Valproate-associated Movement Disorder: A Literature Review

Abstract

Valproate (VPA) was first synthesized in 1882, but it was only in the early 1960s that its anticonvulsant properties were discovered. The aim of this literature review is to evaluate the clinical epidemiological profile, pathological mechanisms, and management of VPA-associated movement disorder (MD). Relevant reports in six databases were identified and assessed by two reviewers without language restriction. A total of 138 reports containing 362 cases of subjects who developed a MD secondary to VPA were reported. The MD identified were parkinsonism (PKN) (252), myoclonus (MCL) (54), dystonia (DTN) (17), dyskinesia (DKN) (16), stutters (4), tics (3), akathisia (AKT) (1). In the not clearly defined group, 15 extrapyramidal symptoms, 3 AKT, 2 DTN, 1 rigidity, 1 unstable gait were assessed. The mean and median age was 55.8 (SD: 16.58) and 61 years (range: 4–87 years). The most common VPA-indication was epilepsy, and 51.36% were males. The mean and median time from the VPA start to the MD onset was 32.75 (SD: 30.05) and 21.15 months (range: 1 day – 20 years). The mean and median time from the VPA withdrawal until the MD recovery was 2.89 (SD: 2.79) and 3 months (1 day – 12 months). The most common management was drug withdrawal. A complete recovery was obtained in 80.61%. VPA-associated MD was extensively reported in the literature. PKN was the most well-described. Future studies need to clearly report the clinical history of the patient, considering the full investigation of other adverse events during their entire life.

Antiseizure Drugs and Movement Disorders

“…Dystonia is less clearly associated with valproate; however, patients have developed this movement disorder while using this drug [141], a patient with acute schizoaffective disorder developed severe anterocollis a few days after the introduction of valproic acid while taking quetiapine [142].…”

Adverse Outcomes Associated With Off-Label Agents Used to Treat Dementia Patients With Psychosis: A Case-Control Medicare Database Study

“…2 Divalproex has a mechanism of action that is distinct from that of most antipsychotics; however, associations between divalproex and adverse effects such as EPS, gastrointestinal complications, urinary tract infections, thrombocytopenia, sedation, or weight gain could similarly contribute to potential underlying causes of death. 16,26,27 Although we were unable to examine the causes of death in our study, data from randomized clinical trials indicate that most deaths in patients with dementia are accounted for by cardiac events (e.g., heart failure and sudden death) and infections (mostly pneumonia). 13 The association of treatment with all-cause mortality in our study (OR, 1.14), though more modest than that reported in previous meta-analyses of short-term randomized placebocontrolled trials (OR, 1.5 10 or 1.6-1.7 13 or observational studies (hazard ratio, 1.23-1.55) 12 was nevertheless substantial and clinically relevant.…”

“… 2 Divalproex has a mechanism of action that is distinct from that of most antipsychotics; however, associations between divalproex and adverse effects such as EPS, gastrointestinal complications, urinary tract infections, thrombocytopenia, sedation, or weight gain could similarly contribute to potential underlying causes of death. 16 , 26 , 27 Although we were unable to examine the causes of death in our study, data from randomized clinical trials indicate that most deaths in patients with dementia are accounted for by cardiac events (e.g., heart failure and sudden death) and infections (mostly pneumonia). 13…”

“…EPS are well-documented side effects of antipsychotic agents that inhibit D 2 receptors in the nigrostriatal system 25 and of divalproex, though the exact mechanism for divalproex is unknown. 26 Other established adverse events of antipsychotics that may contribute as potential underlying causes of death include cerebrovascular adverse events, sedation, weight gain, diabetes, metabolic syndrome, cognitive worsening, and in the case of conventional antipsychotics, anticholinergic effects, postural hypotension, and prolonged QT interval. 2 Divalproex has a mechanism of action that is distinct from that of most antipsychotics; however, associations between divalproex and adverse effects such as EPS, gastrointestinal complications, urinary tract infections, thrombocytopenia, sedation, or weight gain could similarly contribute to potential underlying causes of death.…”

Flapping Tremor: Unraveling Asterixis—A Narrative Review

“…The occurrence of asterixis can be attributed to the direct effect of the drug on the CNS and the indirect effect ( Table 6 ) [ 7 , 70 , 73 , 74 , 75 , 76 , 77 , 78 , 79 , 80 , 81 , 82 , 83 , 84 , 85 , 86 , 87 , 88 , 89 , 90 , 91 , 92 , 93 , 94 , 95 ]. The direct effect can be explained by abnormalities in the neurotransmitter levels and toxic levels of the medications.…”