Myelin protein zero mutation-related hereditary neuropathies: Neuropathological insight from a new nerve biopsy cohort.

Myelin protein zero (MPZ/P0) is a major structural protein of peripheral nerve myelin. Disease-associated variants in the MPZ gene cause a wide phenotypic spectrum of inherited peripheral neuropathies. Previous nerve biopsy studies showed evidence for subtype-specific morphological features. Here, we aimed at enhancing the understanding of these subtype-specific features and pathophysiological aspects of MPZ neuropathies. We examined archival material from two Central European centers and systematically determined genetic, clinical, and neuropathological features of 21 patients with MPZ mutations compared to 16 controls. Cases were grouped based on nerve conduction data into congenital hypomyelinating neuropathy (CHN; n = 2), demyelinating Charcot-Marie-Tooth (CMT type 1; n = 11), intermediate (CMTi; n = 3), and axonal CMT (type 2; n = 5). Six cases had combined muscle and nerve biopsies and one underwent autopsy. We detected four MPZ gene variants not previously described in patients with neuropathy. Light and electron microscopy of nerve biopsies confirmed fewer myelinated fibers, more onion bulbs and reduced regeneration in demyelinating CMT1 compared to CMT2/CMTi. In addition, we observed significantly more denervated Schwann cells, more collagen pockets, fewer unmyelinated axons per Schwann cell unit and a higher density of Schwann cell nuclei in CMT1 compared to CMT2/CMTi. CHN was characterized by basal lamina onion bulb formation, a further increase in Schwann cell density and hypomyelination. Most late onset axonal neuropathy patients showed microangiopathy. In the autopsy case, we observed prominent neuromatous hyperinnervation of the spinal meninges. In four of the six muscle biopsies, we found marked structural mitochondrial abnormalities. These results show that MPZ alterations not only affect myelinated nerve fibers, leading to either primarily demyelinating or axonal changes, but also affect non-myelinated nerve fibers. The autopsy case offers insight into spinal nerve root pathology in MPZ neuropathy. Finally, our data suggest a peculiar association of MPZ mutations with mitochondrial alterations in muscle.

Ectopic intracranial retinoblastoma in a 3.5-month-old infant without eye involvement and without evidence of heritability.

Heritable retinoblastoma can rarely be associated with a midline intracranial neuroblastic tumor, referred to as trilateral retinoblastoma. We present an unusual midline brain tumor in an infant that was identified as ectopic retinoblastoma by histopathology, DNA methylation analysis, and molecular genetic detection of biallelic somatic inactivation of the RB1 gene. There was no ocular involvement, and germline mutation was excluded. In this nonresectable tumor, treatment with systemic chemotherapy including high-dose therapy with autologous stem cell transplantation, but without definite local therapy, resulted in long-lasting tumor control.

Correlation of Dynamic O-(2-[18F]Fluoroethyl)-L-Tyrosine Positron Emission Tomography, Conventional Magnetic Resonance Imaging, and Whole-Brain Histopathology in a Pretreated Glioblastoma: A Postmortem Study.

OBJECTIVE: Amino acid positron emission tomography (PET) using O-(2-[18F]fluoroethyl)-L-tyrosine (FET) provides important additional information on the extent of viable tumor tissue of glioblastoma compared with magnetic resonance imaging (MRI). Especially after radiochemotherapy, progression of contrast enhancement in MRI is equivocal and may represent either tumor progression or treatment-related changes. Here, the first case comparing postmortem whole-brain histology of a patient with pretreated glioblastoma with dynamic in vivo FET PET and MRI is presented. METHODS: A 61-year-old patient with glioblastoma initially underwent partial tumor resection and died 11 weeks after completion of chemoradiation with concurrent temozolomide. Three days before the patient died, a follow-up FET PET and MRI scan indicated tumor progression. Autopsy was performed 48 hours after death. After formalin fixation, a 7-cm bihemispherical segment of the brain containing the entire tumor mass was cut into 3500 consecutive 20µm coronal sections. Representative sections were stained with hematoxylin and eosin stain, cresyl violet, and glial fibrillary acidic protein immunohistochemistry. An experienced neuropathologist identified areas of dense and diffuse neoplastic infiltration, astrogliosis, and necrosis. In vivo FET PET, MRI datasets, and postmortem histology were co-registered and compared by 3 experienced physicians. RESULTS: Increased uptake of FET in the area of equivocal contrast enhancement on MRI correlated very well with dense infiltration by vital tumor cells and showed tracer kinetics typical for malignant gliomas. An area of predominantly reactive astrogliosis showed only moderate uptake of FET and tracer kinetics usually observed in benign lesions. CONCLUSIONS: This case report impressively documents the correct imaging of a progressive glioblastoma by FET PET.

