Objective: Valproic Acid, a branched short chain fatty acid, is widely used as an epileptic drug and mood stabilizer [1]. Its mechanism of action is related primarily to neurotransmission and modulation of intracellular pathway. In particular, Valproic acid affects neuronal survival/apoptosis and proliferation /differentiation balance, as well as synaptic plasticity, by acting both directly on neurons and indirectly through glial cells [2]. Dystonia occurs when subtle changes in neuronal function corrupt normal co-ordination and lead to disabling motor disorder [3]. Axonal stretch injury not only damages cytoskeleton but also disrupts membrane permeability thus causes reversal of Na+/Ca2+ antiporter in the axolemma leading to increase in Ca2+ within the cell which causes mitochondrial damage [4].

Background: Dystonia comprise a group of movement disorders that is characterized by involuntary movements and postures [3]. It may be associated with pain and disability. Clinical Electrophysiological studies show that CNS exhibit aberrant plasticity-perhaps related to deficient inhibitory neurotransmission [5]. It can be focal, segmental, axial or generalized. Dystonias are classified according to cause into primary which is idiopathic and secondary which include drug induced dystonia, post traumatic, brain tumors, post anoxic, psychogenic, infectious, pseudodystonia [6]. Traumatic Brain Injury lead to dynamic stretch injury of axons which causes proteolytic disruption of the cytoskeleton ultimately leading to influx of calcium through Voltage Gated Calcium Channels modulated by mechanically sensitive Sodium Channels [7] and reversal of Na+-Ca2+ exchangers. Calcium flows into the cell and activates phospholipases and other proteolytic enzymes ultimately leading to mitochondrial dysfunction [8]. Rigidity and decerbrate posturing occurs with lesion in the midbrain blocking normal inhibitory signals to pontine and vestibular nuclei. Thus, nuclei become active and spinal reflexes become hyper excitable [9] and decreases threshold for excitation of a motor response. Valproic acid is widely used as an anti epileptic and mood stabilizer. Anti epileptic properties have been attributed to inhibition of GABA Transaminobutyrate and ion channels. Besides the elevation of GABA levels, Valproic acid reduces the high frequency firing of neurons by blocking Voltage gated Na+channels, K+ and Ca2+ channels [2]. In my patient, generalized dystonic posturing hypothesized to be dramatically reduced by the administration of Valproic acid in addition to Midazolam. The idea behind this is that Valproic acid in addition to inhibiting the excitatory signals also minimizes the entry of Calcium within the axons and inhibits the excitatory signals thus minimizing the decerbrate rigidity.

Methods: Written informed consent was obtained from the patient for publication of this case report.

Results: A 24-year-old man of Asian origin presented with 3-day history of fall from an electric pole (20 foot) and 2-day history of altered sensorium. This was followed by intermittent moderate to high-grade fever, tachypnea (33 Respiratory Rate), tachycardia (115/min Heart Rate), excessive sweating and extensor posturing. Examination revealed consciousness of 3/15 on Glasgow Coma Scale, pupils bilaterally equally reactive to light, increased tone of all limbs of the body and decerebrate posturing. CT Scan Brain showed Brain stem 2*2 cm hyper density. Patient was intubated and ventilator support was adjusted. Conservative Management was started, in addition to continual infusion of Midazolam administered@10 microdrops/min, Valproic Acid was also administered@500mg Intravenously B.D. Patient showed dramatic improvement in a period of 3 weeks.

Conclusions: Besides the role of valproic acid as anti epileptic, it can also be used to reduce the dystonic posturing in a patient with traumatic brain injury. Valproic acid antagonizes the transmitters both at cellular and molecular level involved in causing dystonia. Thus, its role in treatment and management of abnormal posturing and movements should further be assessed

References: 1.    Chateaurieux S, Morceau F, Dicato M, Diederich M. Molecular and Therapeutic Potential and Toxicity of Valproic Acid. Journal of Biomedicine and Biotechnology 2010; 2010: 479364. 2.    Monti B, Polazzi E, Contestabile A. Biochemical Molecular and Epigenetic Mechanisms of Valproic Acid Neuroprotection. CurrMol Pharmacol 2009 Jan; 2(1): 95-109. 3.    Breakefield XO, Blood AJ, Li Y, Hallett M, Hanson PI, Standaert DG. The Pathophysiological Basis of Dystonia. Nature Reviews of Neuroscience 2008 Mar; 9(3): 222-234. 4.    Stys P.K. Anoxic and ischemic injury of myelinated axons in CNS white matter: From mechanistic concepts to therapeutics. J Cerebral Blood Flow Metabolism 1998; 18(1): 2-25. 5.    Lauren M. Tanabe, Connie E. Kim, Noga Alagem, William T. Dauer. Primary dystonia: molecules and mechanisms. Nat Rev Neurol. 2009 Nov; 5(11): 598–609. 6.    Baquley IJ, Heriseanu RE, Cameron ID, Nott MT, Slewa-Younan S. A critical review of pathophysiology of dystonia following traumatic brain injury. Neurocrit. care 2008; 8(2): 293-300. 7.    Iwata A, Stys PK, Wolf JA, Chen XH, Taylor AG, Meaney DF, Smith DH. Traumatic axonal injury induces proteolytic cleavage of the voltage-gated sodium channels modulated by tetrodotoxin and protease inhibitors. J Neurosci. 2004 May 12; 24(19): 4605-13. 8.    Banik NL, Hogan EL, Hsu CY. The multimoloecular cascade of spinal cord injury. Studies on prostanoids, calcium, and proteinases. Neurochem Pathol. 1987 Aug; 7(1): 57-77. 9.    Blackman JA, Patrick PD, Buck ML. Rust RS. Paroxysmal Autonomic Instability with dystonia after traumatic brain injury. Arch Neurol, 2004; 61(3): 321-328.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/effect-of-valproic-acid-on-dystonia-in-a-patient-with-traumatic-brain-injury-a-case-report/