ABSTRACT
A 69-year-old man developed reduced consciousness of sudden onset. Examination and parameters were normal, except for a Glasgow Coma Scale (GCS) score of six. Brain imaging and blood tests were also normal, except for high plasma ammonia. His past medical history included epilepsy, hypertension and colitis. He was taking multiple antiepileptic medications, including sodium valproate, with no recent dose alterations. Medical intervention led to the sodium valproate being stopped and naloxone being administered. The patient's level of responsiveness and ammonia levels gradually improved. The patient was also being treated with ciprofloxacin for a urinary tract infection and a newly developed syndrome of inappropriate antidiuretic hormone secretion treated with demeclocycline. There is an association between long-term sodium valproate use and low carnitine levels, especially in the setting of polypharmacy. This in turn precipitates hyperammonaemia and encephalopathy. This case highlights the importance of an adequate drug history and the awareness of serious but uncommon adverse effects.
KEYWORDS: Sodium valproate, hyperammonaemia, encephalopathy, naloxone
Case summary
A 69-year-old man was referred to the emergency department after he developed a reduced level of consciousness and paroxysmal breathing.
The patient was undergoing rehabilitation following a fractured femur. His significant past medical history included epilepsy secondary to superior sagittal sinus thrombosis, colitis with no current exacerbation, and hypertension. His drug history included: sodium valproate 500 mg in the morning, 1 g in the evening; benzhexol 4 mg daily; phenobarbital 1 g four times daily; carbamazepine 200 mg three times daily; clopixol 200 mg monthly injections; calcium supplements twice daily; and enoxaparin 20 mg daily subcutaneous injections. He had also been treated for the previous 6 days with ciprofloxacin for a pseudomonal urinary tract infection (UTI) and had started treatment with demeclocycline 300 mg 3 days previously because of newly developed syndrome of inappropriate antidiuretic hormone secretion (SIADH), which was still being investigated. There had been no recent dose adjustments to his antiepileptic treatment. He was a retired teacher living in a nursing home and was semi-dependent in personal activities of daily living. He did not have any cognitive impairment, drank alcohol socially and was an ex-smoker.
On examination, he was responsive to pain and noncommunicative. Parameters, including blood glucose, were stable. His chest was clear, heart sounds were normal and his abdomen was soft and nontender. His lower limbs had no signs of deep venous thrombosis. Neurologically, a left-sided mouth deviation was noted, power and sensation could not be assessed and muscle tone was flaccid throughout. His reflexes, including plantars, were normal, and his pupils were equal and reactive. Blood tests, including electrolytes, sodium valproate levels and arterial blood gasses, were normal. Computed tomography (CT) scan of the head was unremarkable. He was reviewed by a neurologist, who suspected metabolic encephalopathy; therefore, ammonia levels were determined and the patient started treatment with intravenous sodium valproate. However, his condition deteriorated and he developed stridor. Ammonia levels were elevated at 114 U/L (normal 7–55 U/L). The patient was not known to have liver disease, alcoholism, renal impairment or malignancy.
A literature review from the UpToDate application was done, and sodium valproate was listed as a possible cause of hyperammonaemia and encephalopathy, for which treatment with either naloxone or carnitine had been used in similar cases with good effect. At this point, naloxone 0.4 mg was administered intravenously as a starting dose. The patient responded immediately; his Glasgow Coma Scale score improved and he regained his ability to communicate. He started treatment with a naloxone infusion of 2 mg over 12 hours and was transferred to an acute medical ward on a monitored bed. He remained well off sodium valproate, which was later replaced with levetiracetam. His ammonia levels normalised gradually and his mental and functional abilities returned to normal.