Development of a Polymer-Based Biodegradable Neurovascular Stent Prototype: A Preliminary In Vitro and In Vivo Study.

Biodegradable stents are not established in neurovascular interventions. In this study, mechanical, radiological, and histological characteristics of a stent prototype developed for neurovascular use are presented. The elasticity and brittleness of PLA 96/4, PLDL 70/30, PCL, and PLGA 85/15 and 10/90 polymers in in vitro experiments are first analyzed. After excluding the inapt polymers, degradability and mechanical characteristics of 78 PLGA 85/15 and PLGA 10/90 stent prototypes are analyzed. After excluding PLGA 10/90 stents because of rapid loss of mass PLGA 85/15 stents in porcine in vivo experiments are analyzed. Angiographic occlusion rates 7 d, 1 month, 3 months, and 6 months after stent implantation are assessed. Histological outcome measures are the presence of signs of inflammation, endothelialization, and the homogeneity of degradation after six months. One case of stent occlusion occurs within the first 7 d. There is a prominent foreign-body reaction with considerable mononuclear and minor granulocytic inflammation combined with incomplete fragmental degradation of the struts. It is possible to produce a stent prototype with dimensions that fit the typical size of carotid arteries. Major improvements concerning thrombogenicity, degradation, and inflammatory response are required to produce biodegradable stents that are suitable for neurovascular interventions.

Dynamic O-(2-18F-fluoroethyl)-L-tyrosine positron emission tomography differentiates brain metastasis recurrence from radiation injury after radiotherapy.

Background: The aim of this study was to investigate the potential of dynamic O-(2-[18F]fluoroethyl)-L-tyrosine (18F-FET) PET for differentiating local recurrent brain metastasis from radiation injury after radiotherapy since contrast-enhanced MRI often remains inconclusive. Methods: Sixty-two patients (mean age, 55 ± 11 y) with single or multiple contrast-enhancing brain lesions (n = 76) on MRI after radiotherapy of brain metastases (predominantly stereotactic radiosurgery) were investigated with dynamic 18F-FET PET. Maximum and mean tumor-to-brain ratios (TBRmax, TBRmean) of 18F-FET uptake were determined (20-40 min postinjection) as well as tracer uptake kinetics (ie, time-to-peak and slope of time-activity curves). Diagnoses were confirmed histologically (34%; 26 lesions in 25 patients) or by clinical follow-up (66%; 50 lesions in 37 patients). Diagnostic accuracies of PET parameters for the correct identification of recurrent brain metastasis were evaluated by receiver-operating-characteristic analyses or the chi-square test. Results: TBRs were significantly higher in recurrent metastases (n = 36) than in radiation injuries (n = 40) (TBRmax 3.3 ± 1.0 vs 2.2 ± 0.4, P < .001; TBRmean 2.2 ± 0.4 vs 1.7 ± 0.3, P < .001). The highest accuracy (88%) for diagnosing local recurrent metastasis could be obtained with TBRs in combination with the slope of time-activity curves (P < .001). Conclusions: The results of this study confirm previous preliminary observations that the combined evaluation of the TBRs of 18F-FET uptake and the slope of time-activity curves can differentiate local brain metastasis recurrence from radiation-induced changes with high accuracy. 18F-FET PET may thus contribute significantly to the management of patients with brain metastases.

