Prognostic utility and characteristics of MIB-1 labeling index as a proliferative activity marker in childhood low-grade glioma: a retrospective observational study.

PURPOSE: The prognostic utility of MIB-1 labeling index (LI) in pediatric low-grade glioma (PLGG) has not yet conclusively been described. We assess the correlation of MIB-1 LI and tumor growth velocity (TGV), aiming to contribute to the understanding of clinical implications and the predictive value of MIB-1 LI as an indicator of proliferative activity and progression-free survival (PFS) in PLGG. METHODS: MIB-1 LI of a cohort of 172 nonependymal PLGGs were comprehensively characterized. Correlation to TGV, assessed by sequential MRI-based three-dimensional volumetry, and PFS was analyzed. RESULTS: Mean MIB-1 LI accounted for 2.7% (range: < 1-10) and showed a significant decrease to 1.5% at secondary surgery (p = .0013). A significant difference of MIB-1 LI in different histopathological types and a correlation to tumor volume at diagnosis could be shown. Linear regression analysis showed a correlation between MIB-1 LI and preoperative TGV (R2 = .55, p < .0001), while correlation to TGV remarkably decreased after incomplete resection (R2 = .08, p = .013). Log-rank test showed no association of MIB-1 LI and 5-year PFS after incomplete (MIB-1 LI > 1 vs ≤ 1%: 48 vs 46%, p = .73) and gross-total resection (MIB-1 LI > 1 vs ≤ 1%: 89 vs 95%, p = .75). CONCLUSION: These data confirm a correlation of MIB-1 LI and radiologically detectable TGV in PLGG for the first time. Compared with preoperative TGV, a crucially decreasing correlation of MIB-1 LI and TGV after surgery may result in limited prognostic capability of MIB-1 LI in PLGG.

Role of high-volume plasmapheresis in the management of paediatric acute liver failure.

OBJECTIVES: Paediatric acute liver failure (PALF) is a life-threatening disease. Management aims to support hepatic regeneration or to bridge to liver transplantation. High-volume plasmapheresis (HVP) removes protein-bound substances, alleviates inflammation, and improves survival in adult acute liver failure. However, experience with HVP in PALF is limited. Aim of this study is to report on feasibility, safety, efficacy and outcomes of HVP in PALF. METHODS: Retrospective observational study in children with PALF. HVP was performed upon identification of negative prognostic indicators, in toxic aetiology or multiorgan failure (MOF). Exchanged volume with fresh-frozen plasma corresponded to 1.5-2.0 times the patient's estimated plasma volume. One daily cycle was performed until the patient met criteria for discontinuation, that is, liver regeneration, liver transplantation, or death. RESULTS: Twenty-two children with PALF (body weight 2.5-106 kg) received 1-7 HVP cycles. No bleeding or procedure-related mortality occurred. Alkalosis, hypothermia and reduction in platelets were observed. Haemolysis led to HVP termination in one infant. Seven children (32%) survived with their native livers, 13 patients (59%) underwent liver transplantation. Two infants died due to MOF. Overall survival was 86%. International normalization ratio (INR), alanine aminotransaminases (ALT), bilirubin and inotropic support were reduced significantly (p < 0.05) after the first HVP-cycle (median): INR 2.85 versus 1.5; ALT 1280 versus 434 U/L; bilirubin 12.7 versus 6.7 mg/dL; norepinephrine dosage 0.083 versus 0.009 µg/kg/min. Median soluble-interleukin-2-receptor dropped significantly following HVP (n = 7): 2407 versus 950 U/mL (p < 0.02). CONCLUSIONS: HVP in PALF is feasible, safe, improves markers of liver failure and inflammation and is associated with lowering inotropic support. Prospective and controlled studies are required to confirm efficacy of HVP in PALF.

Influence of sex and disease etiology on the development of papilledema and optic nerve sheath extension in the setting of intracranial pressure elevation in children.

