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P.5.c.002 Non-fatal and fatal liver failure associated with valproic acid
P.5.c. Dementia and neurological disorders − Neurological disorders (clinical)
P.5.c. Dementia and neurological disorders − Neurological disorders (clinical) P.5.c.001 The importance of depression and anxiety level for the functioning and life quality of multiple sclerosis patients P. Ionescu1 ° , S. Petrescu2 , N. Munjev2 , R.O. Gheorghe3 , M.R. Stoean4 , O. Boanta-Serban4 1 Promemoria Medical Center, Psychiatry, Bucharest, Romania; 2 The Emergency University Hospital Elias, Neurology, Bucharest, Romania; 3 Titan Medical Clinic, Psychiatry, Bucharest, Romania; 4 Psychiatry Hospital “Prof. Dr. Al Obregia”, Psychiatry, Bucharest, Romania Purpose of the study: It is well known that patients with multiple sclerosis (MS) have frequently affective and anxiety spectrum disorders. Depressive syndrome has a lifetime prevalence of 50% among MS patients [1]. Anxiety disorders like generalized anxiety disorder, panic disorder and obsessive-compulsive disorder have lifetime prevalence 3 to 4 times higher in MS patients than in the general population [2]. Our aim was to asses the relations between anxious and depressive symptoms on one hand and the quality of life (QoL) and daily activities and abilities on the other, in patients diagnosed with MS. We measured the intensity of depression using HAM-D 17 and the intensity of anxiety using HAM-A scale. We also measured the expanded disability status scale (EDSS) score for each patient. EDSS is a validated scale for physical disability in MS and it could be an important variable for our study. Methods used: Our batch was composed of 112 patients diagnosed with different forms of multiple sclerosis. The patients with relapsing remitting MS were free of acute neurological deficits during the examination. For every patient we performed neurological examination (EDSS), and the assessment of depression (HAM-D 17), of anxiety (HAM-A), of daily activities (activities of daily living [ADL] and instrumental activities of daily living [IADL]) and of the quality of life − score and grade (QoL score and QoL grade). We made statistical correlations between all the variables above using Pearson and Kendall methods. Summary of results: At first we found strong correlations between neurological deficit (measured by EDSS) and HAM-A, HAM-D, ADL, IADL, QoL score and QoL grade (using Pearson method): p = 0.0001 for each. For different levels of EDSS score we tried to correlate HAM-A and HAM-D with ADL, IADL, QoL score and grade. To start a valid Kendall correlation we needed a minimum of 9 patients in an EDSS group. Thus this correlation was possible only for the EDSS groups with the EDSS scores of 1.0, 2.0, 2.5, 3.0, 3.5, 4.0 and 6.5. Therefore 88 patients out of 112 were included in this analysis. The correlations mentioned above were all valid with a stronger connection in the groups with a higher EDSS score. Excluding the EDSS variable we found strong correlations between HAM-A and ADL, IADL, QoL score and grade: p = 0.0001 for each, except from IADL: p = 0.001. Excluding the EDSS variable we found strong correlations between HAM-D and ADL, IADL, QoL score and grade: p = 0.0001 for each, except again from IADL: p = 0.001. There was also a powerful correlation between HAM-A and HAM-D values p = 0.001.
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Conclusions: We found that the level of anxiety and the level of depression are in a potent relation with the daily functioning level and the quality of life for all the stages and severity degrees of the MS patients. Anxiety and depression levels grow together with the EDSS score. We managed to indirectly emphasize the major role that a psychiatrist could play in the life of the patients with this neurological condition. References [1] S.B. Patten, MD, PhD; C.A. Beck, MD; J.V.A. Williams, MSc; C. Barbui, MD; and L.M. Metz, MD. Major depression in multiple sclerosis − a population-based perspective. Neurology 2003; 61: 1524–1527. [2] Korostil M. Feinstein A. Anxiety disorders and their clinical correlates in multiple sclerosis patients. Multiple Sclerosis 2007 Jan; 13(1): 67−72.
