Development Of Motor Deficits Research Articles

Molecular signatures in prion disease: altered death receptor pathways in a mouse model.

Prion diseases are transmissible and fatal neurodegenerative diseases characterized by accumulation of misfolded prion protein isoform (PrPSc), astrocytosis, microgliosis, spongiosis, and neurodegeneration. Elevated levels of cell membrane associated PrPSc protein and inflammatory cytokines hint towards the activation of death receptor (DR) pathway/s in prion diseases. Activation of DRs regulate, either cell survival or apoptosis, autophagy and necroptosis based on the adaptors they interact. Very little is known about the DR pathways activation in prion disease. DR3 and DR5 that are expressed in normal mouse brain were never studied in prion disease, so also their ligands and any DR adaptors. This research gap is notable and investigated in the present study. C57BL/6J mice were infected with Rocky Mountain Laboratory scrapie mouse prion strain. The progression of prion disease was examined by observing morphological and behavioural abnormalities. The levels of PrP isoforms and GFAP were measured as the marker of PrPSc accumulation and astrocytosis respectively using antibody-based techniques that detect proteins on blot and brain section. The levels of DRs, their glycosylation and ectodomain shedding, and associated factors warrant their examination at protein level, hence western blot analysis was employed in this study. Prion-infected mice developed motor deficits and neuropathology like PrPSc accumulation and astrocytosis similar to other prion diseases. Results from this research show higher expression of all DR ligands, TNFR1, Fas and p75NTR but decreased levels DR3 and DR5. The levels of DR adaptor proteins like TRADD and TRAF2 (primarily regulate pro-survival pathways) are reduced. FADD, which primarily regulate cell death, its level remains unchanged. RIPK1, which regulate pro-survival, apoptosis and necroptosis, its expression and proteolysis (inhibits necroptosis but activates apoptosis) are increased. The findings from the present study provide evidence towards the involvement of DR3, DR5, DR6, TL1A, TRAIL, TRADD, TRAF2, FADD and RIPK1 for the first time in prion diseases. The knowledge obtained from this research discuss the possible impacts of these 16 differentially expressed DR factors on our understanding towards the multifaceted neuropathology of prion diseases and towards future explorations into potential targeted therapeutic interventions for prion disease specific neuropathology.

When biopsy goes wrong: a case series of misdiagnoses and complications from biopsies of masses of unknown origin potentially originating from a peripheral nerve.

Biopsies of peripheral nerve tumors (PNTs) are often used to plan an efficient treatment strategy. However, performing a biopsy is controversial when the mass is likely to be a benign PNT (BPNT). The aim of this study was to evaluate the side effects of biopsies in patients with potential PNTs. A retrospective and cross-sectional study was conducted on 24 patients who underwent biopsy of a mass of unknown origin potentially originating from a peripheral nerve (MUOPON), performed in nonspecialty services, and who were later referred to the authors' service for resection of their lesion between January 2005 and December 2022. The patients were evaluated for pain score, presence of a motor or sensory deficit, biopsy diagnosis, and definitive histopathological postsurgical diagnosis. The location of the tumor was supraclavicular in 7 (29.2%) patients, in the axillary region in 3 (12.5%), in the upper limb in 7 (29.2%), and in the lower limb in 7 (29.2%). Twenty-one (87.5%) patients were evaluated by MRI before biopsy, and 3 (12.5%) underwent ultrasound. One patient did not have an examination before the procedure. Based on the biopsy findings, 12 (50%) analyses had an inconclusive histopathological result. The preexisting pain worsened, as measured 1 week after biopsy, in all patients and had remained unchanged at the first evaluation by the authors (median 3 months, range 2-4 months). In 1 case, the open biopsy had to be interrupted because the patient experienced excruciating pain. Four (16.7%) patients developed motor deficits. Subsequent surgery was hampered by scar formation and intratumoral hemorrhage in 5 (20.8%) patients. The initial diagnosis obtained by biopsy differed from the final histopathological diagnosis in all patients, of whom 21 (87.5%) had BPNTs, 2 (8.3%) malignant peripheral nerve sheath tumors, and 1 (4.2%) an ancient schwannoma. Biopsies of PNTs are controversial and may result in misdiagnosis, neuropathic pain, or neurological deficit due to axonal damage, and they may also hinder microsurgical resection when if performed when not indicated. Indications for biopsy of an MUOPON must be carefully considered, especially if BPNT is a possible diagnosis.

Optimization of Radiofrequency Needle Placement in Percutaneous Cordotomy Using Electromyography in the Deeply Sedated Patient.

