Appendicular lean mass index and motor function in ambulatory patients with Duchenne muscular dystrophy.

INTRODUCTION/AIMS: Appendicular lean mass index (ALMI) has been linked to motor function in patients with Duchenne muscular dystrophy (DMD). However, quantification of the relationship between ALMI and disease-specific clinical outcome assessment trajectories is needed. The purpose of this study was to determine associations between dual-energy x-ray absorptiometry (DXA) derived estimates of ALMI and motor function in ambulatory patients with DMD. METHODS: A retrospective analysis of longitudinal clinical visit data from 137 glucocorticoid-treated patients with DMD collected via structured motor assessment protocol evaluated associations between ALMI and motor function indexed by the North Star Ambulatory Assessment (NSAA) and 10 Meter Walk/run Test (10MWT). Body composition was assessed using DXA. ALMI was calculated by dividing arm and leg lean mass by height in m2; fat mass index (FMI) was calculated by dividing whole body fat mass by height in m2. Linear mixed-effects models were used to estimate associations between ALMI and motor function, controlling for age and FMI. RESULTS: The full prediction model (age, age,2 ALMI, and FMI) explained 57% of the variance in NSAA scores and 63% of the variance in 10MWT speed. A 1 kg/m2 higher ALMI value predicted a 5.4-point higher NSAA score (p < .001) and 0.45 m/s faster 10MWT speed (p < .001). A 1 kg/m2 higher FMI value predicted a 1.5-point lower NSAA score (p < .001) and 0.14 meters/second slower 10MWT speed (p < .001). DISCUSSION: DXA-derived estimates of ALMI and FMI are associated with motor function in DMD and may explain variation in DMD disease progression.

Risks and Impact of Angiotensin-Converting Enzyme Inhibitors or Angiotensin-Receptor Blockers on SARS-CoV-2 Infection in Adults: A Living Systematic Review.

BACKGROUND: The role of angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin-receptor blockers (ARBs) in coronavirus disease 2019 (COVID-19) susceptibility, severity, and treatment is unclear. PURPOSE: To evaluate, on an ongoing basis, whether use of ACEIs or ARBs either increases risk for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection or is associated with worse COVID-19 disease outcomes, and to assess the efficacy of these medications for COVID-19 treatment. DATA SOURCES: MEDLINE (Ovid) and Cochrane Database of Systematic Reviews from 2003 to 4 May 2020, with planned ongoing surveillance for 1 year; the World Health Organization database of COVID-19 publications and medRxiv.org through 17 April 2020; and ClinicalTrials.gov to 24 April 2020, with planned ongoing surveillance. STUDY SELECTION: Observational studies and trials in adults that examined associations and effects of ACEIs or ARBs on risk for SARS-CoV-2 infection and COVID-19 disease severity and mortality. DATA EXTRACTION: Single-reviewer abstraction confirmed by another reviewer, independent evaluation by 2 reviewers of study quality, and collective assessment of certainty of evidence. DATA SYNTHESIS: Two retrospective cohort studies found that ACEI and ARB use was not associated with a higher likelihood of receiving a positive SARS-CoV-2 test result, and 1 case-control study found no association with COVID-19 illness in a large community (moderate-certainty evidence). Fourteen observational studies, involving a total of 23 565 adults with COVID-19, showed consistent evidence that neither medication was associated with more severe COVID-19 illness (high-certainty evidence). Four registered randomized trials plan to evaluate ACEIs and ARBs for treatment of COVID-19. LIMITATION: Half the studies were small and did not adjust for important confounding variables. CONCLUSION: High-certainty evidence suggests that ACEI or ARB use is not associated with more severe COVID-19 disease, and moderate-certainty evidence suggests no association between use of these medications and positive SARS-CoV-2 test results among symptomatic patients. Whether these medications increase the risk for mild or asymptomatic disease or are beneficial in COVID-19 treatment remains uncertain. PRIMARY FUNDING SOURCE: None. (PROSPERO: registration number pending).

Progression of Ankle Plantarflexion Contractures and Functional Decline in Duchenne Muscular Dystrophy: Implications for Physical Therapy Management.

