Li can be safely used even in cognitively impaired elderly (Aprahamian et al. 2014) and Li-treated elderly individuals even show superior general and mental health outcomes than their BD counterparts who are not treated with Li . ...
Background
Since its debut in 1949, lithium (Li) has been regarded as a gold standard therapy for mood stabilization. Neuroprotective effects of Li have been replicated across many different paradigms ranging from tissue cultures to human studies. This has generated interest in potentially repurposing this drug. However, the optimal dosage required for neuroprotective effects remains unclear and may be different than the doses needed for treatment of bipolar disorders. Recent studies on trace-Li levels in the water suggest that Li, could slow cognitive decline and prevent dementia with long-term use even at very low doses. The current review aims to synthesize the data on the topic and challenge the conventional high-dose paradigm.
Results
We systematically reviewed five available studies, which reported associations between trace-Li in water and incidence or mortality from dementia. Association between trace-Li levels and a lower risk or mortality from dementia were observed at concentrations of Li in drinking water as low as 0.002 mg/L and 0.056 mg/L. Meanwhile, levels below 0.002 mg/L did not elicit this effect. Although three of the five studies found dementia protective properties of Li in both sexes, a single study including lower Li levels (0.002 mg/l) found such association only in women.
Conclusion
The reviewed evidence shows that trace-Li levels in the water are sufficient to lower the incidence or mortality from dementia. Considering the lack of options for the prevention or treatment of dementia, we should not ignore these findings. Future trials of Li should focus on long term use of low or even micro doses of Li in the prevention or treatment of dementia.
... 10 Según compilaciones realizadas por Adityajee hasta el 2005, solamente unos 90 casos de toxicidad irreversible han sido reportados. 7 El presente reporte de caso clínico fue llevado a cabo de acuerdo a los lineamientos del CARE (Guidelines for Case Reports). 11 ...
... Lithium has a narrow therapeutic index and acute toxicity is associated with various neurological signs including encephalopathy, tremor, and cerebellar and brainstem dysfunction; less commonly, downbeat nystagmus, choreoathetoid movements, peripheral neuropathy, myopathy, and optic neuritis have been described [1]. Risk factors for toxicity include renal failure, dehydration, duration of exposure to elevated serum lithium levels, existence of previous neurological sequela, concomitant consumption of neuroleptics or valproate, fever, hyponatremia, nephrogenic diabetes insipidus, age > 50 years, thyroid dysfunction, and impaired creatinine clearance [2,3]. Acute toxicity is reversible with drug discontinuation and hemodialysis if indicated. ...
We report a case study of a 60-year-old man with bipolar disorder on stable lithium treatment who developed severe toxicity while admitted to ICU with sepsis and multiorgan failure. Despite unchanged lithium administration, his serum levels escalated due to renal dysfunction, resulting in lithium toxicity. After regaining consciousness, he exhibited a cerebellar syndrome marked by ataxia, tremor, and scanning speech. MRI revealed cerebellar atrophy. Following discontinuation of lithium and hemodialysis, the patient’s symptoms remained static. The patient was diagnosed with syndrome of irreversible lithium-effectuated neurotoxicity (SILENT), a chronic cerebellar disorder characterized by persistent ataxia, nystagmus, and gait abnormalities extending beyond two months post-lithium exposure. The disorder has a predilection for cerebellar and basal ganglia dysfunction. MRI findings include cerebellar gliosis and atrophy and leptomeningeal enhancement. This case report highlights that SILENT is both preventable and permanent, urging heightened awareness among clinicians to facilitate early detection and intervention. Patients on lithium with compromised renal function or fever necessitate vigilant lithium level monitoring, dose adjustment, or cessation, to forestall enduring morbidity. This case emphasizes the significance of recognizing and managing SILENT, particularly in critical care settings, to mitigate long-term cerebellar impairment and optimize patient outcomes.
... There are many risk factors for developing lithium-induced neurologic sequelae, such as fever, acute intoxications or abrupt discontinuation of lithium, rapid correction of hypernatremia or hyperlithemia, concomitant use of antidepressants and antipsychotics, neurologic illness, hypertension, and chronic renal disease. In this way, it is essential to continuously monitor lithium serum levels and establish stricker exclusion criteria for initiating therapy [18]. To further investigate and exclude SILENT, an EMG was also performed, which provided evidence ruling out lithium-induced irreversible neurotoxicity. ...
Lithium salts (lithium) is a psychotropic drug widely used as a pharmacological option in managing bipolar disorder. Regular monitoring of serum levels is necessary due to the narrow therapeutic range of lithium. Typically, the diagnosis of lithium intoxication is based on the presence of elevated plasma levels. Nevertheless, poisoning can ensue from either acute ingestion or chronic use, even in patients with normal plasma levels. The utilization of lithium has been decreasing due to its potential for multiorgan toxicity. Lithium accumulation in renal distal tubular cells is a prevalent cause of acquired arginine vasopressin resistance (AVP-R), previously known as nephrogenic diabetes insipidus (DI). Some patients might also experience neurologic persistent symptoms after plasma level normalization, a condition known as the syndrome of irreversible lithium-effectuated neurotoxicity (SILENT). We present a case report of acquired AVP-R following prolonged lithium use. This case report aims to increase awareness, particularly among those who may be unfamiliar with the use of lithium and its associated adverse reactions. In addition, it seeks to highlight the dissociation between clinical manifestations and lithium plasma levels, emphasizing the need for careful evaluation in patients receiving lithium treatment.
... The present study found that patients with severely lithium intoxication (>3 mmol/L) experienced more severe neurological problems than those with mild and moderate toxicity (<1.2 and 1.2-3 mmol/L, respectively). Over than 100 instances of lithium neurotoxicity have been documented thus far (50). Traditionally, it was believed that lithium-associated neurotoxicity was transitory; unfortunately, Cohen and Cohen's 1976 publication of irreparable brain damage linked to the combination of lithium and haloperidol raised awareness of the danger of irreversible brain damage linked to lithium (51). ...