P.5.c.002 Non-fatal and fatal liver failure associated with valproic acid C. Sch¨onfeldt-Lecuona1 ° , B. Connemann1 , M. Gahr1 , F. Keller2 , C. Hiemke3 , R.W. Freudenmann1 1 University of Ulm, Dept. of Psychiatry and Psychotherapy III, Ulm, Germany; 2 University of Ulm, Dept. of Child Psychiatry and Psychotherapy, Ulm, Germany; 3 University of Mainz, Dept. of Psychiatry and Psychotherapy, Mainz, Germany Background: Valproic acid (VPA), which is increasingly used for various indications (epilepsy, bipolar affective disorder, migraine and cluster headaches), is generally safe when administered according to well-established therapeutic serum drug levels. Often VPA is administered in combination with other antiepileptic drugs, antidepressants or antipsychotics. Side effects typically evolve acutely, and most frequently observed side effects include fatigue, nausea, vomiting, haemorrhages, seizures, and ataxia. Liver failure, bleeding, and pancreatitis represent rare, but life-threatening adverse events. Reports of severe or fatal liver failure related to VPA are anecdotal, and systematic analyses of these complications are scarce. This aim encouraged us to collect more representative data by summarising all reported serious VPA hepatotoxic side effects in Germany in relation to the presence or absence of comedication. Methods: We studied all cases of VPA-induced serious hepatic side effects reported to the German Federal Institute for Drugs and Medical Devices (BfArM), between 1993 and 2009. Results: Over the 16-year period, 132 cases of serious VPAassociated liver failure were reported to the BfArM. The sample consisted of 76 female and 54 male patients, resulting in a femaleto-male ratio of 1.41 to 1. The median of age was 16.0 years (range 10 months to 86 years). Approximately one third of these cases (34.8%) occurred under VPA monotherapy, and two thirds were reported in patients treated with VPA in addition to co-medication, most frequently antiepileptics (34.8%), benzodiazepines (16.7%), antipsychotics (6.8%) and antidepressants (5.3%). Within the total sample 34 (25.8%) had a fatal outcome. Of these cases 32.4% were under monotherapy and 67.6% under concomitant medication. Almost half of the incidents were reported for patients aged 0 to 10 years. However, the proportion of fatalities was lower in this age group (17% versus 34% in patients older than 10 years). In contrast to a preponderance of female patients in the total number of cases, no differences in the number of fatal
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P.5.e. Dementia and neurological disorders − Other (clinical)
cases were found for men and women (17 vs. 17). However, the association between gender and outcome (fatal vs. non-fatal) was not statistically significant (Chi2 = 1.36, df = 1, p = 0.244). Regarding age, there was no overall significant difference between the groups (fatal and non-fatal liver failure) (z = −1.61, p = 0.106). When inspecting the age distribution of the two groups, there seemed to be an increased incidence of serious hepatic side effects in children under 11 (0−10) years, while the rate of fatalities seemed equally distributed. An exploratory post hoc test of significance revealed that children under 11 have a lower risk of fatality (9 out of 54 = 17%) as compared to patients with higher age (23 out of 67 = 34%) (Chi2 = 4.79, df = 1, p = 0.029). This pharmacovigilance study indicates that VPA-associated liver failure is often fatal under monotherapy. Co-medication does not per se increase this risk. P.5.c.003 Association of ABCB1 and SCN1A gene polymorphisms with response to sodium valproate and carbamazepine in Ukrainian patients with epilepsy M.M. Oros1 ° , O.O. Yevtushenko2 , G.P. Reynolds3 1 Clinic “Vodolij”, Clinic “Vodolij”, Khust, Ukraine; 2 Institute of Pharmacology and Toxicology AMS Ukraine, Department of Neuropharmacology, Kyiv, Ukraine; 3 Sheffield Hallam University, Biomedical Research Centre, Sheffield, United Kingdom Background: In spite of variety of antiepileptic drugs (AED), treatment remains ineffective in 30% of epilepsy patients (Kwan et al., 2000). Pharmacoresistance is a major problem which is multifactorial by nature. Genetic factors can significantly influence the outcome of drug therapy. Recently there have been multiple studies implicating genetic variations of drug transporter proteins as well as alpha subunit of neuronal voltage-gated sodium channel in