Cordotomy, the selective disconnection of the nociceptive fibers in the spinothalamic tract, is used to provide pain palliation to oncological patients suffering from intractable cancer-related pain. Cordotomies are commonly performed using a cervical (C1-2) percutaneous approach under imaging guidance and require patients' cooperation to functionally localize the spinothalamic tract. This can be challenging in patients suffering from extreme pain. It has recently been demonstrated that intraoperative neurophysiology monitoring by electromyography may aid in safe lesion positioning. The aim of this study was to evaluate the role of compound muscle action potential (CMAP) in deeply sedated patients undergoing percutaneous cervical cordotomy (PCC). A retrospective analysis was conducted of all patients who underwent percutaneous cordotomy while deeply sedated between January 2019 and November 2022 in 2 academic centers. The operative report, neuromonitoring logs, and clinical medical records were evaluated. Eleven patients underwent PCC under deep sedation. In all patients, the final motor assessment prior to ablation was done using the electrophysiological criterion alone. The median threshold for evoking CMAP activity at the lesion site was 0.9 V ranging between 0.5 and 1.5 V (average 1 V ± 0.34 V SD). An immediate, substantial decrease in pain was observed in 9 patients. The median pain scores (Numeric Rating Scale) decreased from 10 preoperatively (range 8-10) to a median 0 (range 0-10) immediately after surgery. None of our patients developed motor deficits. CMAP-guided PCC may be feasible in deeply sedated patients without added risk to postoperative motor function. This technique should be considered in a group of patients who are not able to undergo awake PCC.

Prognostic Factors in Patients with Metastatic Spinal Cord Compression Secondary to Lung Cancer-A Retrospective UK Single-Centre Study.

Metastatic spinal cord compression (MSCC) is a severe complication of cancer that can lead to irreversible neurological impairment, necessitating prompt recognition and intervention. This retrospective, single-centre study aimed to determine the prognostic factors and survival rates among patients presenting with MSCC secondary to lung cancer. We identified 74 patients with epidural metastases-related spinal cord compression and a history of lung cancer through the electronic database of Medway Maritime Hospital in the United Kingdom (UK), spanning the period from April 2016 to September 2021. Among them, 39 were below 55 years old, while 35 were aged 55 years or older; 24 patients were diagnosed with small cell lung cancer (SCLC), and 50 patients had non-small cell lung cancer (NSCLC). The median overall survival (OS) was 5.5 months, with 52 out of 74 patients dying within 6 months of diagnosis with MSCC. For the entire cohort, the statistically significant variables on multi-variate analysis were cancer type (NSCLC had improved OS), the number of involved vertebrae (one to two vertebrae involvement had improved OS), and the time taken to develop motor deficits (≤10 days to develop motor deficits had worsened OS). For the NSCLC cohort, the statistically significant variables on multivariate analysis were molecular alterations (patients with epidermal growth factor receptor (EGFR) mutation), pre-treatment ambulatory status, Eastern Cooperative Oncology Group (ECOG) performance status, and the time taken to develop motor deficits. Within the entire cohort, patients diagnosed with NSCLC and spinal metastases affecting one to two vertebrae exhibited enhanced OS. Within the NSCLC subgroup, those with EGFR mutations who were ambulatory and possessed an ECOG performance status of 1-2 demonstrated improved OS. In both the entire cohort and the NSCLC subgroup, the development of motor deficits within a period of ≤10 days was associated with poor OS.

Magnetic Resonance Tractography and Intraoperative Direct Electrical Stimulation in Eloquent Area Glioma Surgery for 102 Cases: A Tertiary Care Center Experience From Northwest India.

Surgery of eloquent area gliomas is challenging and requires monitoring of the nearby white fiber tracts. In the present study, we analyzed 102 patients with eloquent region gliomas and discussed the concept of intraoperative dynamic white fiber tract navigation and monitoring. A total of 102 patients with an eloquent area glioma (52 insular, 29 motor area, 21 temporoparietal) were evaluated. The position of the white fiber tracts (corticospinal tract [or motor fiber; CST], inferior fronto-occipital fasciculus [ventral language fiber; IFOF], superior longitudinal fasciculus [SLF], and arcuate fasciculus [dorsal language fiber; AF) was recorded. Awake mapping of the cortical and subcortical eloquent structures was performed for all 102 patients. The suction stimulator was coregistered and used as a dynamic stimulator navigator. Of the 102 patients, 60 were men and 42 were women, with an average age of 39.8 years. Most of the white fiber tracts were normal (CST, 31.3%; IFOF, 39.2%; SLF/AF, 40.19%) or displaced (CST, 59.8%; IFOF, 47.05%; AF/SLF, 44.11%). A few were disrupted (CST, 8.8%; IFOF, 13.7%; SLF/AF, 15.7%). The extent of tumor resection was 82.8%, 86.5%, and 94% for those with insular glioma, motor area glioma, and temporoparietal glioma, respectively. Of the 102 patients, 18 had developed transient speech and language disturbances with improvement, and 14 had developed motor deficits, of whom, all except for 2, had shown gradual improvement. When the dynamic suction stimulator navigator was used, the extent of resection was 96.5%, without any added deficits. The use of intraoperative neuronavigation and neurophysiological assessment can help achieve maximal tumor resection of eloquent area gliomas. Use of the integrated suction stimulator navigator provided dynamic navigation and mapping of the peritumoral eloquent fibers.

