Transplanted human neural stem cells rescue phenotypes in zQ175 Huntington's disease mice and innervate the striatum.

Huntington's disease (HD), a genetic neurodegenerative disorder, primarily affects the striatum and cortex with progressive loss of medium-sized spiny neurons (MSNs) and pyramidal neurons, disrupting cortico-striatal circuitry. A promising regenerative therapeutic strategy of transplanting human neural stem cells (hNSCs) is challenged by the need for long-term functional integration. We previously described that, with short-term hNSC transplantation into the striatum of HD R6/2 mice, human cells differentiated into electrophysiologically active immature neurons, improving behavior and biochemical deficits. Here, we show that long-term (8 months) implantation of hNSCs into the striatum of HD zQ175 mice ameliorates behavioral deficits, increases brain-derived neurotrophic factor (BDNF) levels, and reduces mutant huntingtin (mHTT) accumulation. Patch clamp recordings, immunohistochemistry, single-nucleus RNA sequencing (RNA-seq), and electron microscopy demonstrate that hNSCs differentiate into diverse neuronal populations, including MSN- and interneuron-like cells, and form connections. Single-nucleus RNA-seq analysis also shows restoration of several mHTT-mediated transcriptional changes of endogenous striatal HD mouse cells. Remarkably, engrafted cells receive synaptic inputs, innervate host neurons, and improve membrane and synaptic properties. Overall, the findings support hNSC transplantation for further evaluation and clinical development for HD.

Epileptic aphasia - A critical appraisal.

INTRODUCTION: Aphasic and other language disturbances occur in patients with epilepsy during and after epileptic seizures. Moreover, the interictal language profile in these patients is heterogeneous, varying from normal language profile to impairment in different language functions. The aim of this paper was to critically review the terms and concepts of ictal language alterations. MATERIAL AND METHOD: For this review we performed an extensive literature search on the term "epileptic aphasia" and analyzed the semiology and terminology indicating language-associated seizure symptoms. In addition, we give an overview on EEG, etiology, and brain imaging findings and ictal language disorders. RESULTS: In the literature, a plethora of terms indicates language-associated seizure symptoms. Simultaneous Video-EEG monitoring represents the gold standard to correctly classify ictal versus postictal language disturbances and to differentiate aphasic symptoms from speech automatisms. Different rhythmic and periodic EEG patterns associated with ictal language disturbances are recognized. Cerebral magnetic resonance imaging (cMRI) is essential in the diagnosis of seizures and epilepsy. Brain tumors and acute or remote cerebrovascular lesions are the most frequently reported structural etiologies underlying ictal language alterations. However, it has to be recognized that brain imaging may show alterations being the consequence of seizures itself rather than its cause. Functional brain imaging might be informative in patients with inconclusive EEG and MRI findings. Overall, seizure-associated aphasia is reported to have good lateralizing significance. CONCLUSION: Various language disturbances are caused by different types of seizures, epilepsies and underlying etiologies. In the clinical context, simultaneous Video-EEG monitoring facilitates precise classification of ictal versus postictal language alterations and differentiation of aphasic symptoms from speech automatisms.

Primed mesenchymal stem cells package exosomes with metabolites associated with immunomodulation.

Mesenchymal stem cell (MSC) based therapies are currently being evaluated as a putative therapeutic in numerous human clinical trials. Recent reports have established that exosomes mediate much of the therapeutic properties of MSCs. Exosomes are nanovesicles which mediate intercellular communication, transmitting signals between cells which regulate a diverse range of biological processes. MSC-derived exosomes are packaged with numerous types of proteins and RNAs, however, their metabolomic and lipidomic profiles to date have not been well characterized. We previously reported that MSCs, in response to priming culture conditions that mimic the in vivo microenvironmental niche, substantially modulate cellular signaling and significantly increase the secretion of exosomes. Here we report that MSCs exposed to such priming conditions undergo glycolytic reprogramming, which homogenizes MSCs' metabolomic profile. In addition, we establish that exosomes derive from primed MSCs are packaged with numerous metabolites that have been directly associated with immunomodulation, including M2 macrophage polarization and regulatory T lymphocyte induction.