the outcome of drug therapy. In the current study, we addressed the question of whether polymorphisms C3435T (rs1045642) and C1236T (rs1128503) of the ABCB1 gene which codes for the P-glycoprotein and rs3812718 of SCN1A gene, encoding the alpha subunit of the neuronal sodium channel, influence response to carbamazepine (CBZ) and valproic acid (VPA) in Ukrainian population. Methods: 183 subjects, 103 males and 80 females, mean age 33.6±13.3y participated in the study. Seizures and epilepsy syndromes were classified according to the International League Against Epilepsy guidelines. Drug treatment of subjects as outpatients was with CBZ (n = 122), VPA (n = 60). The patients were considered to be drug responsive if they had not experienced any type of seizures for a minimum of 1 year after receiving AED. Drug-resistant epilepsy was defined as uncontrolled seizures over a year despite attempts to treat with three or more different AEDs. Results: C3435T genotype of ABCB1 was significantly associated with drug resistance. CC carriers exhibited significantly higher resistance to drug response compared to T allele carriers counterparts: CC (n = 27 of 39 patients) vs. CT/TT (n = 60/143), p = 0.003. This effect was independent of age or sex of the patients, and remained significant in each of the drug groups: p = 0.013 (CBZ) and p = 0.022 (VPA). There was no significant association of C1236T genotype with drug response: CC (n = 29/50) vs. CT (n = 45/92) vs. TT (n = 13/40), p = 0.053. The effect did not reach significance after grouping patience either in CC vs CT/TT carriers groups (p = 0.091) or CBZ vs VPA groups, p = 0.266 and p = 0.077, respectively.
rs3812718 genotype of SCN1A gene was significantly associated with developing resistance in response to CBZ and VPA. TT carriers exhibited higher prevalence of resistance to antiepileptic treatment: CC/CT (30/119) vs. TT (57/63), p < 0.001. This effect was independent on age or sex of the patients and remained significant in each of drug groups: p = 0.000 (CBZ) and p = 0.000 (VPA). There was no apparent interaction between C3435T and rs3812718 polymorphisms in determining drug resistance. A combination of C3435T and rs3812718 polymorphisms gave 100% sensitivity and 60% specificity in identifying drug non-responders. Conclusion: This study demonstrated significant associations in common polymorphisms of the ABCB1 and SCN1A genes with resistance to CBZ and VPA treatment. The polymorphisms appear to demonstrate an additive effect and indicate the future potential for genetic testing of drug resistance in patients with epilepsy. References [1] Kwan, P., Brodie, M.J., 2000. Early identification of refractory epilepsy. N Engl J Med 342, 314–319. [2] Sisodiya, S.M., Marini, C., 2009. Genetics of antiepileptic drug resistance. Curr Opin Neurol 22, 150–156. [3] Schmidt, D., L¨oscher, W., 2005. Drug resistance in epilepsy: putative neurobiologic and clinical mechanisms. Epilepsia 46, 858–877.
P.5.e. Dementia and neurological disorders − Other (clinical) P.5.e.001 Delirium of elderly patients in the emergency room J. Woo1 ° , J. Lee1 , S.Y. Park2 1 Catholic University of Daegu School of Medicine, psychiatry, Daegu, South-Korea; 2 Yeungnam University Hospital, Emergency Medicine, Daegu, South-Korea Purpose: Delirium is a neuropsychiatric syndrome with core features of acute onset and fluctuating course, attentional deficits and generalized severe disorganization of behavior [1]. It is known that delirium is common among elderly patients and is associated with poor clinical outcomes, including prolonged hospital stay time and mortality [2]. As a number of elderly patients have been increasing in emergency department, the prevalence of delirium has been on the rise. However, delirium has been likely to be under-recognized by emergency medical teams [3]. Our study was designed to evaluate the frequency, the clinical effects and risk factors of delirium of hospitalized elderly patients in emergency department. Methods: We retrospectively reviewed the 414 cases of elderly patients admitted to emergency department and stayed over 24 hours between January 2008 and December 2009. We examined the frequency and assessed the clinical effects and risk factors. The clinical effects were assessed by hospital stay time and mortality. The candidates of risk factors included personal history (age, sex, alcohol abuse, smoking), transfer from nursing home, cognitive disorder (dementia, depression), neurologic disorder (stroke), medical condition (malnutrition, dehydration, infection, hypoxia, metabolic derangements, electrolyte imbalance, hemodynamic instability, visual impairment, hearing loss), drugs (3 or more medications, anesthetics, analgesics, sedatives, antibiotics, anticholinergics, antihistamines, bronchodilators, cardiac medications, diuretics, steroids). Each of the candidate risk factors