A New Scoring Tool to Estimate Post-Treatment Ambulatory Status after Radiotherapy of Metastatic Spinal Cord Compression

<h3>Purpose/Objective(s)</h3> To improve treatment personalization of patients irradiated for metastatic spinal cord compression (MSCC), a score predicting post-treatment ambulatory status after radiotherapy (RT) alone (without surgery) was presented in 2008. Since then, upfront decompressive surgery has become more popular, which may decrease the predictive value of this score. A new scoring tool may be helpful. <h3>Materials/Methods</h3> Data of 283 patients treated with RT alone for MSCC in three prospective trials since 2010 were re-evaluated. Dose-fractionation of RT and 12 factors were analyzed including age (<=67 <i>vs</i> >67 years), gender, tumor type (breast ca. <i>vs</i> prostate ca. <i>vs</i> myeloma/lymphoma <i>vs</i> lung ca. <i>vs</i> others), interval from tumor diagnosis to MSCC (<=6 <i>vs</i> >6 months), number of affected vertebrae (1-2 <i>vs</i> >=3), further bone lesions (no <i>vs</i> yes), visceral metastases (no <i>vs</i> yes), time developing motor deficits (<=7 <i>vs</i> >7 days), pre-RT ambulatory status (ambulatory without aid <i>vs</i> ambulatory with aid <i>vs</i> not ambulatory), performance score (ECOG-PS 1-2 <i>vs</i> 3-4), sensory deficits (no <i>vs</i> yes), and sphincter dysfunction (no <i>vs</i> yes). For each factor that achieved significance in the multivariate analysis (logistic regression model) after backward regression modelling, scoring points were calculated by dividing the post-RT ambulatory rates (in %) by 10. The scoring points of these factors were added for each patient. The new score was compared to the previous tool for prediction (positive predictive value, PPV) of ambulatory and non-ambulatory status after RT. <h3>Results</h3> In the multivariate analysis, primary tumor type (p=0.010), sensory deficits (p=0.002), sphincter dysfunction (p=0.017), pre-RT ambulatory status (p<0.001) and ECOG-PS (p<0.001) were significant; a trend was found for the time developing motor deficits (p=0.054). Five of these factors were included in the score and available for 278 patients. ECOG-PS was not included, since ambulatory status and ECOG-PS were confounding variables. For internal validation, bootstrapping with 1000 replications was used. Corrected C-statistic accounting for overfitting was 0.91, which demonstrated good predictive performance of the model. Based on post-RT ambulatory rates, three prognostic groups (25-29, 30-38 and 39-45 points) were designed with ambulatory rates of 11% (5/44), 64% (49/77) and 97% (152/157), respectively. Rates of local control of MSCC were 100%, 82% and 94% at 1 year, and 100%, 82% and 87% at 2 years. Survival rates were 20%, 21% and 55% at 1 year, and 13%, 12% and 39% at 2 years. PPVs of the new score to predict ambulatory and non-ambulatory status were 97% and 89% <i>vs</i> 98% and 79% when using the previous score. <h3>Conclusion</h3> The new score appeared more precise than the previous one in predicting non-ambulatory status after RT. Depending on survival prognosis, patients with <=38 points likely benefit from upfront surgery. Since patients of the 39-45 points group had very high rates of post-RT ambulatory status and local control, they may not require surgery.

Surgical outcome of pediatric patients with symptomatic tethered cord syndrome at a tertiary care hospital

Introduction: Patients with tethered cord syndrome become symptomatic during the period of their growth spurt. Apart from progressive foot and spinal deformities, patients also develop motor deficits and bladder and bowel dysfunction. Early diagnosis and adequate release of the tethered cord are indispensable to successful management.&#x0D; Objectives: To study the trends in the neurological outcome after surgical treatment of cord tethering in pediatric population.&#x0D; Methodology: Study was carried out from January 2018 to December 2019 at neurosurgery department, Fauji Foundation Hospital Rawalpindi. Thirty-five patients were included in the study who fulfilled the inclusion criteria.&#x0D; Results: The average age of the patients at the time of the intervention was 11 years. There were 21 females (60.0%) and 14 males (40.0%). The distribution of neurological status improvement tells improvement in back pain in 28 patients (80%), improvement in motor function in 14 patients (40%), and improvement in urinary incontinence in 7 patients (20%).&#x0D; Conclusion: This study concludes that back ache improves significantly after surgery while urinary incontinence is the least benefited symptom. Untethering along with the rehabilitation also helps majority of the patients with motor deficit. The ratio of symptomatic relief was best for backache and motor function and then improvement in the urinary control.

Identifying patients with malignant spinal cord compression (MSCC) near end of life who can benefit from palliative radiotherapy

BackgroundA previous score predicted death ≤ 2 months following radiotherapy for MSCC. For patients with a high probability of early death, best supportive care was recommended. However, some of these patients may benefit from radiotherapy regarding preservation or improvement of motor function. To identify these patients, an additional score was developed.MethodsPre-treatment factors plus radiotherapy regimen were retrospectively evaluated for successful treatment (improved motor function or remaining ambulatory without aid) and post-treatment ambulatory status in 545 patients who died ≤ 2 months. Factors included age, interval from tumor diagnosis until MSCC, visceral metastases, further bone metastases, primary tumor type, sex, time developing motor deficits, pre-treatment ambulatory status, and number of affected vertebrae. Factors significant on both multivariable analyses were included in the score (worse outcomes 0 points, better outcomes 1 point).ResultsOn multivariable analyses, myeloma/lymphoma, time developing motor deficits > 14 days, and pre-treatment ambulatory status were significantly associated with both successful treatment and ambulatory status, affection of 1–2 vertebrae with successful treatment only. On univariable analyses, 1 × 8 and 5 × 4 Gy were not inferior to 5 × 5 Gy and longer-course regimens. Considering the three factors significant for both endpoints, three groups were designed (0, 1, 2–3 points) with treatment success rates of 4%, 15% and 39%, respectively (p < 0.0001), and post-treatment ambulatory rates of 4%, 43% and 86%, respectively (p < 0.0001).ConclusionThis score helps identify patients with MSCC who appear to benefit from palliative radiotherapy in terms of improved motor function or remaining ambulatory in spite of being near end of life.