Mesenchymal stem/stromal cells genetically engineered to produce vascular endothelial growth factor for revascularization in wound healing and ischemic conditions.

Mesenchymal stem/stromal cells (MSCs) may be able to improve ischemic conditions as they can actively seek out areas of low oxygen and secrete proangiogenic factors. In more severe trauma and chronic cases, however, cells alone may not be enough. Therefore, we have combined the stem cell and angiogenic factor approaches to make a more potent therapy. We developed an engineered stem cell therapy product designed to treat critical limb ischemia that could also be used in trauma-induced scarring and fibrosis where additional collateral blood flow is needed following damage to and blockage of the primary vessels. We used MSCs from normal human donor marrow and engineered them to produce high levels of the angiogenic factor vascular endothelial growth factor (VEGF). The MSC/VEGF product has been successfully developed and characterized using good manufacturing practice (GMP)-compliant methods, and we have completed experiments showing that MSC/VEGF significantly increased blood flow in the ischemic limb of immune deficient mice, compared to the saline controls in each study. We also performed safety studies demonstrating that the injected product does not cause harm and that the cells remain around the injection site for more than 1 month after hypoxic preconditioning. An on-demand formulation system for delivery of the product to clinical sites that lack cell processing facilities is in development.

Generalized nonmotor (absence) seizures-What do absence, generalized, and nonmotor mean?

OBJECTIVE: Clinical absences are now classified as "generalized nonmotor (absence) seizures" by the International League Against Epilepsy (ILAE). The aim of this paper is to critically review the concept of absences and to put the accompanying focal and motor symptoms into the context of the emerging pathophysiological knowledge. METHODS: For this narrative review we performed an extensive literature search on the term "absence," and analyzed the plethora of symptoms observed in clinical absences. RESULTS: Arising from the localization and the involved cortical networks, motor symptoms may include bilateral mild eyelid fluttering and mild myoclonic jerks of extremities. These motor symptoms may also occur unilaterally, analogous to a focal motor seizure with Jacksonian march. Furthermore, electroencephalography (EEG) abnormalities may exhibit initial frontal focal spikes and consistent asymmetries. Electroclinical characteristics support the cortical focus theory of absence seizures. Simultaneous EEG/functional magnetic resonance imaging (fMRI) measurements document cortical deactivation and thalamic activation. Cortical deactivation is related to slow waves and disturbances of consciousness of varying degrees. Motor symptoms correspond to the spike component of the 3/s spike-and-wave-discharges. Thalamic activation can be interpreted as a response to overcome cortical deactivation. Furthermore, arousal reaction during drowsiness or sleep triggers spikes in an abnormally excitable cortex. An initial disturbance in arousal mechanisms ("dyshormia") might be responsible for the start of this abnormal sequence. SIGNIFICANCE: The classification as "generalized nonfocal and nonmotor (absence) seizure" does not covey the complex semiology of a patient's clinical events.

Comprehensive Proteomic Analysis of Mesenchymal Stem Cell Exosomes Reveals Modulation of Angiogenesis via Nuclear Factor-KappaB Signaling.

Mesenchymal stem cells (MSC) are known to facilitate healing of ischemic tissue related diseases through proangiogenic secretory proteins. Recent studies further show that MSC derived exosomes function as paracrine effectors of angiogenesis, however, the identity of which components of the exosome proteome responsible for this effect remains elusive. To address this we used high-resolution isoelectric focusing coupled liquid chromatography tandem mass spectrometry, an unbiased high throughput proteomics approach to comprehensively characterize the proteinaceous contents of MSCs and MSC derived exosomes. We probed the proteome of MSCs and MSC derived exosomes from cells cultured under expansion conditions and under ischemic tissue simulated conditions to elucidate key angiogenic paracrine effectors present and potentially differentially expressed in these conditions. In total, 6,342 proteins were identified in MSCs and 1,927 proteins in MSC derived exosomes, representing to our knowledge the first time these proteomes have been probed comprehensively. Multilayered analyses identified several putative paracrine effectors of angiogenesis present in MSC exosomes and increased in expression in MSCs exposed to ischemic tissue-simulated conditions; these include platelet derived growth factor, epidermal growth factor, fibroblast growth factor, and most notably nuclear factor-kappaB (NFkB) signaling pathway proteins. NFkB signaling was identified as a key mediator of MSC exosome induced angiogenesis in endothelial cells by functional in vitro validation using a specific inhibitor. Collectively, the results of our proteomic analysis show that MSC derived exosomes contain a robust profile of angiogenic paracrine effectors, which have potential for the treatment of ischemic tissue-related diseases.