Autosomal dominant spinal muscular atrophy with lower extremity predominance: A recognizable phenotype of BICD2 mutations.

INTRODUCTION: Heterozygous BICD2 gene mutations cause a form of autosomal dominant spinal muscular atrophy with lower extremity predominance (SMALED). METHODS: We analyzed the BICD2 gene in a selected group of 25 index patients with neurogenic muscle atrophy. RESULTS: We identified 2 new BICD2 missense mutations, c.2515G>A, p.Gly839Arg, in a family with autosomal dominant inheritance, and c.2202G>T, p.Lys734Asn, as a de novo mutation in an isolated patient with similar phenotype. The patients had congenital foot contractures, muscle atrophy of the legs, and slowly progressive weakness of the shoulder girdle. There was no apparent sensory or brain dysfunction. One patient died of unrelated reasons at age 52 years. Autopsy revealed no upper motor neuron and only moderate lower motor neuron loss, but there was distal corticospinal tract degeneration and marked neurogenic muscular atrophy. CONCLUSION: These findings give further insight into the clinical and pathoanatomical consequences of BICD2 mutations. Muscle Nerve 54: 496-500, 2016.

Differences in degradation behavior of two non-cross-linked collagen barrier membranes: an in vitro and in vivo study.

OBJECTIVES: Collagen barrier membranes are used in guided bone regeneration/guided tissue regeneration because of their excellent bio- and cytocompatibility. However, they are considered to have limitations in clinical outcome because of rapid and unpredictable degradation profiles. The aim of this study was to investigate the degradation behavior of two porcine-based, non-cross-linked collagen membranes in vitro and in vivo. MATERIALS AND METHODS: Remaix™ (RX; Matricel GmbH, Herzogenrath, Germany) and Bio-Gide® (BG; Geistlich Pharma AG, Wolhusen, Switzerland) membranes were characterized by testing mechanical strength, denaturation temperature, enzymatic degradation and hydroxyproline content in vitro (n = 5 up to 16). Thereafter, both membranes were implanted subcutaneously in rats (n = 20) for up to 20 weeks to investigate tissue compatibility with respect to membrane thickness. RESULTS: BG contained a significant higher hydroxyproline content compared with RX, but RX showed a higher stress at break (dry: 11.4 (SD 2.9) vs. 5.5 (SD 1.5) N/mm(2)), higher suture retention (wet: 5.6 (SD 1.3) vs. 2.7 (SD 0.7) N), increased denaturation temperature (55.1 (SD 1) vs. 49.4 (SD 0.6)°C) and an almost twofold reduction in degradation rate (15.6% (SEM 1.3)/h vs. 24.8% (SEM 2.9)/h) in vitro. In the rat model, both membranes showed excellent tissue compatibility without signs of inflammatory reactions. Shortly after implantation, RX and BG showed moderate infiltration of mononuclear cells that appeared not to be influenced by the surface texture of the membranes. In the histomorphometric analysis, both membranes showed significant different thickness over the 20 weeks period (P = 0.0002). Although the thickness remained almost stable during the first 9 weeks after implantation, after 20 weeks, the thickness of RX decreased only slightly, whereas BG showed a thickness loss of around 50% and stronger degradation than RX. Therefore, the higher stability of RX against biodegradation found in vitro was confirmed in the animal study. CONCLUSION: This study shows differences in the biodegradation characteristics of two non-cross-linked collagen membranes in vitro and in vivo. Whether the higher stability of RX is of clinical relevance should be analyzed in future clinical investigations.

The proximal medial sural nerve biopsy model: a standardised and reproducible baseline clinical model for the translational evaluation of bioengineered nerve guides.