Background: Lithium was once the drug of choice for treating bipolar disorder. It has a low therapeutic efficacy and frequently appears in hazardous concentrations in clinical practice. It has been found that long-term lithium intoxication, which is caused by lithium gradually building up, is more common. The overwhelming majority of the symptoms are neurological; commonly, the mental state is disturbed and could even become coma-like. Aim: To measure the clinical, laboratory, and neurological changes of lithium toxicity in patients with bipolar disorder in correlation with these effects with periodic lithium level monitoring. Methods: In order to pinpoint individuals with euthymic BD based on various serum concentrations (<1.2, 1.2-3, and >3 mmol/L), the cohort research was carried out in Al Azhar New Damietta Hospital from September 1, 2022 to the end of January 2023. Disease was confirmed using the Young Mania Rating Scaling (YMRS) and the structured diagnostic examination for DSM-V axis I disorders. Demographic, clinical, and laboratory data were obtained for analysis. Results: The distribution of severe/moderate/mild neurological symptoms for the >3 mmol/L, 1.2-3 mmol/L and <1.2 mmol/L groups were 0/10/40, 10/15/10 and 20/0/0 % respectively (p< 0.05). Cardiovascular symptoms appeared more common in patients receiving >3 mmol/L of lithium than those receiving 1.2-3 mmol/L and <1.2 mmol/L of lithium level (10% versus 5 and 0%, respectively p < 0.05). The blood urea nitrogen, creatinine and TSH levels significantly increased in severe toxic lithium level (>3 mmol/L, p<0.05). e380 Clinical, laboratory and neurological assessment of lithium toxicity in patients with bipolar disorders JPopulTherClinPharmacolVol30(4):e379-e391;17March2023. ThisarticleisdistributedunderthetermsoftheCreativeCommonsAttribution-Non Commercial 4.0InternationalLicense.©2021MuslimOTet al. Conclusion: Participants receiving continuous lithium treatment should be closely watched for its toxicity and administered right away in the event of poisoning due to the outstanding results of detoxification programs.
... In 1980s it was first instituted that neurotoxicity with lithium is not merely an acute complication and for symptoms persisting beyond 2 months, a new term was coined -SILENT (11). In a review by Adityanjee et al of 90 cases of patients with persistent deficits the clinical manifestations varied from cerebellar dysfunction, extrapyramidal syndrome, brainstem dysfunction or dementia with varying organic mental syndromes to atypical presentations such as downbeat nystagmus, retrobulbar optic neuritis, persistent papilledema, choreoathetoid movements, peripheral neuropathy (both motor and sensory), myopathy and blindness due to central pontine myelinolysis (12). Our patient had bilateral sensory and motor neuropathy in the lower limbs. ...
Objective: Lithium is a principal drug used in the treatment of bipolar disorder (BPD). Due to its narrow therapeutic index, serum levels need to be monitored regularly. In elderly patients with renal dysfunction lithium toxicity can develop paradoxically within the therapeutic range. This can lead to erroneous diagnosis and delayed treatment resulting in irreversible neurological sequelae as is described in our case. Case Presentation: A 65-year-old hypertensive female, with a 7-year history of BPD presented with decreased oral intake since 5-7 days, followed by altered sensorium. Neurological examination revealed coarse tremors in bilateral upper and lower limbs with spasticity, hyperreflexia, bilateral knee clonus. Twenty-five days earlier, she was prescribed Lithium carbonate. On evaluation she was found to have chronic kidney disease. Serum lithium levels came out to be 1.18 mg/dL (borderline high). After ruling out other differentials, a diagnosis of lithium toxicity was considered and she underwent two sessions of hemodialysis (HD) leading to significant improvement in sensorium; however, the patient had persistent dysarthria, difficulty in walking and proximal myopathy predominantly in the lower limbs. Nerve conduction studies confirmed the presence of axonal neuropathy. These findings of peripheral neuropathy (both sensory and motor) were suggestive of SILENT (syndrome of irreversible lithium-effectuated neurotoxicity). Conclusion: Unintended lithium toxicity can occur even at therapeutic levels especially in the elderlies owing to its narrow therapeutic window, complex pharmacokinetics and numerous drug interactions. Lithium can result in irreversible neurotoxicity including SILENT; therefore, a high level of suspicion is required to prevent such permanent disability.
... Lithium poisoning has characteristic acute symptoms as well as a long-term syndrome of irreversible lithium-effectuated neurotoxicity (SILENT) [1], but possible persistent cognitive impairment has not been widely discussed. A patient who presented with a lithium serum level of 3.3 was found to have progressively declining mental status for months after discharge. ...
A 49-year-old female taking lithium for bipolar affective disorder for over 20 years presented with lithium toxicity resulting in declining mentation. Lithium poisoning has been well documented to cause acute gastrointestinal, cardiac, and neurological side effects, along with long-term neurologic sequelae. There has, however, been scant discussion on the potential long-term effects on mentation. The following case report illustrates a possible example.
... Chronic diseases and lifestyle habits linked to clinically increased inflammation in mood disorders are included in our model. Weight gain,low HDL levels, increased triglyceride levels, chronically raised blood pressure, medical treatment of hypothyroidism, migraines, rheumatoid arthritis, adult beginning diabetes, inflammatory bowel disorders, inflammatory skin types,and daily practices such as smoking and chronic pressure are all part of this "inflamed depression" model [6]. Hypothyroidism is diagnosed based on your warning signs and the outcomes of blood tests that detect TSH and, in some cases, thyroxine, the thyroid hormone. ...
Background: To determine the impact of treating clinical hypothyroidism during gestation on maternal depressive symptoms. Methods: Females with singleton pregnancies identified clinical hypothyroidism were randomised to prenatal thyroxine medication or sample in an auxiliary study to a multicenter trial. At the end of the pregnancy, the treatment was stopped. Females with overt thyroid disorder, diabetes, autoimmune disorder, or depression were excluded from the study. Before taking the survey medicine (between 3-4 months of pregnancy), between 32 and 38 weeks of pregnancy, and at one year post-delivery, contestants were examined for forbidding symptoms with the help of the Center for Epidemiological Studies-Anxiety zone(CES-D). The primary result was a score on the CES-D for mother depressive symptoms. Results: In individuals with schizophrenia spectrum disorders, imbalanced thyroid hormonal state in general, as well as hypothyroidism and hyperthyroidism, were found in 29.3, 25.17, and 4.08 percent, respectively. These figures were similar to those seen in patients with mental abnormalities (23.24, 21.62 and 1.62 percent, respectively). Anti TPO positivity was found in 11 of the 18 patients with schizophrenia scale illness. There were no distinctions based on gender. Conclusions: Patients with schizophrenia-spectrum disease and mood swings both had thyroid abnormalities. Patients with schizophrenia-spectrum abnormalities were more probably to have autoimmune thyroid disease than those with mood swings. The results highlight the importance of evaluating individuals with schizophrenia-scale abnormalities for thyroid hormone abnormalities and how it affects hypothyroidism.
... Lithium is well recognized mood stabilizer and state of the art treatment for bipolar affective disorder. Treatment with Lithium has been known to be associated with adverse side effects if serum lithium monitoring is not done [1][2]. Lithium is known to cause neurotoxicity and nephrotoxicity at high therapeutic doses and its manifestations vary from coarse tremors to coma [3]. ...
... Respecto al abordaje terapéutico del SILENT, en general las secuelas son persistentes y no existe un tratamiento eficaz. Se ha propuesto la hemodiálisis como tratamiento en la fase precoz de la intoxicación por litio, con controles de los niveles plasmáticos durante y posterior al procedimiento 1,10 . En nuestro caso se inició tratamiento con levodopa/carbidopa, con alivio sintomático parcial de los movimientos coreoatetósicos. ...