PURPOSE: This study characterizes the progressive loss of ankle dorsiflexion range of motion in boys with Duchenne muscular dystrophy (DMD), the relationship to functional decline, and the implications for physical therapy management. METHODS: Longitudinal data for 332 boys with DMD were extracted from medical records and analyzed. Summary statistics for age, number of visits, ankle dorsiflexion measures, and North Star Ambulatory Assessment (NSAA) scores were computed. RESULTS: Ankle dorsiflexion motion ranged from -32.5 to 25 degrees. Progression of ankle contractures is demonstrated by a trend line: slope -1.43 per year. NSAA score was estimated to decline approximately 0.23 points per 1 degree of ankle dorsiflexion lost. CONCLUSIONS: The results of this study describe the progression of ankle contractures and functional decline in DMD. The findings may help inform decisions regarding interventions to support participants with DMD and their families.

Development of an Infantile GM2 Clinical Rating Scale: Remote Assessment of Clinically Meaningful Health-Related Function.

GM2 gangliosidoses (GM2) are a group of rare lysosomal storage disorders in which accumulation of GM2 gangliosides results in progressive central nervous system damage. The infantile GM2 phenotype is characterized by delays in milestones by 6 months of age, followed by rapid loss of motor, cognitive, and visual function. Advancements in early diagnosis and pharmacotherapies provide promise for improved outcomes. However, the lack of feasible and clinically meaningful clinical outcome assessments for GM2 poses a challenge to characterizing GM2 natural history and selecting clinical trial endpoints. The purpose of this study was to develop a remotely administered infantile GM2 rating scale to measure health-related function in children with infantile GM2. A 2-phase mixed methods design was employed. In phase 1 of the study, 8 families of children with Infantile GM2 completed a natural history survey and a 1:1 semistructured interview to provide caregiver perspectives on the impacts of GM2 on health-related function. In phase 2 of the study, 8 expert clinicians provided feedback via surveys and participated in videoconference-hosted focus groups to refine scale administration and scoring procedures. These methods guided the development of 16 scale items to assess function in 5 health-related function domains: vision, hand and arm use, communication, gross motor, and feeding. This study used caregiver perspectives and expert clinician feedback to develop a remotely administered clinical outcome assessment of clinically meaningful health-related function in children with infantile GM2. Future studies will further evaluate the feasibility, reliability, and validity of the Infantile GM2 Clinical Rating Scale.

Safety and efficacy of gravitational shunt valves in patients with idiopathic normal pressure hydrocephalus: a pragmatic, randomised, open label, multicentre trial (SVASONA).

OBJECTIVES: To investigate whether gravitational valves reduce the risk of overdrainage complications compared with programmable valves in ventriculoperitoneal (VP) shunt surgery for idiopathic normal pressure hydrocephalus (iNPH). BACKGROUND: Patients with iNPH may benefit from VP shunting but are prone to overdrainage complications during posture changes. Gravitational valves with tantalum balls are considered to reduce the risk of overdrainage but their clinical effectiveness is unclear. METHODS: We conducted a pragmatic, randomised, multicentre trial comparing gravitational with non-gravitational programmable valves in patients with iNPH eligible for VP shunting. The primary endpoint was any clinical or radiological sign (headache, nausea, vomiting, subdural effusion or slit ventricle) of overdrainage 6 months after randomisation. We also assessed disease specific instruments (Black and Kiefer Scale) and Physical and Mental Component Scores of the Short Form 12 (SF-12) generic health questionnaire. RESULTS: We enrolled 145 patients (mean (SD) age 71.9 (6.9) years), 137 of whom were available for endpoint analysis. After 6 months, 29 patients in the standard and five patients in the gravitational shunt group developed overdrainage (risk difference -36%, 95% CI -49% to -23%; p<0.001). This difference exceeded predetermined stopping rules and resulted in premature discontinuation of patient recruitment. Disease specific outcome scales did not differ between the groups although there was a significant advantage of the gravitational device in the SF-12 Mental Component Scores at the 6 and 12 month visits. CONCLUSIONS: Implanting a gravitational rather than another type of valve will avoid one additional overdrainage complication in about every third patient undergoing VP shunting for iNPH.

Association of Chiari malformation and vitamin B12 deficit in a family.