Introduction: Dilatation of the optic nerve sheath diameter and swelling of the optic disc are known phenomena associated with intracranial pressure elevation. Research question: Do sex and disease etiology have an impact on the development of optic disc elevation and optic nerve sheath extension in children in the setting of ICP elevation? Fundoscopic papilledema and point-of-care-ultrasound techniques-optic nerve sheath diameter (US-ONSD) and optic disc elevation (US-ODE) - were compared in this regard. Material and methods: 72 children were included in this prospective study; 50 with proven pathology (e.g. pseudotumor cerebri, tumor), 22 with pathology excluded. Bilateral US-ONSD and US-ODE were quantified by US using a 12-MHz-linear-array-transducer. This was compared with fundoscopic optic disc findings and in 28 patients with invasive ICP values, stratified for sex and etiology. Results: In patients with proven disease, significant more girls (69%) had fundoscopic papilledema compared with boys (37%, p < 0.05). Girls had also larger US-ODE values (0.86 ± 0.36 mm vs. 0.65 ± 0.40 mm in boys). 80% of tumor patients had initial papilledema (100% girls, 79% boys), compared with 50% in pseudotumor cerebri (PTC) (83% girls, 30% boys). US-ONSD had no sex- and no etiology-specificity. Discussion and conclusion: Presence of papilledema appears to be influenced by sex and etiology, whereas US-ONSD is not. Girls seem more likely to develop papilledema under similar conditions. Male sex and PTC appear as risk factors for being undetected by fundoscopic findings. US-ONSD and US-ODE seem useful tools to identify pathologies with potentially increased ICP requiring treatment in children regardless of sex and etiology.

Ultrasound-guided initial diagnosis and follow-up of pediatric idiopathic intracranial hypertension.

BACKGROUND: Idiopathic intracranial hypertension in children often presents with non-specific symptoms found in conditions such as hydrocephalus. For definite diagnosis, invasive intracranial pressure measurement is usually required. Ultrasound (US) of the optic nerve sheath diameter provides a non-invasive method to assess intracranial pressure. Transtemporal US allows imaging of the third ventricle and thus assessment for hydrocephalus. OBJECTIVE: To investigate whether the combination of US optic nerve sheath and third ventricle diameter can be used as a screening tool in pediatric idiopathic intracranial hypertension to indicate elevated intracranial pressure and exclude hydrocephalus as an underlying pathology. Further, to analyze whether both parameters can be used to monitor treatment outcome. MATERIALS AND METHODS: We prospectively included 36 children with idiopathic intracranial hypertension and 32 controls. Using a 12-Mhz linear transducer and a 1-4-Mhz phased-array transducer, respectively, optic nerve sheath and third ventricle diameters were determined initially and during the course of treatment. RESULTS: In patients, the mean optic nerve sheath diameter was significantly larger (6.45±0.65 mm, controls: 4.96±0.32 mm) and the mean third ventricle diameter (1.69±0.65 mm, controls: 2.99±1.31 mm) was significantly smaller compared to the control group, P<0.001. Optimal cut-off values were 5.55 mm for the optic nerve sheath and 1.83 mm for the third ventricle diameter. CONCLUSIONS: The combined use of US optic nerve sheath and third ventricle diameter is an ideal non-invasive screening tool in pediatric idiopathic intracranial hypertension to indicate elevated intracranial pressure while ruling out hydrocephalus. Treatment can effectively be monitored by repeated US, which also reliably indicates relapse.

Transorbital point-of-care ultrasound versus fundoscopic papilledema to support treatment indication for potentially elevated intracranial pressure in children.