The path to successful commercialization of cell and gene therapies: empowering patient advocates.

Often, novel gene and cell therapies provide hope for many people living with incurable diseases. To facilitate and accelerate a successful regulatory approval and commercialization path for effective, safe and affordable cell and gene therapies, the involvement of patient advocacy groups (PAGs) should be considered early in the development process. This report provides a thorough overview of the various roles PAGs play in the clinical translation of cell and gene therapies and how they can bring about positive changes in the regulatory process, infrastructure improvements and market stability.

Human Mesenchymal Stem Cells Genetically Engineered to Overexpress Brain-derived Neurotrophic Factor Improve Outcomes in Huntington's Disease Mouse Models.

Huntington's disease (HD) is a fatal degenerative autosomal dominant neuropsychiatric disease that causes neuronal death and is characterized by progressive striatal and then widespread brain atrophy. Brain-derived neurotrophic factor (BDNF) is a lead candidate for the treatment of HD, as it has been shown to prevent cell death and to stimulate the growth and migration of new neurons in the brain in transgenic mouse models. BDNF levels are reduced in HD postmortem human brain. Previous studies have shown efficacy of mesenchymal stem/stromal cells (MSC)/BDNF using murine MSCs, and the present study used human MSCs to advance the therapeutic potential of the MSC/BDNF platform for clinical application. Double-blinded studies were performed to examine the effects of intrastriatally transplanted human MSC/BDNF on disease progression in two strains of immune-suppressed HD transgenic mice: YAC128 and R6/2. MSC/BDNF treatment decreased striatal atrophy in YAC128 mice. MSC/BDNF treatment also significantly reduced anxiety as measured in the open-field assay. Both MSC and MSC/BDNF treatments induced a significant increase in neurogenesis-like activity in R6/2 mice. MSC/BDNF treatment also increased the mean lifespan of the R6/2 mice. Our genetically modified MSC/BDNF cells set a precedent for stem cell-based neurotherapeutics and could potentially be modified for other neurodegenerative disorders such as amyotrophic lateral sclerosis, Alzheimer's disease, and some forms of Parkinson's disease. These cells provide a platform delivery system for future studies involving corrective gene-editing strategies.

ACL double-bundle reconstruction with one tibial tunnel provides equal stability compared to two tibial tunnels.

PURPOSE: The purpose of this study was to investigate whether an anterior cruciate ligament (ACL) double-bundle reconstruction with one tibial tunnel displays the same in vitro stability as a conventional double-bundle reconstruction with two tibial tunnels when using the same tensioning protocol. METHODS: In 11 fresh-frozen cadaveric knees, ACL double-bundle reconstruction with one and two tibial tunnels was performed. The two grafts were tightened using 80 N in different flexion angles (anteromedial-bundle at 60° and posterolateral-bundle at 15°). Anterior tibial translation (134 N) and translation with combined rotatory and valgus loads (10 Nm valgus stress and 4 Nm internal tibial torque) were determined at 0°, 30°, 60° and 90° flexion. Measurements were taken in intact ACL, resected ACL, three-tunnel reconstruction and four-tunnel reconstruction. Additionally, the tension on the grafts was determined. Student's t test was performed for statistical analysis of the related samples. Significance was set at p < 0.017 according to Bonferroni correction. RESULTS: The two reconstructive techniques displayed no significant differences in comparison with the intact ACL in anterior tibial translation at 0°, 60° and 90° of flexion. The same results were obtained for the anterior tibial translation with a combined rotatory load at 60° and 90°. When directly comparing both reconstructive techniques, there were no significant differences for the anterior tibial translation and combined rotatory load at all flexion angles. The measured tension on grafts displayed similar load sharing between both bundles. Except at full extension, both grafts displayed a significantly different tension increase under anterior tibial translation for both techniques (p = 0.0086). CONCLUSIONS: Tightening both bundles in ACL double-bundle reconstruction with one or two tibial tunnels in different flexion angles achieved comparable restoration of stability, although there was different load sharing on the bundles. With regard to individualized ACL reconstruction, the double-bundle technique with one tibial tunnel offers a possibility to address small tibial insertion sites without compromising the advantages of a double-bundle procedure.