... High Li levels can also lead to dysfunction of sinus node dysfunction, prothrombin ratio (PR), QT prolongation (a measure between Q wave and T wave in the heart's electrical cycle), heart blocks, and ventricular tachyarrhythmias (Goldberger, 2007;Mehta and Vannozzi, 2017;Waring, 2007). Lithium overdose can induce several nephrological disorders in humans such as cognitive impairment, coma, autism, and stupor, and weight gain (McKnight et al., 2012;Munshi and Thampy, 2005). ...
With the ever-increasing demand for lithium (Li) for portable energy storage devices, there is a global concern associated with environmental contamination of Li, via the production, use, and disposal of Li-containing products, including mobile phones and mood-stabilizing drugs. While geogenic Li is sparingly soluble, Li added to soil is one of the most mobile cations in soil, which can leach to groundwater and reach surface water through runoff. Lithium is readily taken up by plants and has relatively high plant accumulation coefficient, albeit the underlying mechanisms have not been well described. Therefore, soil contamination with Li could reach the food chain due to its mobility in surface- and ground-waters and uptake into plants. High environmental Li levels adversely affect the health of humans, animals, and plants. Lithium toxicity can be considerably managed through various remediation approaches such as immobilization using clay-like amendments and/or chelate-enhanced phytoremediation. This review integrates fundamental aspects of Li distribution and behaviour in terrestrial and aquatic environments in an effort to efficiently remediate Li-contaminated ecosystems. As research to date has not provided a clear picture of how the increased production and disposal of Li-based products adversely impact human and ecosystem health, there is an urgent need for further studies on this field.
... Lithium administration inhibits GSK3 in mouse models of AD and promotes Aβ and Tau neuropathology, facilitates LTP (long-term potentiation) induction and improves cognitive performance [175,[227][228][229]. Lithium also reduces neuronal dysfunction in an Drosophila model of AD in which Aβ is inducibly-overexpressed in adult flies [230]. However, lithium is a poor drug candidate for use in humans because of its narrow therapeutic window and serious side effects, including neurotoxicity, particularly in the elderly [231][232][233]. Lithium is also known to inhibit other enzymes and that its beneficial effects in AD mice is due to inhibition of GSK3 has yet to be established [234,235]. ...
Alzheimer’s disease (AD) is a mostly sporadic brain disorder characterized by cognitive decline resulting from selective neurodegeneration in the hippocampus and cerebral cortex whereas Huntington’s disease (HD) is a monogenic inherited disorder characterized by motor abnormalities and psychiatric disturbances resulting from selective neurodegeneration in the striatum. Although there have been numerous clinical trials for these diseases, they have been unsuccessful. Research conducted over the past three decades by a large number of laboratories has demonstrated that abnormal actions of common kinases play a key role in the pathogenesis of both AD and HD as well as several other neurodegenerative diseases. Prominent among these kinases are glycogen synthase kinase (GSK3), p38 mitogen-activated protein kinase (MAPK) and some of the cyclin-dependent kinases (CDKs). After a brief summary of the molecular and cell biology of AD and HD this review covers what is known about the role of these three groups of kinases in the brain and in the pathogenesis of the two neurodegenerative disorders. The potential of targeting GSK3, p38 MAPK and CDKS as effective therapeutics is also discussed as is a brief discussion on the utilization of recently developed drugs that simultaneously target two or all three of these groups of kinases. Multi-kinase inhibitors either by themselves or in combination with strategies currently being used such as immunotherapy or secretase inhibitors for AD and knockdown for HD could represent a more effective therapeutic approach for these fatal neurodegenerative diseases.
Aim of the study was to evaluate the effect of lithium- and melatonin-containing sorbent based on aluminum oxide and polydimethylsiloxane on changes in the number of platelets during hemosorption modeling and on the features of the hemostatic response during dosed contact of the sorbent with blood in an in vitro experiment. Material and methods . An analysis of the effect of the porous sorbent modified with melatonin (MT, 0.15 %) and lithium (0.5 %) based on aluminum oxide and polydimethylsiloxane (Al 2 O 3 @PDMS/MT-Li) was carried out in comparison with sorbent without modifiers (Al 2 O 3 @PDMS) and modified with MT (Al 2 O 3 @PDMS/MT) on a number of donor blood clotting parameters under in vitro hemosorption conditions. Studies of the hemostatic system included assessment of platelet count, chronometric parameters, fibrinogen concentration, antithrombin activity and plasminogen content. For integral assessment, calibrated thrombography and computer thromboelastometry were used. Results and discussion. Contact of all studied sorbents with blood causes a moderate decrease in the number of platelets (by 5.3–10.1 % from initial). Comparison sorbents reduce fibrinogen concentration by 7.1–7.7 %, Al 2 O 3 @PDMS/MT-Li – by 2.6 times, which is likely due to the methodology for determining this protein against the background of the independent anticoagulant activity of lithium ions. Al 2 O 3 @PDMS and Al 2 O 3 @PDMS/MT cause the development of a hypercoagulable shift, as evidenced by a shortening of kaolin time (by 27.5 and 22.1 %, respectively) and of activated partial thromboplastin time (APTT) by 7.1 % for both sorbents. At the same time, when lithium was included in the sorbent, not only did the hypercoagulation shift not occur, but blood clotting was also inhibited, as evidenced by an increase in kaolin time and APTT by 1.2 and 1.6 times, respectively, as well as in silicone time. Conclusions. Modifying sorbents with biologically active substances, lithium and MT, makes it possible to obtain an original hemosorbent with new properties. The presented results demonstrated the absence of a hypercoagulable shift in donor blood after contact with a lithium-, MTcontaining sorbent in vitro and indicate the potential for its using as a basis for the development of safe drugs.
Introduction:
The Extracorporeal Treatments in Poisoning (EXTRIP) workgroup suggests hemodialysis in severe lithium poisoning if specific criteria are met. One criterion is if the expected time to obtain a lithium concentration <1.0 mEq/L with optimal management is >36 h. There are a lack of data regarding which patient characteristics are associated with the rate at which patients achieve a lithium concentration <1.0 mEq/L.
Methods:
We conducted a retrospective chart review analyzing hospital electronic medical records. Inclusion criteria consisted of a lithium concentration >1.2 mEq/L during hospitalization. We excluded patients who received extracorporeal treatment before 36 h elapsed from time of initial lithium concentration >1.2 mEq/L. The primary analysis consisted of a Cox regression and a secondary analysis evaluated the nomogram method described by Buckley and colleagues for predicting prolonged supratherapeutic lithium concentration.
Results:
One hundred and one patients were included in the study. The median time to reach a lithium concentration <1.0 mEq/L was 42.5 h (IQR: 33.8-51.1). Older patients, patients taking a thiazide, angiotensin-converting enzyme inhibitor or angiotensin receptor blocker, patients with a higher initial lithium concentration, and patients with higher sodium concentrations achieved a lithium concentration <1 mEq/L at a slower rate. For the nomogram analysis, sensitivity (61.5%) and specificity (54.5%) were moderate, the positive predictive value (16.7%) was poor, and the negative predictive value (90.6%) was excellent.
