**1. Introduction**

Valproic acid or sodium valproate (VPA) is an antiepileptic drug commonly used for treatment of epilepsies [Aldenkamp et al. 2006; Ben-Menachem et al. 2006; Iivanainen & Alvarez 1998; Perucca et al. 2006). It affects the function of the neurotransmitter GABA in the human brain by enhancing the neurotransmission of GABA (Rosenberg, 2007). VPA is known to cause many harmful side effects such as hepatotoxicity (Koenig et al. 2006) and carnitine deficiency (Coppola et al. 2006). Carnitine as a healing agent has begun to play an important role in VPAinduced hepatotoxicity. When signs of hepatotoxicity occur, it is important to discontinue VPA immediately and substitute carnitine i.v (Koenig et al. 2006). Inhibitions of the β-oxidation, oxidative phoshorylation and urea synthesis and a decrease of intracellular carnitine are supposed to induce hepatopathy (Cotarlu & Zaldman 1988; Hjelm et al. 1987; Murakami et al. 1996). It has been reported that urinary concentration of a VPA metabolite, 4-en VPA, is markedly increased in acute VPA intoxication (Murakami et al. 1996). It is believed that this metabolite of VPA is responsible for developing hepatotoxicity. VPA metabolism returns to normal after L-carnitine supplementation (Murakami et al. 1996). Thurston & Hauhart 1993 reported that a reduction of intracellular CoA may be the central common pathway for VPAinduced hepatotoxicity.

The clinical relevance of coagulopathies, known as side effects of VPA, especially thrombo‐ cytopenia, von Willebrand disease and a decrease of factor XIII, is still unclear (Gerstner et al. 2006). The incidence of coagulation disorders related to VPA in children is estimated to be nearly 4% (Gerstner et al. 2006).

© 2014 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

It has been reported that VPA may be associated with hyperammonemia and thrombocyto‐ penia, but the aetiology of valproic acid-induced thrombocytopenia has not been elucidated (Mallet et al. 2004). In patients receiving long-term VPA VPA-induced hyperammonaemic encephalopathy may occur (Lheureux et al. 2005). It is suggested that this severe side-effect may be promoted by a pre-existing carnitine deficiency or by deficiency induced by VPA (Lheureux et al. 2005). Because the onset of the clinical symptoms of VPA-associated hepato‐ toxicity, especially in patients with intellectual disability, is sudden and unpredictable, the aim of our study was to find out suitable biochemical and haematological markers to prevent this state of illness.

Many structural, biochemical and physiological changes take place in the brain following head trauma which in turn account for epileptogenesis (Katayama et al. 1990). For example, seizures occur in rats shortly after traumatic injury lead to increase in glutamate and aspartate levels which explain possible involvement in epileptogenesis (Nilson et al. 1994). Antiepileptic drugs affect hepatic enzyme levels in patients known to have a coexisting hepatic abnormality, those who develop symptoms of hepatic involvement while receiving AEDs, and perhaps those receiving bitherapy with high serum AED levels (Verma & Haidukewych, 1994). Rao et al. (1993) reported 72% of the AED-treated patients and 33% of the unmedicated patients showed an increase in one or several serum liver enzymes [alanine aminotransferase (ALT), aspartate aminotransferase (AST), and/or gamma-glutamyl transferase (gamma-GT)]; particularly

Clinical and Hematological Profiles During Valproate Treatment of Epileptic Patients with...

http://dx.doi.org/10.5772/57369

275

The World Health Organisation defines anaemia as < 13 g Hb/dL for men and < 12 g Hb/dL for women (2001), accepting that women generally have lower haemoglobin concentrations than men. However, when ferritin levels (Waalen et al. 2002), is considered then the difference may be due to hormonal influences on red cell production (Shahidi, 1973), the do not support this (Waalen et al. 2002). Platelet counts have been found to be significantly higher in women (Butkiewicz et al.2006), with possible explanations of increased thrombopoietin in women being reported. Total leukocyte count showed to be significantly higher in women than men due to a highly significant difference in neutrophil count, with no significant correlation

This study is in line with the earlier observations that VPA may induce thrombocytopenia (Koenig et al. 2006; Gerstner et al. 2006; Mallet et al. 2004). According to Gerstner et al. 2006 thrombocytopenia is the most common haematological adverse effect of VPA. An incidence varies from 5% to 60% (Gerstner et al. 2006; Zeller et al. 1999). It is suggested that there are two possible mechanisms inducing thrombocytopenia. First mechanism is that VPA have a direct toxic effect on bone marrow (Gertsner et al. 2006). Second mechanism is that VPA seems to induce the formation of autoantibody against platelets (Sandler et al. 1978). We found that contents of thrombocytes and erythrocytes lowered approximately 30 % and 10 %, respective‐ ly, in patients on VPA monotherapy. This observation supports the hypothesis that VPA seems

To prevent severe hepatotoxicity in patients on long-term VPA therapy, it is important to control contents of thrombocytes and erythrocytes and to determine the level of serum free carnitine, regularly. If the level of serum free carnitine and the thrombocyte counts are lowered, addition of carnitine to long-term VPA regimen of epileptic patients may be indicated. Further investigations are needed to evaluate appropriate dosages of L-carnitine supplementation to

Valproic acid (N-dipropylacetic acid, or 2-propylpentanoic acid) is one of the mainstays of therapy for epilepsy and bipolar mood disorders, due to its anticonvulsant and moodstabilizing effects (Blaheta & Cinatl, 2002). It is a branched short-chain fatty acid with a halflife of 9 to 16 hours. Clinically, VPA is usually administered as uncoated tablets, but may also be administered in the form of syrup, capsules and enteric-coated tablets. Ninety per cent of VPA in the blood is bound to albumin (Cramer & Mattson, 1979), and despite its hydrophilic

between monocytes, basophils and gender (Bain & England, 1975).

to have a direct toxic effect on bone marrow (Gerstner et al. 2006).

epileptic patients on long-term VPA therapy.

gamma-GT.

### **2. Case presentation**

Blood samples for assays of sodium (Na), potassium (K), aspartate aminotransferase (ASAT), alanine aminotranferase (ALAT), amylase, alkaline phosphatase, c-reactive protein (CRP), creatinine, haemoglobin, mean cell volume, haematocrit, erythrocytes, thrombocytes and leukocytes were obtained from ID patients with epilepsy and on VPA and from healthy persons of hospital staff after overnight fasting. All patients in this study used VPA as a monotherapy. Vacuette serum tubes were used to obtain serum samples and vacuette K2EDTA tubes were used to obtain haematological samples. All assays were made immediately after sampling in the same day. The whole large patient material was from Rinnekoti hospital, Espoo-Finland. Sex and age varied in the VPA and control groups. Approximately 50% from the whole patient and control material was male. The mean ages for the VPA group and the control group were 37±15 years and 50±10 years, respectively. Laboratory determinations and reagents:Serum sodium (Na), potassium (K), aspartate aminotransferase (ASAT), alanine aminotransferase (ALAT), amylase, alkaline phosphatase, c-reactive protein (CRP) and creatinine were analyzed with Cobas Mira analyzer. Haemoglobin, mean cell volume (MCV), hematocrit, erythrocytes, thrombocytes and leukocytes were assayed with Sysmex KX-21N analyzer. All used reagents were reagent grade. All laboratory determinations were controlled with the control samples from Labquality Ltd, Helsinki, Finland.
