Suna Su Aksay

Spontaneous arterial dissection: phenotype and molecular pathogenesis

Arterial dissection (AD) is defined as the longitudinal splitting up of the arterial wall caused by intramural bleeding. It can occur as a spontaneous event in all large and medium sized arteries. The histological hallmark of AD is medial degeneration. Histological investigations, gene expression profiling and proteome studies of affected arteries reveal disturbances in many different biological processes including inflammation, proteolytic activity, cell proliferation, apoptosis and smooth muscle cell (SMC) contractile function. Medial degeneration can be caused by various rare dominant Mendelian disorders. Genetic linkage analysis lead to the identification of mutations in different disease-causing genes involved in the biosynthesis of the extracellular matrix (FBN1, COL3A1), in transforming growth factor (TGF) beta signaling (FBN1, TGFBR1, TGFBR2) and in the SMC contractile system (ACTA2, MYH11). Genome wide association studies suggest that the CDKN2A/CDKN2B locus plays a role in the etiology AD and other arterial diseases.

New evidence for seizure quality improvement by hyperoxia and mild hypocapnia.

Introduction Preoxygenation and hyperventilation (with oxygen) in electroconvulsive therapy (ECT) may improve not only safety but also seizure quality. Methods We retrospectively examined transcutaneous tissue partial pressure of oxygen (tcpO2) and carbon dioxide (tcpCO2) in 441 ECT sessions of 37 consecutive patients. All patients received standard face mask airway management. In parallel, seizure quality markers such as seizure duration, seizure amplitude, central inhibition, interhemispheric coherence, and sympathetic activation were documented and used to build up a seizure quality sum score. Results Mean (SD) tcpO2 was 289 (123) mm Hg and for tcpCO2 41 (11) mm Hg. A multivariate repeated measurement regression analysis revealed that the ratio of tcpO2/tcpCO2 had a significant influence on the seizure quality sum score (P = 0.033). Furthermore, a corresponding regression analysis with charge (“stimulation energy”) as a dependent variable showed a significant influence of tcpO2 (P = 0.019) and of tcpO2/tcpCO2 (P = 0.03), too. Conclusions We observed, in our typical clinical ECT sample of 37 patients, a significant and synergistic influence of tcpO2/tcpCO2 on seizure quality. Partial pressure of oxygen covaried with lower stimulation energy. The ratio tcpO2/tcpCO2 was associated with lower stimulation energy and still better seizure quality.

Adult-onset autosomal dominant leukodystrophy due to LMNB1 gene duplication

Adult-onset autosomal dominant leukodystrophy (ADLD, OMIM accession number 169500) is a slowly progressive neurological disorder involving early autonomic dysfunction, cognitive impairment, pyramidal lesions, and cerebellar dysfunction. Onset is usually in the fourth or fifth decade of life. The disease is caused by a duplication of a region on chromosome 5q23.2 including the Lamin B1 gene (LMNB1) [1]. Neuroradiological characteristics are symmetrical extensive white matter changes predominantly in the frontal and parietal lobes, middle cerebellar peduncles, and specific brain stem tracts. Furthermore, atrophy of the corpus callosum and the brain stem develop. Sparing or less severe alteration of the periventricular white matter is a typical finding [2]. We report on a 47-year-old male patient with a 2-year history of gait disturbance and micturition problems with imperative strangury and, as mentioned by family members, personality changes and depression. On examination he had moderately severe gait ataxia, symmetrical appendicular ataxia, mild spastic paraparesis, brisk deep tendon reflexes, and bilaterally positive Babinski signs. MR imaging of the brain showed extensive bilateral T2hyperintense lesions in the subcortical and deep cerebral white matter with relative sparing of a periventricular rim and the corpus callosum. The middle cerebellar peduncles, the pyramidal tracts, and medial lemniscus in the midbrain, pons, and medulla, and the decussation of the superior cerebellar peduncles were also affected (Fig. 1). Neuropsychological testing yielded results below average regarding the following domains: verbal fluency and flexibility, verbal memory, verbal recall, working memory, several executive functions, and general working velocity. Lumbar puncture, evoked potentials, nerve conduction studies, and electromyography were without abnormal findings. Blood and urine analysis of amino acids, long-chain fatty acids, and lysosomal enzymes (arylsulfatase A, galactocerebrosidase, alpha-galactosidase) were normal. The pedigree showed numerous affected members of father’s family within three generations. Four out of five uncles and aunts and in the grandparents’ generation, six out of eight family members were affected, mainly by gait disturbance but also by neuropsychiatric symptoms (Fig. 2). Seven affected siblings had died; age at death varied between 46 and 71 years. Because of the mode of inheritance and the clinical and MRI findings, ADLD was supposed and the lamin B1 gene was analyzed. Genomic DNA was extracted from venous blood and hybridized on Affymetrix GeneChip Human Mapping SNP6.0 arrays, following the manufacturer’s instructions. M. M. Dos Santos (&) A. J. Grau Department of Neurology, Klinikum Ludwigshafen, Bremserstrasse 79, 67063 Ludwigshafen, Germany e-mail: santosm@klilu.de