Discussion:
The results from our primary analysis suggest that identifying higher serum sodium concentration and use of certain antihypertensives that decrease glomerular filtration rate as predictors of an increased time to reach a therapeutic lithium concentration may help identify patients who meet the Extracorporeal Treatments in Poisoning criteria for hemodialysis. The nomogram method performed similarly to prior validation studies.
Conclusions:
In this retrospective chart review of patients with supratherapeutic lithium concentrations, we identified several risk factors for prolonged supratherapeutic lithium concentrations.
Many geriatric psychiatry cases are initially encountered in the general hospital or emergency room, where the psychiatric services rendered are accomplished by the consultation-liaison psychiatry (formerly psychosomatic medicine) service. As such, the areas of responsibility of consultation-liaison psychiatrists and geriatric psychiatrists overlap significantly. Specific areas of clinical expertise that are priorities for consultation-liaison psychiatrists include determinations of decisional capacity, evaluation and management of neurocognitive disorders, and assessment and management of catatonia, neuroleptic malignant syndrome, serotonin syndrome, and the toxicity states associated with CNS-active medications. The psychotherapeutic role of the consultation-liaison psychiatrist is commingled with the medical management role. Patients in the hospital, particularly geriatric patients, are at risk for many psychiatric syndromes (including depressive disorders and posttraumatic stress disorder) that are directly referable to the disruptive and traumatic experiences of medical/surgical illness, traumatic injury, and existential matters of disability and death. Consultation-liaison psychiatry, therefore, is an integrative subspecialty of psychiatry that occupies a crucial place “between” psychiatry and the numerous other medical specialists working with hospitalized patients. The authors highlight some important roles for consultation-liaison psychiatrists and present two complex cases to illustrate the framework of consultation-liaison psychiatry and various illness-specific psychiatric interventions.
Background: Bipolar disorder (BD) affects a significant portion of the global population, with lithium being a cornerstone in its treatment. However, the therapeutic index of lithium is narrow, and its effectiveness can be overshadowed by the risk of toxicity, especially at higher serum levels. Understanding the impact of varying lithium concentrations on clinical, biochemical, and neurological outcomes is crucial in the management of BD. Objective: To assess the clinical, biochemical, and neurological changes associated with different levels of lithium toxicity in patients with bipolar disorder and to determine the safe and effective range of lithium serum levels. Methods: A prospective cross-sectional study was conducted at Jinnah Post Graduate Medical Center, Karachi, involving 100 bipolar disorder patients on lithium therapy, categorized into three groups based on their serum lithium levels: Category I (<1.2 mmol/L), Category II (1.2 – 2.5 mmol/L), and Category III (>2.5 mmol/L). Clinical assessments, laboratory investigations (including renal and thyroid function tests), and neurological evaluations were conducted. Data were analyzed using SPSS version 25, with the t-test and Chi-square test employed for quantitative and qualitative comparisons, respectively. Results: Patients with serum lithium levels above 2.5 mmol/L (Category III) demonstrated significantly higher rates of clinical toxicity, renal dysfunction, and neurological complications compared to lower lithium level groups. Renal function parameters (serum creatinine and urea) and thyroid function (TSH levels) were notably altered in Category III. The incidence of neuropsychiatric symptoms was also significantly higher in this group, with severe neurotoxic effects observed in 27% of these patients. Conclusion: The study highlights the critical importance of maintaining serum lithium levels within a therapeutic range to avoid severe adverse effects. Lithium levels above 2.5 mmol/L significantly increase the risk of renal dysfunction, thyroid abnormalities, and neurotoxicity. Regular monitoring and individualized treatment adjustments are essential for optimizing patient safety and treatment efficacy.
A 67-year-old female taking lithium for mood disorder presented with lithium toxicity resulting in altered sensorium. Lithium toxicity leads to neurological, cardiac, and gastric side effects along with long-term neurologic consequences. Intelligence and mental activity can also be affected. The following case report illustrates the fact that lithium might lead to altered sensorium.
This text discusses a case report of an affected person with bipolar ailment who developed the syndrome of irreversible lithium effectuated neurotoxicity (SILENT). In this case of a 62-year-old man with bipolar affective disorder, we found how continual lithium therapy can position a patient requiring chronic mood stabilizer treatment vulnerable to developing the silent syndrome. The case presentation covered a set of symptoms inclusive of encephalopathy, cerebellar dysfunction, stress, and limb tremors at the time of admission. A serial neurological examination and mental status examination for ascertaining the diagnosis of the silent syndrome were carried out, and the affected person was advised to discontinue lithium and was handled symptomatically for other symptoms. We ought to identify and manage the hazard elements contributing to the development of this syndrome.
Sole litu są powszechnie stosowanym stabilizatorem nastroju o wąskim zakresie terapeutycznym. Jego przekroczenie oraz długotrwała terapia obarczone są ryzykiem wystąpienia ostrych i przewlekłych powikłań ze strony układów: sercowo-naczyniowego, pokarmowego, moczowego oraz dokrewnego. Do najczęstszych zaliczana jest hiperkalcemia mogąca stanowić niezależną przyczynę objawów układowych. Omówiono przypadek 66-letniej chorej długotrwale stosującej lit z powodu choroby afektywnej dwubiegunowej, u której wystąpiły objawy neuropsychiatryczne z towarzyszącymi wykładnikami ostrego uszkodzenia nerek. W toku diagnostyki stwierdzono hiperkalcemię oraz przedawkowanie litu. Dodatkowo pacjentka prezentowała liczne zaburzenia mogące wynikać z ostrego zatrucia litem, ale także toksyczności przewlekłej w tym: niedoczynność tarczycy, bradykardię, zespół parkinsonowski. Po odstawieniu litu i zastosowaniu leczenia zachowawczego hiperkalcemii oraz ostrego uszkodzenia nerek uzyskano znaczną poprawę kliniczną. Natomiast parametry nerkowe oraz stężenie wapnia w surowicy krwi powróciły do normy dopiero po upływie sześciu miesięcy od wypisu ze szpitala. Celem pracy było nakreślenie profilu możliwych działań niepożądanych leczenia litem, które składają się na złożony obraz kliniczny. Przedstawiono postępowanie diagnostyczno-terapeutyczne w hiperkalcemii i zatruciu litem oraz sposoby zapobiegania ich wystąpieniu.
A variety of etiologies can cause cerebellar dysfunction, leading to ataxia symptoms. Therefore, the accurate diagnosis of the cause for cerebellar ataxia can be challenging. A step-wise investigation will reveal underlying causes, including nutritional, toxin, immune-mediated, genetic, and degenerative disorders. Recent advances in genetics have identified new genes for both autosomal dominant and autosomal recessive ataxias, and new therapies are on the horizon for targeting specific biological pathways. New diagnostic criteria for degenerative ataxias have been proposed, specifically for multiple system atrophy, which will have a broad impact on the future clinical research in ataxia. In this article, we aim to provide a review focus on symptoms, laboratory testing, neuroimaging, and genetic testing for the diagnosis of cerebellar ataxia causes, with a special emphasis on recent advances. Strategies for the management of cerebellar ataxia is also discussed.