A New Clinical Instrument for Estimating the Ambulatory Status after Irradiation for Malignant Spinal Cord Compression.

Simple SummarySince 2005, upfront surgery has been increasingly used in addition to radiotherapy for patients with malignant spinal cord compression (MSCC). As spinal surgery includes significant risks, careful patient selection is crucial. Individual risks and benefits should be considered when choosing an optimal treatment strategy. Benefits include preserving or regaining a patient’s ambulatory function. To facilitate the decision pro or contra upfront surgery, a new prognostic score was developed to predict ambulatory status after radiotherapy alone. This clinical score was created from data of patients previously treated in prospective trials. It includes three prognostic groups (17–21, 22–31, and 32–37 points) with post-radiotherapy ambulatory rates of 10%, 65%, and 97%, respectively. Patients of the 32–37 points group may not require upfront surgery. The new instrument achieved very high accuracy in predicting post-radiotherapy ambulatory and non-ambulatory status and was more precise than a previous prognostic score in predicting non-ambulatory status.Estimating post-treatment ambulatory status can improve treatment personalization of patients irradiated for malignant spinal cord compression (MSCC). A new clinical score was developed from data of 283 patients treated with radiotherapy alone in prospective trials. Radiotherapy regimen, age, gender, tumor type, interval from tumor diagnosis to MSCC, number of affected vertebrae, other bone metastases, visceral metastases, time developing motor deficits, ambulatory status, performance score, sensory deficits, and sphincter dysfunction were evaluated. For factors with prognostic relevance in the multivariable logistic regression model after backward stepwise variable selection, scoring points were calculated (post-radiotherapy ambulatory rate in % divided by 10) and added for each patient. Four factors (primary tumor type, sensory deficits, sphincter dysfunction, ambulatory status) were used for the instrument that includes three prognostic groups (17–21, 22–31, and 32–37 points). Post-radiotherapy ambulatory rates were 10%, 65%, and 97%, respectively, and 2-year local control rates were 100%, 75%, and 88%, respectively. Positive predictive values to predict ambulatory and non-ambulatory status were 97% and 90% using the new score, and 98% and 79% using the previous instrument. The new score appeared more precise in predicting non-ambulatory status. Since patients with 32–37 points had high post-radiotherapy ambulatory and local control rates, they may not require surgery.

Prognostic Value of Preclinical Markers after Radiotherapy of Metastatic Spinal Cord Compression-An Additional Analysis of Patients from Two Prospective Trials.

Simple SummaryFor personalized treatment of metastatic spinal cord compression (MSCC), a patient’s remaining lifespan plays an important role, which can be estimated using prognostic factors. This study used data from 190 patients with poor or intermediate survival prognoses previously included in prospective trials to evaluate the prognostic role of preclinical markers including hemoglobin, neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), lactate dehydrogenase (LDH), and c-reactive protein (CRP) plus clinical factors. On univariate analyses, NLR, LDH, CRP, and clinical factors tumor type, ambulatory status, and sphincter function were significantly associated with survival. On multivariate analysis, LDH, CRP, tumor type, and ambulatory status proved to be independent predictors of survival. In addition to clinical factors, preclinical markers may support physicians to estimate survival prognoses and contribute to the treatment personalization of patients with MSCC.For optimal personalization of treatment for metastatic spinal cord compression (MSCC), the patient’s survival prognosis should be considered. Estimation of survival can be facilitated by prognostic factors. This study investigated the prognostic value of pre-treatment preclinical markers, namely hemoglobin, neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), lactate dehydrogenase (LDH), and c-reactive protein (CRP), in 190 patients from two prospective trials who had poor or intermediate survival prognoses and were irradiated for MSCC with motor deficits. In addition, clinical factors including radiation regimen, age, gender, tumor type, interval from tumor diagnosis to MSCC, number of affected vertebrae, visceral metastases, other bone metastases, time developing motor deficits, ambulatory status, sensory function, and sphincter function were evaluated. On univariate analyses, NLR (p = 0.033), LDH (p < 0.001), CRP (p < 0.001), tumor type (p < 0.001), pre-radiotherapy ambulatory status (p < 0.001), and sphincter function (p = 0.011) were significant. In the subsequent Cox regression analysis, LDH (p = 0.007), CRP (p = 0.047), tumor type (p = 0.003), and ambulatory status (p = 0.010) maintained significance. In addition to clinical factors, preclinical markers may help in estimating the survival of patients irradiated for MSCC. Additional prospective trials are warranted.

