Transversal investigation of the risk of valproic-acid-induced tremor in
a secondary epilepsy center: clinical, neuroimaging, and genetic factors
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.