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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.
... 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 . ...
... Lithium intoxication is associated with several neurological symptoms, such as tremor, ataxia, encephalopathy, comatous mental change, and dysarthria. 8 Also, SILENT mostly induces cerebellar and extrapyramidal symptoms. 8 Neuroleptic malignant syndrome (NMS) is an idiosyncratic and potentially life-threatening reaction, characterized by hyperpyrexia, muscle rigidity, autonomic dysfunction, mental status change, tremors, leukocytosis, and creatinine kinase (CK) elevation. ...
... 8 Also, SILENT mostly induces cerebellar and extrapyramidal symptoms. 8 Neuroleptic malignant syndrome (NMS) is an idiosyncratic and potentially life-threatening reaction, characterized by hyperpyrexia, muscle rigidity, autonomic dysfunction, mental status change, tremors, leukocytosis, and creatinine kinase (CK) elevation. [9][10][11] Although the reported incidence of NMS is reported to be just 0.01% to 0.02%, it is responsible for a significant portion of morbidity and mortality in patients who use antipsychotics. ...
... 4,5 In 1987, the first case report of SILENT, which represents persistent and irreversible neurotoxic sequelae of lithium, was described. [6][7][8] In a literature review, SI-LENT was mostly associated with extrapyramidal features and cerebellar symptoms. 8,27 In the present case, the persistent catatonic features of the patient raised the suspicion of NMS. ...
Background:
Lithium can cause not only acute neurotoxicity but also chronic and persistent neurotoxicity known as syndrome of irreversible lithium-effectuated neurotoxicity (SILENT). The combined use of lithium and antipsychotics increases the possibility of SILENT. Neuroleptic malignant syndrome (NMS) is a reversible, idiosyncratic, and potentially life-threatening reaction, which is usually caused by antipsychotics and other agents, such as mood stabilizers (eg, lithium and metoclopramide). Neuroleptic malignant syndrome is characterized by hyperpyrexia, muscle rigidity, and altered mental status. We describe a case of SILENT combined with NMS in this case report.
Case report:
A 46-year-old man who had been treated with lithium for bipolar II disorder since 2008 was prescribed lorazepam, lithium, and aripiprazole at his last outpatient visit. The patient experienced financial difficulties (bankruptcy) and suffered severe emotional stress. Subsequently, he overused lorazepam, lithium, and aripiprazole. Two days after the overdose, he experienced a high fever, confused mental status, and rhabdomyolysis and was diagnosed with NMS. However, even after resolution of NMS-related symptoms, quadriplegia, visual field defects, ataxia, and severe dysarthria persisted. A positron emission tomography-computed tomography brain scan showed decreased 15F-fludeoxyglucose uptake in bilateral primary motor cortices and in the thalamus, midbrain, and cerebellum. Brain magnetic resonance imaging diffusion tensor imaging and diffusion tensor tractography of the subcortical tracts revealed structural disruptions, especially in the corticospinal tract, dentatorubrothalamic tract, and optic radiation, which seemed to be correlated with the clinical symptoms of the patient.
Conclusion:
This case suggests that the clinical use of diffusion tensor tractography could be helpful to explain the clinical features in the case of SILENT combined with NMS.
... In some cases, neurologic complications did not disappear despite the successful removal of lithium by hemodialysis. [21] These prolonged neurologic sequelae consist of cerebellar dysfunction, extrapyramidal symptoms, brainstem dysfunction, dementia, nystagmus, choreoathetoid movements, myopathy, and blindness. [21,22] Demyelination in the nerve system was proposed as the cause, which was consistent with the nerve conduction test report of our patient, sensorimotor polyneuropathy with conduction block. ...
... [21] These prolonged neurologic sequelae consist of cerebellar dysfunction, extrapyramidal symptoms, brainstem dysfunction, dementia, nystagmus, choreoathetoid movements, myopathy, and blindness. [21,22] Demyelination in the nerve system was proposed as the cause, which was consistent with the nerve conduction test report of our patient, sensorimotor polyneuropathy with conduction block. The prolonged neurologic sequelae could continue for months and, in rare cases, for years. ...