Safety and efficacy of a tCD25 preselective combination anti-HIV lentiviral vector in human hematopoietic stem and progenitor cells.

The successful suppression of human immunodeficiency virus (HIV) in the "Berlin Patient" has highlighted the ability of HIV-resistant hematopoietic stem cells to offer a potential functional cure for HIV-infected patients. HIV stem cell gene therapy can mimic this result by genetically modifying a patient's own cells with anti-HIV genes. Previous attempts of HIV gene therapy have been hampered by a low percentage of transplanted HIV-resistant cells which has led to minimal clinical efficacy. In our current study, we have evaluated the in vitro and in vivo safety and efficacy of a truncated/mutated form of human CD25 preselective anti-HIV lentiviral vector in human hematopoietic stem cells. This preselective vector allows us to purify vector-transduced cells prior to transplantation so an increased percentage of gene-modified cells can be delivered. Here, we demonstrate the safety of this strategy with successful engraftment and multilineage hematopoiesis of transduced cells in a humanized NOD-RAG1-/-IL-2rγ-/- knockout mouse model. Efficacy was also demonstrated with significant protection from HIV-1 infection including maintenance of human CD4+ cell levels and a decrease in HIV-1 plasma viremia. Collectively, these results establish the utility of this HIV stem cell gene therapy strategy and bring it closer to providing a functional cure for HIV-infected patients.

Putting a price tag on novel autologous cellular therapies.

Cell therapies, especially autologous therapies, pose significant challenges to researchers who wish to move from small, probably academic, methods of manufacture to full commercial scale. There is a dearth of reliable information about the costs of operation, and this makes it difficult to predict with confidence the investment needed to translate the innovations to the clinic, other than as small-scale, clinician-led prescriptions. Here, we provide an example of the results of a cost model that takes into account the fixed and variable costs of manufacture of one such therapy. We also highlight the different factors that influence the product final pricing strategy. Our findings illustrate the need for cooperative and collective action by the research community in pre-competitive research to generate the operational models that are much needed to increase confidence in process development for these advanced products.

Gene therapy for adenosine deaminase-deficient severe combined immune deficiency: clinical comparison of retroviral vectors and treatment plans.

We conducted a gene therapy trial in 10 patients with adenosine deaminase (ADA)-deficient severe combined immunodeficiency using 2 slightly different retroviral vectors for the transduction of patients' bone marrow CD34(+) cells. Four subjects were treated without pretransplantation cytoreduction and remained on ADA enzyme-replacement therapy (ERT) throughout the procedure. Only transient (months), low-level (< 0.01%) gene marking was observed in PBMCs of 2 older subjects (15 and 20 years of age), whereas some gene marking of PBMC has persisted for the past 9 years in 2 younger subjects (4 and 6 years). Six additional subjects were treated using the same gene transfer protocol, but after withdrawal of ERT and administration of low-dose busulfan (65-90 mg/m(2)). Three of these remain well, off ERT (5, 4, and 3 years postprocedure), with gene marking in PBMC of 1%-10%, and ADA enzyme expression in PBMC near or in the normal range. Two subjects were restarted on ERT because of poor gene marking and immune recovery, and one had a subsequent allogeneic hematopoietic stem cell transplantation. These studies directly demonstrate the importance of providing nonmyeloablative pretransplantation conditioning to achieve therapeutic benefits with gene therapy for ADA-deficient severe combined immunodeficiency.

The TT-TG Index: a new knee size adjusted measure method to determine the TT-TG distance.