A New and Easy-to-Use Survival Score for Patients Irradiated for Metastatic Epidural Spinal Cord Compression

PurposeA survival score was created in 2008 to improve treatment personalization of patients irradiated for metastatic epidural spinal cord compression (MESCC). Since then, targeted therapies improved survival of patients with cancer, which may decrease this score's predictive value. A new score appears necessary. Methods and MaterialsTwo hundred sixty-four patients receiving radiation therapy without surgery in prospective trials (2010-2021) were included. A dose-fractionation regimen plus 15 factors were analyzed: age, sex, tumor type, interval tumor diagnosis to MESCC, MESCC sites, affected vertebrae, additional bone lesions, other distant lesions (yes or no), number of organs involved by metastases, time developing motor deficits, ambulatory status, sensory function, sphincter dysfunction, pain, and distress. Six-month survival rates (%) of independent prognostic factors were divided by 10 and summed for each patient. The score was compared with the previous tool for predicting death ≤6 months and survival ≥6 months. ResultsIn a multivariate analysis, tumor type (P = .001), other distant lesions (P < .001), and ambulatory status (P < .001) were significant. Based on 6-month survival rates, 4 groups (8-9, 10-13, 14-17, and 18 points) were created with 6-month survival rates of 12.8%, 34.7%, 62.8%, and 90.0%, respectively (version A). For version B, “other distant lesions” was replaced by “number of organs involved by metastases.” Version B included 4 groups (8-10, 11-14, 15-16, and 17 points) with 6-month survival rates of 11.1%, 42.0%, 68.6%, and 91.7%, respectively. Positive predictive values to predict death ≤6 months were 87.2% (version A) and 88.9% (version B) versus 76.6% (3 groups) and 84.6% (5 groups) for the previous score. Positive predictive values to predict survival ≥6 months were 90.0% and 91.7% versus 59.0% and 64.3%. ConclusionsBoth versions of the new score were more precise than the previous tool. Version B appears slightly superior to version A but requires more extensive diagnostic staging that may not be readily available when emergently treating.

TGR5 Agonist INT-777 Alleviates Inflammatory Neurodegeneration in Parkinson’s Disease Mouse Model by Modulating Mitochondrial Dynamics in Microglia

Parkinson’s disease (PD) is one of the most common chronic progressive neurodegenerative diseases that affects both motor and non-motor functions. Bile acids modulate the immune system by targeting brain receptors. INT-777, a 6α-ethyl-23(S)-methyl derivative of cholic acid (S-EMCA), acts as an agonist for Takeda G protein-coupled receptor-5 (TGR5) and has neuroprotective properties. However, the effects of INT-777 on PD have not yet been investigated. In a subchronic PD model, mice treated with 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) developed motor deficits and cognitive impairment that were ameliorated after intranasal administration of INT-777. INT-777 prevented MPTP-induced neurodegeneration and microglia activation in the substantia nigra pars compacta, hippocampus, and cortical layer V. Based on bioinformatics and wet lab data, INT-777 inhibited microglia activation by suppressing the release of tumor necrosis factor alpha (TNF-α) in the hippocampus, along with secondary chemokines (C–C motif ligand 3 (CCL3) and CCL6) in these three brain regions. INT-777 inhibited TNF-α production by repairing mitochondrial damage, which was associated with nuclear factor-erythroid 2-related factor-2 (NRF2) activation and p62/LC3B-mediated autophagy. INT-777 reversed the downregulation of heme oxygenase-1 (HO1), NAD(P)H quinone oxidoreductase-1 (NQO1) and accumulation of p62 in microglia treated with 1-methyl-4-phenylpyridinium (MPP+). However, TGR5 knockdown in microglia abolished INT-777′s inhibition of TNF-α release, resulting in neuronal death. Therefore, PD cognitive impairment is associated with hippocampal TNF-α elevation as a result of mitochondrial damage in microglia. Our data reveal the potential role of TGR5 in modulating inflammation-mediated neurodegeneration in PD, and provides new insights for bile acid metabolites as promising disease-modifying drugs for PD.

Radiotherapy with or without Decompressive Surgery for Metastatic Spinal Cord Compression: A Retrospective Matched-Pair Study Including Data from Prospectively Evaluated Patients.