... The prolonged neurologic sequelae could continue for months and, in rare cases, for years. [21,23] On account of the narrow therapeutic window of lithium, as well as the dramatic changes in oral intake and fluid status following bariatric surgery, caution should be taken in managing patients who take lithium. A protocol has been proposed by a previous literature, the authors of which suggest checking lithium level weekly during the first 6 postoperative weeks, then every 2 weeks until 6 months postsurgery, and later monthly until 1-year postsurgery. ...
Rationale:
Lithium is the first-line medication for bipolar disorder, given a narrow therapeutic window of 0.8 to 1.2 mEq/L. Change of lithium pharmacokinetics following bariatric surgery may lead to lithium toxicity, which is particularly concerned.
Patient concerns:
We presented a 39-year-old man with morbid obesity and bipolar affective disorder for 20 years, who was treated with lithium. He developed serious lithium toxicity following sleeve gastrectomy and prolonged neurologic sequelae.
Diagnoses:
He suffered from persistent watery diarrhea, general weakness, and then drowsy consciousness. Lithium level was checked immediately to be 3.42 mEq/L and lithium toxicity was diagnosed.
Interventions:
After 3 courses of hemodialysis, his serum lithium level subsequently declined to 0.63 mEq/L, while his consciousness returned normal. Lithium was replaced by lamotrigine.
Outcomes:
The patient was discharged thirty-five days after admission, while his serum lithium declined to 0.06 mEq/L. Neurologic sequelae were noted by muscle weakness and pain sensation in both feet. The nerve conduction test revealed sensorimotor polyneuropathy with conduction block. He was advised to keep a passive range of motion exercise.
Lessons:
Although the consensus guideline remains lacking, our report reviewed cases of relevance in the literature and highlighted the awareness of the potential risk of lithium toxicity following bariatric surgery. We suggest close monitoring of the lithium levels and perhaps a dosage adjustment for the postoperative period.
... Dysfunction of the basal ganglia, such as akathisia and dyskinesia, and cortical dysfunction such as dementia have frequently been reported. Also, brainstem dysfunction and in rare cases atypical symptoms may appear such as papillary edema, neuritis optica, downbeat nystagmus, peripheral neuropathy, myopathy, choreo-athetosis and blindness [3][4][5]. ...
... At this time, the mechanism of persistent toxicity is not well understood. There is a hypothesis that demyelination in different parts of the brain is involved [4,5]. Fever, the combination of lithium and antipsychotics, overdose and high serum lithium levels are described as potential risk factors and could have played a role in our patient developing persistent sequelae. ...
... Once the diagnose of SILENT is made, lithium is contraindicated due to the risk of further toxicity. Treatment is currently limited to support measures such as physiotherapy, physiotherapy and general rehabilitation [5]. ...
... Hence, monitoring of lithium levels cannot be overemphasized. The syndrome of irreversible lithium-effectuated neurotoxicity (SILENT) has been coined after case reports of persistent neurologic deficits after lithium toxicity despite normalization of lithium levels [5]. It is a rare sequela of lithium toxicity. ...
... It also has atypical presentations which includes downbeat nystagmus, retrobulbar optic neuritis, persistent papilledema, choreoathetoid movements, peripheral neuropathy (both motor and sensory), myopathy, and blindness (due to central pontine myelinolysis). Only one case reported encephalopathic illness as a deficit (Table 1) [5]. ...
... In the background of chronic lithium exposure, the rise in lithium levels has started the cascade of events leading our patient to this encephalopathic state. Demyelination caused by lithium at multiple sites in the nervous system is hypothesized to be the cause of SILENT [5]. ...