PURPOSE: To compare transorbital point-of-care ultrasound techniques -optic nerve sheath diameter (US-ONSD) and optic disc elevation (US-ODE)- with fundoscopic papilledema to detect potentially raised intracranial pressure (ICP) with treatment indication in children. METHODS: In a prospective study, 72 symptomatic children were included, 50 with later proven disease associated with raised ICP (e.g. pseudotumour cerebri, brain tumour, hydrocephalus) and 22 with pathology excluded. Bilateral US-ONSD and US-ODE were quantified by US using a 12-MHz-linear-array transducer. This was compared to fundoscopic optic disc findings (existence of papilledema) and, in 28 cases, invasively measured ICP values. RESULTS: The sensitivity and specificity of a cut-off value of US-ONSD (5.73 mm) to detect treatment indication for diseases associated with increased ICP was 92% and 86.4%, respectively, compared to US-ODE (0.43 mm) with sensitivity: 72%, specificity: 77.3%. Fundoscopic papilledema had a sensitivity of 46% and a specificity of 100% in this context. Repeatability and observer-reliability of US-ODE examination was eminent (Cronbach's α = 0.978-0.989). Papilledema was detected fundoscopically only when US-ODE was > 0.67 mm; a US-ODE > 0.43 mm had a positive predictive value of 90% for potentially increased ICP. CONCLUSION: In our cohort, transorbital point-of-care US-ONSD and US-ODE detected potentially elevated ICP requiring treatment in children more reliably than fundoscopy. US-ONSD and US-ODE indicated the decrease in ICP after treatment earlier and more reliably than fundoscopy. The established cut-off values for US-ONSD and US-ODE and a newly developed US-based grading of ODE can be used as an ideal first-line screening tool to detect or exclude conditions with potentially elevated ICP in children.

A further case of AFG2B-related neurodevelopmental disorder with hearing loss and microcephaly allows further clarification of pathogenicity of the variant c.1313T>C, p.(Leu438Pro).

BACKGROUND: Bi-allelic variants in AFG2B (previously known as SPATA5L1) have recently been associated with a neurodevelopmental disorder with hearing loss and spasticity, as well as isolated hearing loss. We report on a 6 1/2-year-old girl with a history of global developmental delay, subsequent intellectual disability without relevant language acquisition, sensorineural hearing loss, muscular hypotonia and microcephaly. METHODS: We performed trio exome sequencing on the patient and her parents. RESULTS: Trio exome sequencing revealed likely pathogenic compound heterozygous missense variants in AFG2B [c.527G>T, p.(Gly176Val) and c.1313T>C, p.(Leu438Pro)] in the patient. CONCLUSION: Of note, the change c.1313T>C, p.(Leu438Pro) has been observed in a previously published patient as part of a complex disease allele along with a second homozygous missense change, so the exact contribution of the two alterations to this patient's disease had initially remained unclear. Our results support the pathogenic relevance of the c.1313T>C, p.(Leu438Pro) allele while providing detailed insights into the disease manifestation of a further patient.

Cerebral venous sinus thrombosis and thrombocytopenia due to heparin-independent anti-PF4 antibodies after adenovirus infection.

Not available.

Long-Term Follow-Up of Pediatric Patients with Dyskinetic Cerebral Palsy and Deep Brain Stimulation.

BACKGROUND: Deep brain stimulation (DBS) has been increasingly used in the management of dyskinetic cerebral palsy (DCP). Data on long-term effects and the safety profile are rare. OBJECTIVES: We assessed the efficacy and safety of pallidal DBS in pediatric patients with DCP. METHODS: The STIM-CP trial was a prospective, single-arm, multicenter study in which patients from the parental trial agreed to be followed-up for up to 36 months. Assessments included motor and non-motor domains. RESULTS: Of the 16 patients included initially, 14 (mean inclusion age 14 years) were assessed. There was a significant change in the (blinded) ratings of the total Dyskinesia Impairment Scale at 36 months. Twelve serious adverse events (possibly) related to treatment were documented. CONCLUSION: DBS significantly improved dyskinesia, but other outcome parameters did not change significantly. Investigations of larger homogeneous cohorts are needed to further ascertain the impact of DBS and guide treatment decisions in DCP. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Genotype-phenotype correlations in RHOBTB2-associated neurodevelopmental disorders.

