Valproate Induced Tremor and Parkinsonism

1. VALPROATE-INDUCED
TREMOR AND PARKINSONISM
Ade Wijaya, MD – December 2018

2. Shih JJ, Tatum WO, Rudzinski LA. New drug classes for the treatment of partial onset epilepsy: focus on perampanel. Therapeutics and clinical risk management. 2013;9:285.

4. VALPROATE-INDUCED TREMOR

5. Valproate-Induced Tremor
◦ Tremor is a well-known side effect of anticonvulsants (45%)
◦ Up to 80 % patients taking valproate
◦ F > M
◦ Upper limb postural and kinetic tremor
◦ Extended release drugs decrease the risk of tremor
◦ Treatment: drug dose reduction, drug discontinuation, or beta blocker
Alonso-Juarez M, Torres-Russotto D, Crespo-Morfin P, Baizabal-Carvallo JF. The clinical features and functional impact of valproate-induced tremor. Parkinsonism & related disorders. 2017 Nov 1;44:147-50.
Ondo WG. Other movement disorders. In: K.R. Chaudhuri and W.G. Ondo, Movement Disorders in Clinical Practice, DOI 10.1007/978-1-84996-065-6_6, © Springer-Verlag London Limited 2010

6. VALPROATE-INDUCED PARKINSONISM

7. Valproate-Induced Parkinsonism
◦ Clinical presentation similar to Parkinson or Parkinson-Plus syndrome
◦ Reversible in 1 year average after valproate discontinuation
◦ Prevalence: 1.4 - 75 % ; F > M
◦ Wide range of age at onset, latency from treatment initiation to first presentation and symptom severity
Brugger F, Bhatia KP, Besag FM. Valproate-associated parkinsonism: a critical review of the literature. CNS drugs. 2016 Jun 1;30(6):527-40.

8. Neuroimaging
◦ White matter changes
◦ Various degrees of cortical/subcortical atrophy with concomitant ventricular enlargement
◦ Lacunar infarcts in the cerebellum, pons and the basal ganglia
◦ Reduced blood flow and hypometabolism in PET/SPECT/DAT Scan
Tada H, Ogihara T, Nakamura T, Sasayama D, Sugiyama N, Takahashi Y, et al. A case of severe parkinsonism in an elderly person induced by valproic acid. Psychogeriatrics 2016.
Brugger F, Bhatia KP, Besag FM. Valproate-associated parkinsonism: a critical review of the literature. CNS drugs. 2016 Jun 1;30(6):527-40.

9. Patophysiology
1. Altered neurotransmitter signaling:
VPA has a strong GABAergic effect
GABA can inhibit dopaminergic activity in the substantia nigra
Excessive GABAergic activity in the globus pallidus externus can lead to overactivity of the indirect basal ganglia
pathway
2. Altered gene expression:
VPA activates the extracellular-regulated kinases (ERK) pathway, which is involved in synaptic plasticity, neurogenesis
and neuronal survival  induce parkinsonism
VPA upregulates the expression of the dopamine transporter and it could thus lead to increased transmitter re-uptake
and decreased availability of dopamine in the synaptic cleft
VPA might affect dopamine signalling by modulating the expression of involved proteins, possibly explaining the
often prolonged recovery period
Brugger F, Bhatia KP, Besag FM. Valproate-associated parkinsonism: a critical review of the literature. CNS drugs. 2016 Jun 1;30(6):527-40.

10. Patophysiology
3. Unmasking subclinical dopaminergic degeneration:
In patients with a subclinical dopaminergic deficit, increased GABAergic activity or an altered gene expression
leads to a breakdown of 14 compensatory processes in the basal ganglia networks and eventually to the
evolution of a clinically manifest syndrome
4. Enhanced neurodegeneration:
By inducing a state of cellular energy deficiency and increased oxidative stress in mitochondria
Manifestation: hearing loss
5. Cooccurence with PD
Brugger F, Bhatia KP, Besag FM. Valproate-associated parkinsonism: a critical review of the literature. CNS drugs. 2016 Jun 1;30(6):527-40.

11. Summary
◦ Valproate in a drug that commonly used for epilepsy treatment
◦ Tremor and Parkinsonism are the common adverse effects of valproate
◦ This adverse effects are reversible
◦ Treatment: reducing dose, drug discontinuation, treat the tremor using beta blocker, and treat the
parkinsonism with dopaminergic agents.