Investigation of the risk of valproic acid–induced tremor: clinical, neuroimaging, and genetic factors

• Published in: Psychopharmacology Vol. 239; no. 1; pp. 173 - 184
• Main Authors: Lan, Lili, Zhao, Xu, Jian, Si, Li, Cun, Wang, Man, Zhou, Qing, Huang, Shanshan, Zhu, Suiqiang, Kang, Huicong, Kirsch, Heidi E.
• Format: Journal Article
• Language: English
• Published: Berlin/Heidelberg Springer Berlin Heidelberg 01.01.2022; Springer; Springer Nature B.V
• Subjects: Anticonvulsants - adverse effects; Atrophy; Biomedical and Life Sciences; Biomedicine; Carbamazepine; Cerebellum; Chi-square test; Complications and side effects; Divalproex; Dosage; Epilepsy; Female; Gene mutations; Genetic aspects; Genetic factors; Health aspects; Hemispheric laterality; Humans; Magnesium; Magnetic resonance imaging; Mutation; Neuroimaging; Neurosciences; Nogo protein; Original Investigation; Pharmacology/Toxicology; Psychiatry; Risk factors; Tremor; Tremor - chemically induced; Tremor - genetics; Valproic acid; Valproic Acid - adverse effects; China; Cerebellar atrophy; LINGO-1; Valproic acid; Essential tremor; Epilepsy
• ISSN: 0033-3158; 1432-2072; 1432-2072
• DOI: 10.1007/s00213-021-06004-5

Rationale Investigation of associated risk factors of valproic acid (VPA)–induced tremor helped in increasing tolerance and optimizing treatment scheme individually. Objectives To determine the risk factors of VPA-induced tremor, with particular attention on identifying tremor-susceptible gene mutations. Methods Epileptic patients taking VPA were divided into a tremor and a non-tremor groups. A mutation of rs9652490 in the leucine-rich repeat and immunoglobulin domain-containing Nogo-receptor-interacting protein 1 (LINGO-1) gene was determined by Sanger sequencing. Cerebellar atrophy was assessed, and various cerebellar dimensions were measured on magnetic resonance imaging (MRI) scans. Results One hundred and eighty-one of 200 subjects were included. Multivariate regression analysis indicated several VPA-induced tremor-related factors: females (OR = 2.718, p  = 0.014), family history of tremor (OR = 7.595, p  = 0.003), treatment duration (> 24 months; OR = 3.294, p  = 0.002), and daily dosage (> 1,000 mg/d; OR = 19.801, p  = 0.008) of VPA. Chi-square tests revealed that treatment with VPA magnesium-ER ( p  = 0.030) and carbamazepine combination ( p  = 0.040) reduced the incidence of tremor. One hundred and seventy-six gene sequencing and 86 MRI results excluded any significant difference between the two groups in the mutation of rs9652490 within LINGO-1, the ratio of cerebellar atrophy or the cerebellar-dimension values ( p  > 0.05). However, mutation of rs9652490 within LINGO-1 was correlated with increased cerebellar atrophy ( p  = 0.001), reduced cerebellar hemisphere thickness ( p  = 0.025), and right cerebellar hemisphere longitudinal diameter ( p  = 0.047). Conclusions Our cohort indicated risk (female, positive family history of tremor, daily dosage > 1000 mg and treatment duration > 24 months of VPA) and protective factors (VPA magnesium-ER and combination with CBZ) of VPA-induced tremor. Mutation of rs9652490 within LINGO-1 correlated with cerebellar atrophy, neither was correlated with VPA-induced tremor.