Discussion
Mechanism of action of sodium valproate
The main component of sodium valproate is valproic acid (VPA), which is a branched short-chain fatty acid. Its main antiepileptic activities are: (i) inhibition of gamma-aminobutyric acid (GABA) transaminase enzyme, thereby increasing GABA levels in the brain; and (ii) blocking ion-gated voltage channels, thereby reducing the frequency of neuronal action potentials.1
Metabolism of sodium valproate
VPA is metabolised in the liver via three main steps: (i) glucuronic acid conjugation within the liver; (ii) ω-oxidation within the cytoplasm, resulting in the toxic metabolite 4-en-VPA; and (iii) β-oxidation within the mitochondria, resulting in the non-toxic metabolite 2-en-VPA. Carnitine facilitates the transport of VPA into the mitochondria to promote β-oxidation. A by-product of β-oxidation is acetyl-CoA, which is used in the urea and Krebs cycles.2
Risk factors for valproate-induced encephalopathy
The cause of valproate-induced encephalopathy secondary to hyperammonaemia can be multifactorial.3 There is a correlation between carnitine deficiency, urea cycle disorders and hyperammonaemia secondary to valproate. Carnitine deficiency can lead to a shift from β-oxidation towards ω-oxidation, resulting in increased 4-en-VPA, which interferes with the urea cycle, thus increasing plasma ammonia levels.4
Carnitine is a nutrient found in meat and dairy products. Primary deficiency in carnitine and defects in the urea cycle can result from rare genetic conditions. Secondary carnitine deficiency can result from: (i) acquired medical conditions (eg chronic liver failure and renal failure); (ii) malabsorption or malnutrition (including in vegetarians, and those with coeliac and inflammatory bowel disease); (iii) a high catabolic state (eg trauma, malignancy or in acutely ill patients); and (iv) drugs, including chemotherapeutic agents, antiretrovirals, antiepileptics and antibiotics.4
VPA causes impaired tubular reabsorption of carnitine. Carnitine deficiency can result from both acute valproate toxicity and the following long-term use of sodium valproate despite normal plasma concentrations, especially when prescribed with other antiepileptic drugs or when concomitant antibiotics are given.4,5
In this case study, carnitine levels were not taken and ammonia levels normalised after naloxone and drug withdrawal. However, the patient was taking multiple antiepileptic drugs, had had a recent UTI treated with antibiotics and had recently started treatment with demeclocycline for SIADH; therefore, renal tubular absorption might have been affected further. He also had a history of colitis, which might result in malabsorption, although he had had no recent exacerbations.
Naloxone in valproic acid-induced encephalopathy
There are a few documented cases of the use of naloxone in the treatment of valproate-induced encephalopathy (Table 1). Its exact mode of action in this setting is still unclear but it is thought to result from its GABA antagonist effects. Naloxone also inhibits postsynaptic GABA transport because of VPA.10
Table 1.
Naloxone in valproate-induced encephalopathy
| Reference | Age (years) | Plasma valproate level | Additional treatment given | Naloxone effective? | Setting |
|---|---|---|---|---|---|
| Thanacoody6 | 76 | 848 μmol/L | Ciprofloxacin for UTI | Yes, within a few minutes | Dehydration and UTI |
| Alberto et al7 | 21 | 180 μg/mL | Multidose charcoal | Yes, within hours | Intentional overdose |
| Eze et al8 | 69 | 107.2 μg/mL | Lactulose enema and arbuterol aerosol | Yes, within 1 day | Polypharmacy |
| Bohmer et al9 | 68 | 254 μmol/L | L-carnitine effective | No, ineffective | Postoperative laparotomy for ileus |
This table details four examples of published cases in which naloxone was used to treat valproic acid-induced encephalopathy. Naloxone was effective to varying degrees.
UTI = urinary tract infection
Conclusion
Encephalopathy is an important differential diagnosis in patients presenting with an altered level of consciousness. In the absence of an obvious cause, it is crucial to review the patient's drug history and be familiar with the adverse effects of any medication. In this case, hyperammonaemia was an uncommon but important and possibly fatal adverse effect of sodium valproate. The medical literature indicates various treatment modalities that have been used in such cases, with L-carnitine being popular, given its role in valproate metabolism. In this case, naloxone and the withdrawal of sodium valproate were sufficient to normalise the patient's ammonia levels.
Consent to publish
Written consent was obtained from the patient to publish the clinical details and images in this article.
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