A reappraisal of the role of fever in the occurrence of neurological sequelae following lithium intoxication: a systematic review.

INTRODUCTION: 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. AREAS COVERED: Case reports were identified from: (i) 6 reviews published up to 2005; (ii) MEDLINE, Web of Sciences, Cochrane Library and PsycINFO search. EXPERT OPINION: We identified 123 SILENT cases published from 1965 to 2019, in which cerebellar sequelae were observed in an overwhelming proportion (79%). SILENT may occur at any time during lithium treatment. This complication is most frequently observed during routine lithium treatment, with fewer than 10% of cases occurring after accidental or intentional overdoses. SILENT may occur even when lithium plasma levels are within the therapeutic range: 63% of cases had 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) and by a history of fever and/or infection. Lithium users should be warned of the need to consult in case of fever to adjust their lithium dosage.

[Water, lithium and sodium: watch out for dangerous injuries]. / Histoire d'eau : le lithium et le sodium, les lésions dangereuses.

Nephrogenic diabetes insipidus due to the inability of the kidneys to concentrate urine is frequently observed during lithium therapy. Lithium concentrates into principal cells in collecting ducts in the kidney and downregulates aquaporin 2 expression, which reduces renal reabsorption of water. This disease is characterized by polyuria - polydipsia leading to intracellular dehydration and hypernatremia. Water deprivation test is performed to confirm insipidus diabetes. The desmopressin permits to distinguish nephrogenic from cranial insipidus diabetes. We report the case of a 64 years old women who presented with global dehydration and severe hypernatremia. Four years ago, she was hospitalized for nephrogenic diabetes insipidus related to a self-induced lithium intoxication. Persistent nephrogenic insipidus diabetes after cessation of lithium therapy are described in literature, and this hypothesis may be consistent with this case report.

[Extracorporeal renal replacement therapies in lithium intoxication].

Drug poisoning is a significant source of morbidity, mortality and health care expenditure worldwide. Lithium, methanol, ethylene glycol and salicylates are the most important ones, included in the list of poisons, that may require extracorporeal depuration. Lithium is the cornerstone of treatment for bipolar disorders, but it has a narrow therapeutic window. The therapeutic range is 0.6-1.2 mEq/L and toxicity manifestations begin to appear as soon as serum levels exceed 1.5 mEq/L. Severe toxicity can be observed when plasma levels are more than 3.5 mEq/L. Lithium poisoning can be life threatening and extracorporeal renal replacement therapies can reverse toxic symptoms. Currently, conventional intermittent hemodialysis (IHD) is the preferred extracorporeal treatment modality. Preliminary data with prolonged intermittent renal replacement (PIRRT) therapies - hybrid forms of renal replacement therapy (RRT) such as sustained low efficiency dialysis (SLED) - seem to justify their role as potential alternative to conventional IHD. Indeed, SLED allows rapid and effective lithium removal with resolution of symptoms, also minimizing rebound phenomenon.

Outcomes of acute exploratory pediatric lithium ingestions.