PURPOSE: Missense variants clustering in the BTB domain region of RHOBTB2 cause a developmental and epileptic encephalopathy with early-onset seizures and severe intellectual disability. METHODS: By international collaboration, we assembled individuals with pathogenic RHOBTB2 variants and a variable spectrum of neurodevelopmental disorders. By western blotting, we investigated the consequences of missense variants in vitro. RESULTS: In accordance with previous observations, de novo heterozygous missense variants in the BTB domain region led to a severe developmental and epileptic encephalopathy in 16 individuals. Now, we also identified de novo missense variants in the GTPase domain in 6 individuals with apparently more variable neurodevelopmental phenotypes with or without epilepsy. In contrast to variants in the BTB domain region, variants in the GTPase domain do not impair proteasomal degradation of RHOBTB2 in vitro, indicating different functional consequences. Furthermore, we observed biallelic splice-site and truncating variants in 9 families with variable neurodevelopmental phenotypes, indicating that complete loss of RHOBTB2 is pathogenic as well. CONCLUSION: By identifying genotype-phenotype correlations regarding location and consequences of de novo missense variants in RHOBTB2 and by identifying biallelic truncating variants, we further delineate and expand the molecular and clinical spectrum of RHOBTB2-related phenotypes, including both autosomal dominant and recessive neurodevelopmental disorders.

Genotype-phenotype correlation and treatment effects in young patients with GNAO1-associated disorders.

BACKGROUND: Patients carrying pathogenic variants in GNAO1 often present with early-onset central hypotonia and global developmental delay, with or without epilepsy. As the disorder progresses, a complex hypertonic and hyperkinetic movement disorder is a common phenotype. A genotype-phenotype correlation has not yet been described and there are no evidence-based therapeutic recommendations. METHODS: To improve understanding of the clinical course and pathophysiology of this ultra-rare disorder, we built up a registry for GNAO1 patients in Germany. In this retrospective, multicentre cohort study, we collected detailed clinical data, treatment effects and genetic data for 25 affected patients. RESULTS: The main clinical features were symptom onset within the first months of life, with central hypotonia or seizures. Within the first year of life, nearly all patients developed a movement disorder comprising dystonia (84%) and choreoathetosis (52%). Twelve (48%) patients suffered life-threatening hyperkinetic crises. Fifteen (60%) patients had epilepsy with poor treatment response. Two patients showed an atypical phenotype and seven novel pathogenic variants in GNAO1 were identified. Nine (38%) patients were treated with bilateral deep brain stimulation of the globus pallidus internus. Deep brain stimulation reduced hyperkinetic symptoms and prevented further hyperkinetic crises. The in silico prediction programmes did not predict the phenotype by the genotype. CONCLUSION: The broad clinical spectrum and genetic findings expand the phenotypical spectrum of GNAO1-associated disorder and therefore disprove the assumption that there are only two main phenotypes. No specific overall genotype-phenotype correlation was identified. We highlight deep brain stimulation as a useful treatment option in this disorder.

Chronic Pleural Effusion in Ventriculoperitoneal Shunt due to Diaphragmatic CSF Fistula: Report of a Case Treated by Endoscopic Choroid Plexus Coagulation and Literature Review.

INTRODUCTION: Chronic pleural cerebrospinal fluid (CSF) effusion is a rare complication after ventriculoperitoneal (VP) shunt insertion and only 18 cases in children and adults have been described so far without catheter dislocation to the intrathoracic cavity. CASE PRESENTATION: We report on a 4-year-old girl with a complex history of underlying neurogenetic disorder, a hypoxic-ischemic encephalopathy after influenza A infection with septic shock and severe acute respiratory distress syndrome, followed by meningitis at the age of 10 months. In consequence, she developed a severe cerebral atrophy and post-meningitic hydrocephalus requiring placement of a VP shunt. At age 4, she was admitted with community-acquired mycoplasma pneumonia and developed increasing pleural effusions leading to severe respiratory distress and requiring continuous chest tube drainage (up to 1,000-1,400 mL/day) that could not be weaned. ß trace protein, in CSF present at concentrations >6 mg/L, was found in the pleural fluid at low concentrations of 2.7 mg/L. An abdomino-thoracic CSF fistula was finally proven by single photon emission computerized tomography combined with low-dose computer tomography. After shunt externalization, the pleural effusion stopped and the chest tube was removed. CSF production rate remains high above 500 mL/24 h. An atrial CSF shunt could not be placed, since a hemodynamically relevant atrial septum defect with frail circulatory balance would not have tolerated the large CSF volumes. Therefore, she underwent a total bilateral endoscopic choroid plexus laser coagulation (CPC) within the lateral ventricles via bi-occipital burr holes. Postoperatively CSF production rate went close to 0 mL and after external ventricular drain removal no signs and symptoms of hydrocephalus developed during a follow-up of now 2.5 years. CONCLUSION: In summary, pleural effusions in patients with VP shunt can rarely be caused by an abdomino-thoracic fistula, with non-elevated ß-trace protein in the pleural fluid. The majority of reported cases in literature were treated by ventriculoatrial shunt. This is the 2nd reported case, which has been successfully treated by radical CPC alone including the temporal horn choroid plexus, making the child shunt independent.