Autologous nerve transplantation (ANT) is the clinical gold standard for the reconstruction of peripheral nerve defects. A large number of bioengineered nerve guides have been tested under laboratory conditions as an alternative to the ANT. The step from experimental studies to the implementation of the device in the clinical setting is often substantial and the outcome is unpredictable. This is mainly linked to the heterogeneity of clinical peripheral nerve injuries, which is very different from standardized animal studies. In search of a reproducible human model for the implantation of bioengineered nerve guides, we propose the reconstruction of sural nerve defects after routine nerve biopsy as a first or baseline study. Our concept uses the medial sural nerve of patients undergoing diagnostic nerve biopsy (≥ 2 cm). The biopsy-induced nerve gap was immediately reconstructed by implantation of the novel microstructured nerve guide, Neuromaix, as part of an ongoing first-in-human study. Here we present (i) a detailed list of inclusion and exclusion criteria, (ii) a detailed description of the surgical procedure, and (iii) a follow-up concept with multimodal sensory evaluation techniques. The proximal medial sural nerve biopsy model can serve as a preliminary nature of the injuries or baseline nerve lesion model. In a subsequent step, newly developed nerve guides could be tested in more unpredictable and challenging clinical peripheral nerve lesions (e.g., following trauma) which have reduced comparability due to the different nature of the injuries (e.g., site of injury and length of nerve gap).

Cetuximab induces eme1-mediated DNA repair: a novel mechanism for cetuximab resistance.

Overexpression of the epidermal growth factor receptor (EGFR) is observed in a large number of neoplasms. The monoclonal antibody cetuximab/Erbitux is frequently applied to treat EGFR-expressing tumors. However, the application of cetuximab alone or in combination with radio- and/or chemotherapy often yields only little benefit for patients. In the present study, we describe a mechanism that explains resistance of both tumor cell lines and cultured primary human glioma cells to cetuximab. Treatment of these cells with cetuximab promoted DNA synthesis in the absence of increased proliferation, suggesting that DNA repair pathways were activated. Indeed, we observed that cetuximab promoted the activation of the DNA damage response pathway and prevented the degradation of essential meiotic endonuclease 1 homolog 1 (Eme1), a heterodimeric endonuclease involved in DNA repair. The increased levels of Eme1 were necessary for enhanced DNA repair, and the knockdown of Eme1 was sufficient to prevent efficient DNA repair in response to ultraviolet-C light or megavoltage irradiation. These treatments reduced the survival of tumor cells, an effect that was reversed by cetuximab application. Again, this protection was dependent on Eme1. Taken together, these results suggest that cetuximab initiates pathways that result in the stabilization of Eme1, thereby resulting in enhanced DNA repair. Accordingly, cetuximab enhances DNA repair, reducing the effectiveness of DNA-damaging therapies. This aspect should be considered when using cetuximab as an antitumor agent and suggests that Eme1 is a negative predictive marker.

Modulation of hippocampal neuroplasticity by Fas/CD95 regulatory protein 2 (Faim2) in the course of bacterial meningitis.

Fas-apoptotic inhibitory molecule 2 (Faim2) is a neuron-specific membrane protein and a member of the evolutionary conserved lifeguard apoptosis regulatory gene family. Its neuroprotective effect in acute neurological diseases has been demonstrated in an in vivo model of focal cerebral ischemia. Here we show that Faim2 is physiologically expressed in the human brain with a changing pattern in cases of infectious meningoencephalitis.In Faim2-deficient mice, there was increased caspase-associated hippocampal apoptotic cell death and an increased extracellular signal-regulated kinase pattern during acute bacterial meningitis induced by subarachnoid infection with Streptococcus pneumoniae type 3 strain. However, after rescuing the animals by antibiotic treatment, Faim2 deficiency led to increased hippocampal neurogenesis at 7 weeks after infection. This was associated with improved performance of Faim2-deficient mice compared to wild-type littermates in the Morris water maze, a paradigm for hippocampal spatial learning and memory. Thus, Faim2 deficiency aggravated degenerative processes in the acute phase but induced regenerative processes in the repair phase of a mouse model of pneumococcal meningitis. Hence, time-dependent modulation of neuroplasticity by Faim2 may offer a new therapeutic approach for reducing hippocampal neuronal cell death and improving cognitive deficits after bacterial meningitis.