PURPOSE: A clear etiology of Chiari malformation is still lacking. Some associations between this disorder and genetical variations have been reported. Documented cases of familial Chiari malformation in three consecutive generations are rare. Furthermore, an association of Chiari disorder and vitamin B12 deficit has rarely been described in literature. METHODS: In this study, three generations of a family suffering from Chiari 1 or Chiari 0 malformation have been examined with MRI, clinically and laboratory (hemograms). RESULTS: Chiari malformation could be confirmed in all presented patients: While the F2 generation (children: 1 × â™€, 1 × â™‚) and the female F1 generation (mother and sister of mother) suffered from Chiari type 1, the male F0 generation showed Chiari 0 malformation. F0 and F1 generation further presented with syringomyelia (F0: C4-D1; F1: C4-D2). All patients except the grandfather (F0) underwent surgical posterior fossa decompression to relive successfully cerebellar and hydrocephalus associated progressing clinical symptoms. The hemograms of generation 1 and 2 revealed familial vitamin B12 deficit. CONCLUSIONS: A hereditary component is discussed in Chiari malformation, yet proved etiology is still lacking. As folic acid plays an important role in the development of the neural tube, vitamin B12 deficit might have some impact on the development of Chiari malformations.

The frontal and temporal horn ratio to assess dimension of paediatric hydrocephalus: a comparative volumetric study.

Magnetic resonance imaging and cranial -ultrasound are the most frequently implemented imaging methods for investigating the infantile hydrocephalic brain. A general and reliable measurement index that can be equally applied in both imaging methods to assess dimension of ventricular dilatation is currently not available. For this purpose, a new parameter called the frontal and temporal horn ratio - determinable in coronal slices of the brain - was developed and evaluated in a comparative volumetric retrospective study: Statistical analyses of 118 MRIs of 46 different shunt-treated pediatric patients revealed a good linear correlation between the new index and the actual ventricular volume.

Automated intracranial pressure-controlled cerebrospinal fluid external drainage with LiquoGuard.

INTRODUCTION: LiquoGuard is a new device for intracranial pressure (ICP)-controlled drainage of cerebrospinal fluid (CSF). This present study evaluates the accuracy of ICP measurement via the LiquoGuard device in comparison with Spiegelberg. Thus, we compared data ascertained from simultaneous measurement of ICP using tip-transducer and tip-sensor devices. MATERIAL AND METHODS: A total of 1,764 monitoring hours in 15 patients (range, 52-219 h) were analysed. All patients received an intraventricular Spiegelberg III probe with the drainage catheter connected to the LiquoGuard system. ICP reading of both devices was performed on an hourly basis. Statistical analysis was done by applying Pearson correlation and Wilcoxon-matched pair test (p < 0.05). RESULTS: Mean ICP values were 11 ± 5 mmHg (Spiegelberg) and 10 ± 7 mmHg (LiquoGuard); the values measured with both devices correlated well (p = 0.001; Pearson correlation =0.349; n = 1,764). In two of the 15 patients with slit ventricles, episodes of significant differences in measured values could be observed. Both patients suffering from slit ventricles failed to produce reliable measurement with the external transducer of the LiquoGuard. CONCLUSIONS: LiquoGuard is a valuable new device for ICP-controlled CSF drainage. However, LiquoGuard tends to provide misleading results in slit ventricles. Thus, before these drawbacks are further analysed, the authors recommend additional ICP measurement with internal tip-sensor devices to avoid dangerous erroneous interpretation of ICP data.

Analytical Validation of a Novel MicroRNA Panel for Risk Stratification of Cognitive Impairment.

We have been developing a novel approach to identify cognitive impairment-related biomarkers by profiling brain-enriched and inflammation-associated microRNA (miRNA) in plasma specimens of cognitively unimpaired and cognitively impaired patients. Here, we present an analytical validation of the novel miRNA panel, CogniMIR®, using two competing quantitative PCR technologies for the expression analysis of 24 target miRNAs. Total RNA from the plasma specimens was isolated using the MagMAX mirVana Kit, and RT-qPCR was performed using stem-loop-based TaqMan and LNA-based qPCR assays. Evaluation of RNA dilution series for our target 24 miRNAs, performed by two operators on two different days, demonstrated that all CogniMIR® panel miRNAs can be reliably and consistently detected by both qPCR technologies, with sample input as low as 20 copies in a qPCR reaction. Intra-run and inter-run repeatability and reproducibility analyses using RNA specimens demonstrated that both operators generated repeatable and consistent Cts, with R2 values of 0.94 to 0.99 and 0.96 to 0.97, respectively. The study results clearly indicate the suitability of miRNA profiling of plasma specimens using either of the qPCR technologies. However, the LNA-based qPCR technology appears to be more operationally friendly and better suited for a CAP/CLIA-certified clinical laboratory.