PURPOSE: Medial transfer of the tibial tubercle has become a standard procedure in cases of patella instability caused by an increased tuberositas tibae-trochlear groove (TT-TG) distance. However, the TT-TG distance has always been assessed as an absolute value without taking individual joint size into consideration. It was assumed that the pathological influence of the TT-TG distance correlates with individual joint size. Aim of the current study therefore was to develop a method to express TT-TG distance in relation to these joint variables. METHODS: Two hundred knee MRI scans of healthy individuals (69 females and 131 males) were evaluated retrospectively in a control group. First, the TT-TG distance was measured as described by Schoettle et al. To determine joint size, the proximal-distal distance between the entrance of the chondral trochlear groove (TE) and the onset of the patella tendon at the tibial tubercle (TT) was selected. Subsequently, the TT-TG/TT-TE ratio expresses the relationship between the TT-TG distance and the proximal-distal distance from the entrance of the chondral trochlear groove to the height of the tibial tubercle. The TT-TG Index can also be expressed as an angle (TT-TG angle). Likewise, in another patient group, 54 knee MRTs of patients with patellofemoral instability were evaluated. RESULTS: The average TT-TG distance of the control group was 7.5±3.5 mm (range 0-17.4 mm) with no significant differences between genders. The mean TT-TE distance was 63.9 mm (range 49-79 mm) with there being significant differences between genders. The resulting mean TT-TG Index was 0.12±0.05 (range 0-0.25). In the patient group, the average TT-TG distance was 13.5±4.1 mm and the average TT-TE distance was 61.3±6.8 mm. The resulting average TT-TG Index of 0.22±0.07 in the patient group (PFI) approximates the threshold determined by the 95% confidence interval in the healthy control group. A direct comparison between the control group and the patient group revealed a significant difference in the TT-TG distance (p=0.0001), in the TT-TE distance (p<0.0042) and in the resulting TT-TG Index (p<0.0001). CONCLUSIONS: The measurement of the TT-TG Index is a reliable and differentiated approach for determining the lateral displacement of the tibial tubercle in relation to the proximal trochlear groove. The pathological influence of the TT-TG distance in case of patella instability depends on individual joint size, confirming the initial hypothesis. We currently consider a TT-TG Index>0.23 to be pathological based on our findings. Particularly, in case of a marginal TT-TG distance, the additional relative TT-TG Index facilitates a decision concerning an indication for a operative medial transfer of the tibial tubercle. LEVEL OF EVIDENCE: II.

Systematic diagnosis and therapy of lateral elbow pain with emphasis on elbow instability.

PURPOSE: In recalcitrant epicondylitis innumerable operative techniques have been published, nevertheless a certain percentage of patients remains symptomatic after operative treatment. We developed an individual, systematic diagnostic pathway including arthroscopic assessment of elbow stability to identify the optimal and respectively less invasive therapy. METHODS: We so far included 40 patients with recalcitrant lateral epicondylitis (mean age 46 ± 11). 5 patients had previous surgery. In all patients, we did an elbow arthroscopy and a systematic arthroscopic stability testing. 25 patients were treated exclusively arthroscopically once instability was excluded. In 13 patients with slight instability, we did an open debridement of the lateral tendon complex and local refixation. Two patients with severe instability were treated with open debridement and additional stabilization of the LUCL with a trizeps graft. With a minimum follow-up of 1 year, we assessed the DASH score and subjective patient satisfaction. RESULTS: Mean follow-up was 24 ± 12 months, mean duration of symptoms before surgery was 19 ± 18 months. The mean DASH score at follow-up was 22 ± 19.36 patients reported symptoms improvement, 34 patients would repeat surgery given the same situation; in 30 cases, patients expectations had been fulfilled. We did not observe any intraoperative complications or infections. One patient developed joint stiffness requiring reoperation. CONCLUSION: Using a systematic diagnostic pathway including assessment of elbow stability and consecutive individualized, respectively, less invasive surgical procedure we acquired high patients satisfaction and good clinical outcome with a low complication rate. LEVEL OF EVIDENCE: Level III.

Generation of an HIV-1-resistant immune system with CD34(+) hematopoietic stem cells transduced with a triple-combination anti-HIV lentiviral vector.

