Adverse events associated with deep brain stimulation in patients with childhood-onset dystonia.

BACKGROUND: Data on pediatric DBS is still limited because of small numbers in single center series and lack of systematic multi-center trials. OBJECTIVES: We evaluate short- and long-term adverse events (AEs) of patients undergoing deep brain stimulation (DBS) during childhood and adolescence. METHODS: Data collected by the German registry on pediatric DBS (GEPESTIM) were analyzed according to reversible and irreversible AEs and time of occurrence with relation to DBS-surgery: Intraoperative, perioperative (<4 weeks), postoperative (4 weeks < 6 months) and long term AEs (>6 months). RESULTS: 72 patients with childhood-onset dystonia from 10 DBS-centers, who received 173 DBS electrodes and 141 implantable pulse generators (IPG), were included in the registry. Mean time of postoperative follow-up was 4.6 ±â€¯4 years. In total, 184 AEs were documented in 53 patients (73.6%). 52 DBS-related AEs in 26 patients (36.1%) required 45 subsequent surgical interventions 4.7 ±â€¯4.1 years (range 3 months-15 years) after initial implantation. The total risk of an AE requiring surgical intervention was 7.9% per electrode-year. Hardware-related AEs were the most common reason for surgery. There was a tendency of a higher rate of AEs in patients aged 7-9 years beyond 6 months after implantation. DISCUSSION: The intraoperative risk of AEs in pediatric patients with dystonia undergoing DBS is very low, whereas the rate of postoperative hardware-related AEs is a prominent feature with a higher occurrence compared to adults, especially on long-term follow-up. CONCLUSION: Factors leading to such AEs must be identified and patient management has to be focused on risk minimization strategies in order to improve DBS therapy and maximize outcome in pediatric patients.

Establishment of detection antibodies BRRs batch 5 for in vitro potency assay of hepatitis A vaccines by ELISA.

The European Pharmacopoeia (Ph. Eur.) standard ELISA method for determination of antigen content of hepatitis A vaccines (HAV) requires specific coating and detection Biological Reference Reagents (BRRs). The 4th batch of detection antibodies BRRs was established in 2017 for use in conjunction with the Ph. Eur. General Chapter 2.7.14 Assay of hepatitis A vaccine. Stocks of these BRRs were running low and therefore the European Directorate for the Quality of Medicines and HealthCare (EDQM) organised a collaborative study to qualify replacement batches. The candidate BRR antibodies batch 5 were prepared under appropriate conditions from starting materials similar to previous batches to ensure continuity. Prior to the study, a low level of detection was obtained with new batches of the HRPO-GAM provided by the established supplier, supposedly due to a manufacturing issue in the conjugation step. Several other batches procured from the same supplier were tested without any success. Consequently HRPO-GAM batches from 3 other suppliers were tested and one batch was chosen to be included as a BRR based on its suitable characteristics. During the collaborative study, the new batches of antibodies were compared to previous batches of BRRs. Results confirmed that they were suitable to be used for the intended purpose, and could be used at the same final concentrations as the previous batch, i.e. 1:500 for the primary antibody and 1:400 for the conjugated secondary antibody. A higher background OD than in previous batches was observed, so it is recommended to subtract the background from the OD values obtained in the test in order to plot the sigmoid curve and calculate the titre of test samples. Moreover it is recommended that the first dilutions used for the IS and BRP2 should be 1:2 and 1:20, respectively, in order to achieve the same ODmax as for the previous BRRs batches. The BRRs were adopted by correspondence in October 2018 by the Ph. Eur. Commission and are presented as a set containing Hepatitis A virus primary detection antibody BRR batch 5 and Conjugated secondary detection antibody BRR batch 5. They are available from the EDQM as Hepatitis A vaccine ELISA detection antibodies set BRR batch 5.

Establishment of detection antibodies BRRs batch 4 for in vitro potency assay of hepatitis A vaccines by ELISA.

The European Pharmacopoeia (Ph. Eur.) standard ELISA method for determination of antigen content of hepatitis A vaccines (HAV) requires specific coating and detection Biological Reference Reagents (BRRs). The 3rd batch of detection antibodies BRRs was established in 2015 for use in conjunction with the Ph. Eur. general chapter 2.7.14 'Assay of hepatitis A vaccine'. Stocks of these BRRs were running low and therefore the European Directorate for the Quality of Medicines & HealthCare (EDQM) organised a collaborative study to qualify replacement batches. The candidate BRR antibodies batch 4 were prepared under appropriate conditions from starting materials similar to previous batches to ensure continuity. During the collaborative study, the new batches of antibodies were compared to previous batches of BRRs. Results confirmed that they were suitable to be used for the intended purpose, and could be used at the same final concentrations as the previous batch, i.e. 1:500 for the primary antibody and 1:400 for the conjugated secondary antibody. They were adopted in June 2017 by the Ph. Eur. Commission as Hepatitis A virus primary detection antibody BRR batch 4 and Conjugated secondary detection antibody BRR batch 4, respectively. They are available from the EDQM as Hepatitis A vaccine ELISA detection antibodies set BRR batch 4.