Simple SummaryIn a retrospective matched-pair study including data of prospectively evaluated patients who were treated for metastatic spinal cord compression, 79 patients assigned to surgery plus radiotherapy were compared to 79 patients receiving radiotherapy alone. Improvement of motor function occurred more significantly often after surgery plus radiotherapy, whereas no significant differences were found for post-treatment ambulatory rates, local progression-free survival, overall survival, and freedom from in-field recurrence. Ten patients died within 30 days after radiotherapy alone and 12 patients within 30 days after surgery. More than one third of surgically treated patients did not complete their radiotherapy due to early death or decreased performance score following surgery. Thus, when selecting a patient for upfront surgery, the individual patient’s prognosis must be considered and weighed against the risk of perioperative complications and 30-day mortality.In 2005, a randomized trial showed that addition of surgery to radiotherapy improved outcomes in patients with metastatic spinal cord compression (MSCC). Since then, only a few studies compared radiotherapy plus surgery to radiotherapy alone. We performed a retrospective matched-pair study including data from prospective cohorts treated after 2005. Seventy-nine patients receiving radiotherapy alone were matched to 79 patients assigned to surgery plus radiotherapy (propensity score method) for age, gender, performance score, tumor type, affected vertebrae, other bone or visceral metastases, interval tumor diagnosis to MSCC, time developing motor deficits, and ambulatory status. Improvement of motor function by ≥1 Frankel grade occurred more often after surgery plus radiotherapy (39.2% vs. 21.5%, p = 0.015). No significant differences were found for post-treatment ambulatory rates (59.5% vs. 67.1%, p = 0.32), local progression-free survival (p = 0.47), overall survival (p = 0.51), and freedom from in-field recurrence of MSCC (90.1% vs. 76.2% at 12 months, p = 0.58). Ten patients (12.7%) died within 30 days following radiotherapy alone and 12 patients (15.2%) died within 30 days following surgery (p = 0.65); 36.7% of surgically treated patients did not complete radiotherapy as planned. Surgery led to significant early improvement of motor function and non-significantly better long-term control. Patients scheduled for surgery must be carefully selected considering potential benefits and risk of perioperative complications.

A stereological study of glial activation in GFAP-IL6 mice: A model of chronic neuroimmune conditions.

Understanding the role of chronic neuroinflammation, described by increased astro- and microglia activation, in the pathogenesis of Alzheimer's disease (AD) is becoming crucial due to its role throughout the disease progression (Deczkowska et al., 2018). In search of a suitable mouse model of chronic glial activation, we characterized the GFAP-IL6 transgenic mouse model in which the pro-inflammatory cytokine interleukine-6 is overexpressed under the control of the glial fibrillary acidic protein (GFAP) promoter (Campbell et al., 1993). The GFAP-IL6 mice display chronic inflammatory conditions in the brain, with the homozygous mice developing an aggressive pathology characterized by tremor, ataxia, and seizures by 6 months of age (Campbell et al., 1993). While the heterozygous phenotype is milder and characterized by astrocytosis, microgliosis, angiogenesis, and neurodegeneration. Moreover, evidences showed that the progressive motor and cognitive impairment is correlated with the level of microgliosis (Heyser et al., 1997). Using immunohistochemically stained brain sections of 3 months old wild-type (WT) (n=4), GFAP-IL6 heterozygous (n=5), and homozygous (n=5) mice, we estimated the absolute number and morphology of Iba1 and GFAP positive cells, microglia and astrocytes respectively. We focused the analysis on cortex, hippocampus, cerebellum, and medial septum (MS) to find a possible connection with the loss of cholinergic neurons during AD. Homozygous GFAP-IL6 mice showed an increase in the number of microglia by 50-80% in all the brain areas compared to the WT, while the increase in the heterozygous was 35-60%. Moreover, homozygous mice increased the number of microglia by 40% in the MS and nearly 50% in the cerebellum compared to the heterozygous. In the MS astrocytes of the homozygous mice are 70% more than in the heterozygous, which are similar to the WT. The glial morphological analysis showed a different ramification and microglial cell body size in the homozygous compared to the heterozygous and WT. The stronger impact of neuroinflammation in the homozygous GFAP-IL6 mice at 3 months old suggests a possible application in evaluating chronic conditions at early stages. Moreover, the results highlight the high vulnerability to inflammation of the MS. Increased cerebellar glial mediated inflammation emphasized the chance to develop motor deficits.

Brachial Plexus Tolerance to Single-Session SABR in a Pig Model

The single-session dose tolerance of the spinal nerves has been observed to be similar to that of the spinal cord in pigs, counter to the perception that peripheral nerves are more tolerant to radiation. This pilot study aims to obtain a first impression of the single-session dose-response of the brachial plexus using pigs as a model. Ten Yucatan minipigs underwent computed tomography and magnetic resonance imaging for treatment planning, followed by single-session stereotactic ablative radiotherapy. A 2.5-cm length of the left-sided brachial plexus cords was irradiated. Pigs were distributed in 3 groups with prescription doses of 16 (n=3), 19 (n=4), and 22 Gy (n=3). Neurologic status was assessed by observation for changes in gait and electrodiagnostic examination. Histopathologic examination was performed with light microscopy of paraffin-embedded sections stained with Luxol fast blue/periodic acid-Schiff and Masson's trichrome. Seven of the 10 pigs developed motor deficit to the front limb of the irradiated side, with a latency from 5 to 8 weeks after irradiation. Probit analysis of the maximum nerve dose yields an estimated ED50 of 19.3 Gy for neurologic deficit, but the number of animals was insufficient to estimate 95% confidence intervals. No motor deficits were observed at a maximum dose of 17.6 Gy for any pig. Nerve conduction studies showed an absence of sensory response in all responders and absent or low motor response in most of the responders (71%). All symptomatic pigs showed histologic lesions to the left-sided plexus consistent with radiation-induced neuropathy. The single-session ED50 for symptomatic plexopathy in Yucatan minipigs after irradiation of a 2.5-cm length of the brachial plexus cords was determined to be 19.3 Gy. The dose-response curve overlaps that of the spinal nerves and the spinal cord in the same animal model. The relationship between the brachial plexus tolerance in pigs and humans is unknown, and caution is warranted when extrapolating for clinical use.