Background:
Lithium is still the first-line agent for bipolar disorder. Despite common knowledge on monitoring lithium levels to prevent toxicity, it still occurs at varying degrees. Here we present a rare sequela of lithium toxicity, the Syndrome of Irreversible Lithium-Effectuated Neurotoxicity (SILENT). Case Presentation. A 56-year-old male war veteran who is fully functional despite being on chronic lithium therapy for Posttraumatic Stress Disorder (PTSD) and bipolar disorder presented at the emergency room with altered mental status and seizures associated with elevated lithium levels and renal insufficiency. Antiepileptic drugs were given for seizure control, and intermittent hemodialysis was done to clear the lithium. Despite clearance of the offending agent, the patient remained to have a generalized slowing on repeated EEG with only eye opening and nonpurposeful limb movements regained even after more than 2 months of lithium cessation.
Conclusion:
SILENT has been coined after reports of persistent neurologic deficits were seen in patients who experienced lithium toxicity more than 2 months after cessation of lithium. Chronic lithium therapy predisposes to gradual accumulation of lithium in the brain. Demyelination is the typically reported feature of SILENT. It can also leave the patient in a persistent encephalopathic state. Chronic lithium toxicity from failure of monitoring puts patients on lithium therapy at risk.
... Despite more than a century of clinical use, lithium's mechanism of toxicity remains poorly understood (16,45). Although lithium may cause comparatively mild gastrointestinal and cardiac toxicity, its major site of therapeutic and toxic action remains the CNS (16,45). ...
... Despite more than a century of clinical use, lithium's mechanism of toxicity remains poorly understood (16,45). Although lithium may cause comparatively mild gastrointestinal and cardiac toxicity, its major site of therapeutic and toxic action remains the CNS (16,45). Ataxia, myoclonus, and tremor are most commonly seen with lithium toxicity; severe symptoms include seizures, delirium, and coma, with fatalities stemming from severe neurotoxicity. ...
... One of the more severe complications of lithium toxicity is permanent neurotoxicity; it is unclear whether extracorporeal treatments affect this (45). Case series are conflicting on whether neurotoxicity is less common or more common after extracorporeal therapy, and it is uncertain if rapid removal of lithium avoids or increases the risk of long-lasting sequelae (45,46). ...
Extracorporeal therapies have been used to remove toxins from the body for over 50 years and have a greater role than ever before in the treatment of poisonings. Improvements in technology have resulted in increased efficacy of removing drugs and other toxins with hemodialysis, and newer extracorporeal therapy modalities have expanded the role of extracorporeal supportive care of poisoned patients. However, despite these changes, for at least the past three decades the most frequently dialyzed poisons remain salicylates, toxic alcohols, and lithium; in addition, the extracorporeal treatment of choice for therapeutic removal of nearly all poisonings remains intermittent hemodialysis. For the clinician, consideration of extracorporeal therapy in the treatment of a poisoning depends upon the characteristics of toxins amenable to extracorporeal removal (e.g., molecular mass, volume of distribution, protein binding), choice of extracorporeal treatment modality for a given poisoning, and when the benefit of the procedure justifies additive risk. Given the relative rarity of poisonings treated with extracorporeal therapies, the level of evidence for extracorporeal treatment of poisoning is not robust; however, extracorporeal treatment of a number of individual toxins have been systematically reviewed within the current decade by the Extracorporeal Treatment in Poisoning workgroup, which has published treatment recommendations with an improved evidence base. Some of these recommendations are discussed, as well as management of a small number of relevant poisonings where extracorporeal therapy use may be considered.
... 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.
... 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. ...
... 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.
... Following lithium toxicity, some patients develop prolonged or permanent neurological sequelae, known as the Syndrome of Irreversible Lithium-Effectuated Neurotoxicity (SILENT), which spans a spectrum of neurological symptoms from mild tremors to debilitating cognitive and motor impairments. 2 While the risks for the development of long-term sequelae are not well characterized, there is an association between the duration of elevated serum lithium concentrations (reflecting a high central nervous system lithium concentration) and an increased likelihood of serious or prolonged symptoms. 3 It follows that expeditious removal of lithium from the body may limit long-term toxicity. ...