Objectives: To date, very little literature describes the outcomes of acute unintentional ingestions of lithium in young children. This study aimed to describe the clinical effects and outcomes reported in these patients reported to the National Poison Data System (NPDS).Methods: This is a retrospective observational study of acute unintentional lithium ingestions in children <6 years of age. The primary intent of the study was to characterize acute unintentional exposures to lithium in children in this age group. As a secondary outcome, we sought to identify a weight-based threshold to empirically refer patients into a healthcare facility for symptoms consistent with moderate effect or worse. The American Association of Poison Control Centers' NPDS was queried for all acute ingestions of lithium salts in children <6 years of age from 2000 to 2018. Inclusion criteria were single substance ingestions, unintentional-general exposure (i.e., exploratory ingestion), and followed to a known outcome or coded as potentially toxic exposure unable to follow and the patient was experiencing symptoms.Results: A total of 3045 single-substance exploratory ingestions of lithium were reported to poison centers that showed a decrease over time, consistent with decreasing use of lithium and decreasing calls to poison centers. Of the 3045 cases, we excluded 1178 leaving 1863 cases for analysis. Median age was 2 years (IQR: 1.5, 2) with 51% male cases. Management site was primarily non-health care facility (n = 808; 43.4%) with 569 (30.5%) already in a healthcare facility (HCF) when the Poison Control Center (PCC) was called and 477 (25.6%) referred to a HCF. The route of exposure was most commonly ingestion (n = 1853; 99.5%) and site of exposure was primarily home (1743; 93.6%). Medical outcomes were predominantly no effect and minor effect. There were 262 related clinical effects were reported in 184 patients (10%). The most frequently reported were vomiting (n = 76), drowsiness/lethargy (n = 58), other (n = 22), and ataxia (n = 20). Clinical effects lasted ≤2 h for 65 (33%), 2-8 h for 57 (28.9%), 8-24 h for 51 (25.9%), 1-3 days for 11 (5.6%), and >3 days to ≤1 week for 1 (0.5%); no cases resulted in clinical effects thought to be permanent and no deaths were reported. There were 1173 treatments provided to 857 patients. The most common treatments were basic and are readily performed at home; dilution (n = 492) and food/snack (n = 180). A smaller subset of patients received care that could likely only be provided in a healthcare facility including IV fluids (n = 173), other (n = 120), whole bowel irrigation (n = 46), single dose activated charcoal (n = 41), syrup of ipecac (n = 34), and lavage (n = 31). No patients received hemodialysis. A total of 425 of the exposures were referred to a healthcare facility by the PCC which had a dose coded. There was no difference in dose that resulted to referral to a healthcare facility over time (p = 0.2747). Due to the small number of moderate/major effect cases with dose information, we were unable to identify a dose-based threshold for referral to HCF.Conclusions: Severe outcomes after unintentional ingestion of lithium in pediatric patients are rare. It is likely that most asymptomatic pediatric patients <6 years do not need to be referred to the hospital after ingestion of lithium.

[Analysis of risk factors, etiology and treatment standard of lithium poisoning]. / Analyse zu Risikofaktoren, Ätiologie und Behandlungsstandard der Lithiumintoxikation.

Despite unlimited access to therapeutic drug monitoring lithium poisoning is still a common and potentially life-threatening but in most cases preventable complication of lithium treatment; however, it is still considered to be the gold standard in the treatment of affective disorders. The necessity of drug monitoring and potential lithium toxicity substantiate the skepticism of many therapists with respect to this often very effective treatment. This therefore limits the use of lithium although the unique therapeutic effects and high efficiency are well known. This retrospective data analysis of risk factors and etiology of lithium poisoning cases identified 58 cases of lithium poisoning, which were treated internally in this hospital between 2010 and 2014. Of the patients 67.2% were female and the majority were classified as chronic poisoning (66.1%). The most relevant patient-related risk factor seemed to be insufficient self-management as 26% of cases of lithium poisoning occurred during febrile infections or exsiccosis. Regarding practitioner-related risk factors, an insufficient consideration of drug interactions, insufficient therapeutic drug monitoring after dose increase and a paucity of experience and knowledge concerning lithium treatment were most relevant. This study illustrates the most important risk factors for lithium poisoning and their frequencies and contributes to raise awareness for this highly relevant topic. These data can help to prevent further cases of lithium poisoning. Furthermore, the results enable a comparison between the actual treatment reality and currently available evidence for the treatment of lithium poisoning.

Lithium intoxication presenting as altered consciousness and arrhythmia with cardiogenic shock: A case report.