Comparison of 5\u2009\xd7\u20095\xa0Gy and 10\u2009\xd7\u20093\xa0Gy for metastatic spinal cord compression using data from three prospective trials

BackgroundIn a palliative situation like metastatic spinal cord compression (MSCC), overall treatment time of radiotherapy should be as short as possible. This study compared 5 × 5 Gy in 1 week to 10 × 3 Gy in 2 weeks in a prospective cohort.MethodsForty patients receiving 5 × 5 Gy in a phase II trial were matched 1:2 to 213 patients receiving 10 × 3 Gy in two previous prospective studies for tumor type, ambulatory status, time developing motor deficits, interval between tumor diagnosis and MSCC and visceral metastases. These factors were consistent in all three patients (triple) used for each 1:2 matching. Groups were compared for local progression-free survival (LPFS), motor function, ambulatory status, and overall survival (OS).ResultsAfter matching, 32 triples remained for analyses (N = 96 in total). Six-month LPFS-rates were 94% after 5 × 5 Gy and 87% after 10 × 3 Gy (p = 0.36), 6-month OS-rates 43% and 35% (p = 0.74). Improvement of motor function was achieved in 59% and 34% of patients (p = 0.028); overall response rates (improvement or no further progression of motor deficits) were 94% and 89% (p = 0.71). Post-treatment ambulatory rates were 81% after 5 × 5 Gy and 85% after 10 × 3 Gy (p = 0.61). Of non-ambulatory patients, 50% (6/12) and 46% (11/24) regained the ability to walk (p = 1.00).Conclusions5 × 5 Gy in 1 week appeared similarly effective as 10 × 3 Gy in 2 weeks. These results may not be applicable to long-term survivors and should be confirmed in a randomized trial directly comparing 5 × 5 Gy and 10 × 3 Gy.Trial registration clinicaltrials.gov NCT03070431. Registered 27 February 2017.

Ablation of C9orf72 together with excitotoxicity induces ALS in rats.

Pathogenesis of familial amyotrophic lateral sclerosis (ALS) linked to expansion of the chromosome 9 open reading frame 72 (C9orf72) hexanucleotide repeat that impairs C9orf72 expression. Loss of function of the C9orf72 protein is one of the three main proposed C9orf72-related ALS mechanisms. However, C9orf72 loss of function, by itself, is insufficient to cause severe phenotypes in mice. Excitotoxicity is another major disease mechanism of ALS. We speculate that loss of C9orf72 protein might cause ALS in combination with excitotoxicity. To date, the effect of C9orf72 deficiency in the background of SD rat has not been examined. To test our hypothesis, we generated a line of rat with a deletion of part of the C9orf72 gene ablating the encoded protein. These animals did not develop any ALS phenotypes; however, when they were treated with kainic acid, an excitotoxicity inducer, the rats developed motor deficits and showed loss of motor neurons (MNs), Golgi complex fragmentation, and abnormal vesicle trafficking. RNA sequencing revealed profound changes in the gene profiles that were primarily associated with neural activity. Our results demonstrated that C9orf72 ablation alone was not enough to cause ALS pathogenesis in rat; but the ablation sensitized MNs to other risk factors that synergistically caused the ALS. These results support a loss of function of C9orf72 mechanism of ALS.

Knock in of a hexanucleotide repeat expansion in the C9orf72 gene induces ALS in rats.

BackgroundThe GGGGCC (G4C2) repeat expansion in the human open reading frame 72 on chromosome 9, C9orf72, is the most common cause of amyotrophic lateral sclerosis (ALS). Studies in transgenic mouse models have linked the pathogenic mechanism of G4C2 repeat expansion to RNA foci or the accumulation of unnatural dipeptide repeats in neurons. However, only one of the existing transgenic mouse lines developed typical ALS.Methods C9orf72 knockin rats were generated by knockin of 80 G4C2 repeats with human flanking fragments within exon1a and exon1b at the rat C9orf72 locus. Protein expression was detected by western blot. Motor coordination and grip force were measured using a Rotarod test and a grip strength test. Neurodegeneration was assessed by Nissl staining with cresyl violet.Results C9orf72 haploinsufficiency reduced C9orf72 protein expression 40% in the cerebrum, cerebellum and spinal cords from knockin rats (P < .05). The knockin (KI) rats developed motor deficits from 4 months of age. Their falling latencies and grip force were decreased by 67% (P < .01) and 44% (P < .01), respectively, at 12 months of age compared to wild‐type (WT) mice. The knockin of the hexanucleotide repeat expansion (HRE) caused a 47% loss of motor neurons in the spinal cord (P < .001) and 25% (5/20) of female KI rats developed hind limb paralysis at 13 to 24 months.ConclusionMotor defects in KI rats may result from neurotoxicity caused by HRE and the resulting reduction in C9orf72 protein due to haploinsufficiency. These KI rats could be a useful model for investigating the contributions of loss‐of‐function to neurotoxicity in C9orf72‐related ALS.