Severe agitation in severe early-onset Alzheimer's disease resolves with ECT

Dementia-related behavioral disturbances are mostly treated with antipsychotics; however, the observed beneficial effects are modest and the risk of serious adverse effects high. We report the case of a 57-year-old woman with severe early-onset Alzheimer’s disease and severe agitation, whom we treated with electroconvulsive therapy (ECT). A significant clinical improvement was achieved over eight ECT sessions, which were tolerated well without cognitive worsening, and lasted approximately 3 months. Our case demonstrates the safe and effective use of ECT in pharmacotherapy-resistant severe agitation in Alzheimer’s disease. The risk–benefit profile of ECT for dementia-related agitation should be further investigated in clinical trials.

Next generation sequencing analysis of patients with familial cervical artery dissection

Background The cause of cervical artery dissection is not well understood. We test the hypothesis that mutations in genes associated with known arterial connective tissue disorders are enriched in patients with familial cervical artery dissection. Patients and methods Patient duos from nine pedigrees with familial cervical artery dissection were analyzed by whole exome sequencing. Single nucleotide variants in a panel of 11 candidate genes (ACTA2, MYH11, FBN1, TGFBR1, TGFBR2, TGFB2, COL3A1, COL4A1, SMAD3, MYLK and SLC2A10) were prioritized according to functionality (stop-loss, nonsense, and missense variants with polyphen-2 score ≥0.95). Variants classified as “benign” or “likely benign” in the ClinVar database were excluded from further analysis. For comparison, non-benign stop-loss, nonsense and missense variants with polyphen-2 score ≥0.95 in the same panel of candidate genes were identified in the European non-Finnish population of the ExAC database (n = 33,370). Results Non-benign Single nucleotide variants in both affected patients were identified in four of the nine cervical artery dissection families (COL3A1; Gly324Ser, FBN1: Arg2554Trp, COL4A1: Pro116Leu, and TGFBR2: Ala292Thr) yielding an allele frequency of 22.2% (4/18). In the comparison group, 1782 variants were present in 33,370 subjects from the ExAC database (allele frequency: 1782/66,740 = 2.7%; p = 0.0008; odds ratio = 14.2; 95% confidence interval = 3.8–52.9). Conclusion Cervical artery dissection families showed enrichment for non-benign variants in genes associated with arterial connective tissue disorders. The observation that findings differed across families indicates genetic heterogeneity of familial cervical artery dissection.

Electroconvulsive therapy selectively enhances amyloid β 1–42 in the cerebrospinal fluid of patients with major depression: A prospective pilot study

A complex interplay between β-amyloid (Aβ), Alzheimer׳s disease (AD) and major depression disorder (MDD) suggests that patients with MDD have an altered cerebral Aβ metabolism and an increased risk of developing AD. In order to elucidate the relationship between antidepressant treatment and Aβ metabolism in humans, we performed a study on Aβ peptides in the cerebrospinal fluid (CSF) in patients with MDD during electroconvulsive therapy (ECT) as an effective antidepressant treatment. We measured the levels of Aβ1-42, Aβ1-40 and of tau proteins in the CSF in 12 patients with MDD before and after a course of ECT. Aβ1-42 was significantly elevated after the ECT treatment compared to baseline, whereas no difference was found for other peptides and proteins such as Aβ1-40, Aβ ratio, total tau protein or its phosphorylated form. The most salient finding was, that the increase of Aβ1-42 after ECT was found in all patients with clinical response to the treatment, but not in those who did not respond. The number of ECT sessions of each responding patient correlated with the increase of Aβ1-42 in the CSF. Our data point towards to a specific antidepressant mechanism which is not based on a general increase of Aβ, but seems to involve merely Aβ1-42, the isoform with highest amyloidogenic potential. We present the first study in humans demonstrating an isolated mobilization of Aβ1-42 in the CSF of patients with depression who respond to an ECT treatment.

