Alpha lipoic acid intoxication, treatment and outcome

Dear Editor,

Alpha lipoic acid (ALA) is a cofactor found in a number of multienzyme complexes. Lipoic acid and its reduced form, dihydrolipoic acid, are antioxidants in vivo. It is a powerful antioxidant acting as a scavenger for reactive oxygen species and is widely used as supplementary treatment of diabetic neuropathy. The intoxication is rare because a daily dose of 200–2400 mg/day of ALA is considered to be safe without side effects in adults but there is no reported dose of safety in children.¹

A 20-month-old (body weight: 10.5 kg) previously healthy boy was admitted to the emergency department with nausea, vomiting, lethargy, involuntary movements for several hours, 4 h after ingesting four pills of 600 mg ALA which was stored separately from other drugs, belonging to a diabetic patient at home. There were last five pills in the case and the patient was found chewing a pill while four were lost. Ingested drug amount was calculated as 226 mg/kg.

On admission, he was lethargic (Glasgow coma scale: 9/15), tachicardic (heart rate: 117/min) and tachipneic (respiratory rate:43/min) without fever (36.7°C), and was normotensive (blood pressure: 106/53 mmHg). His initial neurological examination revealed mid-dilated pupils with delayed pupillary reflex, bilateral extensor toe sign, and myoclonic seizures involving all extremities. The seizures were unresponsive to bolus midazolam injection and fenitoin infusion at 20 mg/kg dose, and thus he was diagnosed as status epilepticus because of prolonged convulsions for half an hour.

The laboratory results revealed no abnormality excluding an infectious disease or a systemic acute or chronic illness with 10900/mm³ leucocytes, 10.4 g/dl hemoglobin, and 312000/mm³ platelets. Blood chemistry including glucose (123 mg/dl), BUN (9.4 mg/dl), creatinin (0.3 mg/dl), SGOT (34 IU/L), SGPT(38 IU/L), CPK (12 U/L), and serum ions were also normal (Na⁺⁺ of 138 mmol/L, K⁺ of 3.2 mmol/L, Cl of 100 mmol/L, and Ca of 8.7 mg/dl). Blood gas analysis revealed metabolic acidosis with high anion gap (pH: 7.1; HCO₃: 15.2 mmol/L; BE: −10.6 mmol/L; and lactate: 3.9 mmol/l).

In follow-up, he required midazolam infusion up to 0.8 mg/kg/h and 5 mg/kg maintenance doses of phenytoin to control seizures continuing 1 h in addition to intravenous hydration and HCO₃ administration to control the myoclonic status present on admission. Metabolic acidosis resolved in 24 h and intermittent short-term seizures were controlled within 48 h due to this treatment. Toxicologic screening of urine for common drugs (Amphetamines, Benzodiazepines, Barbiturates, Cocaine, Ecstasy, Marijuana, Methadone, Methamphetamines, Opiates, Oxycodone, Phencylindine, and Tricyclic Antidepressants) was negative while cranial CT excluded an underlying intracranial abnormality. In the following few days he became conscious and his neurological findings disappeared without further seizure recurrence and with normal electroencephalography. He was discharged on the fifth day without sequelae.

Evidence from literature shows that ALA is able to decrease oxidative stress caused by high levels of reactive oxygen and other free radicals. Furthermore, ALA has some activities that provide a cofactor for glucose metabolism in mitochondria. These effects are supposed to be beneficial for cellular damage and hence its usage in diabetic patients, especially for whom neuropathy is common.² Half life of orally administered ALA is merely 30 min.³ In animal studies, high levels of ALA were reported to cause apathy, hypokinesis, convulsions, and hepatotoxicity. Although there is no reported toxic dose in childhood, our patient likely ingested 226 mg/kg, which is above the LD50 for cats and dogs.⁴ ALA has prooxidant effects at high doses, causing redox reactions with iron and affecting mitochondrial permeability.² Metabolic acidosis may thus be due to direct mitocondrial effect of ALA. We also speculate that high levels of ALA may attenuate energy utilization in brain and cause resistant convulsions. Our patient's improvement may also be attributed to symptomatic management and the short elimination time of ALA.

That's why pediatricians and pediatric emergency medicine physicians should keep in mind ALA intoxication in children admitting with seizure, acidosis, and unconsciousness especially with a household treated for diabetic neuropathy.

Declaration of interest

The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.