Outcome analysis of upper and lower limb motor functions after anterior cervical discectomy and fusion for degenerative cervical disc disease

Background: Anterior cervical discectomy and fusion (ACDF) is the most commonly performed surgical procedure for symptomatic cervical disc disease. In this study, we analysed the upper and lower limb motor functions after ACDF for disc prolapse in patients with degenerative cervical disc disease.&#x0D; Methods: One hundred consecutive adult patients who underwent ACDF for single or two-level cervical disc prolapse during the study period (October 2015 to October 2017) were included in the study.&#x0D; Results: Preoperative motor deficits in limbs were noted in 73% (73/100) of the patients. Enhance recovery of motor deficits was noted in 72.6% (53/73) of these patients and persisting motor deficits in the remaining patients (20/73- 27.4%). Five patients (5/27- 18.5%) without any preoperative motor deficits developed motor deficits after ACDF. Detailed pre and postoperative (at the time of discharge) motor power (graded by MRC grade) in all 4 limbs (Shoulder abduction/adduction/flexion/extension, elbow flexion/extension, wrist flexion/extension, hip abduction/adduction/flexion/extension, knee flexion/extension, ankle flexion/extension) was recorded. Statistically significant improvement in motor power (as recorded at the time of discharge) was noted in all the tested muscle groups after ACDF.&#x0D; Conclusion: Early improvement in preoperative motor deficits can be expected in the majority of the patients with cervical PIVD following ACDF.

Combined surgical treatment of the cerebral arteriovenous malformations in patients with the torpid course of the disease

Objective – to optimize the results of surgical treatment of the cerebral arteriovenous malformations (AVM) with a torpid clinical course of the disease.Materials and methods. The results of combined surgical treatment of cerebral AVMs of 36 patients without a history of AVM rupture were analyzed (this variant of clinical course was defined as «torpid»). Patients were treated in the departments of vascular neurosurgery at the Romodanov Neurosurgery Institute NAMS of Ukraine during the period from 2010 till September 2019. Among the patients there were 18 (50 %) men and 18 (50 %) women. The average age of patients was 28.1 years (10–47 years). Clinical, neurological, laboratory, instrumental, functional and morphological methods of examination were used as well as neuroimaging evaluation and follow-up investigation.Results. The «torpid» course of disease in patients with AVM was presented as heterogeneous epileptiform manifestations in 24 (66.7 %) cases. One (2.8 %) patient had seizure that were combined with internal hydrocephalus, 9 (25 %) patients had different severity cephalalgic syndrome (according to the International classification of headache – 3β). Progressive neurological deficit was detected in 2 (5.55 %) patients. The distribution of AVMs according Spetzler–Martin scale (1986) was as follows: grade I – in 2 (5.55 %) patients, grade II – in 10 (27.8 %), grade III – in 13 (36.1 %), grade IV – in 9 (25.0 %), grade V – in 2 (5.55 %). In most cases (94.44 %), AVMs were supratentorial, and in 2 (5.55 %) cases they were subtentorial. The average AVM size in the largest dimension was 3.7 cm (2.8–6.7 cm). Intranidal aneurysms in the AVM structure were diagnosed in 8 (22.2 %) patients, fistulas – in 7 (19.4 %) cases. In all cases, at the first stage, endovascular embolization (EE) of AVM was performed. All 36 patients underwent 64 endovascular procedures. Curative treatment after 1 stage was performed in 16 (44.4 %) patients, after 2 stages – in 13 (36.1%), after 3 stage – in 6 (16.66 %), and after 4 stage in 1 (2.77 %) patient. In 36 (56.25 %) cases, embolization was performed with Onyx composition (eV3), in 24 (37.5 %) – with n-butylcyanoacrylate, and in 3 (4.7 %) – with their combination. In 1 (1.56 %) patient, the fistula was excluded from the blood flow using detached balloon-catheter. Embolization was supplemented with radiosurgical treatment (RST) in 30 (83.3 %) cases, microsurgical removal – in 2 (5.55 %), radiotherapy – in 2 (5.55 %) patients. In 1 (2.77 %) case EE was combined with shunting procedure and RST. One (2.77 %) patient after EE with RST suffered hemorrhagic stroke with intracerebral hematoma formation. An operation was performed for hematoma removal and partially functioning AVM resection. In 7 (10.9 %) cases after EE of AVM, patients developed motor deficits. At the time of discharge, they regressed completely in 6 patients, and partially in 1 patient. In (1.5 %) case homonymous hemianopsia had occurred. After RST, total obliteration of AVM was achieved in 17 (58.6 %) patients, in 5 (17.2 %) – subtotal (repeated RST was recommended). In 7 (24.1 %) cases, positive signs of AVM obliteration was noted, and the timing of radiation exposure did not reach the recommended ones. In 2 (3.1 %) patients after microsurgical resection, the AVM was removed completely, which was confirmed by cerebral angiography. After radiotherapy, decreasing of the AVM size and a positive neurological dynamics were noted. There were no fatal outcomes. According to the modified Rankine scale, patients were distribution to group 0 (33 (91.7 %)) and group I (3 (8.3 %)).Conclusions. The obtained data indicate the promising result of combined surgical treatment of cerebral AVM with a torpid type of clinical manifestations. The leading technique in the applied staged combined surgical treatment of AVM was EE. Its successful use is due to the effectiveness of its impact on all components of the «complex» AVM.