ECT seizure quality and serum BDNF, revisited

expected since seizures with lower adequacy (and lower antidepressive effect) are still seizures producing a lower (or less effective) but still present BDNF rise.To cope with this problem (not to “control” for covari-ates), we added an ANCOVA (as Molendijk and Polyakova suggested), including an interaction term for the delay of blood sampling and high versus low seizure quality. ANCOVA (STATA, StataCorp, Texas 77845, USA, version 11) then reveals a significant model (

Ketamin als Anästhetikum bei der Elektrokrampftherapie

BACKGROUND Electroconvulsive therapy (ECT) is a well-established, safe and effective treatment for severe psychiatric disorders. Ketamine is known as a core medication in anesthesiology and has recently gained interest in ECT practice as there are three potential advantages: (1) ketamine has no anticonvulsive actions, (2) according to recent studies ketamine could possess a unique intrinsic antidepressive potential and (3) ketamine may exhibit neuroprotective properties, which again might reduce the risk of cognitive side effects associated with ECT. OBJECTIVES The use of ketamine in psychiatric patients has been controversially discussed due to its dose-dependent psychotropic and psychotomimetic effects. This study was carried out to test if the occurrence of side effects is comparable and if seizure quality is better with ketamine when compared to thiopental. MATERIAL AND METHODS This retrospective study analyzed a total of 199 patients who received ketamine anesthesia for a total of 2178 ECT sessions. This cohort was compared to patients who were treated with thiopental for 1004 ECT sessions. RESULTS AND DISCUSSION A repeated measurement multiple logistic regression analysis revealed significant advantages in the ketamine group for seizure concordance and postictal suppression (both are surrogates for central inhibition). S-ketamin also necessitated the use of a higher dose of urapidil and a higher maximum postictal heart frequency. Clinically relevant psychiatric side effects were rare in both groups. No psychiatric side effects occurred in the subgroup of patients with schizophrenia (ketamine: n = 30). The mean dose of S-ketamine used increased in the first years but stabilized at 63 mg per patient in 2014. From these experiences it can be concluded that S-ketamine can be recommended at least as a safe alternative to barbiturates.

Antidepressant efficacy of electroconvulsive therapy is associated with a reduction of the innate cellular immune activity in the cerebrospinal fluid in patients with depression.

Abstract Objectives: A bidirectional link between the antidepressant effects of electroconvulsive therapy (ECT) and the modulation of the immune system has been proposed. To elucidate the interplay between antidepressant treatment and macrophage/microglia activation in humans, we performed a study on the effects of the antidepressant treatment by ECT on markers of macrophage/microglia activation in patients with depression. Methods: We measured six different markers (IL-6, neopterin, sCD14, sCD163 MIF and MCP1) of macrophage/microglia activation in the cerebrospinal fluid (CSF) and blood of 12 patients with a severe, treatment-resistant depressive episode before and after a course of ECT. Results: Some markers in the CSF of remitters were reduced after the ECT course and differed from non-remitters, but no differences were found before and after ECT independently from the antidepressant efficacy. CSF baseline levels of some markers could predict the reduction of depressive psychopathology during ECT. Higher CSF levels indicating increased macrophage/microglia activation at baseline predicted a better treatment response to ECT. Conclusions: Although the sample size was small, our data suggest that macrophages/microglia are involved in the pathophysiology of major depression and that antidepressant efficacy by ECT might be partly explained by the modulation of the innate immune system within the brain.

Electroconvulsive therapy enhances endocannabinoids in the cerebrospinal fluid of patients with major depression: a preliminary prospective study

Despite the lack of clinical data about the role of the endocannabinoid system (ECS) in affective disorders, preclinical work suggests that the ECS is relevant in both with regard to the etiology of depression as well as the mediation of antidepressant effects. We measured the intraindividual levels of the endocannabinoids N-arachidonoylethanolamine (AEA) and 2-arachidonoylglycerol (2-AG) in the cerebrospinal fluid of 12 patients suffering from a major depressive episode before and after the antidepressant treatment by electroconvulsive therapy (ECT). AEA was significantly elevated after ECT as compared to baseline. The AEA increase positively correlated with the number of individually performed ECT sessions. Although the sample size was small and confounders were not rigorously controlled for, our finding corroborates preclinical work and should encourage further exploration of the involvement of the ECS in depressive disorder.