Lithium Toxicity Viva

Long Case Viva Defence

Candidate's opening statement (model answer)

"Mrs Margaret Chen is a 72-year-old retired pharmacist presenting with a 5-day history of progressive confusion, unsteadiness, a worsening coarse tremor, slurred speech, and nausea. She has a 25-year history of bipolar I disorder, maintained on lithium carbonate 1000 mg at night with a long-stable level of 0.75 millimoles per litre. [1]

Two weeks ago her GP and cardiologist started three new medications: indapamide 1.5 mg for hypertension, ibuprofen 400 mg three times daily for osteoarthritic knee pain, and ramipril 2.5 mg for a recent myocardial infarction with mild heart failure. Her lithium was not dose-adjusted and was not checked after these changes. The combination of a thiazide-like diuretic, an NSAID, and an ACE inhibitor — all of which increase serum lithium levels through distinct mechanisms — precipitated acute-on-chronic lithium toxicity. [1]

On examination she is drowsy with a Glasgow Coma Scale of 13, disoriented, and has a coarse tremor of both hands and her jaw, ataxia on heel-to-shin testing, hyperreflexia, occasional myoclonic jerks, and slurred speech. Her temperature is 37.2, blood pressure 105 over 62, pulse 88 in sinus rhythm. Her serum lithium level is 3.0 millimoles per litre. Her creatinine is 152 micromoles per litre, risen from a baseline of 92. Her ECG shows a QTc of 480 milliseconds with T-wave flattening in the lateral leads. Her TSH is mildly elevated at 7.8, consistent with her known lithium-related hypothyroidism, and her corrected calcium is mildly elevated at 2.62, raising the possibility of lithium-induced hyperparathyroidism. [1]

Her main problems are:

1. Acute-on-chronic lithium toxicity at 3.0 millimoles per litre with significant neurological toxicity and acute kidney injury — an immediate threat that meets the EXTRIP criteria for consideration of haemodialysis.
2. Acute kidney injury complicating the reduced lithium clearance, with a background of probable lithium-induced chronic interstitial nephritis given her 25-year lithium history and baseline eGFR of 52.
3. QT prolongation on the ECG, a cardiac conduction effect of lithium toxicity.
4. The three precipitating drug interactions — indapamide, ibuprofen, and ramipril — all of which must be stopped and the mechanisms understood to prevent recurrence.
5. The chronic lithium end-organ effects — hypothyroidism, mild hypercalcaemia, and probable chronic interstitial nephritis — requiring assessment and a longer-term management plan.
6. The underlying bipolar I disorder — the indication for lithium must be revisited with her psychiatrist. [1]

My immediate plan is to stop the lithium and the three interacting drugs, assess and resuscitate with ABCDE, and give aggressive intravenous normal saline to restore her volume and enhance renal lithium excretion. Given her level of 3.0 with decreased consciousness and acute kidney injury, I am discussing urgent intermittent haemodialysis with the nephrology and toxicology teams, as she meets the EXTRIP criteria. I will not give loop diuretics, which paradoxically raise the lithium level. I will check serial lithium levels every 2 hours, and after any dialysis I will check a post-dialysis rebound level at 4 to 6 hours because lithium redistributes from the tissues. Once she has recovered, I will work with her psychiatrist and her GP to decide whether to restart lithium at a reduced dose or switch to an alternative mood stabiliser, and I will ensure her renal, thyroid, and calcium monitoring is structured and communicated." [1]

Examiner probing questions and model answers

Q1: "Walk me through the pharmacological mechanisms by which indapamide, ibuprofen, and ramipril each increased the lithium level." [1]