P.5.c. Dementia and neurological disorders − Neurological disorders (clinical) P.5.c.001 The importance of depression and anxiety level for the functioning and life quality of multiple sclerosis patients P. Ionescu1 ° , S. Petrescu2 , N. Munjev2 , R.O. Gheorghe3 , M.R. Stoean4 , O. Boanta-Serban4 1 Promemoria Medical Center, Psychiatry, Bucharest, Romania; 2 The Emergency University Hospital Elias, Neurology, Bucharest, Romania; 3 Titan Medical Clinic, Psychiatry, Bucharest, Romania; 4 Psychiatry Hospital “Prof. Dr. Al Obregia”, Psychiatry, Bucharest, Romania Purpose of the study: It is well known that patients with multiple sclerosis (MS) have frequently affective and anxiety spectrum disorders. Depressive syndrome has a lifetime prevalence of 50% among MS patients [1]. Anxiety disorders like generalized anxiety disorder, panic disorder and obsessive-compulsive disorder have lifetime prevalence 3 to 4 times higher in MS patients than in the general population [2]. Our aim was to asses the relations between anxious and depressive symptoms on one hand and the quality of life (QoL) and daily activities and abilities on the other, in patients diagnosed with MS. We measured the intensity of depression using HAM-D 17 and the intensity of anxiety using HAM-A scale. We also measured the expanded disability status scale (EDSS) score for each patient. EDSS is a validated scale for physical disability in MS and it could be an important variable for our study. Methods used: Our batch was composed of 112 patients diagnosed with different forms of multiple sclerosis. The patients with relapsing remitting MS were free of acute neurological deficits during the examination. For every patient we performed neurological examination (EDSS), and the assessment of depression (HAM-D 17), of anxiety (HAM-A), of daily activities (activities of daily living [ADL] and instrumental activities of daily living [IADL]) and of the quality of life − score and grade (QoL score and QoL grade). We made statistical correlations between all the variables above using Pearson and Kendall methods. Summary of results: At first we found strong correlations between neurological deficit (measured by EDSS) and HAM-A, HAM-D, ADL, IADL, QoL score and QoL grade (using Pearson method): p = 0.0001 for each. For different levels of EDSS score we tried to correlate HAM-A and HAM-D with ADL, IADL, QoL score and grade. To start a valid Kendall correlation we needed a minimum of 9 patients in an EDSS group. Thus this correlation was possible only for the EDSS groups with the EDSS scores of 1.0, 2.0, 2.5, 3.0, 3.5, 4.0 and 6.5. Therefore 88 patients out of 112 were included in this analysis. The correlations mentioned above were all valid with a stronger connection in the groups with a higher EDSS score. Excluding the EDSS variable we found strong correlations between HAM-A and ADL, IADL, QoL score and grade: p = 0.0001 for each, except from IADL: p = 0.001. Excluding the EDSS variable we found strong correlations between HAM-D and ADL, IADL, QoL score and grade: p = 0.0001 for each, except again from IADL: p = 0.001. There was also a powerful correlation between HAM-A and HAM-D values p = 0.001.
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Conclusions: We found that the level of anxiety and the level of depression are in a potent relation with the daily functioning level and the quality of life for all the stages and severity degrees of the MS patients. Anxiety and depression levels grow together with the EDSS score. We managed to indirectly emphasize the major role that a psychiatrist could play in the life of the patients with this neurological condition. References [1] S.B. Patten, MD, PhD; C.A. Beck, MD; J.V.A. Williams, MSc; C. Barbui, MD; and L.M. Metz, MD. Major depression in multiple sclerosis − a population-based perspective. Neurology 2003; 61: 1524–1527. [2] Korostil M. Feinstein A. Anxiety disorders and their clinical correlates in multiple sclerosis patients. Multiple Sclerosis 2007 Jan; 13(1): 67−72.