Lithium’s (Li) ubiquitous distribution in the environment is a rising concern due to its rapid proliferation in the modern electronic industry. Li enigmatic entry into the terrestrial food chain raises many questions and uncertainties that may pose a grave threat to living biota. We examined the leverage existing published articles regarding advances in global Li resources, interplay with plants, and possible involvement with living organisms, especially humans and animals. Globally, Li concentration (<10–300 mg kg−1) is detected in agricultural soil, and their pollutant levels vary with space and time. High mobility of Li results in higher accumulation in plants, but the clear mechanisms and specific functions remain unknown. Our assessment reveals the causal relationship between Li level and biota health. For example, lower Li intake (<0.6 mM in serum) leads to mental disorders, while higher intake (>1.5 mM in serum) induces thyroid, stomach, kidney, and reproductive system dysfunctions in humans and animals. However, there is a serious knowledge gap regarding Li regulatory standards in environmental compartments, and mechanistic approaches to unveil its consequences are needed. Furthermore, aggressive efforts are required to define optimum levels of Li for the normal functioning of animals, plants, and humans. This review is designed to revitalize the current status of Li research and identify the key knowledge gaps to fight back against the mountainous challenges of Li during the recent digital revolution. Additionally, we propose pathways to overcome Li problems and develop a strategy for effective, safe, and acceptable applications.
Lithium remains the drug of first choice for prophylactic treatment of bipolar disorder, preventing the recurrences of manic and depressive episodes. The longitudinal experiences with lithium administration greatly exceed those with other mood stabilizers. Among the adverse side effects of lithium, renal, gastrointestinal, neurological, thyroid, metabolic, cognitive, dermatological, cardiologic, and sexual are listed. Probably, the most important negative effect of lithium, occurring mostly after 10–20 years of its administration, is interstitial nephropathy. Beneficial side-effects of long-term lithium therapy also occur such as anti-suicidal, antiviral, and anti-dementia ones. Pharmacokinetic and pharmacodynamic interactions of lithium, mostly those with other drugs, may have an impact on the success of long-term lithium treatment. This paper makes the narrative updated review of lithium-induced side-effects and interactions that may influence its prophylactic effect in bipolar disorder. Their description, mechanisms, and management strategies are provided. The papers appearing in recent years focused mainly on the long-term lithium treatment are reviewed in detail, including recent research performed at Department of Psychiatry, Poznan University of Medical Sciences, Poland. Their own observations on ultra-long lithium treatment of patients with bipolar disorder are also presented. The review can help psychiatrists to perform a successful lithium prophylaxis in bipolar patients.
The developmental history of lithium and its physicochemical properties, pharmacokinetics, and mechanisms of action are presented. Among the latter, the effect on the phosphatidylinositol (PI) system and the inhibition of the glycogen synthase kinase 3beta (GSK-3β) activity are the most important. Lithium makes a prototype of the mood-stabilizing drug, is regarded as the drug of the first choice for the prophylaxis of bipolar disorders, and, as a monotherapy, surpasses all other mood stabilizers. The drug can also be used in the treatment of acute episodes of mood disorders, especially for the augmentation of antidepressants in treatment-resistant depression. Lithium possesses significant anti-suicidal properties, the strongest among all mood stabilizers. The drug exerts antiviral, especially against herpes infection, and immunomodulatory influence. The evidence has also been accumulated for the neurotrophic and neuroprotective effects of lithium. Neuroimaging studies in bipolar subjects showed an increase in the volume of some brain structures during lithium administration. Lithium therapy is associated with numerous side effects, most of them can be successfully managed. Given lithium superiority for the prophylaxis of mood disorders, together with its anti-suicidal, immunomodulatory, and neuroprotective effects, the drug is currently greatly underprescribed, and its therapeutic potential in patients with bipolar disorder is not sufficiently utilized. Recently, epidemiological data suggest an association between lithium intake and dementia risk reduction. In experimental models of neurodegenerative disorders, lithium exhibits significant therapeutic activity. Promising results have also been obtained in some clinical studies.
Lamotrigine（LTG）は，てんかんや双極性障害に対し小児から成人まで幅広く投与されている薬剤である。今回我々は，初期投与量のLTG 25mg/dayで皮膚粘膜眼症候群（Stevens–Johnson症候群：SJS）を発症し集中治療の末救命しえたが，リチウム中毒によると思われる失調性構音障害を残した症例を経験した。本例の初期症状は急性咽頭炎様の所見を呈し，口腔粘膜症状や皮疹に乏しく感染症との鑑別を要し，SJSの診断に難渋した。症例報告をするとともに文献的考察を行い，近年報告されているLTGによる重症薬疹の注意喚起をし，リチウム服用者の留意点についてリチウム中毒による神経学的後遺症の観点から述べる。 Recently, patients with epilepsy or bipolar disorder increasingly are prescribed lamotrigine (LTG). A 31–year–old woman presented with Stevens–Johnson syndrome (SJS) because of an initial dosage of LTG 25mg/day and was treated by intensive care. Furthermore, she also suffered from ataxic dysarthria possible to be caused by lithium toxicity. She initially presented with only fever and throat pain, and so it was difficult to differentiate SJS from other infectious diseases. We report and describe this case using a literature study. We call attention to serious adverse drug eruption induced by Lamotrigine and to neurological sequelae due to lithium toxicity.
BACKGROUND
Bipolar disorder is a chronic psychological disorder and lithium remains the mainstay of therapy. Lithium toxicity can be acute or chronic and the effects may be disabling or life-threatening. The presence of risk factors can increase the chances of lithium toxicity in a patient on long-term lithium therapy. We hereby report a case of chronic lithium toxicity in a patient with a known case of bipolar disorder.
CASE PRESENTATION
A 44-year-old female patient who is a known case of bipolar disorder presented with altered sensorium, seizures and renal insufficiency. On admission, the patient was severely dehydrated and the serum lithium level was 3.43mEq/L. Hemodialysis was performed and she improved gradually.
CONCLUSION
Over the years from its approval, lithium constantly proves to be effective in reducing suicidal rates in patients with bipolar disorder. However, its use is limited due to the risk of toxicity. The chances of developing toxicity are more in patients who are on long-term lithium therapy. Patients with high risk factors for toxicity should be monitored frequently as the effects of lithium toxicity can be fatal.
A combination of treatments are usually preferred by psychiatrists in managing acute manic exacerbations in patients with bipolar disorder. The most commonly used mix of psychotropic drugs to control mania consists of a known mood stabilizer - such as lithium or divalproex - plus an antipsychotic, though, these drugs can cause serious side effects. Neuroleptic Malignant Syndrome (NMS) occurs rarely in patients taking antipsychotic drugs and this infrequency makes diagnosis difficult in critically ill, Intensive Care Unit (ICU) patients. On the other hand, lithium toxicity can occur frequently in patients with bipolar disorder due to its narrow therapeutic index. Although rare, lithium toxicity and NMS may occur simultaneously in patients using antipsychotics and lithium together, resulting in severe morbidity or even mortality. The following research describes a patient on concomitant olanzapine and lithium treatment, who was diagnosed with NMS and lithium toxicity.
