Discussion
Valproate and its related forms, such as divalproex, often are used in the treatment of generalized or partial seizures, psychiatric disorders, and the prophylaxis of migraine headaches. Common ADRs include gastrointestinal symptoms, sedation, and dose-related thrombocytopenia, among many others. Rare ADRs include fulminant hepatitis, pancreatitis, hyperammonemia, and peripheral edema.1 There have been case reports of valproate-induced peripheral edema, which seems to be an idiosyncratic ADR that occurs after long-term administration of the medication.2,3 Early studies reported valproate-related edema in the context of valproate-induced hepatic injury.4 However, in more recent case reports, valproate-related edema has been found in patients without hepatotoxicity or supratherapeutic drug levels.1,2
The exact mechanism by which valproate causes peripheral edema is unknown. It has been reported that medications affecting the γ-aminobutyric acid (GABA) system such as benzodiazepines, for example, can cause this rare ADR.5 Unlike benzodiazepines, valproate has an indirect effect on the GABA system, through increasing availability of GABA.6 GABA receptors have been identified on peripheral tissues, suggesting that GABAergic medications also may have an effect on regional vascular resistance.7 This mechanism was proposed by prior case reports but has yet to be proven in studies.2
In this case, initiation of lacosamide temporally coinciding with development of the patient’s edema leads one to question whether lacosamide may have caused this ADR. Other medications commonly used in seizure management (such as benzodiazepines and gabapentin) have been reported to cause new onset peripheral edema.5,8 To date, however, there are no reported cases of peripheral edema due to lacosamide. While there are known interactions between various AEDs that may impact drug levels of valproate, there are no reported drug-drug interactions between lacosamide and valproate.9
Conclusions
Our case adds to the small but growing body of literature that suggests peripheral edema is a rare but clinically significant ADR of valproate. With its broad differential diagnosis, new onset peripheral edema is a concern that often warrants an extensive evaluation for underlying causes. Clinicians should be aware of this ADR as use of valproate becomes increasingly common so that an extensive workup is not always performed on patients with peripheral edema.