P.5.c.002 Non-fatal and fatal liver failure associated with valproic acid C. Sch¨onfeldt-Lecuona1 ° , B. Connemann1 , M. Gahr1 , F. Keller2 , C. Hiemke3 , R.W. Freudenmann1 1 University of Ulm, Dept. of Psychiatry and Psychotherapy III, Ulm, Germany; 2 University of Ulm, Dept. of Child Psychiatry and Psychotherapy, Ulm, Germany; 3 University of Mainz, Dept. of Psychiatry and Psychotherapy, Mainz, Germany Background: Valproic acid (VPA), which is increasingly used for various indications (epilepsy, bipolar affective disorder, migraine and cluster headaches), is generally safe when administered according to well-established therapeutic serum drug levels. Often VPA is administered in combination with other antiepileptic drugs, antidepressants or antipsychotics. Side effects typically evolve acutely, and most frequently observed side effects include fatigue, nausea, vomiting, haemorrhages, seizures, and ataxia. Liver failure, bleeding, and pancreatitis represent rare, but life-threatening adverse events. Reports of severe or fatal liver failure related to VPA are anecdotal, and systematic analyses of these complications are scarce. This aim encouraged us to collect more representative data by summarising all reported serious VPA hepatotoxic side effects in Germany in relation to the presence or absence of comedication. Methods: We studied all cases of VPA-induced serious hepatic side effects reported to the German Federal Institute for Drugs and Medical Devices (BfArM), between 1993 and 2009. Results: Over the 16-year period, 132 cases of serious VPAassociated liver failure were reported to the BfArM. The sample consisted of 76 female and 54 male patients, resulting in a femaleto-male ratio of 1.41 to 1. The median of age was 16.0 years (range 10 months to 86 years). Approximately one third of these cases (34.8%) occurred under VPA monotherapy, and two thirds were reported in patients treated with VPA in addition to co-medication, most frequently antiepileptics (34.8%), benzodiazepines (16.7%), antipsychotics (6.8%) and antidepressants (5.3%). Within the total sample 34 (25.8%) had a fatal outcome. Of these cases 32.4% were under monotherapy and 67.6% under concomitant medication. Almost half of the incidents were reported for patients aged 0 to 10 years. However, the proportion of fatalities was lower in this age group (17% versus 34% in patients older than 10 years). In contrast to a preponderance of female patients in the total number of cases, no differences in the number of fatal
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P.5.e. Dementia and neurological disorders − Other (clinical)
cases were found for men and women (17 vs. 17). However, the association between gender and outcome (fatal vs. non-fatal) was not statistically significant (Chi2 = 1.36, df = 1, p = 0.244). Regarding age, there was no overall significant difference between the groups (fatal and non-fatal liver failure) (z = −1.61, p = 0.106). When inspecting the age distribution of the two groups, there seemed to be an increased incidence of serious hepatic side effects in children under 11 (0−10) years, while the rate of fatalities seemed equally distributed. An exploratory post hoc test of significance revealed that children under 11 have a lower risk of fatality (9 out of 54 = 17%) as compared to patients with higher age (23 out of 67 = 34%) (Chi2 = 4.79, df = 1, p = 0.029). This pharmacovigilance study indicates that VPA-associated liver failure is often fatal under monotherapy. Co-medication does not per se increase this risk. P.5.c.003 Association of ABCB1 and SCN1A gene polymorphisms with response to sodium valproate and carbamazepine in Ukrainian patients with epilepsy M.M. Oros1 ° , O.O. Yevtushenko2 , G.P. Reynolds3 1 Clinic “Vodolij”, Clinic “Vodolij”, Khust, Ukraine; 2 Institute of Pharmacology and Toxicology AMS Ukraine, Department of Neuropharmacology, Kyiv, Ukraine; 3 Sheffield Hallam University, Biomedical Research Centre, Sheffield, United Kingdom Background: In spite of variety of antiepileptic drugs (AED), treatment remains ineffective in 30% of epilepsy patients (Kwan et al., 2000). Pharmacoresistance is a major problem which is multifactorial by nature. Genetic factors can significantly influence the outcome of drug therapy. Recently there have been multiple studies implicating genetic variations of drug transporter proteins as well as alpha subunit of neuronal voltage-gated sodium channel in the outcome of drug therapy. In the current study, we addressed the question of whether polymorphisms C3435T (rs1045642) and C1236T (rs1128503) of the ABCB1 gene which codes for the P-glycoprotein and rs3812718 of SCN1A gene, encoding the alpha subunit of the neuronal sodium channel, influence response to carbamazepine (CBZ) and valproic acid (VPA) in Ukrainian population. Methods: 183 subjects, 103 males and 80 females, mean age 33.6±13.3y participated in the study. Seizures and epilepsy syndromes were classified according to the International League Against Epilepsy guidelines. Drug treatment of subjects as outpatients was with CBZ (n = 122), VPA (n = 60). The patients were considered to be drug responsive if they had not experienced any type of seizures for a minimum of 1 year after receiving AED. Drug-resistant epilepsy was defined as uncontrolled seizures over a year despite attempts to treat with three or more different AEDs. Results: C3435T genotype of ABCB1 was significantly associated with drug resistance. CC carriers exhibited significantly higher resistance to drug response compared to T allele carriers counterparts: CC (n = 27 of 39 patients) vs. CT/TT (n = 60/143), p = 0.003. This effect was independent of age or sex of the patients, and remained significant in each of the drug groups: p = 0.013 (CBZ) and p = 0.022 (VPA). There was no significant association of C1236T genotype with drug response: CC (n = 29/50) vs. CT (n = 45/92) vs. TT (n = 13/40), p = 0.053. The effect did not reach significance after grouping patience either in CC vs CT/TT carriers groups (p = 0.091) or CBZ vs VPA groups, p = 0.266 and p = 0.077, respectively.