RATIONALE: Lithium has been used to treat bipolar disorder. Lithium has a narrow therapeutic index, with a therapeutic level between 0.6 and 1.5 mEq/L. The possible complications of lithium overdose include altered mental status, hand tremor, muscle weakness, nausea, vomiting, diarrhea, seizure, syncope, and arrhythmia. Lithium intoxication can be fatal and is difficult to diagnose in patients without a history of lithium intake. The occurrence of serious cardiac arrhythmias is rare in lithium intoxication. PATIENT CONCERNS: An 81-year-old man was brought to the emergency department because of consciousness disturbance for 2 days. According to his daughter, he had a history of hypertension and diabetes. Recently, his family also observed slurring of speech and easy choking. The physical examination findings were unremarkable. DIAGNOSIS: Blood examination only revealed impaired renal function. Twelve-lead electrocardiography revealed sinus rhythm with first-degree atrioventricular block. Chest radiography revealed mediastinal widening. The blood pressures obtained from the 4 limbs showed no significant differences. Subsequently, brain computed tomography revealed no obvious intracranial lesion. A neurologist was consulted, and a recent ischemic stroke could not be ruled out. While in the observation area, his systolic blood pressure decreased to <90 mm Hg and he showed bradycardia, and 12-lead electrocardiography revealed an AV block and long pulse. Contrast-enhanced chest computed tomography revealed no evidence of aortic dissection. Another family member reported a history of lithium intake for bipolar disorder for >30 years. Blood examination revealed a lithium concentration of 2.65 mEq/L. INTERVENTIONS: A nephrologist was consulted, and emergency hemodialysis was indicated. Dopamine was administered for his shock status via a right neck central venous catheter. OUTCOMES: His lithium level gradually declined after the hemodialysis, and blood pressure and consciousness level improved subsequently. The patient was discharged 9 days later in a stable condition. LESSONS: If an emergency physician encounters a patient with altered consciousness and arrhythmia with cardiogenic shock, the patient's drug intake history should be carefully reviewed to rule out cardiovascular problems on the basis of the patient's clinical condition.

Reference values of lithium in postmortem femoral blood.

INTRODUCTION: The main recipients of lithium, people diagnosed with bipolar disorder, show an increased mortality in both natural and unnatural causes of death. Based on international data persons diagnosed with bipolar disorder comprise 2.3-9.6% of all suicidal deaths. In cases of suicide among those suffering from bipolar disorder, 17-53% are due to fatal intoxications. Diagnosing fatal intoxications is often challenging, particularly when the reference information needed to interpret the concentration of a drug is lacking or scarce. AIM: The aim of this study was to establish postmortem femoral blood reference concentrations of lithium, providing both fatal and "normal" postmortem concentrations, as well as to investigate the impact of the mode of intoxication and to study the co-detection of lithium and antidepressant drugs in intoxications and controls. METHOD: In Sweden, forensic autopsies are performed in unnatural and obscure deaths. This study included all autopsies in which lithium was found during the study period (1992-2010). Lithium was not included in the regular drug screen, but analysed upon request using flame photometry, ion-selective electrode detection or atomic absorption spectrophotometry. Each case was evaluated according to an established strategy, with strict inclusion and exclusion criteria followed by a multi-observer manual review (Fig. 1, Table 1). The cases included were classified as single intoxications (group A), multi-drug intoxications (group B) or controls (group C). The control group only included cases where death by intoxication and antemortem incapacitation by drugs could be ruled out. RESULTS AND DISCUSSION: During the study period, lithium was found in 124 cases. After application of inclusion and exclusion criteria and the subsequent manual review, 21 cases were classified as group A (n=4), group B, (n=7) and group C (n=10). The femoral blood lithium concentrations in group A (median 2.69mmol/l) and group B (median 2.10mmol/l) were significantly different (p=0.01) compared to group C (median 0.2mmol/l). There were however no statistically significant difference between the concentrations in groups A and B. The most common mode of death in intoxications was acute-on-chronic (n=10), but the impact of chronic use on the fatal blood concentrations could not be evaluated since there was just one case without previous use. There was no difference in the proportion of co-detections of lithium and antidepressants between intoxication cases and controls.

[Syndrome of Irreversible Lithium-Effectuated NeuroToxicity]. / Síndrome de Neurotoxicidade Irreversível Causada por Lítio.

Lithium has a narrow therapeutic window. Frequent monitoring of both serum levels and clinical signs of toxicity is warranted because toxicity may be present even when concentrations are within the therapeutic range. We report the case of a man with lithium poisoning, with persistent neurologic signs and symptoms even after removal of lithium from circulation - a diagnosis of syndrome of irreversible lithium-effectuated neurotoxicity (SILENT) was made.