Psychotropic medications can have direct and indirect renotoxic effects on the kidneys that lead to both transient and chronic renal impairment. This chapter will review the effects of psychotropic use on renal function, including acute toxicity, chronic kidney injury, nephrogenic diabetes insipidus and SILENT as related to lithium therapy, and SIADH related to antidepressant and antipsychotic therapies. This chapter also discusses suggested monitoring parameters and clinical best practices for management of drug-related renal impairment to maintain optimal renal function and/or decrease the risk of renal impairment with the use of psychotropic medications.
The rat functional observational battery is the regulatory standard assay for the assessment of the central nervous system prior to the first dose administration in man. This chapter describes the utility and scientific foundation for the general adoption of this technique by both European and the United States drug regulatory agencies.
Several drugs produce cerebellar dysfunction as a part of encephalopathy. Cerebellar hemorrhage may occur following the use of anticoagulants or thrombolytics. This chapter includes discussion of drug-induced adverse effects where cerebellar disorder either is mentioned specifically or is a prominent feature. Main symptoms of cerebellar disorders are ataxia and dysarthria. As drug-induced effects, they are not progressive and may regress after discontinuation of the offending drug. Prolonged use of neurotoxic drugs may produce cerebellar degeneration that is not reversible. Drugs producing cerebellar disorders and the pathomechanism involved are described in this chapter. Antineoplastics and phenytoin (an antiepileptic drug) are prominent among the drugs that produce cerebellar disorders.
Lithium therapy can induce acute toxic reactions especially during overdosage. Exceptionally, permanent neurologic sequelae persist after the acute toxic reaction. These sequelae are more often cerebellar symptoms. Dementia, parkinsonian syndromes, choreoathetosis, brain stem syndromes and peripheral neuropathies have also been described. They are defined as irreversible if they persist more than two months after the interruption of lithium treatment. These neurologic complications occur frequently after voluntary or accidental poisoning but they may be observed even if the serum lithium dosage is below toxic level. Risk factors other than overdose are not well identified. Neurologic lesions induced by lithium can occur in the first days of the treatment as well as after years of maintenance therapy. Age and psychiatric diagnosis do not seem to be correlated with an increased risk of lithium induced neurotoxicity. Sex may be a risk factor, because of an overrepresentation of women among the case reports. The lithium-neuroleptic combination is another possible (although controversial) risk factor precipitating the occurrence of irreversible neurologic sequelae. Haloperidol was first implicated, but it has been shown that others neuroleptics, in combination with lithium, can induce similar toxic reactions. Intercurrent somatic illness with pyrexia often precedes the acute toxic reaction, and special attention must be paid to patients treated by lithium when they become hyperthermic. Major surgery, concurrent treatment with diuretics, renal failure, low food intake or low-salt diet are more uncommon precipitating factors. Available pharmacological treatments have not yet proved to be helpful. Even when the lesions are irreversible, a functional improvement can be obtained by rehabilitation. Thirty one cases of irreversible neurologic sequelae are reviewed.
The increasing use of lithium increases the chances of lithium intoxication. Usually in such cases the neurological symptomatology is transient and the cardiac involvement is mild. In this case a patient was seen in whom both severe cardiovascular consequences and permanent neurological damage occured. The patient, a 28-year-old manic depressive woman who was on lithium carbonate developed impaired consciousness, twitchings and fasciculations. She had alternating paroxysmal atrial fibrillation and sinus-node abnormalities with prolonged pauses of sinus arrest. During these pauses nodal escape beats and nodal rhythm appeared. The serum lithium level was 3.9 mmol/l. After peritoneal dialysis the cardiac rhythm reverted to normal. In spite of an initial neurological amelioration, permanent neurological sequelae persisted.
Two years later she was still ataxic and had sporadic choreoathetoid movements.
When lithium was first used as an anti-manic agent, evidence accumulated that it was only effective at 12-hour blood levels above 1 mmol/l and possibly at levels only just below the toxic levels of 2 mmol/l. This made careful monitoring of plasma levels very important in the management of lithium treatment to control mania. It was necessary, therefore, to adjust the dosage of lithium salts to obtain blood levels within a comparatively narrow range, and the margin between effectiveness and absence of toxicity was small.
• The development of organic brain syndrome (OBS) was studied in a small group of survivors from a longitudinal investigation of aging twins. At the time of initial evaluation, the frequency of moderate to severe OBS was 25%. Among the 22 survivors who had a second psychiatric evaluation after approximately six years, the corrected rate for the development of OBS among those without it at the initial examination was 16%. Thus, the vast majority of those diagnosed as being without OBS at about the age of 80 years remained asymptomatic in subsequent years, supporting the view that OBS is not a necessary concomitant of old age, but the result of disease for which prevention and cure should be sought. Persons originally diagnosed as having OBS had the higher mortality, an observation in accord with prior reports in the literature. In the present study, the increased mortality was related to the severity of OBS but apparently independent of coexisting physical illness, again supporting the argument that OBS represents pathological as distinct from physiological aging.
Four acutely agitated patients with diagnoses of mania were treated with a combined regimen of lithium carbonate and high doses of haloperidol—a form of therapy that had been used previously in Metropolitan Hospital without reported adverse effects. In these four, severe encephalopathic syndromes developed. Symptoms consisted of lethargy, fever, tremulousness, confusion, and extrapyramidal and cerebellar dysfunction, accompanied by leukocytosis and elevated levels of serum enzymes, blood urea nitrogen, and fasting blood glucose. Two patients suffered widespread, devastating, irreversible brain damage. Two others were left with persistent dyskinesias. Causal factors have not been identified.(JAMA 230:1283-1287, 1974)
EVEN though the title of this article refers to the past of lithium treatment, I shall spare the reader a lengthy account of its history and instead concentrate more on the situation today and the tasks for tomorrow.PAST: EFFICACY
It is, however, only appropriate that I mention here the two clinical psychiatrists who have been key figures in the development of lithium treatment: John Cade, MD,1 who in the late 1940s gave lithium to psychiatric patients and discovered its antimanic action, and Poul Christian Baastrup, MD,2,3 who saw and participated in the documentation of its relapse-preventive or prophylactic action against not only manic but also depressive recurrences. Cade and Baastrup were conscientious clinicians who knew their patients well and who had keen observational powers (Figure).Lithium treatment has gone through a number of developmental phases and crises. They dealt with whether it worked at all or merely
Central pontine myelinolysis (CPM) is removal of myelin material from neural elements in a way that is not clearly known as yet. In this case of CPM, blindness was encountered and was thought to be “hysterical.” The blindness went away after four months. After reviewing the literature we suggest the CPM was a complication of lithium toxicity which affected the lateral geniculate nucleus which produced blindness.