rs3812718 genotype of SCN1A gene was significantly associated with developing resistance in response to CBZ and VPA. TT carriers exhibited higher prevalence of resistance to antiepileptic treatment: CC/CT (30/119) vs. TT (57/63), p < 0.001. This effect was independent on age or sex of the patients and remained significant in each of drug groups: p = 0.000 (CBZ) and p = 0.000 (VPA). There was no apparent interaction between C3435T and rs3812718 polymorphisms in determining drug resistance. A combination of C3435T and rs3812718 polymorphisms gave 100% sensitivity and 60% specificity in identifying drug non-responders. Conclusion: This study demonstrated significant associations in common polymorphisms of the ABCB1 and SCN1A genes with resistance to CBZ and VPA treatment. The polymorphisms appear to demonstrate an additive effect and indicate the future potential for genetic testing of drug resistance in patients with epilepsy. References [1] Kwan, P., Brodie, M.J., 2000. Early identification of refractory epilepsy. N Engl J Med 342, 314–319. [2] Sisodiya, S.M., Marini, C., 2009. Genetics of antiepileptic drug resistance. Curr Opin Neurol 22, 150–156. [3] Schmidt, D., L¨oscher, W., 2005. Drug resistance in epilepsy: putative neurobiologic and clinical mechanisms. Epilepsia 46, 858–877.
P.5.e. Dementia and neurological disorders − Other (clinical) P.5.e.001 Delirium of elderly patients in the emergency room J. Woo1 ° , J. Lee1 , S.Y. Park2 1 Catholic University of Daegu School of Medicine, psychiatry, Daegu, South-Korea; 2 Yeungnam University Hospital, Emergency Medicine, Daegu, South-Korea Purpose: Delirium is a neuropsychiatric syndrome with core features of acute onset and fluctuating course, attentional deficits and generalized severe disorganization of behavior [1]. It is known that delirium is common among elderly patients and is associated with poor clinical outcomes, including prolonged hospital stay time and mortality [2]. As a number of elderly patients have been increasing in emergency department, the prevalence of delirium has been on the rise. However, delirium has been likely to be under-recognized by emergency medical teams [3]. Our study was designed to evaluate the frequency, the clinical effects and risk factors of delirium of hospitalized elderly patients in emergency department. Methods: We retrospectively reviewed the 414 cases of elderly patients admitted to emergency department and stayed over 24 hours between January 2008 and December 2009. We examined the frequency and assessed the clinical effects and risk factors. The clinical effects were assessed by hospital stay time and mortality. The candidates of risk factors included personal history (age, sex, alcohol abuse, smoking), transfer from nursing home, cognitive disorder (dementia, depression), neurologic disorder (stroke), medical condition (malnutrition, dehydration, infection, hypoxia, metabolic derangements, electrolyte imbalance, hemodynamic instability, visual impairment, hearing loss), drugs (3 or more medications, anesthetics, analgesics, sedatives, antibiotics, anticholinergics, antihistamines, bronchodilators, cardiac medications, diuretics, steroids). Each of the candidate risk factors