Intraventricular cooling during CSF infusion studies.

We implemented ventricular infusion studies on 33 patients suspected of idiopathic normal pressure hydrocephalus (iNPH), benign intracranial hypertension (BIH) or occlusive hydrocephalus (HOC) in order to confirm shunt indications. The initial scope was to study O(2) supply during infusion tests to exclude further violation of already vulnerable brains during ICP elevation. Intraventricular infusion was performed via ventricle catheters with the ICP tip sensor, while brain tissue oxygenation was measured with intraparenchymal Raumedic PTO probes. In 15 out of 23 (65%; 8 NPH, 2BIH, 5 HOC), pO(2) increased constantly (average 140%), while brain temperature decreased (range: 0.2-4.5°C) during the infusion studies. In another six patients, O(2) values remained largely stable during the infusion studies (4NPH, 1BIH, 1HOC). Cerebral deoxygenation during infusion tests occurred only in two patients (1NPH, 1HOC).Overall cerebral oxygenation and temperature inversely correlated well with some temporary delay regarding oxygenation state as a consequence of cerebral temperature. Probably, this effect is a consequence of reduced cerebral metabolism caused by local cooling. We hypothesise that such cooling is mediated via the large basal arteries and suggest that such a pathophysiology, ICP-controlled local cooling, might offer a new option for brain protection (e.g. in an ICP crisis).

Subdural or intraparenchymal placement of long-term telemetric intracranial pressure measurement devices?

We established a CE-certified telemetric device to measure intracranial pressure (ICP) noninvasively. To evaluate whether subdural or intraparenchymal insertion of such devices should be preferred, we implanted these telemetric ICP measurement devices (Raumedic, Rautel) in both locations. The study was performed in nine minipigs. The telemetric data were validated every 3 months using conventional intraparenchymal ICP measurement probes.The intraparenchymal telemetric device failed in one animal 12 months after insertion. Computed tomography (CT) revealed first hints for failure: Despite the implantation in adult animals, the skull dimensions seemingly increased after implantation, and the sensor tip was dislocated on the tabula interna level. This finding could also be verified by histopathological examination which would explain the reason for mismeasurement. The subdural catheter failed after 9 months. CT and histopathological examination revealed a bony encapsulation of a large catheter part, which had been located correctly initially. We propose that chronic pulsatile stress on the device was the underlying reason for this phenomenon, comparable to that in meningeal arteries.In some of the other animals, failure of subdural catheters could be detected. Histopathological examinations in these cases are still pending. Nevertheless, we assume similar underlying reasons for failure in these subdural probes.In conclusion, we favour intraparenchymal placement of telemetric ICP measurement devices.

Pathophysiology of brainstem lesions due to overdrainage.

Overdrainage in hydrocephalus therapy is a common shunt complication responsible for many different side effects. Especially an association with an impairment of upper brainstem structures causing symptoms of a dorsal midbrain syndrome (DMS) has already been described. Yet apart from these known mesencephalic lesions, we found several more brainstem signs and symptoms resulting from overdrainage. Parinaud's syndrome was diagnosed in all six patients examined; moreover, parkinsonism, memory disturbances, fluctuations in the level of consciousness, and hypothalamic dysfunctions could be detected in five of six patients. In addition hypersalivation combined with peripheral facial nerve palsy and blepharospasm occurred in two patients each, respectively. We postulate an upward herniation of the midbrain into the tentorial notch causing a secondary aqueductal stenosis as causal. An obstructed Sylvian aqueduct and the occurrence of shunt failure can lead to a bulging or enlargement of the third ventricle resulting in diencephalic lesions. If combined with fourth ventricle outlet occlusion, secondary aqueductal stenosis aggravates the situation with a fourth ventricle entrapment. Symptomatology and proposed pathophysiology are presented.