O lítio é um fármaco com janela terapêutica estreita, exigindo monitorização frequente dos seus níveis séricos e da clínica, pois a toxicidade pode surgir mesmo com níveis terapêuticos. Apresentamos o caso de um homem com intoxicação por lítio, com persistência de alterações neurológicas mesmo após normalização dos seus níveis séricos, permitindo-nos fazer o diagnóstico de síndrome de neurotoxicidade irreversível causada pelo lítio (SILENT).

Cognitive sequelae of lithium intoxication: a case report.

Lithium intoxication is known to induce cognitive deficits along with motor and behavioral changes, even in association with normal serum levels. However, cases with comprehensive neuropsychological assessment of the deficits are rare. In our patient, we initially found severe cognitive deficits, including apraxia and visuo-constructive problems, and temporo-parietal FDG-PET hypometabolism. Neuropsychological and imaging findings were highly suggestive of Alzheimer's disease. However, lithium intoxication was suspected to account for these findings because of a Parkinson's syndrome, despite serum levels being in the upper therapeutic range. This was confirmed as cessation of lithium medication not only let the Parkinson's syndrome disappear, but also lead to dramatic improvements with respect to cognition.

Atypical permanent neurological sequelae after an acute intoxication with lithium and aripiprazole.

OBJECTIVES: The aim of the present case report was to describe atypical neurological sequelae after a lithium and aripiprazole co-intoxication in a suicide attempt. METHODS: We report the case of a 31-year-old patient with bipolar disorder who developed, after lithium and aripiprazole massive ingestion, a severe pseudobulbar dysarthria and motor disorders suggestive of basal ganglia micro lesions. We review literature on neurological sequelae due to acute lithium intoxications. RESULTS: Acute lithium intoxication can cause permanent neurological sequelae, the most frequent clinical feature being a permanent cerebellar syndrome. Moreover, the widely-prescribed combination of lithium with antipsychotics increases the neurotoxicity in lithium intoxications. In this case, both atypical neurological syndrome and normal paraclinical investigations lead first to misdiagnose the lithium neurological damages. CONCLUSIONS: This case illustrates that acute lithium intoxications can result in serious and potentially permanent neurological deficits, which remain difficult to diagnose. Imaging abnormalities are not constant, and neurological presentation can be atypical.

Neurobehavioral effects of lithium in the rat: Investigation of the effect/concentration relationships and the contribution of the poisoning pattern.

Severity of lithium poisoning depends on the ingested dose, previous treatment duration and renal function. No animal study has investigated neurobehavioral differences in relation to the lithium poisoning pattern observed in humans, while differences in lithium pharmacokinetics have been reported in lithium-pretreated rats mimicking chronic poisonings with enhanced brain accumulation in rats with renal failure. Our objectives were: 1)-to investigate lithium-related effects in overdose on locomotor activity, anxiety-like behavior, spatial recognition memory and anhedonia in the rat; 2)-to model the relationships between lithium-induced effects on locomotion and plasma, erythrocyte, cerebrospinal fluid and brain concentrations previously obtained according to the poisoning pattern. Open-field, elevated plus-maze, Y-maze and sucrose consumption tests were used. In acutely lithium-poisoned rats, we observed horizontal (p<0.001) and vertical hypolocomotion (p<0.0001), increased anxiety-like behavior (p<0.05) and impaired memory (p<0.01) but no altered hedonic status. Horizontal (p<0.01) and vertical (p<0.001) hypolocomotion peaked more markedly 24h after lithium injection and was more prolonged in acute-on-chronically vs. acutely lithium-poisoned rats. Hypolocomotion in chronically lithium-poisoned rats with impaired renal function did not differ from acutely poisoned rats 24h after the last injection. Interestingly, hypolocomotion/concentration relationships best fitted a sigmoidal Emax model in acute poisoning and a linear regression model linked to brain lithium in acute-on-chronic poisoning. In conclusion, lithium overdose alters rat behavior and consistently induces hypolocomotion which is more marked and prolonged in repeatedly lithium-treated rats. Our data suggest that differences between poisoning patterns regarding lithium-induced hypolocomotion are better explained by the duration of lithium exposure than by its brain accumulation.