Uptake of O-(2-[18F]fluoroethyl)-L-tyrosine in reactive astrocytosis in the vicinity of cerebral gliomas.

UNLABELLED: PET using O-(2-[(18)F]fluoroethyl)-L-tyrosine ((18)F-FET) allows improved imaging of tumor extent of cerebral gliomas in comparison to MRI. In experimental brain infarction and hematoma, an unspecific accumulation of (18)F-FET has been detected in the area of reactive astrogliosis which is a common cellular reaction in the vicinity of cerebral gliomas. The aim of this study was to investigate possible (18)F-FET uptake in the area of reactive gliosis in the vicinity of untreated and irradiated rat gliomas. METHODS: F98-glioma cells were implanted into the caudate nucleus of 33 Fisher CDF rats. Sixteen animals remained untreated and in 17 animals the tumor was irradiated by Gamma Knife 5-8 days after implantation (2/50 Gy, 3/75 Gy, 6/100 Gy, 6/150 Gy). After 8-17 days of tumor growth the animals were sacrificed following injection of (18)F-FET. Brains were removed, cut in coronal sections and autoradiograms of (18)F-FET distribution were produced and compared with histology (toluidine blue) and reactive astrogliosis (GFAP staining). (18)F-FET uptake in the tumors and in areas of reactive astrocytosis was evaluated by lesion to brain ratios (L/B). RESULTS: Large F98-gliomas were present in all animals showing increased (18)F-FET-uptake which was similar in irradiated and non-irradiated tumors (L/B: 3.9 ± 0.8 vs. 4.0 ± 1.3). A pronounced reactive astrogliosis was noted in the vicinity of all tumors that showed significantly lower (18)F-FET-uptake than the tumors (L/B: 1.5 ± 0.4 vs. 3.9 ± 1.1). The area of (18)F-FET-uptake in the tumor was congruent with histological tumor extent in 31/33 animals. In 2 rats irradiated with 150 Gy, however, high (18)F-FET uptake was noted in the area of astrogliosis which led to an overestimation of the tumor size. CONCLUSIONS: Reactive astrogliosis in the vicinity of gliomas generally leads to only a slight (18)F-FET-enrichment that appears not to affect the correct definition of tumor extent for treatment planning.

Fetuin-a in the developing brain.

The serum protein fetuin-A is essential for mineral homeostasis and shows immunomodulatory functions, for example by binding to TGF superfamily proteins. It proved neuroprotective in a rat stroke model and reduced lethality after systemic lipopolysaccharide challenge in mice. Serum fetuin-A concentrations are highest during intrauterine life. Different species show intrauterine cerebral fetuin-A immunoreactivity, suggesting a contribution to brain development. We therefore aimed at specifying fetuin-A immunoreactivity in brains of newborn rats (age P0-P28) and human neonates (20-40 weeks of gestation). In humans and rats, fetuin-A was found in cortex, white matter, subplate, hippocampus, subventricular zone, and ependymal cells which supports a global role for brain function. In rats, overall fetuin-A immunoreactivity decreased with age. At P0 fetuin-A immunoreactivity affected most brain structures. Thereafter, it became increasingly restricted to distinct cells of the hippocampus, cingular gyrus, periventricular stem cell layer, and ependyma. In ependymal cells the staining pattern complied with active transependymal transport from cerebrospinal fluid. Double immunofluorescence studies revealed colocalization with NeuN (mature neurons), beta III tubulin (immature neurons), GFAP (astrocytes), and CD68 (activated microglia). This points to a role of fetuin-A in different brain functional systems. In human neonatal autopsy cases, frequently affected from severe neurological and non-neurological diseases, fetuin-A immunoreactivity was heterogeneous and much less associated with age than in healthy tissues studied earlier, suggesting an impact of exogeneous noxious factors on fetuin-A regulation. Further research on the role of fetuin-A in the neonatal brain during physiological and pathological conditions is recommended.