HIV gene therapy has the potential to offer an alternative to the use of current small-molecule antiretroviral drugs as a treatment strategy for HIV-infected individuals. Therapies designed to administer HIV-resistant stem cells to an infected patient may also provide a functional cure, as observed in a bone marrow transplant performed with hematopoietic stem cells (HSCs) homozygous for the CCR5-Δ32-bp allele. In our current studies, preclinical evaluation of a combination anti-HIV lentiviral vector was performed, in vivo, in humanized NOD-RAG1(-/-) IL2rγ(-/-) knockout mice. This combination vector, which displays strong preintegration inhibition of HIV-1 infection in vitro, contains a human/rhesus macaque TRIM5α isoform, a CCR5 short hairpin RNA (shRNA), and a TAR decoy. Multilineage hematopoiesis from anti-HIV lentiviral vector-transduced human CD34(+) HSCs was observed in the peripheral blood and in various lymphoid organs, including the thymus, spleen, and bone marrow, of engrafted mice. Anti-HIV vector-transduced CD34(+) cells displayed normal development of immune cells, including T cells, B cells, and macrophages. The anti-HIV vector-transduced cells also displayed knockdown of cell surface CCR5 due to the expression of the CCR5 shRNA. After in vivo challenge with either an R5-tropic BaL-1 or X4-tropic NL4-3 strain of HIV-1, maintenance of human CD4(+) cell levels and a selective survival advantage of anti-HIV gene-modified cells were observed in engrafted mice. The data provided from our study confirm the safety and efficacy of this combination anti-HIV lentiviral vector in a hematopoietic stem cell gene therapy setting for HIV and validates its potential application in future clinical trials.

Concise review: Induced pluripotent stem cell-derived mesenchymal stem cells: progress toward safe clinical products.

Adult stem cell therapies have provided success for more than 50 years, through reconstitution of the hematopoietic system using bone marrow, umbilical cord blood, and mobilized peripheral blood transplantation. Mesenchymal stem cell (MSC)-mediated therapy is a fast-growing field that has proven safe and effective in the treatment of various degenerative diseases and tissue injuries. Since the first derivation of embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs), there has been impressive progress toward developing safe clinical applications from PSCs. Recent successes in transgene-free iPSC reprogramming have brought attention to the potential of clinical applications of these pluripotent cells, but key hurdles must be overcome, which are discussed in this review. Looking to the future, it could be advantageous to derive MSC from iPSC or human ESC in cases where genetic engineering is needed, since in the PSCs, clones with "safe harbor" vector integration could be selected, expanded, and differentiated. Here, we describe the status of the progress of the use of MSC and PSCs in clinical trials and analyze the challenges that should be overcome before iPSC-derived MSC therapy can be used widely in the clinic.

Good Manufacturing Practices (GMP) manufacturing of advanced therapy medicinal products: a novel tailored model for optimizing performance and estimating costs.

BACKGROUND AIMS: Advanced therapy medicinal products (ATMP) have gained considerable attention in academia due to their therapeutic potential. Good Manufacturing Practice (GMP) principles ensure the quality and sterility of manufacturing these products. We developed a model for estimating the manufacturing costs of cell therapy products and optimizing the performance of academic GMP-facilities. METHODS: The "Clean-Room Technology Assessment Technique" (CTAT) was tested prospectively in the GMP facility of BCRT, Berlin, Germany, then retrospectively in the GMP facility of the University of California-Davis, California, USA. CTAT is a two-level model: level one identifies operational (core) processes and measures their fixed costs; level two identifies production (supporting) processes and measures their variable costs. The model comprises several tools to measure and optimize performance of these processes. Manufacturing costs were itemized using adjusted micro-costing system. RESULTS: CTAT identified GMP activities with strong correlation to the manufacturing process of cell-based products. Building best practice standards allowed for performance improvement and elimination of human errors. The model also demonstrated the unidirectional dependencies that may exist among the core GMP activities. When compared to traditional business models, the CTAT assessment resulted in a more accurate allocation of annual expenses. The estimated expenses were used to set a fee structure for both GMP facilities. A mathematical equation was also developed to provide the final product cost. CONCLUSIONS: CTAT can be a useful tool in estimating accurate costs for the ATMPs manufactured in an optimized GMP process. These estimates are useful when analyzing the cost-effectiveness of these novel interventions.