Lithium Toxicity in a Pregnant Woman.

Lithium is recommended in bipolar disorder and can be accompanied by significant toxicity in pregnant women. A 25-year-old single-gestation pregnant woman (28 weeks) was referred with suspicion of lithium toxicity. Serum lithium was 2.1 meq/L. Despite conservative therapy with intravenous fluids, lithium concentration increased to 5.0 meq/L 6 hr after admission mandating an emergent haemodialysis during which foetal heart rate decreased to 90 bpm. The gynaecologist ordered termination of pregnancy while the mother was still on haemodialysis. Caesarean section was carried out, but the born baby had an apgar of 2 and died. Autopsy findings of the foetus revealed a cord blood lithium concentration of 4.8 mEq/L with no physical abnormalities. Although the foetus had the signs/symptoms of distress, continuation of haemodialysis could probably have saved it as it saved its mother's life. In lithium toxicity in a pregnant woman, it is reasonable to continue haemodialysis even with the signs and symptoms of foetal distress. In similar situations, emergency haemodialysis instead of immediate caesarean section should be considered.

[Lithium poisoning: neurological signs, nephrological therapy]. / Intossicazione da litio: clinica neurologica, terapia nefrologica.

Lithium is an effective drug in the treatment of bipolar disorder and other psychiatric and neurological diseases. Unfortunately, its therapeutic index is narrow. There are three types of lithium poisoning: acute poisoning (in untreated patients), acute on chronic poisoning, when an overdose is taken accidentally or with suicidal intent, in patients under treatment and chronic poisoning (patient treated with lithium) when drug intake is correct but excessive in relation to its elimination (increased dose or more often reduced clearance) resulting in lithium overload. In this last condition, the clinical presentation is primary neurological while therapy involves the nephrologist provided that lithium clearance is mainly renal and hemodialysis is the most effective method for removal.

Antihypertensive therapy in patients on chronic lithium treatment for bipolar disorders.

Bipolar disorders are chronic conditions treated with lithium, which exerts deleterious effects on the kidney, among which nephrogenic diabetes insipidus, tubular acidosis and ultimately chronic kidney disease. Conversely, drugs that alter renal function can modify its serum levels and lead to the potentially fatal lithium intoxication. A search in the main library databases from 1975 to 2015 to identify interactions between antihypertensive drugs and lithium using the Population Intervention Comparison Outcome strategy provided only 30 reports of lithium intoxication. A regression analysis showed that the severity of lithium intoxication was significantly predicted by female, age, and use of certain classes of antihypertensive agents. A model including certain albeit not all diuretics and/or inhibitors of the renin-angiotensin system, but not age, serum lithium or creatinine levels at baseline and/or on admission to the hospital, predicted lithium toxicity. The true incidence of lithium intoxication is unknown but probably low, albeit underestimated. Nonetheless, in patients treated with lithium, monitoring of the serum lithium levels and clinical conditions is mandatory after the introduction of antihypertensive drugs, as diuretics and renin-aldosterone system inhibitors.

Hemodialysis for lithium poisoning.

BACKGROUND: Lithium salts, particularly lithium carbonate, are frequently used to treat bipolar disorder and mania. Lithium poisoning, which can occur as a result of reduced renal elimination, prescribing error, drug-drug interactions, or deliberate overdosage, produces neurologic injury that can be permanent. Hemodialysis is often recommended to treat lithium poisoning. Although hemodialysis clearly enhances the elimination of lithium, it is unclear whether this translates into improved patient outcomes. Evidence from observational studies, generally of low methodological quality, shows similar outcomes in patients managed with or without the use of hemodialysis. OBJECTIVES: To determine whether hemodialysis, applied in addition to standard therapy, reduces the likelihood, severity, or duration of neurological sequelae following lithium poisoning. SEARCH METHODS: We ran the search on 15 May 2015. We searched the Cochrane Injuries Group's Specialised Register, Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library), MEDLINE (OvidSP), Embase Classic+Embase (OvidSP), CINAHL Plus, clinical trials registers and four other databases. We screened the reference lists of relevant studies, textbook chapters, and review articles, and performed a Google search to identify grey literature. SELECTION CRITERIA: In the context of this review, hemodialysis was defined as any extracorporeal technique to filter and extract toxicants from the serum, including all forms of hemodialysis, hemofiltration, and continuous renal replacement techniques, but not peritoneal dialysis. We included any clinical trials in which patients were randomly allocated to receive, or not receive, hemodialysis in addition to standard care for lithium poisoning. DATA COLLECTION AND ANALYSIS: Two authors reviewed the abstracts of all identified articles. If either author identified an article as potentially meeting the inclusion criteria, both authors reviewed the full text of the article. MAIN RESULTS: No randomized controlled trials of hemodialysis therapy for lithium poisoning were identified. AUTHORS' CONCLUSIONS: Although the use of hemodialysis to enhance the elimination of lithium in patients with lithium poisoning appears logical, there is no evidence from randomized controlled trials to support nor refute the use of hemodialysis in the management of patients with lithium poisoning.