The three-dimensional structure of amyloid beta peptide (25-35), which has neurotoxic activity, in lithium dodecyl sulfate micelles was determined by two-dimensional 1H NMR spectroscopy with simulated annealing calculations. A total of 20 converged amyloid beta peptide structures were obtained on the basis of 110 experimental constraints, including 106 distance constraints reduced from the nuclear Overhauser effect (NOE) connectivities and four torsion angle (phi) constraints. The atomic root mean square difference about averaged coordinates is 1.04 +/- 0.25 A for the backbone atoms (N, C alpha, C) and 1.39 +/- 0.27 A for all heavy atoms of the entire peptide. The molecular structure of amyloid beta peptide in membrane-mimicking environment is composed of a short alpha helix in the C terminal position. The three residues from the N-terminus are disordered, but the remaining eight C-terminal residues are well-ordered, which is supported by the RMSD values of the C-terminal region, Lys28-Leu34. In this region, the RMS differences from averaged coordinates are 0.26 +/- 0.11 A for the backbone atoms (N, C alpha, C) and 0.77 +/- 0.21 A for all heavy atoms, which is very low compared with those for the entire peptide. The four amino acid residues from the N-terminus are hydrophilic and the other seven amino acid residues in C-terminus are hydrophobic. So, our results show that the C-terminal region of amyloid beta peptide (25-35) is buried in the membrane and assumes alpha-helical structure, whereas the N-terminal region is exposed to the solvent with a flexible structure. This structure is very similar to membrane-mediated structure of substance P previously reported. The three-dimensional structure of a non-neurotoxic mutant of amyloid beta peptide (25-35), where Asn27 is replaced by Ala, in lithium dodecyl sulfate micelles was also determined. The structure is similar to that of the wild type amyloid beta peptide (25-35) in the C-terminal region, but the N-terminal flexible region is different. The structural comparison of amyloid beta peptide (25-35), its non-neurotoxic mutant and substance P gives a structural basis to understand the mechanism of neurotoxicity caused by amyloid beta peptide.
Hospital records of 425 patients who had been treated simultaneously with lithium carbonate and haloperidol were examined. Adverse reactions in these patients were the same as in patients given lithium alone or haloperidol alone. None of the patients developed a syndrome resembling that described by others in patients treated with a lithium and haloperidol combination.(JAMA 236:2645-2646, 1976)
This syndrome followed the use of a commercial salt substitute containing lithium chloride, citric acid and potassium iodide. The changes which occurred were profound and severe, yet transient, and the patient made a rapid and complete recovery. The signal symptoms and signs as they successively occurred over a period of a week included anorexia, rapid change in personality, lethargy, dysphagia and pain on swallowing, bradycardia, cutaneous hyperesthesia and hyperalgesia, muscular hyperirritability, profound general and multiple myoclonus and mental obfuscation.REPORT OF CASE
The patient was an 82 year old man previously rather vigorous and alert. He was hospitalized January 9 at the Cedars of Lebanon Hospital, Los Angeles, on arrival from another locale for further convalescence. Immediate previous diagnoses included: (1) simple fractures, right fourth, fifth and sixth ribs incurred Dec. 11, 1948; (2) rectal prolapse; (3) urinary bladder retention and infection; (4) bronchopneumonia with onset on Dec. 27, 1948,
To the Editor:—
I have recently observed that one of the table salt substitutes (westsal®, marketed by Westwood Pharmaceuticals, Division of Foster-Milburn Co., Buffalo, N. Y.) may cause toxic symptoms in patients following a 200 mg. low sodium diet. This salt substitute contains 25.00 per cent lithium chloride, 0.20 per cent citric acid and 0.01 per cent potassium iodide. I feel that it is important to bring this observation to the attention of the practitioner because these symptoms may simulate those which are already present or may occur, because of the very disease for which the low sodium diet is being given. The 2 patients whom I am reporting in some detail (Univ. Hosp. Bull., Ann Arbor 15:9-10 [Feb.] 1949), after taking westsal® a few months, showed jerky tremor of the arms, unsteadiness in gait, generalized weakness, exhaustion and blurred vision. These symptoms were entirely new to the patients
During an investigation on the action of uric acid under Professor Haskins, I had occasion to take rather large doses of lithium chlorid, and experienced toxic symptoms differing in some respects from the hitherto described phenomena of lithium poisoning.In the first experiment, 2 gm, of the chlorid were taken in a glass of water after each meal for three meals (about 1 p. m., 9 p. m. and 7 a. m.) and then, after skipping one meal, another dose was taken about 7 p. m., making a total of 8 gm., about 125 grains, in twenty-eight hours. Symptoms showed themselves three or four hours after the first dose, consisting in slight dizziness and fulness in the head. Nothing more was noted after the second dose, which was taken in the evening. Soon after the third dose there was so much blurring of vision that it was impossible to read
In view of the increasing emphasis on restriction of sodium intake in the management of cardiac decompensation and other conditions, a harmless substitute for salt in the seasoning of food has been widely sought and is much to be desired. Recently a 25 per cent solution of lithium chloride, which has a taste similar to table salt, has been made commercially available. Although there are in the older literature scattered records suggesting that ingestion of inorganic lithium salts may cause weakness, tremors and blurring of vision, the solution has been marketed with the assurance of the distributors that it is "perfectly safe," but they recommend that it be used only under the supervision of a physician. Our acquaintance with lithium began in the last two months of 1948, when we undertook the study of the absorption, distribution and excretion of lithium chloride as part of a long range investigation of
AcknowledgementsReferencesDiscussionReferences
Brust et al reported a case of acute generalized polyneuropathy accompanying lithium poisoning. We have recorded a similar patient in the Japanese literature. The mild weakness, hyporeflexia, mild sensory deficits, and electrophysiological and histological findings in this case all are consistent with peripheral neuropathy. Temporal events incriminate lithium as the likely cause.
There have been many reports of probable lithium-induced organic brain syndromes occurring when serum lithium levels are within or close to the therapeutic range. The authors report on five patients who developed clinical syndromes suggestive of severe neurotoxicity during lithium treatment. In all cases lithium levels were between .75 and 1.7 mEq/liter. The patients who developed neurotoxicity had markedly higher global ratings of psychotic symptomatology and anxiety in the pretoxic period than did patients who never deveoped neurotoxicity. When the acute manic state is characterized by marked psychotic symptoms and intense anxiety, it may be associated with increased vulnerability to the development of severe lithium neurotoxicity.