The role of microstructured and interconnected pore channels in a collagen-based nerve guide on axonal regeneration in peripheral nerves.

The use of bioengineered nerve guides as alternatives for autologous nerve transplantation (ANT) is a promising strategy for the repair of peripheral nerve defects. In the present investigation, we present a collagen-based micro-structured nerve guide (Perimaix) for the repair of 2 cm rat sciatic nerve defects. Perimaix is an open-porous biodegradable nerve guide containing continuous, longitudinally orientated channels for orientated nerve growth. The effects of these nerve guides on axon regeneration by six weeks after implantation have been compared with those of ANT. Investigation of the regenerated sciatic nerve indicated that Perimaix strongly supported directed axon regeneration. When seeded with cultivated rat Schwann cells (SC), the Perimaix nerve guide was found to be almost as supportive of axon regeneration as ANT. The use of SC from transgenic green-fluorescent-protein (GFP) rats allowed us to detect the viability of donor SC at 1 week and 6 weeks after transplantation. The GFP-positive SC were aligned in a columnar fashion within the longitudinally orientated micro-channels. This cellular arrangement was not only observed prior to implantation, but also at one week and 6 weeks after implantation. It may be concluded that Perimaix nerve guides hold great promise for the repair of peripheral nerve defects.

Surgical Results and Microscopic Analysis of the Tissue Reaction following Implantation and Explantation of an Intraocular Implant for Epiretinal Stimulation in Minipigs.

AIMS: For the purpose of visual rehabilitation of subjects with photoreceptor degeneration, an implantable microelectronic device for epiretinal stimulation was developed. Our study aimed to show whether implantation and explantation could be conducted safely and to investigate tissue compatibility. METHODS: The device was implanted in 5 Göttinger minipigs. Four weeks later, the implant was surgical- ly removed. Histopathological examination that followed aimed at detecting inflammatory or proliferative changes. Stains used were hematoxylin and eosin, leukocyte common antigen, CD68 and glial fibrillary acidic protein. A grinding technique was used to visualize the retinal tissue in conjunction with the retinal tacks. RESULTS: The implantation of the devices was successful in all cases. The explantation was complicated by intraoperative hemorrhages. Complete explantation could only be achieved after modifying the implantation strategy. Histopathology revealed a mild degree of cystic disaggregation of the retina. Immunohistochemically, an increased glial fibrillary acidic protein expression of Müller cells was found, which shows a moderate glial cell activation. Inflammatory cells were absent. Using the grinding technique, tissue adjacent to the retinal tacks showed a mild gliosis. DISCUSSION: The viability of implantation and explantation of the implant in minipigs has been shown. The absence of immunoreactive cells or a considerable glial reaction suggest that the device may be considered safe and suitable for further implantation in humans.

Magnetic microparticles for endovascular aneurysm treatment: in vitro and in vivo experimental results.