Aims:
Two guidelines for haemodialysis in lithium poisoning, one from the Extracorporeal TReatments in Poisoning (EXTRIP) workgroup and a single centre retrospective one (Paris) differ. We compared outcomes in lithium poisoning based on these criteria with a primary outcome of worsening neurological symptoms in patients for whom EXTRIP and Paris criteria were discordant.
Methods:
Poison centre data were queried for lithium poisoned patients for whom haemodialysis was either recommended or performed. Patients were categorized according to EXTRIP and Paris criteria and excluded if the peak lithium concentration was <1.2 mmol/L or if neurological follow-up was unavailable. Comparative analyses were only performed when both criteria could be assessed.
Results:
In total, 219 patients were analysed. Paris criteria were met in 70 and EXTRIP criteria in 178. Forty two patients were excluded because Paris criteria could not be evaluated. When Paris and EXTRIP both supported haemodialysis, 50/57 (88%) of patients who received haemodialysis improved, as did all 3 who did not receive haemodialysis. When Paris and EXTRIP did not support haemodialysis, all nondialysed patients did well. Among the 86 patients for whom EXTRIP supported haemodialysis but Paris did not, 4/19 (21%) patients not dialysed deteriorated (P = .02; odds ratio = 8.7, 95% confidence interval = 1.5-51.8), 1 of whom died. All 8 patients for whom Paris criteria supported haemodialysis but EXTRIP did not were dialysed and improved.
Conclusions:
When the EXTRIP and Paris criteria are discordant, EXTRIP criteria outperforms the Paris criteria at identifying potentially ill patients who might benefit from haemodialysis.
... Following lithium toxicity, some patients develop prolonged or permanent neurological sequelae, known as the Syndrome of Irreversible Lithium-Effectuated Neurotoxicity (SILENT), which spans a spectrum of neurological symptoms from mild tremors to debilitating cognitive and motor impairments. [2] While the risks for the development of long-term sequelae are not well characterized, there is an association between the duration of elevated serum lithium concentrations (reflecting a high CNS lithium concentration) and an increased likelihood of serious or prolonged symptoms. [3] It follows that expeditious removal of lithium from the body may limit long-term toxicity. ...
... SILENT is characterized by a broad spectrum of neuropsychiatric symptoms that follows lithium toxicity and may persist long after serum lithium normalization. Clinical features may include brainstem and/or cerebellar dysfunction, extrapyramidal features, and cognitive impairment [14]. Prognosis is worst when symptoms persist for a longer period. ...
Lithium is the most effective therapy for bipolar
and schizoaffective disorders. Despite its efficacy, lithium has a narrow
therapeutic index and adverse effects are frequent. Lithium intoxication
(LI) generally affects brain, but less frequently can affect kidneys,
thyroid, and parathyroid. Here, we report the case of a patient with
lithium neurotoxic effects complicated by parathyroid and renal adverse
effects. The patient was a 52-year-old woman treated with lithium, who was
recently diagnosed with hypercalcemia and hyperparathyroidism. She was
admitted for severe agitation, confusion, and diffuse tremor. Despite
serum lithium and calcium normalization, laboratory tests revealed a
life-threatening hypernatremia caused by nephrogenic diabetes insipidus
(NDI). Hemodialysis was started, but after the first treatment the patient
died for cardiac arrest. Neurological symptoms of LI may occur even if the
dosage is close to the normal therapeutic range. Hypercalcemia and NDI are
rare, but should be promptly diagnosed and treated. In case of poor
clinical outcome, hemodialysis should be performed independently of
lithium serum level.
... В том случае если обнаруженные нарушения при использовании исследуемого вещества в дозах, соотносимых с терапевтическими, необратимы, следует признать, что дальнейшая разработка нецелесообразна, поскольку купировать повреждения нейронной сети практически невозможно, и по этой причине невозможно обеспечить безопасность применения даже высокотаргетного ЛС [41]. ...
