Lili Lan1, Xu Zhao2, Si Jian2, Cun Li1, Man Wang1, Qing Zhou1, Shanshan Huang1, Suiqiang Zhu1, Huicong Kang3, Heidi E Kirsch4. 1. Department of Neurology, Tongji Hospital Affiliated To Tongji Medical College, Huazhong University of Science and Technology, No. 1095 Jiefang Blvd, Wuhan, 430030, People's Republic of China. 2. Department of Radiology, Tongji Hospital Affiliated To Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, People's Republic of China. 3. Department of Neurology, Tongji Hospital Affiliated To Tongji Medical College, Huazhong University of Science and Technology, No. 1095 Jiefang Blvd, Wuhan, 430030, People's Republic of China. kanghuicong@163.com. 4. Department of Neurology and Radiology & Biomedical Imaging, Epilepsy Center, University of California, San Francisco, CA, 94143-0628, USA.
Abstract
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.
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.
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