Valproate-induced Pedal Edema: Troublesome Side Effect yet Neglected?

Valproate is a commonly used mood stabiliser that has various adverse effects. One such adverse effect is peripheral edema. This case report highlights a case of a 25-year-old female patient who presented with severe pedal edema after starting treatment with valproate for bipolar disorder. The patient had a few other risk factors for edema which makes the diagnosis challenging. Pedal edema is a troublesome adverse effect that can significantly impact the quality of life of patients taking valproate, yet it is often neglected. This case report emphasizes the importance of recognizing and managing valproate-induced peripheral edema in clinical practice.

Valproate is a commonly used mood stabiliser that has various adverse effects.One such adverse effect is peripheral edema.This case report highlights a case of a 25-year-old female patient who presented with severe pedal edema after starting treatment with valproate for bipolar disorder.The patient had a few other risk factors for edema which makes the diagnosis challenging.Pedal edema is a troublesome adverse effect that can significantly impact the quality of life of patients taking valproate, yet it is often neglected.This case report emphasizes the importance of recognizing and managing valproateinduced peripheral edema in clinical practice.

INTRODUCTION
Sodium valproate, also known as Epilim, is a mood stabiliser and is indicated for the treatment of acute manic episodes and as maintenance therapy for bipolar disorder in psychiatry 1 .Its extensive use as an adjuvant to antipsychotic in the treatment of psychotic disorder and in the prevention of migraines has been established by the recent expansion of its therapeutic indications 2 .Like all other medications, it has typical adverse reactions that are frequently observed in daily clinical practise such as tremors and alopecia, but it also causes uncommon adverse reactions that one should be aware of.Peripheral edoema precipitated by sodium valproate is among the unusual ones.It has been noted that taking drugs in high quantities or for an extended period of time may result in this unique side effect 3. In this case report, besides taking sodium valproate, the patient also has underlying hepatitis B, which may have contributed to the development of the edema.Moreover, of complete blood cell count, electrolytes, blood urea nitrogen, serum creatinine, free thyroxine, free triiodothyronine, and thyroid-stimulating hormone, were also within normal limits.Repeated sodium valproate level was 72.9.
Olanzapine dosage was then tapered down to 5mg ON within one month.However, the pedal edema progressed up to mid-shin, disrupting patient's daily activities.Therefore, we switched sodium valproate to lamotrigine 100mg ON while continuing olanzapine 5mg ON.
After two weeks of discontinuing sodium valproate, the pedal edema resolved and patient maintained euthymic with lamotrigine 100mg ON and olanzapine 5mg ON.The score of the Naranjo algorithm, or Adverse Drug Reaction (ADR) Probability Scale, was 5, which corresponded to probable ADR.Later, we managed to off olanzapine and she was maintaining well with monotherapy of lamotrigine 100mg ON.

DISCUSSION
Pedal edema is one of the dominant signs of a systemic illness such as congestive heart failure, liver and thyroid disease.But it can also be due to local causes such as adverse drug reaction (ADR).Valproate is one of many medications that may cause peripheral edema.Underrecognized and frequently misdiagnosed, valproate-induced peripheral edema typically results in a prescription cascade 6 .
Sodium valproate acts by increasing the amount of gamma-aminobutyric acid (GABA) in the brain through a number of different production and breakdown mechanisms as well as by influencing other neurotransmitters.The medication's usual side effects include tremor, gastrointestinal disturbances, sedation, alopecia, increased hunger, and weight gain 7 .Although the precise mechanism of action is unknown, a speculative explanation for the valproate-related peripheral oedema could be that the drug specifically enhances GABAergic activity by increasing GABA levels, which affects body fluid dynamics and peripheral vascular resistance and results in a corresponding oedema 7 .
On the basis of earlier findings and our case report, we would like to draw the conclusion that edema brought on by valproate should not be neglected.Because this edema is self-limiting and has no impact on the underlying illness process, clinicians typically disregard the complaint.Even though it is a non-threatening symptom, it can interfere with a patient's everyday activities, causes significant distress in the patient and may lead to treatment non-adherence.
Peripheral edema associated with valproate is a clinically significant side effect which might manifest in days as opposed to years.Early diagnosis and discontinuation of it appears to totally reverse it.Clinicians should therefore be mindful of its potential link to peripheral edema as the therapeutic applications of this medicine are expanded and its subsequent use rises.

Source of fund: Nil
Conflict of Interest:The authors declare no conflict of interest.Ethical clearence: NilAUTHORS'S CONTRIBUTION:Data gathering and idea owner of this case: Siti Nur Najibah Fauzi Study design: Aisyah Che Rahimi Data gathering: Arifah Ismail & Siti Nur Najibah Fauzi Writing and submitting manuscript: Arifah Ismail & Siti Nur Najibah Fauzi Editing and approval of final draft: Aisyah Che Rahimi