"All three drugs converge on reducing renal lithium clearance, but through distinct mechanisms. Indapamide is a thiazide-like diuretic. It causes volume and sodium depletion at the distal tubule. The kidney compensates by increasing proximal tubular reabsorption of sodium, and because lithium is a monovalent cation handled like sodium in the proximal tubule, lithium reabsorption increases in parallel. This typically raises the lithium level by 25 to 40 percent within days, and it is the classic and most clinically important lithium drug interaction. Ibuprofen is a non-steroidal anti-inflammatory. NSAIDs reduce renal prostaglandin production, which reduces renal blood flow and the glomerular filtration rate, and increases proximal lithium reabsorption. All NSAIDs carry this risk; indometacin is the most studied, but ibuprofen is clinically significant. The effect is additive to the thiazide effect. Ramipril is an ACE inhibitor. It reduces angiotensin II, which normally constricts the efferent arteriole of the glomerulus to maintain the filtration pressure; blocking angiotensin II dilates the efferent arteriole, reducing the glomerular filtration pressure and the filtered load of lithium. ACE inhibitors also alter proximal tubular handling to further increase lithium reabsorption. The effect builds over 1 to 4 weeks. The combination of all three, started simultaneously without a lithium dose reduction or a level check, predictably precipitated toxicity. The correct approach when starting any of these drugs in a patient on lithium is to reduce the lithium dose by 25 to 50 percent and check a level within 5 to 7 days." [1]

Q2: "Her lithium level is 3.0 and she is drowsy. What are the EXTRIP criteria for haemodialysis, and does she meet them?" [1]

"The EXTRIP Workgroup published its consensus recommendations in 2015 (PMID 25871131). The recommended indications (grade 1D) for extracorporeal treatment are: a serum lithium concentration above 4.0 millimoles per litre regardless of symptoms; the presence of a decreased level of consciousness, seizures, or life-threatening dysrhythmias irrespective of the serum level; and impaired kidney function with a level above 4.0. The suggested indications (grade 2D) are: a level above 5.0; significant confusion; and an expected time to reduce the level below 1.0 of more than 36 hours. Intermittent haemodialysis is the preferred modality over continuous renal replacement therapy. For this patient: her level of 3.0 is above 2.5 (the severe threshold) but below 4.0. However, she has a decreased level of consciousness (GCS 13), which is a recommended indication for dialysis irrespective of the level. She also has impaired renal function with an acute kidney injury. So she meets the EXTRIP criteria on the basis of her decreased consciousness and her renal impairment, and I would proceed with urgent intermittent haemodialysis in addition to the intravenous normal saline, after discussion with the nephrology and toxicology teams." [1]

Q3: "After haemodialysis, her level comes back at 0.7. Can you send her to the ward?" [1]

"Not yet. Post-dialysis rebound is the rule in lithium toxicity, not the exception. Lithium has a volume of distribution approaching total body water, and the vast majority of the body burden sits in the tissue compartment, not the plasma. Haemodialysis rapidly clears the plasma, but lithium then redistributes from the tissues back into the plasma, and the level can rebound above the toxic threshold within 4 to 6 hours. A single post-dialysis level of 0.7 does not exclude a rebound. The EXTRIP guidance is to obtain serial lithium measurements over 12 hours after stopping extracorporeal treatment. So I would keep her in a monitored setting, check a level at 4 to 6 hours, and if it has rebounded significantly — for example, back above 2.0 with ongoing symptoms — I would repeat the haemodialysis session. Some centres use a continuous low-dose dialysis or CRRT after the initial intermittent session to blunt the rebound, particularly in a chronically toxic patient like this one with a large tissue burden. I would also continue the intravenous normal saline, monitor her renal function and her ECG, and reassess her clinical state. Once the level is stably below 1.0 millimoles per litre over several measurements and she is clinically improving, she can step down to the ward." [1]

Q4: "Her corrected calcium is 2.62 and she has been on lithium for 25 years. What is going on, and what will you do about it?" [1]

"This is most likely lithium-induced hyperparathyroidism. Lithium increases the set-point of the calcium-sensing receptor on the parathyroid chief cells, so that a higher serum calcium is required to suppress parathyroid hormone secretion. The result is inappropriately non-suppressed PTH in the face of hypercalcaemia. The prevalence of lithium-associated hyperparathyroidism is around 4 to 6 percent — far higher than the 0.5 percent population prevalence of primary hyperparathyroidism. A distinguishing feature is that lithium-induced hyperparathyroidism has a higher rate of multiglandular disease, around 50 percent, which has implications for surgical management. I will confirm the diagnosis by checking a parathyroid hormone level — I expect it to be in the high-normal or frankly elevated range, which is inappropriate given the hypercalcaemia (PTH should be suppressed). I will also check a 24-hour urinary calcium to exclude familial hypocalciuric hypercalcaemia, which produces a similar biochemistry but with low urinary calcium and is managed conservatively. Vitamin D levels should be checked. In the first instance, the management is monitoring — her calcium is only mildly elevated and she is asymptomatic from it. If it rises further or she develops symptoms, the options are a calcimimetic such as cinacalcet, or parathyroidectomy (recognising the higher rate of multiglandular disease, which may require a more extensive operation). This is a longer-term issue and I will address it after the acute toxicity has been managed, at her follow-up." [1]