OBJECTIVE: Endovascular treatment of intracranial aneurysms employing endosaccular coiling can be associated with aneurysm perforation, coil herniation or incomplete obliteration fueling the interest to investigate novel endovascular techniques. We aimed to test a novel embolization material in experimental aneurysms in vitro and in vivo whereby intra-arterially administered magnetic microparticles (MMPs) are navigated into the lumen of vascular aneurysms with assistance from an external magnetic field. METHODS: MMPs are core-shell particles suspended in saline that have a shell made of a polymeric material and a core made of magnetite (Fe3O4). They have a diameter of 1.4 µm. During MMP administration via a microcatheter, a magnetic field was applied externally to direct the particles with the use of a solid-state neodymium magnet. Experiments were performed in a perfused silicone vessel and aneurysm model to evaluate application techniques and fluid dynamics and in the elastase aneurysm model in rabbits to evaluate in vivo compatibility, including multiorgan histological examinations and long-term stability of aneurysm embolization. RESULTS: It was possible to steer and hold the MMPs within the aneurismal cavity where they occluded the lumen progressively. After removal of the external magnetic field, the results remained stable in vivo for the remainder of the observational period (30 minutes); after a 12-week observational period, recanalization of the aneurysm occurred. CONCLUSION: MMPs can be magnetically directed into aneurysms, allowing short-term obliteration. Although the method has yet to show reliable long-term stability, these experiments provide proof of concept, encouraging further investigation of intravascular magnetic compounds.

Clinical and neuropathological study about the neurotization of the suprascapular nerve in obstetric brachial plexus lesions.

BACKGROUND: The lack of recovery of active external rotation of the shoulder is an important problem in children suffering from brachial plexus lesions involving the suprascapular nerve. The accessory nerve neurotization to the suprascapular nerve is a standard procedure, performed to improve shoulder motion in patients with brachial plexus palsy. METHODS: We operated on 65 patients with obstetric brachial plexus palsy (OBPP), aged 5-35 months (average: 19 months). We assessed the recovery of passive and active external rotation with the arm in abduction and in adduction. We also looked at the influence of the restoration of the muscular balance between the internal and the external rotators on the development of a gleno-humeral joint dysplasia. Intraoperatively, suprascapular nerve samples were taken from 13 patients and were analyzed histologically. RESULTS: Most patients (71.5%) showed good recovery of the active external rotation in abduction (60 degrees -90 degrees). Better results were obtained for the external rotation with the arm in abduction compared to adduction, and for patients having only undergone the neurotization procedure compared to patients having had complete plexus reconstruction. The neurotization operation has a positive influence on the glenohumeral joint: 7 patients with clinical signs of dysplasia before the reconstructive operation did not show any sign of dysplasia in the postoperative follow-up. CONCLUSION: The neurotization procedure helps to recover the active external rotation in the shoulder joint and has a good prevention influence on the dysplasia in our sample. The nerve quality measured using histopathology also seems to have a positive impact on the clinical results.

Obstetric brachial plexus palsy: treatment strategy, long-term results, and prognosis.

BACKGROUND: Obstetric brachial plexus palsy is rare, but the limb impairments are manifold and often long-lasting. Physiotherapy, microsurgical nerve reconstruction, secondary joint corrections, and muscle transpositions are employed with success. The role of conservative and operative treatment options should be regularly reviewed. METHODS: Selective literature review (evidence levels 3 and 4) and analysis of personal clinical operative and scientific experience over the past 15 years. RESULTS: Children with upper and total plexus palsy displaying nerve root avulsions and/or -ruptures are treated today by early primary nerve reconstruction in the first few months of life followed by secondary corrections, with good functional results. The late complications, with muscle weakness, impaired motion patterns, and joint dysplasia, are often underrated. CONCLUSIONS: The potential for scientific analysis is limited, due to the rarity and interindividual variability of the lesions and the varying effects on function and growth. Expectations and compliance are different in every patient. Surgical techniques are not yet standardized. Knowledge of the consequences for joint growth and congruence is inadequate. Today, functional improvement can be achieved by surgery in most clinical manifestations of obstetric brachial plexus palsy, within the framework of an interdisciplinary treatment concept.

Implantation and explantation of a wireless epiretinal retina implant device: observations during the EPIRET3 prospective clinical trial.