German registry of paediatric deep brain stimulation in patients with childhood-onset dystonia (GEPESTIM).

BACKGROUND: Data on paediatric deep brain stimulation (DBS) is limited, especially for long-term outcomes, because of small numbers in single center series and lack of systematic multi-center trials. OBJECTIVES: We seek to systematically evaluate the clinical outcome of paediatric patients undergoing DBS. METHODS: A German registry on paediatric DBS (GEPESTIM) was created to collect data of patients with dystonia undergoing DBS up to the age of 18 years. Patients were divided into three groups according to etiology (group 1 inherited, group 2 acquired, and group 3 idiopathic dystonia). RESULTS: Data of 44 patients with a mean age of 12.8 years at time of operation provided by 6 German centers could be documented in the registry so far (group 1 n = 18, group 2 n = 16, group 3 n = 10). Average absolute improvement after implantation was 15.5 ± 18.0 for 27 patients with pre- and postoperative Burke-Fahn-Marsden Dystonia Rating scale movement scores available (p < 0.001) (group 1: 19.6 ± 19.7, n = 12; group 2: 7.0 ± 8.9, n = 8; group 3: 19.2 ± 20.7, n = 7). Infection was the main reason for hardware removal (n = 6). 20 IPG replacements due to battery expiry were necessary in 15 patients at 3.7 ± 1.8 years after last implantation. DISCUSSION: Pre- and postoperative data on paediatric DBS are very heterogeneous and incomplete but corroborate the positive effects of DBS on inherited and acquired dystonia. Adverse events including relatively frequent IPG replacements due to battery expiry seem to be a prominent feature of children with dystonia undergoing DBS. The registry enables collaborative research on DBS treatment in the paediatric population and to create standardized management algorithms in the future.

Cerebroretinal microangiopathy with calcifications and cysts (CRMCC).

Extensive intracranial calcifications and leukoencephalopathy are seen in both Coats plus and leukoencephalopathy with calcifications and cysts (LCC; Labrune syndrome). Coats plus syndrome is additionally characterized by the presence of bilateral retinal telangiectasia and exudates while LCC shows the progressive formation of parenchymal brain cysts. Despite these apparently distinguishing features, recent evidence suggests that Coats plus and LCC represent the same clinical entity with a common primary pathogenesis involving a small vessel obliterative microangiopathy. Here, we describe eight previously unreported cases, and present an update on one of the original Coats plus patients to highlight the emerging core clinical features of the "cerebroretinal microangiopathy with calcification and cysts" (CRMCC) phenotype.

Nemaline myopathy with exclusively intranuclear rods and a novel mutation in ACTA1 (Q139H).

Nemaline myopathies (NM) are a rare group of muscle disorders, but represent one of the most common forms of congenital myopathy. The clinical picture ranges from severe muscular hypotonia often leading to death during childhood to mild forms with long life expectancy. Diagnosis is made by muscle biopsy showing characteristic sarcoplasmic and sometimes intranuclear rod bodies. So far, disease-associated mutations have been detected in six genes without any simple correlation between genotype and phenotype or histological findings. We report a patient with a phenotype typical of congenital onset nemaline myopathy and exclusively intranuclear rods. Mutation analysis revealed a new heterozygous missense mutation in exon 3 of the ACTA1 gene (Q139H). Molecular modelling predicts that substitution of Q139 for H139 alters the amino acid side chains and hydrogen bonding which may alter the nucleotide binding cleft by adding 'bulk' to the mutated molecule. Two-dimensional gel electrophoresis demonstrates that mutant actin Q139H is expressed at approximately half the level of wild-type actin in the patient's muscle. We speculate that these alterations, although not directly affecting the nuclear export signal, negatively interfere with the nuclear export of the mutated protein and thereby cause retention of mutant actin and intranuclear rod formation.

[Acute complications of colorectal cancer]. / Akute Komplikation kolorektaler Karzinome.

Surgery was applied to 152 cases for colorectal carcinoma at the Surgical Department of Friedrichshain Hospital through a period of two years (1986/1987). Emergency laparotomy had to be performed on 31 patients (20 per cent) for acute complications, with colonic ileus being the most common problem. Primary lethality amounted to 25.8 per cent.