Neurotoxic effects are one of the common reasons for discontinuation of preclinical and/or clinical studies. Preclinical evaluation of neurotoxic effects is complicated due to a wide range of manifestations and degrees of severity. Current experimental approaches to neurotoxicity assessment are cumbersome, laborious and not adapted enough for preclinical studies in the early stages of drug development. The aim of the study was to review existing approaches to experimental assessment of neurotoxic potential of new drugs and to discuss the need for and feasibility of developing and using integrated rapid neurotoxicity tests for early assessment of a pharmacological project’s potential. The authors reviewed scientific literature and guidance documents and analysed current approaches to chemical compound neurotoxicity assessment in laboratory animals. The paper analyses the main issues of neurotoxicity assessment for new drugs and compares Irwin tests with the functional observation battery. It analyses issues related to assessment of drugs’ effects on the development and maturation of central nervous system functions at pre- and postnatal stages. It was determined that the current practice is not sufficient for assessment of potential adverse effects on cognitive functions. The authors assessed factors affecting cognitive functions of rodents during studies. The “Acute suppression of the exploratory and orientation response” and “Extrapolation escape task” tests were proposed for validation as potential rapid tests for detection of an array of organic and functional neurotoxic disorders at early stages of preclinical studies.
... 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. ...
... 11 A more unusual chronic finding is the syndrome of irreversible lithium-effectuated neurotoxicity that includes cerebellar and cognitive deficits, and may be the result of demyelination. 12 For acute intoxication, with levels less than 2.5 mEq/L, volume expansion with isotonic saline is usually sufficient, as drug-induced urinary concentrating defects and volume depletion are typical. Although volume resuscitation may improve kidney function and endogenous renal lithium clearance, forced diuresis does not increase lithium clearance. ...
Extracorporeal modalities have been used for detoxification for decades, with hemodialysis the preferred and most commonly used modality. Salicylates, lithium, methanol, and ethylene glycol are the most common poisonings treated with dialysis. For each of these common poisonings, a description of the toxidrome including pharmacokinetics, clinical presentation, an overview of treatment, and the role and application of dialysis is outlined. Inhibition of alcohol dehydrogenase to prevent the formation of toxic metabolites in methanol and ethylene glycol is discussed in detail, including the use of fomepizole and ethanol to complement and in some cases prevent the need for hemodialysis. Hemodialysis has been attempted to treat many poisonings, often without success. A description of EXTRIP (Extracorporeal Treatments in Poisoning), a multidisciplinary project examining the evidence for extracorporeal treatments in poisoning, is also described. Recommendations for poisoning with acetaminophen, baclofen, barbiturates, carbamazepine, digoxin, metformin, phenytoin, thallium, theophylline, tricyclic antidepressants, and valproic acid are provided in a comprehensive table.
... Additionally, acute lithium toxicity can lead to permanent neurological damage. This phenomenon is known as the Syndrome of Irreversible Lithium-Effectuated Neurotoxicity (SILENT) ( Munshi et al., 2005) and is linked in particular to cerebellar dysfunction, extrapyramidal symptoms and brain stem dysfunction ( . This can cause permanent eye, speech and loco-motor coordination which will permanently impair daily functioning of affected patients (Niethammer and Ford, 2007). ...
