Retrospective cohort study

N= 26,179

Pediatric patients (n= 8598)

Adult patients (n= 16,476)

Older adult patients (n= 1105)

Concomitant drugs

No ASMs

Monotherapy

Polytherapy

28.6%

28.0%

43.4%

16.7%

34.1%

49.2%

28.2%

37.0%

34.8%

13.2%

11.8%

10.9%

Retrospective review

N= 846

Levetiracetam (n= 564)

Phenytoin (n= 282)

Primary: Incidence of hyponatremia

Secondary: Treatment rates for hyponatremia, sodium levels at discharge, length of stay, mortality

Retrospective Swedish population–based case–control study

N = 71,742

Cases (n= 14,359)

Controls (n= 57,383)

Hyponatremia-Induced Epileptic Seizure Provoked by Levetiracetam and Pain Medication Intake in a Patient with Central Diabetes Insipidus

Design

Case presentation

A 67-year-old male with a history of transnasal hypophysectomy for craniopharyngioma six years prior, maintained on hydrocortisone 25 mg/day, levothyroxine 112 µg/day, intranasal desmopressin, and transdermal testosterone, presented following a first tonic-clonic seizure triggered by a bee sting to the left temporal region, prolonged car travel, and sleep deprivation. At the time of the first seizure, his sodium level was 140 mmol/L, and brain MRI was unremarkable. Due to seizure risk, levetiracetam 500 mg twice daily was initiated while his desmopressin dose and water intake remained unchanged. Four days later, he experienced a second focal aware seizure, at which time blood tests revealed severe hyponatremia (124 mmol/L). Levetiracetam was discontinued and replaced with lacosamide, analgesics were tapered, and sodium levels normalized over the following seven days, reaching 141 mmol/L. Subsequent MRI remained normal, and EEG performed three days after the second seizure showed transient left frontotemporal slow-wave activity, with follow-up EEGs returning to normal. Laboratory testing after recovery confirmed adequate cortisol replacement, normal plasma and urine osmolality, and undetectable copeptin levels. No further seizures occurred over a three-month follow-up period.

Study Author Conclusions

Recurrent Hyponatremia: Levetiracetam ‑ An Uncommon Cause

Design

Case presentation

A 50-year-old male with a history of traumatic brain injury was started on prophylactic levetiracetam. He experienced three admissions for hyponatremia: the first involved seizures and a serum sodium level of 118 mmol/L, the second with dizziness and a sodium level of 131 mmol/L, and the third with drowsiness and a sodium level of 108 mmol/L. During the latter two admissions, investigations suggested the presence of syndrome of inappropriate antidiuretic hormone secretion (SIADH), and a tolvaptan regimen was initiated. Despite the use of tolvaptan, the hyponatremia persisted until levetiracetam was discontinued, after which the patient experienced no further episodes of hyponatremia. The diagnostic workup ruled out other causes, indicating levetiracetam-induced hyponatremia. This finding was supported by a Naranjo Adverse Drug Reaction Probability Scale score of 7, categorizing levetiracetam as a "probable" cause. Following the discontinuation of levetiracetam, alternative antiseizure medications were not initiated since seizures were not observed without levetiracetam, and prophylactic anti-seizure medication is not typically administered for mild traumatic brain injuries with normal imaging.

Study Author Conclusions

Iatrogenic Hyponatremia Following Levetiracetam, About a Case

Design

Case presentation

A 53-year-old female with no significant medical or surgical history presented to the emergency department with acute headache, nausea, and vomiting. On admission, she presented with a Glasgow Coma Scale score of 13, blood pressure 159/99 mmHg, heart rate 108 bpm, respiratory rate 22/min, SpO₂ 92% on room air, and no neurological deficits or history of convulsions. A computed tomography (CT) scan of the brain revealed a subarachnoid hemorrhage due to rupture of an aneurysm of the left anterior communicating artery, confirmed by CT angiography, and she underwent uneventful endovascular embolization the following day.

Within 24 hours post-procedure, the patient developed neurological deterioration with generalized tonic-clonic seizures controlled with midazolam, and repeat CT demonstrated rebleeding. She was sedated for 48 hours and initiated on levetiracetam 10 mg/kg along with standard supportive care. The patient subsequently developed ventilator-associated pneumonia with Pseudomonas aeruginosa, treated with imipenem and amikacin.

On hospital day 6, she developed hypoosmolar hyponatremia with a sodium level of 129 mmol/L, initially managed with hydroelectrolytic supplementation and sodium administration at 10 g/day without improvement. By day 11, sodium had further declined to 118 mmol/L, prompting replacement of levetiracetam with sodium valproate. Sodium levels normalized within two days following this change, consistent with the temporal association shown on the natremia kinetic curve.

Study Author Conclusions

Levetiracetam—induced hyponatremia

Design

Case presentation

A 73-year-old male was admitted to the hospital following two generalized tonic–clonic seizures. He had a history of complete recovery from a traumatic intracerebral hemorrhage one year before and was not on any medications nor using substances like alcohol or tobacco. Initial examinations, including neurological evaluation and laboratory tests, were unremarkable. Despite a normal brain CT showing only mild cortical atrophy and a normal EEG, the patient was treated with valproate (VPA) at 1000 mg/day. Five days later, the patient's serum sodium dropped to 127 mM, and serum osmolality decreased, indicating potential Syndrome of Inappropriate Antidiuretic Hormone secretion (SIADH), despite other parameters being normal. Urine analysis suggested SIADH with high urine sodium and osmolality. The patient was switched from VPA to levetiracetam (LEV) 1000 mg/day, accompanied by fluid restriction. However, his serum sodium further declined to 119 mM, prompting the discontinuation of LEV and administration of hypertonic saline. Topiramate (TPM) 50 mg/day was started, leading to improvement in hyponatremia; serum sodium rose to 134 mM over nine days, normalizing serum osmolality. The patient's condition stabilized, and he remained seizure-free on TPM for one year with normal serum sodium levels. A re-challenge with LEV was avoided due to concerns of medication-induced hyponatremia and successful seizure management with TPM. 

