Parkinsonism: A Rare Adverse Effect of Valproic Acid

Valproic acid (VPA) is an anti-epileptic drug (AED) used as a first-choice agent for most forms of epilepsy. It is used in the treatment of manic episodes, bipolar disorder, migraine prevention, and impulse control. Hence it is one of the most commonly prescribed drugs by physicians nowadays. VPA acts by increasing gama amino butyric acid (GABA) levels, and also reduces neuronal activation by blocking voltage-gated sodium, potassium, and calcium channels. VPA has various adverse effects like thrombocytopenia, hyperammonemia, teratogenicity causing spina bifida in newborns when exposed in utero. The focus of this review is to research one such easily overlooked adverse effect of VPA, which is VPA-induced Parkinsonism. We carried out a review of literature and gathered all comprehensive peer-reviewed articles from PubMed. The data for this research were collected ethically and legally after a thorough examination of the literature. Data obtained from the studies have suggested that Parkinsonism is an adverse effect of VPA. Chronic usage of VPA causes Parkinsonism. It occurs equally in males and females, more common in older people usually above the age of 55 years and not dose-dependent. According to the data obtained, all patients who developed Parkinsonism had serum levels in the therapeutic range (50-100 mcg/mL). Thus the chronic intake of maintenance dose of VPA seems to be the leading cause. The symptoms usually improve over a few weeks and fully resolve in a few months after stopping the drug. When the patient's symptoms do not improve, it means VPA has unmasked the underlying potential for developing Parkinson's disease. Such patients benefit from levodopa therapy. However, the mechanism of how VPA causes Parkinsonism remains unknown. Based on the articles reviewed, we hypothesize that VPA’s mechanism of neuronal inactivation by blocking membrane channels across the neuronal membrane, primarily when used chronically could be the mechanism by which it causes Parkinsonism. VPA causes down regulation of sodium and potassium channels on neuronal membrane in order to stop the neurons from firing. Thereby a decrease in action potential across the neurons causes a temporary physiological inactivation of the neuron. When multiple neurons are inactivated in the basal ganglia of the brain, the patient develops symptoms of Parkinsonism. As the neurons are only temporarily inactivated physiologically, when the drug is stopped the membrane receptors are reactivated on the neuronal membranes. This leads to neuronal activation and neuronal membrane potential becomes the same as before. The above mechanism clarifies why the symptoms settle down when the medication is stopped.