Bipolar disorder is a chronic affective disorder affecting 1 to 3% of the adult population worldwide and has a high level of comorbidity with suicide rates, substance abuse and other harmful conditions. The disorder has possible ties to schizophrenia and has been observed to have a strong genetic component. The exact biological underpinnings have not been firmly established, however abnormalities in limbic subcortical and prefrontal areas have been observed.Ever since its discovery more than half a century ago, a daily intake of Lithium salts has arguably become the most reliable treatment of the disorder, despite us possessing little to no understanding of its biochemical action. In order to shed some light on the effect of Lithium in the brain, we have developed Lithium-7 MR imaging at 7 and 17 Tesla in order to assess its cerebral concentration and distribution. Specifically, I worked on developing and validating several acquisition, reconstruction and quantification methods dedicated to 7Li MRI and MRS. Those methods were first applied to study ex vivo the cerebral distribution of lithium in rats. These rats were pretreated for 28 days with Li2CO3, sacrificed and their head fixated with PFA. Using a home-made 1H/7Li radiofrequency surface coil and a 7Li Turbo Spin echo acquisition and a modified phantom replacement method for quantification, we were able to measure Li concentration maps. Regional Li concentration values were then compared with those obtained with mass spectrometry.After this preclinical proof-of-concept study, an in vivo 7Li MRI protocol was designed to map the cerebral Li concentration in euthymic bipolar subjects at 7T. These individuals all followed a regular lithium treatment. For this study, we chose to use an ultra-short echo-time Steady State Free Precession sequence with non-Cartesian k-space sampling. A quantification and analysis pipeline similar to the one used for our preclinical study was applied for this study, with the addition of a correction step for B0 inhomogeneities. After conducting a statistical analysis at the cohort level, it was assessed that the left hippocampus, a major part of the limbic system that has been associated with BD on multiple occasions, exhibited systematically a high level of lithium. Finally, I developed a quantification method accounting for the different relaxation times of 7Li in the CSF and in the brain parenchyma. This method was applied to image lithium at 7T in a subset of bipolar patients reducing drastically the differences initially observed between the SSFP and bSSFP sequences.
... Syndrome of irreversible lithium effectuated neurotoxicity (SILENT) is a persistent sequelae of lithium intoxication and may persist for weeks or even up to years. Patients present most commonly with cerebellar dysfunction as a result of lithium-induced demyelination in the CNS [57,58]. & Expert panel recommendations for RRT in lithium intoxication: We recommend intermittent HD as the preferred RRT modality for lithium intoxication. ...
Background
Intentional or unintentional ingestions among children and adolescents are common. There are a number of ingestions amenable to renal replacement therapy (RRT).
Methods
We systematically searched PubMed/Medline, Embase, and Cochrane databases for literature regarding drugs/intoxicants and treatment with RRT in pediatric populations. Two experts from the PCRRT (Pediatric Continuous Renal Replacement Therapy) workgroup assessed titles, abstracts, and full-text articles for extraction of data. The data from the literature search was shared with the PCRRT workgroup and two expert toxicologists, and expert panel recommendations were developed.
Results and Conclusions
We have presented the recommendations concerning the use of RRTs for treatment of intoxications with toxic alcohols, lithium, vancomycin, theophylline, barbiturates, metformin, carbamazepine, methotrexate, phenytoin, acetaminophen, salicylates, valproic acid, and aminoglycosides.
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.
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.
A trend in the increasing use of prescription psychoactive drugs (PADs), including antidepressants, antipsychotics, and mood stabilizers, has been reported in the United States and globally. In addition, there has been an increase in the production and usage of illicit PADs and emergence of new psychoactive substances (NPSs) all over the world. PADs pose unique challenges for critical care providers who may encounter toxicology issues due to drug interactions, side effects, or drug overdoses. This article provides a summary of the toxicologic features of commonly used and abused PADs: antidepressants, antipsychotics, mood stabilizers, hallucinogens, NPSs, caffeine, nicotine, and cannabis.
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.
Electroconvulsive therapy and concomitant lithium therapy remain a matter of debate because of increased rates of adverse events. Current recommendations include monitoring lithium levels and reducing lithium to minimally effective dose. We present a report on protracted effects of lithium intoxication as electroconvulsive therapy 8 days after intoxication and under normal lithium serum levels resulted in a prolonged seizure. Electroencephalogram recordings before stimulation showed electroencephalogram correlates of subsiding lithium intoxication most likely due to protracted lithium influx and efflux of the central nervous system.