[Intermittent hemodialysis, irreplaceable in specific cases of severe poisoning]. / L'hémodiayse intermittente, irremplaçable dans certains cas d'intoxications sévères.

The medical practitioner is in general well aware of the indications for hemodialysis in severe, acute or chronic renal insufficiency. Apart from the traditional indications for renal replacement therapy, there are some cases such as metfomin and ethylene glycol poisoning, lithium intoxication severe hypercalcemia and tumor lysis syndrome, in which intermittent hemodialysis is the most effective treatment, or sometimes the only effective one. Although these situations remain infrequent, it is crucial to recognize them as quickly as possible.

Extracorporeal Treatment for Lithium Poisoning: Systematic Review and Recommendations from the EXTRIP Workgroup.

The Extracorporeal Treatments in Poisoning Workgroup was created to provide evidence-based recommendations on the use of extracorporeal treatments in poisoning. Here, the EXTRIP workgroup presents its recommendations for lithium poisoning. After a systematic literature search, clinical and toxicokinetic data were extracted and summarized following a predetermined format. The entire workgroup voted through a two-round modified Delphi method to reach a consensus on voting statements. A RAND/UCLA Appropriateness Method was used to quantify disagreement, and anonymous votes were compiled and discussed in person. A second vote was conducted to determine the final workgroup recommendations. In total, 166 articles met inclusion criteria, which were mostly case reports, yielding a very low quality of evidence for all recommendations. A total of 418 patients were reviewed, 228 of which allowed extraction of patient-level data. The workgroup concluded that lithium is dialyzable (Level of evidence=A) and made the following recommendations: Extracorporeal treatment is recommended in severe lithium poisoning (1D). Extracorporeal treatment is recommended if kidney function is impaired and the [Li(+)] is >4.0 mEq/L, or in the presence of a decreased level of consciousness, seizures, or life-threatening dysrhythmias irrespective of the [Li(+)] (1D). Extracorporeal treatment is suggested if the [Li(+)] is >5.0 mEq/L, significant confusion is present, or the expected time to reduce the [Li(+)] to <1.0 mEq/L is >36 hours (2D). Extracorporeal treatment should be continued until clinical improvement is apparent or [Li(+)] is <1.0 mEq/L (1D). Extracorporeal treatments should be continued for a minimum of 6 hours if the [Li(+)] is not readily measurable (1D). Hemodialysis is the preferred extracorporeal treatment (1D), but continuous RRT is an acceptable alternative (1D). The workgroup supported the use of extracorporeal treatment in severe lithium poisoning. Clinical decisions on when to use extracorporeal treatment should take into account the [Li(+)], kidney function, pattern of lithium toxicity, patient's clinical status, and availability of extracorporeal treatments.

Lithium overdose: early hemodialysis is the key!

A 65-year-old gentleman was referred to our hospital with encephalopathy and renal failure. His medications included lithium for the treatment of bipolar disorder. The clinical examination and the laboratory investigations that followed revealed findings classical of lithium overdose. The patient was successfully managed and discharged from the hospital on Day 9 of admission. Clinicians should be aware of this rather unusual and relatively rare differential cause of acute on chronic renal failure with encephalopathy.