PURPOSE: Visual sensations in patients with blindness and retinal degenerations may be restored by electrical stimulation of retinal neurons with implantable microelectrode arrays. A prospective trial was initiated to evaluate the safety and efficacy of a wireless intraocular retinal implant (EPIRET3) in six volunteers with blindness and RP. METHODS: The implant is a remotely controlled, fully intraocular wireless device consisting of a receiver and a stimulator module. The stimulator is placed on the retinal surface. Data and energy are transmitted via an inductive link from outside the eye to the implant. Surgery included removal of the lens, vitrectomy, and implantation of the EPIRET3 device through a corneal incision. The clinical outcome after implantation and explantation of the device was determined. The implant was removed after 4 weeks, according to the study protocol. RESULTS: Implantation was successful in all six patients. While the anterior part was fixed with transscleral sutures, the stimulating foil was placed onto the posterior pole and fixed with retinal tacks. The implant was well tolerated, causing temporary moderate postoperative inflammation, whereas the position of the implant remained stable until surgical removal. In all cases explantation of the device was performed successfully. Adverse events were a sterile hypopyon effectively treated with steroids and antibiotics in one case and a retinal break in a second case during explantation requiring silicone oil surgery. CONCLUSIONS: The EPIRET3 system can be successfully implanted and explanted in patients with blindness and RP. The surgical steps are feasible, and the postoperative follow-up disclosed an acceptable range of adverse events.

In vitro cell alignment obtained with a Schwann cell enriched microstructured nerve guide with longitudinal guidance channels.

Therapeutic benefits of autologous nerve grafting in repair of peripheral nerve lesions have not been reached using any alternative nerve guide. Nevertheless, issues of co-morbidity and limited availability of donor nerves urgently ask for a need of bioartificial nerve guides which could either replace or complement autologous nerve grafts. It is increasingly appreciated that optimal nerve guides comprise both physical and molecular cues in support of peripheral axon regeneration. Now, we present a collagen-based microstructured 3D nerve guide containing numerous longitudinal guidance channels with dimensions resembling natural endoneurial tubes. Moreover, these nerve guides could be functionalized by Schwann cell (SC) seeding. Viable SCs did not only adhere to the nerve guide, but also migrated throughout the guidance channels. Of particular importance was the observation that SCs within the guidance channels formed cellular columns reminiscent of "Bands of Büngner", which are crucial structures in the natural process of peripheral nerve regeneration during the Wallerian degeneration. We, therefore, conclude that our orientated 3D nerve guides (decorated with SCs) with their physical and molecular properties may hold great promise in the repair of peripheral nerve lesion and serve as a basis for future experimental regeneration studies.

In vitro assessment of axonal growth using dorsal root ganglia explants in a novel three-dimensional collagen matrix.

The goal of this study was the development of a bioartificial nerve guide to induce axonal regeneration in the peripheral nervous system (PNS). In this in vitro study, the ability of a novel, 3-dimensional (3D), highly oriented, cross-linked porcine collagen scaffold to promote directed axonal growth has been studied. Collagen nerve guides with longitudinal guidance channels were manufactured using a series of chemical and mechanical treatments with a patented unidirectional freezing process, followed by freeze-drying (pore sizes 20-50 microm). Hemisected rat dorsal root ganglia (DRG) were positioned such that neural and non-neural elements could migrate into the collagen scaffold. After 21 days, S100-positive Schwann cells (SCs) migrated into the scaffold and aligned within the guidance channels in a columnar fashion, resembling "Bands of Büngner." Neurofilament-positive axons (mean length +/- SD 756 microm +/- 318 microm, maximum 1496 microm) from DRG neurons entered the scaffold where the growth within the guidance channels was closely associated with the oriented SCs. This study confirmed the importance of SCs in the regeneration process (neurotrophic theory). The alignment of SCs within the guidance channels supported directional axonal growth (contact guidance theory). The microstructural properties of the scaffold (open, porous, longitudinal pore channels) and the in vitro data after DRG loading (axonal regeneration along migrated and columnar-aligned SCs resembling "Band of Büngner") suggest that this novel oriented 3D collagen scaffold serves as a basis for future experimental regeneration studies in the PNS.