Lithium is widely used in the treatment of bipolar disorder. Here we describe the syndrome of irreversible lithium-effectuated neurotoxicity in a patient within therapeutic doses and levels, which persisted after discontinuation of Lithium. A 50-year-old gentleman with Bipolar disorder presented with symptoms of Mania following drug default. Lithium was initiated as a mood stabilizer. On day 4, the patient developed abdominal pain, itching, and sore throat. On day 5, lithium levels were 0.9 mEq/L. Subsequently, the patient was noted to have slurring of speech, dysarthria, past pointing, and dysdiadochokinesis. Lithium was withdrawn on day 7. When lithium was re-introduced at a lower dose, the neurological symptoms re-appeared after 2 days and lithium was discontinued. Mild degree of slurring of speech persisted at 2-month follow-up. The patient had no history of side effects with antipsychotics in the past or current episode. In the absence of predisposing factors, Lithium has resulted in neurotoxicity at therapeutic doses and levels. Slurring of speech persisted despite adequate dose of anticholinergics. In addition to presumed neuroprotective effects of lithium, it can produce neurotoxic symptoms at therapeutic doses and levels.
Subacute toxic encephalopathies are challenging to identify due to their often insidious tempo of evolution, nonspecific manifestations, relative infrequency as individual entities, and frequent lack of specific diagnostic testing. Yet they are crucial to recognize-in aggregate, subacute toxic encephalopathies are a common problem that can lead to severe, irreversible harm if not diagnosed and treated efficiently. This article reviews the clinically relevant aspects of some of the more important subacute toxic encephalopathy syndromes caused by inorganic toxins, carbon monoxide, antibiotics, antineoplastic agents, and psychiatric medications.
Introduction
Adverse events (AEs) monitoring of mood stabilizers (MS) is essential during the treatment of mood disorders as safety and tolerability profiles of MS may greatly influence treatment adherence, patient’s compliance and discontinuation rate. Therefore, clinicians should be aware of their AEs profile and tapering a variety of strategies to manage them, according to an evidence-based approach.
Areas covered
We aimed at critically summarizing the tolerability and safety profile for each non-antipsychotic MS, providing evidence-based strategies able to manage these AEs, in order to increase clinically useful strategies which may allow clinicians enhancing adherence and therapeutic compliance, the impact on quality of life and treatment efficacy in psychiatric conditions.
Expert opinion
The management of the safety and tolerability profile of each MS comprises an initial assessment of the symptoms/signs to be observed/measured during the therapy, including a psychoeducational activity, a periodical monitoring with a specific timing depending on clinical parameters and each prescribed MS, but also an evaluation if a treatment modification (in terms of dose adjustment, discontinuation or additional medication to be prescribed) is required as well as which combination therapy is allowed and which caution should be posed by clinicians in some special conditions, including pregnancy and breastfeeding.
Lithium has been the gold standard in the long-term treatment of bipolar disorder for more than 40 years 1. Due to a narrow therapeutic index lithium intoxication still is a common but potentially avoidable clinical problem 2. The possibility of SILENT-syndrome (syndrome of irreversible lithium-effectuated neurotoxicity) illustrates that prevention and optimal treatment of lithium intoxication is vitally important 3.
Polypharmacy is common in patients with a diagnosis of bipolar disorder. Although polypharmacy is known to increase the risk of iatrogenic neurological conditions, the recovery of cognitive function after drug withdrawal has been rarely documented in psychiatric patients using standardized neuropsychological methods. We present a neuropsychological case report of patient SN, a 41-year-old woman who developed a socially and occupationally detrimental condition of cognitive dysfunction likely induced by long-term exposure to lithium and other psychiatric medications. To shed light on SN’s cognitive deficits and their recovery after drug withdrawal, neuropsychological assessments were conducted before, and approximately 2 years after, lithium and other psychiatric drugs were discontinued. Selective cognitive impairments were observed before drug discontinuation in visuomotor speed, visuoperceptual reasoning and delayed visual memory. Partial, but not complete, recovery of function was observed 2 years after drug withdrawal.