Dynamics of cerebrospinal fluid flow in slit ventricle syndrome.

INTRODUCTION: Although slit ventricle syndrome (SVS) is identified as a serious complication in shunt-treated hydrocephalus, cerebral spinal fluid (CSF) flow via external ventricular drainage (EVD) or shunts in SVS have not been studied up to now. MATERIAL AND METHODS: A new apparatus (LiquoGuard(®); Möller-Medical, Fulda, Germany) was used for EVD in a child with SVS. The LiquoGuard actively controls CSF drainage, based on intracranial pressure (ICP). RESULTS: To achieve well-tolerated clinical conditions, an ICP level of 4 mmHg was necessary; realizable by drainage rates between 0 and 35 mL/h. Drainage rate variations typically occurred with repetitive time intervals of 2 h causing a "saw tooth" shaped CSF flow pattern throughout 24 h. DISCUSSION: SVS seems to be characterized largely by quickly varying CSF drainage demands. Whether this is a general phenomenon or just true for this case has still to be studied and needs further clarification.

Intracranial pressure telemetry: first experience of an experimental in vivo study using a new device.

OBJECTIVE: To test two new telemetric intracranial pressure (ICP) probes (NEUROVENT(®)-P-tel, NEUROVENT(®)-S-tel) in a porcine model. We aimed to intraoperatively correlate the telemetric probes to parenchymal ICP probes and study their reliability in the first hours after implantation. The experimental set-up, new telemetric technology and first data will be presented. METHODS: We implanted a right parietal (parenchymal) and left parietal (subdural) telemetric ICP probe in 13 Göttingen mini-pigs under general anaesthesia. Through the left parietal burr hole a parenchymal ICP probe (Neurovent(®) ICP) was introduced. Intraoperatively, the head position was changed to provoke ICP changes every 10 min. The telemetric probes were left in situ and finally the parenchymal ICP probe was removed. We correlated mean differences between each telemetric probe and the conventional ICP measurement and Bland-Altman plots were generated for statistical analysis. RESULTS: We present first data containing intraoperative measurements of 26 telemetric probes after implantation. Intraoperatively, mean differences of 2.48 ± 1.52 mmHg SD (NEUROVENT(®)-P-tel) and 2.64 ± 1.79 mmHg (NEUROVENT(®)-S-tel) were observed. The Bland-Altman plot demonstrates good correlation of the telemetric probes compared with parenchymal ICP probes. CONCLUSION: We present a new telemetric technology that was experimentally compared with a parenchymal ICP probe. We provide data that the new telemetric probes will comparably measure ICP vs an external ICP probe. This stand-alone ICP tool may allow permanent measurement of ICP in hydrocephalus patients. Further continuation of our study will demonstrate whether this system guarantees acceptable long-term reliability.

Telemetric ICP measurement with the first CE-approved device: data from animal experiments and initial clinical experiences.

The objective was to evaluate the qualification of the new telemetric intracranial pressure (ICP) measurement (t-ICP) device Raumedic(®) NEUROVENT P-Tel and S-Tel. The proof of concept was examined in a pilot animal study measuring intraperitoneal pressure with a telemetric and a conventional ICP measurement probe at five rates for 1 h each. Moderate external pressure load allowed measuring values between 0 and 40 mmHg. To estimate long-term performance 18 t-ICP devices were implanted subdurally or intraparenchymally into minipigs. Reference measurements were performed regularly using conventional ICP probes. From the short-term as well as from the long-term perspective t-ICP proved to have excellent dynamic ICP signal components perception (e.g. pulse amplitude). Some zero drift of static ICP was found, ranging between 5 and 8 mmHg. While all telemetric, intraparenchymal probes kept their functionality throughout the follow-up, 33% of the subdurals failed for reasons detailed in another paper. Raumedic's NEUROVENT(®) P-Tel/S-Tel proved to provide reliable data over periods of up to 18 months. Minor zero drift can be well tolerated as the dynamic ICP signal is measured with excellent stability. Clinicians should focus more on such ICP dynamic signal information than on static ICP when using the device over longer follow-up periods.