Twenty-three patients were studied, 21 of whom developed intoxication during maintenance therapy with a lithium dosage which had been unchanged for months to years. Toxic effects on brain, heart and kidneys were found and the severity of lithium intoxication seemed to depend on at least three factors: the height of the serum lithium concentration (SLi), the duration of lithium intoxication and individual tolerance. Disorders of water and electrolyte metabolism preceded lithium intoxication in the majority of the patients. Water loss due to impaired renal concentrating ability seemed to be a major predisposing factor. Renal insufficiency was apparent in 17 of the patients on admission and five of these did not regain normal renal function. In seven patients, renal biopsy showed abnormalities which suggest that a chronic nephropathy, possibly caused by lithium, might be another predisposing factor. Treatment with sodium chloride infusion had no specific effect on lithium excretion and led to hypernatraemia in some patients and is therefore not recommended. Hemodialysis is the most effective method available for removing the lithium ion from intoxicated patients. Hemodialysis should be carried out long enough to secure a SLi of less than 1 mmol/l after redistribution of lithium in the body. Treatment by peritoneal dialysis is appropriate only if hemodialysis facilities are unavailable. Lithium intoxication is a serious condition. Of the 23 patients reported, two died and two developed persisting neurological sequelae. The best way to prevent lithium intoxication is to control the serum concentration and to assess renal function and renal concentrating ability regularly during therapy.
In a middle-aged man with depression, treated with high doses of lithium carbonate (2,700 mg a day) for ten days, lithium intoxication leading to semicoma developed. His serum lithium level was 7.6 mEq per liter. Possible contributing factors were decreased food and fluid intake; fluid loss; alcohol; and tranquilizer intake. The patient's condition responded to intensive care, forced diuresis and other supportive measures; however, sequelae persisted six months after discharge. Cerebellar and upper motor neuron symptoms, a myocardial infarct and liver damage with persistently increased enzymes occurred. The need for accurate diagnosis, appropriate selection of dosage and careful monitoring of patients taking lithium is stressed. Familiarity with the pharmacology and toxicology of lithium is a matter of considerable importance. The potential toxicity of lithium and its narrow therapeutic-toxic range have been discussed.
Brain Damage with Lithium/Haloperidol - Volume 134 Issue 5 - C. J. Thomas
The peripheral and central neurotoxic effects of lithium carbonate are illustrated by 4 case histories. Lithium neurotoxicity is likely to be more common than the literature suggests. Neurological sequelae may be irreversible and may be associated with therapeutic serum levels. Prevention may be facilitated by more stringent case selection, EEG and clinical monitoring and the development of improved methods of drug level assessment.
A patient with diagnosis of manic-depressive illness, circular type, and receiving therapeutic dosages of lithium carbonate, developed papilledema that seemed to be directly related to the drug. Although this is an extremely rare complication, the authors suggest that fundal exams may be considered in patients treated with lithium.
One may not rely solely on serum lithium levels to detect or prevent lithium intoxication. A review of the reported cases of serious lithium intoxication despite "therapeutic" blood levels of lithium is presented, along with a discussion of possible explanations for the phenomenon. Possible alternate means of following a patient on lithium carbonate are discussed.
Synopsis
The plasma lithium levels of 18 subjects receiving one standard and two slow-release preparations of lithium carbonate were measured at frequent intervals during the 24 hours following oral ingestion of a single dose of the drug. Although the slow-release tablets showed slow-release in vitro , this was not so in vivo. One slow-release preparation, in particular, was ineffectively absorbed by some subjects. There was no difference in the rate of absorption and excretion between the other slow-release product and the standard BP preparation. The implications of the results are discussed.
Hospital records of 425 patients who had been treated simultaneously with lithium carbonate and haloperidol were examined. Adverse reactions in these patients were the same as in patients given lithium alone or haloperidol alone. None of the patients developed a syndrome resembling that described by others in patients treated with a lithium and haloperidol combination.
One of the most alarming and potentially serious complications of Lithium Carbonate therapy is the emergence of central nervous system toxicity. This paper discusses the clinical changes that may occur with illustrative case histories. The role that such factors as serum Lithium levels, sodium balance, organic brain damage, clinical typology, concurrent physical illness and drug interaction play in the genesis of this disorder is discussed. Permanent neurological damage following Lithium poisoning is discussed and guidelines for appropriate use and monitoring of Lithium in psychiatric disorders is outlined.
Severe lithium intoxication was seen in a 57-year-old woman despite close monitoring of blood lithium levels over 23 months. High blood lithium levels were aggravated by drug induced hyponatremia. Neurological sequelae were still present six months after admission,
Two cases of toxic reaction to lithium carbonate are reported. The first patient displayed symptoms resembling those of organic brain syndrome which was not associated with a high serum lithium level. The influence of diuretic therapy in combination with lithium is felt to enhance the risk of intoxication. The second case depicts acute CNS toxicity with known fatal potential. Conservative lithium administration is recommended for acute manic psychosis and reference is made to the beneficial effects of urea and aminophylline on renal lithium elimination in the active treatment of lithium poisoning.
The authors report two cases of pseudotumor cerebri in patients taking lithium for treatment of bipolar disorder. Pseudotumor cerebri is a poorly understood syndrome characterized by chronic headaches, bilateral papilledema, and increased intracranial pressure without localized neurologic signs or symptoms, intracranial mass, or hydrocephalus. Ventriculography, computed tomography, and nuclear magnetic resonance imaging reveal normal or small ventricles. Multiple etiologies may include Vitamin A toxicity, obesity, head trauma, hypothyroidism or hyperthyroidism, prolonged steroid therapy or its withdrawal, Addison's disease, Cushing's disease, pituitary insufficiency, and lithium therapy. Patients treated with lithium whose antidiuretic hormone-cyclic adenosine monophosphate mechanism is disturbed are most likely to develop pseudotumor cerebri via disregulation of sodium balance, thyroid-stimulating hormone production, and glucose metabolism. The authors recommend careful medical monitoring to avoid iatrogenic effects of lithium, including pseudotumor cerebri.
Though the acute complications of lithium toxicity involving the central nervous system have been known for more than 70 years, it is only recently that the longlasting sequelae of lithium intoxication have come to be discussed at length; about fifty-five cases have been reported so far. The acronym SILENT (Syndrome of Irreversible Lithium-Effectuated Neurotoxicity) has been coined recently to denote these sequelae. The present report describes the typical profile of SILENT (persisting cerebellar dysfunction) and suggests measures to decrease the incidence of this potentially serious condition, for which no definitive treatment is available.
Prior neurologic illness or CNS insult of any kind is known to increase the vulnerability to neurotoxicity of lithium. In this event the occurrence of neurotoxicity does not correlate with serum lithium levels. The authors describe a patient with hemiparesis who developed the syndrome of irreversible lithium-effectuated neurotoxicity (SILENT) while being treated with lithium for a manic episode. The authors review the literature on this aspect and highlight the dangers of starting lithium treatment in patients with neurologic impairment.
In 2 patients receiving a long-term lithium carbonate therapy, persistent cerebellar, pyramidal, and extrapyramidal signs were observed, following a febrile pulmonary event. The mechanism of these disturbances is discussed, emphasizing the lithium-neuroleptics interaction as well as the possible role of hyperthermia.
This report describes a young patient with acute overdose lithium toxicity, who developed severe memory impairment in spite of treatment with haemodialysis. His memory showed gradual recovery, but definite impairment could still be detected 2 months after the overdose.