Acute Motor Sensory Axonal Neuropathy (AMSAN) is a rare and severe variant of Guillain-Barré syndrome (GBS) that has a prolonged recovery course. GBS is often suspected due to ascending muscle weakness, sensation difficulties, respiratory compromise, and antecedent diarrhea. The diagnosis of GBS is supported by cerebrospinal fluid analysis showing albuminocytologic dissociation. Electromyogram and nerve conduction study confirm the diagnosis and allow for further classification by variant. Treatment involves either IV immune globulins or plasmapheresis, and patients typically recover. However, depending on the variant and severity, patients may ultimately require prolonged mechanical ventilation with tracheostomy. In these cases, they may continue to have persistent muscle and sensation abnormalities requiring long-term care. We present a unique case of a 38-year-old female patient with decade-long use of lithium for bipolar disorder that presented with acute lithium toxicity. Though she was ultimately diagnosed with AMSAN, the Syndrome of Irreversible Lithium-Effectuated Neurotoxicity (SILENT) may have also contributed to her persistent neurological sequelae.
To compare the health risks of multiple metal(loid)s in groundwater, and discuss the feasibility of drinking water standards, 66 groundwater samples were collected from the Hetao Plain in October 2017. Eighteen metal(loid) species (boron (B), manganese (Mn), iron (Fe), strontium (Sr), barium (Ba), lithium (Li), scandium (Sc), titanium (Ti), vanadium (V), cobalt (Co), nickel (Ni), copper (Cu), zinc (Zn), arsenic (As), selenium (Se), rubidium (Rb), molybdenum (Mo), uranium (U)) were analyzed, and the related non-carcinogenic risks were assessed. The results showed that 83.3% of the groundwater samples had As and Fe contents above the maximum allowed contaminant levels (MCLs) in drinking water standards, followed by Mn (70.2%), B (65.2%), Se (60.6%), U (18.2%), Ni (18.2%) and Mo (1.50%). Compared with the dermal exposure pathway, oral ingestion made a risk contribution of more than 99% for all target metal(loid)s. Site-specific hazard quotient (HQ) values ranged from 2.30E+00 to 1.75E+02, indicating that multiple metal(loid)s in the drinking groundwater cause a serious non-carcinogenic risk to the local people. The risk contributions (mean value) were ranked as As (55.2%) > U (25.5%) > Li (10.8%) > other total metal(loid)s (8.60%), and the contributions of U and Li could reach 91.7% (site 20) and 69.8% (site 56), respectively. The calculation of specific health risks further indicated that the MCLs of metal(loid)s do not match the corresponding health risk well. Some metal(loid)s such as Li that showed high exposure risks in this study, still have no MCL values until now. Therefore, current drinking water standards need to be updated.
Résumé
Les ataxies cérébelleuses sont d’origines diverses. Les plus fréquentes sont les origines dégénératives et génétiques mais les causes acquises, notamment toxiques médicamenteuses surtout dues aux sels de lithium doivent être systématiquement recherchées. Les sels de lithium, plus que le carbonate de lithium, sont utilisés depuis le XIXe siècle d’abord en médecine pour le traitement de certaines maladies telle que la goutte et l’hypertension artérielle, puis plus récemment en psychiatrie pour les troubles bipolaires et de l’humeur. Cependant, leur utilisation requière une surveillance particulière du fait de leurs effets secondaires qui peuvent être potentiellement graves, voire engager le pronostic vital en fonction de la durée et la quantité de l’exposition. Sur le plan neurologique, les effets secondaires du lithium peuvent toucher aussi bien le système nerveux central que périphérique. L’atrophie cérébelleuse est rare mais elle reste l’une des complications les plus handicapantes suite à l’intoxication au lithium. Dans la littérature, de rares et anciens cas d’ataxie cérébelleuse due au lithium avaient été décrits mais devant la grande prévalence dans la population générale des patients sous lithium, il semble opportun de rapporter de nouveaux cas afin de maintenir l’attention sur la surveillance de ces prescriptions. Nous rapportons deux cas récents d’atrophie cérébelleuse secondaire à une intoxication aiguë au lithium lors de tentative de suicide.
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.
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.