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Transversal investigation of the risk of valproic-acid-induced tremor in a secondary epilepsy center: clinical, neuroimaging, and genetic factors
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  • Lili Lan,
  • Xu Zhao,
  • Si Jian,
  • Cun Li,
  • Man Wang,
  • Qing Zhou,
  • Shanshan Huang,
  • Suiqiang Zhu,
  • Huicong Kang,
  • Heidi Kirsch
Lili Lan
Tongji Hospital of Tongji Medical College of Huazhong University of Science and Technology
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Xu Zhao
Tongji Hospital of Tongji Medical College of Huazhong University of Science and Technology
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Si Jian
Tongji Hospital of Tongji Medical College of Huazhong University of Science and Technology
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Cun Li
Tongji Hospital of Tongji Medical College of Huazhong University of Science and Technology
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Man Wang
Tongji Hospital of Tongji Medical College of Huazhong University of Science and Technology
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Qing Zhou
Tongji Hospital of Tongji Medical College of Huazhong University of Science and Technology
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Shanshan Huang
Tongji Hospital of Tongji Medical College of Huazhong University of Science and Technology
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Suiqiang Zhu
Tongji Hospital of Tongji Medical College of Huazhong University of Science and Technology
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Huicong Kang
Tongji Hospital of Tongji Medical College of Huazhong University of Science and Technology
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Heidi Kirsch
UCSF
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Abstract

Aim: To determine the risk factors of valproic acid (VPA)-induced tremor, with particular attention on characterizing cerebellar atrophy and identifying tremor-susceptible gene mutations. Methods: Epileptic patients taking VPA were divided into two groups, a tremor and a non-tremor group, based on self-reported or clinically assessed tremors. 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: Among 200 subjects enrolled, 181 were included for analysis (mean age 33.28±11.78 years old, male:female=2.77:1). In the tremor group, the percentage of females (p=0.036), positive tremor family history (p=0.001), and incidence of polytherapy (p=0.034), treatment duration (>12 months [p=0.013] or >24 months [p=0.008]), and daily dosage (>1,000 mg/d; p=0.003) of VPA, were significantly higher than in the non-tremor group. Treatment with VPA magnesium (p=0.030), alone or in combination with carbamazepine (p=0.040), reduced the incidence of tremor. Furthermore, 176 gene sequencing results ruled out any significant difference between the two groups in the mutation of rs9652490 within LINGO-1 (p=0.443); 86 subjects’ MRI scans indicated no significant differences in 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). Conclusion: Our cohort indicated risk and protective factors of VPA-induced tremor. Although mutation of rs9652490 within LINGO-1 correlated with cerebellar atrophy, neither was correlated with VPA-induced tremors.