Q5: "How would you counsel her and her family to prevent this happening again?" [1]

"I would explain that lithium is an excellent medication for her bipolar disorder but that it has a very narrow safe range, and that common medications — water tablets for blood pressure, anti-inflammatories for pain, and heart-failure tablets — can interfere with the way the body clears lithium and push the level into the toxic range. I would explain that the three new medications she was started on all had this effect, and that the build-up caused her confusion and unsteadiness. I would give her a written list of the medications to avoid or to use only with a lithium level check — thiazide diuretics, NSAIDs, and ACE inhibitors or ARBs — and I would tell her that any time she is prescribed a new medication, she should mention that she is on lithium and ask whether a level check is needed. I would also counsel her on the early symptoms of toxicity — a worsening or coarsening of her tremor, nausea, diarrhoea, slurred speech, unsteadiness, and confusion — and tell her to stop the lithium and seek urgent medical review if these develop, particularly during an illness when she is dehydrated. I would communicate the same information in writing to her GP, her cardiologist, and her psychiatrist, with a clear plan for the medication changes and the monitoring. The education and the communication are as important as the acute management — this episode was preventable, and the recurrence is preventable with structured counselling and coordination." [1]

DCE Short-Case Viva — The Neurological Examination of the Lithium-Toxic Patient

Examiner instruction: "This 68-year-old man, who is on lithium for bipolar disorder, has been brought in with confusion and unsteadiness. Please examine his neurological system and present your findings." [1]

Candidate's examination routine (narrated)

"I would introduce myself, confirm the patient's identity, and explain that I am going to examine his nervous system. I would first ask him a few simple questions to assess his mental state and his speech — orientation, naming, and a short sentence — looking for confusion, dysarthria, and dysphasia. [1]

I begin with general observation. I note his level of alertness — is he drowsy, agitated, or appropriately responsive? I observe his posture and his movements at rest, looking for a tremor (is it a fine physiological tremor, or a coarse tremor involving the hands and the jaw?), and for any involuntary movements such as fasciculations or myoclonic jerks. [1]

I assess his speech for slurring (dysarthria is common in lithium toxicity) and for any dysphasia. [1]

I examine the cranial nerves, with particular attention to the pupils (are they equal and reactive?), the eye movements (is there nystagmus?), and the fundi (to exclude papilloedema). [1]

I assess the motor system in the upper and lower limbs. I examine tone — is there rigidity (lead-pipe rigidity suggests neuroleptic malignant syndrome, not lithium), hypotonia, or a normal tone? I assess power. I examine for fasciculations in the tongue and the limb muscles. I test the reflexes — hyperreflexia is typical of lithium toxicity. I check the plantar responses. [1]

I assess coordination — the finger-to-nose test for upper limb past-pointing and intention tremor, the heel-to-shin test for lower limb coordination, and I look for cerebellar dysmetria and dysdiadochokinesia. Ataxia is a hallmark of lithium toxicity. [1]

I examine the sensation — light touch, pinprick, vibration, and joint position sense — to exclude a peripheral neuropathy or a spinal cord lesion. [1]

I assess the gait — is there an ataxic gait (wide-based, staggering), and can he tandem-walk? The gait is often the most sensitive test of cerebellar involvement. [1]

Finally, I stand back and integrate the findings: the coarse tremor, the ataxia, the hyperreflexia, the fasciculations and myoclonus, the dysarthria, and the confusion together form the classic picture of lithium neurotoxicity, and I would then check a serum lithium level and an ECG and proceed with the toxicological management." [1]

