The relationship between valproate induced tremors and circulating neurotransmitters: a preliminary study.

Patients with epilepsy and on valproate (VPA) therapy may develop tremors as a common adverse effect; however, its exact mechanisms are unknown. We hypothesize that VPA-induced tremors may be related to the disturbances in dopamine (DA) and catecholamines (norepinephrine (NE) and epinephrine (E)) concentrations (which are also involved in VPA anticonvulsant effect). We aimed to determine the frequency and type of VPA-induced tremors and their risk factors and to investigate whether or not they are related to the plasma DA, NE and E concentrations. This study included 75 adults with primary epilepsy (mean age: 31.90 ± 5.62 years) and on VPA therapy for 10.57 ± 3.55 years and 40 matched healthy controls. Patients were divided according to the absence or presence of tremors. Blood samples were analyzed for DA, NE and E. Intermittent action tremors in both hands were reported in 31 (41.33%). Chronic standard VPA therapy, older age, longer treatment duration and higher serum concentrations of VPA are risk factors for tremors. None of the patients on controlled release VPA had tremors. Compared to controls, patients (without and with tremors) had lower DA (p = 0.0001) and NE (p = 0.01) concentrations. Compared to patients without tremors, patients with tremors had lower levels DA (p = 0.045) and NE (p = 0.01). Significant correlations were identified between DA with NE (r = 0.540, p = 0.001) concentrations and serum VPA with DA (r = -0.285, p = 0.045) and NE (r = -0.358, p = 0.01) plasma levels. We conclude that benign action tremors are common with standard VPA. Mechanisms underlying VPA-induced tremors may involve abnormalities of DA and NE neurotransmitters.

Fatty liver in adults receiving antiepileptic medications: relationship to the metabolic risks.

This study aimed to determine the frequency of fatty liver disease (FLD) induced by antiepileptic drugs (AEDs) and its relationship to the metabolic profile. This study included 130 patients (valproate or VPA = 75; carbamazepine or CBZ = 40; lamotrigine or LTG = 15). Liver ultrasonography (US) was done. Serum lipids, uric acid, free fatty acids (FFAs), glucose, insulin and leptin were measured. Compared to controls and patients on CBZ or LTG, higher BMI; TC, TG, LDL-c, uric acid, FFAs, glucose, insulin and leptin concentrations and enlarged liver lobes volume and span and insulin resistance (45%) were reported with VPA. With FLD, significant correlations were reported between BMI with leptin (r = 0.390;p < 0.01), insulin (r = 0.655;p < 0.001) and FFAs (r = 0.570;p < 0.001) and insulin with leptin (r = 0.355;p < 0.01). In multivariate analysis, with FLD, liver span was correlated with BMI (OR:4.50;95%CI:1.54-13.3,p = 0.01) and leptin concentrations (OR:2.55;95%CI:1.04-6.27,p = 0.045). We conclude that VPA therapy is a risk for FLD and is correlated with the associated adverse metabolic profile.

Seminal fluid analysis and testicular volume in adults with epilepsy receiving valproate.

Epilepsy and its medications adversely affect reproductive and sexual functions and fertility. This study aimed to assess sperm parameters and testicular volume in men with epilepsy on valproate (VPA). Included were 55 patients with idiopathic epilepsy with a mean age of 31.86 ± standard deviation (SD) 6.55 years, mean illness duration of 12.50 ± SD 5.10 years, and a mean treatment time of 9.55 ± SD 0.85 years. Sex hormone profile, semen analysis, testicular volume and total seminal plasma carnitine were determined. Compared to controls, patients had lower levels of free testosterone (p<0.01), sperm concentration (p<0.0001) and count (p<0.0001), carnitine (p<0.01), and testicular volume (p<0.01), and higher rates of immotile sperm (p<0.001) and abnormal forms (p<0.0001). Significant correlations were identified between sperm count, motility, immotile sperm, abnormal forms, testicular volume, carnitine levels and duration of illness, duration of treatment with VPA and VPA dose. Multivariable analysis demonstrated that duration of treatment with VPA, sperm count, motility and abnormal forms were significantly associated with seminal plasma carnitine. Long-term VPA treatment is adversely associated with reduced sperm count and motility, increased abnormal sperm count and reduced testicular volume. This may contribute to reduced fertility.

Risks of suicidality in adult patients with epilepsy.

AIM: To determine the prevalence and risks of suicidality in a group of patients with epilepsy. METHODS: Included were 200 adult patients and 100 matched healthy subjects. The clinical interview using The Diagnostic and Statistical Manual of Mental Disorders (4th edition), Beck Depression Inventory (2nd edition) (BDI-II), Hamilton Anxiety Rating Scale (HAM-A), Yale-Brown Obsessive Compulsive Scale (Y-BOCS) and Eysenck Personality Questionnaire-Revised Rating Scale testings were used for diagnosis and assessment of severity of psychiatric symptoms. Blood concentrations of serotonin, catecholamines and dopamine were also measured. RESULTS: Suicidality was reported in 35% (compared to 9% for controls), of them 80%, 72.86%, 55.71% and 52.9% had depression, anxiety, obsession and aggression respectively. Patients with suicidality had higher scores of BDI-II (P = 0.0001), HAM-A (P = 0.0001), and Y-BOCS (P = 0.037) and lower scores of psychotic (P = 0.0001) and extroversion (P = 0.025) personality traits. Regardless the presence or absence of suicidality, patients with epilepsy had low serotonin (P = 0.006), noradrenaline (P = 0.019) and adrenaline (P = 0.0001) levels. With suicidality, significant correlations were identified between: (1) age and scores of BDI-II (r = 0.235, P = 0.0001) and HAM-A (r = 0.241, P = 0.046); (2) age at onset and concentrations of noradrenaline (r = -0.502, P = 0.024); (3) duration of illness and scores of BDI-II (r = 0.247, P = 0.041), Y-BOCS (r = 0.270, P = 0.025) and neurotic personality trait (r = -0.284, P = 0.018); and (4) doses of antiepileptic drugs and scores of psychotic personality traits (r = -0.495, P = 0.006 for carbamazepine; r = -0.508, P = 0.0001 for valproate). CONCLUSION: This is the first study which systematically estimated the prevalence and risks of suicidality in a homogenous group of patients with epilepsy. This study emphasizes the importance of epilepsy itself as a risk for suicidality and not its treatment.