Evaluating the safety of perioperative dexamethasone treatment: A retrospective analysis of a single center pediatric low-grade glioma cohort.

In addition to surgical management, corticosteroids have proven to be beneficial in the management of acute symptoms related to CNS tumors, and have been widely used for many decades, with dexamethasone (DM) representing the most commonly used agent. However, lately published in vitro data possibly indicates a DM-induced suppression of oncogene-induced senescence (OIS) in a preclinical pediatric low-grade glioma (pLGG) model, which, alongside data associating perioperative DM treatment with reduced event-free survival in adult glioma, raises questions concerning the safety of DM treatment in pLGG. A total of 172 patients with pLGG were retrospectively analyzed concerning the impact of perioperative DM application on postoperative short- and long-term tumor growth velocity and progression-free survival (PFS). Three-dimensional volumetric analyses of sequential MRI follow-up examinations were used for assessment of tumor growth behavior. Mean follow-up period accounted for 60.1 months. Sixty-five patients (45%) were perioperatively treated with DM in commonly used doses. Five-year PFS accounted for 93% following gross-total resection (GTR) and 57% post incomplete resection (IR). Comparison of short- and long-term postoperative tumor growth rates in patients with vs without perioperative DM application showed no significant difference (short-term: 0.022 vs 0.023 cm3 /month, respectively; long-term: 0.019 vs 0.023 cm3 /month, respectively). Comparison of PFS post IR (5-year-PFS: 65% vs 55%, respectively; 10-year-PFS: 52% vs 53%, respectively) and GTR (5- and 10-years-PFS: 91% vs 92%, respectively) likewise showed similarity. This data emphasizes the safety of perioperative DM application in pLGG, adding further evidence for decision making and requested future guidelines.

Botulinum neurotoxin type A in the interdisciplinary treatment of sialorrhea in adults and children-update and practice recommendations.

Sialorrhea is defined as a chronic excessive flow of saliva from the mouth, often with adverse consequences for health and quality of life of patients. In addition to currently used non-drug treatment and systemic drugs, intraglandular Botulinum Neurotoxin A (BoNT/A) injections have been examined in case studies, controlled trials and clinical practice. Two pivotal Phase III trials recently led to market approval in the USA and EU for IncobotulinumtoxinA [Xeomin®, IncoBoNT/A, Clostridium botulinum neurotoxin type A (150 kD), free from complexing proteins, Merz Pharmaceuticals GmbH] for treatment of chronic sialorrhea in adults and pediatric patients. This review provides a multidisciplinary approach to discuss the current state of sialorrhea therapy as well as benefits and current limitations of BoNT/A injections. A consensus regarding treatment recommendations made available to physicians in Germany in 2022 has now been updated here for presentation to an international audience. This review provides a framework including a flow chart for patient selection, recommendations for dosing and the injection process, as well as a discussion of therapeutic goals, long-term benefits and safety aspects. This review is aimed at supporting physicians in developing multidisciplinary and individualized treatment approaches to achieve optimal benefits for patients.

Non-Invasive Quantitative Approximation of Intracranial Pressure in Pediatric Idiopathic Intracranial Hypertension Based on Point-of-Care Ultrasound of the Optic Nerve Sheath Diameter.

