Lithium neurotoxicity with electroencephalogram changes

Abstract

Lithium is a medication with a variety of medical usage for various diseases including bipolar mood disorder. As the therapeutic window of lithium is narrow, its usage is commonly associated with toxicity. Lithium toxicity affects multiple systems especially the central nervous system, leading to neuropsychiatric complications. Haemodialysis is an effective method for lithium removal especially in severe lithium toxicity such as neurotoxicity with electroencephalogram changes. We describe a case of lithium neurotoxicity with electroencephalographic abnormalities which was reversed following haemodialysis.

Background

Lithium has a variety of medical usage in the treatment of gout, thyrotoxicosis, depression, bipolar mood disorders and as a salt substitute for heart failure. It also acts as a mood stabilising agent as it also transiently increases the release of serotonin. Clinical features of toxicity can occur at plasma lithium concentrations at the upper limit of therapeutic range due to the narrow therapeutic index. Lithium can have significant multisystemic effects especially in the central nervous system. This case highlights lithium neurotoxicity effects may be profound and lead to electroencephalogram (EEG) changes.

Case presentation

A 46-year-old woman presented with altered behaviour for a 2-week duration. She was found by her family to be depressed, irritable with sleep disturbance, reduced oral intake and visual hallucinations. She admitted having ingested a whole bottle of lithium tablets. She had a medical background of bipolar mood disorder, diabetes mellitus and hyperlipidaemia, with a suicidal attempt 8 years ago when she jumped off a building and sustained multiple spinal and leg fractures with intra-abdominal hematoma. She had recovered gradually after several operations and was able to ambulate using a walking frame. Her medications consisted of lithium 450 mg t.i.d., olanzapine 5 mg daily, mirtazapine 30 mg daily, metformin 1 g b.i.d. and simvastatin 20 mg daily. She had serial lithium level monitoring in the outpatient clinics, which was normal between 1.06 and 1.11 mmol/L (therapeutic range 0.6–1.2).

Initial assessment revealed a confused woman with Glasgow coma scale of 14/15. The blood pressure was 104/63 mm Hg, pulse rate 102 beats per minute and temperature of 37°C. Her body mass index was 17.8 kg/m². Her pupils were equal and reactive bilaterally. She was lethargic with slurred speech and coarse tremors of her hands. Apart from hyperreflexia, the muscle tone and power of the limbs were normal and plantar reflexes were flexor bilaterally. The other systemic examinations were unremarkable.

Investigations

Her blood investigations revealed acute kidney injury with blood urea of 15.1 mmol/L and creatinine 223.8 µmol/L with an estimated glomerular filtration rate of 20.4 mL/min/1.73 m². Apart from hyponatremia 130 mmol/L and hypercalcemia 2.59 mmol/L, the other serum electrolytes were normal (potassium 3.7 mmol/L, calcium, magnesium 0.86 mmol/L and phosphate 1.04 mmol/L). Her full blood count showed haemoglobin 12.1 g/dL, total white cell count 15.9×10⁹/L with absolute lymphocyte count 0.6×10⁹/L, platelet count 290×10⁹/L and C reactive protein was 0.79 mg/dL. On admission, lithium level was in the toxic range 3.34 mmol/L (therapeutic range 0.6–1.2, toxic range >1.5), 2.97 mmol/L and 1.45 mmol/L on the second and third day, respectively.

Other investigations including chest radiograph and brain CT were normal. Cerebrospinal fluid analysis showed normal protein and glucose with negative cultures. Her EEG revealed diffuse asynchronous high amplitude theta activity (figure 1).

Figure 1.

Electroencephalogram pre-treatment showed diffuse asynchronous high amplitude theta activity.

Differential diagnosis

Meningoencephalitis was excluded as the brain imaging and cerebrospinal fluid analysis was normal. Uremia encephalopathy was considered as the patient had altered cognition in the presence of renal abnormalities. However, the renal profile showed normalisation after adequate hydration was given.

Treatment

Lithium was stopped and she was given adequate hydration with improvement and normalisation of renal function after 3 days. Serum lithium level reduced to 2.97 mmol/L and 1.45 mmol/L by the second and third day, respectively, which was still above the therapeutic range. However, her clinical condition did not improve with the supportive treatment and she remained to be dysarthric and tremulous. She was subsequently commenced on haemodialysis. After one course of haemodialysis over 4 hours, there was improvement of consciousness and tremors, and she was able to sit up and converse the following day. Her serum lithium level reduced significantly to less than 0.1 mmol/L. She was monitored closely for any further neurological symptoms but did not exhibit any new signs.