Study Author Conclusions

The first case of levetiracetam-induced and tolvaptan-resistant hyponatremia

Design

Case presentation

A 74-year-old male with a 10-year history of chronic heart failure, valvular heart disease with a mechanical aortic valve, and epilepsy presented with worsening heart failure symptoms and severe hyponatremia. His chronic medications included carvedilol, furosemide, trandolapril, spironolactone/hydrochlorothiazide, warfarin, and levetiracetam 500 mg twice daily. On admission, he was lethargic, confused, and pale, with a serum sodium level of 118 mmol/L, serum osmolality 250 mOsm/L, and urine sodium and osmolality of 143 mmol/L and 650 mOsm/L, respectively. Despite intravenous furosemide, hypertonic saline, and subsequent tolvaptan therapy, sodium levels remained between 115–120 mmol/L and neurological symptoms persisted, suggesting a normovolemic hyponatremia consistent with SIADH. Endocrine workup was normal, and no malignancy was identified.

Given the persistence of hyponatremia despite guideline-directed therapy, levetiracetam was suspected as a contributing factor. It was discontinued and replaced with sodium valproate. Following discontinuation, serum sodium gradually improved, reaching 128 mmol/L by day 7 and 135 mmol/L by day 9, accompanied by resolution of confusion, lethargy, dyspnea, and pretibial edema. At three-month follow-up, no recurrence of severe hyponatremia was observed.

Study Author Conclusions

Incidence of hyponatremia in patients given levetiracetam vs. phenytoin for early posttraumatic seizure prophylaxis

Design

Case presentation

A 76-year-old man experienced complex partial seizures, sometimes progressing to secondary generalization, beginning four months earlier. Initially treated with phenobarbital at 100 mg daily, the medication was discontinued due to daytime drowsiness and replaced with levetiracetam at a dose of 1000 mg twice daily. Six months later, he was admitted to a neurology clinic following a tonic-clonic seizure. His medical history included hypertension and anxiety, managed with amlodipine and lorazepam. Upon admission, an EEG showed lateralized temporal epileptiform activity, while brain MRI and chest CT were normal. Blood tests revealed hyponatremia with a serum sodium level of 127 mM (normal: 135-145) and osmolality at 290 mOsm/kg (normal: 280-300), while urine sodium and osmolality were reduced. Other biochemical parameters, including renal, cardiac, and hepatic functions, were normal. Due to levetiracetam's lack of efficacy, it was discontinued and valproic acid at 600 mg daily was initiated. The sodium level normalized to 136 mM a week later, leading to his discharge. However, due to a medication error, levetiracetam was restarted at home at 500 mg twice daily, yet no further seizures occurred. Though asymptomatic, a subsequent check revealed the serum sodium level at 130 mM. With the discontinuation of levetiracetam again, sodium levels normalized after four days. Levetiracetam, although known for a low toxicity profile, has common adverse effects like somnolence and dizziness. In this patient, asymptomatic hyponatremia was noted after levetiracetam challenges, both as monotherapy and in combination with other medications. While amlodipine has been linked to hyponatremia in isolated reports, it remained unlikely as the cause, given the stable dose during the levetiracetam trials. Exclusion of other hyponatremia causes and the temporal link between levetiracetam's use and sodium level changes suggest an association, possibly due to the drug's rapid peak effect and short half-life. This case adds to evidence suggesting levetiracetam may induce hyponatremia, although the mechanism remains unclear.

Study Author Conclusions

Hyponatremia Associated with Repeated Use of Levetiracetam

Design

Case presentation

A 65-year-old woman with new-onset complex partial seizures was initially treated with carbamazepine (CBZ) 200 mg twice daily. Two months later, she was admitted with confusion; vital signs were stable, and EEG revealed complex partial status epilepticus. Laboratory evaluation demonstrated hyponatremia (Na 122 mmol/L), hypoosmolality (267 mOsm/kg), and elevated urine sodium (106 mmol/L) and osmolality (676 mOsm/kg), consistent with SIADH. CBZ was discontinued, and valproic acid (VPA) was briefly initiated but stopped due to diffuse itching. Fluid restriction (<1,500 mL/day) and levetiracetam (LEV) 500 mg twice daily were started for seizure control. Sodium initially increased to 130 mmol/L by day 3 but declined again to 122 mmol/L by day 5 despite hypertonic saline, furosemide, and demeclocycline, with persistent hypoosmolality (266 mOsm/kg) and elevated urine sodium (165 mmol/L) and osmolality (603 mOsm/kg). Extensive imaging (brain MRI, CT chest/abdomen/pelvis) and CSF studies were unremarkable.

On day 7, both levetiracetam and pantoprazole were discontinued, and topiramate (TPM) 50 mg daily was initiated for seizure control, resulting in a 10 mmol/L sodium increase within 2 days. Due to the risk of nephrolithiasis with TPM under fluid restriction, TPM was replaced with LEV 500 mg twice daily, after which sodium rapidly declined to 117 mmol/L over 4 days. Discontinuation of LEV again led to normalization of sodium within 2 days. VPA was reintroduced without adverse effects, and the patient was discharged in stable condition with a sodium level of 140 mmol/L one week later.

Study Author Conclusions