Presentation template (model answer)

"This 68-year-old man on lithium for bipolar disorder is drowsy with a Glasgow Coma Scale of 13 and is disoriented to time. His speech is slurred but not dysphasic. He has a coarse tremor at approximately 6 to 8 hertz affecting both hands and his jaw, present at rest and on action. His cranial nerves are intact with no nystagmus. In the limbs, his tone is normal, his power is preserved, and his reflexes are brisk symmetrically. He has visible fasciculations in the quadriceps and occasional myoclonic jerks of the hands. His coordination is impaired, with dysmetria on finger-to-nose testing bilaterally and a marked ataxic, wide-based gait. His sensation is intact. My findings localise to a diffuse encephalopathy with cerebellar and neuromuscular involvement, and in the context of his lithium therapy, the most likely diagnosis is lithium toxicity. I would now check a serum lithium level, a renal function, an ECG, and proceed with the toxicological management — stop the lithium, give intravenous normal saline, and assess for haemodialysis using the EXTRIP criteria." [1]

Examiner discussion

Q: "How do you distinguish the tremor of lithium toxicity from an essential tremor and a Parkinsonian tremor?" [1]

"The tremor of lithium toxicity is coarse, at roughly 6 to 8 hertz, and it is present both at rest and on action, affecting the hands and sometimes the jaw. An essential tremor is a fine, action tremor at 8 to 12 hertz, absent at rest and worsened by movement and emotion, typically in a patient with a family history and a long-standing, slowly progressive course. A Parkinsonian tremor is a resting, pill-rolling tremor at 4 to 6 hertz, which decreases on voluntary movement, and it is accompanied by bradykinesia and rigidity. The coarse tremor of lithium toxicity is a red flag — its appearance in a patient on lithium, particularly if it is new or worsening, demands an immediate lithium level. The fine tremor of therapeutic lithium levels is common and benign, but the coarse tremor signals toxicity." [1]

Q: "What is SILENT, and how does it affect your management?" [1]

"SILENT is the Syndrome of Irreversible Lithium-Effectuated NeuroToxicity. It describes the persistence of neurological deficits — most commonly cerebellar dysfunction (ataxia, nystagmus, dysarthria) and cognitive impairment — after the serum lithium level has normalised. It occurs after a severe or a prolonged episode of toxicity, and the deficits may be permanent. The mechanism is thought to be irreversible neuronal injury in the cerebellum and the cortex from prolonged exposure to toxic tissue lithium levels. There is no specific treatment. This is why the early recognition and the aggressive management of lithium toxicity — including prompt haemodialysis for the patients who meet the criteria — is so important. Preventing SILENT by removing the lithium quickly is the only effective strategy. I would counsel the patient and the family about the possibility of persistent deficits after a severe episode, and I would arrange rehabilitation — physiotherapy for the ataxia, occupational therapy for the activities of daily living, and cognitive assessment and support — as part of the recovery plan." [1]

Q: "Why does lithium cause a concentrating defect in the kidney, and how is it managed?" [1]

"Lithium enters the principal cells of the collecting duct through the epithelial sodium channel, ENaC. Once intracellular, it is not efficiently pumped out, and it downregulates the aquaporin-2 water channels — both by disrupting the cAMP-mediated signalling downstream of vasopressin and through cAMP-independent pathways including GSK-3 beta disruption. The result is that the collecting duct becomes insensitive to vasopressin and cannot reabsorb water, producing nephrogenic diabetes insipidus with polyuria and polydipsia. This affects 20 to 40 percent of patients on chronic lithium. The diagnosis is an inappropriately dilute urine despite an elevated or high-normal serum osmolality. Amiloride is the preferred diuretic in patients on lithium who need one, because it blocks ENaC and thereby reduces lithium entry into the principal cell, partially restoring the concentrating ability. Desmopressin does not work, because the problem is nephrogenic (the kidneys cannot respond to vasopressin), not central. In the acute management of lithium toxicity, the polyuria from the diabetes insipidus compounds the dehydration and the reduced clearance, which is why the aggressive intravenous normal saline is so important." [1]