Outcome and follow-up

A repeated EEG showed improvement (figure 2). She was discharged well after 9 days of hospitalisation with further outpatient psychiatry evaluation.

Figure 2.

Electroencephalogram post-treatment showed normal alpha rhythm.

Discussion

Lithium toxicity can present with a diverse range of clinical manifestations that can be classified as acute, acute on chronic or chronic.¹ In a report of lithium poisoning, 18% were found to be unintentional.² Acute poisoning occurs following an overdose while chronic poisoning occurs when there is excessive lithium intake on a chronic basis. In acute-on-chronic poisoning, there is an acute overdose in patients who are already receiving lithium treatment, similar to this patient. This was precipitated by dehydration leading to volume depletion as evidenced by elevated urea and creatinine levels. Factors that can cause lithium toxicity include drug interactions that reduced glomerular filtration rate such as non-steroidal anti-inflammatory drugs and thiazide diuretics which disrupt renal tubular reabsorption. Prescribing errors, intercurrent illnesses and lithium-induced nephrogenic diabetes insipidus also contribute to this problem.

Apart from nausea, vomiting and diarrhoea, the manifestations of toxicity include sinus bradycardia, ST-segment elevation,³ prolonged QT interval,⁴ nephropathy and nephrogenic diabetes insipidus.⁵ Clinical features of neurotoxicity include lethargy, ataxia, confusion, agitation, seizures and neuromuscular excitability (coarse tremors, fasciculations, myoclonic jerks, hyperreflexia). The classification of lithium toxicity with its plasma concentrations by Hansen was as followed: Grade 1 (1.5–2.5 mmol/L): nausea, vomiting, tremor, hyperreflexia, agitation, ataxia, muscle weakness; Grade 2 (2.5–3.5 mmol/L): stupor, rigidity, hypertonia, hypotension; and Grade 3 (more than 3.5 mmol/L): coma, convulsions, myoclonus, collapse.⁶ This patient can be classified into Grade 2 toxicity although her signs were mainly tremors and hyperreflexia. Her risk was higher as lithium has been distributed to a steady state in the central nervous system with chronic use. Thus, a smaller amount of lithium was required to distribute to the central nervous system to cause toxicity. The pharmacokinetic disposition of lithium is described as an open, two-compartment model with variable rates of elimination.⁷ Even with the reduction or normalisation of the lithium level, there may still be symptoms of intoxication.^{8 9} Lithium neurotoxicity has been described in a case report of a patient with reversible symptoms of dementia while on treatment with lithium at therapeutic levels.¹⁰ Thus, our patient still exhibited features of neurotoxicity despite reduction of the lithium levels as long-term ingestion of lithium is more likely to be associated with higher tissue concentrations.

As neurotoxicity predominates the clinical presentation, hence EEG plays an important role in diagnosing and monitoring lithium poisoning.¹¹ Previous studies have documented EEG changes in patients with lithium toxicity such as diffuse slowing, non-convulsive status epilepticus^{12 13} and Creutzfeldt-Jakob-like changes.¹⁴ This patient exhibited asynchronous theta activity during the period of lithium toxicity which improved after treatment with haemodialysis.

Management of lithium toxicity includes assessment and stabilisation of the airway, breathing and circulation. Appropriate monitoring of the cardiac, renal and nervous systems must be carried out. Supportive measures including hydration, maintenance of airway and gastrointestinal decontamination with polyethylene glycol solution to reduce the absorption of lithium. The physical property of lithium that makes it readily dialyzable includes small molecule, unbound to plasma proteins, small volume of distribution and slow endogenous clearance. This supports the rationale that extracorporeal treatments help to reduce the risk or duration of toxicity in high-risk exposures. Intermittent haemodialysis or continuous renal replacement therapy are equally acceptable as an extracorporeal treatment for lithium toxicity.¹⁵ The patient had close monitoring after haemodialysis as a rebound of lithium from extravascular space may occur.

Learning points.

• As lithium is widely used in medical conditions, there is a need for vigilant monitoring of patients for clinical features of toxicity.

• Apart from laboratory investigations and lithium levels, electroencephalogram is a good modality to provide supportive evidence in the diagnosis and management of neurotoxicity.

• Lithium neurotoxicity warrants institution of extracorporeal treatment to aid in the improvement of the clinical features.

Ethics statements

Patient consent for publication

Consent obtained directly from patient(s).