BACKGROUND: To investigate whether ultrasound-based optic nerve sheath diameter (US-ONSD) is a reliable measure to follow up children with idiopathic intracranial hypertension (IIH). In addition, to analyze the inter- and intra-individual relationships between US-ONSD and intracranial pressure (ICP), and to investigate whether an individualized mathematical regression equation obtained from two paired US-ONSD/ICP values can be used to approximate ICP from US-ONSD values. METHODS: 159 US examinations and 53 invasive ICP measures via lumbar puncture (LP) were performed in 28 children with IIH. US-ONSD was measured using a 12 Mhz linear transducer and compared to ICP values. In 15 children, a minimum of 2 paired US-ONSD/ICP determinations were performed, and repeated-measures correlation (rmcorr) and intra-individual correlations were analyzed. RESULTS: The cohort correlation between US-ONSD and ICP was moderate (r = 0.504, p < 0.01). Rmcorr (r = 0.91, p < 0.01) and intra-individual correlations (r = 0.956-1) of US-ONSD and ICP were excellent. A mathematical regression equation can be calculated from two paired US-ONSD/ICP values and applied to the individual patient to approximate ICP from US-ONSD. CONCLUSIONS: Related to excellent intra-individual correlations between US-ONSD and ICP, an individualized regression formula, created from two pairs of US-ONSD/ICP values, may be used to directly approximate ICP based on US-ONSD values. Hence, US-ONSD may become a non-invasive and reliable measure to control treatment efficacy in pediatric IIH.

Resection extent and BRAF V600E mutation status determine postoperative tumor growth velocity in pediatric low-grade glioma: results from a single-center cohort analysis.

PURPOSE: Despite excellent long-term overall survival rates, pediatric low-grade gliomas (pLGG) show high variety of clinical behavior regarding progress or senescence post incomplete resection (IR). This study retrospectively analyzes tumor growth velocity (TGV) of pLGG before surgery and after IR to investigate the impact of surgical extent, tumor location and molecular BRAF status on postoperative residual tumor growth behavior. METHODS: Of a total of 172 patients with pLGG receiving surgical treatment, 107 underwent IR (66%). Fifty-three vs 94 patients could be included in the pre- and post-operative cohort, respectively, and were observed over a mean follow-up time of 40.2 vs 60.1 months. Sequential three-dimensional MRI-based tumor volumetry of a total of 407 MRI scans was performed to calculate pre- and postoperative TGV. RESULTS: Mean preoperative TGV of 0.264 cm3/month showed significant deceleration of tumor growth to 0.085 cm3/month, 0.024 cm3/month and -0.016 cm3/month after 1st, 2nd, and 3rd IR, respectively (p < 0.001). Results remained significant after excluding patients undergoing (neo)adjuvant treatment. Resection extent showed correlation with postoperative reduction of TGV (R = 0.97, p < 0.001). ROC analysis identified a residual cut-off tumor volume > 2.03 cm3 associated with a higher risk of progress post IR (sensitivity 78,6%, specificity 76.3%, AUC 0.88). Postoperative TGV of BRAF V600E-mutant LGG was significantly higher than of BRAF wild-type LGG (0.123 cm3/month vs. 0.016 cm3/month, p = 0.047). CONCLUSION: This data suggests that extensive surgical resection may impact pediatric LGG growth kinetics post incomplete resection by inducing a significant deceleration of tumor growth. BRAF-V600E mutation may be a risk factor for higher postoperative TGV.

[Treatment of Sialorrhea with Botulinum Neurotoxin Type A - Consensus Practice Recommendations for Children and Adults]. / Behandlung der Sialorrhoe mit Botulinum Neurotoxin Typ A ­ Konsentierte Praxisempfehlungen für Kinder und Erwachsene.

Sialorrhea, uncontrolled, excessive drooling, accompanies different, mostly neurological disorders from childhood to adulthood. With incobotulinumtoxinA (Xeomin, IncoBoNT/A, Merz Pharmaceuticals GmbH), an approved medication for the treatment of sialorrhea has been available since 2019. Patient selection, possible therapy goals, treatment and the management of specific treatment situations build the focus of this interdisciplinary expert consensus recommendations with the intent to facilitate access to treatment and to contribute to qualified botulinum toxin therapy.

Hematopoietic Stem Cell Transplantation with Mesenchymal Stromal Cells in Children with Metachromatic Leukodystrophy.