Cause-specific mortality among patients with epilepsy: results from a 30-year cohort study.

PURPOSE: Death rates of patients with epilepsy are two to three times higher than expected. The aim of our study was to further delineate the causes and the patterns of premature death in patients with epilepsy. METHODS: We included all patients who were prospectively enrolled between 1970 and 1999 in our epilepsy outpatient clinical database. Patients were followed until death or December 31, 2003. Standardized mortality ratios (SMRs) were calculated using reference rates from the same region. KEY FINDINGS: After 48,595 person years of follow-up, 648 of 3,334 patients had died, resulting in an overall SMR of 2.2 (95% confidence interval [CI] 2.0-2.4). The highest SMRs were for patients aged 26-45 years (6.8, 95% CI 3.8-11.2) and with symptomatic epilepsies (3.1, 95% CI 2.3-4.9); those for cryptogenic causes (2.2, 95% CI 1.6-3.1) were also elevated, whereas those for idiopathic causes were not increased (2.7, 95% CI 0.7-7.0) after 2 years of follow-up. SMRs for patients with persistent seizures (3.3, 95% CI 2.6-4.4) were higher than those for seizure-free patients (1.4, 95% CI 0.8-2.3). The highest cause-specific SMRs were for epilepsy (91.6, 95% CI 66.3-123.4), brain tumors (22.7, 95% CI 15.7-31.8), and external causes (2.4, 95% CI 1.8-3.3) at end of study period. SIGNIFICANCE: Epilepsy patients have a higher-than-expected risk of death throughout life and especially during the first 2 years following diagnosis. Standardized mortality rates were especially high in younger patients and in patients with symptomatic epilepsies. Persistent seizures are strongly related to excess mortality.

Unified EEG terminology and criteria for nonconvulsive status epilepticus.

The diagnosis of nonconvulsive status epilepticus (NCSE) relies largely on electroencephalography (EEG) findings. The lack of a unified EEG terminology, and of evidence-based EEG criteria, leads to varying criteria for and ability to diagnose NCSE. We propose a unified terminology and classification system for NCSE, using, as a template, the Standardised Computer-based Organised Reporting of EEG (SCORE). This approach integrates the terminology recently proposed for the rhythmic and periodic patterns in critically ill patients, the electroclinical classification of NCSE (type of NCSE) and the context for the pathologic conditions and age-related epilepsy syndromes. We propose flexible EEG criteria that employ the SCORE system to assemble a database for determining evidence-based EEG criteria for NCSE.

The influence of risk factors on clinical outcomes following anatomical medial patellofemoral ligament (MPFL) reconstruction using the gracilis tendon.

PURPOSE: Patellofemoral instability is influenced by ligamentous, boney and neuromuscular factors. The most important variables are trochlea geometry, medial patellofemoral ligament (MPFL), patella height, tibial tuberosity-trochlea groove distance (TT-TG) and the extensor muscles. Treatment is complicated by these multifactorial conditions. This prospective study examined the influence of risk factors on clinical results and athletic activities where treatment was confined to ligamentous procedures only. METHODS: Fifty patients with chronic patellofemoral instability were treated with MPFL reconstruction using an autologous gracilis tendon. Clinical data, radiographs and magnetic resonance imaging (MRI) were prospectively evaluated pre- and postoperative (minimum follow-up 12 month) to detect existing risk factors for patellofemoral instability and to evaluate clinical and sport ability scores (Kujala, Valderrabano). RESULTS: There was a low rate of redislocation (2 %) and an average Kujala score of 87 ± 13 points postoperative. The MRI showed good integration of the reconstructed MPFL and a positive effect regarding the decrease of patella tilt (16.1° to 11.2°). A negative relationship was found between the degree of trochlear dysplasia and outcomes. 80 % of all patients returned to the same or higher level of physical activity. CONCLUSIONS: Addressing only ligamentous factors through MPFL reconstruction leads to satisfying clinical results and low redislocation rates in most patients. In cases with a high degree of trochlear dysplasia and enlarged TT-TG, additional procedures such as trochleaplasty and tibial tuberosity transfer should be considered as well. LEVEL OF EVIDENCE: IV.