Frontal and temporal horn ratio: a valid and reliable index to determine ventricular size in paediatric hydrocephalus patients?

Because there is currently no sufficient and prevalent parameter for estimating ventricular size in paediatric hydrocephalus patients by using cranial ultrasound, a new measurement index, called the "frontal and temporal horn ratio", is presented in this study. The advantage of the new quotient is that it can be detected in easily obtainable coronal ultrasound planes. A retrospective analysis of 149 MRIs of young hydrocephalus patients proved the new index to be a promising parameter of ventricular size assessment. Statistical comparison between the "frontal and temporal horn ratio" and the already validated "frontal and occipital horn ratio" revealed a strong and linear correlation between the two quotients. Current research is now evaluating the reliability of the new index in the context of an ultrasound study; first results indicate similar positive findings.

Microstructural alterations of silicone catheters in an animal experiment: histopathology and SEM findings.

INTRODUCTION: Biocompatibility of implants in humans has been classified as "inert," "tolerated," and "bioactive." In shunt-treated patients, catheter-induced complications account for up to 70% of all hardware failures. Our objective was to study whether foreign body reactions to silicone shunt catheters in subcutaneous tissue and at their distal, intraperitoneal ends leading to occlusion can be reproduced in an animal model. MATERIALS AND METHODS: Twelve different silicone catheters were implanted in 6-week-old Wistar rats: (a) purely in the subcutaneous tissue and (b) through the subcutaneous tissue into the peritoneal cavity. One of the catheters was of our own design with a silicated surface. After 1 year, all catheters were explanted and were examined by histopathology and scanning electron microscopy (SEM). RESULTS: Histopathological analysis revealed the development of collagenous membranes and chronic immune reactions around the catheters. Completely organized intraluminal obliteration was seen in six intraperitoneally inserted catheters. SEM demonstrated calcifications and signs of biodegradation. Silicated catheters showed the most extensive calcifications. DISCUSSION: Hydrocephalus shunt catheters cannot be termed "inert" or "biotolerated." Rather, they must be regarded as "bio-active" implants. The extensive reaction on silicated catheters can act as reference to estimate the biocompatibility of surface modifications. The model proved appropriate for further studies.

On the method of a randomised comparison of programmable valves with and without gravitational units: the SVASONA study.

OBJECTIVE: The supremacy of low-pressure valves (LPV) in the therapy of patients with idiopathic normal pressure hydrocephalus (iNPH) has been proven by the Dutch NPH study. The downside of LPVs is the high rate of overdrainage complications. In the meantime gravitational units have been developed with the objective of minimising overdrainage complications. Do these gravitational units allow the same favourable outcomes as in the Dutch NPH study without overdrainage complications? The goal of this prospective randomised controlled multicentre trial is to compare the rate of overdrainage complications after shunt surgery with programmable valves with or without a gravitational unit. METHOD: Patients suspected with iNPH with gait ataxia and one or two other symptoms of Hakim's triad and enlarged ventricles on CT or MRI underwent a cerebrospinal fluid (CSF) infusion test, CSF tap test and/or continuous ICP measurement in seven experienced centres. If iNPH was diagnosed the patients were randomised to receive a ventriculoperitoneal shunt with a programmable valve with or without a gravitational unit. The patients were followed up for 3, 6 and 12 months after surgery. The primary hypothesis of the study was that programmable valves with gravitational units will reduce the rate of overdrainage from 25% to 10%. The outcome measured by iNPH-specific outcome scales (Kiefer score, Black grading scale) and the generic quality of life (short form 12, SF12) was defined as the secondary endpoint. To detect the hypothesised difference in the incidence of overdrainage with a type I error of 5% and a type II error of 20%, correcting for multiple testing and an anticipated drop-out rate of 10%, we planned to enrol 250 patients. To ensure safety and efficacy we performed a planned interim analysis halfway. RESULTS: The study design has been found to be effective with regard to the primary hypothesis. CONCLUSION: The design of the SVASONA study was developed to be able to confirm the primary hypothesis. Thus, the method of the study should solve the dilemma of the Dutch NPH study by the randomised comparison of LPVs with and without gravitational units.