Metachromatic leukodystrophy (MLD) is a lysosomal storage disorder primarily affecting the white matter of the nervous system that results from a deficiency of the arylsulfatase A (ARSA). Mesenchymal stem cells (MSCs) are able to secrete ARSA and have shown beneficial effects in MLD patients. In this retrospective analysis, 10 pediatric MLD patients [mesenchymal stem cell group (MSCG)] underwent allogeneic hematopoietic stem cell transplantation (HSCT) and received two applications of 2 × 106 MSCs/kg bodyweight at day +30 and +60 after HSCT between 2007 and 2018. MSC safety, occurrence of graft-versus-host disease (GvHD), blood ARSA levels, chimerism, cell regeneration and engraftment, magnetic resonance imaging (MRI) changes, and the gross motor function were assessed within the first year of HSCT. The long-term data included clinical outcomes and safety aspects of MSCs. Data were compared to a control cohort of seven pediatric MLD patients [control group (CG)] who underwent HSCT only. The application of MSC in pediatric MLD patients after allogeneic HSCT was safe and well tolerated, and long-term potentially MSC-related adverse effects up to 13.5 years after HSCT were not observed. Patients achieved significantly higher ARSA levels (CG: median 1.03 nmol·10-6 and range 0.41-1.73 | MSCG: median 1.58 nmol·10-6 and range 0.44-2.6; P < 0.05), as well as significantly higher leukocyte (P < 0.05) and thrombocyte (P < 0.001) levels within 365 days of MSC application compared to CG patients. Statistically significant effects on acute GvHD, regeneration of immune cells, MRI changes, gross motor function, and clinical outcomes were not detected. In conclusion, the application of MSCs in pediatric MLD patients after allogeneic HSCT was safe and well tolerated. The two applications of 2 × 106/kg allogeneic MSCs were followed by improved engraftment and hematopoiesis within the first year after HSCT. Larger, prospective trials are necessary to evaluate the impact of MSC application on engraftment and hematopoietic recovery.

Quality of Life After Deep Brain Stimulation of Pediatric Patients with Dyskinetic Cerebral Palsy: A Prospective, Single-Arm, Multicenter Study with a Subsequent Randomized Double-Blind Crossover (STIM-CP).

BACKGROUND: Patients with dyskinetic cerebral palsy are often severely impaired with limited treatment options. The effects of deep brain stimulation (DBS) are less pronounced than those in inherited dystonia but can be associated with favorable quality of life outcomes even in patients without changes in dystonia severity. OBJECTIVE: The aim is to assess DBS effects in pediatric patients with pharmacorefractory dyskinetic cerebral palsy with focus on quality of life. METHODS: The method used is a prospective, single-arm, multicenter study. The primary endpoint is improvement in quality of life (CPCHILD [Caregiver Priorities & Child Health Index of Life with Disabilities]) from baseline to 12 months under therapeutic stimulation. The main key secondary outcomes are changes in Burke-Fahn-Marsden Dystonia Rating Scale, Dyskinesia Impairment Scale, Gross Motor Function Measure-66, Canadian Occupational Performance Measure (COPM), and Short-Form (SF)-36. After 12 months, patients were randomly assigned to a blinded crossover to receive active or sham stimulation for 24 hours each. Severity of dystonia and chorea were blindly rated. Safety was assessed throughout. The trial was registered at ClinicalTrials.gov, number NCT02097693. RESULTS: Sixteen patients (age: 13.4 ± 2.9 years) were recruited by seven clinical sites. Primary outcome at 12-month follow-up is as follows: mean CPCHILD increased by 4.2 ± 10.4 points (95% CI [confidence interval] -1.3 to 9.7; P = 0.125); among secondary outcomes: improvement in COPM performance measure of 1.1 ± 1.5 points (95% CI 0.2 to 1.9; P = 0.02) and in the SF-36 physical health component by 5.1 ± 6.2 points (95% CI 0.7 to 9.6; P = 0.028). Otherwise, there are no significant changes. CONCLUSION: Evidence to recommend DBS as routine treatment to improve quality of life in pediatric patients with dyskinetic cerebral palsy is not yet sufficient. Extended follow-up in larger cohorts will determine the impact of DBS further to guide treatment decisions in these often severely disabled patients. © 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.